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OKAY, GOOD MORNING, EVERYONE,

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AND WELCOME TO THE SIXTH

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BIENNIAL STRATEGIES FOR AN HIV

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CURE MEETING.

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THIS MEETING BEGAN IN 2012, AS

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AN ATTEMPT TO BRING TOGETHER

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RESEARCHERS AND THE COMMUNITY

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WITH A SHARED INTEREST IN HIV

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CURE RESEARCH, WHICH AT THAT

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TIME WAS A RATHER NASCENT FIELD.

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IT QUICKLY GREW TO BECOME THE

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LARGEST SCIENTIFIC MEETING

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DEDICATED SOLELY TO HIV CURE

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RESEARCH.

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AND IT NOW SERVES AS THE JOINT

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MEETING OF THE NIH MARTIN

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DELANEY COLLABORATORIES FOR HIV

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CURE RESEARCH PROGRAM.

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TO GET US STARTED THIS MORNING,

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IT'S MY PLEASURE TO INTRODUCE

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OUR NEW DIRECTOR AT NIAID,

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DR. JEANNE MARRAZZO.

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THIS IS HER THIRD WEEK ON THE

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JOB, SO SHE'S STILL VERY FRESH

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TO THE JOB.

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DR. MARRAZZO EARNED HER

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BACHELOR'S AT HARVARD AND MD

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FROM THOMAS JEFFERSON

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UNIVERSITY.

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HER MPH IN EPIDEMIOLOGY FROM

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WASHINGTON UNIVERSITY.

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SHE THEN COMPLETED RESIDENCY AND

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CHIEF RESIDENCY IN INTERNAL

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MEDICINE AT YALE AND PRIOR TO

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JOINING NIAID, SHE WAS DIRECTOR

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OF THE DIVISION OF INFECTIOUS

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DISEASES AT THE UNIVERSITY OF

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ALABAMA AT BIRMINGHAM.

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SO WITH THAT, WELCOME,

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DR. MARRAZZO.

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THANK YOU FOR GETTING US

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STARTED.

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>> THANKS, KARL.

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CAN YOU ALL HEAR ME OKAY?

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I'M GOING TO ASSUME THAT'S A

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YES.

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WELL, I AM THRILLED TO BE HERE

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VIRTUALLY.

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I APOLL JAIZ FOR APOLOGIZE FOR E

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VIRTUALLY.

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AS YOU CAN SEE, I AM IN THE

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THROES OF MOVING LITERALLY, I'M

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HOPING TO BE UP IN MARYLAND THIS

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WEEKEND, BUT I REALLY COULDN'T

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TURN DOWN THE OPPORTUNITY TO

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ACTUALLY HAVE MY VERY FIRST

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OFFICIAL WELCOME BE FOR THIS

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GROUP.

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AS YOU CAN SEE FROM THE FIRST

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SLIDE AND AS I THINK EVERYBODY

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IN THIS ROOM IS SUPER DEDICATED

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TO DEVELOPING AN APPROACH FOR

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THE TREATMENT AND CURE OF HIV

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INFECTIONS, IT'S REALLY ONE OF

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THE TOP PRIORITIES FOR NIAID,

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AND IT'S ESPECIALLY IMPORTANT

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BECAUSE IT'S AN THAT HAS

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REQUIRED VERY CLOSE

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COLLABORATION WITH THE

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COMMUNITY, BOTH THE SCIENTIFIC

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AND COMMUNITY STAKEHOLDERS.

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I THINK THAT EVERYONE IN THIS

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AUDIENCE IS EXTREMELY AWARE OF

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THE NEED FOR A CURE.

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DON'T NEED TO REITERATE THESE

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STATISTICS, I THINK, FOR THIS

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GROUP, BUT HAVING LIVED FOR THE

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LAST SEVEN YEARS IN A PART OF

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THE WORLD THAT IN THE U.S. HAS

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OVER 50% OF NEW INFECTIONS, I'M

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EXQUISITELY AWARE OF THE NEED TO

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REALLY FUNDAMENTALLY ADDRESS

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CURE.

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THE EXISTING INTERVENTIONS WE

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HAVE ARE FANTASTIC, BUT THEY ARE

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SIMPLY NOT GOING TO GET US WHERE

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WE NEED TO BE, AND WHEN YOU LOOK

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AT THAT NEED GLOBALLY, THE NEED

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FOR CURE IS EVEN MORE INTENSE.

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IT LOOKS LIKE YOU'VE MOVED ME

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ALONG TO THE THIRD SLIDE.

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THAT'S OKAY.

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YOU CAN GO AHEAD, BECAUSE THE

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REAL MEAT OF THIS IS JUST TO

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THANK YOU ALL FOR YOUR WORK AS

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PART OF THE MARTY DELANEY

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COLLABORATORIES, REALLY AN

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INCREDIBLE PARTNERSHIP WITH

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COFUNDING ACROSS SEVERAL

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INSTITUTES AT NIH, AND THIS

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REALLY IS THE FLAGSHIP PROGRAM

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FOR CURE RESEARCH, AND IT'S

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IMPORTANT PARTICULARLY BECAUSE

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IT SPANS TRANSLATIONAL RESEARCH

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SINCE 2011.

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THIS IS JUST TO ACKNOWLEDGE THE

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CRITICAL ROLE THAT MARTY DELANEY

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PLAYED AS AN ACTIVIST IN THIS

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AREA, WAS INCREDIBLY IMPORTANT

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IN FAST TRACKING REVIEWS OF AIDS

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DRUGS, FAIR PRICING, AND, OF

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COURSE, AN AVID ADVOCATE FOR

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COMMUNITY EDUCATION BEFORE HIS

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UNTIMELY DEATH IN 2009.

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SO A HUGE MOVER AND SHAKER THAT

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WE HAVE TO THANK FOR WHAT'S

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HAPPENING TODAY.

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I JUST WANT TO POINT OUT THAT

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NIH'S INVESTMENT IN THE CURE

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PROGRAM HAS GROWN STEADILY WITH

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EACH FIVE-YEAR ITERATION,

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STARTING WITH THREE

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COLLABORATORY AWARDS IN 2011 AND

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GROWING AS KARL MENTIONED TO A

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TOTAL OF 10 IN THE CURRENT

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ITERATION.

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AND YOU CAN SEE THE TOTAL

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FUNDING IS NOW ALMOST

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$270 MILLION.

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BUT GIVEN THAT, WE STILL HAVE A

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WAYS TO GO.

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WHEN YOU LOOK AT HIV CURE

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RESEARCH RELATIVE TO THE OTHER

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BUCKETS THAT WE ARE CURRENTLY

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FUNDING, INCLUDING CO-OCCURRING

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CONDITIONS, CROSS-CUTTING

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RESEARCH, NEXT GEN THERAPIES AND

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REDUCTION OF INCIDENCE, I.E.,

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PRIMARY PREVENTION, WE ARE STILL

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NOT ALLOCATING, I THINK, A

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PROPORTIONATE AMOUNT OF FUNDS TO

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THIS AREA.

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SO RIGHT NOW HIV CURE RESEARCH

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TAKES UP ABOUT 7% OF THE TOTAL

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HIV/AIDS BUDGET.

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SO THAT CLEARLY NEEDS TO BE

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FOREFRONT, I THINK, IN OUR

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DISCUSSIONS WHEN WE THINK STA TK

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STRATEGICALLY ABOUT MOVING

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FORWARD.

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SO THIS IS JUST A SLIDE TO SHOW

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YOU WHERE THESE COLLABORATORIES

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ARE.

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AGAIN I KNOW YOU'RE ALL THERE

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TODAY, AND I'M REALLY SORRY I

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CAN'T BE THERE TO HEAR ABOUT THE

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PROGRESS.

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I'M REALLY IMPRESSED AT THE WORK

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THAT THIS GROUP HAS DONE.

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AND I HOPE THAT YOU HAVE GREAT

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MEETING, AND I LOOK FORWARD TO

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SEEING YOU ALL IN PERSON VERY

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SOON.

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WITH THAT, I'LL TURN IT BACK TO

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KARL, AND WISH YOU A REALLY

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GREAT DAY.

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AND THANKS FOR GIVING ME THE

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OPPORTUNITY TO SAY WELCOME.

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[APPLAUSE]

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>> THANK YOU SO MUCH,

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DR. MARRAZZO.

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SO NOW WE'LL MOVE ON TO THE

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PRESENTATIONS FROM THE

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INDIVIDUAL MARTIN DELANEY

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COLLABORATORIES.

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AS YOU'LL NOTICE IN THE PROGRAM,

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THESE ARE ALL STRUCTURED AROUND

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THE SAME RESEARCH FOCI, SO

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RESEARCH FOCUS ONE IS FOCUSED ON

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BASIC RESEARCH AND UNDERSTANDING

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POST TREATMENT CONTROL, RESEARCH

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FOCUS TWO IS DEVELOPING STRAT 

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STRATEGIES FOR A DURABLE CONTROL

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OF VIRAL REBOUND IN THE ABSENCE

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OF ANTIRETROVIRAL DRUGS, AND

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THEN RESEARCH FOCUS THREE IS

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DEDICATED TO REDUCING THE SIZE

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OF THE RESERVOIR TOWARDS THE

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ULTIMATE GOAL OF EVENTUALLY

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ERADICATING HIV FROM THE BODY.

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SO WITH THAT, I INTRODUCE DIANE

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LAWRENCE, THE PROGRAM OFFICER

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FOR THE FIRST COLLABORATORY.

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>> GOOD MORNING, EVERYONE.

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DIANE LAWRENCE, I'M A PROGRAM

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OFFICER IN THE BASIC SCIENCE

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PROGRAM, DIVISION OF AIDS AT

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NIAID, AND I'M VERY PLEASED TO

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INTRODUCE OUR FIRST

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COLLABORATORY GROUP

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PRESENTATIONS THIS MORNING.

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THE CARE COLLABORATORY IS

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CURRENTLY IN ITS THIRD CYCLE

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WITH OUR MARTIN DELANEY PROGRAM.

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AND SO LEADING US OFF IS THE

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PRINCIPAL INVESTIGATOR,

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DR. DAVID MARGOLIS FROM THE

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UNIVERSITY OF NORTH CAROLINA

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CHAPEL HILL.

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DAVID?

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WELCOME.

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>> THANK YOU, DIANE.

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SO I'LL JUST GIVE A QUICK

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OVERVIEW FOLLOWED BY THE

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SCIENTIFIC PRESENTATION.

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SO FIRST, THANKS TO ALL THE

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PEOPLE INVOLVED, A FEW OF WHOM

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ARE PICTURED HERE.

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OUR MANY INVESTIGATORS,

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TRAINEES, STUDENTS, INDUSTRY

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COLLABORATORS, AND MEMBERS OF

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THE COMMUNITY THAT HELP US DO

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ALL OF THIS IMPORTANT WORK,

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THANKS VERY MUCH.

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SO THE FUNDAMENTAL IDEA THAT

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UNDERPINS OUR WORK TO EITHER

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ERADICATE OR CONTROL HIV

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INFECTION COMES FROM THIS

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PARADIGM, WHICH IS A PARADIGM

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WHICH HAS SORT OF UNDERLAID THE

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FIELD FOR QUITE A NUMBER OF

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YEARS.

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I WOULD JUST WANT TO SAY THAT

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THIS HAS BEEN A DIFFICULT PATH

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FORWARD, BUT I THINK THAT IF YOU

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LOOK CAREFULLY, I THINK WE'RE

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MAKING SIGNIFICANT BUT

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INCREMENTAL PROGRESS AND

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HOPEFULLY WE WILL GET TO THE

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DESIRED OUTCOME.

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THE ADVANCES IN THE FIELD OVER

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THE LAST YEARS HAVE LED TO A

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NUMBER OF TRIALS GIVING LATENCY

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REVERSAL AGENTS AND

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IMMUNOTHERAPIES TOGETHER.

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NONE OF THOSE TRIALS, AT LEAST

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TO MY KNOWLEDGE OR OPINION, HAVE

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RESULTED IN A REALLY SUBSTANTIAL

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DEPLETION OF PERSISTENT

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INFECTION, WHICH IS, I THINK, AN

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IMPORTANT GOAL SHOWING THAT WE

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HAVE MADE THE NEXT STEP FORWARD.

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CERTAINLY THE TRIALS HAVE SHOWN

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THAT LATENCY REVERSALS WITH THE

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AGENCY WE CURRENTLY HAVE

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MEASURED WITH THE ASSAYS NEW AND

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OLD CAN BE GIVEN SAFELY AND

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EFFECTIVELY AND MONITORED.

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IMMUNOTHERAPIES CAN BE GIVEN AND

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IN SAIR J VARIOUS TRIALS SIGNIFT

261
00:09:25,131 --> 00:09:26,166
ALTERATIONS IN THE IMMUNE

262
00:09:26,166 --> 00:09:27,534
RESPONSE WERE DEMONSTRATED BY

263
00:09:27,534 --> 00:09:28,768
THESE THERAPIES BUT SO FAR THE

264
00:09:28,768 --> 00:09:31,304
COMBINATION OF THOSE TWO EVENTS

265
00:09:31,304 --> 00:09:33,573
HAVE NOT LED TO DEPLETION OF

266
00:09:33,573 --> 00:09:34,474
PERSISTENT INFECTION, AND THAT'S

267
00:09:34,474 --> 00:09:36,075
REALLY WHERE I THINK WE NEED TO

268
00:09:36,075 --> 00:09:40,113
GET NEXT.

269
00:09:40,113 --> 00:09:41,981
A BIT AGO, STARTING IN THE LAST

270
00:09:41,981 --> 00:09:46,186
CYCLE OF THIS FUNDING MECHANISM,

271
00:09:46,186 --> 00:09:49,122
A REALLY COLLABORATIVE EFFORT

272
00:09:49,122 --> 00:09:52,725
ACROSS INDUSTRY AND ACADEMIA

273
00:09:52,725 --> 00:09:55,328
DISCOVERED OR RE-DISCOVERED THE

274
00:09:55,328 --> 00:09:59,165
USE OF THE NON-CANONICAL NF KB

275
00:09:59,165 --> 00:10:00,800
SIGNALING CIRCUIT, THE ABILITY

276
00:10:00,800 --> 00:10:02,001
TO REVERSE LATENCY IN AN

277
00:10:02,001 --> 00:10:03,636
EFFECTIVE WAY IN BOTH THE

278
00:10:03,636 --> 00:10:05,939
HUMANIZED MOUSE AND THE PRIMATE

279
00:10:05,939 --> 00:10:11,077
MODEL AND INDUCE VERY WIDESPREAD

280
00:10:11,077 --> 00:10:12,178
LATENCY REVERSAL WITHIN TISSUES

281
00:10:12,178 --> 00:10:13,913
AS WELL.

282
00:10:13,913 --> 00:10:15,782
AND SO THIS PARTICULAR DRUG IS

283
00:10:15,782 --> 00:10:17,417
NOW BEING WIDELY USED IN THE

284
00:10:17,417 --> 00:10:19,919
FIELD AS A TOOL MOLECULE, BUT

285
00:10:19,919 --> 00:10:21,588
WE'VE NOT YET BEEN ABLE TO MOVE

286
00:10:21,588 --> 00:10:23,556
THIS APPROACH INTO HUMAN

287
00:10:23,556 --> 00:10:26,392
STUDIES.

288
00:10:26,392 --> 00:10:29,662
SO THE FIRST EFFORTS ARE AROUND

289
00:10:29,662 --> 00:10:31,965
THE BIOLOGY OF LATENCY.

290
00:10:31,965 --> 00:10:34,901
WE HAVE A NUMBER OF EFFORTS

291
00:10:34,901 --> 00:10:36,836
ONGOING, AND I'LL JUST HIGHLIGHT

292
00:10:36,836 --> 00:10:38,438
SOME THAT WILL BE DISCUSSED AT

293
00:10:38,438 --> 00:10:40,507
THE MEETING.

294
00:10:40,507 --> 00:10:43,543
MIKE LIMMERMAN'S GROUP DID A

295
00:10:43,543 --> 00:10:46,079
VERY NOVEL SCREEN USING CRISPR

296
00:10:46,079 --> 00:10:47,147
TECHNOLOGY TO DISCOVER A NUMBER

297
00:10:47,147 --> 00:10:49,916
OF NEW LATENCY REVERSAL TARGETS.

298
00:10:49,916 --> 00:10:50,683
UNFORTUNATELY MICHAEL IS

299
00:10:50,683 --> 00:10:52,318
STRUGGLING WITH ANOTHER VIRUS AT

300
00:10:52,318 --> 00:10:56,356
HOME, AND SO TODAY ED BROWNE

301
00:10:56,356 --> 00:10:57,557
WILL TALK ABOUT HIS WORK THAT

302
00:10:57,557 --> 00:10:59,025
FOLLOWS THAT, TAKING MICHAEL'S

303
00:10:59,025 --> 00:11:01,261
WORK AND MOVING IT FORWARD INTO

304
00:11:01,261 --> 00:11:03,363
A NEW SCREEN TO DISCOVER AND

305
00:11:03,363 --> 00:11:05,765
VALIDATE OTHER TARGETS.

306
00:11:05,765 --> 00:11:07,300
IN THE POSTER SESSION, WHICH I

307
00:11:07,300 --> 00:11:08,601
HOPE YOU'LL ALL BE ABLE TO

308
00:11:08,601 --> 00:11:12,438
PARTICIPATE IN, I THINK PROBABLY

309
00:11:12,438 --> 00:11:14,073
THE MOST IMPORTANT PART OF THIS

310
00:11:14,073 --> 00:11:17,911
MEETING, WE HAVE A NUMBER OF

311
00:11:17,911 --> 00:11:19,112
EFFORTS LOOKING AT DIFFERENT

312
00:11:19,112 --> 00:11:21,414
KINDS OF EPIGENETIC

313
00:11:21,414 --> 00:11:22,515
MODIFICATION, VALIDATING SOME

314
00:11:22,515 --> 00:11:24,918
NEW TARGETS THAT HAVE BEEN

315
00:11:24,918 --> 00:11:26,319
DISCOVERED, AND TRYING TO

316
00:11:26,319 --> 00:11:30,256
UNDERSTAND SOME BASIC MECHANISMS

317
00:11:30,256 --> 00:11:33,660
OF LATENCY REGULATION.

318
00:11:33,660 --> 00:11:35,395
ANOTHER SUBSTANTIAL EFFORT IS TO

319
00:11:35,395 --> 00:11:38,231
UNDERSTAND PERSISTENCE IN A VERY

320
00:11:38,231 --> 00:11:40,333
DETAILED WAY WITHIN TISSUES

321
00:11:40,333 --> 00:11:41,634
USING SOME OF THE LATEST

322
00:11:41,634 --> 00:11:46,072
ADVANCES IN TECHNOLOGY.

323
00:11:46,072 --> 00:11:48,575
RECENTLY ONE OF THOSE EFFORTS

324
00:11:48,575 --> 00:11:54,647
LED BY DR. TANG AND DR. JANG

325
00:11:54,647 --> 00:11:57,584
SHOWED BRAIN MICROGLIA ARE A

326
00:11:57,584 --> 00:11:58,818
PERSISTENT RESERVOIR OF

327
00:11:58,818 --> 00:12:00,119
INFECTION IN DURABLY TREATED

328
00:12:00,119 --> 00:12:00,386
PATIENTS.

329
00:12:00,386 --> 00:12:01,654
THIS WAS A UNIQUE COLLABORATION

330
00:12:01,654 --> 00:12:04,857
WITH THE LAST COHORT IN UCSD

331
00:12:04,857 --> 00:12:06,025
WHICH WE'RE VERY GRATEFUL FOR.

332
00:12:06,025 --> 00:12:07,927
I THINK THIS WAS AN IMPORTANT

333
00:12:07,927 --> 00:12:11,998
DESCRIPTION OF A NEW TARGET.

334
00:12:11,998 --> 00:12:14,734
AT THE MEETING, SEVERAL

335
00:12:14,734 --> 00:12:15,501
INVESTIGATORS WILL SHOW SOME OF

336
00:12:15,501 --> 00:12:18,037
THEIR EARLY WORK LOOKING AT

337
00:12:18,037 --> 00:12:20,773
TISSUE RESERVOIRS IN THE G.I.

338
00:12:20,773 --> 00:12:22,408
TRACT, IN LYMPH NODES, AND

339
00:12:22,408 --> 00:12:23,509
DIFFERENCES IN INFECTION BETWEEN

340
00:12:23,509 --> 00:12:26,579
MEN AND WOMEN.

341
00:12:26,579 --> 00:12:28,581
ANOTHER PRINCIPLE THAT WE --

342
00:12:28,581 --> 00:12:29,749
THAT HAS BEEN DISCOVERED

343
00:12:29,749 --> 00:12:32,251
RECENTLY IS THE IDEA OF WHEN THE

344
00:12:32,251 --> 00:12:34,120
LATENCY IS -- WHEN THE LATENT

345
00:12:34,120 --> 00:12:36,623
RESERVOIR IS FORMED FROM WHICH

346
00:12:36,623 --> 00:12:37,390
VIRUSES.

347
00:12:37,390 --> 00:12:39,892
THIS ORIGINALLY CAME OUT OF

348
00:12:39,892 --> 00:12:43,196
OBSERVATIONS IN A COLLABORATION

349
00:12:43,196 --> 00:12:45,832
WITH THE CAPRISA COHORT.

350
00:12:45,832 --> 00:12:47,133
AND YOU CAN SEE HERE THAT THE

351
00:12:47,133 --> 00:12:51,404
PINK RESERVOIR VIRUSES IN MOST

352
00:12:51,404 --> 00:12:55,875
PATIENTS, MOST PEOPLE, COME FROM

353
00:12:55,875 --> 00:12:57,243
VIRUSES THAT WERE CIRCULATING

354
00:12:57,243 --> 00:12:58,645
NEAR THE TIME OF THERAPY

355
00:12:58,645 --> 00:12:59,846
INITIATION.

356
00:12:59,846 --> 00:13:01,481
AND THIS GAVE US SORT OF A NEW

357
00:13:01,481 --> 00:13:04,984
WAY OF LOOKING AT THE POPULATION

358
00:13:04,984 --> 00:13:07,820
OF VIRUSES IN THE LATENT

359
00:13:07,820 --> 00:13:08,087
RESERVOIR.

360
00:13:08,087 --> 00:13:11,991
MOST OF THEM ORIGINATED IN BLUE

361
00:13:11,991 --> 00:13:13,092
FROM TIMES CLOSE TO THE

362
00:13:13,092 --> 00:13:14,394
INITIATION OF THERAPY, GIVING US

363
00:13:14,394 --> 00:13:19,032
A NEW WAY TO INTERVENE INSTEAD

364
00:13:19,032 --> 00:13:20,733
OF GIVING LATENCY REVERSAL

365
00:13:20,733 --> 00:13:21,601
AGENTS OR IN ADDITION TO SOME

366
00:13:21,601 --> 00:13:24,137
DAY GIVING LATENCY REVERSAL

367
00:13:24,137 --> 00:13:25,538
AGENTS ONCE VIREMIA HAS BEEN

368
00:13:25,538 --> 00:13:26,539
WELL SUPPRESSED.

369
00:13:26,539 --> 00:13:29,475
WE ALSO HAVE THE OPPORTUNITY TO

370
00:13:29,475 --> 00:13:31,878
UNDERSTAND HOW LATENCY IS

371
00:13:31,878 --> 00:13:33,713
FOUNDED AND HOW THAT BIOLOGICAL

372
00:13:33,713 --> 00:13:36,082
PROCESS CAN BE INHIBITED AND WE

373
00:13:36,082 --> 00:13:37,250
COULD PREVENT THE FOUNDATION OF

374
00:13:37,250 --> 00:13:39,419
LATENCY IN THE FIRST PLACE.

375
00:13:39,419 --> 00:13:41,187
THE OTHER PIECE OF INFORMATION

376
00:13:41,187 --> 00:13:43,589
THAT'S NOT KNOWN IS THE TIMING

377
00:13:43,589 --> 00:13:46,426
OF ENTRY OF VIRUSES INTO THE

378
00:13:46,426 --> 00:13:48,194
RESERVOIR OVER THE TIME OF

379
00:13:48,194 --> 00:13:49,395
VIREMIA, AND SO SOME EARLY DATA

380
00:13:49,395 --> 00:13:53,433
WILL BE SHOWN BY OLIVIA COUNSELL

381
00:13:53,433 --> 00:13:54,534
HERE IN THE POSTER SESSION ABOUT

382
00:13:54,534 --> 00:13:56,069
THAT.

383
00:13:56,069 --> 00:13:59,238
THE SECOND GOAL HAS TO DO WITH

384
00:13:59,238 --> 00:14:01,741
CONTROLLING VIRAL REBOUND,

385
00:14:01,741 --> 00:14:04,143
POTENTIALLY ALSO CLEARING THE

386
00:14:04,143 --> 00:14:05,478
RESERVOIR.

387
00:14:05,478 --> 00:14:06,879
GUIDO FERRARI WILL SHORTLY TALK

388
00:14:06,879 --> 00:14:09,615
ABOUT NUMBER OF YEARS OF WORK

389
00:14:09,615 --> 00:14:13,152
LOOKING AT TARGETING SELLS USING

390
00:14:13,152 --> 00:14:18,157
THE HLA-E ACCESS, AND SOME

391
00:14:18,157 --> 00:14:20,460
IMPORTANT EARLY DATA IN AN IN

392
00:14:20,460 --> 00:14:22,028
VIVO MODEL FROM VICTOR GARCIA

393
00:14:22,028 --> 00:14:23,196
ABOUT THAT.

394
00:14:23,196 --> 00:14:25,164
ADDITIONALLY, WE'RE WORKING WITH

395
00:14:25,164 --> 00:14:27,133
MICHAEL FORSIAN AS WELL AS

396
00:14:27,133 --> 00:14:28,434
WORKING WITH SEVERAL OF THE

397
00:14:28,434 --> 00:14:31,938
OTHER COLLABORATORY GROUPS ON AN

398
00:14:31,938 --> 00:14:33,172
ECE4 APPROACH TO SUPPRESS

399
00:14:33,172 --> 00:14:33,973
VIREMIA.

400
00:14:33,973 --> 00:14:36,008
RECENTLY MICHAEL HAS BEEN

401
00:14:36,008 --> 00:14:37,410
ADVANCING B CELL EDITING AS A

402
00:14:37,410 --> 00:14:42,181
WAY TO MAKE IMPROVED ANTIBODIES

403
00:14:42,181 --> 00:14:44,317
AND AT THIS MEETING IN MATT

404
00:14:44,317 --> 00:14:49,021
GARDENER'S LAB, THEY WILL

405
00:14:49,021 --> 00:14:50,656
PRESENT SOME DATA ABOUT SOME NEW

406
00:14:50,656 --> 00:14:51,858
APPROACHES TO DELIVER THESE

407
00:14:51,858 --> 00:14:56,062
MOLECULES WITHIN AAV VECTOR.

408
00:14:56,062 --> 00:15:01,467
FINALLY STUDYING LATENCY AND

409
00:15:01,467 --> 00:15:02,535
PERSISTENCE.

410
00:15:02,535 --> 00:15:05,438
IN IN VIVO MODELS, WE'VE

411
00:15:05,438 --> 00:15:08,674
CONTINUED TO ITERATIVELY USE

412
00:15:08,674 --> 00:15:09,876
PRIMATE AND MOUSE MODELS AND

413
00:15:09,876 --> 00:15:13,579
I'LL TALK ABOUT SOME OF THE WORK

414
00:15:13,579 --> 00:15:14,680
THAT GEE COWAS GOING TO PRESENT

415
00:15:14,680 --> 00:15:16,215
IN THE PRIMATE MODEL LATER.

416
00:15:16,215 --> 00:15:21,587
SO LET ME NOW ASK ED TO COME UP

417
00:15:21,587 --> 00:15:27,827
AND TALK  HIS WORK.

418
00:15:27,827 --> 00:15:28,294
 ABOUT HIS WORK.

419
00:15:28,294 --> 00:15:29,428
>> GOOD MORNING.

420
00:15:29,428 --> 00:15:30,696
THANK YOU FOR THE OPPORTUNITY TO

421
00:15:30,696 --> 00:15:30,997
PRESENT.

422
00:15:30,997 --> 00:15:33,533
WE ARE INTERESTED IN IDENTIFYING

423
00:15:33,533 --> 00:15:35,268
NEW FACTORS THAT REGULATE HIV

424
00:15:35,268 --> 00:15:39,038
LATENCY.

425
00:15:39,038 --> 00:15:43,576
HIV IS ABLE TO PERSIST DURING

426
00:15:43,576 --> 00:15:46,746
THERAPY TO ENTER A STATE OF

427
00:15:46,746 --> 00:15:50,583
VIRAL LATENCY, THESE CELLS CAN

428
00:15:50,583 --> 00:15:51,784
REACTIVATE, WHICH IS KIND OF THE

429
00:15:51,784 --> 00:15:52,785
DEFINITION OF LATENCY.

430
00:15:52,785 --> 00:15:54,320
THIS CAN HAPPEN SPORADICALLY OR

431
00:15:54,320 --> 00:15:56,055
IT CAN OCCUR UNDER THE INFLUENCE

432
00:15:56,055 --> 00:15:58,124
OF LATENCY REVERSING AGENTS.

433
00:15:58,124 --> 00:16:00,193
BUT THUS FAR OUR CURRENT TOOLBOX

434
00:16:00,193 --> 00:16:03,262
FOR LATENCY REVERSING AGENTS IS

435
00:16:03,262 --> 00:16:04,463
INSUFFICIENT TO BROAD

436
00:16:04,463 --> 00:16:05,798
REACTIVATION OF THE LATENT

437
00:16:05,798 --> 00:16:06,098
RESERVOIR.

438
00:16:06,098 --> 00:16:09,035
SO OUR HYPOTHESIS IS THAT BY

439
00:16:09,035 --> 00:16:10,169
UNDERSTANDING THE BASIC BIOLOGY

440
00:16:10,169 --> 00:16:11,470
OF HIV TRANSCRIPTION AND

441
00:16:11,470 --> 00:16:12,772
EXPRESSION, WE COULD POTENTIALLY

442
00:16:12,772 --> 00:16:14,640
IDENTIFY NEW FACTORS THAT

443
00:16:14,640 --> 00:16:16,275
REGULATE HIV LATENCY THAT CAN BE

444
00:16:16,275 --> 00:16:17,510
TARGETED TO IMPROVE THE BREADTH

445
00:16:17,510 --> 00:16:19,345
OF OUR ABILITY TO TARGET THE

446
00:16:19,345 --> 00:16:21,881
LATENT RESERVOIR.

447
00:16:21,881 --> 00:16:23,182
SO TO DO THIS, WE'VE BEEN

448
00:16:23,182 --> 00:16:24,917
RELYING HEAVILY ON A MODEL

449
00:16:24,917 --> 00:16:25,785
SYSTEM OF LATENCY.

450
00:16:25,785 --> 00:16:29,755
WE HAVE A PRIMARY CD4 MODEL, WE

451
00:16:29,755 --> 00:16:31,591
CAN MAKE LATENTLY INFECTED CELLS

452
00:16:31,591 --> 00:16:33,125
IN OUR LAB IN LARGE NUMBERS AND

453
00:16:33,125 --> 00:16:34,994
WE CAN USE THIS SYSTEM TO DO A

454
00:16:34,994 --> 00:16:35,862
BUNCH OF DIFFERENT THINGS.

455
00:16:35,862 --> 00:16:38,064
WE CAN DO OBSERVATIONAL STUDIES

456
00:16:38,064 --> 00:16:39,799
LIKE SINGLE CELL OMICS, WHAT

457
00:16:39,799 --> 00:16:40,800
THESE CELLS LOOK LIKE, WHAT'S

458
00:16:40,800 --> 00:16:42,101
GOING ON INSIDE THEM.

459
00:16:42,101 --> 00:16:44,704
WE CAN LOOK AT HISTONE MARKS AND

460
00:16:44,704 --> 00:16:46,973
FUNCTIONAL STUDIES SO QUITE

461
00:16:46,973 --> 00:16:48,341
EFFICIENT CRISPR KNOCKOUT IN

462
00:16:48,341 --> 00:16:49,642
THESE PRIMARY CELLS, TAKE OUT

463
00:16:49,642 --> 00:16:50,743
SPECIFIC GENES AND ASK QUESTIONS

464
00:16:50,743 --> 00:16:52,044
ABOUT WHAT THEY DO, AND WE CAN

465
00:16:52,044 --> 00:16:55,248
ALSO DO CHEMICAL SCREENS, SEE

466
00:16:55,248 --> 00:16:56,749
WHAT CAUSES THINGS TO HAPPEN TO

467
00:16:56,749 --> 00:16:59,051
THE LATENTLY AFFECTED CELLS.

468
00:16:59,051 --> 00:17:01,020
THIS IS OUR APPROACH STARTING

469
00:17:01,020 --> 00:17:02,655
WITH OBSERVATIONAL STUDY, THEN

470
00:17:02,655 --> 00:17:03,856
USING FUNCTIONAL STUDIES TO KIND

471
00:17:03,856 --> 00:17:06,926
OF VALIDATE WHAT WE SEE.

472
00:17:06,926 --> 00:17:07,894
THE MAIN EXPERIMENT WE'VE DONE

473
00:17:07,894 --> 00:17:09,428
IN THE LAST COUPLE YEARS, WE

474
00:17:09,428 --> 00:17:11,964
TOOK A POPULATION OF LATENTLY

475
00:17:11,964 --> 00:17:13,266
INFECTED CELLS, ABOUT 100,000

476
00:17:13,266 --> 00:17:14,667
CELLS AND STIMULATED WITH THREE

477
00:17:14,667 --> 00:17:15,935
DIFFERENT LATENCY REVERSING

478
00:17:15,935 --> 00:17:18,170
AGENTS TO INDUCE VIRAL

479
00:17:18,170 --> 00:17:18,838
TRANSCRIPTION.

480
00:17:18,838 --> 00:17:20,373
AND THEN WE PROFILED ALL THESE

481
00:17:20,373 --> 00:17:21,908
CELLS USING A COMBINED

482
00:17:21,908 --> 00:17:23,109
MULTI-OMICS APPROACH.

483
00:17:23,109 --> 00:17:25,511
WE DID COMBINE SINGLE CELL RNA

484
00:17:25,511 --> 00:17:32,518
SEQ AND ATAC SEQ, DYNAMIC

485
00:17:32,518 --> 00:17:34,353
CHROMATIN PEAKS WHICH ALLOWS US

486
00:17:34,353 --> 00:17:35,688
TO INFER THE ACTIVITY OF

487
00:17:35,688 --> 00:17:37,423
DIFFERENT TRANSCRIPTION FACTORS

488
00:17:37,423 --> 00:17:38,524
IN EACH CELL.

489
00:17:38,524 --> 00:17:40,726
FAIRLY SIMPLE MINOR APPROACH TO

490
00:17:40,726 --> 00:17:41,894
TAKE ALL THIS DATA AND A

491
00:17:41,894 --> 00:17:43,229
CORRELATE IT WITH HIV EXPRESSION

492
00:17:43,229 --> 00:17:44,864
ACROSS THIS POPULATION OF CELLS,

493
00:17:44,864 --> 00:17:46,999
LEADING US TO ABOUT 300

494
00:17:46,999 --> 00:17:48,401
DIFFERENT CELLULAR FACTORS THAT

495
00:17:48,401 --> 00:17:50,036
WERE TO SOME DEGREE CORRELATED

496
00:17:50,036 --> 00:17:51,971
WITH HIV EXPRESSION.

497
00:17:51,971 --> 00:17:53,606
THESE ARE TRANSCRIPTS OR

498
00:17:53,606 --> 00:17:54,774
TRANSCRIPTION FACTORS.

499
00:17:54,774 --> 00:17:55,908
SO SINCE DOING THAT, WE HAVE

500
00:17:55,908 --> 00:17:58,144
TURNED THIS INTO A TARGETED

501
00:17:58,144 --> 00:17:59,545
CRISPR LAB SO WE CAN KNOCK OUT

502
00:17:59,545 --> 00:18:01,280
ALL THESE LATENCY CORRELATED

503
00:18:01,280 --> 00:18:02,815
FACTORS -- SORRY -- HIV

504
00:18:02,815 --> 00:18:04,050
CORRELATED FACTORS IN PARALLEL.

505
00:18:04,050 --> 00:18:06,686
THIS IS THE PART WE DID IN

506
00:18:06,686 --> 00:18:09,822
COLLABORATION WITH MIKE'S LAB, A

507
00:18:09,822 --> 00:18:12,391
VERY COOL STRATEGY FOR DOING

508
00:18:12,391 --> 00:18:13,993
CRISPR SCREENS WHERE THEY HAVE A

509
00:18:13,993 --> 00:18:15,428
LENGTHY GUIDE RNA VECTOR FOR THE

510
00:18:15,428 --> 00:18:17,330
CRISPR THAT HAS A PACKAGING

511
00:18:17,330 --> 00:18:19,365
SIGNAL SO THAT WHEN YOU

512
00:18:19,365 --> 00:18:21,000
INACTIVATE A LATENCY MAINTENANCE

513
00:18:21,000 --> 00:18:22,401
FACTOR YOU GET RELEASE OF VIRAL

514
00:18:22,401 --> 00:18:25,204
PARTICLES THAT CONTAIN -- FOR

515
00:18:25,204 --> 00:18:26,906
THE RNA SEQ SO YOU CAN SEQUENCE

516
00:18:26,906 --> 00:18:31,811
THE SUPER NAY TE -- TO FIND OUT

517
00:18:31,811 --> 00:18:32,678
WHAT'S DOING THINGS.

518
00:18:32,678 --> 00:18:36,749
WE DID THIS IN TWO DIFFERENT

519
00:18:36,749 --> 00:18:41,988
J-LAT LINES.

520
00:18:41,988 --> 00:18:44,290
WE DID THIS SCREEN IN

521
00:18:44,290 --> 00:18:45,825
COMBINATION WITH DIFFERENT

522
00:18:45,825 --> 00:18:47,560
LRAs TO TRY TO FIND

523
00:18:47,560 --> 00:18:48,461
SYNERGISTIC COMBINATIONS OF

524
00:18:48,461 --> 00:18:50,096
KNOCKOUTS AND LRAs THAT COULD

525
00:18:50,096 --> 00:18:51,397
COMBINE TOGETHER TO GET BETTER

526
00:18:51,397 --> 00:18:54,367
REACTIVATION.

527
00:18:54,367 --> 00:18:55,868
TO CUT A LONG STORY SHORT WE

528
00:18:55,868 --> 00:18:58,404
HAVE A BUNCH OF INTERESTING HITS

529
00:18:58,404 --> 00:19:00,806
THAT CAME OUT OF THIS.

530
00:19:00,806 --> 00:19:02,108
DOWN TO ABOUT 20 DIFFERENT

531
00:19:02,108 --> 00:19:03,442
TARGETS OF INTEREST THAT WE

532
00:19:03,442 --> 00:19:04,410
THINK ARE INTERESTING TO FOLLOW

533
00:19:04,410 --> 00:19:05,511
UP FOR VALIDATION STUDIES.

534
00:19:05,511 --> 00:19:06,812
I DON'T HAVE TIME TO GO THROUGH

535
00:19:06,812 --> 00:19:08,080
ALL THE DIFFERENT TARGETS BUT

536
00:19:08,080 --> 00:19:09,582
I'LL TALK TO YOU ABOUT JUST A

537
00:19:09,582 --> 00:19:10,549
HANDFUL OF THESE THINGS WE'RE

538
00:19:10,549 --> 00:19:12,051
DOING OUR FOLLOW-UP STUDIES ON.

539
00:19:12,051 --> 00:19:17,990
SO THESE ARE CTCF, RAD 21, CDK6,

540
00:19:17,990 --> 00:19:18,391
ETS1.

541
00:19:18,391 --> 00:19:24,363
SO CTCF RAD 21 -- THESE THINGS

542
00:19:24,363 --> 00:19:26,065
ALL CAME OUT OF THE SCREEN AND

543
00:19:26,065 --> 00:19:27,933
PART OF THE SAME COMPLEX.

544
00:19:27,933 --> 00:19:29,702
THIS IS A MACROMOLECULAR

545
00:19:29,702 --> 00:19:31,203
STRUCTURE WHICH IS INVOLVED IN

546
00:19:31,203 --> 00:19:37,209
FORMING LONG RANGE DNA LOOPS, SO

547
00:19:37,209 --> 00:19:39,178
WE THINK THAT THIS STRUCTURE IS

548
00:19:39,178 --> 00:19:40,513
SOMEHOW IMPORTANT IN MAINTAINING

549
00:19:40,513 --> 00:19:41,380
LATENCY IN SOME CELLS.

550
00:19:41,380 --> 00:19:43,449
WE DON'T KNOW EXACTLY HOW.

551
00:19:43,449 --> 00:19:44,683
PREVIOUS WORK IN MY LAB HAS

552
00:19:44,683 --> 00:19:46,852
SHOWN THAT WHEN YOU KNOCK OUT

553
00:19:46,852 --> 00:19:49,255
CTCF, YOU CAN REACTIVATE HIV

554
00:19:49,255 --> 00:19:50,456
FROM LATENCY.

555
00:19:50,456 --> 00:19:53,092
ANOTHER HIT WITH CDK6, THIS IS A

556
00:19:53,092 --> 00:19:55,928
CELL CYCLE ASSOCIATED KINASE

557
00:19:55,928 --> 00:19:57,029
ABUNDANTLY EXPRESSIONED IN

558
00:19:57,029 --> 00:19:58,097
ACTIVATED T-CELLS.

559
00:19:58,097 --> 00:20:03,369
WHEN WE KNOCK IT OUT, WE GET

560
00:20:03,369 --> 00:20:06,972
POTENT EXPRESSION.

561
00:20:06,972 --> 00:20:10,476
THIS WAS DONE BY A STUDENT IN MY

562
00:20:10,476 --> 00:20:16,482
LAB.

563
00:20:16,482 --> 00:20:17,583
SHOWED THAT THIS INHIBITOR WAS

564
00:20:17,583 --> 00:20:21,287
ABLE TO PREVENT REACTIVATION SO

565
00:20:21,287 --> 00:20:23,923
I THINK CDK6 IS IMPORTANT FOR

566
00:20:23,923 --> 00:20:25,991
EXPRESSION OF HIV IN ACTIVELY

567
00:20:25,991 --> 00:20:27,293
INFECTED CELLS AND ALSO

568
00:20:27,293 --> 00:20:31,363
REACTIVATION FROM LATENCY.

569
00:20:31,363 --> 00:20:33,432
ANOTHER HIT WAS ETS1,

570
00:20:33,432 --> 00:20:34,433
TRANSCRIPTION FACTOR THAT'S

571
00:20:34,433 --> 00:20:35,401
WIDELY EXPRESSED IN T-CELLS.

572
00:20:35,401 --> 00:20:37,036
WE CAN KNOCK IT OUT VERY

573
00:20:37,036 --> 00:20:40,439
EFFICIENTLY AS SEEN BY THIS

574
00:20:40,439 --> 00:20:42,508
WESTERN BLOT IN CRISPR IN

575
00:20:42,508 --> 00:20:44,043
PRIMARY CELLS.

576
00:20:44,043 --> 00:20:45,778
WE SEE A SIGNIFICANT BOOST TO

577
00:20:45,778 --> 00:20:47,213
HIV EXPRESSION IN CELLS THAT ARE

578
00:20:47,213 --> 00:20:48,080
IN A RESTING STATE.

579
00:20:48,080 --> 00:20:50,049
THIS IS A NEW REPRESSOR WE THINK

580
00:20:50,049 --> 00:20:51,884
OF HIV THAT'S POTENTIALLY

581
00:20:51,884 --> 00:20:52,151
IMPORTANT.

582
00:20:52,151 --> 00:20:58,691
SO IN ADDITION TO DOING ALL

583
00:20:58,691 --> 00:21:01,093
THESE CRISPR KNOCKOUT, WE'VE

584
00:21:01,093 --> 00:21:03,629
TAKEN THIS MULTI-OMICS DATA, SO

585
00:21:03,629 --> 00:21:05,931
THE TASK WE GAVE TO THIS

586
00:21:05,931 --> 00:21:09,201
BOOSTING BASED ALGORITHM, CAN WE

587
00:21:09,201 --> 00:21:10,603
PREDICT FROM MULTI-OMIC DATA

588
00:21:10,603 --> 00:21:11,504
WHETHER OR NOT THE CELLS IN THE

589
00:21:11,504 --> 00:21:13,539
TOP 10% OF HIV EXPRESSING CELLS

590
00:21:13,539 --> 00:21:15,774
WITHIN THE POPULATION, AND THIS

591
00:21:15,774 --> 00:21:18,711
WAS REASONABLY SUCCESSFUL.

592
00:21:18,711 --> 00:21:20,679
THESE TELLS YOU HOW WELL THIS

593
00:21:20,679 --> 00:21:25,484
MODEL WORKS.

594
00:21:25,484 --> 00:21:28,554
SO THE MODEL THAT WE DEVELOPED

595
00:21:28,554 --> 00:21:36,095
WAS ABLE TO PREDICT TO 75 TO

596
00:21:36,095 --> 00:21:37,763
80% -- FROM THE ATAC SEQ DATA.

597
00:21:37,763 --> 00:21:40,666
THIS MO EL DID PREDICTED NICELY

598
00:21:40,666 --> 00:21:43,169
ACROSS DONORS, STILL PREDICTS ON

599
00:21:43,169 --> 00:21:44,537
A SECOND DONOR.

600
00:21:44,537 --> 00:21:45,938
SO LASTLY, CHEMICAL SCREEN.

601
00:21:45,938 --> 00:21:47,373
SO WE'RE INTERESTED IN NEW

602
00:21:47,373 --> 00:21:48,374
COMPOUNDS THAT CAN DO THINGS TO

603
00:21:48,374 --> 00:21:48,808
LATENCY.

604
00:21:48,808 --> 00:21:50,442
SO WE COLLABORATED WITH LINDSAY

605
00:21:50,442 --> 00:21:52,945
JAMES AT UNC, A BIOLOGICAL

606
00:21:52,945 --> 00:21:56,549
CHEMIST, AND THIS EXPERIMENT

607
00:21:56,549 --> 00:21:59,518
DONE BY SAM BURGOS, TARGETING

608
00:21:59,518 --> 00:22:01,987
CHROMATIN REGULATING ENZYMES.

609
00:22:01,987 --> 00:22:05,958
SO SAM EFFECTED SON CELLS IN THE

610
00:22:05,958 --> 00:22:08,027
PRESENCE OF THESE COMPOUNDS AND

611
00:22:08,027 --> 00:22:09,461
PROFILED THESE CELLS WITH FLOW

612
00:22:09,461 --> 00:22:10,563
CYTOMETRY TO LOOK AT THE LATENT

613
00:22:10,563 --> 00:22:11,864
AND ACTIVE POPULATIONS.

614
00:22:11,864 --> 00:22:13,399
THIS IS A DUAL COLOR REPORTER

615
00:22:13,399 --> 00:22:13,933
VIRUS.

616
00:22:13,933 --> 00:22:14,867
SO TWO DRUGS THAT HAVE COME OUT

617
00:22:14,867 --> 00:22:19,505
OF THIS APPROACH WE THINK ARE

618
00:22:19,505 --> 00:22:29,782
INTERESTING.

619
00:22:32,484 --> 00:22:35,487
BAY299, TAF1 IS A COMPONENT OF

620
00:22:35,487 --> 00:22:38,324
THE TF2D GENERAL TRANSCRIPTION

621
00:22:38,324 --> 00:22:39,525
FACTOR COMPLEX THAT'S IMPORTANT

622
00:22:39,525 --> 00:22:40,993
FOR INITIATING TRANSCRIPTION.

623
00:22:40,993 --> 00:22:46,432
SAM KNOCKED OUT TAF1 AND BID1 IN

624
00:22:46,432 --> 00:22:49,401
A MODEL OF LATENCY AND SHOWED

625
00:22:49,401 --> 00:22:51,136
REACTIVATION OF TAF1 WAS

626
00:22:51,136 --> 00:22:52,538
SUFFICIENT TO REACTIVATE HIV

627
00:22:52,538 --> 00:22:52,972
FROM LATENCY.

628
00:22:52,972 --> 00:22:54,840
I THINK THIS IS IMPORTANT FOR

629
00:22:54,840 --> 00:22:55,941
REPRESSING HIV IN SOME CELLS AT

630
00:22:55,941 --> 00:22:56,275
LEAST.

631
00:22:56,275 --> 00:23:02,147
SO LASTLY, UNC9153, THIS IS A

632
00:23:02,147 --> 00:23:03,916
TRANS PHRASE THAT ASSOCIATES

633
00:23:03,916 --> 00:23:08,721
WITH ACTIVELY TRANSCRIBING

634
00:23:08,721 --> 00:23:09,788
RNA -- 2.

635
00:23:09,788 --> 00:23:11,824
TO THE GENE BODIES OF ACTIVELY

636
00:23:11,824 --> 00:23:15,427
EXPRESSED GENES, INHIBITED BY

637
00:23:15,427 --> 00:23:16,428
UNC9153.

638
00:23:16,428 --> 00:23:17,830
SO WE CAN INHIBIT THIS ENZYME

639
00:23:17,830 --> 00:23:20,232
AND ALSO KNOCK OUT WITH CRISPR

640
00:23:20,232 --> 00:23:23,969
IN THIS CASE, WHEN YOU DO THAT

641
00:23:23,969 --> 00:23:25,704
YOU CAN SEE A SIGNIFICANT

642
00:23:25,704 --> 00:23:29,108
REDUCTION IN HIV EXPRESSION SO

643
00:23:29,108 --> 00:23:30,209
SETD2 WE THINK IS REQUIRED TO

644
00:23:30,209 --> 00:23:32,278
SUSTAIN ACTIVELY LEVELS OF HIV

645
00:23:32,278 --> 00:23:32,578
EXPRESSION.

646
00:23:32,578 --> 00:23:34,580
SO PUTTING IT ALL TOGETHER INTO

647
00:23:34,580 --> 00:23:37,149
OUR MODEL, SO THE APPROACH OF

648
00:23:37,149 --> 00:23:38,517
TAKING AN OBSERVATIONAL APPROACH

649
00:23:38,517 --> 00:23:39,952
FOLLOWED BY FUNCTIONAL STUDIES I

650
00:23:39,952 --> 00:23:41,553
THINK WAS REASONABLY SUCCESSFUL.

651
00:23:41,553 --> 00:23:42,554
WE'VE GOT NEW THINGS TO PLAY

652
00:23:42,554 --> 00:23:47,159
WITH TO LOOK AT IN TERMS OF --

653
00:23:47,159 --> 00:23:49,028
SO SET -- WE THINK ARE REQUIRED

654
00:23:49,028 --> 00:23:50,763
FOR HIV EXPRESSION AND ACTIVELY

655
00:23:50,763 --> 00:23:51,430
TRANSCRIBING CELLS.

656
00:23:51,430 --> 00:23:52,865
THESE COULD BE LIMITING FACTORS

657
00:23:52,865 --> 00:23:55,067
FOR EXAMPLE IN LATENTLY AFFECTED

658
00:23:55,067 --> 00:23:58,737
CELLS THAT WE CAN OVEREXPRESS OR

659
00:23:58,737 --> 00:23:59,071
DELIVER.

660
00:23:59,071 --> 00:24:00,606
NEW THINGS WE THINK ARE

661
00:24:00,606 --> 00:24:04,009
REPRESSING HIV, SO TAF1,

662
00:24:04,009 --> 00:24:05,844
ETS1 AND THE COHESION COMPLEX.

663
00:24:05,844 --> 00:24:08,247
WE ARE FOLLOWING UP ON ALL THESE

664
00:24:08,247 --> 00:24:10,115
HITS FIGURING OUT

665
00:24:10,115 --> 00:24:10,983
MECHANISTICALLY HOW DO THEY

666
00:24:10,983 --> 00:24:13,719
WORK, WHAT ARE THEY DOING, IN TE

667
00:24:13,719 --> 00:24:14,720
CLINICAL RESERVOIR WOULD BE THE

668
00:24:14,720 --> 00:24:17,656
NEXT STEP.

669
00:24:17,656 --> 00:24:18,524
TAKE-HOME MESSAGE FOR THE

670
00:24:18,524 --> 00:24:19,224
COMMUNITY, THE QUESTION WE'RE

671
00:24:19,224 --> 00:24:20,859
TRYING TO ADDRESS IS WHY DOES

672
00:24:20,859 --> 00:24:27,499
HIV SHUT DOWN IN SOME CELLS, HAY

673
00:24:27,499 --> 00:24:28,467
I THINGS IN THE ENVIRONMENT

674
00:24:28,467 --> 00:24:29,468
REGULATING THAT.

675
00:24:29,468 --> 00:24:31,003
WE FOUND NEW THINGS THAT

676
00:24:31,003 --> 00:24:32,204
REGULATE HIV ACTIVITY IN

677
00:24:32,204 --> 00:24:33,339
LATENTLY AFFECTED CELLS.

678
00:24:33,339 --> 00:24:34,740
OUR NEXT STEP IS TO FIND DRUGS

679
00:24:34,740 --> 00:24:36,141
THAT COULD TARGET THESE GENES TO

680
00:24:36,141 --> 00:24:38,677
HELP CLEAR HIV INFECTED CELLS.

681
00:24:38,677 --> 00:24:41,080
SPECIAL THANKS TO MY LAB,

682
00:24:41,080 --> 00:24:43,916
SPECIAL SHOUT OUT TO JACKSON,

683
00:24:43,916 --> 00:24:46,652
THESIS MONDAY, WAY TO GO, JACK

684
00:24:46,652 --> 00:24:46,985
JACKSON.

685
00:24:46,985 --> 00:24:49,488
THANKS TO EVERYBODY ELSE, ALL

686
00:24:49,488 --> 00:24:51,357
OUR FUNDERS AND COLLABORATORS

687
00:24:51,357 --> 00:24:51,557
HERE.

688
00:24:51,557 --> 00:24:56,729
[APPLAUSE]

689
00:24:56,729 --> 00:24:59,431
>> ALL RIGHT.

690
00:24:59,431 --> 00:25:03,469
THANK YOU FOR THIS.

691
00:25:03,469 --> 00:25:06,138
WE'RE A PART OF -- AS YOU HEARD

692
00:25:06,138 --> 00:25:09,608
THE RESEARCH FOCUS STRATEGY IS

693
00:25:09,608 --> 00:25:12,010
TO ELIMINATE THE RESERVOIR.

694
00:25:12,010 --> 00:25:18,484
WHY ARE WE INTERESTED IN HLA-E?

695
00:25:18,484 --> 00:25:21,754
THE GERMINAL OBSERVATIONS WERE

696
00:25:21,754 --> 00:25:25,591
REPORTED BY DR. SPEAKER'S GROUP

697
00:25:25,591 --> 00:25:32,564
WHO EVALUATED IMMUNOGENICITY --

698
00:25:32,564 --> 00:25:34,099
OF THE SIV GAG AND REPEAT LID

699
00:25:34,099 --> 00:25:35,534
DEMONSTRATED THAT IT COULD

700
00:25:35,534 --> 00:25:37,936
ELIMINATE INFECTION IN 60% OF

701
00:25:37,936 --> 00:25:43,308
THE VACCINATED RHESUS MACAQUES.

702
00:25:43,308 --> 00:25:45,611
THE PROTECTION WAS CORRELATED

703
00:25:45,611 --> 00:25:49,848
WITH THE CD8 T-CELLS TO

704
00:25:49,848 --> 00:25:51,049
RECOGNIZE SIV GAG PEPTIDES IN

705
00:25:51,049 --> 00:25:55,120
THE CONTEXT OF THE HLA-E

706
00:25:55,120 --> 00:25:55,454
MOLECULES.

707
00:25:55,454 --> 00:25:59,258
AS A REMINDER, IMMUNE RESPONSES

708
00:25:59,258 --> 00:26:01,126
INVOLVING HLA-E, ITS RELATED

709
00:26:01,126 --> 00:26:03,328
FUNCTIONS CAN BE DIVIDED IN

710
00:26:03,328 --> 00:26:05,898
MAJOR AND MINOR.

711
00:26:05,898 --> 00:26:07,433
THE MAJOR ARE REALLY RELATED TO

712
00:26:07,433 --> 00:26:10,369
THE PRESENTATION OF ENDOGENOUS

713
00:26:10,369 --> 00:26:15,774
VL9 PEPTIDES THAT ARE RECOGNIZED

714
00:26:15,774 --> 00:26:20,045
BY RECEPTORS AND REGULATE THE NK

715
00:26:20,045 --> 00:26:21,346
FUNCTION.

716
00:26:21,346 --> 00:26:28,153
THE MINOR ARE RELATED TO THE

717
00:26:28,153 --> 00:26:30,722
GENERATION OF NON-VL9 PEPTIDES

718
00:26:30,722 --> 00:26:33,058
THAT DERIVE FROM THE PROCESSING

719
00:26:33,058 --> 00:26:35,494
OF THE ANTIGENS OF SEVERAL

720
00:26:35,494 --> 00:26:36,428
DIFFERENT PATHOGENS, AND THEY

721
00:26:36,428 --> 00:26:39,398
CAN BE RECOGNIZED BY THE

722
00:26:39,398 --> 00:26:40,699
CD8 T-CELLS AND ELIMINATE THE

723
00:26:40,699 --> 00:26:42,034
CELLS.

724
00:26:42,034 --> 00:26:44,770
THESE MECHANISM ESSENTIALLY

725
00:26:44,770 --> 00:26:46,071
COUNTERBALANCE THE INHIBITORY

726
00:26:46,071 --> 00:26:48,941
EFFECT OF THE PATHOGENS THAT ARE

727
00:26:48,941 --> 00:26:52,311
TRYING TO INCREASE THE HLA-E

728
00:26:52,311 --> 00:26:54,179
EXPRESSION OF THE INFECTED CELLS

729
00:26:54,179 --> 00:26:56,915
AND INHIBIT THE NK CELLS'

730
00:26:56,915 --> 00:26:59,518
ACTIVITY.

731
00:26:59,518 --> 00:27:01,186
SO WE AIM AT ANSWERING THE

732
00:27:01,186 --> 00:27:05,858
QUESTION, CAN HUMAN MAKE HLA-E

733
00:27:05,858 --> 00:27:13,198
RESTRICTED T-CELLS RESPONSES TO

734
00:27:13,198 --> 00:27:14,199
HIV?

735
00:27:14,199 --> 00:27:22,841
WE WERE ABLE TO ISOLAT ISOLATEDT

736
00:27:22,841 --> 00:27:24,710
CAN BE PRESENTED IN THE CONTEXT

737
00:27:24,710 --> 00:27:26,678
OF THE HLA MOLECULES.

738
00:27:26,678 --> 00:27:29,381
T-CELLS WERE PRIMED IN VITRO

739
00:27:29,381 --> 00:27:31,683
HUGHESING HLA-E PEPTIDES BY

740
00:27:31,683 --> 00:27:34,586
CULTURING THEM WITH DENDRITIC

741
00:27:34,586 --> 00:27:36,522
CELLS IN PRESENCE OF EXCESS

742
00:27:36,522 --> 00:27:37,055
PEPTIDES.

743
00:27:37,055 --> 00:27:40,893
AND T-CELL CLONES WERE SORTED

744
00:27:40,893 --> 00:27:42,761
USING SPECIFIC TETRAMERS.

745
00:27:42,761 --> 00:27:48,000
WE WERE ABLE TO ISOLATE 45

746
00:27:48,000 --> 00:27:52,137
EPITOPE RELATED TO IL9 AND 15

747
00:27:52,137 --> 00:27:57,376
AJV GAG EPITOPE RL9 T-CELL

748
00:27:57,376 --> 00:27:57,709
CLONES.

749
00:27:57,709 --> 00:28:04,850
THE NEXT QUESTION WAS, CAN HLA-E

750
00:28:04,850 --> 00:28:08,554
RESTRICTED -- THE APPROACH WAS

751
00:28:08,554 --> 00:28:10,856
TO INFECT THE CELLS IN VITRO

752
00:28:10,856 --> 00:28:14,326
USING THE NL4 -- 3 ISOLATE, ADD

753
00:28:14,326 --> 00:28:20,065
THE T-CELL CLONE IN THE

754
00:28:20,065 --> 00:28:20,866
RAVIL9 CLONES, CULTURE FOR FIVE

755
00:28:20,866 --> 00:28:22,801
DAYS AND THEN IDENTIFY THE

756
00:28:22,801 --> 00:28:25,337
REMAINING INFECTED CELLS, THE

757
00:28:25,337 --> 00:28:28,173
INTRACELLULAR P24 STAINING.

758
00:28:28,173 --> 00:28:31,009
AS YOU CAN SEE IN THIS PANEL, IN

759
00:28:31,009 --> 00:28:33,078
THE CONTROL YOU HAVE A

760
00:28:33,078 --> 00:28:35,614
POPULATION OF POSITIVE P24

761
00:28:35,614 --> 00:28:36,148
INFECTED CELLS.

762
00:28:36,148 --> 00:28:40,085
WHEN YOU ADD THE CLONES, THESE

763
00:28:40,085 --> 00:28:41,286
POPULATION ARE REDUCED AND THEY

764
00:28:41,286 --> 00:28:42,988
ARE DEFINITELY REDUCED COMPARED

765
00:28:42,988 --> 00:28:46,425
TO WHEN YOU ADD THE CLONES THAT

766
00:28:46,425 --> 00:28:49,194
ARE SARS-COV-2 OR IRRELEVANT TO

767
00:28:49,194 --> 00:28:52,431
AJV.

768
00:28:52,431 --> 00:28:54,199
DR. YANG DEMONSTRATED THAT WHEN

769
00:28:54,199 --> 00:28:56,068
YOU LOOK AT ALL THE CLONES IN

770
00:28:56,068 --> 00:28:58,036
GENERAL, THE AVERAGE OF

771
00:28:58,036 --> 00:28:59,438
INHIBITION OBSERVED IS

772
00:28:59,438 --> 00:29:01,640
SIGNIFICANTLY HIGHER THAN WHAT

773
00:29:01,640 --> 00:29:05,043
YOU OBSERVE USING THE KNOWN

774
00:29:05,043 --> 00:29:07,646
RELEVANT SARS-COV-2 CLONES.

775
00:29:07,646 --> 00:29:09,815
THE OTHER ASPECT WAS

776
00:29:09,815 --> 00:29:11,683
INVESTIGATED BY DR. RAY WHO

777
00:29:11,683 --> 00:29:13,552
SEQUENCED THE T-CELL RECEPTOR OF

778
00:29:13,552 --> 00:29:19,891
THE RL9 CLONES, IDENTIFY THE PCR

779
00:29:19,891 --> 00:29:22,628
CHAIN, SYNTHESIZE THE FULL

780
00:29:22,628 --> 00:29:25,464
CONCERT AND TRANSDUCE THEM INTO

781
00:29:25,464 --> 00:29:28,967
THE CD8 T-CELLS.

782
00:29:28,967 --> 00:29:36,742
THESE CLONES REPORT IN THE BARS

783
00:29:36,742 --> 00:29:37,876
HERE -- SIGNIFICANT INHIBITION

784
00:29:37,876 --> 00:29:39,344
OF THE VIRUS REPLICATION

785
00:29:39,344 --> 00:29:44,383
COMPARED TO WHAT OBSERVED BY THE

786
00:29:44,383 --> 00:29:46,351
HLA-E B27 RESTRICTED KK10

787
00:29:46,351 --> 00:29:46,585
CLONES.

788
00:29:46,585 --> 00:29:48,987
AND YOU CAN SEE THE DIFFERENCE

789
00:29:48,987 --> 00:29:50,656
BETWEEN -- IN THE GREEN BARS

790
00:29:50,656 --> 00:29:55,127
THAT IF YOU ARE HLA-E B27

791
00:29:55,127 --> 00:29:56,428
POSITIVE, YOU CAN OBSERVE

792
00:29:56,428 --> 00:29:57,963
REDUCTION IN THE INFECTION,

793
00:29:57,963 --> 00:30:00,599
WHEREAS IF YOU ARE B27 NEGATIVE,

794
00:30:00,599 --> 00:30:01,266
YOU CANNOT.

795
00:30:01,266 --> 00:30:04,202
THIS IS NOT THE CASE WHEN YOU'RE

796
00:30:04,202 --> 00:30:07,572
USING THE HLA-E CLONES, IT'S

797
00:30:07,572 --> 00:30:11,443
IRRELEVANT TO YOUR HLA-B27

798
00:30:11,443 --> 00:30:15,881
STATUS.

799
00:30:15,881 --> 00:30:19,418
CAN SPECIFIC T-CELL CLONES

800
00:30:19,418 --> 00:30:20,285
CONTROL IN VIVO.

801
00:30:20,285 --> 00:30:23,989
THIS WAS WORK CONDUCTED IN

802
00:30:23,989 --> 00:30:26,291
DR. GARCIA'S LAB WITH HIS

803
00:30:26,291 --> 00:30:29,795
COLLABORATION, BLT MICE WERE

804
00:30:29,795 --> 00:30:33,732
USED TO GENERATE THE HLA-E TRANS

805
00:30:33,732 --> 00:30:36,234
DUCK TANT CD8 T-CELLS.

806
00:30:36,234 --> 00:30:42,574
THE MICE WERE INFUSED WITH THESE

807
00:30:42,574 --> 00:30:47,713
TRANS DUCTANT CLONES, AND 24

808
00:30:47,713 --> 00:30:49,681
HOURS LATER INFECTED WITH THE

809
00:30:49,681 --> 00:30:50,882
HIV.

810
00:30:50,882 --> 00:30:52,551
ONE WEEK LATER, THERE WAS A

811
00:30:52,551 --> 00:31:01,059
SECOND INFUSION, AT THE END OF

812
00:31:01,059 --> 00:31:03,462
THE STUDY, THE ORGANS WERE

813
00:31:03,462 --> 00:31:05,263
COLLECTED.

814
00:31:05,263 --> 00:31:08,834
WHAT WAS OBSERVED IS THAT IN THE

815
00:31:08,834 --> 00:31:10,769
LONGITUDAL SAMPLES, THE PLASMA

816
00:31:10,769 --> 00:31:13,371
VIREMIA STARTED TO DECLINE, AND

817
00:31:13,371 --> 00:31:16,908
IT REACHED SIGNIFICANT

818
00:31:16,908 --> 00:31:20,645
DIFFERENCE IN THE LOWER LEVEL

819
00:31:20,645 --> 00:31:23,915
AFTER 28 DAYS OF POST INFUSION.

820
00:31:23,915 --> 00:31:26,418
WHEN WE LACK AT THE DISTRIBUTION

821
00:31:26,418 --> 00:31:27,886
OF THESE TRANSDUCTANT CLONES

822
00:31:27,886 --> 00:31:31,022
INTO THE TISSUES, YOU CAN SEE

823
00:31:31,022 --> 00:31:34,092
THAT THE CLONES SPECIFIC FOR HIV

824
00:31:34,092 --> 00:31:37,362
WERE HIGHLY AND SIGNIFICANTLY

825
00:31:37,362 --> 00:31:38,463
ACCUMULATING IN THE BONE MARROW

826
00:31:38,463 --> 00:31:40,132
AND IN THE LYMPH NODE.

827
00:31:40,132 --> 00:31:44,803
WHAT HAPPENED ABOUT THE VIRAL

828
00:31:44,803 --> 00:31:47,873
RNA WAS OVERALL ACROSS ALL THE

829
00:31:47,873 --> 00:31:50,942
TISSUE A SIGNIFICANTLY LOWER

830
00:31:50,942 --> 00:31:52,577
LEVEL OF VIRAL RNA IN THE

831
00:31:52,577 --> 00:31:54,112
ANIMALS WHO WERE TRANSDUCED WITH

832
00:31:54,112 --> 00:31:57,816
THE CLONES, AND SPECIFICALLY

833
00:31:57,816 --> 00:32:01,920
LYMPH NODE AND LIVER PRESENTED

834
00:32:01,920 --> 00:32:04,523
LESS VIRUS LOAD.

835
00:32:04,523 --> 00:32:06,158
WITHOUT REACHING SIGNIFICANCE,

836
00:32:06,158 --> 00:32:08,026
LOWER VIRAL RNA WAS OBSERVED IN

837
00:32:08,026 --> 00:32:14,933
ALL THE OTHER TISSUES.

838
00:32:14,933 --> 00:32:17,769
SO I THINK THESE DATA

839
00:32:17,769 --> 00:32:20,172
DEMONSTRATE THAT THE HLA-E

840
00:32:20,172 --> 00:32:22,374
RESTRICTED T-CELLS CAN EXIST AND

841
00:32:22,374 --> 00:32:23,909
CAN BE PRIMED AND CLONED.

842
00:32:23,909 --> 00:32:27,512
THEY CAN SUPPRESS BOTH IN VIVO

843
00:32:27,512 --> 00:32:30,615
AND IN VITRO VIRUS REPLICATION.

844
00:32:30,615 --> 00:32:33,885
AND THESE FUNCTIONAL ASSAYS ARE

845
00:32:33,885 --> 00:32:39,457
RELEVANT TO OUR GOALS.

846
00:32:39,457 --> 00:32:40,759
WHERE WE'RE GOING FROM HERE IS

847
00:32:40,759 --> 00:32:42,527
THERE'S ALREADY THE OBSERVATION

848
00:32:42,527 --> 00:32:44,262
BY DR. PICKERS OF THE IMPORTANCE

849
00:32:44,262 --> 00:32:44,930
FOR VACCINES.

850
00:32:44,930 --> 00:32:48,867
WE KNOW THAT THESE HLA-E CLONES

851
00:32:48,867 --> 00:32:54,105
CAN OVERCOME THE RESTRICTION

852
00:32:54,105 --> 00:32:57,042
SPECIFIC FOR HLA-E -- AND IT CAN

853
00:32:57,042 --> 00:32:58,810
BE A UNIVERSAL METHOD.

854
00:32:58,810 --> 00:33:00,245
IT'S DOWN REGULATED IF NOTHING

855
00:33:00,245 --> 00:33:01,780
ELSE IS UPREGULATED DURING

856
00:33:01,780 --> 00:33:03,648
INFECTION AND WE CAN EXPLOIT

857
00:33:03,648 --> 00:33:06,685
BOTH NK AND T-CELL RESPONSES.

858
00:33:06,685 --> 00:33:11,389
SO FOR US, THIS IS IMPORTANT

859
00:33:11,389 --> 00:33:12,390
BECAUSE WE ANSWER THE KEY

860
00:33:12,390 --> 00:33:14,226
QUESTION, CAN WE USE

861
00:33:14,226 --> 00:33:16,394
ANTIBODY-BASED MOLECULES THAT

862
00:33:16,394 --> 00:33:18,396
CAN ALLOW KILLER CELLS OF OUR

863
00:33:18,396 --> 00:33:19,931
IMMUNE SYSTEM TO RECOGNIZE THE

864
00:33:19,931 --> 00:33:22,801
INFECTED CELLS IN A WAY THAT IS

865
00:33:22,801 --> 00:33:24,102
UNIVERSAL AND NOT RESTRICTED BY

866
00:33:24,102 --> 00:33:26,171
THE GENETIC-BASED DIFFERENCE IN

867
00:33:26,171 --> 00:33:28,139
EACH INDIVIDUAL'S IMMUNE CELLS?

868
00:33:28,139 --> 00:33:32,744
THE FINDINGS, REPORTED RESULTS

869
00:33:32,744 --> 00:33:33,845
OBTAINED BY EXPERIMENTS

870
00:33:33,845 --> 00:33:35,280
CONDUCTED USING HUMAN CELLS IN

871
00:33:35,280 --> 00:33:37,782
THE LABORATORY AND IN MOUSE

872
00:33:37,782 --> 00:33:39,751
MODEL IN VIVO INDICATED THAT

873
00:33:39,751 --> 00:33:41,386
THIS APPROACH CAN BE SUCCESSFUL.

874
00:33:41,386 --> 00:33:44,656
AND WE STILL HAVE WORK TO DO,

875
00:33:44,656 --> 00:33:46,958
BOTH IN THE SMALL HUMAN ANIMAL

876
00:33:46,958 --> 00:33:48,493
MODEL AND THEN MOVING THIS INTO

877
00:33:48,493 --> 00:33:52,097
THE NON-HUMAN PRIMATE TO

878
00:33:52,097 --> 00:33:53,431
UNDERSTAND HOW WE CAN BETTER

879
00:33:53,431 --> 00:33:55,166
EXPLOIT ALL OF THIS.

880
00:33:55,166 --> 00:33:58,136
AND I WANT TO ACKNOWLEDGE ALL

881
00:33:58,136 --> 00:33:59,537
OUR COLLABORATORS.

882
00:33:59,537 --> 00:34:09,414
[APPLAUSE]

883
00:34:09,414 --> 00:34:12,884
>> SO THANKS.

884
00:34:12,884 --> 00:34:14,719
NOW I'LL TALK A BIT ABOUT SOME

885
00:34:14,719 --> 00:34:19,891
OF THE STUDIES DONE IN NON-HUMAN

886
00:34:19,891 --> 00:34:22,193
PRIMATES.

887
00:34:22,193 --> 00:34:25,797
THE GROUP HAS BASICALLY LOOKED

888
00:34:25,797 --> 00:34:28,867
AT PERSISTENCE AND CONTROL OF

889
00:34:28,867 --> 00:34:31,469
PERSISTENT INFECTION IN TWO

890
00:34:31,469 --> 00:34:33,238
SETTINGS.

891
00:34:33,238 --> 00:34:34,639
THE FIRST, THE SORT OF -- OR THE

892
00:34:34,639 --> 00:34:37,075
SECOND, THE MORE TRADITIONAL

893
00:34:37,075 --> 00:34:40,111
ONE, THAT'S NUMBER TWO, WHERE

894
00:34:40,111 --> 00:34:43,081
ANIMALS ARE INFECTED, SUPPRESSED

895
00:34:43,081 --> 00:34:44,382
ON THERAPY AND THEN AN

896
00:34:44,382 --> 00:34:46,017
INTERVENTION IS DONE WITH A

897
00:34:46,017 --> 00:34:46,685
DISTAL READOUT.

898
00:34:46,685 --> 00:34:50,956
THE NEWER WAY IS TO TRY TO

899
00:34:50,956 --> 00:34:52,057
INTERVENE EARLY, THAT'S NUMBER

900
00:34:52,057 --> 00:34:57,062
ONE HERE.

901
00:34:57,062 --> 00:34:58,697
WHERE ANIMALS ARE INFECTED, AN

902
00:34:58,697 --> 00:35:00,131
INTERVENTION IS DONE CLOSE AFTER

903
00:35:00,131 --> 00:35:01,967
ART IS INITIATED, AND THEN A

904
00:35:01,967 --> 00:35:03,535
READOUT IS DONE AT THE END OF

905
00:35:03,535 --> 00:35:06,571
THE STUDY.

906
00:35:06,571 --> 00:35:08,773
SO I'M SORRY, I GUESS I MISSED A

907
00:35:08,773 --> 00:35:09,541
NUMBER OF THESE.

908
00:35:09,541 --> 00:35:10,609
SO THE FIRST THING I'LL TALK

909
00:35:10,609 --> 00:35:15,547
ABOUT IS NUMBER TWO.

910
00:35:15,547 --> 00:35:16,781
THIS IS THE STUDY THAT WE

911
00:35:16,781 --> 00:35:21,886
ALLUDED TO EARLIER USING THE

912
00:35:21,886 --> 00:35:22,554
NON-CANONICAL APPROACH.

913
00:35:22,554 --> 00:35:24,556
THIS WAS PUBLISHED BY A BROAD

914
00:35:24,556 --> 00:35:28,226
GROUP OF INVESTIGATORS SHOWN

915
00:35:28,226 --> 00:35:30,128
HERE, AND HAS BEEN A SIGNIFICANT

916
00:35:30,128 --> 00:35:31,863
ADVANCE IN LATENCY REVERSAL

917
00:35:31,863 --> 00:35:35,567
THAT'S BEING USED ACROSS MANY IN

918
00:35:35,567 --> 00:35:43,575
VIVO MODELS CURRENTLY.

919
00:35:43,575 --> 00:35:45,110
BUT THE GROUP WANTED TO GO

920
00:35:45,110 --> 00:35:46,411
BEYOND THIS AND ADD TO THIS.

921
00:35:46,411 --> 00:35:51,016
IN THIS REGARD, THEY USED THE

922
00:35:51,016 --> 00:35:53,985
SUPER AGONIST APPROACH.

923
00:35:53,985 --> 00:35:55,053
SOMETHING THAT'S ALREADY BEEN

924
00:35:55,053 --> 00:35:57,889
TESTED IN CLINICAL TRIALS, HAS

925
00:35:57,889 --> 00:35:59,758
BROAD EFFECTS ON THE IMMUNE

926
00:35:59,758 --> 00:36:02,661
SYSTEM, AND COULD ACT AS AN LRA

927
00:36:02,661 --> 00:36:06,998
IN VITRO.

928
00:36:06,998 --> 00:36:10,602
AND IN ANOTHER PREVIOUS STUDY,

929
00:36:10,602 --> 00:36:13,672
IN THE CONTEXT OF CD8 DEPLETION

930
00:36:13,672 --> 00:36:24,215
IN THE USE OF N-803, MCBRIEN --

931
00:36:27,819 --> 00:36:30,622
WE WANTED TO GO OUT AND TRY

932
00:36:30,622 --> 00:36:32,157
ANOTHER IMMUNOTHERAPY, BASICALLY

933
00:36:32,157 --> 00:36:34,759
THE BEST THAT WE COULD FIND TO

934
00:36:34,759 --> 00:36:37,629
TEST IN THE PRIMATE MODEL AT THE

935
00:36:37,629 --> 00:36:40,565
TIME, AND HERE WE WERE HELPED

936
00:36:40,565 --> 00:36:46,705
GREATLY BY THE WORK OF THE NIH

937
00:36:46,705 --> 00:36:48,006
AND THE FREMONT GROUP THAT

938
00:36:48,006 --> 00:36:49,340
PRODUCED THESE ANTIBODIES.

939
00:36:49,340 --> 00:36:57,315
THEY SELECTED FOUR SPECIFICALLY

940
00:36:57,315 --> 00:36:58,850
MONOCLONALS THAT HAD BROAD

941
00:36:58,850 --> 00:37:01,820
EFFECTS IN POTENCY AND

942
00:37:01,820 --> 00:37:03,555
NEUTRALIZATION, IN NOT JUST

943
00:37:03,555 --> 00:37:05,423
NEUTRALIZATION BUT IN ANTIVIRAL

944
00:37:05,423 --> 00:37:08,159
EFFECT IN ADCC.

945
00:37:08,159 --> 00:37:10,028
AND THESE SELECTED ANTIBODIES

946
00:37:10,028 --> 00:37:12,664
ARE SHOWN HERE.

947
00:37:12,664 --> 00:37:15,200
ITS08 TO 113.

948
00:37:15,200 --> 00:37:20,038
SO IN THIS STUDY, THEY INFECTED

949
00:37:20,038 --> 00:37:21,539
ANIMALS, SUPPRESSED THEM

950
00:37:21,539 --> 00:37:24,609
DURABLY, AND THEN GAVE THIS

951
00:37:24,609 --> 00:37:30,849
INTERVENTION, EITHER ART ALONE,

952
00:37:30,849 --> 00:37:35,553
ART PLUS AZD, OR N-803.

953
00:37:35,553 --> 00:37:37,088
SO WE LOOKED AT THE COMBINATION

954
00:37:37,088 --> 00:37:40,492
OF THESE EFFECTS.

955
00:37:40,492 --> 00:37:46,498
WITH THE USE OF ANTIBODIES.

956
00:37:46,498 --> 00:37:47,565
THE ANTIBODY INFUSIONS ARE IN

957
00:37:47,565 --> 00:37:47,799
GREY.

958
00:37:47,799 --> 00:37:50,535
YOU CAN SEE THEM GIVEN TWICE IN

959
00:37:50,535 --> 00:37:52,003
THE LATENCY REVERSAL

960
00:37:52,003 --> 00:37:54,372
INTERVENTIONS ARE IN RED AND

961
00:37:54,372 --> 00:37:57,675
PURPLE.

962
00:37:57,675 --> 00:38:02,747
SO GOING TO THE KEY RESULT,

963
00:38:02,747 --> 00:38:03,848
BECAUSE EACH ANIMAL -- BECAUSE

964
00:38:03,848 --> 00:38:07,752
WE NEEDED TO LOOK AT ANIMALS AS

965
00:38:07,752 --> 00:38:09,187
A GROUP.

966
00:38:09,187 --> 00:38:12,924
WE SAW THAT BEFORE THE

967
00:38:12,924 --> 00:38:13,658
INTERVENTION, AS A GROUP THE

968
00:38:13,658 --> 00:38:17,829
DIFFERENT GROUPS WERE THE SAME,

969
00:38:17,829 --> 00:38:19,097
THAT'S UP IN THE TOP THERE AS

970
00:38:19,097 --> 00:38:21,099
FAR AS DNA LEVELS IN THE VARIOUS

971
00:38:21,099 --> 00:38:21,432
TISSUES.

972
00:38:21,432 --> 00:38:22,634
SO THEY WERE STARTING IN THE

973
00:38:22,634 --> 00:38:26,237
SAME PLACE.

974
00:38:26,237 --> 00:38:29,007
THEN AT THE END, AFTER

975
00:38:29,007 --> 00:38:30,108
INTERVENTION, EITHER LOOKING AT

976
00:38:30,108 --> 00:38:32,977
RECOVERY OF REPLICATION

977
00:38:32,977 --> 00:38:38,216
COMPETENT SIV BY AN IUPM OR CUVO

978
00:38:38,216 --> 00:38:39,417
ASSAY, WE SAW A SIGNIFICANT

979
00:38:39,417 --> 00:38:41,252
DECREASE OF REPLICATION

980
00:38:41,252 --> 00:38:42,387
COMPETENT VIRUS IN THE LYMPH

981
00:38:42,387 --> 00:38:44,923
NODES ON THE RIGHT, AND LOOKING

982
00:38:44,923 --> 00:38:47,859
AT DNA, WE SAW SIGNIFICANT

983
00:38:47,859 --> 00:38:49,928
DECREASES IN SIV DNA ACROSS

984
00:38:49,928 --> 00:39:00,205
SEVERAL VARIOUS TISSUES.

985
00:39:00,205 --> 00:39:02,173
SO THE OTHER STUDY THAT WE HAVE

986
00:39:02,173 --> 00:39:05,610
DONE LOOKS AT THE OTHER MODALITY

987
00:39:05,610 --> 00:39:07,245
INTERVENING EARLY IN THE CONTEXT

988
00:39:07,245 --> 00:39:09,314
OF RECENT ART, TRYING TO

989
00:39:09,314 --> 00:39:11,616
DECREASE THE SIZE OF THE

990
00:39:11,616 --> 00:39:15,553
RESERVOIR IN THAT MODALITY.

991
00:39:15,553 --> 00:39:18,423
AND HERE, WE STUDIED THE IMPACT

992
00:39:18,423 --> 00:39:23,995
OF AZD AGAIN IN COMBINATION WITH

993
00:39:23,995 --> 00:39:27,065
AN IL-15 ACCESS, HERE USING THE

994
00:39:27,065 --> 00:39:31,202
HETEROAMERICA IL-15 MOLECULE IN

995
00:39:31,202 --> 00:39:31,502
COMBINATION.

996
00:39:31,502 --> 00:39:33,538
THIS STUDY HAS REALLY JUST BEGUN

997
00:39:33,538 --> 00:39:37,575
AND SO WE'RE JUST SORT OF GIVING

998
00:39:37,575 --> 00:39:39,877
YOU -- AT FUTURE MEETINGS WE

999
00:39:39,877 --> 00:39:47,051
HOPE TO SEE WHETHER THE EFFECTS

1000
00:39:47,051 --> 00:39:48,353
THESE COMBINED INTERVENTIONS

1001
00:39:48,353 --> 00:39:49,821
REDUCES THE LIFESPAN OF INFECTED

1002
00:39:49,821 --> 00:39:55,126
CELLS.

1003
00:39:55,126 --> 00:39:56,427
SO FAR WE SEE GOOD VIRAL

1004
00:39:56,427 --> 00:39:59,831
SUPPRESSION IN ALL THE ANIMALS.

1005
00:39:59,831 --> 00:40:01,899
PERHAPS WITH SOME EVIDENCE THAT

1006
00:40:01,899 --> 00:40:05,970
THERE IS SOME -- THERE'S SOME

1007
00:40:05,970 --> 00:40:08,706
DIFFERENCES, LET'S JUST SAY,

1008
00:40:08,706 --> 00:40:09,908
BETWEEN THE ARMS AT THIS POINT,

1009
00:40:09,908 --> 00:40:11,776
ALTHOUGH A SUPPRESSION APPEARS

1010
00:40:11,776 --> 00:40:13,544
TO BE QUITE EFFECTIVE.

1011
00:40:13,544 --> 00:40:17,248
SO THIS IS REALLY EARLY DATA,

1012
00:40:17,248 --> 00:40:18,583
AND HOPEFULLY PERHAPS AT THE

1013
00:40:18,583 --> 00:40:19,550
BEGINNING OF NEXT YEAR, WE'LL

1014
00:40:19,550 --> 00:40:20,885
HAVE MORE DEFINITIVE RESULTS

1015
00:40:20,885 --> 00:40:24,722
ABOUT THESE OUTCOMES.

1016
00:40:24,722 --> 00:40:26,357
SO OVERALL, OUR KEY QUESTION

1017
00:40:26,357 --> 00:40:28,326
WAS, COULD WE REDUCE EITHER THE

1018
00:40:28,326 --> 00:40:29,928
ESTABLISHMENT OR THE PERSISTENCE

1019
00:40:29,928 --> 00:40:33,464
OF THE VIRAL RESERVOIR, AND HERE

1020
00:40:33,464 --> 00:40:36,234
WE'RE ABLE TO USE PRIMATE MODEL

1021
00:40:36,234 --> 00:40:38,803
AS WE HAVE USED HUMANIZED MOUSE

1022
00:40:38,803 --> 00:40:40,905
MODEL AS YOU SAW IN GUIDO'S TALK

1023
00:40:40,905 --> 00:40:47,378
TO TEST THESE CONCEPTS.

1024
00:40:47,378 --> 00:40:48,913
SO AGAIN THIS IS REALLY A BROAD

1025
00:40:48,913 --> 00:40:58,923
GROUP INVOLVING MANY PEOPLE WHO

1026
00:40:58,923 --> 00:41:00,224
I NEED TO SHARE.

1027
00:41:00,224 --> 00:41:01,759
I'M SORRY, I'M GETTING SOMETHING

1028
00:41:01,759 --> 00:41:12,270
FLASHING AT ME ON THE SCREEN.

1029
00:41:14,672 --> 00:41:15,707
I'M TRYING TO GO TO THE NEXT

1030
00:41:15,707 --> 00:41:16,040
PRESENTATION.

1031
00:41:16,040 --> 00:41:16,674
HERE WE ARE.

1032
00:41:16,674 --> 00:41:17,442
OKAY.

1033
00:41:17,442 --> 00:41:20,678
SO NOW I'D LIKE TO INTRODUCE

1034
00:41:20,678 --> 00:41:24,349
TONYA DEL SOLDATA WHO LEADS OUR

1035
00:41:24,349 --> 00:41:28,619
COMMUNITY ENGAGEMENT GROUP, AND

1036
00:41:28,619 --> 00:41:29,520
SHE'LL TELL YOU ABOUT THEIR

1037
00:41:29,520 --> 00:41:30,088
ACTIVITIES.

1038
00:41:30,088 --> 00:41:39,263
[APPLAUSE]

1039
00:41:39,263 --> 00:41:40,565
>> HI, EVERYONE.

1040
00:41:40,565 --> 00:41:41,432
HOW ARE YOU DOING?

1041
00:41:41,432 --> 00:41:42,100
GOOD MORNING.

1042
00:41:42,100 --> 00:41:52,510
MY NAME IS TO TONYA DEL SODA TT.

1043
00:41:52,510 --> 00:41:53,644
I'VE BEEN WORKING IN THE HIV

1044
00:41:53,644 --> 00:41:54,912
FIELD FOR OVER 25 YEARS AND I

1045
00:41:54,912 --> 00:41:57,348
CHOSE THIS FIELD WHEN I WAS AN

1046
00:41:57,348 --> 00:41:59,650
INFECTIOUS DISEASE CLASS FOR MY

1047
00:41:59,650 --> 00:42:02,053
BIOLOGY DEGREE, AND WAS SHOCKED

1048
00:42:02,053 --> 00:42:04,155
WITH THE STIGMA AND THE

1049
00:42:04,155 --> 00:42:05,156
DISCRIMINATION AGAINST PEOPLE

1050
00:42:05,156 --> 00:42:08,092
LIVING WITH HIV AND AIDS.

1051
00:42:08,092 --> 00:42:10,495
SO THEN I WANTED TO MAKE A

1052
00:42:10,495 --> 00:42:16,868
CHANGE AND I'M STILL HERE.

1053
00:42:16,868 --> 00:42:18,403
THIS IS A WHEEL THAT I CREATED

1054
00:42:18,403 --> 00:42:21,672
TO ENGAGE THE THE COMMUNITY, AND

1055
00:42:21,672 --> 00:42:25,176
FOR EDUCATION.

1056
00:42:25,176 --> 00:42:32,183
IT'S A TOOL TO TEACH HIV 101.

1057
00:42:32,183 --> 00:42:37,021
IT ASKS BASIC QUESTIONS TO TEST

1058
00:42:37,021 --> 00:42:39,957
HIV 101, THEIR KNOWLEDGE, IN

1059
00:42:39,957 --> 00:42:41,392
EDUCATING THE COMMUNITY IS

1060
00:42:41,392 --> 00:42:44,562
ABSOLUTELY NEEDED.

1061
00:42:44,562 --> 00:42:51,035
I BELIEVE EDUCATION REDUCES

1062
00:42:51,035 --> 00:42:53,237
STIGMA, AND IT ALSO REDUCES OR

1063
00:42:53,237 --> 00:42:54,972
COULD LEAD TO PREVENTION.

1064
00:42:54,972 --> 00:42:57,809
FOR SURE.

1065
00:42:57,809 --> 00:43:02,747
SO THE WAY THAT WE DO EDUCATION

1066
00:43:02,747 --> 00:43:05,483
THROUGHOUT TO REACH A BROADER

1067
00:43:05,483 --> 00:43:07,585
COMMUNITY IS WE CREATED

1068
00:43:07,585 --> 00:43:07,919
PARTNERSHIPS.

1069
00:43:07,919 --> 00:43:12,256
WE HAVE THREE PARTNERSHIPS

1070
00:43:12,256 --> 00:43:13,925
THROUGHOUT RALEIGH-DURHAM CHAPEL

1071
00:43:13,925 --> 00:43:16,461
HILL AREA OF NORTH CAROLINA, AND

1072
00:43:16,461 --> 00:43:18,729
IT'S NORTH CAROLINA AIDS ACTION

1073
00:43:18,729 --> 00:43:20,631
NETWORK.

1074
00:43:20,631 --> 00:43:23,267
AND WE TALKED TO THE GENERAL

1075
00:43:23,267 --> 00:43:24,769
ASSEMBLY TO CHANGE POLICIES THAT

1076
00:43:24,769 --> 00:43:29,574
AFFECT PEOPLE LIVING WITH HIV.

1077
00:43:29,574 --> 00:43:30,708
SECOND ONE IS ALLIANCE OF AIDS.

1078
00:43:30,708 --> 00:43:33,978
IT'S A COMMUNITY-BASED

1079
00:43:33,978 --> 00:43:37,381
ORGANIZATION, AND EL CENTRO IS

1080
00:43:37,381 --> 00:43:38,883
ALSO ANOTHER COMMUNITY-BASED

1081
00:43:38,883 --> 00:43:39,917
ORGANIZATION FOR THE HISPANIC

1082
00:43:39,917 --> 00:43:43,521
COMMUNITY.

1083
00:43:43,521 --> 00:43:50,094
THIS IS HIV SPEAKS ON JONES

1084
00:43:50,094 --> 00:43:51,529
STREET PUT ON BY THE NORTH

1085
00:43:51,529 --> 00:43:53,064
CAROLINA AIDS ACTION NETWORK,

1086
00:43:53,064 --> 00:43:54,398
AND IT'S ON JONES STREET BECAUSE

1087
00:43:54,398 --> 00:43:56,234
THAT'S WHERE THE LEGISLATIVE

1088
00:43:56,234 --> 00:43:57,268
BUILDING IS AND GENERAL

1089
00:43:57,268 --> 00:43:58,903
ASSEMBLY.

1090
00:43:58,903 --> 00:44:01,205
THIS WAS EXTRA AMAZING THIS YEAR

1091
00:44:01,205 --> 00:44:03,708
BECAUSE I DID GET TO MEET HAROLD

1092
00:44:03,708 --> 00:44:05,476
J. PHILLIPS, WHICH IS THE

1093
00:44:05,476 --> 00:44:07,778
DIRECTOR OF THE WHITE HOUSE

1094
00:44:07,778 --> 00:44:08,546
OFFICE OF THE NATIONAL AIDS

1095
00:44:08,546 --> 00:44:09,647
POLICY.

1096
00:44:09,647 --> 00:44:16,954
THAT WAS COOL.

1097
00:44:16,954 --> 00:44:20,258
SO THIS IS A SLIDE OF WHEN WE

1098
00:44:20,258 --> 00:44:25,830
DID A PRESENTATION FOR EL

1099
00:44:25,830 --> 00:44:26,063
CENTRO.

1100
00:44:26,063 --> 00:44:30,134
THIS WAS PUT ON BY MARIA ABAD, A

1101
00:44:30,134 --> 00:44:31,769
RESEARCHER WITH CARE, SO TO MEET

1102
00:44:31,769 --> 00:44:33,604
EVERYONE WHERE THEY ARE IS

1103
00:44:33,604 --> 00:44:38,676
EXTREMELY IMPORTANT.

1104
00:44:38,676 --> 00:44:41,846
JUST LAST WEEK, WE PUT ON A

1105
00:44:41,846 --> 00:44:45,349
LUNCH AND LEARN MEETING FOR THE

1106
00:44:45,349 --> 00:44:48,719
COMMUNITY.

1107
00:44:48,719 --> 00:44:49,854
IT WAS ON OCTOBER 5TH.

1108
00:44:49,854 --> 00:44:54,091
THIS WAS OUR FLYER, AND IT'S TO

1109
00:44:54,091 --> 00:44:58,496
ENGAGE THE COMMUNITY.

1110
00:44:58,496 --> 00:45:00,998
SO WE DID USE THE WHEEL I SPOKE

1111
00:45:00,998 --> 00:45:07,138
ABOUT TO ENGAGE THE COMMUNITY.

1112
00:45:07,138 --> 00:45:10,074
YOU USE THAT TO TEST KNOWLEDGE,

1113
00:45:10,074 --> 00:45:12,376
BREAK THE ICE, AND THEY GET SOME

1114
00:45:12,376 --> 00:45:13,377
CARE SWAG THAT YOU SEE ON THE

1115
00:45:13,377 --> 00:45:14,612
TABLE.

1116
00:45:14,612 --> 00:45:16,480
AND GET FED.

1117
00:45:16,480 --> 00:45:18,416
EDUCATION IS VITAL BECAUSE THERE

1118
00:45:18,416 --> 00:45:21,786
IS A BASIC LACK OF INFORMATION

1119
00:45:21,786 --> 00:45:23,788
IN THE COMMUNITY FOR HIV.

1120
00:45:23,788 --> 00:45:25,756
AND THERE IS DR. MARGOLIS

1121
00:45:25,756 --> 00:45:28,826
EXPLAINING THE RESEARCH FOR THE

1122
00:45:28,826 --> 00:45:31,462
CURE FOR HIV.

1123
00:45:31,462 --> 00:45:36,934
THIS IS ME DOING ANOTHER OU

1124
00:45:36,934 --> 00:45:38,669
OUTREACH ENGAGING THE COMMUNITY.

1125
00:45:38,669 --> 00:45:43,741
THIS WAS AT RALEIGH PRIDE.

1126
00:45:43,741 --> 00:45:47,245
AND RIGHT HERE IS ANOTHER

1127
00:45:47,245 --> 00:45:48,212
ENGAGEMENT TOOL THAT YOU MIGHT

1128
00:45:48,212 --> 00:45:51,983
HAVE NOTICED.

1129
00:45:51,983 --> 00:45:57,188
ON THE TABLE RIGHT BEHIND ME.

1130
00:45:57,188 --> 00:46:00,725
IT SAYS, "WHAT WOULD A CURE MEAN

1131
00:46:00,725 --> 00:46:01,459
TO YOU?"

1132
00:46:01,459 --> 00:46:05,196
THIS IS FOR THE COMMUNITY TO --

1133
00:46:05,196 --> 00:46:08,366
IT'S ANOTHER ENGAGEMENT TOOL.

1134
00:46:08,366 --> 00:46:12,737
AND A FEW OF THEM WAS THAT WHAT

1135
00:46:12,737 --> 00:46:14,972
DOES A CURE MEAN TO THEM IS

1136
00:46:14,972 --> 00:46:16,173
HAPPINESS.

1137
00:46:16,173 --> 00:46:19,577
NO MORE TAKING MEDS.

1138
00:46:19,577 --> 00:46:23,281
REDUCING -- NO MORE STIGMA.

1139
00:46:23,281 --> 00:46:24,649
AND FREEDOM.

1140
00:46:24,649 --> 00:46:30,221
AND A CHANCE TO SMILE AGAIN.

1141
00:46:30,221 --> 00:46:32,290
SO THERE YOU ARE, RESEARCHERS.

1142
00:46:32,290 --> 00:46:33,624
THIS IS WHAT IT MEANS, AND THIS

1143
00:46:33,624 --> 00:46:36,027
IS WHAT YOUR WORK IS GOING FOR.

1144
00:46:36,027 --> 00:46:39,430
SO THANK YOU ALL SO MUCH.

1145
00:46:39,430 --> 00:46:40,197
AND THANKS.

1146
00:46:40,197 --> 00:46:48,105
[APPLAUSE]

1147
00:46:48,105 --> 00:46:48,973
>> THANKS VERY MUCH.

1148
00:46:48,973 --> 00:46:50,875
WE NOW HAVE ABOUT 10 MINUTES FOR

1149
00:46:50,875 --> 00:46:53,010
Q & A FOR THE CARE

1150
00:46:53,010 --> 00:46:53,344
COLLABORATORY.

1151
00:46:53,344 --> 00:46:55,680
SO I'LL ASK DR. MARGOLIS TO

1152
00:46:55,680 --> 00:46:57,014
MODERATE, AND IF ANYONE HAS ANY

1153
00:46:57,014 --> 00:46:59,417
QUESTIONS, WE HAVE STAND

1154
00:46:59,417 --> 00:47:01,619
MICROPHONES, AND IF YOU HAVE

1155
00:47:01,619 --> 00:47:04,689
TROUBLE GETTING OUT OF YOUR ROW,

1156
00:47:04,689 --> 00:47:05,890
JUST STAND UP OR RAISE YOUR HAND

1157
00:47:05,890 --> 00:47:07,324
AND WE CAN GET THE MICROPHONE TO

1158
00:47:07,324 --> 00:47:07,758
YOU.

1159
00:47:07,758 --> 00:47:10,294
WE ALSO IF YOU'RE WATCHING

1160
00:47:10,294 --> 00:47:11,295
ONLINE, THERE'S A Q & A
BUTTON

1161
00:47:11,295 --> 00:47:13,464
AT THE BOTTOM OF THE SCREEN, SO

1162
00:47:13,464 --> 00:47:16,000
PLEASE FEEL FREE TO SUBMIT

1163
00:47:16,000 --> 00:47:17,334
QUESTIONS AND AS TIME ALLOWS,

1164
00:47:17,334 --> 00:47:18,836
WE'LL DO OUR BEST TO GET TO YOUR

1165
00:47:18,836 --> 00:47:20,104
QUESTIONS.

1166
00:47:20,104 --> 00:47:21,138
OKAY, DR. MARGOLIS.

1167
00:47:21,138 --> 00:47:22,206
>> SO WE HAVE TO PRESS THE

1168
00:47:22,206 --> 00:47:24,075
BUTTON BEFORE WE TALK, AND IF

1169
00:47:24,075 --> 00:47:25,943
YOU'D LIKE TO ASK US SOMETHING,

1170
00:47:25,943 --> 00:47:28,913
WAVE, BECAUSE THE LIGHT IS RIGHT

1171
00:47:28,913 --> 00:47:30,481
IN OUR EYES AND I CAN HARDLY

1172
00:47:30,481 --> 00:47:31,549
SEE, BUT I THINK THAT'S

1173
00:47:31,549 --> 00:47:31,849
PROBABLY --

1174
00:47:31,849 --> 00:47:32,516
>> IT'S BRAD.

1175
00:47:32,516 --> 00:47:33,217
>> BRAD, YEAH.

1176
00:47:33,217 --> 00:47:33,684
GO AHEAD.

1177
00:47:33,684 --> 00:47:36,420
>> I HAVE A QUESTION FOR
GUIDO.

1178
00:47:36,420 --> 00:47:37,722
SO BEAUTIFUL WORK.

1179
00:47:37,722 --> 00:47:40,691
KUDOS ON PULLING UP 45 CTL

1180
00:47:40,691 --> 00:47:41,559
CLONES, THAT'S A LOT OF WORK.

1181
00:47:41,559 --> 00:47:44,095
SO WHEN YOU GIVE THOSE HLA-E

1182
00:47:44,095 --> 00:47:45,362
RESTRICTED CLONES, YOU KILL 80%

1183
00:47:45,362 --> 00:47:46,464
OF THE INFECTED CELLS.

1184
00:47:46,464 --> 00:47:48,332
I'M INTERESTED IN THOSE 20% OR

1185
00:47:48,332 --> 00:47:49,300
SO THAT SURVIVE.

1186
00:47:49,300 --> 00:47:51,502
EVEN THOUGH YOU HAVE ABOUT A

1187
00:47:51,502 --> 00:47:53,270
5 TO 1 RATIO OF CTL TO TARGET.

1188
00:47:53,270 --> 00:47:55,573
SO IF WE USE CONVENTIONAL CTL,

1189
00:47:55,573 --> 00:47:57,341
ONE OF THE THINGS WE SEE IS THAT

1190
00:47:57,341 --> 00:47:58,576
SURVIVORS ARE SELECTED FOR THOSE

1191
00:47:58,576 --> 00:48:01,612
THAT ARE MHC1 LOW BECAUSE OF THE

1192
00:48:01,612 --> 00:48:03,280
ACTIONS OF NEF.

1193
00:48:03,280 --> 00:48:04,482
PRESUMABLY YOU WOULDN'T SEE THAT

1194
00:48:04,482 --> 00:48:05,816
WITH YOUR HLA-E RESTRICTED

1195
00:48:05,816 --> 00:48:06,817
CELLS, SO ARE THEY SELECTED FOR

1196
00:48:06,817 --> 00:48:08,252
LOWER LEVELS OF HLA-E OR DO YOU

1197
00:48:08,252 --> 00:48:10,087
KNOW ANYTHING ABOUT THOSE

1198
00:48:10,087 --> 00:48:10,354
SURVIVORS?

1199
00:48:10,354 --> 00:48:12,323
>> IT'S A VERY GOOD
QUESTION.

1200
00:48:12,323 --> 00:48:14,825
I DON'T THINK THAT WE HAVE

1201
00:48:14,825 --> 00:48:17,795
LOOKED AT THE LEVEL OF HLA-E IN

1202
00:48:17,795 --> 00:48:20,297
THE TARGET THAT ARE SURVIVING.

1203
00:48:20,297 --> 00:48:22,633
THIS IS WORK THAT IS IN

1204
00:48:22,633 --> 00:48:24,368
PROGRESS.

1205
00:48:24,368 --> 00:48:27,972
I ALSO WONDER, THESE ARE 5 TO 28

1206
00:48:27,972 --> 00:48:30,174
DAYS ASSAYS.

1207
00:48:30,174 --> 00:48:35,112
WHAT I THINK NEEDS TO BE DONE

1208
00:48:35,112 --> 00:48:36,247
THAT IS IN THE PIPELINE IS A

1209
00:48:36,247 --> 00:48:38,315
LOOK AT THE FUNCTIONALITY OF

1210
00:48:38,315 --> 00:48:39,817
THESE CLONES OVER TIME.

1211
00:48:39,817 --> 00:48:44,155
I THINK THESE ARE ALL THE BIG --

1212
00:48:44,155 --> 00:48:45,456
YOU KNOW, MOVING FORWARD THE

1213
00:48:45,456 --> 00:48:47,358
QUESTIONS THAT WE NEED TO HAVE.

1214
00:48:47,358 --> 00:48:50,528
THERE IS DEFINITELY AN ACUTE

1215
00:48:50,528 --> 00:48:52,062
EFFECT, AS YOU CAN SEE.

1216
00:48:52,062 --> 00:48:54,365
NOW WE NEED TO UNDERSTAND WHAT

1217
00:48:54,365 --> 00:48:57,868
IS GOING TO HAPPEN AFTER.

1218
00:48:57,868 --> 00:49:03,908
AND I THINK THAT ALSO SOME OF

1219
00:49:03,908 --> 00:49:06,644
THIS MODELING WILL HAVE TO FEED

1220
00:49:06,644 --> 00:49:08,078
IN WHAT IS DONE IN CANCER WITH

1221
00:49:08,078 --> 00:49:08,946
THESE CELLS.

1222
00:49:08,946 --> 00:49:10,614
>> AND HAVE YOU EVER TRIED

1223
00:49:10,614 --> 00:49:12,016
COMBINING AN HLA-E RESTRICTED

1224
00:49:12,016 --> 00:49:13,384
CLONE WITH A CONVENTIONAL CLONE

1225
00:49:13,384 --> 00:49:16,720
TO SEE IF THEY SYNERGIZE?

1226
00:49:16,720 --> 00:49:19,523
>> YEAH, SO THE
CONVENTIONAL

1227
00:49:19,523 --> 00:49:21,292
CLONES WERE ALL THE SARS-COV-2

1228
00:49:21,292 --> 00:49:25,029
CLOSARS-COV-2CLONES I SHOWED ATD

1229
00:49:25,029 --> 00:49:26,096
YOU CAN SEE THOSE, BUT IT WOULD

1230
00:49:26,096 --> 00:49:27,298
BE NICE TO SEE FOR THOSE CELLS

1231
00:49:27,298 --> 00:49:28,866
WHAT ARE THE DIFFERENCE, IF THIS

1232
00:49:28,866 --> 00:49:30,401
IS WHAT YOU MEAN, ABSOLUTELY

1233
00:49:30,401 --> 00:49:31,302
RIGHT.

1234
00:49:31,302 --> 00:49:36,774
>> THANKS.

1235
00:49:36,774 --> 00:49:38,742
>> VERY EXCITING WORK WITH
THE

1236
00:49:38,742 --> 00:49:40,511
HLA-E ANGLE AS WELL.

1237
00:49:40,511 --> 00:49:43,347
I'M OVER HERE.

1238
00:49:43,347 --> 00:49:45,549
SO SIMPLE QUESTION, HAVE YOU

1239
00:49:45,549 --> 00:49:47,384
EVER SEEN EVIDENCE FOR SCAPE IN

1240
00:49:47,384 --> 00:49:50,154
THE HLA-E RESTRICTED EPITOPES?

1241
00:49:50,154 --> 00:49:53,023
>> NO.

1242
00:49:53,023 --> 00:49:54,758
WE HAVEN'T DONE THAT YET.

1243
00:49:54,758 --> 00:49:55,759
>> OKAY.

1244
00:49:55,759 --> 00:49:57,728
AND WHAT ABOUT THE MONOCLONAL

1245
00:49:57,728 --> 00:50:01,131
ANTIBODY THAT CAN RECOGNIZE THE

1246
00:50:01,131 --> 00:50:03,000
HLA-E PEPTIDE COMPLEX, HOW IS

1247
00:50:03,000 --> 00:50:03,767
THAT GOING?

1248
00:50:03,767 --> 00:50:06,070
>> YES.

1249
00:50:06,070 --> 00:50:07,638
SO THAT IS PART OF MY SECOND

1250
00:50:07,638 --> 00:50:08,973
TALK THIS AFTERNOON, BUT IT IS

1251
00:50:08,973 --> 00:50:11,242
IN THE PIPELINE WITH DR. --

1252
00:50:11,242 --> 00:50:11,942
>> EXCITING.

1253
00:50:11,942 --> 00:50:14,979
>> YES.

1254
00:50:14,979 --> 00:50:16,814
>> STEWART SHAPIRO,
DIVISION OF

1255
00:50:16,814 --> 00:50:17,047
AIDS.

1256
00:50:17,047 --> 00:50:18,482
SO I HAVE ANOTHER QUESTION FOR

1257
00:50:18,482 --> 00:50:19,483
GUIDO.

1258
00:50:19,483 --> 00:50:22,319
SORRY TO THE REST OF YOU, BUT SO

1259
00:50:22,319 --> 00:50:26,490
WE HAD A WORKSHOP IN AUGUST ON

1260
00:50:26,490 --> 00:50:29,360
T-CELL B CELL SYNERGY IN HIV

1261
00:50:29,360 --> 00:50:31,962
PREVENTION VACCINES, AND A POINT

1262
00:50:31,962 --> 00:50:34,598
WAS MADE BY CLAUSE FRUE, WHO

1263
00:50:34,598 --> 00:50:37,401
WORKS WITH LEWIS PICKER ON THE

1264
00:50:37,401 --> 00:50:40,004
HLA-E, THE CYTOMEGLOVIRUS

1265
00:50:40,004 --> 00:50:42,439
VACCINE, THAT IT SEEMED TO BE

1266
00:50:42,439 --> 00:50:45,609
PREVENTING THE ESTABLISHMENT OF

1267
00:50:45,609 --> 00:50:46,610
LATENCY.

1268
00:50:46,610 --> 00:50:49,446
AND THAT WAS ONE OF THE KEY

1269
00:50:49,446 --> 00:50:50,981
FACTORS ON HOW IT WORKED, IN

1270
00:50:50,981 --> 00:50:52,750
ADDITION TO KILLING HIV INFECTED

1271
00:50:52,750 --> 00:50:53,651
CELLS.

1272
00:50:53,651 --> 00:50:56,253
AND SO I'M WONDERING IF IN YOUR

1273
00:50:56,253 --> 00:50:59,356
STUDIES, YOU LOOK AT -- YOU

1274
00:50:59,356 --> 00:51:04,395
COMPARE THE HLA-E KILLING WITH

1275
00:51:04,395 --> 00:51:07,932
CD8 KILLING MEDIATED BY MHC1 TO

1276
00:51:07,932 --> 00:51:09,233
SEE IF THERE ARE DIFFERENCES IN

1277
00:51:09,233 --> 00:51:11,402
HOW CELLS ARE KILLED THAT MIGHT

1278
00:51:11,402 --> 00:51:15,472
ILLUMINATE DIFFERENCES IN

1279
00:51:15,472 --> 00:51:16,707
NORMALLY INFECTED CELLS AS

1280
00:51:16,707 --> 00:51:19,343
OPPOSED TO LATENTLY -- THE

1281
00:51:19,343 --> 00:51:21,745
LATENT RESERVOIR AND WHERE ITS

1282
00:51:21,745 --> 00:51:22,646
LOCATION IS AND OTHER THINGS

1283
00:51:22,646 --> 00:51:25,749
LIKE THAT.

1284
00:51:25,749 --> 00:51:28,252
>> STEWART, I THINK THOSE
ARE

1285
00:51:28,252 --> 00:51:31,021
THE OTHER SECTION OF ANALYSIS

1286
00:51:31,021 --> 00:51:35,859
FROM THE BLT MODEL, THAT VICTOR

1287
00:51:35,859 --> 00:51:37,061
AND THE GROUPS ARE DOING.

1288
00:51:37,061 --> 00:51:41,632
I ONLY PRESENTED HERE THE VIRUS

1289
00:51:41,632 --> 00:51:43,534
RNA AS PROOF OF CONCEPT OF THE

1290
00:51:43,534 --> 00:51:45,502
ELIMINATION OF THE CELLS.

1291
00:51:45,502 --> 00:51:49,540
THERE IS ALL THE OTHER PART OF

1292
00:51:49,540 --> 00:51:50,541
UNDERSTANDING, THE SEATING OF

1293
00:51:50,541 --> 00:51:51,241
THE RESERVOIR.

1294
00:51:51,241 --> 00:51:52,710
IN THAT MODEL AS YOU NOTICED,

1295
00:51:52,710 --> 00:51:56,146
THERE WAS AN INFUSION OF THE

1296
00:51:56,146 --> 00:52:00,317
TRANSDUCTANT.

1297
00:52:00,317 --> 00:52:01,385
 -- INFECTION IN A SECOND

1298
00:52:01,385 --> 00:52:01,652
INFUSION.

1299
00:52:01,652 --> 00:52:03,420
SO THE QUESTION IS REALLY HOW

1300
00:52:03,420 --> 00:52:05,723
WAS THE PREEXISTENCE PRESENCE OF

1301
00:52:05,723 --> 00:52:08,292
THESE CLONES IMPACTING THE EARLY

1302
00:52:08,292 --> 00:52:12,196
RESERVOIR.

1303
00:52:12,196 --> 00:52:15,499
SO IT'S IN THE LINE IN WHAT HAS

1304
00:52:15,499 --> 00:52:16,133
TO BE DONE NEXT.

1305
00:52:16,133 --> 00:52:18,469
>> YOU HAVE A GREAT TOOL
HERE

1306
00:52:18,469 --> 00:52:19,136
FOR ILLUMINATING THE

1307
00:52:19,136 --> 00:52:19,903
ESTABLISHMENT OF LATENCY, WHICH

1308
00:52:19,903 --> 00:52:20,804
IS REALLY IMPORTANT.

1309
00:52:20,804 --> 00:52:23,207
>> I THINK -- I WANT TO
TRY TO

1310
00:52:23,207 --> 00:52:24,541
GET IN THESE LAST THREE PEOPLE

1311
00:52:24,541 --> 00:52:28,912
REALLY QUICKLY.

1312
00:52:28,912 --> 00:52:30,214
>> THANK YOU.

1313
00:52:30,214 --> 00:52:31,782
I ACTUALLY HAD ONE QUESTION FOR

1314
00:52:31,782 --> 00:52:33,550
GUIDO AND ONE QUESTION FOR

1315
00:52:33,550 --> 00:52:34,184
EDWARD.

1316
00:52:34,184 --> 00:52:35,953
GUIDO, FOLLOWING UP ON WHAT BRAD

1317
00:52:35,953 --> 00:52:37,721
SAID ABOUT THE DOWN REGULATED

1318
00:52:37,721 --> 00:52:39,890
HLA-E ON THE SURVIVORS, DO YOU

1319
00:52:39,890 --> 00:52:41,992
THINK IN AN ANIMAL MODEL THAT

1320
00:52:41,992 --> 00:52:44,528
WOULD HAVE WELL CONSTITUTED NK

1321
00:52:44,528 --> 00:52:45,963
CELLS THAT YOU WOULD SEE

1322
00:52:45,963 --> 00:52:47,898
EXPANSION OF THE NKD2A

1323
00:52:47,898 --> 00:52:49,466
POPULATION BECAUSE YOU BASICALLY

1324
00:52:49,466 --> 00:52:50,801
LOSE THAT INHIBITORY SIGNAL?

1325
00:52:50,801 --> 00:52:53,871
I'M NOT SURE WITH VICTOR'S B █LT

1326
00:52:53,871 --> 00:52:55,639
MODEL HOW GOOD THE NK CELLS ARE

1327
00:52:55,639 --> 00:52:59,610
BUT MAYBE IN AN NHP MODEL YOU'D

1328
00:52:59,610 --> 00:53:00,811
BE ABLE TO SEE SOMETHING LIKE

1329
00:53:00,811 --> 00:53:01,011
THAT?

1330
00:53:01,011 --> 00:53:02,146
>> THAT'S A GOOD POINT.

1331
00:53:02,146 --> 00:53:04,448
I THINK IT HAS TO BE EVALUATED.

1332
00:53:04,448 --> 00:53:07,584
>> THE NK CELLS ARE
FUNCTIONAL

1333
00:53:07,584 --> 00:53:09,153
IN THE -- MOUSE MODEL AS WELL.

1334
00:53:09,153 --> 00:53:12,222
>> RIGHT, BUT THE POINT
WITH THE

1335
00:53:12,222 --> 00:53:14,758
IL15 MODEL FOR THE MOUSE MODEL

1336
00:53:14,758 --> 00:53:19,630
WILL PROBABLY SOLVE THE BETTER.

1337
00:53:19,630 --> 00:53:21,265
FOR THE NK, WHAT I WAS PRESENTED

1338
00:53:21,265 --> 00:53:25,469
HERE ARE TRA TRANSDUCTANT TO CDO

1339
00:53:25,469 --> 00:53:28,205
WE WERE LOOKING AT -- IF YOU

1340
00:53:28,205 --> 00:53:29,640
REMEMBER THE MAJOR AND MINOR, WE

1341
00:53:29,640 --> 00:53:33,043
WERE FOCUSING ON THE MINOR POINT

1342
00:53:33,043 --> 00:53:34,912
OF THE HLA-E EFFECT.

1343
00:53:34,912 --> 00:53:38,649
SO IF WE WANT TO EXPLORE BOTH AS

1344
00:53:38,649 --> 00:53:41,185
MENTIONING THE LAST SLIDE, THE

1345
00:53:41,185 --> 00:53:42,052
IL15 CONCEPT COMES ALONG VERY

1346
00:53:42,052 --> 00:53:43,620
WELL.

1347
00:53:43,620 --> 00:53:44,321
>> PERFECT.

1348
00:53:44,321 --> 00:53:45,122
THANK YOU.

1349
00:53:45,122 --> 00:53:47,057
AND EDWARD JUST ASKED -- SORRY,

1350
00:53:47,057 --> 00:53:48,158
ONE QUICK QUESTION.

1351
00:53:48,158 --> 00:53:49,893
YOUR VOLCANO PLOTS ARE REALLY

1352
00:53:49,893 --> 00:53:50,994
INTERESTING AND CLEARLY YOU HAD

1353
00:53:50,994 --> 00:53:52,129
A SET OF GENES YOU WERE GOING

1354
00:53:52,129 --> 00:53:53,564
AFTER FOR VALIDATION, BUT IN THE

1355
00:53:53,564 --> 00:53:55,866
REST OF THE GENES, WE SAW SOME

1356
00:53:55,866 --> 00:53:57,301
VERY INTERESTING HITS KIND OF

1357
00:53:57,301 --> 00:54:00,370
RELATED TO SOME OF THE HITS WE

1358
00:54:00,370 --> 00:54:02,706
SEE IN SURVIVORS FROM NK CELL

1359
00:54:02,706 --> 00:54:04,241
KILLING, SO DO YOU KNOW IF ANY

1360
00:54:04,241 --> 00:54:06,343
OF THOSE OTHER HITS ARE RELATED

1361
00:54:06,343 --> 00:54:07,911
TO TNF SIGNALING OR INTERFERON

1362
00:54:07,911 --> 00:54:09,113
SIGNALING?

1363
00:54:09,113 --> 00:54:14,485
>> -- INTERFERON
SIGNALING?

1364
00:54:14,485 --> 00:54:16,420
>> LIKE INTERFERON
SIGNATURES AT

1365
00:54:16,420 --> 00:54:16,587
ALL.

1366
00:54:16,587 --> 00:54:17,588
>> OH.

1367
00:54:17,588 --> 00:54:20,424
NO, WE HAVEN'T SEEN ANY

1368
00:54:20,424 --> 00:54:22,593
INTERFERON SIGNATURES IN THE

1369
00:54:22,593 --> 00:54:24,228
HITS SO FAR, AT LEAST I DON'T

1370
00:54:24,228 --> 00:54:24,561
THINK SO.

1371
00:54:24,561 --> 00:54:25,829
WHAT WAS THE OTHER THING YOU

1372
00:54:25,829 --> 00:54:26,096
MENTIONED?

1373
00:54:26,096 --> 00:54:30,634
>> IT WAS TNF OR NF KAPPA
BY

1374
00:54:30,634 --> 00:54:30,901
SIGNALING.

1375
00:54:30,901 --> 00:54:32,569
>>  -- 20 BASICALLY WHICH
IS FOR

1376
00:54:32,569 --> 00:54:35,506
THE FEEDBACK, THAT DEFINITELY

1377
00:54:35,506 --> 00:54:38,709
REACTIVATES IN -- IT SOMETIMES

1378
00:54:38,709 --> 00:54:40,344
WORKS IN PRIMARY CELLS BUT

1379
00:54:40,344 --> 00:54:42,546
THAT'S ONE THAT CAME OUT OF IT,

1380
00:54:42,546 --> 00:54:43,680
THAT IS A SIGNALING PATHWAY.

1381
00:54:43,680 --> 00:54:44,381
>> THANK YOU.

1382
00:54:44,381 --> 00:54:45,883
I'D ENCOURAGE YOU TO GO SEE

1383
00:54:45,883 --> 00:54:47,050
POSTER?

1384
00:54:47,050 --> 00:54:47,217
 70.

1385
00:54:47,217 --> 00:54:48,919
>> ONE LAST QUESTION
REALLY

1386
00:54:48,919 --> 00:54:49,153
QUICKLY.

1387
00:54:49,153 --> 00:54:52,189
>> QUESTION FOR ED I'M

1388
00:54:52,189 --> 00:54:55,425
INTERESTED IN YOUR SET D2 STORY

1389
00:54:55,425 --> 00:54:56,193
THERE.

1390
00:54:56,193 --> 00:54:58,061
WE IDENTIFIED -- AS A METHYL

1391
00:54:58,061 --> 00:55:02,299
TRANS PHRASE ALSO TARGETING --

1392
00:55:02,299 --> 00:55:05,636
WE DID NOT FIND AN EFFECTIVE

1393
00:55:05,636 --> 00:55:08,005
HK336 TRI-METHYL ON THE PROMOTER

1394
00:55:08,005 --> 00:55:08,939
PARTICULARLY IN CONTROLLING

1395
00:55:08,939 --> 00:55:09,173
LATENCY.

1396
00:55:09,173 --> 00:55:10,574
I WANTED TO SEE IF YOU FOUND OR

1397
00:55:10,574 --> 00:55:12,376
HAVE ANY EVIDENCE FOR THIS.

1398
00:55:12,376 --> 00:55:14,144
>> SO WE HAVE LOOKED AT
THAT, SO

1399
00:55:14,144 --> 00:55:15,679
WE'RE WORKING ON THE MECHANISMS.

1400
00:55:15,679 --> 00:55:16,780
WE DEFINITELY SEE REDUCTION OF

1401
00:55:16,780 --> 00:55:18,081
THE PROTEIN LEVEL FOR HIV

1402
00:55:18,081 --> 00:55:20,117
EXPRESSION WHEN YOU AT A SET

1403
00:55:20,117 --> 00:55:20,450
D2 INHIBITOR.

1404
00:55:20,450 --> 00:55:22,186
IT SEEMS TO BE ALL POST

1405
00:55:22,186 --> 00:55:22,819
TRANSCRIPTIONAL.

1406
00:55:22,819 --> 00:55:23,854
TRANSCRIPTION IS NOT CHANGED AT

1407
00:55:23,854 --> 00:55:25,189
ALL.

1408
00:55:25,189 --> 00:55:26,390
SO WE STILL ARE TRYING TO FIGURE

1409
00:55:26,390 --> 00:55:27,691
OUT EXACTLY HOW IT WORKS.

1410
00:55:27,691 --> 00:55:29,126
OUR BEST GUESS IS IT'S PROBABLY

1411
00:55:29,126 --> 00:55:30,694
TO DO WITH SPLICING OR TO DO

1412
00:55:30,694 --> 00:55:31,895
WITH SOMETHING LIKE RNA

1413
00:55:31,895 --> 00:55:32,996
METHYLATION SO WE'RE TRYING TO

1414
00:55:32,996 --> 00:55:34,131
FOLLOW UP ON THOSE TWO LEADS SO

1415
00:55:34,131 --> 00:55:36,333
YES, I THINK IT'S POST

1416
00:55:36,333 --> 00:55:36,700
TRANSCRIPTIONAL.

1417
00:55:36,700 --> 00:55:39,836
>> OKAY, THANKS.

1418
00:55:39,836 --> 00:55:43,073
>> ONE MORE QUESTION.

1419
00:55:43,073 --> 00:55:45,909
>> HI, I WANT TO MAKE A
COMMENT

1420
00:55:45,909 --> 00:55:47,511
TO ANSWER SOME OF THE PREVIOUS

1421
00:55:47,511 --> 00:55:49,112
QUESTIONS ABOUT MHC RESTRICTED

1422
00:55:49,112 --> 00:55:53,817
T-CELLS IN THE MON K MONKEY MOD.

1423
00:55:53,817 --> 00:55:55,052
GUIDO, NICE DATA, BUT PART OF

1424
00:55:55,052 --> 00:55:57,888
THE ISSUE IS NOT NECESSARILY

1425
00:55:57,888 --> 00:56:01,024
THAT THEY'RE MHCU RESTRICTED BUT

1426
00:56:01,024 --> 00:56:01,992
IT'S ALSO THE TIMING.

1427
00:56:01,992 --> 00:56:04,161
SO THE FACT THAT THE INTERCEPT

1428
00:56:04,161 --> 00:56:05,596
AND REPLICATION ARREST OCCURS

1429
00:56:05,596 --> 00:56:07,364
BEFORE THE RESERVOIR IS SET

1430
00:56:07,364 --> 00:56:09,032
MATCHES WHAT WE SEE WITH EARLY

1431
00:56:09,032 --> 00:56:11,535
ART, AND THE LOSS OF CELLS AND

1432
00:56:11,535 --> 00:56:13,303
THE CLEARANCE OF INFECTION HAS

1433
00:56:13,303 --> 00:56:14,438
THE SAME TIMING AS IF YOU PUT

1434
00:56:14,438 --> 00:56:15,872
THE ANIMALS ON EARLY ART.

1435
00:56:15,872 --> 00:56:18,609
SO WHAT WE THINK IS HAPPENING,

1436
00:56:18,609 --> 00:56:20,510
WHEN MHC RESTRICTED T-CELLS IN

1437
00:56:20,510 --> 00:56:22,913
VIVO IN THE CNV MODEL IS THERE'S

1438
00:56:22,913 --> 00:56:24,748
REPLICATION ARREST WHICH IS NOT

1439
00:56:24,748 --> 00:56:25,582
NECESSARILY KILLING THE CELLS

1440
00:56:25,582 --> 00:56:27,017
BUT STOPPING VIRAL SPREAD, AND

1441
00:56:27,017 --> 00:56:28,318
THAT OCCURS BEFORE THE LONG

1442
00:56:28,318 --> 00:56:30,387
LIVED RESERVOIR.

1443
00:56:30,387 --> 00:56:31,989
AND THAT'S WHY WE SEE WHAT WE

1444
00:56:31,989 --> 00:56:32,756
SEE.

1445
00:56:32,756 --> 00:56:33,957
WE LOOK CAREFULLY FOR ESCAPE IN

1446
00:56:33,957 --> 00:56:35,259
THE NON-PROTECTED ANIMALS.

1447
00:56:35,259 --> 00:56:37,494
THERE'S NO EVIDENCE OF

1448
00:56:37,494 --> 00:56:38,562
MUTATIONAL ESCAPE, AND THAT'S

1449
00:56:38,562 --> 00:56:40,664
AGAIN BECAUSE OF THE EARLY

1450
00:56:40,664 --> 00:56:41,798
INTERCEPT THAT OCCURS PROBABLY

1451
00:56:41,798 --> 00:56:42,899
IN THE FIRST SEVEN DAYS.

1452
00:56:42,899 --> 00:56:44,735
IT EITHER STOPS IT OR IT

1453
00:56:44,735 --> 00:56:47,170
DOESN'T, AND THAT TENDS TO BE A

1454
00:56:47,170 --> 00:56:48,238
FUNCTION MORE OF THE PROGRAMMING

1455
00:56:48,238 --> 00:56:50,274
OF THE CELLS BY THE INNATE

1456
00:56:50,274 --> 00:56:51,908
IMMUNE RESPONSE AS OPPOSED TO --

1457
00:56:51,908 --> 00:56:53,777
SO THERE'S NO EVIDENCE OF

1458
00:56:53,777 --> 00:56:56,346
MUTATIONAL ESCAPE.

1459
00:56:56,346 --> 00:56:59,383
>> I GUESS I WOULD JUST
SAY SORT

1460
00:56:59,383 --> 00:57:01,919
OF ORTHOGONALLY, PLEASE LOOK AT

1461
00:57:01,919 --> 00:57:03,887
THIS EXPERIMENT THAT WAS

1462
00:57:03,887 --> 00:57:04,988
PRESENTED AS A PRELIMINARY

1463
00:57:04,988 --> 00:57:07,090
EXPERIMENT SHOWING SOME KIND OF

1464
00:57:07,090 --> 00:57:09,293
ANTIVIRAL ACTIVITY, WHICH WAS

1465
00:57:09,293 --> 00:57:10,360
REALLY ALL THAT IT SHOWED.

1466
00:57:10,360 --> 00:57:11,628
ALL OF THE MECHANISM QUESTIONS

1467
00:57:11,628 --> 00:57:14,364
THAT WERE ASKED, VERY IMPORTANT,

1468
00:57:14,364 --> 00:57:17,634
BUT REQUIRE FURTHER STUDY.

1469
00:57:17,634 --> 00:57:19,069
THIS WAS ACUTE INFECTION AND

1470
00:57:19,069 --> 00:57:20,971
JUST HAVING THE CELLS THERE

1471
00:57:20,971 --> 00:57:22,606
DURING ACUTE VIREMIA, AND THERE

1472
00:57:22,606 --> 00:57:23,774
WAS AN ANTIVIRAL EFFECT.

1473
00:57:23,774 --> 00:57:27,878
SO EXACTLY WHAT'S GOING ON, HOW

1474
00:57:27,878 --> 00:57:29,079
THAT CAN BE USED, IS SOMETHING

1475
00:57:29,079 --> 00:57:30,314
THAT REQUIRES A LOT MORE WORK.

1476
00:57:30,314 --> 00:57:31,548
>> ABSOLUTELY.

1477
00:57:31,548 --> 00:57:33,150
AND WE'VE ALSO SEEN SIMILAR IN

1478
00:57:33,150 --> 00:57:36,586
VITRO ACTIVITY.

1479
00:57:36,586 --> 00:57:46,763
[APPLAUSE]

1480
00:58:26,036 --> 00:58:28,205
>> ENTERPRISE FOR RESEARCH
AND

1481
00:58:28,205 --> 00:58:31,375
ADVOCACY TO STOP AND ERADICATE

1482
00:58:31,375 --> 00:58:31,808
HIV.

1483
00:58:31,808 --> 00:58:35,112
I'M HAPPY TO INTRODUCE THE

1484
00:58:35,112 --> 00:58:37,214
CONTACT PI, DR. MIRKO PAIARDINI.

1485
00:58:37,214 --> 00:58:41,618
HE'S A PROFESSOR AT EMMY EMORY

1486
00:58:41,618 --> 00:58:43,687
UNIVERSITY AND IT ALSO HAPPENS

1487
00:58:43,687 --> 00:58:45,355
TO BE HIS BIRTHDAY TODAY.

1488
00:58:45,355 --> 00:58:46,890
IF YOUR TEAM FINISHES EARLY, WE

1489
00:58:46,890 --> 00:58:48,425
COULD ALSO SING HAPPY BIRTHDAY.

1490
00:58:48,425 --> 00:58:49,059
TAKE IT AWAY.

1491
00:58:49,059 --> 00:58:51,862
>> THAT'S A GOOD EXCUSE,
THANK

1492
00:58:51,862 --> 00:58:54,965
YOU FOR THAT INTRODUCTION IN

1493
00:58:54,965 --> 00:58:59,770
PRESENTING.

1494
00:58:59,770 --> 00:59:01,972
THESE SLIDES ARE JUST TO SHOW

1495
00:59:01,972 --> 00:59:04,975
YOU OUR THEME IS COMPOSED OF 14

1496
00:59:04,975 --> 00:59:06,042
DIFFERENT PATTERNS, AT LEAST IN

1497
00:59:06,042 --> 00:59:07,677
THIS MAP, AND FROM FIVE

1498
00:59:07,677 --> 00:59:09,179
DIFFERENT COUNTRIES AND TO

1499
00:59:09,179 --> 00:59:13,750
HIGHLIGHT OUR INDUSTRY AND

1500
00:59:13,750 --> 00:59:14,217
COMMUNITY.

1501
00:59:14,217 --> 00:59:16,620
I WANT TO ALSO SHOW AND THANK

1502
00:59:16,620 --> 00:59:20,891
THE MEMBERS OF THE ADVISORY

1503
00:59:20,891 --> 00:59:24,161
BOARD AND THE MEMBER THAT IS IN

1504
00:59:24,161 --> 00:59:26,196
THE AUDIENCE FOR THIS MEETING.

1505
00:59:26,196 --> 00:59:29,132
SO WE ARE A NEWLY FUNDED

1506
00:59:29,132 --> 00:59:31,067
COLLABORATORY SINCE 2 1/2 YEARS

1507
00:59:31,067 --> 00:59:32,602
NOW, AND I BELIEVE WE'VE BEEN

1508
00:59:32,602 --> 00:59:36,406
QUITE PRODUCTIVE.

1509
00:59:36,406 --> 00:59:38,175
ERASE HIV -- MEMBERS OF THE TEAM

1510
00:59:38,175 --> 00:59:39,209
HAVE BEEN PRESENTING AT

1511
00:59:39,209 --> 00:59:40,610
CONFERENCE AND ACADEMIC

1512
00:59:40,610 --> 00:59:41,778
INSTITUTION IN MORE THAN 100

1513
00:59:41,778 --> 00:59:43,814
LOCATION AND WE HAVE 36

1514
00:59:43,814 --> 00:59:45,615
PUBLISHED PAPERS, 17 OF THEM

1515
00:59:45,615 --> 00:59:48,218
WITH TWO OR MORE MEMBERS OF THE

1516
00:59:48,218 --> 00:59:49,419
COLLABORATORY, AND THESE ARE

1517
00:59:49,419 --> 00:59:51,888
PAPERS NOT ONLY FUNDED BY ERASE

1518
00:59:51,888 --> 00:59:53,223
HIV BUT REALLY SUMMARIZED IN

1519
00:59:53,223 --> 00:59:57,127
SOME OF THESE MANUSCRIPT ON THE

1520
00:59:57,127 --> 00:59:59,930
SLIDE FOCUS ON THE KEY GOAL OF

1521
00:59:59,930 --> 01:00:02,666
THE ERASE HIV COLLABORATORY.

1522
01:00:02,666 --> 01:00:04,234
AND TO SPEAK ABOUT THE KEY GOAL,

1523
01:00:04,234 --> 01:00:06,870
WE ARE REALLY FOCUSED ON TRYING

1524
01:00:06,870 --> 01:00:08,305
TO UNDERSTAND TWO VERY IMPORTANT

1525
01:00:08,305 --> 01:00:10,073
QUESTIONS FOR HIV PERSISTENCE,

1526
01:00:10,073 --> 01:00:15,512
WHAT ARE THE MECHANISM --

1527
01:00:15,512 --> 01:00:18,415
PERSISTENCE, FAVOR THE SURVIVAL

1528
01:00:18,415 --> 01:00:19,416
DESPITE THEY'RE INFECTED AND

1529
01:00:19,416 --> 01:00:21,151
WHAT ARE THE MECHANISMS LIMITING

1530
01:00:21,151 --> 01:00:22,853
THE CAPACITY OF THE SYSTEM TO

1531
01:00:22,853 --> 01:00:24,521
INTERCEPT AND ELIMINATE THESE

1532
01:00:24,521 --> 01:00:24,821
CELLS.

1533
01:00:24,821 --> 01:00:28,658
AND WE ARE ABLY FOCUSED ALSO AT

1534
01:00:28,658 --> 01:00:31,261
PERFORMING IMMUNOSTUDY IN IMMUNE

1535
01:00:31,261 --> 01:00:32,596
BASED INTERVENTIONS WHEN WE TRY

1536
01:00:32,596 --> 01:00:34,831
TO UNDERSTAND THESE MECHANISMS

1537
01:00:34,831 --> 01:00:35,632
WITH INTERVENTION TO HOPEFULLY

1538
01:00:35,632 --> 01:00:37,868
BE ABLE TO CONTROL HIV.

1539
01:00:37,868 --> 01:00:39,836
AND TODAY'S PRESENTATION IS

1540
01:00:39,836 --> 01:00:41,671
GOING TO BE FOCUSED ON THIS KEY

1541
01:00:41,671 --> 01:00:43,406
GOAL OF THE ERASE COLLABORATORY

1542
01:00:43,406 --> 01:00:45,041
AND I APOLOGIZE FOR SOME LAST

1543
01:00:45,041 --> 01:00:47,077
MINUTE CHANGES, SO RESEARCH

1544
01:00:47,077 --> 01:00:48,945
FOCUS ONE IS GOING TO PRESENT ON

1545
01:00:48,945 --> 01:00:51,548
MECHANISM OF CD8 CYTOLYTIC

1546
01:00:51,548 --> 01:00:55,151
FUNCTION BUT ALSO PRO LATENCY

1547
01:00:55,151 --> 01:00:56,653
ACTIVITY, AND DEANNA KULPA WAS

1548
01:00:56,653 --> 01:00:58,088
SUPPOSED TO PRESENT BUT DEANNA

1549
01:00:58,088 --> 01:00:59,523
JUST TESTED POSITIVE FOR COVID,

1550
01:00:59,523 --> 01:01:01,758
SO BRAD WILL TAKE IT OVER FOR

1551
01:01:01,758 --> 01:01:03,593
THE ENTIRE RF1.

1552
01:01:03,593 --> 01:01:07,998
RF2 IS GOING TO BE MYSELF AND

1553
01:01:07,998 --> 01:01:12,836
PRITI KUMAR, TO TRY TO INTERCEPT

1554
01:01:12,836 --> 01:01:14,804
THE REBOUNDING OF THE VIRUS.

1555
01:01:14,804 --> 01:01:16,406
AND THE RESEARCH FOCUS THREE IS

1556
01:01:16,406 --> 01:01:18,608
GOING TO BE FOCUSED ON THE

1557
01:01:18,608 --> 01:01:19,910
MECHANISM THAT FAVOR THE

1558
01:01:19,910 --> 01:01:22,312
SURVIVAL OF -- PARTICULARLY THE

1559
01:01:22,312 --> 01:01:28,618
EXPRESSION OF B CE BCL-2 AND HOE

1560
01:01:28,618 --> 01:01:34,357
CAN TARGET THAT PATHWAY.

1561
01:01:34,357 --> 01:01:38,295
TTHOMAS CANNOT MAKE IT SO ANDREW

1562
01:01:38,295 --> 01:01:39,796
WILL TAKE OVER FOR HIM.

1563
01:01:39,796 --> 01:01:45,268
FINALLY WE'LL FINISH WITH PRITI

1564
01:01:45,268 --> 01:01:46,036
BHANDARI SPEAKING ABOUT OUR

1565
01:01:46,036 --> 01:01:47,404
COMMUNITY WORK.

1566
01:01:47,404 --> 01:01:50,240
ALL THIS WORK WE ARE DOING IN

1567
01:01:50,240 --> 01:01:53,743
THE 2 1/2 YEARS OF THE ERASE HIV

1568
01:01:53,743 --> 01:01:54,511
COLLABORATORY IS FOCUSED TO

1569
01:01:54,511 --> 01:01:56,546
SELECT THE MOST EFFECTIVE IMMUNE

1570
01:01:56,546 --> 01:02:00,083
BASED INTERVEX THA INTERVENTIONE

1571
01:02:00,083 --> 01:02:03,620
PERFORMED AS DR. MARGOLIS WAS

1572
01:02:03,620 --> 01:02:04,588
HIGHLIGHTING BEFORE TO REDUCE

1573
01:02:04,588 --> 01:02:05,589
THE ESTABLISHMENT OF THE

1574
01:02:05,589 --> 01:02:07,824
RESERVOIR, AND THEN TO BE

1575
01:02:07,824 --> 01:02:12,529
PERFORMED -- WHICH ALREADY

1576
01:02:12,529 --> 01:02:14,264
REDUCE -- AND FURTHER IMPROVE TO

1577
01:02:14,264 --> 01:02:15,365
NOW CONTROL THE REBOUNDING

1578
01:02:15,365 --> 01:02:16,199
VIRUS.

1579
01:02:16,199 --> 01:02:19,703
AND WITH THAT, I WILL HAVE BRAD

1580
01:02:19,703 --> 01:02:26,376
START WITH RF1.

1581
01:02:26,376 --> 01:02:29,479
>> THANK YOU, MIRKO.

1582
01:02:29,479 --> 01:02:35,819
I'M GOING TO TELL YOU ABOUT IT.

1583
01:02:35,819 --> 01:02:39,589
AZEMETOSTA, A -- SO OUR GOAL ISO

1584
01:02:39,589 --> 01:02:43,193
TEST A MO VEL THERAPEUTIC

1585
01:02:43,193 --> 01:02:45,161
APPROACH -- WE'VE LEARNED THAT

1586
01:02:45,161 --> 01:02:48,198
IN CELL CULTURE, THIS APPROVED

1587
01:02:48,198 --> 01:02:50,400
DRUG HELPS EXPOSE HIV INFECTED

1588
01:02:50,400 --> 01:02:53,303
CELLS TO CD8 CELLS RESULTING IN

1589
01:02:53,303 --> 01:02:54,304
MORE KILLING AND MOUSE

1590
01:02:54,304 --> 01:02:57,607
EXPERIMENTS ARE STILL ONGOING

1591
01:02:57,607 --> 01:02:58,708
BUT THERE'S SOME EARLY

1592
01:02:58,708 --> 01:03:00,844
SUGGESTION IT MAY EMPOWER

1593
01:03:00,844 --> 01:03:02,145
CD8 CELLS TO BETTER CONTROL

1594
01:03:02,145 --> 01:03:05,115
VIRAL REPLICATION IN VIVO.

1595
01:03:05,115 --> 01:03:06,683
IT'S AN APPROVED DRUG THAT CAN

1596
01:03:06,683 --> 01:03:07,617
BE CONSIDERED FOR CLINICAL

1597
01:03:07,617 --> 01:03:09,552
TRIALS IN PEOPLE LIVING WITH HIV

1598
01:03:09,552 --> 01:03:16,993
TO ENHANCE CD8 T-CELLS.

1599
01:03:16,993 --> 01:03:19,029
WE'RE REALLY INTERESTED IN THE

1600
01:03:19,029 --> 01:03:20,563
INFECTED CELLS THAT SURVIVE

1601
01:03:20,563 --> 01:03:22,399
KILLING ONCE YOU EXPOSE TO

1602
01:03:22,399 --> 01:03:23,600
CONDITIONS IN VITRO, THERE'S

1603
01:03:23,600 --> 01:03:24,668
ALWAYS SOME SURVIVORS.

1604
01:03:24,668 --> 01:03:25,869
WE SAW THAT ALSO IN THE TALK

1605
01:03:25,869 --> 01:03:26,302
EARLIER.

1606
01:03:26,302 --> 01:03:28,271
WE'VE BEEN PROFILING THESE CELLS

1607
01:03:28,271 --> 01:03:29,339
AND SEEN A NUMBER OF DIFFERENT

1608
01:03:29,339 --> 01:03:30,006
HITS.

1609
01:03:30,006 --> 01:03:30,874
SO THERE'S GOING TO BE

1610
01:03:30,874 --> 01:03:33,276
PRESENTATIONS LATER ABOUT

1611
01:03:33,276 --> 01:03:34,978
BCL2 AND BCL2 FAMILY MEMBERS.

1612
01:03:34,978 --> 01:03:36,379
THIS IS BCLXL.

1613
01:03:36,379 --> 01:03:38,415
WHEN WE EXPOSE TO CTL, WE SEE

1614
01:03:38,415 --> 01:03:40,183
THE INFECTED CELLS THAT SURVIVE

1615
01:03:40,183 --> 01:03:41,484
HAVE BEEN SELECTED FOR THOSE

1616
01:03:41,484 --> 01:03:44,487
THAT ARE BCL2 HIGH.

1617
01:03:44,487 --> 01:03:47,223
EZH2 AS WELL IS ONE OF THESE

1618
01:03:47,223 --> 01:03:48,091
THAT'S OVEREXPRESSED IN THESE

1619
01:03:48,091 --> 01:03:49,693
CELLS THAT SURVIVE KILLING.

1620
01:03:49,693 --> 01:03:51,795
WHEN YOU EXPOSE TO CTL KILLING,

1621
01:03:51,795 --> 01:03:53,963
IT'S UP IN THE SURVIVORS.

1622
01:03:53,963 --> 01:03:55,665
SO WHAT IS EZH2?

1623
01:03:55,665 --> 01:03:59,736
IT'S PART OF THE POLY -- RE PRE

1624
01:03:59,736 --> 01:04:01,604
SIEVE COMPLEX AND IT ACTS BY

1625
01:04:01,604 --> 01:04:03,540
METHYLATING HISTONE 3 AT LYSINE

1626
01:04:03,540 --> 01:04:04,074
27.

1627
01:04:04,074 --> 01:04:06,376
SO THIS HAS A LOT OF EFFECTS ON

1628
01:04:06,376 --> 01:04:07,477
THE CELL, BUT ONE OF THE THINGS

1629
01:04:07,477 --> 01:04:09,179
THAT IT DOES IS REPRESS

1630
01:04:09,179 --> 01:04:11,915
EXPRESSION OF NLRC5, WHICH IS

1631
01:04:11,915 --> 01:04:14,417
IMPORTANT IN DRIVING

1632
01:04:14,417 --> 01:04:16,119
MHC1 UPREGULATION IN RESPONSE TO

1633
01:04:16,119 --> 01:04:17,320
INTERFERON GAMMA.

1634
01:04:17,320 --> 01:04:20,857
SO IT'S KNOWN IN VARIOUS TUMORS

1635
01:04:20,857 --> 01:04:23,293
THAT SOME TUMORS OVEREXPRESS

1636
01:04:23,293 --> 01:04:24,394
EZH2.

1637
01:04:24,394 --> 01:04:26,329
THIS PREVENTS MHC1 UPREGULATION

1638
01:04:26,329 --> 01:04:32,869
AND THIS IS A MECHANISM OF

1639
01:04:32,869 --> 01:04:33,870
IMMUNOINVASION SO IS SOMETHING

1640
01:04:33,870 --> 01:04:35,171
HAPPENING IN THE CONTEXT OF HIV.

1641
01:04:35,171 --> 01:04:39,609
FIRST WASN'T TODAY ASK ARE THE Y

1642
01:04:39,609 --> 01:04:41,811
DEFICIENT IN SURFACE MHC1.

1643
01:04:41,811 --> 01:04:42,946
IF THAT'S THE CASE MAYBE WE DO

1644
01:04:42,946 --> 01:04:43,947
SOMETHING ABOUT IT BY

1645
01:04:43,947 --> 01:04:45,281
INTERFERING WITH EZH2.

1646
01:04:45,281 --> 01:04:46,416
THESE ARE THE RESULTS OF A

1647
01:04:46,416 --> 01:04:48,184
KILLING ASSAY WITH THE CTL

1648
01:04:48,184 --> 01:04:48,384
CLONE.

1649
01:04:48,384 --> 01:04:49,819
WE CAN SEE THAT WITHOUT APPLYING

1650
01:04:49,819 --> 01:04:51,387
THE CLONE, THE INFECTED CELLS

1651
01:04:51,387 --> 01:04:54,691
HAVE A SMEAR TOWARDS BEING

1652
01:04:54,691 --> 01:04:56,226
MHC1 LOW THROUGH THE ACTIONS OF

1653
01:04:56,226 --> 01:04:58,261
NEF BUT IF WE KILL WITH THE CTL

1654
01:04:58,261 --> 01:04:59,129
CLONE WE CUT OFF THIS PART OF

1655
01:04:59,129 --> 01:05:00,530
THE CURVE, WE SELECT FOR KURNS

1656
01:05:00,530 --> 01:05:02,632
WHICH ARE MORE MHC1 LOW, LESS

1657
01:05:02,632 --> 01:05:03,900
ABLE TO BE SEEN BY THE IMMUNE

1658
01:05:03,900 --> 01:05:04,300
SYSTEM.

1659
01:05:04,300 --> 01:05:05,969
SO CAN WE DO SOMETHING ABOUT

1660
01:05:05,969 --> 01:05:08,972
THIS BY UPREGULATING MHC1.

1661
01:05:08,972 --> 01:05:11,407
WE TEST THIS IN AN IN VITRO CTL

1662
01:05:11,407 --> 01:05:14,611
KILLING ASSAY.

1663
01:05:14,611 --> 01:05:18,782
INFECTED CDR -- EXPOSED TO

1664
01:05:18,782 --> 01:05:20,450
CYTOTOXIC T-CELL CLONE AND WE'RE

1665
01:05:20,450 --> 01:05:21,551
LOOKING AT THE DEGREE OF KILLING

1666
01:05:21,551 --> 01:05:23,686
OF THESE INFECTED CELLS.

1667
01:05:23,686 --> 01:05:25,321
THESE ARE VERY SIMILAR PLOTS TO

1668
01:05:25,321 --> 01:05:27,357
WHAT GUIDO SHOWED EARLIER.

1669
01:05:27,357 --> 01:05:29,025
SO CD4 T-CELLS ALONE WE CAN SEE

1670
01:05:29,025 --> 01:05:30,360
THIS PORTION OF INFECTED CELLS.

1671
01:05:30,360 --> 01:05:32,362
WE ADD THE CTL CLONE AND WE KILL

1672
01:05:32,362 --> 01:05:33,763
THE MAJORITY OF THESE CELLS, BUT

1673
01:05:33,763 --> 01:05:35,632
WE NEVER KILL ALL OF THEM.

1674
01:05:35,632 --> 01:05:37,033
THERE'S ALWAYS THESE SURVIVORS

1675
01:05:37,033 --> 01:05:41,404
IN THESE KILLING ASSAYS.

1676
01:05:41,404 --> 01:05:43,573
THESE ARE THE SAME RESULTS, IT'S

1677
01:05:43,573 --> 01:05:44,774
PROJECTING A LITTLE BIT ODDLY

1678
01:05:44,774 --> 01:05:46,242
HERE, BUT WHERE WE PRE-TREAT

1679
01:05:46,242 --> 01:05:47,377
WITH TAZEMETOSTAT, AND NOW YOU

1680
01:05:47,377 --> 01:05:49,445
CAN SEE WE'VE CUT DEEPER INTO

1681
01:05:49,445 --> 01:05:51,314
THESE CELLS, SO A PROPORTION OF

1682
01:05:51,314 --> 01:05:52,816
THE CELLS THAT WOULD HAVE

1683
01:05:52,816 --> 01:05:54,217
SURVIVED ARE KILLED OFF WHEN WE

1684
01:05:54,217 --> 01:05:54,884
TREAT WITH TAZEMETOSTAT, AND

1685
01:05:54,884 --> 01:05:57,487
THIS IS ASSOCIATED WITH, INDEED,

1686
01:05:57,487 --> 01:06:00,924
A CONSISTENT UPREGULATION OF

1687
01:06:00,924 --> 01:06:04,427
MHC1 WE SEE IN

1688
01:06:04,427 --> 01:06:05,528
TAZEMETOSTAT-TREATED CELLS.

1689
01:06:05,528 --> 01:06:07,797
IT'S JUST PUSHING MHC1 LEVELS UP

1690
01:06:07,797 --> 01:06:10,099
ON EVERYTHING, SO THAT THE

1691
01:06:10,099 --> 01:06:11,501
MHC1 DOWN REGULATED INFECTED

1692
01:06:11,501 --> 01:06:13,436
CELLS CAN BE SEEN BETTER BY THE

1693
01:06:13,436 --> 01:06:14,103
CTL.

1694
01:06:14,103 --> 01:06:17,106
SO HERE'S DIFFERENT EFFECT

1695
01:06:17,106 --> 01:06:17,974
EFFECTOR-TARGET RATIOS.

1696
01:06:17,974 --> 01:06:20,410
SORRY THIS IS PROJECTING PRETTY

1697
01:06:20,410 --> 01:06:22,579
STRANGELY HERE BUT EACH DOT IS A

1698
01:06:22,579 --> 01:06:24,214
DIFFERENT BIOLOGICAL REPLICATE.

1699
01:06:24,214 --> 01:06:25,615
WE LOOK AT THE PROPORTION THAT

1700
01:06:25,615 --> 01:06:28,251
SURVIVE UPON CTL EXPOSURE IF

1701
01:06:28,251 --> 01:06:28,918
THEY'VE BEEN TREATED WITH

1702
01:06:28,918 --> 01:06:30,186
TAZEMETOSTAT OR NOT, SO WE KILL

1703
01:06:30,186 --> 01:06:32,055
OFF AN EXTRA ABOUT 50% OF THE

1704
01:06:32,055 --> 01:06:33,690
WOULD-BE SURVIVORS IN THESE IN

1705
01:06:33,690 --> 01:06:35,625
VITRO ASSAYS.

1706
01:06:35,625 --> 01:06:36,926
SO WE'VE DONE MANY VERSIONS OF

1707
01:06:36,926 --> 01:06:38,228
THIS ASSAY AND SEEN VERY

1708
01:06:38,228 --> 01:06:38,661
CONSISTENT RESULTS.

1709
01:06:38,661 --> 01:06:39,996
SO THEN WE WANT TO MOVE THIS IN

1710
01:06:39,996 --> 01:06:40,396
VIVO.

1711
01:06:40,396 --> 01:06:41,598
SO TO DO THIS, WE USE WHAT WE

1712
01:06:41,598 --> 01:06:46,035
CALL OUR PA PARTICIPANT DERIVED

1713
01:06:46,035 --> 01:06:50,406
MOUSE MODEL, ENGRAFTED WITH

1714
01:06:50,406 --> 01:06:51,441
CD4 T-CELLS FROM A PERSON LIVING

1715
01:06:51,441 --> 01:06:52,242
WITH HIV.

1716
01:06:52,242 --> 01:06:55,511
THEN WE CAN COME IN WITH

1717
01:06:55,511 --> 01:06:56,145
CD8 T-CELLS FROM THE SAME

1718
01:06:56,145 --> 01:06:57,981
INDIVIDUAL AND TEST THE

1719
01:06:57,981 --> 01:07:00,049
ANTIVIRAL ACTIVITY OF THAT

1720
01:07:00,049 --> 01:07:01,351
PARTICIPANT'S CD8 T-CELLS IN A

1721
01:07:01,351 --> 01:07:01,651
MOUSE MODEL.

1722
01:07:01,651 --> 01:07:03,186
WHAT I CAN TELL YOU VERY CLEARLY

1723
01:07:03,186 --> 01:07:04,821
SO FAR IS THAT IF YOU TREAT

1724
01:07:04,821 --> 01:07:06,789
THESE MICE WITH TAZEMETOSTAT,

1725
01:07:06,789 --> 01:07:09,259
YOU SEE NICE UPREGULATION OF

1726
01:07:09,259 --> 01:07:10,894
MHC1 ON THEIR CD4 T-CELLS.

1727
01:07:10,894 --> 01:07:11,895
SO THIS IMPORTANT IMPACT THAT

1728
01:07:11,895 --> 01:07:15,131
WE'RE SEEING IN VITRO IS CLEARLY

1729
01:07:15,131 --> 01:07:16,099
RECAPITULATED IN THIS MOUSE

1730
01:07:16,099 --> 01:07:18,301
MODEL.

1731
01:07:18,301 --> 01:07:19,502
THESE RESULTS I WOULD FLAG AS A

1732
01:07:19,502 --> 01:07:20,837
LITTLE BIT MORE PRELIMINARY

1733
01:07:20,837 --> 01:07:21,871
BECAUSE WE NEED TO REPEAT THE

1734
01:07:21,871 --> 01:07:23,106
EXPERIMENT, BUT ALSO VERY

1735
01:07:23,106 --> 01:07:23,406
TANTALIZING.

1736
01:07:23,406 --> 01:07:25,441
SO HERE'S THE VIRAL LOAD

1737
01:07:25,441 --> 01:07:26,342
TRAJECTORIES IN MICE.

1738
01:07:26,342 --> 01:07:28,411
THESE TWO GROUPS HAVE RECEIVED

1739
01:07:28,411 --> 01:07:29,512
CD8 T-CELLS, SO JUST BY

1740
01:07:29,512 --> 01:07:31,214
RECEIVING CD8 T-CELLS FROM THIS

1741
01:07:31,214 --> 01:07:32,882
PERSON LIVING WITH HIV, WE HAVE

1742
01:07:32,882 --> 01:07:36,052
A NICE IMPACT ON THE VIRAL LOAD.

1743
01:07:36,052 --> 01:07:38,655
WE SUPPRESS ON ANTIRETROVIRAL

1744
01:07:38,655 --> 01:07:41,257
THERAPY FOR A BRIEF TIME IN THIS

1745
01:07:41,257 --> 01:07:43,660
THERAPY AND TREAT OR NOT WITH

1746
01:07:43,660 --> 01:07:44,327
TAZEMETOSTAT AND THE QUESTION IS

1747
01:07:44,327 --> 01:07:45,361
WHAT HAPPENS TO VIRAL REBOUND.

1748
01:07:45,361 --> 01:07:46,996
YOU CAN SEE THERE'S SOMEWHAT

1749
01:07:46,996 --> 01:07:47,864
CURVED REBOUND IN THE MIGHT

1750
01:07:47,864 --> 01:07:50,566
TREATED WITH CD8 T-CELLS BUT THE

1751
01:07:50,566 --> 01:07:51,801
MICE THAT RECEIVED TAZEMETOSTAT,

1752
01:07:51,801 --> 01:07:54,304
WE SEE MORE OF A REDUCTION IN

1753
01:07:54,304 --> 01:07:56,105
THIS VARIABLE REBOUND.

1754
01:07:56,105 --> 01:07:57,640
SO TANTALIZING DATA, BUT AGAIN,

1755
01:07:57,640 --> 01:07:58,541
THIS PART IS SOMETHING THAT

1756
01:07:58,541 --> 01:08:02,345
NEEDS TO BE FOLLOWED UP ON.

1757
01:08:02,345 --> 01:08:04,514
SO I WANT TO ACKNOWLEDGE ANDREA

1758
01:08:04,514 --> 01:08:06,916
WHO'S BEEN DRIVING THIS WORK IN

1759
01:08:06,916 --> 01:08:14,657
OUR LAB AS WELL AS ALI.

1760
01:08:14,657 --> 01:08:17,193
HERE'S █ANOTHER SIDE OF THE COI,

1761
01:08:17,193 --> 01:08:19,195
THE MACH BRIEN PAPER MENTIONED

1762
01:08:19,195 --> 01:08:22,632
EARLIER SHOWS CD8 T-CELLS CAN

1763
01:08:22,632 --> 01:08:26,135
ALSO POTENTIALLY INDUCE LATENCY

1764
01:08:26,135 --> 01:08:27,136
IN CD4 T-CELLS.

1765
01:08:27,136 --> 01:08:28,304
THIS WAS SEEN IN MICE THAT

1766
01:08:28,304 --> 01:08:31,474
RECEIVED THE IL15 SUPERAGONIST,

1767
01:08:31,474 --> 01:08:34,310
YOU SAW MUCH GREATER LATENCY

1768
01:08:34,310 --> 01:08:34,711
REVERSAL.

1769
01:08:34,711 --> 01:08:36,579
SO WE WANT TO KNOW WHY

1770
01:08:36,579 --> 01:08:37,880
CD8 T-CELLS CAN HAVE THIS

1771
01:08:37,880 --> 01:08:38,748
POTENTIALLY DETRIMENTAL EFFECT

1772
01:08:38,748 --> 01:08:43,119
AND BLOCK THAT, SO THAT WE CAN

1773
01:08:43,119 --> 01:08:44,988
HARNESS THEIR POSITIVE EFFECT OF

1774
01:08:44,988 --> 01:08:46,055
KILLING CELLS.

1775
01:08:46,055 --> 01:08:47,256
SO BRIEFLY THAT'S WHAT WE'RE

1776
01:08:47,256 --> 01:08:49,759
LOOKING AT, WHY DO SOME

1777
01:08:49,759 --> 01:08:51,060
CD8 T-CELLS PROMOTE LATENCY, IF

1778
01:08:51,060 --> 01:08:52,729
WE IDENTIFY THIS PATHWAY, CAN WE

1779
01:08:52,729 --> 01:08:55,198
BLOCK THIS PATHWAY AND THEN

1780
01:08:55,198 --> 01:08:59,135
IMPROVE LATENCY REVERSAL.

1781
01:08:59,135 --> 01:09:00,536
SO ERASE PUBLISHED THIS PAPER IN

1782
01:09:00,536 --> 01:09:01,838
IMMUNITY EARLIER THIS YEAR

1783
01:09:01,838 --> 01:09:03,139
LOOKING AT THE MECHANISMS BY

1784
01:09:03,139 --> 01:09:04,474
WHICH CD8 CELLS CAN PROMOTE

1785
01:09:04,474 --> 01:09:04,707
LATENCY.

1786
01:09:04,707 --> 01:09:08,077
THIS USES THIS IN VITRO ASSAY.

1787
01:09:08,077 --> 01:09:11,781
IF YOU USE JUST X VEE VO

1788
01:09:11,781 --> 01:09:12,949
CD8 T-CELLS IN PEOPLE WITHOUT

1789
01:09:12,949 --> 01:09:15,151
HIV, SO THESE DON'T HAVE

1790
01:09:15,151 --> 01:09:17,120
HIV-SPECIFIC CTLs IN THEM,

1791
01:09:17,120 --> 01:09:19,122
WHAT WE SEE IS THIS CO-CULTURE

1792
01:09:19,122 --> 01:09:20,023
DOES SEE A REDUCTION IN THE

1793
01:09:20,023 --> 01:09:21,724
PERCENTAGE OF CELLS THAT EXPRESS

1794
01:09:21,724 --> 01:09:22,992
GAG BUT NOT A REDUCTION IN THE

1795
01:09:22,992 --> 01:09:26,262
FREQUENCY OF INTEGRATED HIV DNA.

1796
01:09:26,262 --> 01:09:27,230
SUGGESTING THAT INSTEAD OF

1797
01:09:27,230 --> 01:09:28,665
KILLING CELLS, THERE'S SOME

1798
01:09:28,665 --> 01:09:32,935
SUPPRESSION OF GAG EXPRESSION.

1799
01:09:32,935 --> 01:09:34,637
SO IN THIS STUDY, DEANNA AND HER

1800
01:09:34,637 --> 01:09:36,272
TEAM WENT ON TO LOOK AT THE

1801
01:09:36,272 --> 01:09:39,742
PROFILE OF THESE CELLS, THE

1802
01:09:39,742 --> 01:09:42,145
CD4 CELLS FOLLOWING CO-CULTURE

1803
01:09:42,145 --> 01:09:43,346
WITH CD8 T-CELLS.

1804
01:09:43,346 --> 01:09:45,548
WHAT THEY SAUL WAS QUIESCENCE

1805
01:09:45,548 --> 01:09:47,717
AND MEMORY PATHWAYS WERE

1806
01:09:47,717 --> 01:09:51,521
UPREGULATED IN THESE

1807
01:09:51,521 --> 01:09:52,288
CD4 T-CELLS, AND SO THESE ARE

1808
01:09:52,288 --> 01:09:53,790
SOME PATHWAYS WE MIGHT BE ABLE

1809
01:09:53,790 --> 01:09:54,891
TO INTERFERE WITH TO PREVENT

1810
01:09:54,891 --> 01:10:01,864
KRCHT D8 T-CELLS FROM -- LATE 

1811
01:10:01,864 --> 01:10:02,098
LATENCY.

1812
01:10:02,098 --> 01:10:03,599
BCL2, WHICH YOU'RE GOING TO HEAR

1813
01:10:03,599 --> 01:10:06,135
ABOUT LATER -- PRO SURVIVAL

1814
01:10:06,135 --> 01:10:07,637
PATHWAYS IN CD4 T-CELLS.

1815
01:10:07,637 --> 01:10:09,038
AND THERE'S SOME NICE

1816
01:10:09,038 --> 01:10:10,573
INTERSECTIONS HERE WITH OTHER

1817
01:10:10,573 --> 01:10:11,574
INVESTIGATORS IN ERASE BECAUSE

1818
01:10:11,574 --> 01:10:18,981
WE DO SEE -- OF -- SWELS

1819
01:10:18,981 --> 01:10:20,383
UPREGULATION OF IL10 WHICH IS

1820
01:10:20,383 --> 01:10:23,019
BEING BLOCKED IN NON-HUMAN

1821
01:10:23,019 --> 01:10:24,520
PRIMATE STUDIES IN OTHER ASPECTS

1822
01:10:24,520 --> 01:10:25,888
OF THE ERASE COLLABORATORY.

1823
01:10:25,888 --> 01:10:29,225
SO WITH THAT, I'LL WRAP UP FOR

1824
01:10:29,225 --> 01:10:31,260
RF1, AND HERE'S DEANNA'S

1825
01:10:31,260 --> 01:10:31,694
ACKNOWLEDGMENTS.

1826
01:10:31,694 --> 01:10:32,595
AND THANK YOU FOR YOUR

1827
01:10:32,595 --> 01:10:32,862
ATTENTION.

1828
01:10:32,862 --> 01:10:39,402
[APPLAUSE]

1829
01:10:39,402 --> 01:10:40,336
>> THANK YOU, BRAD.

1830
01:10:40,336 --> 01:10:44,807
NOW STARTING WITH RF2, IMMUNE

1831
01:10:44,807 --> 01:10:47,310
BASED INTERVENTION.

1832
01:10:47,310 --> 01:10:49,846
MANY MANUSCRIPTS INCLUDING --

1833
01:10:49,846 --> 01:10:51,447
AND SOME FROM OUR GROUP HAVE

1834
01:10:51,447 --> 01:10:55,284
SHOWN THAT CD4 T-CELLS THAT

1835
01:10:55,284 --> 01:10:59,322
EXPRESS -- INCLUDING PD-1 AND

1836
01:10:59,322 --> 01:11:00,056
CTL4 COULD CONTRIBUTE TO THE

1837
01:11:00,056 --> 01:11:02,892
PERSISTENCE OF THE VIRUS

1838
01:11:02,892 --> 01:11:04,994
INCLUDING ANTIRETROVIRAL

1839
01:11:04,994 --> 01:11:05,328
THERAPY.

1840
01:11:05,328 --> 01:11:07,463
A FEW YEARS AGO WE COMPLETED A

1841
01:11:07,463 --> 01:11:09,332
BLOCKADE AND PROVED THERE WAS

1842
01:11:09,332 --> 01:11:13,035
SUPERIOR -- COMPARED TO -- ON

1843
01:11:13,035 --> 01:11:15,104
ANTIRETROVIRAL THERAPY REDUCING

1844
01:11:15,104 --> 01:11:16,639
SEVERE ACTIVATION BUT WAS NOT

1845
01:11:16,639 --> 01:11:19,142
SUFFICIENT TO CONTROL VIRAL

1846
01:11:19,142 --> 01:11:22,645
REBOUND AFTER -- INTERRUPTION.

1847
01:11:22,645 --> 01:11:24,247
WE PROPOSE THE BLOCKADE MAY BE

1848
01:11:24,247 --> 01:11:26,549
MORE BENEFICIAL DURING --

1849
01:11:26,549 --> 01:11:28,518
TREATMENT INTERRUPTION SO WHEN

1850
01:11:28,518 --> 01:11:31,254
YOU CAN -- REBOUNDING VIRUS AND

1851
01:11:31,254 --> 01:11:33,089
PROPOSE THERE MAY BE MORE

1852
01:11:33,089 --> 01:11:35,825
BENEFITS WITH THERAPEUTIC

1853
01:11:35,825 --> 01:11:37,126
VACCINE OR -- BLOCK CADE.

1854
01:11:37,126 --> 01:11:39,862
THE REASON WE'RE INTERESTED WITH

1855
01:11:39,862 --> 01:11:43,900
IL10 IS -- HIV INVESTIGATOR

1856
01:11:43,900 --> 01:11:47,370
SHOWED LAST YEAR -- CONTRIBUTE

1857
01:11:47,370 --> 01:11:51,641
TO ESTABLISHMENT AND PERSISTENCE

1858
01:11:51,641 --> 01:11:56,646
IN SIV INFECTED MACAQUES -- IN

1859
01:11:56,646 --> 01:11:57,413
HUMAN WITH HIV.

1860
01:11:57,413 --> 01:11:59,148
YOU CAN SEE ON THE RIGHT OF THIS

1861
01:11:59,148 --> 01:12:03,686
SLIDE PUBLISHED SHOWING THAT --

1862
01:12:03,686 --> 01:12:06,022
IS ACTUALLY VERY IMPORTANT FOR

1863
01:12:06,022 --> 01:12:08,090
THE -- OF THE SILENT AND ACTIVE

1864
01:12:08,090 --> 01:12:09,425
RESERVOIR.

1865
01:12:09,425 --> 01:12:11,794
SO TOGETHER THIS DATA REALLY

1866
01:12:11,794 --> 01:12:15,965
PROVIDE THE RATIONALE TO

1867
01:12:15,965 --> 01:12:17,400
TARGET IL10 SIGNALING IN

1868
01:12:17,400 --> 01:12:20,469
COMBINATION WITH THE --

1869
01:12:20,469 --> 01:12:20,770
BLOCKADE.

1870
01:12:20,770 --> 01:12:22,839
THIS IS WHAT WE DID IN THIS

1871
01:12:22,839 --> 01:12:25,908
STUDY CO-LED WITH -- AND

1872
01:12:25,908 --> 01:12:28,077
COLLABORATOR MERCK WHERE WE

1873
01:12:28,077 --> 01:12:30,680
INFECTED 28 RHESUS MACAQUES

1874
01:12:30,680 --> 01:12:34,450
WITH -- STARTED ANTIRETROVIRAL

1875
01:12:34,450 --> 01:12:35,184
THERAPY SIX WEEKS AFTER

1876
01:12:35,184 --> 01:12:36,385
INFECTION AND KEEP THE ANIMAL

1877
01:12:36,385 --> 01:12:37,987
ALIVE FOR 14 MONTHS BEFORE

1878
01:12:37,987 --> 01:12:38,754
STARTING INTERVENTION.

1879
01:12:38,754 --> 01:12:47,630
SO THE CONTROL IN BLACK -- AND

1880
01:12:47,630 --> 01:12:50,032
RECEIVE -- YOU CAN SEE WE

1881
01:12:50,032 --> 01:12:51,434
CONTINUE TO TREAT AFTER

1882
01:12:51,434 --> 01:12:53,402
INTERRUPTION UP TO 14 WEEKS.

1883
01:12:53,402 --> 01:12:55,404
AND I'M GOING TO SHOW ONLY ONE

1884
01:12:55,404 --> 01:12:58,641
RESULT BUT WHAT WE FOUND IS

1885
01:12:58,641 --> 01:13:02,345
THAT -- BLOCKADE IN BLUE HAVE

1886
01:13:02,345 --> 01:13:04,213
IMPORTANT CONTROL OF SEVERE

1887
01:13:04,213 --> 01:13:05,281
REPLICATION AFTER INTERRUPTION

1888
01:13:05,281 --> 01:13:08,317
WITH 90% OF THE ANIMAL HAVING AT

1889
01:13:08,317 --> 01:13:11,254
LEAST ONE BUT LARGELY MULTIPLE

1890
01:13:11,254 --> 01:13:15,091
TIME POINT -- A THOUSAND COPY.

1891
01:13:15,091 --> 01:13:16,392
THERE WAS NO EXPANSION OF THE

1892
01:13:16,392 --> 01:13:17,893
VIRAL RESERVOIR NEITHER IN THE

1893
01:13:17,893 --> 01:13:19,996
LYMPH NODE NOR THE BLOOD SO THE

1894
01:13:19,996 --> 01:13:23,599
CONTROL INCREASE -- AND IL10

1895
01:13:23,599 --> 01:13:24,233
BLOCKADE, THERE WAS NO

1896
01:13:24,233 --> 01:13:26,102
EXPANSION.

1897
01:13:26,102 --> 01:13:28,170
SO WE BELIEVE THESE ARE EXCITING

1898
01:13:28,170 --> 01:13:30,906
DATA, PROOF OF CONCEPT WE CAN --

1899
01:13:30,906 --> 01:13:33,175
TO CONTROL AT LEAST FOR SOME

1900
01:13:33,175 --> 01:13:34,610
TIME THESE REBOUNDING VIRUS

1901
01:13:34,610 --> 01:13:36,245
WHERE WE HAVE IMPORTANT

1902
01:13:36,245 --> 01:13:37,580
CHALLENGE WE TRY TO NOW SOLVE AS

1903
01:13:37,580 --> 01:13:40,716
PART OF THE NEXT -- SO ONE IS

1904
01:13:40,716 --> 01:13:41,050
SAFETY.

1905
01:13:41,050 --> 01:13:43,286
WE DO SEE SOME TOXICITY BY

1906
01:13:43,286 --> 01:13:45,721
BLOCKING THESE TWO IMPORTANT

1907
01:13:45,721 --> 01:13:46,522
REGULATOR OF THE IMMUNE SYSTEM,

1908
01:13:46,522 --> 01:13:49,225
SO WE NEED TO TRY TO REDUCE THE

1909
01:13:49,225 --> 01:13:51,427
SIDE EFFECTS.

1910
01:13:51,427 --> 01:13:53,362
AND A VERY IMPORTANT POINT OF

1911
01:13:53,362 --> 01:13:54,664
THE LONGEVITY OF THE RESPONSE.

1912
01:13:54,664 --> 01:13:56,866
SO THE DATA THAT I SHOWED UNTIL

1913
01:13:56,866 --> 01:13:59,869
NOW WAS UNTIL WEEK 24 --

1914
01:13:59,869 --> 01:14:01,470
INDICATED BY THESE BLACK LINE IN

1915
01:14:01,470 --> 01:14:02,305
THIS GRAPH.

1916
01:14:02,305 --> 01:14:05,908
SO WHEN THE DEPLETING --

1917
01:14:05,908 --> 01:14:07,510
BLOCKING -- WAS STILL IN THE

1918
01:14:07,510 --> 01:14:07,743
SYSTEM.

1919
01:14:07,743 --> 01:14:09,145
WE FOLLOWED THIS ANIMAL FOR MANY

1920
01:14:09,145 --> 01:14:10,379
MORE WEEKS AND AS YOU CAN SEE,

1921
01:14:10,379 --> 01:14:11,714
WE HAVE SOME ANIMALS THAT ROMAN

1922
01:14:11,714 --> 01:14:14,750
CATHRETURNTO A NORMAL SET POINTE

1923
01:14:14,750 --> 01:14:15,518
VIRAL LOAD GO BACK.

1924
01:14:15,518 --> 01:14:18,654
WE HAVE THREE ANIMAL --

1925
01:14:18,654 --> 01:14:20,623
REBOUNDED BUT MAINTAINING LOWER

1926
01:14:20,623 --> 01:14:21,857
VIREMIA AROUND A THOUSAND COPY

1927
01:14:21,857 --> 01:14:23,893
AND WE HAVE TWO ANIMALS THAT

1928
01:14:23,893 --> 01:14:26,729
FULLY CONTROL LESS THAN 15 COPY

1929
01:14:26,729 --> 01:14:28,698
DESPITE ONE YEAR OF --

1930
01:14:28,698 --> 01:14:29,565
INTERRUPTION.

1931
01:14:29,565 --> 01:14:30,967
INTERESTINGLY WE DECIDE TO

1932
01:14:30,967 --> 01:14:31,834
RETREAT THESE THREE ANIMALS THAT

1933
01:14:31,834 --> 01:14:33,602
WE ARE MAINTAINING LOW LEVEL OF

1934
01:14:33,602 --> 01:14:36,639
VIRAL LOAD FOR SIX MONTHS AND

1935
01:14:36,639 --> 01:14:39,909
WITH THE -- THREE DOSES -- AFTER

1936
01:14:39,909 --> 01:14:42,078
THE FIRST DOSE, 10 MONTHS AFTER

1937
01:14:42,078 --> 01:14:43,946
INTERRUPTION WE'RE STILL ABLE TO

1938
01:14:43,946 --> 01:14:45,047
COMPLETELY BLOCK VIRAL

1939
01:14:45,047 --> 01:14:46,749
REPLICATION LESS THAN 15 COPY.

1940
01:14:46,749 --> 01:14:49,185
SO ALL TOGETHER, THIS SHOWS WE

1941
01:14:49,185 --> 01:14:51,354
ARE ABLE TO TIP THE BALANCE

1942
01:14:51,354 --> 01:14:52,955
TOWARD IMMUNE CONTROL EVEN AFTER

1943
01:14:52,955 --> 01:14:53,856
ALMOST ONE YEAR OF INTERRUPTION,

1944
01:14:53,856 --> 01:14:55,491
BUT AGAIN AS YOU SEE, THOSE

1945
01:14:55,491 --> 01:14:57,593
ANIMALS REBOUND WHEN ANTIBODY --

1946
01:14:57,593 --> 01:15:00,963
SO WE NEED TO IMPROVE SAFETY AND

1947
01:15:00,963 --> 01:15:03,599
IMPROVE THE LONGEVITY OF THE

1948
01:15:03,599 --> 01:15:04,567
RESPONSE THAT IS CONTROLLING THE

1949
01:15:04,567 --> 01:15:05,101
VIRUS.

1950
01:15:05,101 --> 01:15:09,238
AND ONE WAY WE'RE TRYING TO DO

1951
01:15:09,238 --> 01:15:11,207
THIS IN THE NEXT GENERATIONAL

1952
01:15:11,207 --> 01:15:13,743
STUDY IS TO USE IL-21.

1953
01:15:13,743 --> 01:15:17,213
SO MY GROUP -- HAS BEEN SHOWN

1954
01:15:17,213 --> 01:15:20,049
THAT IL10 T1 IS ABLE TO REDUCE

1955
01:15:20,049 --> 01:15:22,752
INFLAMMATION BY IMPROVING --

1956
01:15:22,752 --> 01:15:24,487
INTEGRITY, SO THIS MAY BE

1957
01:15:24,487 --> 01:15:27,590
IMPORTANT AFTER INTERRUPTION AND

1958
01:15:27,590 --> 01:15:32,061
THOSE -- IMPORTANT TO EXPAND NK

1959
01:15:32,061 --> 01:15:41,137
CELLS THAT IS -- IL21 IS HIGHLY

1960
01:15:41,137 --> 01:15:42,872
SYNERGISTIC WITH -- BLOCKADE AND

1961
01:15:42,872 --> 01:15:46,041
ACTUALLY THE MECHANISM SEEMS TO

1962
01:15:46,041 --> 01:15:50,279
BE -- FAVOR THE LONG TERM

1963
01:15:50,279 --> 01:15:55,050
MAINTENANCE OF -- CELLS SO BASED

1964
01:15:55,050 --> 01:15:56,185
ON THIS DATA, THIS IS THE

1965
01:15:56,185 --> 01:15:57,386
ONGOING STUDY.

1966
01:15:57,386 --> 01:15:59,722
WE HAVE 32 ANIMALS DIVIDED IN

1967
01:15:59,722 --> 01:16:01,624
FOUR EXPERIMENTAL ARMS, 8 IN

1968
01:16:01,624 --> 01:16:03,926
EACH ARM, SO ONE GROUP IS ONLY

1969
01:16:03,926 --> 01:16:05,261
CONTROL WITH ANTIRETROVIRAL

1970
01:16:05,261 --> 01:16:06,462
THERAPY, ONE GROUP IS MIMICKING

1971
01:16:06,462 --> 01:16:08,631
THE PREVIOUS STUDY WITH IL10 AND

1972
01:16:08,631 --> 01:16:09,365
PD-1.

1973
01:16:09,365 --> 01:16:12,134
IN ONE GROUP WE ARE ALSO NOW

1974
01:16:12,134 --> 01:16:15,905
ADDING IL -- GENERATED BY THE

1975
01:16:15,905 --> 01:16:20,209
BLO A CADEBLOCKADE MAKING IT LOG

1976
01:16:20,209 --> 01:16:21,944
AND ONE GROUP TO TRY TO REDUCE

1977
01:16:21,944 --> 01:16:25,648
TOXICITY WE ARE ELIMINATING IL10

1978
01:16:25,648 --> 01:16:26,415
AND -- COMBINATION AND WE'RE

1979
01:16:26,415 --> 01:16:29,452
ALSO HAVING A QR AFTER

1980
01:16:29,452 --> 01:16:31,554
INTERRUPTION AND TREATMENT WITH

1981
01:16:31,554 --> 01:16:34,957
THE HOPE THAT IN THE SECOND

1982
01:16:34,957 --> 01:16:36,659
INTERRUPTION START WITH LOWER

1983
01:16:36,659 --> 01:16:37,326
RESERVOIR IMMUNE BASED

1984
01:16:37,326 --> 01:16:38,527
INTERVENTION MAY BE EVEN MORE

1985
01:16:38,527 --> 01:16:42,031
EFFECTIVE.

1986
01:16:42,031 --> 01:16:43,899
SO THE CONCLUSION AND COMMUNITY

1987
01:16:43,899 --> 01:16:45,167
SUMMARY, WE BELIEVE THAT CONTROL

1988
01:16:45,167 --> 01:16:47,269
OF HIV WILL REQUIRE COMBINED

1989
01:16:47,269 --> 01:16:48,804
APPROACH THAT TAKES INTO ACCOUNT

1990
01:16:48,804 --> 01:16:50,873
THE LARGE COMPLEXITY OF THE

1991
01:16:50,873 --> 01:16:52,708
PERSISTENT RESERVOIR, AND THAT

1992
01:16:52,708 --> 01:16:54,910
SIGNALING FOR NEGATIVE

1993
01:16:54,910 --> 01:16:55,978
REGULATOR, DATA FROM MANY IN

1994
01:16:55,978 --> 01:16:57,613
THIS AUDIENCE WHO WILL SPEAK AND

1995
01:16:57,613 --> 01:17:00,382
MANY OTHERS, CONTRIBUTE TO HIV

1996
01:17:00,382 --> 01:17:03,886
PERSISTENCE AND IN PARTICULAR

1997
01:17:03,886 --> 01:17:07,456
PD-1 AND IL-10 AND WE BRIEF THIE

1998
01:17:07,456 --> 01:17:11,694
THIS STUDY BY BLOCKING THESE

1999
01:17:11,694 --> 01:17:13,662
RECEPTORS WE CAN -- ABLE TO

2000
01:17:13,662 --> 01:17:14,763
CONTROL SIV.

2001
01:17:14,763 --> 01:17:16,298
AND AGAIN AS THINGS WE NEED TO

2002
01:17:16,298 --> 01:17:17,500
IMPROVE, LIMITING THE SIDE

2003
01:17:17,500 --> 01:17:19,468
EFFECTS AND INCREASING THE

2004
01:17:19,468 --> 01:17:21,637
LONGEVITY OF THE RESPONSE, AND

2005
01:17:21,637 --> 01:17:22,838
ANOTHER DIRECTION WE'RE

2006
01:17:22,838 --> 01:17:24,473
INVESTIGATING AS BRAD JUST

2007
01:17:24,473 --> 01:17:26,876
SHOWED IN DEANNA'S WORK, IL-10

2008
01:17:26,876 --> 01:17:28,511
ALSO SEEMS TO BE PART OF THE PRO

2009
01:17:28,511 --> 01:17:32,248
LATENCY MECHANISM OF CD8 T-CELLS

2010
01:17:32,248 --> 01:17:35,050
SO -- IMPROVING THE CD8 T-CELL

2011
01:17:35,050 --> 01:17:37,386
FUNCTION BUT ALSO REDUCING THE

2012
01:17:37,386 --> 01:17:38,821
PRO LATENCY ACTIVITY TO USE TO

2013
01:17:38,821 --> 01:17:39,155
OUR ADVANTAGE.

2014
01:17:39,155 --> 01:17:40,156
SO WITH THAT, I WOULD LIKE TO

2015
01:17:40,156 --> 01:17:43,092
THANK ALL THE KEY MEMBERS AND

2016
01:17:43,092 --> 01:17:44,426
COLLABORATORS OF THIS STUDY

2017
01:17:44,426 --> 01:17:45,060
LISTED ON THIS SLIDE.

2018
01:17:45,060 --> 01:17:46,362
I DON'T HAVE TIME TO GO OVER ALL

2019
01:17:46,362 --> 01:17:49,532
OF THEM BUT I WANT TO REALLY

2020
01:17:49,532 --> 01:17:51,934
HIGHLIGHT RAFIC, SUSAN, AND ALL

2021
01:17:51,934 --> 01:17:54,870
THE MEMBERS OF MY LAB AND CLAB

2022
01:17:54,870 --> 01:17:55,204
COLLABORATORS.

2023
01:17:55,204 --> 01:18:01,810
THANK YOU.

2024
01:18:01,810 --> 01:18:03,646
>> I CONTINUE WITH
INTERVENTIONS

2025
01:18:03,646 --> 01:18:07,716
THAT MAY BE USED TO REDUCE

2026
01:18:07,716 --> 01:18:08,918
THE -- VIRAL REBOUND.

2027
01:18:08,918 --> 01:18:12,621
I STARTED WITH ACKNOWLEDGMENT TO

2028
01:18:12,621 --> 01:18:13,155
COCOLLABORATORS AS WELL AS

2029
01:18:13,155 --> 01:18:13,923
PEOPLE IN THE LAB THAT HAVE

2030
01:18:13,923 --> 01:18:15,257
CONTRIBUTED TO THE WORK THAT I'M

2031
01:18:15,257 --> 01:18:16,859
GOING TO BE SHOWING.

2032
01:18:16,859 --> 01:18:18,627
TO VERY BRIEFLY SUM UP THE

2033
01:18:18,627 --> 01:18:20,396
COMMUNITY SLIDE, WE ARE TESTING

2034
01:18:20,396 --> 01:18:22,765
IF WE ARE LOOKING AT A NEW MORE

2035
01:18:22,765 --> 01:18:25,935
IMPORTANT MOLECULE WHICH HAS THE

2036
01:18:25,935 --> 01:18:27,570
ABILITY TO SENSITIZE HIV

2037
01:18:27,570 --> 01:18:32,274
INFECTED CELLS TO KILLING BY

2038
01:18:32,274 --> 01:18:36,078
WEEK -- MOST PEOPLE WITH HIV.

2039
01:18:36,078 --> 01:18:39,381
WE HAVE TESTED THIS MOLECULE IN

2040
01:18:39,381 --> 01:18:41,417
HUMANIZED MOUSE STUDY AND FIND

2041
01:18:41,417 --> 01:18:44,820
IT REDUCES THE RESERVOIR.

2042
01:18:44,820 --> 01:18:47,990
 -- CLOSED OR -- INACCESSIBLE TO

2043
01:18:47,990 --> 01:18:48,991
ANTIBODIES THAT BIND TO THE

2044
01:18:48,991 --> 01:18:50,826
CLUSTER A DOMAIN OF THE

2045
01:18:50,826 --> 01:18:52,461
CORECEPTOR-BINDING SITE.

2046
01:18:52,461 --> 01:18:56,398
EXPOSURE OF THIS GP120 TO SMALL

2047
01:18:56,398 --> 01:18:59,034
MOLECULES -- OPENS UP THE

2048
01:18:59,034 --> 01:19:00,569
ENVELOPE TO CONFIRMATION THAT

2049
01:19:00,569 --> 01:19:02,738
CAN ENABLE BINDING TO THESE

2050
01:19:02,738 --> 01:19:04,173
ANTIBODIES BY EXPOSING THESE

2051
01:19:04,173 --> 01:19:05,874
EPITOPES.

2052
01:19:05,874 --> 01:19:07,343
THESE ANTIBODIES WHICH ARE ALSO

2053
01:19:07,343 --> 01:19:12,247
CALLED CD4 INDUCED ANTI ANTIBODS

2054
01:19:12,247 --> 01:19:16,552
CAN NOW ELICIT IMMUNE CELLS --

2055
01:19:16,552 --> 01:19:17,519
THAT LEAD TO TARGETED

2056
01:19:17,519 --> 01:19:18,387
DESTRUCTION OF THE INFECTED

2057
01:19:18,387 --> 01:19:18,954
CELL.

2058
01:19:18,954 --> 01:19:20,923
SO IN RECENTLY PUBLISHED STUDY,

2059
01:19:20,923 --> 01:19:23,125
OUR GROUP HAS REPORTED THE

2060
01:19:23,125 --> 01:19:25,961
DEVELOPMENT OF NOVEL AND MORE

2061
01:19:25,961 --> 01:19:30,699
POTENT CD4 -- LONGING TO THE --

2062
01:19:30,699 --> 01:19:34,203
COMPOUNDS, COMPARED TO THE LEAD

2063
01:19:34,203 --> 01:19:39,441
COMPOUND OF THE PREVIOUS CLASS,

2064
01:19:39,441 --> 01:19:41,610
REFERRING TO CJF IN MY TALK WAS

2065
01:19:41,610 --> 01:19:44,780
FOUND TO BE MORE POTENT AND HAS

2066
01:19:44,780 --> 01:19:46,649
BROAD -- AGAINST VARIETY OF HIV

2067
01:19:46,649 --> 01:19:48,183
VIRUS STRAINS BELONGING TO

2068
01:19:48,183 --> 01:19:53,522
SEVERAL CLADES, AND ALSO COULD

2069
01:19:53,522 --> 01:19:56,825
MEDIATE UTILIZATION -- 117.

2070
01:19:56,825 --> 01:19:58,260
SO IN VITRO DATA WHICH IS SHOWN

2071
01:19:58,260 --> 01:20:02,631
IN BLUE HERE, THE CGF3 ALONG

2072
01:20:02,631 --> 01:20:04,266
WITH -- COULD VERY EASILY ELICIT

2073
01:20:04,266 --> 01:20:06,869
KILLING OF INFECTED CD4 T-CELLS

2074
01:20:06,869 --> 01:20:10,039
IN THE PLASMA FROM HIV INFECTED

2075
01:20:10,039 --> 01:20:11,807
INDIVIDUALS AND DID THIS MUCH

2076
01:20:11,807 --> 01:20:15,878
BETTER THAN BNM-III170 SHOWN IN

2077
01:20:15,878 --> 01:20:16,612
PURPLE.

2078
01:20:16,612 --> 01:20:17,613
INTERESTINGLY IT COULD MEDIATE

2079
01:20:17,613 --> 01:20:19,782
WITH THE HELP OF ONLY ONE CLASS

2080
01:20:19,782 --> 01:20:22,951
OF ANTIBODIES WITH THE

2081
01:20:22,951 --> 01:20:27,890
CORECEPTOR-BINDING SITE.

2082
01:20:27,890 --> 01:20:31,794
SO -- HUMANIZED MICE -- STRAIN

2083
01:20:31,794 --> 01:20:34,096
THAT ENABLES EFFECTOR FUNCTIONS,

2084
01:20:34,096 --> 01:20:37,266
THE IDEA WAS TO TREAT THESE MICE

2085
01:20:37,266 --> 01:20:40,002
WHICH WERE WILDLY SUPPRESSED

2086
01:20:40,002 --> 01:20:41,136
WITH ANTIRETROVIRAL THERAPY, AT

2087
01:20:41,136 --> 01:20:43,305
THE TIME -- OR AT THE TIME OF

2088
01:20:43,305 --> 01:20:45,474
INITIATION OF ART, AND LOOK AT

2089
01:20:45,474 --> 01:20:46,875
VIRUS REBOUND WITH TIME UNDER

2090
01:20:46,875 --> 01:20:48,310
THE IMPRESSION -- UNDER THE

2091
01:20:48,310 --> 01:20:51,347
ASSUMPTION THAT TIME TO -- IS

2092
01:20:51,347 --> 01:20:52,681
CORRELATED WITH THE SIZE OF THE

2093
01:20:52,681 --> 01:20:53,549
VIRAL RESERVOIR.

2094
01:20:53,549 --> 01:20:54,783
THE DATA I'M GOING TO SHOW YOU

2095
01:20:54,783 --> 01:20:56,185
IN THE NEXT FEW SLIDES ARE

2096
01:20:56,185 --> 01:20:57,252
PRELIMINARY AND ARE CURRENTLY

2097
01:20:57,252 --> 01:20:58,554
BEING EXPANDED ON IN EXPERIMENTS

2098
01:20:58,554 --> 01:20:59,221
IN THE LAB.

2099
01:20:59,221 --> 01:21:01,623
THIS IS THE DATA WITH MICE

2100
01:21:01,623 --> 01:21:05,260
TREATED AT THE TIME OF

2101
01:21:05,260 --> 01:21:06,095
ANTIRETROVIRAL WITHDRAWAL, FOUND

2102
01:21:06,095 --> 01:21:07,763
THAT THE VIRUS REBOUNDS IN THESE

2103
01:21:07,763 --> 01:21:09,998
MICE BY ABOUT THREE TO FIVE DAYS

2104
01:21:09,998 --> 01:21:11,600
POST TREATMENT AND THESE ARE

2105
01:21:11,600 --> 01:21:12,434
CONTROLLED COHORTS.

2106
01:21:12,434 --> 01:21:16,939
WHEN MICE WERE TREATED WITH

2107
01:21:16,939 --> 01:21:19,675
CJF-III IN COMBINATION WE FOUND

2108
01:21:19,675 --> 01:21:21,543
THE TIME TO REBOUND COULD BE

2109
01:21:21,543 --> 01:21:24,379
DELAYED BY ABOUT THREE WEEKS

2110
01:21:24,379 --> 01:21:27,449
POST ANTIRETROVIRAL WITHDRAWAL

2111
01:21:27,449 --> 01:21:28,217
INDICATING THERE WAS AN EFFECT

2112
01:21:28,217 --> 01:21:28,984
ON THE RESERVOIR.

2113
01:21:28,984 --> 01:21:30,719
WE THEN PERFORMED THE EXPERIMENT

2114
01:21:30,719 --> 01:21:32,488
IN MICE THAT WERE TREATED AT THE

2115
01:21:32,488 --> 01:21:34,223
TIME OF ANTIRETROVIRAL THERAPY.

2116
01:21:34,223 --> 01:21:36,225
WHILE THIS DID NOT AFFECT THE

2117
01:21:36,225 --> 01:21:38,494
REBOUND KINETICS IN CONTROL MICE

2118
01:21:38,494 --> 01:21:40,362
EITHER MOCK TREATED OR TREATED

2119
01:21:40,362 --> 01:21:42,564
WITH CJF-III, WE FOUND

2120
01:21:42,564 --> 01:21:43,766
INTERESTING DIFFERENCES IN MICE

2121
01:21:43,766 --> 01:21:45,267
TREATED WITH CJF AND THE

2122
01:21:45,267 --> 01:21:46,268
COMBINATION OF ANTIBODIES.

2123
01:21:46,268 --> 01:21:49,438
I SHOW HERE THE DATA IN THREE

2124
01:21:49,438 --> 01:21:50,205
INDEPENDENT MICE.

2125
01:21:50,205 --> 01:21:52,174
IN MOUSE NUMBER ONE ON YOUR

2126
01:21:52,174 --> 01:21:53,909
EXTREME LEVEL PANEL, DELAYED

2127
01:21:53,909 --> 01:21:56,111
VIRAL REBOUND BY ABOUT

2128
01:21:56,111 --> 01:21:57,312
1.5 MONTHS POST ANTIRETROVIRAL

2129
01:21:57,312 --> 01:21:58,614
WITHDRAWAL.

2130
01:21:58,614 --> 01:22:01,350
AND IN THE OTHER MICE, WE COULD

2131
01:22:01,350 --> 01:22:03,986
SEE THAT VIRAL REBOUND WAS

2132
01:22:03,986 --> 01:22:05,454
DURABLY SUPPRESSED FOR UP TO

2133
01:22:05,454 --> 01:22:07,489
FOUR MONTHS POST ART WITHDRAWAL

2134
01:22:07,489 --> 01:22:10,893
DESPITE THE APPEARANCE OF BLIPS,

2135
01:22:10,893 --> 01:22:12,294
AND -- FOUR MONTHS POST

2136
01:22:12,294 --> 01:22:14,696
WITHDRAWAL BUT THERE WAS

2137
01:22:14,696 --> 01:22:16,131
EXTENDED DELAY IN THE VIRAL

2138
01:22:16,131 --> 01:22:22,271
REBOUND EVEN IN TERMS OF BLIPS.

2139
01:22:22,271 --> 01:22:25,007
 -- FIVE DAYS POST WITHDRAWAL WE

2140
01:22:25,007 --> 01:22:26,642
FOUND VIRAL DNA LEVELS WERE

2141
01:22:26,642 --> 01:22:28,076
HUGELY REDUCED IN MOST OF THE

2142
01:22:28,076 --> 01:22:30,446
TISSUES.

2143
01:22:30,446 --> 01:22:32,347
WHEN WE LOOK AT TIME TO REBOUND,

2144
01:22:32,347 --> 01:22:34,116
WE ALSO CONDUCTED THIS

2145
01:22:34,116 --> 01:22:36,618
EXPERIMENT WITH CJF -- WITH THE

2146
01:22:36,618 --> 01:22:40,022
MICE TREATED WITH CJF AND ONLY

2147
01:22:40,022 --> 01:22:40,689
THE -- ANTIBODY.

2148
01:22:40,689 --> 01:22:42,758
THIS IS SHOWN IN MAGENTA.

2149
01:22:42,758 --> 01:22:44,827
EVEN THIS ALLOWED DELAY IN VIER

2150
01:22:44,827 --> 01:22:46,128
REBOUND BUT OUR BEST EFFECTS

2151
01:22:46,128 --> 01:22:48,897
WERE SEEP WITH CJF IN

2152
01:22:48,897 --> 01:22:50,065
COMBINATION WITH TWO ANTIBODIES.

2153
01:22:50,065 --> 01:22:51,633
SO ESSENTIALLY TIME TO REBOUND,

2154
01:22:51,633 --> 01:22:53,135
WE CONCLUDE TIME TO REBOUND IS

2155
01:22:53,135 --> 01:22:55,204
DEPENDENT ON TREATMENT -- IS

2156
01:22:55,204 --> 01:22:56,939
BETTER WHEN TREATED AT

2157
01:22:56,939 --> 01:22:59,041
INITIATION OF ART AND WITH THE

2158
01:22:59,041 --> 01:23:01,009
COMBINATION OF ANTIBODIES.

2159
01:23:01,009 --> 01:23:03,512
SO SUMMARY -- SIGNIFICANTLY

2160
01:23:03,512 --> 01:23:05,180
DELAYS VIRAL REBOUND.

2161
01:23:05,180 --> 01:23:09,117
CJF CAN EXERT THESE EFFECTS WITH

2162
01:23:09,117 --> 01:23:14,690
ONLY -- AND TREATMENT WITH

2163
01:23:14,690 --> 01:23:16,525
CJF-THREE-288/CD4I ANTIBODIES

2164
01:23:16,525 --> 01:23:18,727
SIGNIFICANTLY REDUCES THE

2165
01:23:18,727 --> 01:23:20,162
RESERVOIR SIZE.

2166
01:23:20,162 --> 01:23:21,930
SO THIS IS MY ACKNOWLEDGMENT

2167
01:23:21,930 --> 01:23:22,865
SLIDE AND THANK YOU FOR YOUR

2168
01:23:22,865 --> 01:23:23,332
ATTENTION.

2169
01:23:23,332 --> 01:23:26,301
[APPLAUSE]

2170
01:23:26,301 --> 01:23:28,570
>>

2171
01:23:28,570 --> 01:23:30,539
>> IN THE NEXT 10 MINUTES
OR SO,

2172
01:23:30,539 --> 01:23:33,175
I'M GOING TO TALK ABOUT THE BCLN

2173
01:23:33,175 --> 01:23:36,979
IN MY LAB AND IN MIRKO'S LAB

2174
01:23:36,979 --> 01:23:39,748
WITH TOMAS.

2175
01:23:39,748 --> 01:23:40,415
BCL2 INHIBITORS HAVE SHOWN

2176
01:23:40,415 --> 01:23:41,850
PROMISE TOWARDS REDUCING

2177
01:23:41,850 --> 01:23:44,253
RESERVOIR SIZE AND WE ASK WHAT'S

2178
01:23:44,253 --> 01:23:45,654
ITS INFECT IN VITRO MODELS AND

2179
01:23:45,654 --> 01:23:46,855
WHAT ARE REASONS WHY IT MIGHT

2180
01:23:46,855 --> 01:23:47,623
NOT WORK.

2181
01:23:47,623 --> 01:23:49,825
SO THIS WORK BEGINS ALMOST 20

2182
01:23:49,825 --> 01:23:52,094
YEARS AGO WHEN WE STARTED WITH

2183
01:23:52,094 --> 01:23:53,328
THE OBSERVATION THAT HIV

2184
01:23:53,328 --> 01:23:54,630
PROTEASE WHEN EXPRESSED IN ANY

2185
01:23:54,630 --> 01:23:55,731
CELL KILLS THAT CELL.

2186
01:23:55,731 --> 01:23:57,032
AND WE THOUGHT THAT WAS AN

2187
01:23:57,032 --> 01:23:58,367
IMPORTANT LEAD SO WE DECIDED TO

2188
01:23:58,367 --> 01:23:59,868
TRACK DOWN THE PATHWAY.

2189
01:23:59,868 --> 01:24:04,473
WE FOUND OUT THAT IF YOU KNOCK

2190
01:24:04,473 --> 01:24:07,643
OUT CASPASE 8, THEREFORE LIKELY

2191
01:24:07,643 --> 01:24:09,611
A TARGET AND WE FOUND OUT THE

2192
01:24:09,611 --> 01:24:11,680
CLEAVAGE SITE WITHIN CASPASE

2193
01:24:11,680 --> 01:24:12,814
8 THAT LEADS TO THE CLEAVAGE

2194
01:24:12,814 --> 01:24:15,083
WHICH RESULTS IN A FRAGMENT

2195
01:24:15,083 --> 01:24:19,454
CALLED CASP8P41.

2196
01:24:19,454 --> 01:24:22,324
IT DOES NOT CONTAIN A CATALYTIC

2197
01:24:22,324 --> 01:24:23,392
CYSTINE DOMAIN BUT IT STILL

2198
01:24:23,392 --> 01:24:25,327
KILLS THE CELL, SO WE MAPPED

2199
01:24:25,327 --> 01:24:27,262
WHAT ARE THE PROTEINS THAT IT

2200
01:24:27,262 --> 01:24:28,363
ASSOCIATES WITH TO RESULT IN

2201
01:24:28,363 --> 01:24:29,564
CELL DEATH AND WE FOUND OUT THAT

2202
01:24:29,564 --> 01:24:31,767
THE PROTEIN IT BINDS TO TO CAUSE

2203
01:24:31,767 --> 01:24:34,803
CELL DEATH IS CALLED BAC.

2204
01:24:34,803 --> 01:24:36,138
WE WORK WOULD WITH SOME

2205
01:24:36,138 --> 01:24:37,306
STRUCTURAL BIOLOGISTS TO FIND

2206
01:24:37,306 --> 01:24:39,174
HOW THIS IS POSSIBLE AND THEY

2207
01:24:39,174 --> 01:24:40,642
SHOWED THE ALPHA HELICAL DOMAIN

2208
01:24:40,642 --> 01:24:42,244
IS FORMED WITHIN THE CLEAVE

2209
01:24:42,244 --> 01:24:43,478
PROTEIN, NOT THE FULL LENGTH

2210
01:24:43,478 --> 01:24:45,981
PROTEIN AND THAT BINDS AND

2211
01:24:45,981 --> 01:24:48,050
ACTIVATES BAK WHICH IS A PRO

2212
01:24:48,050 --> 01:24:49,351
APOPTOTIC BCL2 FAMILY MEMBER

2213
01:24:49,351 --> 01:24:51,653
THAT CAUSES POOR FORMATION AND

2214
01:24:51,653 --> 01:24:52,988
SUBSEQUENTLY CELL DEATH.

2215
01:24:52,988 --> 01:24:56,592
SO THEN WE ASKED WHY IS IT THE

2216
01:24:56,592 --> 01:25:01,196
CASPASE 8P41 DOESN'T KILL ALL

2217
01:25:01,196 --> 01:25:03,598
CELLS?

2218
01:25:03,598 --> 01:25:05,000
IT CAN ALSO BIND TO OTHER

2219
01:25:05,000 --> 01:25:07,869
PROTEINS WHICH HAVE THE GROOVE

2220
01:25:07,869 --> 01:25:10,706
THAT BINDS, THAT'S CALLED THE

2221
01:25:10,706 --> 01:25:11,139
BH3 GROOVE.

2222
01:25:11,139 --> 01:25:14,009
THOSE INCLUDE THE ANTIA POP TO

2223
01:25:14,009 --> 01:25:16,078
TICK PROTEINS.

2224
01:25:16,078 --> 01:25:18,380
SO THIS ALLOWED US TO PROPOSE

2225
01:25:18,380 --> 01:25:20,582
THE MODEL THAT WHETHER YOU

2226
01:25:20,582 --> 01:25:22,417
REACTIVATE OR REP TI KATE HIV

2227
01:25:22,417 --> 01:25:26,321
YOU CREATE PROTEASE, A CLEAVES,

2228
01:25:26,321 --> 01:25:28,357
BINDS TO ONE OF TWO TARGETS,

2229
01:25:28,357 --> 01:25:30,959
EITHER BCL2 IN WHICH CASE THE

2230
01:25:30,959 --> 01:25:32,828
CELL SURVIVES, OR BAK IN WHICH

2231
01:25:32,828 --> 01:25:34,029
CASE THE CELL DIES.

2232
01:25:34,029 --> 01:25:36,331
THIS GIVES THE POTENTIAL FOR

2233
01:25:36,331 --> 01:25:36,965
INTERVENTION.

2234
01:25:36,965 --> 01:25:37,633
THE FIRST INTERVENTION IS YOU

2235
01:25:37,633 --> 01:25:40,569
COULD BLOCK THE ABILITY OF

2236
01:25:40,569 --> 01:25:44,840
CASPASE 8P41 TO BIND TO, THE

2237
01:25:44,840 --> 01:25:46,274
OTHER POSSIBILITY IS YOU CAN

2238
01:25:46,274 --> 01:25:52,180
CAUSE CASPASE 8P41 LEVELS -- NOW

2239
01:25:52,180 --> 01:25:53,615
ENTERING PHASE TWO CLINICAL

2240
01:25:53,615 --> 01:25:55,150
TRIALS WITH ATCG.

2241
01:25:55,150 --> 01:25:58,820
SHOWN ON THE RIGHT IS RESULTS --

2242
01:25:58,820 --> 01:26:01,356
IN THE MIDDLE PANEL YOU SEE IF

2243
01:26:01,356 --> 01:26:03,992
YOU TRANSFECT A CELL IN THE

2244
01:26:03,992 --> 01:26:05,427
PRESENCE, ROUGHLY 50% OF THE

2245
01:26:05,427 --> 01:26:07,162
CELLS DIE.

2246
01:26:07,162 --> 01:26:08,463
WHEREAS IF YOU TRANS EFFECT

2247
01:26:08,463 --> 01:26:11,900
CELLS WITH GFP CASPASE 8P41 IN

2248
01:26:11,900 --> 01:26:13,301
THE PRESENCE, NOW ABOUT 80% OF

2249
01:26:13,301 --> 01:26:15,937
THE CELLS DIE.

2250
01:26:15,937 --> 01:26:18,573
SO IT AUGMENTS THE ABILITY OF

2251
01:26:18,573 --> 01:26:20,642
CASPASE 8P41 TO KILL CELLS.

2252
01:26:20,642 --> 01:26:22,944
WE THEN WENT ON AND OUR GROUP

2253
01:26:22,944 --> 01:26:25,547
AND OTHER GROUPS HAVE LOOKED AT

2254
01:26:25,547 --> 01:26:26,882
THE EFFECT ON CELL KILLING IN A

2255
01:26:26,882 --> 01:26:28,350
VARIETY OF MODELS.

2256
01:26:28,350 --> 01:26:30,752
THIS IS IN AN ACUTE INFECTION

2257
01:26:30,752 --> 01:26:33,155
MODEL, THIS IS IN A HOMEOSTATIC

2258
01:26:33,155 --> 01:26:33,922
PROLIFERATION MODEL AND THIS IS

2259
01:26:33,922 --> 01:26:42,130
IN AN IN VIVO HUME HUGH HUMANIZE

2260
01:26:42,130 --> 01:26:43,098
MODEL.

2261
01:26:43,098 --> 01:26:47,269
IN THIS INCIDENCE, VENETOC LAX

2262
01:26:47,269 --> 01:26:48,770
INCREASES THE NUMBER OF MICE

2263
01:26:48,770 --> 01:26:53,208
WITH UNDETECTABLE RESERVOIR SI 

2264
01:26:53,208 --> 01:26:54,943
SIZE.

2265
01:26:54,943 --> 01:26:56,711
TOMAS IN MIRKO'S LAST WENT ON TO

2266
01:26:56,711 --> 01:26:59,081
DO THIS STUDY IN THE LAST

2267
01:26:59,081 --> 01:27:00,749
ITERATION OF THE ERASE WHERE WE

2268
01:27:00,749 --> 01:27:05,654
DID AN S AN SID STUDY WHERE MICE

2269
01:27:05,654 --> 01:27:08,390
TREATED WITH EARLY ART, EARLY

2270
01:27:08,390 --> 01:27:11,993
ART PLUS VENETOC LAX OR

2271
01:27:11,993 --> 01:27:12,360
CD8 DEPLETION.

2272
01:27:12,360 --> 01:27:14,196
THE RATIONALE FOR THE

2273
01:27:14,196 --> 01:27:15,397
CD8 DEPLETION WAS MENTIONED BY

2274
01:27:15,397 --> 01:27:16,398
DAVE MARGOLIS IN HIS

2275
01:27:16,398 --> 01:27:17,799
PRESENTATION IN THAT IT ACTS AS

2276
01:27:17,799 --> 01:27:24,539
AN LRA EFFECT.

2277
01:27:24,539 --> 01:27:25,807
WHAT WAS SHOWN IN THIS STUDY IS

2278
01:27:25,807 --> 01:27:27,709
THE VENATOCLAX ALONE ALTERS THE

2279
01:27:27,709 --> 01:27:29,678
DECAY RATE OF VIRAL PLASMA LOAD.

2280
01:27:29,678 --> 01:27:31,980
THERE'S A MINIMAL DIFFERENCE

2281
01:27:31,980 --> 01:27:34,983
BETWEEN VENATOCLAX PLUS CD8 IN

2282
01:27:34,983 --> 01:27:36,251
THAT THERE ARE TWO POSSIBILITIES

2283
01:27:36,251 --> 01:27:38,854
AS TO WHY THIS DECAY RATE IS

2284
01:27:38,854 --> 01:27:39,154
DIFFERENT.

2285
01:27:39,154 --> 01:27:40,722
ONE OF WHICH IS THAT THERE'S

2286
01:27:40,722 --> 01:27:42,424
DELAYED ESTABLISHMENT OF THE HIV

2287
01:27:42,424 --> 01:27:43,825
RESERVOIR SIZE.

2288
01:27:43,825 --> 01:27:45,927
SO THE GROUP WENT ON TO ANALYZE

2289
01:27:45,927 --> 01:27:48,563
HIV RESERVOIR SIZE BY IPDA

2290
01:27:48,563 --> 01:27:49,564
MEASUREMENT, AND WHAT YOU CAN

2291
01:27:49,564 --> 01:27:53,835
SEE IS THAT IPDA MESH MANAGEMENT

2292
01:27:53,835 --> 01:27:56,438
RESULTS IN LOWER RESERVOIR SIZE

2293
01:27:56,438 --> 01:27:58,740
IN THE VENATOCLAX-TREATED GROUP,

2294
01:27:58,740 --> 01:28:00,175
EXPRESSES TOTAL NUMBER OF

2295
01:28:00,175 --> 01:28:03,478
COPIES, OR AS EXPRESSED BY PER

2296
01:28:03,478 --> 01:28:04,146
ML OF BLOOD.

2297
01:28:04,146 --> 01:28:05,447
SO NOW WE'VE SEEN IN A VARIETY

2298
01:28:05,447 --> 01:28:07,849
OF MODELS THAT VENATOCLAX HAS A

2299
01:28:07,849 --> 01:28:09,918
BENEFICIAL EFFECT, AND BY SHEER

2300
01:28:09,918 --> 01:28:12,020
COINCIDENCE, THE GROUP OUT OF

2301
01:28:12,020 --> 01:28:14,422
AUSTRALIA WITH SHARON LUEN AND

2302
01:28:14,422 --> 01:28:16,491
OTHERS JUST PUBLISHED A PAPER

2303
01:28:16,491 --> 01:28:18,260
LOOKING AT THE EFFECT IN CHRONIC

2304
01:28:18,260 --> 01:28:20,562
INFECTION ALONG WITH ART IN A

2305
01:28:20,562 --> 01:28:21,663
HUMANIZED MODEL WHERE THEY

2306
01:28:21,663 --> 01:28:23,431
SHOWED CONCEPTUALLY SIMILAR

2307
01:28:23,431 --> 01:28:25,066
EFFECTS, DELAYED VIRAL REBOUND

2308
01:28:25,066 --> 01:28:27,369
AS A RESULT OF VENATOCLAX

2309
01:28:27,369 --> 01:28:32,073
TREATMENT FOMMINGTREATMENT FOLLL

2310
01:28:32,073 --> 01:28:32,440
REBOUND.

2311
01:28:32,440 --> 01:28:37,045
WE THEN HAD THE INTEREST OF

2312
01:28:37,045 --> 01:28:44,586
LOOKING -- SUGGESTS THAT

2313
01:28:44,586 --> 01:28:46,321
FOLLOWING REACTIVATION FROM

2314
01:28:46,321 --> 01:28:48,423
LATENCY OF THE CASPASE 8P41

2315
01:28:48,423 --> 01:28:50,392
PATHWAY SHOULD BE INVOKED SO WE

2316
01:28:50,392 --> 01:28:51,826
WENT ON AND TESTED THAT AND WE

2317
01:28:51,826 --> 01:28:53,862
DID, IN FACT, SHOW THAT CASPASE

2318
01:28:53,862 --> 01:28:55,797
8P41 IS EXPRESSED IN A LATENT

2319
01:28:55,797 --> 01:28:57,098
CELL POPULATION FOLLOWING

2320
01:28:57,098 --> 01:28:58,633
REACTIVATION FROM LATENCY, AND

2321
01:28:58,633 --> 01:29:00,368
THEN WE WANTED TO TEST

2322
01:29:00,368 --> 01:29:02,804
VENATOCLAX IN THAT MODEL.

2323
01:29:02,804 --> 01:29:04,105
WE FIRST DID THIS SOME NUMBER OF

2324
01:29:04,105 --> 01:29:08,176
YEARS AGO USING BULK PRIMARY

2325
01:29:08,176 --> 01:29:09,811
PVMCs OF HIV INFECTED SUBJECTS

2326
01:29:09,811 --> 01:29:12,347
AND WE WERE ABLE TO SHOW IN THE

2327
01:29:12,347 --> 01:29:13,882
MAJORITY OF PATIENTS RESERVOIR

2328
01:29:13,882 --> 01:29:15,283
SIDE WAS INDUCED.

2329
01:29:15,283 --> 01:29:17,152
BRAD AND HIS TEAM DID A SIMILAR

2330
01:29:17,152 --> 01:29:19,821
STUDY USING CD4s WITH AND

2331
01:29:19,821 --> 01:29:23,191
WITHOUT CTLs AND SHOWED THAT

2332
01:29:23,191 --> 01:29:25,727
WITH CTLs AND VENATOCLAX,

2333
01:29:25,727 --> 01:29:36,404
RESERVOIR SEI SIZE IS REDUCED.

2334
01:29:37,706 --> 01:29:40,041
AND TRAIL MEDIATED PATHWAYS.

2335
01:29:40,041 --> 01:29:42,143
SO VENETOCLAX HAS BEEN USED

2336
01:29:42,143 --> 01:29:44,980
EXTENSIVELY IN HEMATOLOGIC

2337
01:29:44,980 --> 01:29:46,648
MALIGNANCIES, MOST NOTABLY CLL.

2338
01:29:46,648 --> 01:29:47,849
THERE ARE PATIENTS WHO HAVE BEEN

2339
01:29:47,849 --> 01:29:49,150
TREATED FOR 8-PLUS YEARS AND

2340
01:29:49,150 --> 01:29:50,552
THEY DO WONDERFULLY WITH IT AND

2341
01:29:50,552 --> 01:29:51,920
IN THE MAJORITY OF CASES, IT

2342
01:29:51,920 --> 01:29:52,220
WORKS.

2343
01:29:52,220 --> 01:29:53,521
BUT IN THE MINORITY OF CASES, IT

2344
01:29:53,521 --> 01:29:54,990
DOES NOT WORK, AND SO A LOT OF

2345
01:29:54,990 --> 01:29:56,057
INTEREST HAS GONE INTO WHY

2346
01:29:56,057 --> 01:29:57,726
DOESN'T IT WORK, AND WHAT WE

2347
01:29:57,726 --> 01:29:59,461
KNOW IS THAT THERE CAN BE

2348
01:29:59,461 --> 01:30:03,298
SOMATIC MUTATION THAT CAUSES

2349
01:30:03,298 --> 01:30:04,933
MUTATIONS WITHIN BCL2 BUT ALSO

2350
01:30:04,933 --> 01:30:06,901
THERE CAN BE PHOSPHORYLATION

2351
01:30:06,901 --> 01:30:08,036
EVENTS WITHIN BCL2.

2352
01:30:08,036 --> 01:30:11,072
IF YOU LOOK AT IT

2353
01:30:11,072 --> 01:30:12,073
MECHANISTICALLY, THIS IS A

2354
01:30:12,073 --> 01:30:14,709
RIBBON STRUCK TOOR OF CASPASE

2355
01:30:14,709 --> 01:30:18,513
8P41 BINDING TO BCL2, THIS IS

2356
01:30:18,513 --> 01:30:21,383
VENETOCLAX BINDING TO BCL2 AND

2357
01:30:21,383 --> 01:30:24,119
THEY BIND TO THE SAME REGION.

2358
01:30:24,119 --> 01:30:25,987
SO WE -- DOES THAT ALTER THE

2359
01:30:25,987 --> 01:30:28,623
ABILITY OF VENETOCLAX TO WORK

2360
01:30:28,623 --> 01:30:33,662
AND DOES IT ALTER THE ABILITY OF

2361
01:30:33,662 --> 01:30:36,731
CASP8P41 TO WORK?

2362
01:30:36,731 --> 01:30:45,373
WE TOOK -- WITH CELLS THAT

2363
01:30:45,373 --> 01:30:47,008
EXPRESS PHOSPHOMIMICS OF BCL2,

2364
01:30:47,008 --> 01:30:50,645
SO WHEN YOU DO A SERINE THAT

2365
01:30:50,645 --> 01:30:52,614
MIMICS PHOSPHORYLATION EVENT, IF

2366
01:30:52,614 --> 01:30:55,950
YOU DO A SERINE E2 THAT CREATES

2367
01:30:55,950 --> 01:30:56,685
A PHOSPHORESISTANT FORM.

2368
01:30:56,685 --> 01:30:58,853
SO SHOWN HERE IS A KNOCKOUT IS

2369
01:30:58,853 --> 01:31:00,088
MISSING BCL-2.

2370
01:31:00,088 --> 01:31:03,124
THESE ARE ALL THE OTHER

2371
01:31:03,124 --> 01:31:03,625
PHOSPHORYLATION EVENTS.

2372
01:31:03,625 --> 01:31:07,062
CAN YOU SEE A SLIGHT SHIFT

2373
01:31:07,062 --> 01:31:08,063
UPWARD CONSISTENT WITH THE

2374
01:31:08,063 --> 01:31:08,963
PHOSPHORYLATION EVENT AND WE

2375
01:31:08,963 --> 01:31:10,365
ASKED WHAT EFFECT DOES THIS HAVE

2376
01:31:10,365 --> 01:31:12,434
ON THE NUMBER OF INFECTED CELLS,

2377
01:31:12,434 --> 01:31:13,768
IN THIS CASE MEASURED BY THE

2378
01:31:13,768 --> 01:31:22,377
NUMBER OF GREEN CELLS.

2379
01:31:22,377 --> 01:31:24,145
NORMALLY WHEN YOU INFECT A

2380
01:31:24,145 --> 01:31:26,214
JURKAT CELL YOU GET A CERTAIN

2381
01:31:26,214 --> 01:31:27,315
EFFECT OF VENETOCLAX.

2382
01:31:27,315 --> 01:31:29,084
HERE IF YOU USE THE S70A

2383
01:31:29,084 --> 01:31:30,218
MUTATION, YOU CAN SEE THAT THE

2384
01:31:30,218 --> 01:31:32,921
EFFECT OF VENETOCLAX IS GROSSLY

2385
01:31:32,921 --> 01:31:33,254
REDUCED.

2386
01:31:33,254 --> 01:31:35,090
SO THIS CAUSES RESISTANCE TO

2387
01:31:35,090 --> 01:31:37,192
VENETOCLAX IN THE HIV MODEL.

2388
01:31:37,192 --> 01:31:39,160
WE'VE ALSO LOOKED AT DOES IT

2389
01:31:39,160 --> 01:31:42,030
ALTER THE BINDING TO BCL2?

2390
01:31:42,030 --> 01:31:43,331
WHAT WE CAN SEE IS THAT HERE

2391
01:31:43,331 --> 01:31:47,402
WE'VE MADE A PHOSPHORYLATED BCLE

2392
01:31:47,402 --> 01:31:47,936
ACTIVITIES.

2393
01:31:47,936 --> 01:31:49,571
WE'VE SHOWN THAT IT'S

2394
01:31:49,571 --> 01:31:51,239
PHOSPHORYLATED ON SERINE 70, AND

2395
01:31:51,239 --> 01:31:54,409
WHAT WE SHOW IS THAT CASPASE

2396
01:31:54,409 --> 01:31:56,478
8P41 BINDING TO PHOSPHORYLATED

2397
01:31:56,478 --> 01:31:58,913
BCL2 IS MUCH MORE AVID AND MUCH

2398
01:31:58,913 --> 01:32:00,982
HIGHER THAN BINDING TO WILD TYPE

2399
01:32:00,982 --> 01:32:03,485
BCL2.

2400
01:32:03,485 --> 01:32:05,487
SO WE'VE GONE ON AND LOOKED AT

2401
01:32:05,487 --> 01:32:08,089
THE EFFECT OF DIFFERENT

2402
01:32:08,089 --> 01:32:09,190
BCL2 PHOSPHOFORMS ON HIV INDUCED

2403
01:32:09,190 --> 01:32:10,392
KILLING VERSUS VENETOCLAX

2404
01:32:10,392 --> 01:32:11,826
EFFECT.

2405
01:32:11,826 --> 01:32:12,727
WE HAVEN'T COMPLETED ALL THIS

2406
01:32:12,727 --> 01:32:14,229
WORK, IT'S A LOT OF WORK, A LOT

2407
01:32:14,229 --> 01:32:16,798
OF CELL LINES, BUT S70A CAUSES

2408
01:32:16,798 --> 01:32:20,201
AN INCREASED NUMBER OF INFECTED

2409
01:32:20,201 --> 01:32:22,804
CELLS, WHEREAS T69E CAUSES

2410
01:32:22,804 --> 01:32:24,239
REDUCED NUMBER OF INFECTED CELLS

2411
01:32:24,239 --> 01:32:25,673
AND THE DIFFERENCE IS QUITE

2412
01:32:25,673 --> 01:32:26,441
DRAMATIC.

2413
01:32:26,441 --> 01:32:29,778
AND AS MENTIONED, HERE'S THE

2414
01:32:29,778 --> 01:32:31,279
BCL2 WILD TYPE EFFECT.

2415
01:32:31,279 --> 01:32:33,481
THE S70A REDUCES THAT EFFECT BUT

2416
01:32:33,481 --> 01:32:36,751
INTERESTINGLY, THE T69A MUTATION

2417
01:32:36,751 --> 01:32:37,652
INCREASES THAT EFFECT.

2418
01:32:37,652 --> 01:32:39,621
SO WE THINK THIS IS AN IMPORTANT

2419
01:32:39,621 --> 01:32:41,456
AVENUE TO PURSUE.

2420
01:32:41,456 --> 01:32:42,657
WE'VE SHOWN -- WE AND OTHERS

2421
01:32:42,657 --> 01:32:45,226
HAVE SHOWN THAT VENETOCLAX IS

2422
01:32:45,226 --> 01:32:46,327
EFFECTIVE IN A VARIETY OF

2423
01:32:46,327 --> 01:32:47,862
DIFFERENT MODELS AND SHORT OF A

2424
01:32:47,862 --> 01:32:50,198
CLINICAL TRIAL, I THINK WE HAVE

2425
01:32:50,198 --> 01:32:51,466
PRETTY ROBUST DATA VENETOCLAX

2426
01:32:51,466 --> 01:32:52,600
HAS AN EFFECT.

2427
01:32:52,600 --> 01:32:55,904
WE'RE LOOKING INTO WHERE BCL2 IS

2428
01:32:55,904 --> 01:32:58,740
PHOSPHORYLATED IN VITRO.

2429
01:32:58,740 --> 01:33:01,376
PART OF THIS IS LIMITED BY THE

2430
01:33:01,376 --> 01:33:03,578
AVAILABILITY OF PHOSPHO-SPECIFIC

2431
01:33:03,578 --> 01:33:04,479
ANTIBODIES, SO THIS HAS TO BE

2432
01:33:04,479 --> 01:33:05,980
DONE WITH A MASS SPEC APPROACH,

2433
01:33:05,980 --> 01:33:07,982
SO IF PEOPLE HAVE MASS SPEC

2434
01:33:07,982 --> 01:33:08,750
CAPABILITIES, WE'D LOVE TO

2435
01:33:08,750 --> 01:33:12,153
PARTNER WITH YOU.

2436
01:33:12,153 --> 01:33:14,889
WE'RE LOOKING AT THE EFFECT OF

2437
01:33:14,889 --> 01:33:17,725
DIFFERENT PHOSPHO FORMS ON

2438
01:33:17,725 --> 01:33:18,960
KILLING AND RESERVOIR EFFECT,

2439
01:33:18,960 --> 01:33:22,097
AND WE PLAN TO GO ON AND LOOK AT

2440
01:33:22,097 --> 01:33:25,733
THE BINDING BY CASPASE 8P41 TO

2441
01:33:25,733 --> 01:33:28,670
THE DIFFERENT PHOSPHOSM FORMS.

2442
01:33:28,670 --> 01:33:29,037
 PHOSPHO FORMS.

2443
01:33:29,037 --> 01:33:31,306
WE WANT TO FIND OUT WHICH

2444
01:33:31,306 --> 01:33:32,774
KINASES ARE RESPONSIBLE FOR

2445
01:33:32,774 --> 01:33:34,409
THESE EVENTS AND HOW CAN WE

2446
01:33:34,409 --> 01:33:35,944
INHIBIT THEM.

2447
01:33:35,944 --> 01:33:37,912
PHOSPHATASES TO NEGATE THE

2448
01:33:37,912 --> 01:33:39,347
EFFECTS AND OF COURSE WE'RE

2449
01:33:39,347 --> 01:33:41,649
INTERESTED IN PURSUING OUR WORK

2450
01:33:41,649 --> 01:33:43,418
WITH VENETOCLAX WITH DIFFERENT

2451
01:33:43,418 --> 01:33:44,419
LATENCY REVERSAL AGENTS.

2452
01:33:44,419 --> 01:33:46,287
SO WITH THAT, WE'LL MOVE IT ON

2453
01:33:46,287 --> 01:33:48,790
TO OUR NEXT SPEAKER.

2454
01:33:48,790 --> 01:33:49,157
[APPLAUSE]

2455
01:33:49,157 --> 01:33:50,024
>> THANK YOU.

2456
01:33:50,024 --> 01:33:53,862
OUR LAST SPEAKER IS PRITI WITH

2457
01:33:53,862 --> 01:33:55,163
OUR WORK FROM THE COMMUNITY.

2458
01:33:55,163 --> 01:33:56,931
>> HI, EVERYONE.

2459
01:33:56,931 --> 01:33:58,800
I'M THE COMMUNITY ENGAGEMENT

2460
01:33:58,800 --> 01:33:59,701
COORDINATOR FORRESTER LOVE.

2461
01:33:59,701 --> 01:34:01,769
WHO IS THE COMMUNITY PARTNER FOR

2462
01:34:01,769 --> 01:34:04,506
ERASE HIV.

2463
01:34:04,506 --> 01:34:05,740
JUST A BRIEF OVERVIEW OF WHO WE

2464
01:34:05,740 --> 01:34:06,040
ARE.

2465
01:34:06,040 --> 01:34:07,942
OUR MISSION IS TO ERADICATE THE

2466
01:34:07,942 --> 01:34:10,011
ADVERSE IMPACTS OF HIV AND

2467
01:34:10,011 --> 01:34:12,347
SEXUAL AND REPRODUCTIVE HEALTH

2468
01:34:12,347 --> 01:34:13,982
INJUSTICE CHALLENGES THAT IMPACT

2469
01:34:13,982 --> 01:34:15,383
WOMEN AND THEIR FAMILIES THROUGH

2470
01:34:15,383 --> 01:34:17,185
A MULTIPRONGED APPROACH OF

2471
01:34:17,185 --> 01:34:19,020
EDUCATION, PREVENTION, SUPPORT,

2472
01:34:19,020 --> 01:34:20,989
RESEARCH AND ADVOCACY, AND WE DO

2473
01:34:20,989 --> 01:34:23,424
THIS BOTH LOCALLY IN ATLANTA, AS

2474
01:34:23,424 --> 01:34:27,295
WELL AS GLOBALLY.

2475
01:34:27,295 --> 01:34:28,997
SO THESE ARE SOME OF OUR TEAM

2476
01:34:28,997 --> 01:34:30,932
MEMBERS, OUR P.I., OUR RESEARCH

2477
01:34:30,932 --> 01:34:32,100
PROGRAM MANAGER AND MYSELF, THE

2478
01:34:32,100 --> 01:34:32,967
COMMUNITY ENGAGEMENT

2479
01:34:32,967 --> 01:34:36,137
COORDINATOR.

2480
01:34:36,137 --> 01:34:37,739
SOME YEAR TWO MILESTONES FOR US

2481
01:34:37,739 --> 01:34:39,941
WERE WE HELD INSTAGRAM LIVE

2482
01:34:39,941 --> 01:34:41,342
SESSIONS WHERE WE DISCUSSED

2483
01:34:41,342 --> 01:34:43,211
TOPICS SURROUNDING HIV CURE AND

2484
01:34:43,211 --> 01:34:45,213
PREVENTION AND WE TITLED THESE

2485
01:34:45,213 --> 01:34:45,847
CURE CONVERSATIONS.

2486
01:34:45,847 --> 01:34:47,315
WE DEVELOPED A COMMUNITY SURVEY

2487
01:34:47,315 --> 01:34:48,583
TO GAUGE THE COMMUNITY'S

2488
01:34:48,583 --> 01:34:50,785
KNOWLEDGE SURROUNDING HIV CURE.

2489
01:34:50,785 --> 01:34:52,453
SISTER LOVE ACTUALLY LAUNCHED A

2490
01:34:52,453 --> 01:34:54,355
MOBILE TESTING UNIT AS WELL ON

2491
01:34:54,355 --> 01:34:55,990
WORLD AIDS DAY CALLED THE

2492
01:34:55,990 --> 01:34:57,525
HEALTHY LOVE BUS THAT OFFERS

2493
01:34:57,525 --> 01:35:00,728
FREE HIV TESTING AROUND ATLANTA.

2494
01:35:00,728 --> 01:35:02,130
WE HELD OUR ANNUAL COMMUNITY

2495
01:35:02,130 --> 01:35:04,666
CURE COOKOUT EVENT WHERE WE

2496
01:35:04,666 --> 01:35:06,000
FOSTERED ENGAGEMENT BETWEEN OUR

2497
01:35:06,000 --> 01:35:09,671
RESEARCHERS AND OUR COMMUNITY.

2498
01:35:09,671 --> 01:35:11,906
WE HELD AB EVENT TITLED STAGES

2499
01:35:11,906 --> 01:35:12,907
TO HIGHLIGHT COMMUNITY STORIES

2500
01:35:12,907 --> 01:35:13,875
THROUGH ART MEDIUMS.

2501
01:35:13,875 --> 01:35:15,076
THIS WAS HELD IN NOVEMBER WITH A

2502
01:35:15,076 --> 01:35:16,844
SPECIFIC FOCUS ON VISUAL ART,

2503
01:35:16,844 --> 01:35:18,413
WHERE WE IT THREE ARTISTS SHARE

2504
01:35:18,413 --> 01:35:20,148
THEIR STORIES ABOUT REPRODUCTIVE

2505
01:35:20,148 --> 01:35:24,252
JUSTICE.

2506
01:35:24,252 --> 01:35:27,722
FINALLY WE PARTICIPATED IN EMORY

2507
01:35:27,722 --> 01:35:29,057
UNIVERSITY'S ART EVENT WHERE WE

2508
01:35:29,057 --> 01:35:31,159
TABLED SHARED INFORMATION ABOUT

2509
01:35:31,159 --> 01:35:33,895
ERASE HIV AS WELL AS WAYS TO GET

2510
01:35:33,895 --> 01:35:38,032
INVOLVED.

2511
01:35:38,032 --> 01:35:40,101
WITH HIRED A NEW COMMUNITY-BASED

2512
01:35:40,101 --> 01:35:42,070
RESEARCH MANAGER.

2513
01:35:42,070 --> 01:35:43,471
WE HELD A COMMUNITY CURE

2514
01:35:43,471 --> 01:35:43,805
COOKOUT.

2515
01:35:43,805 --> 01:35:45,240
THIS WAS HOSTED AT THE

2516
01:35:45,240 --> 01:35:46,107
MOTHERHOUSE, WHICH IS THE HOUSE

2517
01:35:46,107 --> 01:35:47,442
WE ALL WORK OUT OF AND THERE'S A

2518
01:35:47,442 --> 01:35:48,977
LOT OF HISTORY ATTACHED TO IT SO

2519
01:35:48,977 --> 01:35:50,278
WE WERE ABLE TO OFFER TOURS OF

2520
01:35:50,278 --> 01:35:52,347
THAT AS WELL.

2521
01:35:52,347 --> 01:35:54,282
WE HIRED THE NEW CEC, MYSELF,

2522
01:35:54,282 --> 01:35:56,851
AND JOINED ERASE HIV'S TEAM FOR

2523
01:35:56,851 --> 01:35:58,019
THE ATLANTA AIDS WALK.

2524
01:35:58,019 --> 01:36:00,188
AND FINALLY COLLABORATED WITH

2525
01:36:00,188 --> 01:36:03,591
RID HIV AND THE HIV AGING AND

2526
01:36:03,591 --> 01:36:04,859
RESEARCH PROJECT PALM SPRINGS

2527
01:36:04,859 --> 01:36:05,927
FOR THEIR CURE RESEARCH EVENT

2528
01:36:05,927 --> 01:36:09,964
HAPPENING IN ATLANTA NEXT WEEK.

2529
01:36:09,964 --> 01:36:11,599
THESE ARE SOME PICTURES FROM OUR

2530
01:36:11,599 --> 01:36:14,369
COMMUNITY CURE COOKOUT IN JUNE.

2531
01:36:14,369 --> 01:36:15,903
AND HERE ARE SOME PICTURES LAST

2532
01:36:15,903 --> 01:36:20,108
MONTH FROM THE AIDS WALK.

2533
01:36:20,108 --> 01:36:20,808
IN ATLANTA.

2534
01:36:20,808 --> 01:36:22,577
AND AS FAR AS OUR PLAN GOING

2535
01:36:22,577 --> 01:36:23,878
FORWARD, WE PLAN TO WORK ON

2536
01:36:23,878 --> 01:36:25,246
REVISING OUR MISSION STATEMENT

2537
01:36:25,246 --> 01:36:29,917
AS WELL AS THE RESPONSIBILITIES.

2538
01:36:29,917 --> 01:36:31,786
WE HELP TO FOSTER COLLABORATION

2539
01:36:31,786 --> 01:36:33,221
AND ENGAGEMENT BETWEEN OUR

2540
01:36:33,221 --> 01:36:34,722
RESEARCHERS AND OUR COMMUNITIES

2541
01:36:34,722 --> 01:36:37,058
AS WELL AS COORDINATE OUR NEXT

2542
01:36:37,058 --> 01:36:37,925
COMMUNITY CURE COOKOUT EVENT.

2543
01:36:37,925 --> 01:36:38,393
THANK YOU.

2544
01:36:38,393 --> 01:36:48,569
[APPLAUSE]

2545
01:36:58,579 --> 01:37:05,653
>> ANY QUESTIONS?

2546
01:37:05,653 --> 01:37:06,754
I'M JUST LOOKING ONLINE IF THERE

2547
01:37:06,754 --> 01:37:08,189
ARE ANY QUESTIONS.

2548
01:37:08,189 --> 01:37:11,259
>> SO BRAD, I HAVE ONE FOR
YOU

2549
01:37:11,259 --> 01:37:14,128
AND ONE FOR YOU, ANDREW.

2550
01:37:14,128 --> 01:37:18,066
SO ECH2 IS -- COMPLEX THAT YOU

2551
01:37:18,066 --> 01:37:20,702
MENTIONED, AND PR C 2 IS VERY

2552
01:37:20,702 --> 01:37:22,336
MUCH INVOLVED IN REDUCING HIV

2553
01:37:22,336 --> 01:37:22,770
LATENCY.

2554
01:37:22,770 --> 01:37:26,174
SO IN YOUR EXPERIMENTS, CAN

2555
01:37:26,174 --> 01:37:27,175
YOU -- THE EFFECT YOU'RE SEEING

2556
01:37:27,175 --> 01:37:29,911
IS NOT ONLY DONE ON

2557
01:37:29,911 --> 01:37:31,679
MHC1 EXPRESSION BUT ALSO ON HIV

2558
01:37:31,679 --> 01:37:31,979
ACTIVATION?

2559
01:37:31,979 --> 01:37:34,015
>> YEAH, SO THANK YOU FOR
THE

2560
01:37:34,015 --> 01:37:34,582
QUESTION.

2561
01:37:34,582 --> 01:37:36,417
I THINK THAT THE EFFECT WE'VE

2562
01:37:36,417 --> 01:37:40,254
SEEN SO FAR, WE CAN RULE OUT

2563
01:37:40,254 --> 01:37:43,591
THAT IT'S BEING IMPACTED BY

2564
01:37:43,591 --> 01:37:44,759
LATENCY REVERSAL BECAUSE WE'RE

2565
01:37:44,759 --> 01:37:48,396
JUST DOG DOING A VERY SHORT

2566
01:37:48,396 --> 01:37:51,332
OVERNIGHT KILLING -- BUT TO YOUR

2567
01:37:51,332 --> 01:37:53,000
POINT I THINK WHAT WE SHOULD DO

2568
01:37:53,000 --> 01:37:54,402
IS ASK THE QUESTION IF WE'RE

2569
01:37:54,402 --> 01:37:55,870
TARGETING EVEN MORE INFECTED

2570
01:37:55,870 --> 01:37:56,971
CELLS THAT WOULD HAVE BEEN

2571
01:37:56,971 --> 01:37:58,606
LATENT BECAUSE WE'RE ALSO

2572
01:37:58,606 --> 01:37:59,774
REVERSING LATENCY AT THE SAME

2573
01:37:59,774 --> 01:38:02,143
TIME WE'RE DRIVING

2574
01:38:02,143 --> 01:38:02,577
MHC1 UPREGULATION.

2575
01:38:02,577 --> 01:38:05,513
SO I THINK THE LATENCY -- IS

2576
01:38:05,513 --> 01:38:06,314
REALLY AN IMPORTANT COMPONENT.

2577
01:38:06,314 --> 01:38:08,649
WE'VE REALLY FOCUSED ON THE CTL

2578
01:38:08,649 --> 01:38:10,284
RESISTANCE ASPECT, BUT WE SHOULD

2579
01:38:10,284 --> 01:38:11,252
LOOK IN THAT DIRECTION AS WELL.

2580
01:38:11,252 --> 01:38:13,588
>> TO GET BACK TO THE
STUDY THAT

2581
01:38:13,588 --> 01:38:18,426
MIRKO PRESENTED, OUR JOINT WORK

2582
01:38:18,426 --> 01:38:28,202
IS, IL10 BOOSTS  -- EHC

2583
01:38:28,202 --> 01:38:29,837
INHIBITORS DOWNSTREAM OF IL10 TO

2584
01:38:29,837 --> 01:38:34,575
TRY TO SYNERGIZE THE EFFECT OF

2585
01:38:34,575 --> 01:38:36,644
ANTIIL10 -- INHIBITORS, SO I'M

2586
01:38:36,644 --> 01:38:38,980
NOT INTERESTED IN CD8 T-CELLS, I

2587
01:38:38,980 --> 01:38:41,716
WORK MOSTLY ON CD4s, SO --

2588
01:38:41,716 --> 01:38:42,984
MIGHT WANT TO DO TOGETHER.

2589
01:38:42,984 --> 01:38:43,484
>> INTERESTING.

2590
01:38:43,484 --> 01:38:44,218
THANK YOU.

2591
01:38:44,218 --> 01:38:48,222
>> SO FOR ANDREW, SO TO
ME, IT'S

2592
01:38:48,222 --> 01:38:50,758
VERY OBVIOUS THAT ONE OF THE

2593
01:38:50,758 --> 01:38:55,496
KINASES THAT ARE INVOLVED IN

2594
01:38:55,496 --> 01:38:57,331
BCL2 MIGHT BE -- KINASE.

2595
01:38:57,331 --> 01:38:59,634
YOU KNOW THERE'S -- KINASE

2596
01:38:59,634 --> 01:39:02,770
INHIBITORS IN CLINICAL TRIALS,

2597
01:39:02,770 --> 01:39:04,172
HAVE YOU LOOKED AT THOSE?

2598
01:39:04,172 --> 01:39:05,106
IT'S VERY OBVIOUS TO ME.

2599
01:39:05,106 --> 01:39:08,176
>> YEAH, SO GREAT
QUESTION.

2600
01:39:08,176 --> 01:39:11,646
SO THERE'S A NUMBER OF KINASES

2601
01:39:11,646 --> 01:39:13,181
REPORTED PHOSPHORYLATE BCL2 OF

2602
01:39:13,181 --> 01:39:14,715
WHICH KINASES ARE ABSOLUTELY

2603
01:39:14,715 --> 01:39:15,149
ONE.

2604
01:39:15,149 --> 01:39:16,083
YES, WE'RE LOOKING AT THOSE.

2605
01:39:16,083 --> 01:39:18,186
PART OF IT HAS TO DO WITH THE

2606
01:39:18,186 --> 01:39:19,053
CUMULATIVE TOXICITY, WITH IS OUR

2607
01:39:19,053 --> 01:39:20,154
CONCERN, SO WE'RE TRYING TO WORK

2608
01:39:20,154 --> 01:39:21,255
THROUGH THAT FIRST, BUT I THINK

2609
01:39:21,255 --> 01:39:23,491
IT'S AN OBVIOUS STRATEGY TO USE

2610
01:39:23,491 --> 01:39:24,792
SELECTED KINASE INHIBITORS AT

2611
01:39:24,792 --> 01:39:29,530
THE RIGHT DOSE, PLUS

2612
01:39:29,530 --> 01:39:29,931
BCL2 ANTAGONISTS.

2613
01:39:29,931 --> 01:39:33,267
>> THE COMPLEXITY OF THE
--

2614
01:39:33,267 --> 01:39:36,204
KINASE INHIBITOR, IT CAN DOWN

2615
01:39:36,204 --> 01:39:37,572
REGULATE STAT5 EXPRESSION SO THE

2616
01:39:37,572 --> 01:39:39,841
PROMOTION OF BCL2 EXPRESSION BUT

2617
01:39:39,841 --> 01:39:41,642
OF COURSE IT WILL HAVE AN

2618
01:39:41,642 --> 01:39:44,412
EFFECT -- THAT THE KINASE -- THE

2619
01:39:44,412 --> 01:39:45,012
KINASE ACTIVITY.

2620
01:39:45,012 --> 01:39:48,716
>> AGREE.

2621
01:39:48,716 --> 01:39:51,319
>> HI THERE.

2622
01:39:51,319 --> 01:39:52,186
 -- FROM WESTERN UNIVERSITY.

2623
01:39:52,186 --> 01:39:54,856
I HAVE A QUESTION ABOUT THE PD-1

2624
01:39:54,856 --> 01:39:56,624
WILL ANTAGONISM EXPERIMENTS IN

2625
01:39:56,624 --> 01:39:57,825
THE RHESUS MACAQUE.

2626
01:39:57,825 --> 01:40:00,895
I'M WONDERING, WE SAW ALSO

2627
01:40:00,895 --> 01:40:03,030
SIMILAR CORRELATIONS BETWEEN

2628
01:40:03,030 --> 01:40:04,465
PD-1 EXPRESSION AND RESERVOIR

2629
01:40:04,465 --> 01:40:06,834
SIZE MEASURED BY THE -- IN OUR

2630
01:40:06,834 --> 01:40:08,402
COHORT IN UGANDA.

2631
01:40:08,402 --> 01:40:10,371
BUT WHEN WE STRATIFIED BY SEX,

2632
01:40:10,371 --> 01:40:12,440
WE DIDN'T SEE THAT CORRELATION

2633
01:40:12,440 --> 01:40:13,207
AMONG FEMALES.

2634
01:40:13,207 --> 01:40:15,443
IT WAS VERY STRONG IN OUR MALE

2635
01:40:15,443 --> 01:40:16,444
PARTICIPANTS AND NOTHING IN THE

2636
01:40:16,444 --> 01:40:17,311
FEMALES.

2637
01:40:17,311 --> 01:40:19,614
I'M WONDERING, DO YOU HAVE BOTH

2638
01:40:19,614 --> 01:40:21,082
FEMALE AND MALE ANIMALS IN YOUR

2639
01:40:21,082 --> 01:40:23,484
STUDY AND HAVE YOU DISAGGREGATED

2640
01:40:23,484 --> 01:40:23,818
BY SEX?

2641
01:40:23,818 --> 01:40:26,420
>> THANK YOU FOR THAT
QUESTION.

2642
01:40:26,420 --> 01:40:29,123
WE HAVE BOTH, THE NUMBER ARE LOW

2643
01:40:29,123 --> 01:40:31,726
BECAUSE WE HAVE 10 ANIMALS FOR

2644
01:40:31,726 --> 01:40:34,228
EACH EXPERIMENT SO IT DIFFICULT

2645
01:40:34,228 --> 01:40:35,162
TO MAKE A CONCLUSION.

2646
01:40:35,162 --> 01:40:37,798
IN TERMS OF THE IMPACT OF THE

2647
01:40:37,798 --> 01:40:41,068
INTERVENTION WAS AGAIN -- DURING

2648
01:40:41,068 --> 01:40:43,738
THE ANTIBODY PHASE IN 90% OF THE

2649
01:40:43,738 --> 01:40:45,039
ANIMAL SO BOTH FEMALE AND MALE

2650
01:40:45,039 --> 01:40:46,707
BUT AGAIN, THE NUMBER ARE LOWER.

2651
01:40:46,707 --> 01:40:49,710
AND IN TERMS OF THE SIZE OF THE

2652
01:40:49,710 --> 01:40:51,679
RESERVOIR, AS I SAID THERE WAS

2653
01:40:51,679 --> 01:40:56,150
NO EXPANSION, SO REMAIN STABLE,

2654
01:40:56,150 --> 01:40:57,685
BUT OVERALL IN THE NUMBER OF --

2655
01:40:57,685 --> 01:40:58,719
THERE WAS NO REDUCTION.

2656
01:40:58,719 --> 01:41:00,354
THERE IS A SUBSET OF ANIMALS IN

2657
01:41:00,354 --> 01:41:02,757
WHICH THERE WAS A SIGNIFICANT

2658
01:41:02,757 --> 01:41:04,225
REDUCTION AND -- WE'RE WORKING

2659
01:41:04,225 --> 01:41:06,327
ON UNDERSTANDING THE MECHANISM,

2660
01:41:06,327 --> 01:41:08,162
BUT OVERALL IT WAS SIMILAR

2661
01:41:08,162 --> 01:41:10,231
BETWEEN MALE AND FEMALE BUT

2662
01:41:10,231 --> 01:41:11,566
AGAIN WITH VERY LOW NUMBERS IT'S

2663
01:41:11,566 --> 01:41:12,433
DIFFICULT TO CONCLUDE.

2664
01:41:12,433 --> 01:41:12,833
>> THANKS.

2665
01:41:12,833 --> 01:41:13,801
>> HI.

2666
01:41:13,801 --> 01:41:16,003
COULD YOU GO INTO A BIT MORE

2667
01:41:16,003 --> 01:41:17,405
DETAIL ABOUT THE ACTUAL CELLULAR

2668
01:41:17,405 --> 01:41:20,508
CHANGES THAT THE ANTIIL10 AND

2669
01:41:20,508 --> 01:41:22,043
PD-1 INCURRED IN THE MONKEYS?

2670
01:41:22,043 --> 01:41:24,278
WAS THERE DECREASES IN T REG

2671
01:41:24,278 --> 01:41:25,913
CELLS, INCREASED ACTUAL

2672
01:41:25,913 --> 01:41:28,215
FUNCTIONALITY OF CD8s, AND WAS

2673
01:41:28,215 --> 01:41:30,785
THAT TEMPORARILY RELATED TO THE

2674
01:41:30,785 --> 01:41:32,286
HALF-LIFE OF THE ANTIBODY IN THE

2675
01:41:32,286 --> 01:41:32,620
MONKEYS?

2676
01:41:32,620 --> 01:41:35,323
AND DID IT GO BACK TO NORM

2677
01:41:35,323 --> 01:41:35,523
AFTER?

2678
01:41:35,523 --> 01:41:37,825
>> SO I DIDN'T HAVE TIME
TO

2679
01:41:37,825 --> 01:41:39,360
PRESENT THAT AND AGAIN THAT'S

2680
01:41:39,360 --> 01:41:41,495
WORK IN COLLABORATION WITH

2681
01:41:41,495 --> 01:41:43,564
RAFICK AND SUSAN.

2682
01:41:43,564 --> 01:41:45,833
I MAKE A SHORT RESPONSE OF A

2683
01:41:45,833 --> 01:41:47,969
LONG -- SO THERE IS MULTIPLE

2684
01:41:47,969 --> 01:41:49,070
MECHANISMS THAT WE ARE SEEING,

2685
01:41:49,070 --> 01:41:53,240
SO ONE IS IMPROVING THE CD4 --.

2686
01:41:53,240 --> 01:42:01,382
THERE IS EVEN -- BUT INNATE INMU

2687
01:42:01,382 --> 01:42:03,317
KNOW RESPONSE WE ARE PROPOSING

2688
01:42:03,317 --> 01:42:04,485
TO TARGET -- COLLABORATORY.

2689
01:42:04,485 --> 01:42:07,555
AND THERE IS A BETTER C

2690
01:42:07,555 --> 01:42:08,322
CD8 RESPONSE.

2691
01:42:08,322 --> 01:42:13,794
AND INTERESTINGLY, YOU HAVE

2692
01:42:13,794 --> 01:42:15,596
EFFECT RIGHT AWAY SO THIS SEEMS

2693
01:42:15,596 --> 01:42:21,369
TO BE PRO -- TOO EARLY, BUT WE

2694
01:42:21,369 --> 01:42:25,773
TRY TO -- SINCE -- CD8 EFFECTOR

2695
01:42:25,773 --> 01:42:26,774
CELLS THAT ARE ACTUALLY ALREADY

2696
01:42:26,774 --> 01:42:28,542
PRONE AND ABLE TO RECENT THE

2697
01:42:28,542 --> 01:42:29,944
REBOUNDING VIRUS.

2698
01:42:29,944 --> 01:42:30,678
AND INTERESTINGLY IF YOU LOOK

2699
01:42:30,678 --> 01:42:34,382
LATER ON, WITH THE -- VIRAL LOAD

2700
01:42:34,382 --> 01:42:37,551
IS VERY DIFFERENT BUT THE

2701
01:42:37,551 --> 01:42:39,020
CD8 REMAIN MORE STEM CELL LIKE,

2702
01:42:39,020 --> 01:42:41,322
FOR EXAMPLE THE LEVEL OF --

2703
01:42:41,322 --> 01:42:43,591
1 AND THAT IS ASSOCIATED WITH

2704
01:42:43,591 --> 01:42:46,027
THE LOWER VIRAL LOAD AND THERE'S

2705
01:42:46,027 --> 01:42:48,162
MECHANISM POTENTIAL T REG AS

2706
01:42:48,162 --> 01:42:48,362
IL10.

2707
01:42:48,362 --> 01:42:50,631
>> SO NO LIFT.

2708
01:42:50,631 --> 01:42:55,736
>>  -- CD4 T-CELLS --

2709
01:42:55,736 --> 01:42:56,504
INTERRUPTIONS STILL ON ART WAS

2710
01:42:56,504 --> 01:42:59,240
LOWER WHEN YOU BROUGHT I LI. 10

2711
01:42:59,240 --> 01:43:06,914
AND CONSISTENT WITH -- BLC2.

2712
01:43:06,914 --> 01:43:08,682
>> I WANTED TO THANK YOU
ALL FOR

2713
01:43:08,682 --> 01:43:10,051
HAVING THAT COMMUNITY SUMMARY

2714
01:43:10,051 --> 01:43:10,918
SLIDE THAT PUTS THINGS INTO

2715
01:43:10,918 --> 01:43:13,020
CONTEXT FOR US WITH SIMPLE

2716
01:43:13,020 --> 01:43:13,888
QUESTIONS, SIMPLE ANSWERS AND

2717
01:43:13,888 --> 01:43:15,089
THEN PUTTING IT INTO THE CONTEXT

2718
01:43:15,089 --> 01:43:16,657
HOW IT RELATES TO CURE FOR US.

2719
01:43:16,657 --> 01:43:17,892
ONE THING THAT I WANTED TO GIVE

2720
01:43:17,892 --> 01:43:19,226
AS A NOTE, THIS IS FOR EVERYBODY

2721
01:43:19,226 --> 01:43:22,563
IN THE ROOM, IS THAT SOMETIMES

2722
01:43:22,563 --> 01:43:24,598
PEOPLE THINK THAT THE USE OF

2723
01:43:24,598 --> 01:43:25,933
COMMUNITY IS BELITTLING SAYING

2724
01:43:25,933 --> 01:43:27,501
THAT THE COMMUNITY IS STUPID,

2725
01:43:27,501 --> 01:43:29,003
CAN'T UNDERSTAND THE SCIENCE AS

2726
01:43:29,003 --> 01:43:30,104
WELL, NEED SPECIAL HELP.

2727
01:43:30,104 --> 01:43:32,540
SO CALLING IT A PLAIN LANGUAGE

2728
01:43:32,540 --> 01:43:33,707
SUMMARY SLIDE IS A WAY AROUND

2729
01:43:33,707 --> 01:43:36,510
THAT SO YOU DON'T

2730
01:43:36,510 --> 01:43:37,078
UNINTENTIONALLY STIGMATIZE

2731
01:43:37,078 --> 01:43:38,913
ANYONE FOR NEEDING SOME HELP

2732
01:43:38,913 --> 01:43:40,481
BECAUSE IT IS OUR JOB AS SCIENCE

2733
01:43:40,481 --> 01:43:42,216
EXEUN KAY TORES TO COMMUNICATE

2734
01:43:42,216 --> 01:43:43,017
EFFECTIVELY SO THAT'S WHAT IT'S

2735
01:43:43,017 --> 01:43:43,217
FOR.

2736
01:43:43,217 --> 01:43:44,452
BUT I WANT TO THANK YOU ALL FOR

2737
01:43:44,452 --> 01:43:45,553
HAVING THEM BECAUSE IT REALLY

2738
01:43:45,553 --> 01:43:47,655
HELPS WITH THE HIRE GLISKS AND

2739
01:43:47,655 --> 01:43:51,192
THE THROAT SINGING THAT

2740
01:43:51,192 --> 01:43:52,593
SOMETIMES SCIENCE SOUNDS LIKE TO

2741
01:43:52,593 --> 01:43:53,394
ME SO THANK YOU VERY MUCH.

2742
01:43:53,394 --> 01:43:57,131
[APPLAUSE]

2743
01:43:57,131 --> 01:43:58,699
>> QUESTION FOR BRAD.

2744
01:43:58,699 --> 01:44:00,167
BRAD, WHAT ARE YOUR THOUGHTS

2745
01:44:00,167 --> 01:44:04,972
ABOUT THE DECREASE OF -- CLASS M

2746
01:44:04,972 --> 01:44:06,307
MORE SENSITIVE FOR NK KILLING?

2747
01:44:06,307 --> 01:44:07,608
BECAUSE YOU DON'T HAVE ANY NKs

2748
01:44:07,608 --> 01:44:10,277
ON YOUR SYSTEM, SO HOW DO YOU

2749
01:44:10,277 --> 01:44:12,680
BALANCE THAT RELATIONSHIP

2750
01:44:12,680 --> 01:44:15,082
BETWEEN GOING TOWARDS NK

2751
01:44:15,082 --> 01:44:15,983
SUSCEPTIBILITY FOR KILLING

2752
01:44:15,983 --> 01:44:19,653
VERSUS THE CD8 INCREASING WITH

2753
01:44:19,653 --> 01:44:20,054
THE DRUG?

2754
01:44:20,054 --> 01:44:21,155
>> IT'S A GREAT QUESTION.

2755
01:44:21,155 --> 01:44:22,356
WE THOUGHT THE SAME THING, THAT

2756
01:44:22,356 --> 01:44:23,724
IT WOULD BE A TRADEOFF, THEN WE

2757
01:44:23,724 --> 01:44:25,259
WERE PLEASANT RI SURPRISED WHEN

2758
01:44:25,259 --> 01:44:27,161
WE DID NK CELL KILLING ASSAYS

2759
01:44:27,161 --> 01:44:28,496
AND FOUND THAT TAZEMETOSTAT

2760
01:44:28,496 --> 01:44:30,030
ACTUALLY SENSITIZES THE CELLS TO

2761
01:44:30,030 --> 01:44:31,765
BETTER NK CELL KILLING.

2762
01:44:31,765 --> 01:44:33,100
WE'RE NOT -- WE HAVEN'T

2763
01:44:33,100 --> 01:44:34,135
PINPOINTED THE MECHANISM YET BUT

2764
01:44:34,135 --> 01:44:35,769
THERE IS UPREGULATION OF SOME

2765
01:44:35,769 --> 01:44:39,039
STRESS LIGANDS AS WELL ON

2766
01:44:39,039 --> 01:44:41,175
EZH2 TREATMENT AND ALSO BASED ON

2767
01:44:41,175 --> 01:44:42,843
PROTEOMICS, IT LOOKS LIKE THREAR

2768
01:44:42,843 --> 01:44:45,179
UPREGULATION OF ICAM1 WHICH

2769
01:44:45,179 --> 01:44:46,814
HELPS WITH ADHESION OF THE NK

2770
01:44:46,814 --> 01:44:48,215
CELLS TO THE TARGET CELLS, SO IT

2771
01:44:48,215 --> 01:44:49,717
LOOKS LIKE THAT'S NOT ACTUALLY

2772
01:44:49,717 --> 01:44:51,485
THE TRADEOFF THAT WE THOUGHT.

2773
01:44:51,485 --> 01:44:54,021
WE ENHANCE NK CELL KILLING AND

2774
01:44:54,021 --> 01:44:55,823
CD8 KILLING AT LEAST IN VITRO.

2775
01:44:55,823 --> 01:45:02,029
>> I HAVE A QUESTION FOR
THE CD 

2776
01:45:02,029 --> 01:45:03,297
MODEL.

2777
01:45:03,297 --> 01:45:07,768
IT'S VERY GOOD TO -- REBOUND, SO

2778
01:45:07,768 --> 01:45:09,703
AT THAT TIME DO YOU THINK THE

2779
01:45:09,703 --> 01:45:13,073
ANTIBODY OR SMALL MOLECULE PK

2780
01:45:13,073 --> 01:45:15,109
ISSUE OR HOW TO EXPLAIN THIS

2781
01:45:15,109 --> 01:45:18,179
PHENOMENON?

2782
01:45:18,179 --> 01:45:20,147
>> SO THE TREATMENT WAS

2783
01:45:20,147 --> 01:45:22,449
PERFORMED ONLY FOR ONE WEEK

2784
01:45:22,449 --> 01:45:24,652
DURING ART SUPPRESSION AND

2785
01:45:24,652 --> 01:45:27,855
FALLING UPON VIRAL REBOUND.

2786
01:45:27,855 --> 01:45:30,157
SO OBVIOUSLY THE MIMETIC AND THE

2787
01:45:30,157 --> 01:45:31,258
ANTIBODY DON'T STICK AROUND THAT

2788
01:45:31,258 --> 01:45:33,827
LONG, SO WE ARE HOPING OUR -- WE

2789
01:45:33,827 --> 01:45:34,695
HAVE TO DO EXPERIMENTS WHERE WE

2790
01:45:34,695 --> 01:45:36,230
CAN GIVE IT FOR A LONGER PERIOD

2791
01:45:36,230 --> 01:45:39,166
OF TIME AND THEN SEE IF IT WOULD

2792
01:45:39,166 --> 01:45:39,700
FURTHER DELAY.

2793
01:45:39,700 --> 01:45:41,335
THIS WAS ONLY AFTER A VERY, VERY

2794
01:45:41,335 --> 01:45:42,203
SHORT EXPOSURE TO THE COMPOUND.

2795
01:45:42,203 --> 01:45:43,871
IT WAS JUST DURING A PERIOD OF

2796
01:45:43,871 --> 01:45:54,048
ONE WEEK.

2797
01:45:54,281 --> 01:46:05,192
>> JUST A QUICK QUESTION
FOR DRO

2798
01:46:06,560 --> 01:46:07,394
CONTROL VIE REAM NA TO 15

2799
01:46:07,394 --> 01:46:07,828
COPIES.

2800
01:46:07,828 --> 01:46:09,163
I WAS WONDERING WHAT WAS SPECIAL

2801
01:46:09,163 --> 01:46:10,297
ABOUT THAT MONKEY AS COMPARED TO

2802
01:46:10,297 --> 01:46:11,165
OTHERS.

2803
01:46:11,165 --> 01:46:14,535
>> SO WE HAVE TWO OF THOSE

2804
01:46:14,535 --> 01:46:16,737
ANIMALS WE SACRIFICE ONE YEAR

2805
01:46:16,737 --> 01:46:18,339
AFTER INTERRUPTION, THEY WERE

2806
01:46:18,339 --> 01:46:22,843
STILL UNDETECTABLE.

2807
01:46:22,843 --> 01:46:25,112
SO AS I SAID BEFORE IF YOU LOOK

2808
01:46:25,112 --> 01:46:27,581
ALL THE GROUP, THERE IS NO

2809
01:46:27,581 --> 01:46:29,016
REDUCTION -- A CONTROL OF

2810
01:46:29,016 --> 01:46:29,783
REBOUNDING VIRUS.

2811
01:46:29,783 --> 01:46:31,352
BUT AS WAS MENTIONED, THERE ARE

2812
01:46:31,352 --> 01:46:33,087
FOUR OF THE 10 ANIMALS WHICH IS

2813
01:46:33,087 --> 01:46:36,957
ACTUALLY A SIGNIFICANT

2814
01:46:36,957 --> 01:46:38,158
REDUCTION -- AND THOSE TWO

2815
01:46:38,158 --> 01:46:42,496
ANIMAL ARE TWO OF THOSE FOUR IN

2816
01:46:42,496 --> 01:46:43,530
WHICH THE TREATMENT WAS

2817
01:46:43,530 --> 01:46:45,933
ASSOCIATED WITH REDUCTION OF

2818
01:46:45,933 --> 01:46:48,369
THE -- RESERVOIR AND THEN BETTER

2819
01:46:48,369 --> 01:46:51,872
CONTROL OF THE REBOUND.

2820
01:46:51,872 --> 01:46:53,807
THAT IS THE MAIN ASSOCIATION,

2821
01:46:53,807 --> 01:46:56,210
THERE'S BEEN A LOT OF WORK

2822
01:46:56,210 --> 01:46:59,613
ONGOING ON THAT -- AND OTHER

2823
01:46:59,613 --> 01:46:59,914
MECHANISMS.

2824
01:46:59,914 --> 01:47:01,715
ONE THING I FORGOT TO MENTION IS

2825
01:47:01,715 --> 01:47:02,850
THAT SINCE THE INTERVENTION

2826
01:47:02,850 --> 01:47:05,552
STARTED TO LATE, WE INFECTED THE

2827
01:47:05,552 --> 01:47:08,055
ANIMAL, KEEP THEM ALIVE FOR MORE

2828
01:47:08,055 --> 01:47:10,658
THAN ONE YEAR, WE WERE ABLE TO

2829
01:47:10,658 --> 01:47:13,093
STRATIFY THE ANIMAL TO BE -- SO

2830
01:47:13,093 --> 01:47:14,528
WE COMPARED THE ANIMAL TO BE NOT

2831
01:47:14,528 --> 01:47:16,163
ONLY ON THE SAME -- HAVING THE

2832
01:47:16,163 --> 01:47:18,332
SAME VIRAL LOAD BEFORE STARTING

2833
01:47:18,332 --> 01:47:19,533
ANTIRETROVIRAL THERAPY BUT HOW

2834
01:47:19,533 --> 01:47:21,201
QUICKLY THEY BECAME UNDETECTABLE

2835
01:47:21,201 --> 01:47:25,773
AND MAIN OT MANY OTHER PARAMETE.

2836
01:47:25,773 --> 01:47:26,707
THE -- POSITIVE OR NOT, ET

2837
01:47:26,707 --> 01:47:27,374
CETERA.

2838
01:47:27,374 --> 01:47:29,109
SO THOSE ARE NOT PARAMETERS THAT

2839
01:47:29,109 --> 01:47:35,316
ARE IMPORTANT FOR THE CONTROL.

2840
01:47:35,316 --> 01:47:36,083
OKAY, THANK YOU.

2841
01:47:36,083 --> 01:47:36,750
[APPLAUSE]

2842
01:47:36,750 --> 01:47:42,623
THANKS A LOT.

2843
01:47:42,623 --> 01:47:43,524
SO I THINK WE WILL GET

2844
01:47:43,524 --> 01:47:45,626
STARTED.

2845
01:47:45,626 --> 01:47:47,861
I AM LEIA NOVACK, A PROGRAM

2846
01:47:47,861 --> 01:47:49,096
OFFICER IN THE PATHOGENESIS AND

2847
01:47:49,096 --> 01:47:50,898
BASIC RESEARCH BRANCH IN THE

2848
01:47:50,898 --> 01:47:52,566
BASIC SCIENCES PROGRAM IN THE

2849
01:47:52,566 --> 01:47:54,902
DIVISION OF AIDS AT NIAID.

2850
01:47:54,902 --> 01:47:57,438
I AM HAPPY TO PRESENT OUR NEXT

2851
01:47:57,438 --> 01:47:59,973
SET OF COLLABORATORY, THE HOPE

2852
01:47:59,973 --> 01:48:02,876
COLLABORATORY BASED AT THE

2853
01:48:02,876 --> 01:48:03,877
GLADSTONE INSTITUTES.

2854
01:48:03,877 --> 01:48:06,280
EXOWP HOPE IS AN ACRONYM FOR HIV

2855
01:48:06,280 --> 01:48:07,781
OBSTRUCTION BY PROGRAMMED

2856
01:48:07,781 --> 01:48:08,716
EPIGENETICS LED BY THREE

2857
01:48:08,716 --> 01:48:10,484
PRINCIPAL INVESTIGATORS.

2858
01:48:10,484 --> 01:48:18,325
MELANIE OTT AT GLADSTONE, LISH

2859
01:48:18,325 --> 01:48:22,262
LOVU AND SUSANA VALENTE.

2860
01:48:22,262 --> 01:48:23,864
I'LL HAND IT OVER TO MELANIE TO

2861
01:48:23,864 --> 01:48:25,099
GET STARTED ON THE OVERVIEW.

2862
01:48:25,099 --> 01:48:29,303
>> THANK YOU, LE.

2863
01:48:29,303 --> 01:48:29,703
IA.

2864
01:48:29,703 --> 01:48:30,270
THANK YOU VERY MUCH.

2865
01:48:30,270 --> 01:48:31,572
WELCOME TO HOPE.

2866
01:48:31,572 --> 01:48:35,342
AS LEIA SAID, I'M MELANIE OTT,

2867
01:48:35,342 --> 01:48:40,814
TOGETHER WITH MY CO-PIs, WE

2868
01:48:40,814 --> 01:48:42,116
CO-LEAD THE HOPE COLLABORATORY.

2869
01:48:42,116 --> 01:48:45,185
HOPE TOGETHER HAS 20 PIs,

2870
01:48:45,185 --> 01:48:47,121
ABOUT 150 MEMBERS AND IS LOCATED

2871
01:48:47,121 --> 01:48:50,124
IN SIX COUNTRIES, INCLUDING

2872
01:48:50,124 --> 01:48:51,992
BRAZIL, UGANDA, THAILAND AND

2873
01:48:51,992 --> 01:48:58,465
GERMANY.

2874
01:48:58,465 --> 01:49:01,535
THE PROGRAM IS BASED ON A BLOCK,

2875
01:49:01,535 --> 01:49:03,103
LOCK AND STOP AGENDA, BLOCK

2876
01:49:03,103 --> 01:49:04,738
MEANS INHIBITING HIV

2877
01:49:04,738 --> 01:49:05,506
TRANSCRIPTION, LOCK MEANS

2878
01:49:05,506 --> 01:49:07,040
KEEPING THE VIRUS BLOCKED

2879
01:49:07,040 --> 01:49:09,643
WITHOUT THERAPY, AND STOP MEANS

2880
01:49:09,643 --> 01:49:11,278
INACTIVATING PRO VIRAL DNA IN

2881
01:49:11,278 --> 01:49:13,680
THE GENOME.

2882
01:49:13,680 --> 01:49:15,082
TOGETHER WE'RE USING BOTH

2883
01:49:15,082 --> 01:49:16,683
CHEMICAL AND GENE THERAPY

2884
01:49:16,683 --> 01:49:18,819
APPROACHES TO PERMANENTLY

2885
01:49:18,819 --> 01:49:19,920
INACTIVATE HIV.

2886
01:49:19,920 --> 01:49:23,023
WE ARE ALSO A NEW COLLABORATORY

2887
01:49:23,023 --> 01:49:24,558
IN OUR THIRD YEAR, AND JUST IN

2888
01:49:24,558 --> 01:49:28,662
THE LAST YEAR -- SORRY, I WANTED

2889
01:49:28,662 --> 01:49:31,198
TO SAY THAT WE THINK THAT THIS

2890
01:49:31,198 --> 01:49:34,134
BLOCK, LOCK AND STOP AGENDA IS

2891
01:49:34,134 --> 01:49:37,304
VERY RELEVANT BASED ON OUR NEW

2892
01:49:37,304 --> 01:49:39,339
KNOWLEDGE THAT TRANSCRIPTIONALLY

2893
01:49:39,339 --> 01:49:41,875
ACTIVE CELLS PERSIST DESPITE ART

2894
01:49:41,875 --> 01:49:43,811
AND THIS IS DONE IN MANY PAPERS

2895
01:49:43,811 --> 01:49:45,245
AND MANY OF THE AUTHORS ARE HERE

2896
01:49:45,245 --> 01:49:50,684
IN THE AUDIENCE.

2897
01:49:50,684 --> 01:49:52,886
THIS REALLY IN THE LAST TWO

2898
01:49:52,886 --> 01:49:53,987
YEARS HAS SHOWN WE HAVE A

2899
01:49:53,987 --> 01:49:56,957
GLARING LOOPHOLE IN OUR ART

2900
01:49:56,957 --> 01:49:59,726
REGIMEN CURRENTLY BECAUSE WE ARE

2901
01:49:59,726 --> 01:50:01,161
NOT INCLUDING ANY DRUGS

2902
01:50:01,161 --> 01:50:01,695
TARGETING TRANSCRIPTION.

2903
01:50:01,695 --> 01:50:04,364
AND I THINK THIS ALLOWS THESE

2904
01:50:04,364 --> 01:50:05,032
TRANSCRIPTIONALLY ACTIVE CELLS

2905
01:50:05,032 --> 01:50:08,001
TO PERSIST AND TO PROLIFERATE,

2906
01:50:08,001 --> 01:50:10,938
AND WE ARE POISED TO AND ARE

2907
01:50:10,938 --> 01:50:16,710
AIMING TO CLOSE THIS LOOPHOLE.

2908
01:50:16,710 --> 01:50:17,144
TRANSCRIPTION -- HIV

2909
01:50:17,144 --> 01:50:19,980
TRANSCRIPTION IS REALLY BASED ON

2910
01:50:19,980 --> 01:50:20,647
THREE FACTORS.

2911
01:50:20,647 --> 01:50:24,751
THE VIRALLY ENCODED -- PROTEIN,

2912
01:50:24,751 --> 01:50:28,255
THE TAR STEM LOOP RNA, AND THE

2913
01:50:28,255 --> 01:50:30,123
HOST SUPER ELONGATION COMPLEX

2914
01:50:30,123 --> 01:50:32,493
ALSO CALLED SEC, THAT TOGETHER

2915
01:50:32,493 --> 01:50:41,969
REALLY ALLOW THE PRO L POLYMERA-

2916
01:50:41,969 --> 01:50:44,471
WE HAD HOPED WE'RE TARGETING

2917
01:50:44,471 --> 01:50:47,207
BOTH THE VIRUS AND THE HOST.

2918
01:50:47,207 --> 01:50:50,677
WITH A PIPELINE OF MODALITIES

2919
01:50:50,677 --> 01:50:54,281
THAT RANGE FROM FDA-APPROVED

2920
01:50:54,281 --> 01:51:04,758
DRUGS LIKE SPEAR K SPIRONOLACTO,

2921
01:51:04,758 --> 01:51:06,960
CDK-9, BUT WE ALSO HAVE

2922
01:51:06,960 --> 01:51:08,428
DEVELOPED SEVERAL MODALITIES

2923
01:51:08,428 --> 01:51:11,698
THAT ARE CRISPR BASED, THAT ARE

2924
01:51:11,698 --> 01:51:13,901
TARGETING EITHER CORECEPTORS OR

2925
01:51:13,901 --> 01:51:16,036
THE SUPERELONGATION COMPLEX.

2926
01:51:16,036 --> 01:51:19,540
TARGETING THE VI VIRUS, WE HAVEA

2927
01:51:19,540 --> 01:51:22,142
LONG-STANDING EFFORT IN

2928
01:51:22,142 --> 01:51:23,877
DEVELOPING TAT INHIBITORS BASED

2929
01:51:23,877 --> 01:51:26,280
ON SUSANA'S EFFORTS THAT REALLY

2930
01:51:26,280 --> 01:51:27,681
RANGE FROM CONTINUOUS SCREENING

2931
01:51:27,681 --> 01:51:29,316
THAT WE'RE CURRENTLY DOING TO

2932
01:51:29,316 --> 01:51:31,184
PRE-CLINICAL TRIALS IN HUMANIZED

2933
01:51:31,184 --> 01:51:33,220
MICE AND NHPs.

2934
01:51:33,220 --> 01:51:36,156
AGAIN, WE'RE USING BASE EDITING

2935
01:51:36,156 --> 01:51:37,724
CRISPR-BASED BASE EDITING TO

2936
01:51:37,724 --> 01:51:41,395
TARGET SEQUENCES IN HIV TO

2937
01:51:41,395 --> 01:51:43,797
INACTIVATE HIV, AND WE'RE ALSO

2938
01:51:43,797 --> 01:51:46,900
WORKING WITH A RECOMBINATION

2939
01:51:46,900 --> 01:51:48,802
CALLED BREC1 THAT DOESN'T

2940
01:51:48,802 --> 01:51:49,903
REQUIRE ANY GUIDE RNA AND

2941
01:51:49,903 --> 01:51:53,173
DIRECTLY IS TRAINED TO RECOGNIZE

2942
01:51:53,173 --> 01:51:56,310
THE HIV PRO VIRUS, EITHER AS

2943
01:51:56,310 --> 01:51:58,078
A -- OF THE ACTIVE FORM FOR

2944
01:51:58,078 --> 01:52:00,681
EXCISION OR AS A CATALYTICALLY

2945
01:52:00,681 --> 01:52:07,287
INACTIVE FORM FOR TARGETING.

2946
01:52:07,287 --> 01:52:08,555
AS I SAID WE'RE A NEW

2947
01:52:08,555 --> 01:52:09,323
COLLABORATORY, IN OUR THIRD

2948
01:52:09,323 --> 01:52:10,757
YEAR, BUT WE HAVE BEEN QUITE

2949
01:52:10,757 --> 01:52:11,925
PRODUCTIVE JUST IN THE LAST

2950
01:52:11,925 --> 01:52:15,095
YEAR, WE HAD ABOUT

2951
01:52:15,095 --> 01:52:18,365
21 PUBLICATIONS.

2952
01:52:18,365 --> 01:52:19,800
AN INTERESTING STUDY IN NATURE

2953
01:52:19,800 --> 01:52:20,968
THAT REALLY TOLD US A LOT MORE

2954
01:52:20,968 --> 01:52:22,603
ABOUT THE BIOPHYSICS OF THE TAR

2955
01:52:22,603 --> 01:52:25,105
ELEMENT THAT WE'RE USING, BUT

2956
01:52:25,105 --> 01:52:27,708
ALSO A VERY INTERESTING STUDY

2957
01:52:27,708 --> 01:52:30,777
USING CHROMATIN AFFINITY

2958
01:52:30,777 --> 01:52:32,946
PURIFICATION AND MASS

2959
01:52:32,946 --> 01:52:33,981
SPECTROMETRY TO REALLY IDENTIFY

2960
01:52:33,981 --> 01:52:35,449
NEW FACTORS AT THE HIV PROMOTER

2961
01:52:35,449 --> 01:52:38,051
THAT IS RELEVANT FOR LATENCY OR

2962
01:52:38,051 --> 01:52:42,089
ACTIVATION.

2963
01:52:42,089 --> 01:52:44,057
IN 2023, WE HAVE LEARNED FROM

2964
01:52:44,057 --> 01:52:45,359
ENDOGENOUS RETROVIRUSES ABOUT

2965
01:52:45,359 --> 01:52:48,095
HIV SILENCING WITH NEW

2966
01:52:48,095 --> 01:52:50,230
COMPUTATIONAL MOLECULES AT BULK

2967
01:52:50,230 --> 01:52:52,866
AND SINGLE CELL RESOLUTION.

2968
01:52:52,866 --> 01:52:55,502
WE HAVE BLOCKED HIV

2969
01:52:55,502 --> 01:52:56,803
TRANSCRIPTION WITH

2970
01:52:56,803 --> 01:52:58,605
SPIRONOLACTONE ALONE OR IN

2971
01:52:58,605 --> 01:53:00,273
COMBINATION WITH HUMAN ICED

2972
01:53:00,273 --> 01:53:01,608
MIETION, NHPs AND IN PEOPLE.

2973
01:53:01,608 --> 01:53:06,680
THIS WILL BE PRESENTED BY SUSANA

2974
01:53:06,680 --> 01:53:07,547
VALENTE FOR RF2.

2975
01:53:07,547 --> 01:53:09,149
WE HAVE RENDERED HUMAN CELLS

2976
01:53:09,149 --> 01:53:10,684
RESISTANT TO HIV TRANSCRIPTION

2977
01:53:10,684 --> 01:53:13,887
THROUGH PRIME EDITING OF THE

2978
01:53:13,887 --> 01:53:16,023
CYCLIN T1 GENE, AND WE HAVE

2979
01:53:16,023 --> 01:53:16,823
REACHED MORE THAN EIGHT'

2980
01:53:16,823 --> 01:53:18,225
THOUSAND PEOPLE IN COMMUNITY

2981
01:53:18,225 --> 01:53:19,626
EVENTS IN THE U.S., CANADA,

2982
01:53:19,626 --> 01:53:22,462
UGANDA AND BRAZIL AND ON SOCIAL

2983
01:53:22,462 --> 01:53:23,964
MEDIA, AND THIS WILL SH

2984
01:53:23,964 --> 01:53:27,367
PRESENTED BY PATRICIA

2985
01:53:27,367 --> 01:53:28,535
DEFECHEREUX FOR THE COMMUNITY

2986
01:53:28,535 --> 01:53:29,636
ENGAGEMENT.

2987
01:53:29,636 --> 01:53:32,172
WE HAVE BROUGHT SIX YOUNG, VERY

2988
01:53:32,172 --> 01:53:34,174
TALENTED YOUNG INVESTIGATORS

2989
01:53:34,174 --> 01:53:35,442
FROM HOPE TO THIS MEETING, AND I

2990
01:53:35,442 --> 01:53:37,177
HOPE YOU WILL ALL MEET THEM AT

2991
01:53:37,177 --> 01:53:38,679
THE POSTER SESSION.

2992
01:53:38,679 --> 01:53:40,714
WE ALSO JUST HAD OUR SECOND

2993
01:53:40,714 --> 01:53:46,420
ANNUAL MEETING AT THE BUC

2994
01:53:46,420 --> 01:53:47,954
INSTITUTE IN MARIN.

2995
01:53:47,954 --> 01:53:49,489
WE HAD VERY SPECIAL GUESTS IN

2996
01:53:49,489 --> 01:53:51,091
THE AUDIENCE.

2997
01:53:51,091 --> 01:53:53,960
WE HAD THE VERY SPECIAL GUESTS

2998
01:53:53,960 --> 01:53:55,495
JOINING US.

2999
01:53:55,495 --> 01:53:56,897
ONE IS PAUL EDMONDS AND I KNOW

3000
01:53:56,897 --> 01:54:00,400
THAT HE'S HERE IN THE AUDIENCE,

3001
01:54:00,400 --> 01:54:04,404
AND THE OTHER ONE WAS MARK, BOTH

3002
01:54:04,404 --> 01:54:05,739
CURED FROM HIV AND IT WAS VERY

3003
01:54:05,739 --> 01:54:07,007
INSPIRING TO HAVE THEM WITH US.

3004
01:54:07,007 --> 01:54:08,208
APART FROM GREAT SCIENCE, WE

3005
01:54:08,208 --> 01:54:10,177
ALSO DID A COMMUNITY ARTS

3006
01:54:10,177 --> 01:54:12,245
INTEGRATED RESEARCH EVENT WHERE

3007
01:54:12,245 --> 01:54:14,514
WE ACTUALLY DANCED THE BLOCK,

3008
01:54:14,514 --> 01:54:20,654
LOCK AND STOP AGENDA.

3009
01:54:20,654 --> 01:54:23,857
PRITI AND I ARE COORGANIZING A

3010
01:54:23,857 --> 01:54:28,428
KEYSTONE MEETING NEXT APRIL IN

3011
01:54:28,428 --> 01:54:29,896
HANOVER, AND WE HOPE THAT WE SEE

3012
01:54:29,896 --> 01:54:33,333
A LOT OF YOU THERE.

3013
01:54:33,333 --> 01:54:35,268
WE HAVE A GREAT WEBSITE IF YOU

3014
01:54:35,268 --> 01:54:38,672
WANT TO LEARN MORE ABOUT OUR

3015
01:54:38,672 --> 01:54:40,407
RESEARCH OR FOLLOW US ON X, AND

3016
01:54:40,407 --> 01:54:42,876
WITHOUT FURTHER ADO, I THANK YOU

3017
01:54:42,876 --> 01:54:44,444
FOR YOUR ATTENTION.

3018
01:54:44,444 --> 01:54:46,179
THE NIH FOR THEIR SUPPORT, AND I

3019
01:54:46,179 --> 01:54:50,917
HAND OVER TO DOUG FOR RF1.

3020
01:54:50,917 --> 01:54:58,291
[APPLAUSE]

3021
01:54:58,291 --> 01:54:59,626
>> THANKS, MELANIE.

3022
01:54:59,626 --> 01:55:01,361
MY NAME IS DOUGLAS NIXON.

3023
01:55:01,361 --> 01:55:03,163
I AM GOING TO GIVE THE OVERVIEW

3024
01:55:03,163 --> 01:55:05,065
FOR RF1.

3025
01:55:05,065 --> 01:55:06,299
AND THIS YEAR WE'RE GOING TO

3026
01:55:06,299 --> 01:55:07,934
FOCUS IN ON ONE OF THE ELEMENTS

3027
01:55:07,934 --> 01:55:11,471
OF RF1, AND IT'S ABOUT

3028
01:55:11,471 --> 01:55:13,673
HARNESSING HUMAN ENDOGENOUS

3029
01:55:13,673 --> 01:55:19,112
RETROVIRUSES AND KRAB ZINC

3030
01:55:19,112 --> 01:55:29,589
FINGER PROTEINS TO LOCK HIV.

3031
01:55:29,923 --> 01:55:30,190
SO

3032
01:55:30,190 --> 01:55:31,291
YOU'VE ALREADY HEARD FROM

3033
01:55:31,291 --> 01:55:32,459
MELANIE ABOUT THE OVERARCHING

3034
01:55:32,459 --> 01:55:35,061
GOALS OF THE HOPE SCIENTIFIC

3035
01:55:35,061 --> 01:55:36,496
PROGRAM TO BLOCK, LOCK AND STOP

3036
01:55:36,496 --> 01:55:37,697
VIRUS.

3037
01:55:37,697 --> 01:55:40,233
AND FOR THE PRESENTATION TODAY,

3038
01:55:40,233 --> 01:55:41,835
WE'RE GOING TO BE FOCUSED ON THE

3039
01:55:41,835 --> 01:55:45,138
LOCK COMPONENT.

3040
01:55:45,138 --> 01:55:48,742
RF1 HAS SOME GREAT MEMBERS,

3041
01:55:48,742 --> 01:55:51,545
CO-DIRECTORS WITH SUSANA VALENTE

3042
01:55:51,545 --> 01:55:54,447
WHO IS PRESENTING FOR RF2, AND I

3043
01:55:54,447 --> 01:55:55,048
THINK ONE OF THE STRENGTHS OF

3044
01:55:55,048 --> 01:55:57,017
HOPE IS THE WAY THAT THE RFs

3045
01:55:57,017 --> 01:55:58,318
INTERACT WITH EACH OTHER AND

3046
01:55:58,318 --> 01:56:04,291
SHARE MEMBERS.

3047
01:56:04,291 --> 01:56:06,059
THIS IS THE BASIC SCIENCE

3048
01:56:06,059 --> 01:56:10,530
COMPONENT, THE HYPOTHESIS THAT

3049
01:56:10,530 --> 01:56:13,033
HIV TRANSCRIPTION AND STRUCTURE

3050
01:56:13,033 --> 01:56:14,234
OF UNIQUE TARGETS FOR SILENCING.

3051
01:56:14,234 --> 01:56:15,235
WE HAVE FOUR GOALS.

3052
01:56:15,235 --> 01:56:20,040
FIRST TO IDENTIFY HOST REGULA 

3053
01:56:20,040 --> 01:56:23,009
REGULATORS, HOW WE POTENTIALLY

3054
01:56:23,009 --> 01:56:26,146
COULD SILENCE HIV, TO DEFINE THE

3055
01:56:26,146 --> 01:56:29,850
ROLE OF TAT IN HIV SILENCING AND

3056
01:56:29,850 --> 01:56:32,452
TO USE ADVANCED OMIC TECHNIQUES

3057
01:56:32,452 --> 01:56:33,553
TO CHARACTERIZE HOW SILENCING

3058
01:56:33,553 --> 01:56:40,460
CAN OCCUR.

3059
01:56:40,460 --> 01:56:41,461
THERE HAS BEEN PUBLICATIONS IN

3060
01:56:41,461 --> 01:56:43,263
ALL OF THESE AREAS WI BUT WE HAE

3061
01:56:43,263 --> 01:56:45,031
CHOSEN TO FOCUS ON ONE STORY

3062
01:56:45,031 --> 01:56:46,366
TODAY FROM GOAL TWO.

3063
01:56:46,366 --> 01:56:49,836
FOR THE PLAIN LANGUAGE SLIDE,

3064
01:56:49,836 --> 01:56:53,673
WHAT'S THE KEY QUESTION?

3065
01:56:53,673 --> 01:56:55,075
ANCIENT VIRUSES WITHIN

3066
01:56:55,075 --> 01:56:56,376
EVERYONE'S DNA IN THIS ROOM THAT

3067
01:56:56,376 --> 01:56:58,678
HAVE BEEN NATURALLY CONTROLLED.

3068
01:56:58,678 --> 01:57:00,981
WE ALSO HAVE THIS ARMY OF KRAB

3069
01:57:00,981 --> 01:57:02,816
ZINC FINGER PROTEINS, WHICH

3070
01:57:02,816 --> 01:57:04,451
REPRESS ENDOGENOUS RETROVIRUS,

3071
01:57:04,451 --> 01:57:05,986
SO THE QUESTION WE WANT TO KNOW

3072
01:57:05,986 --> 01:57:08,722
IS, CAN WE LEARN FROM THESE

3073
01:57:08,722 --> 01:57:10,724
ELEMENTS HOW TO POTENTIALLY

3074
01:57:10,724 --> 01:57:12,559
CONTROL THE HIV VIRUSES THAT ARE

3075
01:57:12,559 --> 01:57:17,130
INFECTING HUMAN CELLS.

3076
01:57:17,130 --> 01:57:19,466
KEY TALK HOME MESSAGE, IMMUNE

3077
01:57:19,466 --> 01:57:21,001
CELLS INFECTED WITH HIV APPEAR

3078
01:57:21,001 --> 01:57:25,505
TO HAVE IMMUNE MECHANISMS

3079
01:57:25,505 --> 01:57:28,108
REGULATING THE ACTIVITY OF

3080
01:57:28,108 --> 01:57:29,476
HERVs, AND IMMUNE CELLS U.S.

3081
01:57:29,476 --> 01:57:31,711
SEPTEMBER IBLG TO INFECTION BY

3082
01:57:31,711 --> 01:57:33,346
HIV ALREADY KNOW HOW TO CONTROL

3083
01:57:33,346 --> 01:57:35,215
THESE VIRUS.

3084
01:57:35,215 --> 01:57:36,716
EXCITINGLY SOME KRAB ZINC FINGER

3085
01:57:36,716 --> 01:57:38,952
PROTEINS CAN DIRECTLY REPRESS

3086
01:57:38,952 --> 01:57:39,452
HIV.

3087
01:57:39,452 --> 01:57:40,654
SO WE MIGHT BE ABLE TO USE THESE

3088
01:57:40,654 --> 01:57:41,855
SAME CELLULAR MECHANISMS THAT

3089
01:57:41,855 --> 01:57:46,993
CONTROL OUR NATURAL ENDOGENOUS

3090
01:57:46,993 --> 01:57:48,728
RETROVIRUSES TO CONTROL HIV PRO

3091
01:57:48,728 --> 01:57:50,263
VIRUSES AND WHY SHOULD WE BE

3092
01:57:50,263 --> 01:57:51,598
EXCITED IN WOULDN'T IT BE COOL

3093
01:57:51,598 --> 01:57:53,533
IF THE WAY OUR CELLS DEFEATED

3094
01:57:53,533 --> 01:57:54,734
THESE ANCIENT VIRUSES COULD LEAD

3095
01:57:54,734 --> 01:57:57,470
TO A NOVEL WAY TO GET RID OF

3096
01:57:57,470 --> 01:57:57,737
HIV.

3097
01:57:57,737 --> 01:58:00,040
ONE OF THE SHOCKS WHEN THE HUMAN

3098
01:58:00,040 --> 01:58:02,542
GENOME WAS SEQUENCED WAS HOW

3099
01:58:02,542 --> 01:58:04,244
SMALL A FRACTION OF THIS PIZZA

3100
01:58:04,244 --> 01:58:06,046
PIE IS FOR CODING GENES, AND A

3101
01:58:06,046 --> 01:58:09,549
LARGE COMPONENT OF THE GENOME

3102
01:58:09,549 --> 01:58:11,952
HAS TRANSPOSABLE ELEMENTS, OF

3103
01:58:11,952 --> 01:58:13,119
WHICH A LARGE COMPONENT ARE

3104
01:58:13,119 --> 01:58:13,653
RETRO ELEMENTS.

3105
01:58:13,653 --> 01:58:15,055
WE'RE GOING TO FOCUS ON THE 8%

3106
01:58:15,055 --> 01:58:17,590
OF THE GENOME, ALL OF OUR

3107
01:58:17,590 --> 01:58:19,259
GENOMES THAT ARE HUMAN

3108
01:58:19,259 --> 01:58:20,760
ENDOGENOUS RETROVIRUSES, THESE

3109
01:58:20,760 --> 01:58:22,595
REPRESENT PAST INFECTIOUS RETRO

3110
01:58:22,595 --> 01:58:25,565
VIE RETROVIRUSES WHICH INFECTED

3111
01:58:25,565 --> 01:58:28,835
GERMLINE CELLS AND HAVE GOT

3112
01:58:28,835 --> 01:58:30,670
PASSED FROM PARENT TO OFFSPRING

3113
01:58:30,670 --> 01:58:33,073
OVER TIME AND HAVE BECOME

3114
01:58:33,073 --> 01:58:36,276
FIXATED, OFTEN DELETED, OFTEN

3115
01:58:36,276 --> 01:58:39,045
MUTATED, AND NOW WE HAVE ABOUT

3116
01:58:39,045 --> 01:58:40,947
400,000 OF THESE FRAGMENTS IN

3117
01:58:40,947 --> 01:58:43,049
OUR GENOME, SCATTERED THROUGHOUT

3118
01:58:43,049 --> 01:58:45,285
THE CHROMOSOMAL MAP, OF WHICH

3119
01:58:45,285 --> 01:58:47,287
3,000 ARE STILL FULL LENGTH PRO

3120
01:58:47,287 --> 01:58:47,620
VIRUSES.

3121
01:58:47,620 --> 01:58:49,255
THERE ARE HUNDREDS OF FAMILIES,

3122
01:58:49,255 --> 01:58:51,858
EACH A DISTINCT RETROVIRUS.

3123
01:58:51,858 --> 01:58:53,927
WE KNOW THAT THERE'S SENSITIVE

3124
01:58:53,927 --> 01:58:55,228
MARKERS OF CELL TYPES AND CELL

3125
01:58:55,228 --> 01:58:56,629
STATES, AND THEY'RE REALLY

3126
01:58:56,629 --> 01:59:00,367
TIGHTLY REGULATED.

3127
01:59:00,367 --> 01:59:02,569
NICK IN MY LAB PRODUCED THIS

3128
01:59:02,569 --> 01:59:06,072
SIMPLIFIED DIAGRAM TO SHARE THE

3129
01:59:06,072 --> 01:59:10,176
MANY TRANSCRIPTIONAL WAYS THAT

3130
01:59:10,176 --> 01:59:12,312
HERVS ARE NORMALLY REPRESSED,

3131
01:59:12,312 --> 01:59:14,514
BOTH PRE AND POST

3132
01:59:14,514 --> 01:59:15,582
TRANSCRIPTIONALLY, AND TODAY I'M

3133
01:59:15,582 --> 01:59:18,651
GOING TO TALK ABOUT WORK FROM

3134
01:59:18,651 --> 01:59:21,488
CEDRIC'S LAB FOR KRAB ZINC

3135
01:59:21,488 --> 01:59:23,323
FINGER PROTEINS WHICH HAVE

3136
01:59:23,323 --> 01:59:25,625
CO-EVOLVES TO SILENCE HUMAN

3137
01:59:25,625 --> 01:59:26,292
ENDOGENOUS RETROVIRUSES.

3138
01:59:26,292 --> 01:59:28,128
WE THINK THAT'S ONE OF THE MAJOR

3139
01:59:28,128 --> 01:59:30,463
ROLES OF THESE KRAB ZINC FINGER

3140
01:59:30,463 --> 01:59:31,031
PROTEINS.

3141
01:59:31,031 --> 01:59:32,332
THERE'S AROUND 400 OF THEM IN

3142
01:59:32,332 --> 01:59:34,734
THE HUMAN GENOME.

3143
01:59:34,734 --> 01:59:36,703
MOST BIND SPECIFIC HERV

3144
01:59:36,703 --> 01:59:38,338
FAMILIES.

3145
01:59:38,338 --> 01:59:39,739
AND THEY'RE HIGHLY REGULATED IN

3146
01:59:39,739 --> 01:59:41,408
HUMAN DEVELOPMENT, BUT THEY

3147
01:59:41,408 --> 01:59:43,309
HAVEN'T BEEN REALLY WELL STUDIED

3148
01:59:43,309 --> 01:59:46,046
IN IMMUNITY AND INFECTION,

3149
01:59:46,046 --> 01:59:47,180
ALTHOUGH THERE'S SOME POSTERS,

3150
01:59:47,180 --> 01:59:53,553
FOR EXAMPLE, FR THAT I WOULD

3151
01:59:53,553 --> 01:59:55,522
ENCOURAGE YOU TO LOOK AT WHICH

3152
01:59:55,522 --> 01:59:59,893
ALSO GO INTO KRAB ZINC FINGER

3153
01:59:59,893 --> 02:00:00,994
PROTEIN.

3154
02:00:00,994 --> 02:00:02,495
WHAT DOES THE BATTLEFIELD LOOK

3155
02:00:02,495 --> 02:00:03,930
LIKE IN T-CELLS DURING HIV

3156
02:00:03,930 --> 02:00:05,031
INFECTION.

3157
02:00:05,031 --> 02:00:07,100
SO SABRINA LEDI REALIZED THAT IN

3158
02:00:07,100 --> 02:00:08,201
THE LITERATURE, THERE WAS SOME

3159
02:00:08,201 --> 02:00:11,004
RNA SEQ DATA THAT SHE COULD MINE

3160
02:00:11,004 --> 02:00:15,375
FROM A PAPER IN EMBO JOURNAL

3161
02:00:15,375 --> 02:00:16,810
WHICH HAD USED PRIMARY CELLS TO

3162
02:00:16,810 --> 02:00:18,445
INFECT WITH HIV AFTER

3163
02:00:18,445 --> 02:00:21,181
ACTIVATION, AND THEN WERE TAKEN

3164
02:00:21,181 --> 02:00:22,816
AT DIFFERENT TIME POINTS.

3165
02:00:22,816 --> 02:00:26,319
AND WE SAW THAT THERE WERE BOTH

3166
02:00:26,319 --> 02:00:31,024
UPREGULATED AND DOWN DIAGNOSE DD

3167
02:00:31,024 --> 02:00:32,125
ENDOGENOUS RETROVIRUSES AS WELL

3168
02:00:32,125 --> 02:00:33,526
AS KRAB ZINC FINGERS.

3169
02:00:33,526 --> 02:00:35,028
SOME OF THESE LOOK QUITE

3170
02:00:35,028 --> 02:00:41,267
FAMILIAR TO CEDRIC.

3171
02:00:41,267 --> 02:00:42,702
BECAUSE THESE HE HAD PREVIOUSLY

3172
02:00:42,702 --> 02:00:46,439
SHOWN TO BE INTIMATELY RELATED

3173
02:00:46,439 --> 02:00:53,279
TO BE SHOWN TO INNATE IMMUNITY.

3174
02:00:53,279 --> 02:00:55,381
MANY PAIRS WERE ANTICORRELATED

3175
02:00:55,381 --> 02:00:57,317
IN EXPRESSION DURING THE HIV

3176
02:00:57,317 --> 02:00:58,952
INFECTION TIME COURSE.

3177
02:00:58,952 --> 02:01:00,587
SO IN OTHER WORDS, IF YOU LOOK

3178
02:01:00,587 --> 02:01:04,457
AT ONE OF THESE, THE LTR12C

3179
02:01:04,457 --> 02:01:05,725
ENDOGENOUS RETROVIRUS AND THE

3180
02:01:05,725 --> 02:01:08,361
ZINC F2, THAT THEY DIVERGE OVER

3181
02:01:08,361 --> 02:01:11,364
THE COURSE OF THE DAYS POST

3182
02:01:11,364 --> 02:01:13,066
INFECTION.

3183
02:01:13,066 --> 02:01:17,537
AND SABRINA WENT ON TO CONFIRM

3184
02:01:17,537 --> 02:01:20,940
THIS BINDING PROFILE.

3185
02:01:20,940 --> 02:01:23,977
SO THERE'S A DYNAMIC INTERPLAY

3186
02:01:23,977 --> 02:01:26,146
BETWEEN HERV AND KRAB ZINC

3187
02:01:26,146 --> 02:01:27,380
FINGER CONTROL ARE DURING HIV

3188
02:01:27,380 --> 02:01:28,781
INFECTION AND THIS CAN MODULATE

3189
02:01:28,781 --> 02:01:31,184
THE IMMUNE RESPONSE TO HIV.

3190
02:01:31,184 --> 02:01:33,153
SO HERVs MAY HAVE EFFECTS ON

3191
02:01:33,153 --> 02:01:35,989
ANTIVIRAL GENES NEARBY, AND THEN

3192
02:01:35,989 --> 02:01:41,995
THIS REPRESSIVE COMPLEX TO

3193
02:01:41,995 --> 02:01:42,962
KAP1 OR -- 28 CAN HAVE AN

3194
02:01:42,962 --> 02:01:45,832
IMPORTANT REPRESSION AND CAN IN

3195
02:01:45,832 --> 02:01:48,768
ESSENCE CONTROL INNATE IMMUNE

3196
02:01:48,768 --> 02:01:49,068
RESPONSES.

3197
02:01:49,068 --> 02:01:51,704
SO THE NEXT QUESTION WAS, COULD

3198
02:01:51,704 --> 02:01:53,373
THESE KRAB ZINC FINGER PROTEINS

3199
02:01:53,373 --> 02:01:54,774
DIRECTLY BIND TO AND REPRESS

3200
02:01:54,774 --> 02:01:56,276
HIV.

3201
02:01:56,276 --> 02:01:58,378
SO AS WE ALL KNOW IN THIS FIELD,

3202
02:01:58,378 --> 02:02:00,113
LIKE MANY INTERESTING IDEAS,

3203
02:02:00,113 --> 02:02:03,283
OTHER PEOPLE WORK ON IT AND WE

3204
02:02:03,283 --> 02:02:06,019
FOUND THAT A GREAT PAPER

3205
02:02:06,019 --> 02:02:08,988
SUDDENLY APPEARED IN OUR

3206
02:02:08,988 --> 02:02:10,490
MAILBOXES, EMAIL BOXES, AND THEY

3207
02:02:10,490 --> 02:02:14,861
HAD DONE THE EXPERIMENT THAT WE

3208
02:02:14,861 --> 02:02:15,962
WERE INTERESTED IN DOG.

3209
02:02:15,962 --> 02:02:18,598
IDOING.IT'S A GREAT PAPER.

3210
02:02:18,598 --> 02:02:20,867
THEY SHOWED THAT MULTIPLE KRAB

3211
02:02:20,867 --> 02:02:22,535
ZINC FINGER PROTEINS COULD

3212
02:02:22,535 --> 02:02:25,138
REPRESS HIV BY BINDING TO THE

3213
02:02:25,138 --> 02:02:27,974
LYSINE IN THE PRIMARY BINDING

3214
02:02:27,974 --> 02:02:28,441
SITE.

3215
02:02:28,441 --> 02:02:29,742
THEY FOLLOWED THIS UP BY SHOWING

3216
02:02:29,742 --> 02:02:31,578
IF YOU DID A KNOCKOUT

3217
02:02:31,578 --> 02:02:32,879
EXPERIMENT, YOU COULD PROMOTE

3218
02:02:32,879 --> 02:02:36,583
HIV ACTIVATION, SO SABRINA IN

3219
02:02:36,583 --> 02:02:40,220
CEDRIC'S GROUP LOOKED TO SEE

3220
02:02:40,220 --> 02:02:41,521
WHETHER THERE WAS A RELATIONSHIP

3221
02:02:41,521 --> 02:02:43,690
IN HIV LATENCY BETWEEN KRAB ZINC

3222
02:02:43,690 --> 02:02:45,425
FINGER PROTEINS AND HIV

3223
02:02:45,425 --> 02:02:47,727
REPRESSION AND SHE IDENTIFIED A

3224
02:02:47,727 --> 02:02:49,495
NUMBER OF KRAB ZINC FINGERS

3225
02:02:49,495 --> 02:02:53,433
WHICH APPEARED TO BE ABLE TO

3226
02:02:53,433 --> 02:02:55,602
REPRESS HIV AND THOSE WERE

3227
02:02:55,602 --> 02:02:56,603
UPREGULATED IN THE CONTEXT OF

3228
02:02:56,603 --> 02:03:03,910
THE LATENCY MODEL.

3229
02:03:03,910 --> 02:03:05,912
ZETRON LI WAS ALSO INVESTIGATING

3230
02:03:05,912 --> 02:03:07,413
DIFFERENT ZINC FINGER PROTEINS,

3231
02:03:07,413 --> 02:03:10,450
3, 4 AND 10, AND THEY COULD

3232
02:03:10,450 --> 02:03:11,784
DIRECTLY REPRESS HIV DIRECTLY IN

3233
02:03:11,784 --> 02:03:15,722
A CELL MODEL, AND INDEED UPON

3234
02:03:15,722 --> 02:03:18,524
HIV INFECTION, ONE OF THESE ZINC

3235
02:03:18,524 --> 02:03:19,959
FINGERS, 304, WAS DOWNREGULATED.

3236
02:03:19,959 --> 02:03:22,061
SO HAVING ESTABLISHED THAT

3237
02:03:22,061 --> 02:03:23,029
THERE'S THIS INTERESTING

3238
02:03:23,029 --> 02:03:28,167
RELATIONSHIP BETWEEN FAMILIES OF

3239
02:03:28,167 --> 02:03:29,802
ENDOGENOUS RETROVIRUSES AND ZINC

3240
02:03:29,802 --> 02:03:31,771
FINGER PROTEIN CONTROL, WE THEN

3241
02:03:31,771 --> 02:03:33,406
WANTED TO TRY AND UNDERSTAND

3242
02:03:33,406 --> 02:03:34,540
MORE ABOUT DIFFERENTIAL

3243
02:03:34,540 --> 02:03:36,676
EXPRESSION OF ENDOGENOUS

3244
02:03:36,676 --> 02:03:37,910
RETROVIRUSES IN HIV INFECTED

3245
02:03:37,910 --> 02:03:40,313
CELLS.

3246
02:03:40,313 --> 02:03:42,382
AND THEY LOOKED AT DIFFERENT

3247
02:03:42,382 --> 02:03:44,784
POPULATIONS OF RESERVOIR

3248
02:03:44,784 --> 02:03:46,753
POTENTIAL CELL TYPES,

3249
02:03:46,753 --> 02:03:48,955
CD4 T-CELLS, MONOCYTES,

3250
02:03:48,955 --> 02:03:51,791
MICROGLIA, AND USED A

3251
02:03:51,791 --> 02:03:52,659
COMPUTATIONAL PROGRAM THAT

3252
02:03:52,659 --> 02:03:57,030
MATTHEW BEND AL IN THE LAB USED

3253
02:03:57,030 --> 02:03:58,631
WHICH ALLOWS YOU TO LOOK AT EGGS

3254
02:03:58,631 --> 02:04:00,633
PRETION OF RETROVIRUSES FROM

3255
02:04:00,633 --> 02:04:02,468
BULK RNA SEQ DATA AND FOUND THAT

3256
02:04:02,468 --> 02:04:03,603
INDEED, THESE DIFFERENT CELL

3257
02:04:03,603 --> 02:04:06,539
TYPES COULD BE MARKED BY

3258
02:04:06,539 --> 02:04:08,741
DIFFERENT DIFFERENTIAL

3259
02:04:08,741 --> 02:04:10,910
EXPRESSION OF ENDOGENOUS

3260
02:04:10,910 --> 02:04:12,345
RETROVIRUSES, IN OTHER WORDS,

3261
02:04:12,345 --> 02:04:14,080
HERV O TYPING, YOU CAN IDENTIFY

3262
02:04:14,080 --> 02:04:16,049
CELLS BASED UPON THE COMPLEXITY

3263
02:04:16,049 --> 02:04:18,685
OF DIFFERENTIALLY EXPRESSED

3264
02:04:18,685 --> 02:04:19,452
ENDOGENOUS RETROVIRUS.

3265
02:04:19,452 --> 02:04:21,621
THEN LOOKING AT THE FAMILY

3266
02:04:21,621 --> 02:04:24,257
LEVEL, DOES THIS ENDOGENOUS

3267
02:04:24,257 --> 02:04:25,224
RETROVIRUS TRANSCRIPTIONAL

3268
02:04:25,224 --> 02:04:28,528
ACTIVITY ALLOW YOU TO

3269
02:04:28,528 --> 02:04:29,495
INVESTIGATE DIFFERENT CELL TYPES

3270
02:04:29,495 --> 02:04:32,231
AND INDEED IT DOES.

3271
02:04:32,231 --> 02:04:34,000
YOU CAN FIND INDIVIDUAL FAMILIES

3272
02:04:34,000 --> 02:04:36,769
WHICH ARE ONLY EXPRESSED IN

3273
02:04:36,769 --> 02:04:38,071
CD4 T-CELLS OR PREDOMINANTLY

3274
02:04:38,071 --> 02:04:39,806
EXPRESSED IN MONOCYTES, AND THEN

3275
02:04:39,806 --> 02:04:44,610
YOU CAN ALSO FIND ENDOGENOUS

3276
02:04:44,610 --> 02:04:46,412
RETROVIRUS FAMILIES EXPRESSED

3277
02:04:46,412 --> 02:04:48,348
BOTH IN MONOCYTES AND

3278
02:04:48,348 --> 02:04:48,648
CD4 T-CELLS.

3279
02:04:48,648 --> 02:04:50,516
SO HAVING IDENTIFIED THAT WE

3280
02:04:50,516 --> 02:04:54,120
COULD HERV TYPE CELLS AT THE

3281
02:04:54,120 --> 02:04:55,888
FAMILY LEVEL, WE WANTED TO ASK

3282
02:04:55,888 --> 02:05:01,461
WITH KECAN WE DO THIS AT THE SIE

3283
02:05:01,461 --> 02:05:02,562
CELL RNA LEVEL.

3284
02:05:02,562 --> 02:05:04,964
IT ALLOWS TO YOU DISCOVER

3285
02:05:04,964 --> 02:05:07,567
HETEROGENEITY, IT ALLOWS YOU TO

3286
02:05:07,567 --> 02:05:13,906
IDENTIFY CELL-CELL INTERACTIONS

3287
02:05:13,906 --> 02:05:21,013
AND -- COULD WE DETECT WITH

3288
02:05:21,013 --> 02:05:21,914
SINGLE CELL RNA SEQ AND WE WENT

3289
02:05:21,914 --> 02:05:27,487
TO A 10X SET FROM ONE HEALTHY

3290
02:05:27,487 --> 02:05:31,991
FEMALE, AND THEY RAN STARSOLO.

3291
02:05:31,991 --> 02:05:34,093
THEY THEN RAN THEIR NEW PROGRAM

3292
02:05:34,093 --> 02:05:35,928
STELLARSCOPE AND THEY COMPLETED

3293
02:05:35,928 --> 02:05:38,765
CELL TYPE ASSIGNMENTS WITH

3294
02:05:38,765 --> 02:05:40,833
AZIMUTH AND PBMC REFERENCES.

3295
02:05:40,833 --> 02:05:42,568
THEY FOUND THAT INDEED YOU COULD

3296
02:05:42,568 --> 02:05:44,637
IDENTIFY A SINGLE CELL LEVEL

3297
02:05:44,637 --> 02:05:46,406
EXPRESSIONS OF ENDOGENOUS

3298
02:05:46,406 --> 02:05:46,739
RETROVIRUSES.

3299
02:05:46,739 --> 02:05:51,144
IT APPEARS THAT DENDRITIC CELLS

3300
02:05:51,144 --> 02:05:54,046
HAVE THE HIGHEST PROPORTION OF

3301
02:05:54,046 --> 02:05:54,914
ENDOGENOUS RETROVIRUS EXPRESSION

3302
02:05:54,914 --> 02:05:56,716
IN THE LEUKOCYTE POPULATIONS AND

3303
02:05:56,716 --> 02:05:59,318
THAT'S DRIVEN BY THE HIGHEST

3304
02:05:59,318 --> 02:06:07,660
EXPRESSION OF PLASMA S -- DIFFET

3305
02:06:07,660 --> 02:06:09,162
AMOUNTS IN DIFFERENT CELL

3306
02:06:09,162 --> 02:06:09,695
SUBTYPES.

3307
02:06:09,695 --> 02:06:10,897
THE ADVANTAGE OF THE SINGLE CELL

3308
02:06:10,897 --> 02:06:13,299
ALLOWS US TO PUT A

3309
02:06:13,299 --> 02:06:15,268
LOCUS-SPECIFIC RESOLUTION ON

3310
02:06:15,268 --> 02:06:15,935
THIS.

3311
02:06:15,935 --> 02:06:18,004
IF WE WERE JUST LOOKING AT THE

3312
02:06:18,004 --> 02:06:19,205
FAMILY LEVEL AND WE PICKED ONE

3313
02:06:19,205 --> 02:06:22,041
OF THESE ENDOGENOUS

3314
02:06:22,041 --> 02:06:26,012
RETROVIRUSES, THE HARLEQUIN

3315
02:06:26,012 --> 02:06:28,781
FAMILY WE WOULD SEE EXPRESSION

3316
02:06:28,781 --> 02:06:30,349
PREDOMINANTLY IN THE PDCs,

3317
02:06:30,349 --> 02:06:31,584
THAT'S AN INTERESTING STORY FOR

3318
02:06:31,584 --> 02:06:32,985
ANOTHER TIME, AND ALSO IN B

3319
02:06:32,985 --> 02:06:33,753
CELLS AND T-CELLS.

3320
02:06:33,753 --> 02:06:36,289
BUT IF YOU LOOK AT INDIVIDUAL

3321
02:06:36,289 --> 02:06:37,323
LOCUS-SPECIFIC ENDOGENOUS RETRO

3322
02:06:37,323 --> 02:06:41,194
RETROVIRUSES, YOU CAN SEE THAT

3323
02:06:41,194 --> 02:06:47,300
THE 1Q321 HALEQUIN RETROVIRUS IS

3324
02:06:47,300 --> 02:06:50,937
OVEREXPRESSED IN SOME, THAT

3325
02:06:50,937 --> 02:06:52,338
17Q12 IS OVEREXPRESSED IN

3326
02:06:52,338 --> 02:06:54,240
T-CELLS AND MONOCYTES HAVE THEIR

3327
02:06:54,240 --> 02:06:54,674
OWN COMPLEMENT.

3328
02:06:54,674 --> 02:06:56,409
SO THE TAKE-HOME IS THERE'S A

3329
02:06:56,409 --> 02:06:59,011
DYNAMIC INTERPLAY BETWEEN KRAB

3330
02:06:59,011 --> 02:07:00,780
ZINC FINGER PROTEINS AND

3331
02:07:00,780 --> 02:07:02,181
HERVs, WHICH MIGHT HAVE DIRECT

3332
02:07:02,181 --> 02:07:03,950
OR INDIRECT EFFECTS ON HIV

3333
02:07:03,950 --> 02:07:04,484
REPLICATION.

3334
02:07:04,484 --> 02:07:05,718
SEVERAL CRAP ZINC FINGER

3335
02:07:05,718 --> 02:07:07,553
PROTEINS MIGHT DIRECTLY BIND AND

3336
02:07:07,553 --> 02:07:12,158
REPRESS HIV, AND HAVE EXPRESSION

3337
02:07:12,158 --> 02:07:13,793
USEFUL FOR CHARACTERIZING SINGLE

3338
02:07:13,793 --> 02:07:14,327
CELLS AND SUBSETS.

3339
02:07:14,327 --> 02:07:17,296
WE THINK THAT LOCUS SPECIFICITY

3340
02:07:17,296 --> 02:07:20,366
OF HER SCRAN SCRIP TOE MIX IS A

3341
02:07:20,366 --> 02:07:22,635
GATEWAY TO STUDYING HERV

3342
02:07:22,635 --> 02:07:24,837
REGULATION, AND THIS NEW PROGRAM

3343
02:07:24,837 --> 02:07:28,875
STELLAR SCOPE WILL ALLOW THE

3344
02:07:28,875 --> 02:07:31,177
ACCURATE LOCUS SPECIFIC HERV

3345
02:07:31,177 --> 02:07:32,612
EXPRESSION IN SINGLE CELLS.

3346
02:07:32,612 --> 02:07:34,146
FROM THE PERSPECTIVE OF MOVING

3347
02:07:34,146 --> 02:07:35,414
FORWARD IN THE HOPE PROGRAM, WE

3348
02:07:35,414 --> 02:07:36,749
THINK THAT KRAB ZINC FINGER

3349
02:07:36,749 --> 02:07:38,184
PROTEINS MIGHT HOLD IMPORTANT

3350
02:07:38,184 --> 02:07:40,920
KEYS TO STRATEGIES TO LOCK HIV,

3351
02:07:40,920 --> 02:07:43,956
AND WE'VE GOT A NUMBER OF

3352
02:07:43,956 --> 02:07:45,057
SYNERGIES WITHIN THE HOPE GROUP

3353
02:07:45,057 --> 02:07:47,894
THAT WE ARE WORKING ON OVER THE

3354
02:07:47,894 --> 02:07:53,466
COURSE OF THE NEXT YEAR TO LEAD

3355
02:07:53,466 --> 02:07:54,901
TOWARDS THE POTENTIAL FOR

3356
02:07:54,901 --> 02:07:56,002
COMBINING KRAB ZINC FINGER

3357
02:07:56,002 --> 02:07:57,870
PROTEINS WITH OTHER REPRESSORS

3358
02:07:57,870 --> 02:08:00,139
FOR A SYNERGISTIC LOCK OF HIV.

3359
02:08:00,139 --> 02:08:02,975
SO ALL OF THIS WORK, OF COURSE,

3360
02:08:02,975 --> 02:08:04,944
DOESN'T TAKE PLACE IN A VACUUM,

3361
02:08:04,944 --> 02:08:08,114
THE LARGE NUMBER OF PEOPLE.

3362
02:08:08,114 --> 02:08:10,616
HOPE HAS GOT INTERNATIONAL

3363
02:08:10,616 --> 02:08:11,817
SITES, DOMESTIC SITE, AND THIS

3364
02:08:11,817 --> 02:08:15,555
WAS A VERY CLOSE COLLABORATION

3365
02:08:15,555 --> 02:08:16,522
BETWEEN A NUMBER OF DIFFERENT

3366
02:08:16,522 --> 02:08:16,856
GROUPS.

3367
02:08:16,856 --> 02:08:19,258
SO THANKS, I'LL HAND OVER TO

3368
02:08:19,258 --> 02:08:19,492
SUSANA.

3369
02:08:19,492 --> 02:08:25,097
[APPLAUSE]

3370
02:08:25,097 --> 02:08:26,599
>> HI, EVERYONE.

3371
02:08:26,599 --> 02:08:28,034
I WAS TASKED TO GIVING YOU AN

3372
02:08:28,034 --> 02:08:31,404
UPDATE OF THE EFFICACY OF

3373
02:08:31,404 --> 02:08:32,271
SPIRONOLACTONE AGAINST HIV IN

3374
02:08:32,271 --> 02:08:33,372
SEVERAL MODELS.

3375
02:08:33,372 --> 02:08:34,574
THIS IS A SUMMARY SLIDE.

3376
02:08:34,574 --> 02:08:36,442
THE QUESTION WE'RE TRYING TO ASK

3377
02:08:36,442 --> 02:08:38,110
IS WHETHER SPIRONOLACTONE WHICH

3378
02:08:38,110 --> 02:08:40,413
IS AN FDA-APPROVED DRUG BLOCKS

3379
02:08:40,413 --> 02:08:43,015
EXPRESSION IN MULTIPLE MODELS OF

3380
02:08:43,015 --> 02:08:43,983
HIV INFECTION AND WHETHER

3381
02:08:43,983 --> 02:08:46,485
THERE'S BENEFIT IN USING IN

3382
02:08:46,485 --> 02:08:48,888
COMBINATION TO BLOCK HIV

3383
02:08:48,888 --> 02:08:49,221
REACTIVATION.

3384
02:08:49,221 --> 02:08:50,356
THE KEY FINDINGS WAS THAT

3385
02:08:50,356 --> 02:08:52,525
LONG-ACTING PELLETS OF

3386
02:08:52,525 --> 02:08:53,326
SPIRONOLACTONE ACCELERATE HIV

3387
02:08:53,326 --> 02:08:56,262
DECAY IN HIV INFECTED MICE

3388
02:08:56,262 --> 02:08:57,463
UNDERGOING ART SUPPRESSION.

3389
02:08:57,463 --> 02:08:59,432
IN RHESUS MACAQUE, SP REDUCES

3390
02:08:59,432 --> 02:09:01,734
THE TARGET PROTEIN XPB WHICH

3391
02:09:01,734 --> 02:09:03,135
PAVES THE WAY TO EFFICACY IN

3392
02:09:03,135 --> 02:09:03,836
THIS MODEL.

3393
02:09:03,836 --> 02:09:06,439
WE HAVE ALREADY ASSEMBLED ASSAYS

3394
02:09:06,439 --> 02:09:07,540
AND NETWORK TO START

3395
02:09:07,540 --> 02:09:09,175
INVESTIGATING ACTIVITY OF SP IN

3396
02:09:09,175 --> 02:09:10,476
PEOPLE LIVING WITH HIV.

3397
02:09:10,476 --> 02:09:12,345
FINALLY, WE FOUND OUT TWO DRUGS

3398
02:09:12,345 --> 02:09:13,646
TOGETHER IS BETTER THAN ONE AT

3399
02:09:13,646 --> 02:09:14,413
BLOCKING HIV.

3400
02:09:14,413 --> 02:09:17,717
THIS IS EXCITING FOR THE CURE

3401
02:09:17,717 --> 02:09:20,219
BECAUSE FOR A NEW DRUG THAT IS

3402
02:09:20,219 --> 02:09:21,854
FDA-APPROVED THAT PUTS -- TO

3403
02:09:21,854 --> 02:09:24,590
SLEEP AND CAN ACCELERATE DRUG

3404
02:09:24,590 --> 02:09:25,124
REPURPOSING.

3405
02:09:25,124 --> 02:09:27,660
THIS IS THE FIRST TIME WE

3406
02:09:27,660 --> 02:09:29,295
DEMONSTRATE WHEN ADDED TO ART

3407
02:09:29,295 --> 02:09:31,263
THIS FIRST MECHANISM OF ACTION

3408
02:09:31,263 --> 02:09:34,967
CAN ACTUALLY ACCELERATE VIRAL

3409
02:09:34,967 --> 02:09:35,635
SUPPRESSION.

3410
02:09:35,635 --> 02:09:37,370
SUPPRESSED WITH SILENCING

3411
02:09:37,370 --> 02:09:40,239
PROMOTING AGENTS, WE CALL THEM

3412
02:09:40,239 --> 02:09:41,007
SPAs, AFTER ART IS

3413
02:09:41,007 --> 02:09:41,474
INTERRUPTED.

3414
02:09:41,474 --> 02:09:43,876
THE FIRST GOAL OF THIS RF2 IS TO

3415
02:09:43,876 --> 02:09:47,580
DETERMINE THE EFFECTS IN VIVO,

3416
02:09:47,580 --> 02:09:49,482
THE SECOND GOAL IS TO DEVELOP

3417
02:09:49,482 --> 02:09:50,816
NOVEL SPAS AND FINALLY THE THIRD

3418
02:09:50,816 --> 02:09:54,587
GOAL IS TO APPLY

3419
02:09:54,587 --> 02:09:56,589
SEQUENCE-SPECIFIC SPAs IN VIVO

3420
02:09:56,589 --> 02:09:57,657
IDENTIFIED IN RF1.

3421
02:09:57,657 --> 02:09:59,625
SO THIS IS THE GROUP OF PEOPLE

3422
02:09:59,625 --> 02:10:02,495
THAT PARTICIPATE IN RF2.

3423
02:10:02,495 --> 02:10:07,199
THISO AS YOU KNOW, HOPE

3424
02:10:07,199 --> 02:10:08,934
COLLABORATORY IS FOCUSED ON

3425
02:10:08,934 --> 02:10:10,569
LOCKING HIV TRANSCRIPTION AND IN

3426
02:10:10,569 --> 02:10:11,570
THE PAST WE'VE PUT A LOT OF

3427
02:10:11,570 --> 02:10:14,306
EFFORTS IN USING AT THAT TIME

3428
02:10:14,306 --> 02:10:15,408
INHIBITORS TO DO SO.

3429
02:10:15,408 --> 02:10:17,276
TODAY I'M GOING TO BE TALKING TO

3430
02:10:17,276 --> 02:10:19,145
YOU ABOUT SPIRONOLACTONE WHICH

3431
02:10:19,145 --> 02:10:20,446
BLOCKS HIV TRANSCRIPTIONAL

3432
02:10:20,446 --> 02:10:21,447
INITIATION.

3433
02:10:21,447 --> 02:10:22,748
SO SPIRONOLACTONE IS AN

3434
02:10:22,748 --> 02:10:23,382
FDA-APPROVED DRUG.

3435
02:10:23,382 --> 02:10:25,251
IT WAS -- IT'S BEEN APPROVED

3436
02:10:25,251 --> 02:10:28,320
SINCE 1959 TO TREAT HIGH BLOOD

3437
02:10:28,320 --> 02:10:29,455
PRESSURE, HEART FAILURE, STROKES

3438
02:10:29,455 --> 02:10:30,189
AND KIDNEY DISEASE.

3439
02:10:30,189 --> 02:10:34,260
THE BRTHE THE MECHANISM OF ACTIS

3440
02:10:34,260 --> 02:10:39,131
THAT IT COMPETES FOR THE

3441
02:10:39,131 --> 02:10:40,232
MINERALCORTICOID

3442
02:10:40,232 --> 02:10:40,766
RECEPTOR-BINDING.

3443
02:10:40,766 --> 02:10:45,004
IT DEGRADES THE XPB SUBUNIT OF

3444
02:10:45,004 --> 02:10:47,106
THE TFIIH COMPLEX.

3445
02:10:47,106 --> 02:10:48,074
WHICH SOMEHOW GOT BLOCKED OUT

3446
02:10:48,074 --> 02:10:50,576
THERE, IT'S RESPONSIBLE FOR THIS

3447
02:10:50,576 --> 02:10:51,811
PHOSPHORYLATION EVENT THAT

3448
02:10:51,811 --> 02:10:53,546
HAPPENS AT RNA POLYMERASE THAT

3449
02:10:53,546 --> 02:10:54,647
STARTS TRANSCRIPTIONAL

3450
02:10:54,647 --> 02:10:55,848
INITIATION.

3451
02:10:55,848 --> 02:10:58,484
SO BY LIMITING XPB, WE CAN

3452
02:10:58,484 --> 02:10:59,919
INHIBIT THIS STEP.

3453
02:10:59,919 --> 02:11:03,089
A PLEUR ON IS ANOTHER MINERAL

3454
02:11:03,089 --> 02:11:04,423
CORTICOID RECEPTOR, THIS DOES

3455
02:11:04,423 --> 02:11:05,825
NOT HAVE THE SOFT TARGET EFFECT

3456
02:11:05,825 --> 02:11:07,493
ON XPB.

3457
02:11:07,493 --> 02:11:12,865
SO THE WAY THIS WORKS, SO THE

3458
02:11:12,865 --> 02:11:15,634
WAY THIS WORKS, EXOWR WE TREAT

3459
02:11:15,634 --> 02:11:16,635
THESE CELLS WITH COMBINATION OF

3460
02:11:16,635 --> 02:11:18,904
THREE DRUGS, ART PLUS -- OR ART

3461
02:11:18,904 --> 02:11:20,539
AND EPL IN THE LIGHT BLUE, YOU

3462
02:11:20,539 --> 02:11:21,307
HAVE NO DIFFERENCE IN

3463
02:11:21,307 --> 02:11:21,841
TRANSCRIPTION.

3464
02:11:21,841 --> 02:11:23,209
NOW, IF YOU ADD SPIRONOLACTONE,

3465
02:11:23,209 --> 02:11:25,678
YOU HAVE THIS VERY NICE

3466
02:11:25,678 --> 02:11:28,748
INHIBITION OF RRL TRANSCRIPTION.

3467
02:11:28,748 --> 02:11:31,250
YOU SEE THERE'S THIS NICE DOSE

3468
02:11:31,250 --> 02:11:33,252
DEPENDENT DEGRADATION OF XPB.

3469
02:11:33,252 --> 02:11:37,189
WE HAVE SHOWN THAT -- IS

3470
02:11:37,189 --> 02:11:39,792
ASSOCIATED SPECIFICALLY WITH XPB

3471
02:11:39,792 --> 02:11:42,862
DEPLETION IF WE KNOCK DOWN XPB

3472
02:11:42,862 --> 02:11:44,196
USING -- RNAs IN GREEN YOU SEE

3473
02:11:44,196 --> 02:11:46,499
THAT YOU OBTAIN THE SAME EFFECT

3474
02:11:46,499 --> 02:11:48,901
AS ON HIV RNA TRANSCRIPTION AS

3475
02:11:48,901 --> 02:11:50,136
YOU DO WITH SPIRONOLACTONE.

3476
02:11:50,136 --> 02:11:51,537
FURTHERMORE, IF WE LOOK WITH RNA

3477
02:11:51,537 --> 02:11:53,405
SEQ STUDIES, WE SEE THAT THERE'S

3478
02:11:53,405 --> 02:11:55,708
A VERY POTENT EFFECT ON HIV

3479
02:11:55,708 --> 02:11:58,110
TRANSCRIPTION WITH ONLY MODEST

3480
02:11:58,110 --> 02:11:59,979
EFFECTS ON CELLULAR GENES.

3481
02:11:59,979 --> 02:12:01,580
SO WE WONDERED WHETHER THIS DRUG

3482
02:12:01,580 --> 02:12:04,150
COULD BE EFFECTIVE IN AN IN VIVO

3483
02:12:04,150 --> 02:12:05,251
MODEL OF HIV INFECTION.

3484
02:12:05,251 --> 02:12:07,386
WE WORKED WITH VETO GARCIA FOR

3485
02:12:07,386 --> 02:12:09,955
THESE STUDIES SMG T.

3486
02:12:09,955 --> 02:12:12,291
WE USED 12 ANIMALS, WE INFECTED

3487
02:12:12,291 --> 02:12:13,359
THEM WITH HIV AND TWO WEEKS

3488
02:12:13,359 --> 02:12:15,327
LATER, WE TREATED SEVEN OF THEM

3489
02:12:15,327 --> 02:12:18,063
WITH ART, A COCKTAIL OF THREE

3490
02:12:18,063 --> 02:12:20,032
DRUGS, AND FIVE OF THEM, THEY

3491
02:12:20,032 --> 02:12:21,567
RECEIVED ART PLUS THEY WERE

3492
02:12:21,567 --> 02:12:23,435
IMPLANTED IN THE BACKS OF THE

3493
02:12:23,435 --> 02:12:26,071
MICE WITH A LONG-ACTING PELLET

3494
02:12:26,071 --> 02:12:29,041
OF 200 MILLIGRAMS OF SP.

3495
02:12:29,041 --> 02:12:30,242
WE FOLLOWED VIRAL TRANSCRIPTION

3496
02:12:30,242 --> 02:12:33,846
FOR THE NEXT 35 DAYS.

3497
02:12:33,846 --> 02:12:36,415
SO THE FIRST GRAPH IN THE BOTTOM

3498
02:12:36,415 --> 02:12:38,350
LEFT SHOWS THE PLASMA

3499
02:12:38,350 --> 02:12:40,419
CONCENTRATION OF SP IN THESE

3500
02:12:40,419 --> 02:12:41,754
ANIMALS WITH THIS IMPLANTED

3501
02:12:41,754 --> 02:12:46,025
PELLET, AND THE DRUGS ARE NOT

3502
02:12:46,025 --> 02:12:47,560
VERY HYUN FORTUNATELY, THAT

3503
02:12:47,560 --> 02:12:52,031
LOOKS MORE LIKE IN THE --

3504
02:12:52,031 --> 02:12:52,598
NANOGRAMS PER ML.

3505
02:12:52,598 --> 02:12:54,800
BUT FORTUNATELY THESE

3506
02:12:54,800 --> 02:12:55,534
CONCENTRATIONS WERE SUFFICIENT

3507
02:12:55,534 --> 02:12:57,403
TO SEE SOME LEVEL OF DEGRADATION

3508
02:12:57,403 --> 02:12:58,304
OF XPB.

3509
02:12:58,304 --> 02:13:00,139
YOU CAN SEE IN THE WESTERN PLOT

3510
02:13:00,139 --> 02:13:01,473
IN THE UPPER RIGHT THERE'S

3511
02:13:01,473 --> 02:13:03,108
DEGRADATION OF XPB, THIS IS THE

3512
02:13:03,108 --> 02:13:04,310
LUNG TISSUE AND IN THE BOTTOM,

3513
02:13:04,310 --> 02:13:06,412
WE HAVE SEVERAL DIFFERENT

3514
02:13:06,412 --> 02:13:07,379
TISSUES.

3515
02:13:07,379 --> 02:13:08,614
THE DIFFERENCE IS NOT

3516
02:13:08,614 --> 02:13:09,481
STATISTICAL SIGNIFICANCE BUT

3517
02:13:09,481 --> 02:13:12,651
THERE WAS THIS -- IMPORTANTLY

3518
02:13:12,651 --> 02:13:13,953
EVEN WITH THESE LOW DOSES WHEN

3519
02:13:13,953 --> 02:13:16,055
WE LOOK AT VIRAL LOADS WE'RE

3520
02:13:16,055 --> 02:13:18,424
VERY SURPRISED TO SEE THERE WAS

3521
02:13:18,424 --> 02:13:21,861
A VERY STRONG EFFECT ALREADY ON

3522
02:13:21,861 --> 02:13:25,297
LIMITING HIV TRANSCRIPTION, AND

3523
02:13:25,297 --> 02:13:26,498
SEVEN DAYS POST IMPLANTATION OF

3524
02:13:26,498 --> 02:13:27,867
THE PELLET WE ALREADY SAW A

3525
02:13:27,867 --> 02:13:29,869
DIFFERENCE IN TWO LOGS IN VIRAL

3526
02:13:29,869 --> 02:13:32,037
LOADS IN THE PLASMA OF THESE

3527
02:13:32,037 --> 02:13:32,705
INFECTED MICE.

3528
02:13:32,705 --> 02:13:35,007
AND YOU SAW AN ACCELERATION

3529
02:13:35,007 --> 02:13:36,542
BELOW DETECTION LIMITS OF OVER A

3530
02:13:36,542 --> 02:13:38,711
WEEK IN THE ANIMALS THAT

3531
02:13:38,711 --> 02:13:39,311
RECEIVED SP.

3532
02:13:39,311 --> 02:13:44,016
SO THESE ANIMALS WERE SAC'D AND

3533
02:13:44,016 --> 02:13:46,018
DAY 35, WES LOOKED AT VIRAL RNA

3534
02:13:46,018 --> 02:13:46,619
TISSUES.

3535
02:13:46,619 --> 02:13:48,187
THIS IS TISSUES FROM LIVER,

3536
02:13:48,187 --> 02:13:50,256
LUNG, LYMPH NODES AND SPLEEN.

3537
02:13:50,256 --> 02:13:51,891
THERE'S A STATISTICAL

3538
02:13:51,891 --> 02:13:52,524
SIGNIFICANCE DIFFERENCE BETWEEN

3539
02:13:52,524 --> 02:13:53,792
THE LEVELS OF RNA IN THESE

3540
02:13:53,792 --> 02:13:54,226
TISSUES.

3541
02:13:54,226 --> 02:13:56,528
WHEN WE LOOKED AT CELLS

3542
02:13:56,528 --> 02:13:58,397
ASSOCIATED -- WE DIDN'T SEE ANY

3543
02:13:58,397 --> 02:14:00,266
DIFFERENCE, AND THIS IS EXPECTED

3544
02:14:00,266 --> 02:14:03,102
FROM TRANSCRIPTIONAL INHIBITOR.

3545
02:14:03,102 --> 02:14:06,071
SO WE WERE VERY INTERESTED IN

3546
02:14:06,071 --> 02:14:07,172
DETERMINING WHETHER THIS

3547
02:14:07,172 --> 02:14:07,940
ACCELERATION OF VIRAL

3548
02:14:07,940 --> 02:14:09,041
SUPPRESSION WAS ALSO CORRELATED

3549
02:14:09,041 --> 02:14:11,310
WITH LOWER LEVELS OF

3550
02:14:11,310 --> 02:14:13,946
INFLAMMATION BY ACCELERATING

3551
02:14:13,946 --> 02:14:16,482
ACTIVE REPLICATION, SO WE LOOKED

3552
02:14:16,482 --> 02:14:18,517
AT DIFFERENTIAL EXPRESSED GENES

3553
02:14:18,517 --> 02:14:21,186
IN THE HUMAN TRANSCRIPTS OF THE

3554
02:14:21,186 --> 02:14:23,255
DIFFERENT TISSUES OF THE MICE.

3555
02:14:23,255 --> 02:14:24,356
I'M SHOWING A PLOT OF JUST THE

3556
02:14:24,356 --> 02:14:24,690
LUNG.

3557
02:14:24,690 --> 02:14:26,025
WE SAW DIFFERENT EXPRESSED

3558
02:14:26,025 --> 02:14:28,427
GENES, BUT WHEN WE LOOK FURTHER

3559
02:14:28,427 --> 02:14:31,830
INTO THE INFLAMMATION-RELATED

3560
02:14:31,830 --> 02:14:33,265
PATHWAYS WE SAW A VERY NICE

3561
02:14:33,265 --> 02:14:34,233
DOWNREGULATION OF MANY OF THESE

3562
02:14:34,233 --> 02:14:35,134
GENES IN THE DIFFERENT TISSUES

3563
02:14:35,134 --> 02:14:36,101
OF THE MICE.

3564
02:14:36,101 --> 02:14:37,870
SO WHETHER THIS IS RELATED TO

3565
02:14:37,870 --> 02:14:39,939
REDUCTION OF INFECTION OR JUST

3566
02:14:39,939 --> 02:14:41,140
ANOTHER DIRECT EFFECT OF SP

3567
02:14:41,140 --> 02:14:42,341
REMAINS TO BE DETERMINED, BUT IN

3568
02:14:42,341 --> 02:14:44,009
A GENERAL MANNER, IT SHOWS THAT

3569
02:14:44,009 --> 02:14:45,978
THERE IS VERY -- THERE'S ADDED

3570
02:14:45,978 --> 02:14:47,980
BENEFIT OF ADDING THIS DRUG TO

3571
02:14:47,980 --> 02:14:49,181
FRONT LINE THERAPY.

3572
02:14:49,181 --> 02:14:50,816
SO NOW WE ARE GEARING UP TO

3573
02:14:50,816 --> 02:14:52,685
STUDY THE EFFECTS OF

3574
02:14:52,685 --> 02:14:53,919
SPIRONOLACTONE IN THE NON-HUMAN

3575
02:14:53,919 --> 02:14:55,120
PRIMATE MODEL, AND WE WORKED

3576
02:14:55,120 --> 02:14:57,089
WITH DAVID EVANS AT THE

3577
02:14:57,089 --> 02:14:58,190
WISCONSIN PRIMATE CENTER FOR

3578
02:14:58,190 --> 02:15:00,359
THESE, AND WE DID A

3579
02:15:00,359 --> 02:15:02,328
PHARMACOKINETIC STUDY WHERE WE

3580
02:15:02,328 --> 02:15:03,696
JUST GAVE ORAL DOSES OF

3581
02:15:03,696 --> 02:15:05,097
SPIRONOLACTONE TO ANIMALS AT

3582
02:15:05,097 --> 02:15:08,300
INCREASING CONCENTRATIONS FROM S

3583
02:15:08,300 --> 02:15:10,502
PER KILOGRAM PER DAY WITH A ONE

3584
02:15:10,502 --> 02:15:12,338
WEEK WASHOUT BETWEEN DOSES, AND

3585
02:15:12,338 --> 02:15:16,241
WE COLLECTED PBMCs AT THE END

3586
02:15:16,241 --> 02:15:17,609
OF EACH TWO WEEKS OF DOSING AND

3587
02:15:17,609 --> 02:15:19,712
WE LOOKED AT XPB DEGRADATION,

3588
02:15:19,712 --> 02:15:20,946
AND IN THE BOTTOM RIGHT, YOU SEE

3589
02:15:20,946 --> 02:15:23,248
THE GRAPH SHOWING THE DIFFERENT

3590
02:15:23,248 --> 02:15:25,884
ANIMALS RECEIVE THIS NICE DOSE

3591
02:15:25,884 --> 02:15:29,855
DEPENDENT DEGRADATION OF XPB IN

3592
02:15:29,855 --> 02:15:31,256
INCREASING CONCENTRATIONS OF

3593
02:15:31,256 --> 02:15:32,358
SPIRONOLACTONE.

3594
02:15:32,358 --> 02:15:33,792
DOSES OVER 24 MILLIGRAMS PER

3595
02:15:33,792 --> 02:15:36,228
KILOGRAM, WE CAN -- MORE THAN

3596
02:15:36,228 --> 02:15:37,429
50% REDUCTION IN XPB.

3597
02:15:37,429 --> 02:15:39,932
ON THE RIGHT SIDE WE HAVE PLASMA

3598
02:15:39,932 --> 02:15:44,336
CONCENTRATION SO WE MANAGED TO

3599
02:15:44,336 --> 02:15:48,007
REACH -- LEVELS DESIRED -- THEY

3600
02:15:48,007 --> 02:15:50,476
DIDN'T CHANGE ANY -- WE DIDN'T

3601
02:15:50,476 --> 02:15:52,211
SEE ANY ADVERSE EVENTS.

3602
02:15:52,211 --> 02:15:53,679
SO FINALLY WE ARE INTERESTED IN

3603
02:15:53,679 --> 02:15:57,483
LOOKING AT THE EFFICACY IN THE

3604
02:15:57,483 --> 02:15:58,050
HUMAN COHORTS.

3605
02:15:58,050 --> 02:16:01,153
SO WE HAVE STARTED TO PUT UP A

3606
02:16:01,153 --> 02:16:04,089
NETWORK WITH DIFFERENT

3607
02:16:04,089 --> 02:16:04,623
COLLABORATORS.

3608
02:16:04,623 --> 02:16:07,593
WITH DAVID SMITH AND -- FOR THE

3609
02:16:07,593 --> 02:16:10,029
LAST -- THE NATURAL HISTORY

3610
02:16:10,029 --> 02:16:14,967
COHORT AND WITH MHRP THE

3611
02:16:14,967 --> 02:16:18,037
AFRICOS, THE RV419 COHORT, THE

3612
02:16:18,037 --> 02:16:19,338
CLINIC LOCATED IN BRAZIL AS WELL

3613
02:16:19,338 --> 02:16:20,105
AS HERE IN WASHINGTON.

3614
02:16:20,105 --> 02:16:22,975
SO JUST OF NOTE THE TRANSGENDER

3615
02:16:22,975 --> 02:16:25,677
POPULATION USES HIGH DOSES OF

3616
02:16:25,677 --> 02:16:28,213
SPIRONOLACTONE DURING THEIR

3617
02:16:28,213 --> 02:16:28,881
FEMINIZING HORMONE THERAPY SO

3618
02:16:28,881 --> 02:16:30,082
WE'RE VERY INTERESTED IN THIS

3619
02:16:30,082 --> 02:16:31,417
POPULATION THAT USES HIGHER

3620
02:16:31,417 --> 02:16:32,484
DOSES OF SPIRONOLACTONE.

3621
02:16:32,484 --> 02:16:34,253
SO FOR INSTANCE, I'M JUST GOING

3622
02:16:34,253 --> 02:16:35,687
TO GIVE YOU AN EXAMPLE OF A

3623
02:16:35,687 --> 02:16:36,789
STUDY THAT WE STARTED LOOKING

3624
02:16:36,789 --> 02:16:37,222
AT.

3625
02:16:37,222 --> 02:16:41,060
SO WE HAVE RECEIVED ALREADY A

3626
02:16:41,060 --> 02:16:42,628
SERIES OF SAMPLES FROM THE

3627
02:16:42,628 --> 02:16:43,362
NATURAL HISTORY STUDY.

3628
02:16:43,362 --> 02:16:44,830
WE HAVE INDIVIDUALS THAT HAD

3629
02:16:44,830 --> 02:16:47,566
RECEIVED SPIRONOLACTONE FOR A

3630
02:16:47,566 --> 02:16:49,768
SERIES OF REASONS, AND WE HAVE

3631
02:16:49,768 --> 02:16:51,570
DIFFERENT TIME POINTS, DIFFERENT

3632
02:16:51,570 --> 02:16:52,504
INDIVIDUALS WITH DIFFERENT

3633
02:16:52,504 --> 02:16:55,107
DURATIONS ON SP AND WE HAVE

3634
02:16:55,107 --> 02:16:56,341
TIMES BEFORE AND AFTER SP

3635
02:16:56,341 --> 02:16:57,776
INITIATION AND WE ARE CURRENTLY

3636
02:16:57,776 --> 02:17:02,147
STUDYING THESE SAMPLES.

3637
02:17:02,147 --> 02:17:04,016
FINALLY I WANT TO TELL YOU OF A

3638
02:17:04,016 --> 02:17:04,850
STUDY IN VITRO LOOKING AT THE

3639
02:17:04,850 --> 02:17:06,752
ABILITY OF USING TWO SPs IN

3640
02:17:06,752 --> 02:17:10,055
EXI NATION.

3641
02:17:10,055 --> 02:17:10,389
COMBINATION.

3642
02:17:10,389 --> 02:17:11,824
WE'RE USING A TAT INHIBITOR THAT

3643
02:17:11,824 --> 02:17:15,260
WILL BLOCK THE RECRUITMENT AND

3644
02:17:15,260 --> 02:17:17,629
WHAT DOES THAT LOOK TOGETHER.

3645
02:17:17,629 --> 02:17:19,164
SO FOR THIS STUDY WE DECIDE TO

3646
02:17:19,164 --> 02:17:20,165
CHOOSE A CELL LINE THAT WAS

3647
02:17:20,165 --> 02:17:21,366
VERY, VERY HARD TO INHIBIT WITH

3648
02:17:21,366 --> 02:17:24,203
A SINGLE INHIBITOR.

3649
02:17:24,203 --> 02:17:28,574
WE USED 10.6 CELLS WHICH HAVE

3650
02:17:28,574 --> 02:17:33,145
GFP IN PLACE OF ENVELOPE.

3651
02:17:33,145 --> 02:17:36,248
AS YOU CAN SEE A SINGLE DRUG SP

3652
02:17:36,248 --> 02:17:42,187
IN BLUE, DCA IN RED, LIMITED IN

3653
02:17:42,187 --> 02:17:44,256
TERMS OF WHAT YOU CAN INHIBIT

3654
02:17:44,256 --> 02:17:45,357
HOWEVER IF YOU USE THEM IN

3655
02:17:45,357 --> 02:17:47,326
COMBINATION YOU SEE THIS NICE

3656
02:17:47,326 --> 02:17:48,127
SUPPRESSION TO BELOW DETECTION

3657
02:17:48,127 --> 02:17:48,560
LEVELS.

3658
02:17:48,560 --> 02:17:49,661
WE ARE VERY INTERESTED IN

3659
02:17:49,661 --> 02:17:50,762
DETERMINING WHETHER THIS IS A

3660
02:17:50,762 --> 02:17:52,197
LONG TERM SUPPRESSION SO WE

3661
02:17:52,197 --> 02:17:56,635
FOREMANNPERFORMED A TREATMENT

3662
02:17:56,635 --> 02:17:57,436
INTERRUPTION STUDY.

3663
02:17:57,436 --> 02:17:59,671
IN LIGHT GREEN YOU SEE THERE WAS

3664
02:17:59,671 --> 02:18:00,772
NO VIRAL REBOUND WHEN TREATED

3665
02:18:00,772 --> 02:18:01,940
WITH THESE TWO DRUGS.

3666
02:18:01,940 --> 02:18:05,477
FURTHERMORE, WE WANTED TO KNOW

3667
02:18:05,477 --> 02:18:07,346
WHETHER THIS WAS SUFFICIENT TO

3668
02:18:07,346 --> 02:18:09,214
REDUCE A STRONG REACTIVATION

3669
02:18:09,214 --> 02:18:12,518
EVENT WITH AN LRA SO FOR THAT WE

3670
02:18:12,518 --> 02:18:14,920
USED PMA.

3671
02:18:14,920 --> 02:18:16,255
ON THE LEFT SIDE YOU HAVE

3672
02:18:16,255 --> 02:18:17,289
WITHOUT STIMULATION, ON THE

3673
02:18:17,289 --> 02:18:19,124
RIGHT SIDE WITH PMA, SO THE

3674
02:18:19,124 --> 02:18:21,960
CONTROL CELLS REACTIVATED BY

3675
02:18:21,960 --> 02:18:23,495
80.1%, AND IN THE PRESENCE --

3676
02:18:23,495 --> 02:18:24,930
NOT PRESENCE, ABSENCE, I MEAN,

3677
02:18:24,930 --> 02:18:26,798
THEY HAD BEEN PRIOR TREATED

3678
02:18:26,798 --> 02:18:28,534
WITHOUT DRUGS FOR 90 DAYS, THERE

3679
02:18:28,534 --> 02:18:32,304
WAS ABSOLUTELY NO REACTIVATION.

3680
02:18:32,304 --> 02:18:33,939
SO THIS IS VERY PROMISING, TWO

3681
02:18:33,939 --> 02:18:36,675
DRUGS TOGETHER PROBABLY VERY

3682
02:18:36,675 --> 02:18:39,211
POTENT AT BLOCKING REACTIVATION

3683
02:18:39,211 --> 02:18:39,545
FROM LATENCY.

3684
02:18:39,545 --> 02:18:46,985
SO THE TAKE HOME MESSAGE -- THIS

3685
02:18:46,985 --> 02:18:50,489
LONG SP FORMULATIONS RESULTS IN

3686
02:18:50,489 --> 02:18:52,224
LOW PLASMA CONCENTRATIONS BUT

3687
02:18:52,224 --> 02:18:54,226
NEVERTHELESS WE SAW VERY NICE,

3688
02:18:54,226 --> 02:18:55,427
EFFICIENT SUPPRESSION AND

3689
02:18:55,427 --> 02:18:56,962
ACCELERATION OF VIRAL

3690
02:18:56,962 --> 02:18:57,529
TRANSCRIPTION.

3691
02:18:57,529 --> 02:19:02,234
SO ADDITION OF SP, WE SAW DOWN

3692
02:19:02,234 --> 02:19:03,135
REGULATES INFLAMMATORY GENES IN

3693
02:19:03,135 --> 02:19:04,670
THE BLT MOUSE.

3694
02:19:04,670 --> 02:19:06,638
ORAL DOSES OF SP OF MORE THAN

3695
02:19:06,638 --> 02:19:08,407
24 MILLIGRAMS PER KILOGRAM IN

3696
02:19:08,407 --> 02:19:10,275
RHESUS MACAQUES SEEMS SUFFICIENT

3697
02:19:10,275 --> 02:19:13,245
TO REDUCE XPB PROTEIN, FORGING

3698
02:19:13,245 --> 02:19:14,680
THE WAY FOR FUTURE STUDIES IN

3699
02:19:14,680 --> 02:19:15,314
THIS MODEL.

3700
02:19:15,314 --> 02:19:17,749
AND WE HAVE NOW ASSEMBLED A

3701
02:19:17,749 --> 02:19:18,517
GLOBAL INFRASTRUCTURE AND

3702
02:19:18,517 --> 02:19:20,719
TECHNIQUES TO INTERROGATE S P

3703
02:19:20,719 --> 02:19:23,155
AND OTHER SPAs IN PEOPLE

3704
02:19:23,155 --> 02:19:25,657
LIVING WITH HIV.

3705
02:19:25,657 --> 02:19:30,128
FINALLY, W USING TWO LATENCY

3706
02:19:30,128 --> 02:19:31,196
PROMOTING AGENTS IN COMBINATION

3707
02:19:31,196 --> 02:19:33,232
HAS SHOWN REALLY GOOD PROMISE IN

3708
02:19:33,232 --> 02:19:34,433
IRREVERSIBLY SILENCING HIV.

3709
02:19:34,433 --> 02:19:40,505
AND I WOULD LIKE TO THANK ALL

3710
02:19:40,505 --> 02:19:44,309
THE FOLKS -- THERE'S NO

3711
02:19:44,309 --> 02:19:45,177
ACKNOWLEDGMENT SLIDE.

3712
02:19:45,177 --> 02:19:48,247
SORRY, IT'S MISSING.

3713
02:19:48,247 --> 02:19:52,351
I ENCOURAGE YOU TO GO SEE THE --

3714
02:19:52,351 --> 02:19:54,453
THEY HAVE POSTERS ON SP, I'D

3715
02:19:54,453 --> 02:19:57,623
LIKE TO THANK VICTOR GARCIA AND

3716
02:19:57,623 --> 02:19:58,557
DAVID EVANS AS WELL AS ALL OF

3717
02:19:58,557 --> 02:19:59,258
THE HOPE FAMILY FOR THIS WORK.

3718
02:19:59,258 --> 02:19:59,558
THANK YOU.

3719
02:19:59,558 --> 02:20:09,601
[APPLAUSE]

3720
02:20:09,601 --> 02:20:12,337
>> I WOULD LIKE TO START
BY

3721
02:20:12,337 --> 02:20:13,872
ACKNOWLEDGING COMEMBERS OF

3722
02:20:13,872 --> 02:20:14,640
RF3 AS WELL AS YOUNG

3723
02:20:14,640 --> 02:20:15,507
INVESTIGATORS FROM OUR

3724
02:20:15,507 --> 02:20:16,541
LABORATORIES WHO HAVE PERFORMED

3725
02:20:16,541 --> 02:20:17,776
THE WORK THAT I'M GOING TO BE

3726
02:20:17,776 --> 02:20:18,810
SHOWING TODAY.

3727
02:20:18,810 --> 02:20:21,680
IN PARTICULAR, I WOULD LIKE TO

3728
02:20:21,680 --> 02:20:25,050
THANK COLLABORATORS -- FROM

3729
02:20:25,050 --> 02:20:25,617
UNIVERSITY OF WISCONSIN WHO

3730
02:20:25,617 --> 02:20:29,021
PERFORMED A LARGE PART OF THE

3731
02:20:29,021 --> 02:20:29,354
WORK.

3732
02:20:29,354 --> 02:20:33,225
SO THE HYPOTHESIS OF RF3 IS THAT

3733
02:20:33,225 --> 02:20:35,227
WE ARE TRYING TO DEVELOP GENOME

3734
02:20:35,227 --> 02:20:36,395
INJURING MOLECULES THAT ARE

3735
02:20:36,395 --> 02:20:37,963
SAFER AND INTRODUCE POINT

3736
02:20:37,963 --> 02:20:39,298
MUTATIONS IN THE PRO VIRUS AND

3737
02:20:39,298 --> 02:20:41,266
HOST DEPENDENCY FACTORS AND THIS

3738
02:20:41,266 --> 02:20:44,436
CAN LEAD TO THE PERMANENT

3739
02:20:44,436 --> 02:20:44,970
INACTIVATION OF HIV.

3740
02:20:44,970 --> 02:20:47,606
THE GOAL IS TO USE PROGRAMMABLE

3741
02:20:47,606 --> 02:20:51,810
DPEGENE EDITING MODULES -- IN TE

3742
02:20:51,810 --> 02:20:52,110
GENOME.

3743
02:20:52,110 --> 02:20:53,545
SO THE IDEA IS TO INTRODUCE

3744
02:20:53,545 --> 02:20:54,880
THESE POINT MUTATIONS IN BOTH

3745
02:20:54,880 --> 02:20:56,648
THE PROVIDERS AND HOST GENE

3746
02:20:56,648 --> 02:20:58,517
PROTEINS THAT CAN CRITICALLY

3747
02:20:58,517 --> 02:21:00,052
BLOCK VIRAL GENE TRANSCRIPTION

3748
02:21:00,052 --> 02:21:03,755
WITHOUT AFFECTING -- ONLY THE

3749
02:21:03,755 --> 02:21:05,424
HOST FUNCTION.

3750
02:21:05,424 --> 02:21:06,391
IMPORTANTLY WE'RE TRYING TO

3751
02:21:06,391 --> 02:21:08,593
DELIVER BY DIRECT DELIVERY TO

3752
02:21:08,593 --> 02:21:13,732
THE CELLS AND TISSUES OF

3753
02:21:13,732 --> 02:21:15,267
INTEREST -- THERAPEUTICS.

3754
02:21:15,267 --> 02:21:17,703
HERE IS THE PLAIN LANGUAGE

3755
02:21:17,703 --> 02:21:20,238
SLIDE, TO DEVELOP SAFER GENE

3756
02:21:20,238 --> 02:21:21,540
THERAPY METHODS FOR THE CURE OF

3757
02:21:21,540 --> 02:21:23,942
HIV PRACTICAL FOR WIDESPREAD

3758
02:21:23,942 --> 02:21:24,109
USE.

3759
02:21:24,109 --> 02:21:25,510
IMPORTANTLY WE ARE TRYING TO

3760
02:21:25,510 --> 02:21:27,245
ADMINISTRATE THESE THERAPEUTIC

3761
02:21:27,245 --> 02:21:28,680
TREATMENTS DIRECTLY WITHOUT

3762
02:21:28,680 --> 02:21:30,115
REQUIRING TRANSPLANT REGIMENS.

3763
02:21:30,115 --> 02:21:31,450
SO ALONG THE LINES OF

3764
02:21:31,450 --> 02:21:32,351
PROGRAMMABLE GENOME EDITING,

3765
02:21:32,351 --> 02:21:35,854
WE'RE USING CAS9 BASE AND PRIME

3766
02:21:35,854 --> 02:21:37,255
EDITING APPROACHES WHICH CAN

3767
02:21:37,255 --> 02:21:39,024
INTRODUCE POINT MUTATIONS AND

3768
02:21:39,024 --> 02:21:40,692
DIRECTLY CONVERT SINGLE

3769
02:21:40,692 --> 02:21:42,427
NUCLEOTIDE BASE CHANGES IN THE

3770
02:21:42,427 --> 02:21:43,495
GENOME WITHOUT INTRODUCING

3771
02:21:43,495 --> 02:21:46,365
DOUBLE STRANDED DNA BREAKS OR --

3772
02:21:46,365 --> 02:21:47,032
THE PLATE.

3773
02:21:47,032 --> 02:21:49,801
SO THESE USE CAS9 -- THE ONE I'M

3774
02:21:49,801 --> 02:21:51,770
GOING TO BE TALKING TODAY USES

3775
02:21:51,770 --> 02:21:53,438
REVERSE TRANSCRIPTASE AND

3776
02:21:53,438 --> 02:21:54,206
INTRODUCES POINT MUTATIONS.

3777
02:21:54,206 --> 02:21:57,042
THE IDEA IS TO AGAIN SEE THAT WE

3778
02:21:57,042 --> 02:22:00,011
CAN DIRE DIRECTLY INACTIVATE THE

3779
02:22:00,011 --> 02:22:01,146
VIRUS OR HOST GENES,

3780
02:22:01,146 --> 02:22:05,050
PARTICULARLY HOST GENES OTHER

3781
02:22:05,050 --> 02:22:06,585
THAN -- EVEN CURTAILING THE

3782
02:22:06,585 --> 02:22:09,688
APPLICATION OF BOTH X4 AND

3783
02:22:09,688 --> 02:22:10,889
R5 HIV ISOLATES.

3784
02:22:10,889 --> 02:22:13,625
SO ALONG THESE LINES, WE'VE BEEN

3785
02:22:13,625 --> 02:22:18,697
LOOKING AT EDITING CYCLIN --

3786
02:22:18,697 --> 02:22:20,132
THESE STUDIES HAVE BEEN DONE IN

3787
02:22:20,132 --> 02:22:21,767
COLLABORATION WITH NATURE LIKE I

3788
02:22:21,767 --> 02:22:22,300
MENTIONED.

3789
02:22:22,300 --> 02:22:25,937
THIS SLIDE SHOWS THE SUPER

3790
02:22:25,937 --> 02:22:27,038
ELONGATION COMPLEX OF HIV AND

3791
02:22:27,038 --> 02:22:28,673
THE SUPER ELONGATION COMPLEX IS

3792
02:22:28,673 --> 02:22:31,543
REQUIRED CRITICALLY FOR

3793
02:22:31,543 --> 02:22:32,844
TRANSCRIPTIONAL ELONGATION OF

3794
02:22:32,844 --> 02:22:35,614
DNA TRANSCRIPTS FROM DNA

3795
02:22:35,614 --> 02:22:35,947
PROVIDERS.

3796
02:22:35,947 --> 02:22:39,651
IN THE GENOME OF THE HOST CELLS.

3797
02:22:39,651 --> 02:22:42,053
SO THE SUPERELONGATION

3798
02:22:42,053 --> 02:22:44,823
COMPLEX -- THE RECRUITMENT IS

3799
02:22:44,823 --> 02:22:46,224
INITIATED WITH THE RECRUITMENT

3800
02:22:46,224 --> 02:22:51,096
OF P-TEFB, AND THIS IS RECRUITED

3801
02:22:51,096 --> 02:22:54,666
BY THE VIRAL TAT PROTEIN --

3802
02:22:54,666 --> 02:22:54,933
STRUCTURE.

3803
02:22:54,933 --> 02:22:58,737
SO VERY EARLY STUDIES HAD SHOWN

3804
02:22:58,737 --> 02:23:01,840
THAT HUMAN -- ALONE IS

3805
02:23:01,840 --> 02:23:03,842
CAPABLE -- THE MURINE IT DOES

3806
02:23:03,842 --> 02:23:05,010
NOT, AS SHOWN ON THE RIGHT PART

3807
02:23:05,010 --> 02:23:05,677
OF THE SLIDE.

3808
02:23:05,677 --> 02:23:07,546
THIS IS BECAUSE INTERACTION WITH

3809
02:23:07,546 --> 02:23:09,347
TAT AND TAR REQUIRES A ZINC ION

3810
02:23:09,347 --> 02:23:10,415
WHICH IS CRITICALLY SUPPORTED

3811
02:23:10,415 --> 02:23:12,784
WITH THE PRESENCE OF A

3812
02:23:12,784 --> 02:23:15,954
CYSTINE -- POSITION 261 OF HUMAN

3813
02:23:15,954 --> 02:23:16,721
CYCLINE T1.

3814
02:23:16,721 --> 02:23:18,990
THE CYSTINE IS MISSING IN THE

3815
02:23:18,990 --> 02:23:21,026
MURINE HOMOLOGUE AND REPRESSING

3816
02:23:21,026 --> 02:23:25,597
THE TYROSINE -- WITH THE CYSTINE

3817
02:23:25,597 --> 02:23:28,667
DISSTODISTORTS INTERACTION WITHT

3818
02:23:28,667 --> 02:23:30,702
AND TAR.

3819
02:23:30,702 --> 02:23:31,937
SO THEY INTRODUCED THE TYROSINE

3820
02:23:31,937 --> 02:23:34,639
OF THE MURINE -- THE MURINE

3821
02:23:34,639 --> 02:23:36,975
TYROSINE RESIDUE IN HUMAN CYCLIN

3822
02:23:36,975 --> 02:23:39,478
T1 WITH TRADITIONAL CASPER CRISP

3823
02:23:39,478 --> 02:23:40,912
9 STRATEGY AND I'M SHOWING YOU

3824
02:23:40,912 --> 02:23:42,247
DATA HERE WITH TWO CLONES THAT

3825
02:23:42,247 --> 02:23:46,418
ARE PRODUCED IN JURKATS, NOW

3826
02:23:46,418 --> 02:23:47,519
INTRODUCING THE TYROSINE

3827
02:23:47,519 --> 02:23:48,987
MUTATION DID NOT CHANGE THE

3828
02:23:48,987 --> 02:23:50,722
EXPRESSION LEVELS OF CCNT1, NOR

3829
02:23:50,722 --> 02:23:53,124
DID IT CHANGE THE PHYSIOLOGY OF

3830
02:23:53,124 --> 02:23:57,229
THESE CELLS, THEY PRO LIVE PROLD

3831
02:23:57,229 --> 02:23:58,096
LIKE WILD TYPE CELLS.

3832
02:23:58,096 --> 02:23:59,831
HOWEVER, WHEN WE CHALLENGED

3833
02:23:59,831 --> 02:24:01,833
THESE CELLS WITH MULTIPLE

3834
02:24:01,833 --> 02:24:06,571
STRAINS OF HIV, BOTH OF THE --

3835
02:24:06,571 --> 02:24:08,673
WE FOUND THAT THE VIRUSES WERE

3836
02:24:08,673 --> 02:24:10,275
UNABLE TO REPLICATE IN THESE

3837
02:24:10,275 --> 02:24:12,444
CELLS AS SHOWN BY FLOW CYTOMETRY

3838
02:24:12,444 --> 02:24:14,679
PLOTS WHERE WE COULD NOT PICK UP

3839
02:24:14,679 --> 02:24:16,481
GAG EXPRESSION INSIDE THE CELLS.

3840
02:24:16,481 --> 02:24:18,783
THESE ARE ALSO NEGATIVE IN --

3841
02:24:18,783 --> 02:24:22,187
WITH CULTURES -- THESE CELLS.

3842
02:24:22,187 --> 02:24:23,622
EXTENDED CULTURE OF THESE CELLS

3843
02:24:23,622 --> 02:24:25,557
WITH HIGH DOSE -- DID NOT LEAD

3844
02:24:25,557 --> 02:24:27,726
TO ANY VIRUS ESCAPE.

3845
02:24:27,726 --> 02:24:30,228
CHALLENGE OF THESE CELLS WITH

3846
02:24:30,228 --> 02:24:31,196
CLINICALLY -- VARIANCE OF HIV

3847
02:24:31,196 --> 02:24:35,233
AFTER THESE CELLS WERE MATRIX --

3848
02:24:35,233 --> 02:24:36,801
SHOWED WERE INCAPABLE OF

3849
02:24:36,801 --> 02:24:41,206
SUPPORTING REPLICATION.

3850
02:24:41,206 --> 02:24:43,308
SINCE -- INVOLVED IN

3851
02:24:43,308 --> 02:24:44,743
TRANSCRIPTION OF MANY VIRAL

3852
02:24:44,743 --> 02:24:46,178
GENES, WE LOOKED AT HOW IT

3853
02:24:46,178 --> 02:24:46,811
AFFECTED THE PHYSIOLOGY OF

3854
02:24:46,811 --> 02:24:47,245
CELLS.

3855
02:24:47,245 --> 02:24:49,814
WE FOUND THAT INTRODUCTION OF

3856
02:24:49,814 --> 02:24:52,450
THE TYROSINE MUTATION IN HUMAN

3857
02:24:52,450 --> 02:24:58,089
CYCLIN T1 DID NOT DISRUPT -- CD

3858
02:24:58,089 --> 02:24:59,090
K-9 AS NORMAL AND WHEN WE LOOKED

3859
02:24:59,090 --> 02:25:00,625
AT THE TRANSCRIPTIONAL PROFILE

3860
02:25:00,625 --> 02:25:03,161
OF MUTATOR CELLS TO THE PARENTAL

3861
02:25:03,161 --> 02:25:05,597
WILD TYPE SHOWN ON THE X AXIS,

3862
02:25:05,597 --> 02:25:07,465
THE MAGNITUDE OF DIFFERENCES IN

3863
02:25:07,465 --> 02:25:08,466
TRANSCRIPTOMIC CHANGES WERE

3864
02:25:08,466 --> 02:25:09,801
RATHER MINOR, ABOUT TWOFOLD,

3865
02:25:09,801 --> 02:25:11,636
COMPARED TO WHAT WE SAW --

3866
02:25:11,636 --> 02:25:13,071
COMPARED TO WHAT WE OBSERVED

3867
02:25:13,071 --> 02:25:15,073
WITH THE VIRAL TAT TRANSCRIPTION

3868
02:25:15,073 --> 02:25:17,976
WHICH IS ABOUT 100 FOLD.

3869
02:25:17,976 --> 02:25:22,113
ANALOGOUS TO THE TAT PROTEIN,

3870
02:25:22,113 --> 02:25:24,449
THE P50 IS ALSO RECRUITED BY

3871
02:25:24,449 --> 02:25:27,752
BLD4, A HUMAN PROTEIN FOR --

3872
02:25:27,752 --> 02:25:30,689
PROMOTERS AND WE LOOKED AT

3873
02:25:30,689 --> 02:25:32,724
THE -- WHICH HAD THE MUTANT

3874
02:25:32,724 --> 02:25:35,060
CYCLIN D1 WE FOUND NO MAJOR

3875
02:25:35,060 --> 02:25:35,694
CHANGES TO.

3876
02:25:35,694 --> 02:25:38,363
WE THEN MOVED ON TO SEE IF WE

3877
02:25:38,363 --> 02:25:41,633
COULD EDIT THE SINGLE NUCLEOTIDE

3878
02:25:41,633 --> 02:25:43,068
GENE USING THE PRIME EDITING

3879
02:25:43,068 --> 02:25:43,501
APPROACH.

3880
02:25:43,501 --> 02:25:44,869
THE PRIME EDITOR WAS DESIGNED TO

3881
02:25:44,869 --> 02:25:49,608
BRING ABOUT A SINGLE -- WHICH

3882
02:25:49,608 --> 02:25:50,475
CREATE THIS HAD RESIDUE.

3883
02:25:50,475 --> 02:25:52,577
WE WERE ABLE TO GET THESE

3884
02:25:52,577 --> 02:25:54,346
MUTATIONS DONE AGAIN IN JURKAT

3885
02:25:54,346 --> 02:25:55,413
CELLS AND WE FIND THAT THESE

3886
02:25:55,413 --> 02:25:57,716
CELLS THAT HAVE BEEN EDITED BY

3887
02:25:57,716 --> 02:25:59,451
PRIME EDITING -- BOTH BY

3888
02:25:59,451 --> 02:26:01,753
REPORTER ASSAYS AND IN ASSAYS

3889
02:26:01,753 --> 02:26:04,623
USING -- WITH CULTURE SUPER

3890
02:26:04,623 --> 02:26:05,290
NATENTS.

3891
02:26:05,290 --> 02:26:07,826
THE NEXT STEPS IS TO ACTUALLY

3892
02:26:07,826 --> 02:26:09,661
DELIVER THESE GENOME EDITING

3893
02:26:09,661 --> 02:26:11,463
MOLECULES TO BRING ABOUT THIS

3894
02:26:11,463 --> 02:26:12,797
CHANGE IN VIVO IN HUMANIZED

3895
02:26:12,797 --> 02:26:13,198
MICE.

3896
02:26:13,198 --> 02:26:15,000
WE PLAN TO DO THIS BY TARGETING

3897
02:26:15,000 --> 02:26:18,503
BOTH HUMAN T-CELLS AS WELL AS

3898
02:26:18,503 --> 02:26:19,304
HEMATOPOIETIC STEM CELLS.

3899
02:26:19,304 --> 02:26:22,907
SO TARGET T-CELLS WE HAVE A

3900
02:26:22,907 --> 02:26:24,042
VIRUS LIKE PLATFORM WHICH

3901
02:26:24,042 --> 02:26:26,978
TARGETS T-CELLS BECAUSE OF --

3902
02:26:26,978 --> 02:26:29,080
BY -- BECAUSE IT'S DECORATED

3903
02:26:29,080 --> 02:26:35,153
WITH ANTIBODIES TOO -- THIS VLP

3904
02:26:35,153 --> 02:26:39,391
PLATFORM PACKAGES RIBO -- THUS

3905
02:26:39,391 --> 02:26:41,493
LEADS TO SCARLESS GENOME EDITING

3906
02:26:41,493 --> 02:26:42,494
AND IN MIXED CULTURES WITH

3907
02:26:42,494 --> 02:26:44,896
T-CELLS AND B CELLS, YOU CAN

3908
02:26:44,896 --> 02:26:47,332
FIND THAT THE REPORTER GFP

3909
02:26:47,332 --> 02:26:48,566
EXPRESSION IS ONLY SEEN IN

3910
02:26:48,566 --> 02:26:50,869
T-CELLS AND NOT IN B CELLS WHICH

3911
02:26:50,869 --> 02:26:55,073
DON'T EXPRESS CD #.

3912
02:26:55,073 --> 02:26:58,910
 CD9.

3913
02:26:58,910 --> 02:27:00,412
VLPs THAT ENCASED --

3914
02:27:00,412 --> 02:27:01,780
ADMINISTERED BY SIMPLE IV

3915
02:27:01,780 --> 02:27:03,114
INJECTIONS TO HUMANIZED MICE

3916
02:27:03,114 --> 02:27:04,749
THAT WERE INFECTED AND

3917
02:27:04,749 --> 02:27:07,118
SUPPRESSED ON ART.

3918
02:27:07,118 --> 02:27:09,254
WHEN THESE MICE WERE RELEASED

3919
02:27:09,254 --> 02:27:10,355
FROM ANTIRETROVIRAL THERAPY WE

3920
02:27:10,355 --> 02:27:12,257
SAW TREATMENT -- WE SAW

3921
02:27:12,257 --> 02:27:16,628
TREATMENT FOR THESE -- THAT

3922
02:27:16,628 --> 02:27:18,263
TARGETED -- LED TO STIMULATION

3923
02:27:18,263 --> 02:27:19,497
OF THESE CELL LEVELS AND

3924
02:27:19,497 --> 02:27:22,267
EXPANSION OF T-CELL LEVELS,

3925
02:27:22,267 --> 02:27:23,601
WHEREAS VIRAL LOADS THAT

3926
02:27:23,601 --> 02:27:24,869
INITIALLY REBOUNDED WERE QUICKLY

3927
02:27:24,869 --> 02:27:26,137
CONTROLLED AND THESE MICE WERE

3928
02:27:26,137 --> 02:27:27,238
ACTUALLY LOOKED AT, WE FOUND

3929
02:27:27,238 --> 02:27:29,874
THAT WE COULD GET -- GREATER

3930
02:27:29,874 --> 02:27:32,577
THAN 60% IN THESE MICE.

3931
02:27:32,577 --> 02:27:34,045
SO WE PLANNED THIS APPROACH

3932
02:27:34,045 --> 02:27:43,822
REALLY TO TARGET CCNT12 1 AS WE.

3933
02:27:43,822 --> 02:27:45,156
 -- HAS BEEN DEVELOPING LIPID

3934
02:27:45,156 --> 02:27:49,527
NANOPARTICLES THAT CAN ENCASE N

3935
02:27:49,527 --> 02:27:51,730
MRNA MOLECULES, WITH SOME

3936
02:27:51,730 --> 02:27:53,965
SPECIAL FEATURES.

3937
02:27:53,965 --> 02:27:58,770
THEY HAVE A LINKAGE THAT

3938
02:27:58,770 --> 02:28:01,806
UNDERGOES HYDROLYSIS AT --

3939
02:28:01,806 --> 02:28:03,308
ENABLES SUFFICIENT

3940
02:28:03,308 --> 02:28:07,011
CYTOPLASMIC -- AT THE ENDOSOMES.

3941
02:28:07,011 --> 02:28:11,082
GREATER POE PENS IT TO TRANSDUCE

3942
02:28:11,082 --> 02:28:12,317
HEMATOPOIETIC STEM CELLS.

3943
02:28:12,317 --> 02:28:16,154
THESE WERE FIRST -- WHICH HAVE A

3944
02:28:16,154 --> 02:28:17,822
PREFLOCKSED -- IN GREEN AND

3945
02:28:17,822 --> 02:28:19,791
CELLS THAT TAKE A LIPID

3946
02:28:19,791 --> 02:28:22,794
NANOPARTICLE WITH THE CRE RNA IN

3947
02:28:22,794 --> 02:28:25,296
T WHEN THESE MICE WERE TREATED

3948
02:28:25,296 --> 02:28:27,132
AND ANALYZED FOUR WEEKS POST

3949
02:28:27,132 --> 02:28:28,900
TREATMENT FOUND THAT UP TO 40%

3950
02:28:28,900 --> 02:28:29,834
OF THE HEMATOPOIETIC STEM CELLS

3951
02:28:29,834 --> 02:28:33,438
IN THE BONE MARROW TURNED GREEN.

3952
02:28:33,438 --> 02:28:35,006
 -- THAT DIFFERENTIATED FROM

3953
02:28:35,006 --> 02:28:36,441
THESE CELLS.

3954
02:28:36,441 --> 02:28:38,009
THE HEMATOPOIETIC STEM CELLS

3955
02:28:38,009 --> 02:28:41,379
WERE ALSO TRANSPLANTABLE TO

3956
02:28:41,379 --> 02:28:45,483
RECIPIENT MICE AND THUS THEY ARE

3957
02:28:45,483 --> 02:28:46,584
TRUE HEMATOPOIETIC STEM CELLS.

3958
02:28:46,584 --> 02:28:48,987
SO CONCLUDE WE ARE DEVELOPING

3959
02:28:48,987 --> 02:28:51,723
THESE -- TESTING THESE MICE FOR

3960
02:28:51,723 --> 02:28:54,559
TARGETING BOTH THE PRO VIRAL DNA

3961
02:28:54,559 --> 02:28:59,430
AS WELL AS CCN NT1.

3962
02:28:59,430 --> 02:29:02,300
THIS IS MY ACKNOWLEDGMENT SLIDE.

3963
02:29:02,300 --> 02:29:02,567
THANK YOU.

3964
02:29:02,567 --> 02:29:08,807
[APPLAUSE]

3965
02:29:08,807 --> 02:29:11,176
>> GOOD MORNING, EVERYONE.

3966
02:29:11,176 --> 02:29:16,181
MY NAME IS PATRICIA DEFECHEREUX.

3967
02:29:16,181 --> 02:29:19,017
I USE MY PRONOUNS SHE AND HER.

3968
02:29:19,017 --> 02:29:20,785
EVEN THOUGH I'M PETRIFIED

3969
02:29:20,785 --> 02:29:22,120
TALKING TO A FULL AUDIENCE AND

3970
02:29:22,120 --> 02:29:23,321
FLYING, I'M HERE TO TALK TO YOU

3971
02:29:23,321 --> 02:29:24,622
ABOUT COMMUNITY ENGAGEMENT

3972
02:29:24,622 --> 02:29:25,723
ACTIVITY FOR THE HOPE

3973
02:29:25,723 --> 02:29:26,324
COLLABORATORY.

3974
02:29:26,324 --> 02:29:27,292
I'M HERE BECAUSE I'M SO BLESSED

3975
02:29:27,292 --> 02:29:31,129
TO BE WORKING WITH THESE FOLKS.

3976
02:29:31,129 --> 02:29:32,664
OUR COMMUNITY VISION WAS BASED

3977
02:29:32,664 --> 02:29:34,465
ON AND IS BASED ON THE BELIEF

3978
02:29:34,465 --> 02:29:36,301
THAT EVERY PARTNER, EVERY WHEEL

3979
02:29:36,301 --> 02:29:39,838
IN THE HOPE MACHINERY HAS AN

3980
02:29:39,838 --> 02:29:41,506
IMPORTANT PART, AN IMPORTANT

3981
02:29:41,506 --> 02:29:45,009
ACTIVITY TO PLAY IN THAT

3982
02:29:45,009 --> 02:29:46,644
BASICALLY EVEN THOUGH WE HAVE

3983
02:29:46,644 --> 02:29:48,613
THIS BELIEF THERE EXISTS A HUGE

3984
02:29:48,613 --> 02:29:50,748
BALANCE OF POWER THAT COMES INTO

3985
02:29:50,748 --> 02:29:51,850
ACTION WHEN WE GET PEOPLE

3986
02:29:51,850 --> 02:29:52,584
TOGETHER.

3987
02:29:52,584 --> 02:29:55,920
AND THAT IS WHY WE HAVE ANCHORED

3988
02:29:55,920 --> 02:29:57,455
AT THE HEART OF OUR HOPE

3989
02:29:57,455 --> 02:29:59,190
COMMUNITY ENGAGEMENT ACTIVITIES

3990
02:29:59,190 --> 02:30:00,758
A COMMUNITY ARTS INTEGRATED

3991
02:30:00,758 --> 02:30:02,927
RESEARCH PROGRAM, WHICH WE HOPE

3992
02:30:02,927 --> 02:30:05,396
HELP ALLEVIATE SOME OF THESE

3993
02:30:05,396 --> 02:30:09,667
CHALLENGES.

3994
02:30:09,667 --> 02:30:10,568
REALLY, HOPE IS ABOUT THE

3995
02:30:10,568 --> 02:30:11,002
PEOPLE.

3996
02:30:11,002 --> 02:30:13,505
AND I REALLY WOULD LIKE AT THIS

3997
02:30:13,505 --> 02:30:20,345
TIME, MY COMMUNITY PARTNER,

3998
02:30:20,345 --> 02:30:21,646
RAEF, IF YOU'RE IN THE AUDIENCE,

3999
02:30:21,646 --> 02:30:25,183
NO PRESSURE, AND ALISHA, THOMAS,

4000
02:30:25,183 --> 02:30:26,384
RICHARD, PLEASE STAND UP.

4001
02:30:26,384 --> 02:30:28,353
I AM SO LUCKY TO BE WORKING WITH

4002
02:30:28,353 --> 02:30:29,554
YOU ALL.

4003
02:30:29,554 --> 02:30:30,755
AND OUR FOLKS -- YEAH.

4004
02:30:30,755 --> 02:30:33,558
[APPLAUSE]

4005
02:30:33,558 --> 02:30:36,728
OUR FOLKS WHO CAN'T BE HERE IN

4006
02:30:36,728 --> 02:30:40,565
BRAZIL, SAO PAULO, UGANDA, WE

4007
02:30:40,565 --> 02:30:41,399
HAVE OUR COMMUNITY ARTS

4008
02:30:41,399 --> 02:30:43,902
INTEGRATED RESEARCH TEAM IN

4009
02:30:43,902 --> 02:30:50,842
CANADA, AND IN OUR OPERATION IN

4010
02:30:50,842 --> 02:30:52,610
SYDNEY, I HAVE UNWAVERING

4011
02:30:52,610 --> 02:30:53,912
COMMITMENT AND SUPPORT FROM OUR

4012
02:30:53,912 --> 02:30:55,146
PIs, SO I WANT TO THANK YOU

4013
02:30:55,146 --> 02:30:55,513
ALL.

4014
02:30:55,513 --> 02:30:57,248
WE BELIEVE THAT EVERYBODY HAS A

4015
02:30:57,248 --> 02:31:01,286
TALENT AND A SKILL THAT CAN BE

4016
02:31:01,286 --> 02:31:03,788
PUT IN LIGHT, IN THE COMMUNITY

4017
02:31:03,788 --> 02:31:05,189
ENGAGEMENT, AND ONE OF THESE

4018
02:31:05,189 --> 02:31:08,459
PERSONS IS RAEF, A VERY

4019
02:31:08,459 --> 02:31:13,097
RESPECTFUL AND TALENTED SOCIAL

4020
02:31:13,097 --> 02:31:14,632
MEDIA, AND HAS REALLY TAKEN UPON

4021
02:31:14,632 --> 02:31:16,601
ITSELF TO CREATE THIS

4022
02:31:16,601 --> 02:31:18,503
HOPE-RELATED HIV CURE-RELATED

4023
02:31:18,503 --> 02:31:21,039
CONTENT ON SEER MHOS.

4024
02:31:21,039 --> 02:31:21,906
 SOCIAL MEDIA WHICH

4025
02:31:21,906 --> 02:31:24,075
INVOLVED NOT ONLY PEOPLE AND

4026
02:31:24,075 --> 02:31:26,244
MEMBERS OF THE HOPE TEAM, BUT

4027
02:31:26,244 --> 02:31:28,212
ALSO FROM OTHER MDCs AND EVEN

4028
02:31:28,212 --> 02:31:30,515
FROM OUR SCIENTIFIC ADVISORY

4029
02:31:30,515 --> 02:31:31,749
BOARD.

4030
02:31:31,749 --> 02:31:33,084
AND THIS IS A WAY FOR US TO

4031
02:31:33,084 --> 02:31:35,820
REACH AUDIENCES WHICH ARE NOT IN

4032
02:31:35,820 --> 02:31:37,855
THE USUAL CIRCLES OF HAVING

4033
02:31:37,855 --> 02:31:41,025
ACCESS TO CURE-RELATED RESEARCH.

4034
02:31:41,025 --> 02:31:43,094
WE HAVE A HUGE CHALLENGE, WHICH

4035
02:31:43,094 --> 02:31:45,463
IS HOW DO WE TRANSLATE THIS VERY

4036
02:31:45,463 --> 02:31:47,665
COMPLEX SCIENCE THAT WE'RE ALL

4037
02:31:47,665 --> 02:31:48,533
LISTENING IN TODAY AND WE'RE

4038
02:31:48,533 --> 02:31:53,204
VERY FAMILIAR WITH THE LANGUAGE

4039
02:31:53,204 --> 02:31:54,339
FOR FOLKS THAT DO NOT HAVE THIS

4040
02:31:54,339 --> 02:31:55,540
BASIC LANGUAGE UNDERSTANDING.

4041
02:31:55,540 --> 02:31:58,276
AND SO ONE OF THE THINGS THAT

4042
02:31:58,276 --> 02:31:59,644
THE TEAM HAS DONE IS REALLY

4043
02:31:59,644 --> 02:32:03,147
BRING TOGETHER CLINICIANS,

4044
02:32:03,147 --> 02:32:05,116
ARTISTS, COMMUNITY MEMBERS AND

4045
02:32:05,116 --> 02:32:08,920
OTHER MEMBERS OF OUR COMMUNITY

4046
02:32:08,920 --> 02:32:10,321
ENGAGEMENT TEAM TO CREATE A

4047
02:32:10,321 --> 02:32:11,522
LITTLE ANIMATION WHICH WE NOW

4048
02:32:11,522 --> 02:32:13,791
HAVE TO CHANGE BECAUSE IT'S NOT

4049
02:32:13,791 --> 02:32:17,261
BLOCK, LOCK -- ANYMORE, IT'S

4050
02:32:17,261 --> 02:32:18,129
BLOCK, LOCK, STOP.

4051
02:32:18,129 --> 02:32:19,230
SO THAT'S SOMETHING WE SHARED

4052
02:32:19,230 --> 02:32:21,532
YESTERDAY AT OUR COMMUNITY

4053
02:32:21,532 --> 02:32:24,669
REUNION, THE RAVE WITH JESSICA,

4054
02:32:24,669 --> 02:32:29,374
AND IF YOU GO BEYOND THEIR VERY

4055
02:32:29,374 --> 02:32:30,808
LIMITED GOOGLE METRIC PERCEPTION

4056
02:32:30,808 --> 02:32:32,310
OF WHAT GENDER IDENTITY IS, WE

4057
02:32:32,310 --> 02:32:34,145
WERE TRYING TO LOOK AT WHERE THE

4058
02:32:34,145 --> 02:32:36,447
AUDIENCES OF ALL OF THE MEDIA,

4059
02:32:36,447 --> 02:32:39,350
THE SOCIAL MEDIA COVERAGE THAT

4060
02:32:39,350 --> 02:32:40,218
RAIF HAS DONE.

4061
02:32:40,218 --> 02:32:41,419
A MAJORITY OF THE PEOPLE ARE IN

4062
02:32:41,419 --> 02:32:43,221
THE U.S. AND INDIA, BUT YOU CAN

4063
02:32:43,221 --> 02:32:44,155
SEE IT'S ALSO IN OTHER PARTS OF

4064
02:32:44,155 --> 02:32:49,727
THE WORLD.

4065
02:32:49,727 --> 02:32:50,695
MAJORITY OF FOLKS BETWEEN THE

4066
02:32:50,695 --> 02:32:53,231
AGE OF 25 AND 44, THAT IS MORE

4067
02:32:53,231 --> 02:32:54,365
FOR THE PEOPLE IN INTERESTED IN

4068
02:32:54,365 --> 02:32:56,234
KIND OF DATA ANALYSIS.

4069
02:32:56,234 --> 02:32:58,569
BUT REALLY, A PICTURE IS WORTH A

4070
02:32:58,569 --> 02:33:00,438
LOT OF WORDS, SO WE'VE CREATED A

4071
02:33:00,438 --> 02:33:01,639
LITTLE VIDEO FOR YOU TODAY THAT

4072
02:33:01,639 --> 02:33:03,775
I'M GOING TO TRY TO PLAY BECAUSE

4073
02:33:03,775 --> 02:33:05,410
I'M KIND OF A TECHNOLOGY CLUT

4074
02:33:05,410 --> 02:33:12,383
HERE. KLUTZ

4075
02:33:12,383 --> 02:33:12,583
HERE.

4076
02:33:12,583 --> 02:33:22,960
CAN WE HAVE THE MUSIC?

4077
02:33:25,563 --> 02:33:26,831
WE TESTED IT AT THE BREAK AND

4078
02:33:26,831 --> 02:33:28,199
THEY TOLD ME IT WAS WORKING SO

4079
02:33:28,199 --> 02:33:29,834
HOPEFULLY WE'LL MAKE IT WORK.

4080
02:33:29,834 --> 02:33:40,144
SORRY ABOUT THAT.

4081
02:33:43,347 --> 02:33:45,083
I CAN IMPROVISE, I CAN DO A

4082
02:33:45,083 --> 02:33:45,950
LITTLE SONG AND DANCE.

4083
02:33:45,950 --> 02:33:47,285
WE DID DANCE AT OUR ANNUAL

4084
02:33:47,285 --> 02:33:49,253
MEETING.

4085
02:33:49,253 --> 02:33:50,955
IN VIDEO IS REALLY, REALLY THE

4086
02:33:50,955 --> 02:33:53,591
PRO DUCT OF ALL OF US WORKING

4087
02:33:53,591 --> 02:33:54,792
TOGETHER, BUT SYDNEY HERE PUT IT

4088
02:33:54,792 --> 02:33:55,760
TOGETHER FOR US.

4089
02:33:55,760 --> 02:33:58,663
AND WHAT YOU CAN SEE ACTUALLY,

4090
02:33:58,663 --> 02:34:00,631
THE COMMUNITY ARTS INTEGRATED

4091
02:34:00,631 --> 02:34:02,500
RESEARCH PROGRAM IS ACTUALLY NOT

4092
02:34:02,500 --> 02:34:05,636
JUST PEOPLE DOING ART, IT'S

4093
02:34:05,636 --> 02:34:08,372
REALLY A BEHAVIORAL SOCIAL

4094
02:34:08,372 --> 02:34:10,975
SCIENCE PROGRAM WHERE PEOPLE NOT

4095
02:34:10,975 --> 02:34:14,045
ONLY RESPOND TO SURVEYS AND HAVE

4096
02:34:14,045 --> 02:34:16,481
FOCUS GROUP KIND OF MODALITIES

4097
02:34:16,481 --> 02:34:20,017
WHERE WE CAN ASK THEM QUESTION

4098
02:34:20,017 --> 02:34:21,452
ABOUT PERCEPTION AROUND HIV CURE

4099
02:34:21,452 --> 02:34:24,088
BUT ALSO BRINGING THE SCIENTISTS

4100
02:34:24,088 --> 02:34:25,123
TO KIND OF MAYBE THINK ABOUT THE

4101
02:34:25,123 --> 02:34:26,724
WAY THEY'RE DOING HIV CURE

4102
02:34:26,724 --> 02:34:28,359
RESEARCH IN DIFFERENT WAYS,

4103
02:34:28,359 --> 02:34:30,862
BECAUSE WE'RE IN A ROOM TOGETHER

4104
02:34:30,862 --> 02:34:31,996
MAKING ART RATHER THAN HAVING

4105
02:34:31,996 --> 02:34:32,830
SOMEBODY TALKING DOWN TO YOU

4106
02:34:32,830 --> 02:34:35,199
FROM A PODIUM OR BEING AN

4107
02:34:35,199 --> 02:34:37,268
INVESTIGATOR COMING WITH

4108
02:34:37,268 --> 02:34:38,603
QUESTIONS, WHEN YOU'RE

4109
02:34:38,603 --> 02:34:39,604
ART-MAKING, YOU'RE ACTUALLY

4110
02:34:39,604 --> 02:34:41,639
SHIFTING YOUR PERSPECTIVES.

4111
02:34:41,639 --> 02:34:43,708
AND SOME OF THESE ART PRODUCTS

4112
02:34:43,708 --> 02:34:45,676
THAT YOU MAY HAVE SEEN ON THE

4113
02:34:45,676 --> 02:34:47,378
VIDEO IS ACTUALLY ALLOWING

4114
02:34:47,378 --> 02:34:48,946
PEOPLE TO TALK ABOUT WHAT IT

4115
02:34:48,946 --> 02:34:52,884
MEANS FOR THEM FOR IDENTITIES,

4116
02:34:52,884 --> 02:34:54,085
COMMUNITY MEMBERS AS WELL AS

4117
02:34:54,085 --> 02:34:55,686
RESEARCHER, WHAT IT MEANS FOR

4118
02:34:55,686 --> 02:34:57,555
THEM TO WORK TOWARDS AN HIV CURE

4119
02:34:57,555 --> 02:35:00,725
TOGETHER.

4120
02:35:00,725 --> 02:35:03,561
THIS IS A LITTLE EXCERPT OF THE

4121
02:35:03,561 --> 02:35:05,096
BLOCK, LOCK, STOP VIDEO I WAS

4122
02:35:05,096 --> 02:35:11,769
TELLING YOU ABOUT.

4123
02:35:11,769 --> 02:35:14,839
WHICH HAS A NARRATIVE DONE BY

4124
02:35:14,839 --> 02:35:16,974
RAIF, WHO'S AN AMAZING SPEAKER.

4125
02:35:16,974 --> 02:35:17,742
I THANK YOU ALL.

4126
02:35:17,742 --> 02:35:18,509
SORRY ABOUT THE MUSIC.

4127
02:35:18,509 --> 02:35:19,811
I DON'T KNOW WHERE IT

4128
02:35:19,811 --> 02:35:20,144
DISAPPEARED.

4129
02:35:20,144 --> 02:35:25,383
[APPLAUSE]

4130
02:35:25,383 --> 02:35:26,918
THANK YOU VERY MUCHMENT
SORRY

4131
02:35:26,918 --> 02:35:29,854
VEVERY MUCH.SORRY ABOUT THE VID.

4132
02:35:29,854 --> 02:35:32,590
IS IT AVAILABLE ON RAIF'S

4133
02:35:32,590 --> 02:35:40,565
YOUTUBE CHANNEL?

4134
02:35:40,565 --> 02:35:42,033
MAYBE WE'LL FIGURE OUT A WAY TO

4135
02:35:42,033 --> 02:35:42,934
SHOW IT AT SOME POINT.

4136
02:35:42,934 --> 02:35:44,468
I KNOW THAT WE ARE SCHEDULED FOR

4137
02:35:44,468 --> 02:35:45,636
LUNCH RIGHT NOW, BUT I WOULD

4138
02:35:45,636 --> 02:35:46,737
LIKE TO OPEN IT UP JUST FOR A

4139
02:35:46,737 --> 02:35:48,039
FEW MINUTES FOR A FEW QUESTIONS

4140
02:35:48,039 --> 02:35:53,377
IF ANYONE HAS QUESTIONS, COME ON

4141
02:35:53,377 --> 02:35:54,879
UP TO THE MIC AND IF ANYONE

4142
02:35:54,879 --> 02:35:56,180
ONLINE HAS QUESTIONS, WE'LL FIND

4143
02:35:56,180 --> 02:35:58,683
OUT FROM OUR PEOPLE IN THE BACK.

4144
02:35:58,683 --> 02:36:03,921
>>  -- MARTINS.  SUSANA,
I'M

4145
02:36:03,921 --> 02:36:07,024
GLAD TO SEE THE STUDIES WITH

4146
02:36:07,024 --> 02:36:08,693
SPIRONOLACTONE ARE GOING SO

4147
02:36:08,693 --> 02:36:08,993
WELL.

4148
02:36:08,993 --> 02:36:11,028
WERE ANY OF YOUR MONKEYS MALES,

4149
02:36:11,028 --> 02:36:12,129
AND IF THEY WERE, DID YOU SEE

4150
02:36:12,129 --> 02:36:13,564
SUPPRESSION IN TESTOSTERONE IN

4151
02:36:13,564 --> 02:36:19,604
THEM?

4152
02:36:19,604 --> 02:36:26,410
>> LOOKED AT THE TESS 
TESTOSTEE

4153
02:36:26,410 --> 02:36:26,978
LEVELS.

4154
02:36:26,978 --> 02:36:28,379
THEY WERE VERY LOW AT THE

4155
02:36:28,379 --> 02:36:29,580
BEGINNING SO WE DIDN'T SEE ANY

4156
02:36:29,580 --> 02:36:30,514
CHANGES.

4157
02:36:30,514 --> 02:36:33,251
TYPICALLY THE TESS  TESTOSTERONE

4158
02:36:33,251 --> 02:36:34,452
LEVELS STAY THE SAME WITH

4159
02:36:34,452 --> 02:36:34,819
SPIRONOLACTONE.

4160
02:36:34,819 --> 02:36:36,053
WHAT HAPPENS IS THERE'S A

4161
02:36:36,053 --> 02:36:36,654
COMPETITION FOR THE RECEPTOR.

4162
02:36:36,654 --> 02:36:37,788
SO THE LEVELS ARE THE SAME, IT'S

4163
02:36:37,788 --> 02:36:39,557
JUST THE FUNCTION THAT IS

4164
02:36:39,557 --> 02:36:39,790
REDUCED.

4165
02:36:39,790 --> 02:36:40,291
>> INTERESTING.

4166
02:36:40,291 --> 02:36:42,026
>> SO WE WOULDN'T EXPECT
ANY

4167
02:36:42,026 --> 02:36:43,427
CHANGES ANYWAY.

4168
02:36:43,427 --> 02:36:44,629
>> OKAY, GOOD.

4169
02:36:44,629 --> 02:36:47,231
>> CHRIS PETERSON, FRED
HUTCH

4170
02:36:47,231 --> 02:36:47,765
FOR PRITI.

4171
02:36:47,765 --> 02:36:49,533
A COUPLE QUESTIONS.

4172
02:36:49,533 --> 02:36:51,402
ONE FOR CYCLIN T1, HAVE YOU

4173
02:36:51,402 --> 02:36:54,505
THOUGHT ABOUT WHAT -- WHAT IS

4174
02:36:54,505 --> 02:36:56,040
THAT MUTATION, WHAT EFFECT IS IT

4175
02:36:56,040 --> 02:36:57,675
GOING TO HAVE ON HUMAN PROTEIN,

4176
02:36:57,675 --> 02:36:59,844
AND NUMBER TWO, IF YOU HAVE

4177
02:36:59,844 --> 02:37:01,912
INDELS THAT YOU GENERATE AT THAT

4178
02:37:01,912 --> 02:37:03,581
SITE WITHOUT INSERTING YOUR

4179
02:37:03,581 --> 02:37:04,782
CHANGE OR INACTIVATING THE

4180
02:37:04,782 --> 02:37:06,117
PROTEIN AND WHAT WILL THAT DO?

4181
02:37:06,117 --> 02:37:07,251
>> SO FOR THE FIRST
QUESTION,

4182
02:37:07,251 --> 02:37:09,320
DID YOU ASK ME WHAT IT DOES TO

4183
02:37:09,320 --> 02:37:10,955
THE PROTEIN LEVEL?

4184
02:37:10,955 --> 02:37:13,024
>> HOW DOES IT IMPACT THE
HUMAN

4185
02:37:13,024 --> 02:37:16,927
PROTEIN FUNCTION VERSUS YOU'RE

4186
02:37:16,927 --> 02:37:17,828
INTRODUCING A MOUSE MUTATION.

4187
02:37:17,828 --> 02:37:20,498
>> IT SEEMS TO BE
PERFECTLY

4188
02:37:20,498 --> 02:37:20,731
NORMAL.

4189
02:37:20,731 --> 02:37:22,033
THAT WAS THE WHOLE IDEA OF THE

4190
02:37:22,033 --> 02:37:22,733
TRANSCRIPTIONAL PROFILING WE

4191
02:37:22,733 --> 02:37:22,934
DID.

4192
02:37:22,934 --> 02:37:25,036
SO WHEN WE LOOK WITH TYROSINE

4193
02:37:25,036 --> 02:37:25,970
MUTATION, IT SEEMS TO WORK

4194
02:37:25,970 --> 02:37:26,604
PERFECTLY NORMALLY.

4195
02:37:26,604 --> 02:37:27,838
IT DOESN'T SEEM TO CHANGE

4196
02:37:27,838 --> 02:37:33,177
ANYTHING WITH RESPECT TO -- IN

4197
02:37:33,177 --> 02:37:34,245
HOST CELLS.

4198
02:37:34,245 --> 02:37:37,281
AND WE ARE USING BASE EDITING

4199
02:37:37,281 --> 02:37:39,817
THAT ONLY CHANGES ONE

4200
02:37:39,817 --> 02:37:42,653
NUCLEOTIDE, IT'S ONE SINGLE

4201
02:37:42,653 --> 02:37:43,788
NUCLEOTIDE IN THE WHOLE PROTEIN

4202
02:37:43,788 --> 02:37:45,489
THAT CHANGES TO MURINE

4203
02:37:45,489 --> 02:37:45,790
HOMOLOGUE.

4204
02:37:45,790 --> 02:37:48,059
SO WE HAVEN'T LOOKED AT INDELS.

4205
02:37:48,059 --> 02:37:49,360
I KNOW FROM THE LITTLE BIT THAT

4206
02:37:49,360 --> 02:37:52,530
WE'VE DONE AT LEAST WITH THE

4207
02:37:52,530 --> 02:37:53,631
PRIMARY EDITING A PROACH, WE'RE

4208
02:37:53,631 --> 02:37:55,666
ONLY ABLE TO SEE THAT PARTICULAR

4209
02:37:55,666 --> 02:37:57,535
CHANGE IN THAT SINGLE NUCLEOTIDE

4210
02:37:57,535 --> 02:37:57,768
CHANGE.

4211
02:37:57,768 --> 02:38:00,037
WE DON'T SEE SOMETHING BEYOND

4212
02:38:00,037 --> 02:38:00,237
THAT.

4213
02:38:00,237 --> 02:38:01,339
>> THE OTHER QUESTION IS,
HOW

4214
02:38:01,339 --> 02:38:05,242
ARE YOU TARGETING YOUR LMPs

4215
02:38:05,242 --> 02:38:06,243
FOR STEM CELLS?

4216
02:38:06,243 --> 02:38:10,715
>> SO THIS WORK IS DONE
WITH --

4217
02:38:10,715 --> 02:38:17,154
GROUP I IN RF3, SO THEY'RE

4218
02:38:17,154 --> 02:38:19,757
ACTUALLY SCREENING NOVEL LIPIDS

4219
02:38:19,757 --> 02:38:21,025
THAT HAVE GOT A HIGHER

4220
02:38:21,025 --> 02:38:23,094
PROPENSITY TO REALLY TARGET THE

4221
02:38:23,094 --> 02:38:24,028
HEMATOPOIETIC STEM CELLS.

4222
02:38:24,028 --> 02:38:27,832
THESE ARE BEING DONE IN VITRO,

4223
02:38:27,832 --> 02:38:29,133
SO WHILE THEY MAY TARGET OTHER

4224
02:38:29,133 --> 02:38:30,568
CELLS AS WELL, THE PROPENSITY TO

4225
02:38:30,568 --> 02:38:31,869
GET TO STEM CELLS IS VERY HIGH

4226
02:38:31,869 --> 02:38:36,841
PAUSE OF THESE NOVEL LIPID

4227
02:38:36,841 --> 02:38:37,141
FORMULATION.

4228
02:38:37,141 --> 02:38:37,408
>> SHARON?

4229
02:38:37,408 --> 02:38:37,742
>> THANKS.

4230
02:38:37,742 --> 02:38:39,243
I HAD TWO QUESTIONS.

4231
02:38:39,243 --> 02:38:40,211
FIRST OF ALL CONGRATULATIONS ON

4232
02:38:40,211 --> 02:38:41,512
THE VIDEO.

4233
02:38:41,512 --> 02:38:45,683
I'M FEELING VERY LOW TECH,

4234
02:38:45,683 --> 02:38:46,951
INDEED YOU'VE RAISED THE BAR ON

4235
02:38:46,951 --> 02:38:48,619
HOW TO PROMOTE WHAT WE DO.

4236
02:38:48,619 --> 02:38:51,122
FABULOUS WORK.

4237
02:38:51,122 --> 02:38:56,894
I HAD A QUESTION FOR SUSANA,

4238
02:38:56,894 --> 02:38:58,729
FIRST TELL US WHY YOU THINK

4239
02:38:58,729 --> 02:39:00,664
SPIRONOLACTONE CAN CREATE

4240
02:39:00,664 --> 02:39:01,766
IRREVERSIBLE SILENCING, WHAT

4241
02:39:01,766 --> 02:39:03,300
LEADS TO THE PERSISTENCE.

4242
02:39:03,300 --> 02:39:04,969
AND THEN ONE QUICKLY FOR PRITI,

4243
02:39:04,969 --> 02:39:06,437
IF YOU CAN TELL US A LITTLE BIT

4244
02:39:06,437 --> 02:39:09,507
ABOUT WHY YOU'RE TARGETING

4245
02:39:09,507 --> 02:39:11,142
CD7 SPECIFICALLY WITH YOUR VLP.

4246
02:39:11,142 --> 02:39:13,244
SO MAYBE SUSANA FIRST, WHAT'S

4247
02:39:13,244 --> 02:39:14,879
MAKING IT IRREVERSIBLE?

4248
02:39:14,879 --> 02:39:16,514
>> SO I DON'T KNOW YET.

4249
02:39:16,514 --> 02:39:17,481
THAT'S WHAT WE'RE TRYING TO

4250
02:39:17,481 --> 02:39:17,782
INVESTIGATE.

4251
02:39:17,782 --> 02:39:19,650
JUST SO YOU KNOW, BY ITSELF,

4252
02:39:19,650 --> 02:39:21,152
SPIRONOLACTONE BY ITSELF, IT'S

4253
02:39:21,152 --> 02:39:22,119
NOT IRREVERSIBLE BECAUSE AS SOON

4254
02:39:22,119 --> 02:39:23,888
AS YOU REMOVE SPIRONOLACTONE,

4255
02:39:23,888 --> 02:39:25,423
YOU HAVE XPB PRODUCTION AGAIN

4256
02:39:25,423 --> 02:39:26,791
AND THERE'S A JUMP START IN

4257
02:39:26,791 --> 02:39:27,124
TRANSCRIPTION.

4258
02:39:27,124 --> 02:39:30,828
SO BY ITSELF, IT'S NOT DOING THE

4259
02:39:30,828 --> 02:39:31,595
BLOCK.

4260
02:39:31,595 --> 02:39:33,998
HOWEVER, IN COMBINATION, IT

4261
02:39:33,998 --> 02:39:35,833
SEEMS THAT IT ACCELERATES THE

4262
02:39:35,833 --> 02:39:37,802
REDUCTION, THERE IS -- AND

4263
02:39:37,802 --> 02:39:39,437
SOMEHOW THERE MIGHT BE SOME

4264
02:39:39,437 --> 02:39:40,171
EPIGENETIC DIFFERENCES.

4265
02:39:40,171 --> 02:39:41,038
THAT'S EXACTLY WHAT WE'RE

4266
02:39:41,038 --> 02:39:43,474
LOOKING INTO RIGHT NOW.

4267
02:39:43,474 --> 02:39:44,975
SO ACTUALLY I DIDN'T SHOW BUT

4268
02:39:44,975 --> 02:39:46,243
THERE'S VERY INTERESTING DATA,

4269
02:39:46,243 --> 02:39:47,678
IT'S LIKE WHEN WE STOP THE

4270
02:39:47,678 --> 02:39:49,680
SINGLE DRUGS ALONE, SO IF WE

4271
02:39:49,680 --> 02:39:52,383
STOP THE SINGLE DRUG AFTER --

4272
02:39:52,383 --> 02:39:54,652
THIS EXPERIMENT IS A LITTLE BIT

4273
02:39:54,652 --> 02:39:55,219
INSANE.

4274
02:39:55,219 --> 02:39:57,721
MORE THAN 400 SOME DAYS, THERE'S

4275
02:39:57,721 --> 02:39:58,923
A LOT OF CRITICISM THAT CAN GO

4276
02:39:58,923 --> 02:40:00,424
INTO THAT, BUT IT'S JUST THE

4277
02:40:00,424 --> 02:40:02,927
ONLY WAY WE HAVE TO GO THIS

4278
02:40:02,927 --> 02:40:04,261
LONG-RANGE AND LOOK AT THE

4279
02:40:04,261 --> 02:40:05,329
EPIGENETIC CHANGES.

4280
02:40:05,329 --> 02:40:09,033
SO WHEN WE STOP SP ALONE, WE SEE

4281
02:40:09,033 --> 02:40:10,134
REBOUND, AND EVENTUALLY IT COMES

4282
02:40:10,134 --> 02:40:11,769
BACK TO KIND OF THE CONTROL OF

4283
02:40:11,769 --> 02:40:13,170
THE ART ALONE LEVELS.

4284
02:40:13,170 --> 02:40:15,439
IF YOU DO THE DCA STOP, WHAT WE

4285
02:40:15,439 --> 02:40:17,942
SAW IN THIS PARTICULAR MODEL, SO

4286
02:40:17,942 --> 02:40:20,478
IF YOU HAVE COMPLETE

4287
02:40:20,478 --> 02:40:21,278
SUPPRESSION -- YOU TYPICALLY

4288
02:40:21,278 --> 02:40:22,646
DON'T HAVE REBOUND BUT IN THIS

4289
02:40:22,646 --> 02:40:23,981
CASE IF IT'S NOT COMPLETELY

4290
02:40:23,981 --> 02:40:24,882
SUPPRESSED, THERE WAS SOME

4291
02:40:24,882 --> 02:40:25,115
REBOUND.

4292
02:40:25,115 --> 02:40:26,283
WHAT YOU'RE SEEING OVER TIME NOW

4293
02:40:26,283 --> 02:40:28,853
IS THAT NOW WE'RE COMING BACK TO

4294
02:40:28,853 --> 02:40:31,155
ALMOST BELOW THE TREATED CELLS

4295
02:40:31,155 --> 02:40:33,657
SO WE'RE BACK TO VERY, VERY

4296
02:40:33,657 --> 02:40:34,725
INDETECTABLE LEVELS.

4297
02:40:34,725 --> 02:40:36,994
SO WHETHER THERE'S PHENOMENON OF

4298
02:40:36,994 --> 02:40:37,761
REACTIVATION AND WE ELIMINATED

4299
02:40:37,761 --> 02:40:39,864
ALL THE TRANSCRIPTIONALLY --

4300
02:40:39,864 --> 02:40:41,932
CELLS AND NOW INCREASING THE

4301
02:40:41,932 --> 02:40:42,967
POPULATION WITH VERY

4302
02:40:42,967 --> 02:40:43,834
TRANSCRIPTIONALLY SILENCED

4303
02:40:43,834 --> 02:40:44,935
POPULATION SO WE NEED TO LOOK AT

4304
02:40:44,935 --> 02:40:47,805
THIS VERY PRECISELY.

4305
02:40:47,805 --> 02:40:50,808
>> PRITI, CD7 TO ARE YOUR

4306
02:40:50,808 --> 02:40:51,108
TARGETING --

4307
02:40:51,108 --> 02:40:54,445
>> CD7 IS A MOLECULE
THAT'S

4308
02:40:54,445 --> 02:40:55,846
PRESENT ON ALMOST ALL T-CELLS

4309
02:40:55,846 --> 02:40:57,381
AND A LARGE PROPORTION OF

4310
02:40:57,381 --> 02:41:00,117
MONOCYTES AS WELL, MONOCYTES AND

4311
02:41:00,117 --> 02:41:00,484
MACROPHAGES.

4312
02:41:00,484 --> 02:41:02,486
SO TARGETING CD7 DOESN'T APPEAR

4313
02:41:02,486 --> 02:41:03,821
TO HAVE ANY DETRIMENTAL EFFECTS

4314
02:41:03,821 --> 02:41:05,089
ON THE T-CELL.

4315
02:41:05,089 --> 02:41:07,458
WE'VE TRIED TARGETING MANY OTHER

4316
02:41:07,458 --> 02:41:08,259
MOOL KEULS BUT WHAT'S

4317
02:41:08,259 --> 02:41:09,927
INTERESTING IS WHEN WE USED OUR

4318
02:41:09,927 --> 02:41:12,096
HUMAN ANTIBODIES AGAINST CD7, IT

4319
02:41:12,096 --> 02:41:14,465
LEADS TO VERY, VERY QUICK

4320
02:41:14,465 --> 02:41:15,733
ENDOCYTOSIS OF THE MOLECULE,

4321
02:41:15,733 --> 02:41:16,634
GETS WITHIN A FEW SECONDS AND

4322
02:41:16,634 --> 02:41:18,168
THEN YOU CAN SEE IT RECYCLE BACK

4323
02:41:18,168 --> 02:41:19,603
TO THE SURFACE IN ABOUT 15

4324
02:41:19,603 --> 02:41:20,471
MINUTES.

4325
02:41:20,471 --> 02:41:22,973
SO IT GIVES YOU A MANNER IN

4326
02:41:22,973 --> 02:41:24,041
WHICH YOU CAN ACTUALLY TARGET

4327
02:41:24,041 --> 02:41:26,877
THE CELL AND WITH -- YOU NEED

4328
02:41:26,877 --> 02:41:27,978
FUSION FROM THE ENDOSOME FOR

4329
02:41:27,978 --> 02:41:29,914
RELEASE OF THE CARGO, SO

4330
02:41:29,914 --> 02:41:31,015
TARGETING SOMETHING TO THE

4331
02:41:31,015 --> 02:41:33,083
ENDOSOME MECHANISM THROUGH RAPID

4332
02:41:33,083 --> 02:41:33,851
ENDOCYTOSIS SEEMS TO BE THE WAY

4333
02:41:33,851 --> 02:41:35,886
TO REALLY GET GOOD EFFICIENCIES

4334
02:41:35,886 --> 02:41:36,987
AND WE FIND EXCELLENT

4335
02:41:36,987 --> 02:41:41,358
EFFICIENCIES BY TARGETING CD7 BY

4336
02:41:41,358 --> 02:41:41,825
USING THE -- APPROACH.

4337
02:41:41,825 --> 02:41:42,927
THAT'S THE REASON WHY WE USE IT.

4338
02:41:42,927 --> 02:41:44,528
>> WE'LL TAKE ONE MORE
QUESTION.

4339
02:41:44,528 --> 02:41:45,996
SORRY, RICH, I DON'T WANT TO

4340
02:41:45,996 --> 02:41:47,698
HOLD UP LUNCH TOO MUCH LONGER.

4341
02:41:47,698 --> 02:41:48,999
>> ANDY FROM NIAID.

4342
02:41:48,999 --> 02:41:50,367
ONE QUICK QUESTION IS, WHAT ARE

4343
02:41:50,367 --> 02:41:52,937
THE SIDE EFFECTS OF SP, AND SORT

4344
02:41:52,937 --> 02:41:55,306
OF A PHILOSOPHICAL QUESTION TOO

4345
02:41:55,306 --> 02:41:56,373
IS, IF YOU GUYS ARE TALKING

4346
02:41:56,373 --> 02:41:58,142
ABOUT USING A COUPLE DIFFERENT

4347
02:41:58,142 --> 02:42:00,311
DRUGS THAT MAY HAVE TO BE TAKEN

4348
02:42:00,311 --> 02:42:02,379
ON A REGULAR BASIS ON A SEMI

4349
02:42:02,379 --> 02:42:04,048
REGULAR BASIS, ISN'T THIS REALLY

4350
02:42:04,048 --> 02:42:06,350
JUST ANOTHER CLASS OF ARVs AND

4351
02:42:06,350 --> 02:42:09,253
NOT NECESSARILY LIKE A CURE

4352
02:42:09,253 --> 02:42:09,787
MODALITY?

4353
02:42:09,787 --> 02:42:10,654
OBVIOUSLY THAT'S NOT THE CASE

4354
02:42:10,654 --> 02:42:12,523
FOR THINGS WHERE YOU WANT TO CUT

4355
02:42:12,523 --> 02:42:14,792
OUT AND PERMANENTLY SILENCE, BUT

4356
02:42:14,792 --> 02:42:16,560
IN SOME OF THE GENES, SP, IF YOU

4357
02:42:16,560 --> 02:42:17,761
TAKE IT AWAY, IT COMES RIGHT

4358
02:42:17,761 --> 02:42:18,295
BACK.

4359
02:42:18,295 --> 02:42:20,364
SO HOW ARE YOU GUYS THINKING OF

4360
02:42:20,364 --> 02:42:20,564
THAT?

4361
02:42:20,564 --> 02:42:21,999
>> SO TO ADDRESS YOUR
FIRST

4362
02:42:21,999 --> 02:42:25,803
QUESTION IN TERMS OF THE

4363
02:42:25,803 --> 02:42:26,870
TOXICITY, SP HAS BEEN USED IN

4364
02:42:26,870 --> 02:42:28,639
DOSES THAT RANGE FROM

4365
02:42:28,639 --> 02:42:31,041
25 MILLIGRAMS PER DAY, 100 -- IN

4366
02:42:31,041 --> 02:42:32,376
SOME CASES 100 MILLIGRAMS PER

4367
02:42:32,376 --> 02:42:34,311
DAY AND THE MAXIMUM TYPICALLY

4368
02:42:34,311 --> 02:42:36,780
DONE DURING TRANSITION,

4369
02:42:36,780 --> 02:42:37,781
FEMINIZING HORMONE THERAPIES,

4370
02:42:37,781 --> 02:42:38,449
400 MILLIGRAMS PER KILOGRAM.

4371
02:42:38,449 --> 02:42:40,184
THERE'S NOT A LOT OF TOXICITY

4372
02:42:40,184 --> 02:42:41,585
ASSOCIATED -- WELL, WITH THE

4373
02:42:41,585 --> 02:42:42,786
400 MILLIGRAMS PER KILOGRAM,

4374
02:42:42,786 --> 02:42:44,655
THERE'S THIS IDEA WHICH IS NOT

4375
02:42:44,655 --> 02:42:46,056
CLEARLY DEFINED IN THE

4376
02:42:46,056 --> 02:42:48,092
LITERATURE EITHER THAT YOU CAN

4377
02:42:48,092 --> 02:42:49,760
BLOCK THE ACTIVITY OF

4378
02:42:49,760 --> 02:42:51,862
TESTOSTERONE AND IT HELPS DURING

4379
02:42:51,862 --> 02:42:52,162
TRANSITION.

4380
02:42:52,162 --> 02:42:53,430
BUT ACTUALLY MANY INDIVIDUALS

4381
02:42:53,430 --> 02:42:54,865
HAVE MOVED AWAY FROM USING

4382
02:42:54,865 --> 02:42:55,232
SPIRONOLACTONE.

4383
02:42:55,232 --> 02:42:56,634
I DON'T KNOW IF IT'S THAT

4384
02:42:56,634 --> 02:42:58,268
EFFICIENT IN THAT RESPECT.

4385
02:42:58,268 --> 02:43:01,205
VERY HIGH DOSES DO AFFECT THE

4386
02:43:01,205 --> 02:43:03,607
TESTIS DEVELOPMENT AND SO FORTH,

4387
02:43:03,607 --> 02:43:06,243
IT'S BEEN SEEN IN DOGS AND RATS

4388
02:43:06,243 --> 02:43:07,544
AND SO FORTH.

4389
02:43:07,544 --> 02:43:08,712
VERY, VERY HIGH DOSES.

4390
02:43:08,712 --> 02:43:10,347
SO IN HUMANS WE NEED TO FIND

4391
02:43:10,347 --> 02:43:12,650
THAT SWEET SPOT WHERE WE SEE

4392
02:43:12,650 --> 02:43:13,617
INHIBITION OF HIV TRANSCRIPTION

4393
02:43:13,617 --> 02:43:15,919
WITHOUT THE EFFECTS OR THESE

4394
02:43:15,919 --> 02:43:17,021
OTHER SIDE EFFECTS, BUT THESE

4395
02:43:17,021 --> 02:43:18,989
TYPICALLY COME WITH THE VERY,

4396
02:43:18,989 --> 02:43:21,058
VERY HAO DOSE.

4397
02:43:21,058 --> 02:43:22,059
 HIGH DOSE.

4398
02:43:22,059 --> 02:43:23,560
LOOKING AT USING DRUGS IN

4399
02:43:23,560 --> 02:43:24,862
COMBINATION OR ARE WE JUST

4400
02:43:24,862 --> 02:43:25,863
REPLACING ART FOR ANOTHER ARKTS

4401
02:43:25,863 --> 02:43:30,200
I TART, ITHINK THERE'S DEFINITET

4402
02:43:30,200 --> 02:43:33,737
OF ADDING TRANSCRIPTIONAL

4403
02:43:33,737 --> 02:43:35,139
INHIBITOR BECAUSE WE ARE

4404
02:43:35,139 --> 02:43:36,407
ACCELERATING VIRAL SUPPRESSION,

4405
02:43:36,407 --> 02:43:36,940
THEREFORE WE'RE PROBABLY

4406
02:43:36,940 --> 02:43:37,975
REDUCING THE SIZE OF THE

4407
02:43:37,975 --> 02:43:40,010
RESERVOIR.

4408
02:43:40,010 --> 02:43:42,012
AND THEN I THINK THE IDEA OF

4409
02:43:42,012 --> 02:43:43,847
USING THIS AS A BLOCK AND

4410
02:43:43,847 --> 02:43:45,082
LOCKAGE IS THAT WE CAN GET TO A

4411
02:43:45,082 --> 02:43:46,817
POINT WHERE WE CAN ACTUALLY

4412
02:43:46,817 --> 02:43:47,217
LEAVE ART FREE.

4413
02:43:47,217 --> 02:43:48,852
SO WE NEED TO UNDERSTAND HOW

4414
02:43:48,852 --> 02:43:50,387
LONG DO WE TREAT WITH ALL THESE

4415
02:43:50,387 --> 02:43:51,055
DIFFERENT DRUGS TOGETHER AND

4416
02:43:51,055 --> 02:43:53,123
BEFORE WE CAN LIFT ART AND HAVE

4417
02:43:53,123 --> 02:43:54,525
THIS ART-FREE PERIOD.

4418
02:43:54,525 --> 02:43:55,926
SO THESE ARE STILL OUTSTANDING

4419
02:43:55,926 --> 02:43:57,361
QUESTIONS THAT WE NEED TO

4420
02:43:57,361 --> 02:44:02,175
ADDRESS IN DIFFERENT MODELS.

4421
02:44:02,175 --> 02:44:03,710
GOOD AFTERNOON.

4422
02:44:03,710 --> 02:44:06,746
I'M A PROGRAM OFFICER IN THE

4423
02:44:06,746 --> 02:44:09,316
DIVISION OF AIDS AT NIAID.

4424
02:44:09,316 --> 02:44:11,618
NEXT WE WILL HEAR TWO

4425
02:44:11,618 --> 02:44:12,919
PRESENTATIONS FROM THE CONSORTIA

4426
02:44:12,919 --> 02:44:15,322
FOR INNOVATIVE HIV/AIDS VACCINE

4427
02:44:15,322 --> 02:44:20,260
AND CURE RESEARCH, ABBREVIATED

4428
02:44:20,260 --> 02:44:20,894
CIAVCRs.

4429
02:44:20,894 --> 02:44:24,397
THE TWO CIAVCRs ARE BASED AT

4430
02:44:24,397 --> 02:44:26,499
EMORY AND DUKE UNIVERSITY.

4431
02:44:26,499 --> 02:44:28,001
THE FIRST PRESENTATION WILL BE

4432
02:44:28,001 --> 02:44:30,003
GIVEN BY DR. ERIC HUNTER FROM

4433
02:44:30,003 --> 02:44:33,206
THE EMORY CONSORTIUM, FOLLOWED

4434
02:44:33,206 --> 02:44:38,245
BY DR. GUIDO FERRARI FROM THE

4435
02:44:38,245 --> 02:44:39,312
DUKE CONSORTIUM AND THEY WILL

4436
02:44:39,312 --> 02:44:40,413
TAKE QUESTIONS AFTERWARDS.

4437
02:44:40,413 --> 02:44:41,848
WITH THAT, I'LL HAND IT OVER TO

4438
02:44:41,848 --> 02:44:48,321
YOU, ERIC.

4439
02:44:48,321 --> 02:44:51,224
>> THANK YOU, BRI GIT.

4440
02:44:51,224 --> 02:44:55,295
 BRIGITTE.

4441
02:44:55,295 --> 02:44:57,931
SO THE EMORY CONSORTIUM FOR

4442
02:44:57,931 --> 02:44:59,532
INNOVATIVE HIV/AIDS VACCINE AND

4443
02:44:59,532 --> 02:45:03,803
CURE RESEARCH, A MOUTHFUL THAT

4444
02:45:03,803 --> 02:45:06,973
WE DON'T RELISH, I MUST ADMIT,

4445
02:45:06,973 --> 02:45:09,476
IS HEADED UP BY MYSELF AND RAMA

4446
02:45:09,476 --> 02:45:11,678
AMARA.

4447
02:45:11,678 --> 02:45:13,546
IT'S REALLY DIVIDED INTO TWO

4448
02:45:13,546 --> 02:45:14,581
SECTIONS.

4449
02:45:14,581 --> 02:45:16,283
FOCUS ONE IS ON PREVENTION AND

4450
02:45:16,283 --> 02:45:18,051
INNOVATIVE VACCINE APPROACHES.

4451
02:45:18,051 --> 02:45:20,420
WE'VE BEEN REALLY PARTICULARLY

4452
02:45:20,420 --> 02:45:23,590
INTERESTED IN COMBINING A

4453
02:45:23,590 --> 02:45:26,793
DURABLE NEUTRALIZING ANTIBODY

4454
02:45:26,793 --> 02:45:32,365
RESPONSE WITH A TISSUE TARGETED

4455
02:45:32,365 --> 02:45:35,869
CDA RESPONSE AS A PREVENTIVE

4456
02:45:35,869 --> 02:45:36,503
VACCINE FOR HIV.

4457
02:45:36,503 --> 02:45:40,106
THERE ARE 10 INVESTIGATORS THAT

4458
02:45:40,106 --> 02:45:42,208
ARE BASED AT EMORY INVOLVED IN

4459
02:45:42,208 --> 02:45:45,045
THE CONSORTIUM WITH

4460
02:45:45,045 --> 02:45:46,379
COLLABORATORS THAT ARE PART OF

4461
02:45:46,379 --> 02:45:49,849
THE CONSORTIUM AT THE LA JOLLA

4462
02:45:49,849 --> 02:45:51,351
INSTITUTE FOR IMMUNOLOGY, THE

4463
02:45:51,351 --> 02:45:53,586
UNIVERSITY OF MINNESOTA,

4464
02:45:53,586 --> 02:45:54,220
STANFORD, UNIVERSITY OF

4465
02:45:54,220 --> 02:45:58,725
WASHINGTON AND LSU.

4466
02:45:58,725 --> 02:46:00,260
FOCUS TWO HAS REALLY BEEN HEADED

4467
02:46:00,260 --> 02:46:04,297
UP BY GEA DOUGH SILVESTRI SO

4468
02:46:04,297 --> 02:46:05,932
I'LL BE SPEAKING ON HIS BEHALF

4469
02:46:05,932 --> 02:46:16,276
THIS AFTERNOON, AND

4470
02:46:18,345 --> 02:46:19,212
COINVESTIGATORS CONTRIBUTING TO

4471
02:46:19,212 --> 02:46:21,915
THE STUDY I'LL BE TALKING ABOUT

4472
02:46:21,915 --> 02:46:24,317
AND WE HAVE A COLLABORATIVE UNIT

4473
02:46:24,317 --> 02:46:29,222
AT UNC CHAPEL HIP WITH NANCY

4474
02:46:29,222 --> 02:46:34,694
ARCHINAND DR. MARGOLIS.

4475
02:46:34,694 --> 02:46:36,796
IT'S BEEN A VERY PRODUCTIVE

4476
02:46:36,796 --> 02:46:41,668
INTERACTION.

4477
02:46:41,668 --> 02:46:45,805
THE FOCUS FROM THE BEGINNING, WE

4478
02:46:45,805 --> 02:46:49,976
HAD A MUCH EASIER ACRONYM,

4479
02:46:49,976 --> 02:46:53,346
CONSORTIUM FOR INNOVATIVE AIDS

4480
02:46:53,346 --> 02:46:56,282
RESEARCH, CIAR, AND THAT FOCUS

4481
02:46:56,282 --> 02:46:59,252
HAS BEEN -- FOCUS TWO, THE CURE

4482
02:46:59,252 --> 02:47:02,522
COMPONENT, HAS PURSUED SHOCK AND

4483
02:47:02,522 --> 02:47:03,523
KILL STRATEGY FOR HIV AND I

4484
02:47:03,523 --> 02:47:04,958
DON'T HAVE TO GO INTO DETAILS ON

4485
02:47:04,958 --> 02:47:07,794
THAT, ALTHOUGH WE HAVE BEEN

4486
02:47:07,794 --> 02:47:10,730
WORKING WITH DAVE AND THE TEAM

4487
02:47:10,730 --> 02:47:17,203
AT UNC ON IDENTIFICATION OF

4488
02:47:17,203 --> 02:47:22,008
NOVEL LATENCY REACTIVATION

4489
02:47:22,008 --> 02:47:27,580
INHIBITORS, LRAs, LET ME JUST

4490
02:47:27,580 --> 02:47:29,983
PUT IT THAT WAY, NOVEL LRAs

4491
02:47:29,983 --> 02:47:32,819
THAT COULD THEN BE TESTED IN

4492
02:47:32,819 --> 02:47:34,921
VIVO IN MACAQUES.

4493
02:47:34,921 --> 02:47:38,191
I GUESS NEITHER BRIGITTE NOR I

4494
02:47:38,191 --> 02:47:39,993
POINTED OUT THAT THE CONSORTIA

4495
02:47:39,993 --> 02:47:41,694
THAT WE'LL BE TALKING ABOUT

4496
02:47:41,694 --> 02:47:48,902
TODAY ARE FOCUSED ON STUDIES IN

4497
02:47:48,902 --> 02:47:50,336
NHPs.

4498
02:47:50,336 --> 02:47:52,739
SO IN THE FIRST ITERATION OF

4499
02:47:52,739 --> 02:47:57,544
THIS IN THE CIAR, WE IDENTIFIED

4500
02:47:57,544 --> 02:48:02,148
SMACK MIMETICS AS A POTENTIAL

4501
02:48:02,148 --> 02:48:02,682
NOVEL LRA.

4502
02:48:02,682 --> 02:48:06,186
IT WAS THE FIRST IN NHP STUDIES,

4503
02:48:06,186 --> 02:48:09,789
A COMBINATION IN NHPs AND

4504
02:48:09,789 --> 02:48:12,625
HUMANIZED MICE, IN THE NIXON ET

4505
02:48:12,625 --> 02:48:14,160
AL. NATURE PAPER, AND THAT

4506
02:48:14,160 --> 02:48:19,732
SHOWED THAT NON-CANONICAL NF CAB

4507
02:48:19,732 --> 02:48:24,571
SIGNALING INDUCED BY

4508
02:48:24,571 --> 02:48:26,206
AZD5822 COULD GENERATE SYSTEMIC

4509
02:48:26,206 --> 02:48:32,111
HIV AND SIV LATENCY REVERSAL.

4510
02:48:32,111 --> 02:48:33,546
ONE OF THE POINTS THAT WAS

4511
02:48:33,546 --> 02:48:37,584
REALLY IMPORTANT, THOUGH, WAS TO

4512
02:48:37,584 --> 02:48:39,552
SHOW THAT THERE COULD BE AN

4513
02:48:39,552 --> 02:48:43,690
ENHANCEMENT OF LATENCY REVERSAL

4514
02:48:43,690 --> 02:48:46,526
BY DEPLETING AT THE SAME TIME

4515
02:48:46,526 --> 02:48:46,860
CD8 T-CELLS.

4516
02:48:46,860 --> 02:48:49,162
AND THAT CAME FROM THE FACT FROM

4517
02:48:49,162 --> 02:48:55,301
DEANNA'S WORK THAT SUGGESTED

4518
02:48:55,301 --> 02:48:57,370
THAT CD8 CELLS, IN ADDITION TO

4519
02:48:57,370 --> 02:48:58,938
THEIR CYTOTOXIC FUNCTION, COULD

4520
02:48:58,938 --> 02:49:02,075
HAVE A SUPPRESSIVE FUNCTION THAT

4521
02:49:02,075 --> 02:49:07,881
ACTUALLY FACILITATED LATENCY

4522
02:49:07,881 --> 02:49:09,182
RATHER THAN KILLING THE CELLS.

4523
02:49:09,182 --> 02:49:13,453
WE WERE ABLE TO SHOW IN THIS

4524
02:49:13,453 --> 02:49:14,754
MCBRIEN, ET AL. PAPER THAT YOU

4525
02:49:14,754 --> 02:49:18,791
COULD GET A VERY ROBUST AND

4526
02:49:18,791 --> 02:49:24,063
PERSISTENT SIV AND REACTIVATION,

4527
02:49:24,063 --> 02:49:28,334
AND HIV REACTIVATION UNDER ART

4528
02:49:28,334 --> 02:49:35,642
BY THE IL15 SUPERAGONIST

4529
02:49:35,642 --> 02:49:38,378
NA03 COMBINED WITH

4530
02:49:38,378 --> 02:49:38,945
CD8 DEPLETION.

4531
02:49:38,945 --> 02:49:40,947
THIS JUST SHOWS THE REACTIVATION

4532
02:49:40,947 --> 02:49:47,153
OF VIRUS UNDER THAT CONDITION,

4533
02:49:47,153 --> 02:49:47,854
REALLY DEMONSTRATING FOR THE

4534
02:49:47,854 --> 02:49:49,789
FIRST TIME, VIRAL LOADS IN

4535
02:49:49,789 --> 02:49:55,628
EXCESS OF 10,000, SOME OF THE

4536
02:49:55,628 --> 02:49:57,430
MOST ROBUST REACTIVATION OF

4537
02:49:57,430 --> 02:50:00,166
VIRUS SEEN AT THAT POINT, BY

4538
02:50:00,166 --> 02:50:04,671
THIS COMBINATION OF

4539
02:50:04,671 --> 02:50:07,840
CD8 DEPLETION AND THE N-803.

4540
02:50:07,840 --> 02:50:10,243
IN THESE STUDIES, N-803 ALONE

4541
02:50:10,243 --> 02:50:14,514
DID NOT RESULT IN ANY BLIPS OF

4542
02:50:14,514 --> 02:50:17,016
VIRUS REACTIVATION, AND SO EVEN

4543
02:50:17,016 --> 02:50:18,985
THOUGH IT HAD BEEN SHOWN IN

4544
02:50:18,985 --> 02:50:21,921
VITRO TO BE A POTENTIAL LRA,

4545
02:50:21,921 --> 02:50:25,658
THAT WAS NOT THE CASE IN THE

4546
02:50:25,658 --> 02:50:27,093
MACAQUES THAT WERE STUDIED IN

4547
02:50:27,093 --> 02:50:28,828
THIS STUDY.

4548
02:50:28,828 --> 02:50:30,597
THAT WAS FOLLOWED UP BY TWO

4549
02:50:30,597 --> 02:50:33,533
ADDITIONAL STUDIES.

4550
02:50:33,533 --> 02:50:36,703
ONE LOOKING AT SHIV REACTIVATION

4551
02:50:36,703 --> 02:50:40,273
AND A SECOND LOOKING INSTEAD AT

4552
02:50:40,273 --> 02:50:44,477
A SECOND LRA, THE SMACK MIMETIC

4553
02:50:44,477 --> 02:50:46,879
AZD5582.

4554
02:50:46,879 --> 02:50:48,514
SO ALL THREE OF THESE REALLY

4555
02:50:48,514 --> 02:50:53,219
SHOWED HOW CD8 DEPLETION COULD

4556
02:50:53,219 --> 02:50:57,490
ENHANCE LATENCY REACTIVATION IN

4557
02:50:57,490 --> 02:51:00,560
VIVO IN MACAQUES.

4558
02:51:00,560 --> 02:51:03,596
BRAD TALKED ABOUT THIS EARLIER

4559
02:51:03,596 --> 02:51:03,830
TODAY.

4560
02:51:03,830 --> 02:51:06,933
THIS IS FROM DEANNA'S LAB, BUT

4561
02:51:06,933 --> 02:51:08,768
IT EXPLAINS TO A CERTAIN EXTENT

4562
02:51:08,768 --> 02:51:10,937
WHY WE'RE SEEING THIS EFFECT IN

4563
02:51:10,937 --> 02:51:13,673
VIVO, AND THAT'S BECAUSE

4564
02:51:13,673 --> 02:51:14,674
CD8 CELLS ARE PROMOTING CHANGES

4565
02:51:14,674 --> 02:51:18,478
IN THE CD4 T-CELL TRANSCRIPTOME

4566
02:51:18,478 --> 02:51:21,681
THAT RESULTS IN INCREASED

4567
02:51:21,681 --> 02:51:27,020
SURVIVAL, QUIESCENCE AND STEM

4568
02:51:27,020 --> 02:51:27,286
CELLNESS.

4569
02:51:27,286 --> 02:51:30,390
ALL OF THOSE THINGS PUSH VIRAL

4570
02:51:30,390 --> 02:51:32,759
TRANSCRIPTION DOWN, ALLOWING

4571
02:51:32,759 --> 02:51:36,429
CELLS TO MORE EASILY GO INTO A

4572
02:51:36,429 --> 02:51:39,499
LATENT STATE.

4573
02:51:39,499 --> 02:51:43,970
THOSE STUDIES SHOWED VERY ROBUST

4574
02:51:43,970 --> 02:51:47,607
LATENCY REACTIVATION, BUT WHAT

4575
02:51:47,607 --> 02:51:49,542
WAS FOUND IN EACH OF THOSE

4576
02:51:49,542 --> 02:51:51,844
STUDIES WAS THAT THERE WAS NO

4577
02:51:51,844 --> 02:51:55,682
IMPACT ON THE SIZE OF THE VIRAL

4578
02:51:55,682 --> 02:51:56,015
RESERVOIR.

4579
02:51:56,015 --> 02:51:57,984
AND SO ONE OF THE QUESTIONS THEN

4580
02:51:57,984 --> 02:52:00,620
ASKED WAS, WE'VE BEEN ABLE TO

4581
02:52:00,620 --> 02:52:02,321
GET THE KICK, WHAT ABOUT THE

4582
02:52:02,321 --> 02:52:02,655
KILL?

4583
02:52:02,655 --> 02:52:06,325
CAN WE ADD ADDITIONAL REAGENTS

4584
02:52:06,325 --> 02:52:07,894
TO THE MIX THAT MIGHT THEN

4585
02:52:07,894 --> 02:52:11,364
REDUCE THE VIRAL RESERVOIR, AND

4586
02:52:11,364 --> 02:52:12,732
THAT WAS FACILITATED BY THE

4587
02:52:12,732 --> 02:52:15,668
AVAILABILITY OF MONOCLONAL

4588
02:52:15,668 --> 02:52:17,437
ANTISIV ANTIBODIES, A VIRUS

4589
02:52:17,437 --> 02:52:19,405
THAT'S ACTUALLY VERY DIFFICULT

4590
02:52:19,405 --> 02:52:21,607
TO RAISE NEUTRALIZING ANTIBODIES

4591
02:52:21,607 --> 02:52:30,550
AGAINST, THAT CAME FROM MARIO

4592
02:52:30,550 --> 02:52:32,652
ROEDERE'S LAB AND IT WAS ALSO

4593
02:52:32,652 --> 02:52:33,820
FACILITATED BY PRODUCTION FOR

4594
02:52:33,820 --> 02:52:37,557
THE NAP STUDIES BY THE CVI.

4595
02:52:37,557 --> 02:52:40,426
SO IN THIS CASE, AS YOU CAN SEE

4596
02:52:40,426 --> 02:52:43,162
THERE ARE FOUR ARMS.

4597
02:52:43,162 --> 02:52:46,632
THE FIRST WAS ART-TREATED, THE

4598
02:52:46,632 --> 02:52:51,270
SECOND WAS ART-TREATED WITH TWO

4599
02:52:51,270 --> 02:52:53,840
DOSES OF ANTIBODY.

4600
02:52:53,840 --> 02:52:57,710
THE THIRD, TWO DOSES OF ANTIBODY

4601
02:52:57,710 --> 02:53:04,717
INCLUDING -- I CAN'T REALLY READ

4602
02:53:04,717 --> 02:53:09,655
THE SLIDES HERE -- INCLUDING THE

4603
02:53:09,655 --> 02:53:11,124
AZD5582, AND THEN THE LAST WAS

4604
02:53:11,124 --> 02:53:15,895
ONE THAT INCLUDED ALSO N-803,

4605
02:53:15,895 --> 02:53:20,700
THE IL15 SUPER AGONIST.

4606
02:53:20,700 --> 02:53:25,905
WE WERE ABLE TO SEE AGAIN A

4607
02:53:25,905 --> 02:53:27,106
ROBUST REACTIVATION IN THESE

4608
02:53:27,106 --> 02:53:32,578
EXPERIMENTS, AND IN THE ANIMALS

4609
02:53:32,578 --> 02:53:36,082
TREATED WITH AZD582 AND

4610
02:53:36,082 --> 02:53:37,517
CD8 DEPLETION ALONG WITH

4611
02:53:37,517 --> 02:53:45,691
ANTIBODIES, WE SAW THE -- WE SAW

4612
02:53:45,691 --> 02:53:50,963
A REDUCTION IN THE VIRAL

4613
02:53:50,963 --> 02:53:52,932
RESERVOIR IN LYMPH NODE CELLS,

4614
02:53:52,932 --> 02:53:55,101
AND THAT WAS CONFIRMED BY A

4615
02:53:55,101 --> 02:53:59,472
REDUCTION -- A SIGNIFICANT

4616
02:53:59,472 --> 02:54:04,277
REDUCTION, ALTHOUGH MODEST

4617
02:54:04,277 --> 02:54:08,347
REDUCTION IN THE QVOA ASSAY.

4618
02:54:08,347 --> 02:54:12,952
THE ANALYSIS OF VI VIREMIA FULLY

4619
02:54:12,952 --> 02:54:15,354
RECAPITULATED THE RESULTS OF

4620
02:54:15,354 --> 02:54:23,863
NIXON AND ALL SHOWIN.

4621
02:54:23,863 --> 02:54:28,467
THIS INFUSION OF THE BROAD

4622
02:54:28,467 --> 02:54:31,204
ANTIBODIES WAS WELL TOLERATED.

4623
02:54:31,204 --> 02:54:32,638
ART INTERRUPTION WAS NOT

4624
02:54:32,638 --> 02:54:34,307
PERFORMED BECAUSE WE WANTED TO

4625
02:54:34,307 --> 02:54:37,109
LOOK AT ALL THE TISSUES, THIS

4626
02:54:37,109 --> 02:54:38,744
LONGITUDINAL ASSESSMENT OF

4627
02:54:38,744 --> 02:54:39,946
RESERVOIR SIZE REVEALED A

4628
02:54:39,946 --> 02:54:41,647
REDUCTION SIGNAL IN LYMPH NODES

4629
02:54:41,647 --> 02:54:44,317
FOR BOTH CELL ASSOCIATED SIV DNA

4630
02:54:44,317 --> 02:54:46,118
AND QVOA.

4631
02:54:46,118 --> 02:54:47,954
AND I THINK OPTIMIZATION OF THIS

4632
02:54:47,954 --> 02:54:50,590
APPROACH MAY LEAD TO ENHANCED

4633
02:54:50,590 --> 02:54:54,961
RESERVOIR CLEARANCE.

4634
02:54:54,961 --> 02:54:56,162
CD8 CELLS THEN CLEARLY PLAY A

4635
02:54:56,162 --> 02:55:06,706
ROLE IN REDUCTION OF -- IN HEL

4636
02:55:07,073 --> 02:55:08,941
HELPING ESTABLISH -- SORRY,

4637
02:55:08,941 --> 02:55:11,277
HELPING MAINTAIN LATENCY.

4638
02:55:11,277 --> 02:55:14,547
BUT WHAT IS THE ROLE OF THESE

4639
02:55:14,547 --> 02:55:16,515
CELLS IN THE ESTABLISHMENT OF

4640
02:55:16,515 --> 02:55:18,484
THE PERSISTENT RESERVOIR OF

4641
02:55:18,484 --> 02:55:21,854
LATENTLY INFECTED CELLS?

4642
02:55:21,854 --> 02:55:24,090
SO WHAT WE'VE RECENTLY DONE IS

4643
02:55:24,090 --> 02:55:25,691
TO ASK, WELL, WHAT HAPPENS IF

4644
02:55:25,691 --> 02:55:31,631
YOU DEEPLY -- IF YOU DEPLETE CD,

4645
02:55:31,631 --> 02:55:35,968
AND THEN PUT THE ANIMALS ON ART,

4646
02:55:35,968 --> 02:55:38,170
PRIOR TO THE ART ITSELF BUT TWO

4647
02:55:38,170 --> 02:55:40,239
WEEKS AFTER INFECTION, COMPARED

4648
02:55:40,239 --> 02:55:42,441
TO ANIMALS THAT WERE SIMPLY

4649
02:55:42,441 --> 02:55:47,346
INFECTED AND PUT ON ART, LEFT

4650
02:55:47,346 --> 02:55:51,517
FOR ALMOST A YEAR ON ART

4651
02:55:51,517 --> 02:55:54,654
SUPPRESSION AND THEN UNDERGOING

4652
02:55:54,654 --> 02:55:58,624
A TREATMENT INTERRUPTION.

4653
02:55:58,624 --> 02:56:00,359
WHAT WE NOTICED WAS THAT IN EACH

4654
02:56:00,359 --> 02:56:02,561
OF THE THREE GROUPS, THE PEAK

4655
02:56:02,561 --> 02:56:05,398
VIRAL LOAD WAS QUITE SIMILAR.

4656
02:56:05,398 --> 02:56:08,234
BUT THERE WAS A VERY DISTINCT

4657
02:56:08,234 --> 02:56:13,272
DIFFERENCE IN THE SLOPE OF VIRAL

4658
02:56:13,272 --> 02:56:17,209
DECAY, AND THAT'S SHOWN HERE

4659
02:56:17,209 --> 02:56:20,913
WHERE THE READ IS -- THE ANIMALS

4660
02:56:20,913 --> 02:56:24,317
THAT WERE TREATED WITH ART --

4661
02:56:24,317 --> 02:56:26,886
SORRY -- WERE DEPLETED OF

4662
02:56:26,886 --> 02:56:30,990
CD8 CELLS PREINFECTION WERE --

4663
02:56:30,990 --> 02:56:35,261
VERSUS THOSE THAT WERE DEPLETED

4664
02:56:35,261 --> 02:56:37,530
IMMEDIATELY BEFORE ART COMPARED

4665
02:56:37,530 --> 02:56:43,336
TO THE CONTROLS.

4666
02:56:43,336 --> 02:56:45,237
BUT DESPITE THAT SLOWER DECAY,

4667
02:56:45,237 --> 02:56:49,275
THERE WAS NO DIFFERENCE IN THE

4668
02:56:49,275 --> 02:56:50,710
SIZE OF THE VIRAL RESERVOIR

4669
02:56:50,710 --> 02:56:52,445
UNDER ART, AND THAT WAS TRUE

4670
02:56:52,445 --> 02:56:53,813
BOTH IN PERIPHERAL CELLS SHOWN

4671
02:56:53,813 --> 02:56:58,751
ON THE LEFT, TOTAL DNA OR INTACT

4672
02:56:58,751 --> 02:57:00,953
VIRUSES, OR IN LYMPH NODES SHOWN

4673
02:57:00,953 --> 02:57:05,124
ON THE RIGHT.

4674
02:57:05,124 --> 02:57:08,294
WITH AGAIN, A TOTAL VIRAL DNA,

4675
02:57:08,294 --> 02:57:09,795
AND INTACT VIRUSES.

4676
02:57:09,795 --> 02:57:11,931
AND IN FACT, THAT WAS BORNE OUT

4677
02:57:11,931 --> 02:57:16,035
BY THE FACT THAT THERE WAS NO

4678
02:57:16,035 --> 02:57:17,370
DIFFERENCE IN THE KINETICS OF

4679
02:57:17,370 --> 02:57:20,539
VIRAL REBOUND AFTER ATI.

4680
02:57:20,539 --> 02:57:23,476
SO CD8 DEPLETION DOES RESULT IN

4681
02:57:23,476 --> 02:57:29,515
A SLOWER DECLINE OF VIRAL

4682
02:57:29,515 --> 02:57:32,118
REBOUND AFTER DAY 15, INDICATING

4683
02:57:32,118 --> 02:57:35,187
THAT CD8 LYMPHOCYTES REDUCE THE

4684
02:57:35,187 --> 02:57:36,622
LIFESPAN OF PRODUCTIVELY

4685
02:57:36,622 --> 02:57:38,591
INFECTED CELLS, PRESUMABLY

4686
02:57:38,591 --> 02:57:40,326
THROUGH SIV-SPECIFIC CTL

4687
02:57:40,326 --> 02:57:40,893
ACTIVITY.

4688
02:57:40,893 --> 02:57:43,396
HOWEVER, IT DIDN'T CHANGE THE

4689
02:57:43,396 --> 02:57:46,232
SIZE OF THE PERSISTENT VIRAL

4690
02:57:46,232 --> 02:57:47,633
RESERVOIR, MEASURED DIRECTLY OR

4691
02:57:47,633 --> 02:57:50,836
BY IPDA OR FUNCTIONALLY BY

4692
02:57:50,836 --> 02:57:52,905
KINETICS OF REBOUND.

4693
02:57:52,905 --> 02:57:55,641
SO IT INDICATES THAT DURING

4694
02:57:55,641 --> 02:57:57,076
EARLY SIV INFECTION, THE

4695
02:57:57,076 --> 02:57:58,044
PERSISTENT RESERVOIR IS

4696
02:57:58,044 --> 02:57:59,045
ESTABLISHED PRIMARILY IN CELLS

4697
02:57:59,045 --> 02:58:02,748
PRIOR TO THE INDUCTION OF CTL

4698
02:58:02,748 --> 02:58:05,051
CONTROL OR INDEPENDENTLY OF CTL

4699
02:58:05,051 --> 02:58:09,655
CONTROL.

4700
02:58:09,655 --> 02:58:11,157
THAT LEADS US TO OUR MOST

4701
02:58:11,157 --> 02:58:12,691
CURRENT STUDIES, WHICH IS CAN

4702
02:58:12,691 --> 02:58:14,326
VACCINE INDUCED T-CELLS IMPACT

4703
02:58:14,326 --> 02:58:16,362
THE ESTABLISHMENT AND STABILITY

4704
02:58:16,362 --> 02:58:25,171
OF THE VIRAL RESERVOIR.

4705
02:58:25,171 --> 02:58:26,539
WE RECENTLY PUBLISHED ON THE

4706
02:58:26,539 --> 02:58:29,775
FACT THAT T-CELL INDUCING

4707
02:58:29,775 --> 02:58:33,045
VACCINE CAN PREVENT MUCOSAL SHIV

4708
02:58:33,045 --> 02:58:36,115
INFECTION EVEN WITH LOW AND

4709
02:58:36,115 --> 02:58:37,416
NEUTRALIZING ANTIBODY TITERS.

4710
02:58:37,416 --> 02:58:42,221
THIS WAS COMBINING THREE

4711
02:58:42,221 --> 02:58:43,622
HETEROLOGOUS VECTOR EXPRESSING

4712
02:58:43,622 --> 02:58:47,059
GAG ALONG WITH TRIMER

4713
02:58:47,059 --> 02:58:49,762
VACCINATION TO GENERATE NEWT

4714
02:58:49,762 --> 02:58:54,700
LASING -- AUTOLOGOUS --

4715
02:58:54,700 --> 02:58:55,568
TR2 AUTOLOGOUS NEUTRALIZING

4716
02:58:55,568 --> 02:58:55,901
ANTIBODY.

4717
02:58:55,901 --> 02:58:57,103
THIS APPROACH RESULTS IN A VERY

4718
02:58:57,103 --> 02:58:59,271
HIGH LEVEL OF CD8 CELLS IN THE

4719
02:58:59,271 --> 02:59:02,241
PERIPHERY AS WELL AS IN TISSUES.

4720
02:59:02,241 --> 02:59:05,845
AND IN FACT WHAT WE SAW WAS THAT

4721
02:59:05,845 --> 02:59:07,279
WHILE ANIMALS WITH A

4722
02:59:07,279 --> 02:59:08,481
NEUTRALIZING TIGHTER GREATER

4723
02:59:08,481 --> 02:59:12,518
THAN 300 WERE PROTECTED FROM

4724
02:59:12,518 --> 02:59:12,852
CHALLENGE.

4725
02:59:12,852 --> 02:59:14,086
THE BULK OF THE ANIMALS THAT

4726
02:59:14,086 --> 02:59:16,789
WERE PROTECTED IN THE CASE OF

4727
02:59:16,789 --> 02:59:20,493
THE HETEROLOGOUS VECTOR PLUS

4728
02:59:20,493 --> 02:59:22,895
SUBSET GROUP HAD TITERS LESS

4729
02:59:22,895 --> 02:59:24,763
THAN 300 AND YET WERE PROTECTED.

4730
02:59:24,763 --> 02:59:28,701
AND THAT'S VERY DISTINCT FROM

4731
02:59:28,701 --> 02:59:31,237
ANIMALS THAT WERE SIMPLY

4732
02:59:31,237 --> 02:59:34,940
VACCINATED, SUGGESTING A REAL

4733
02:59:34,940 --> 02:59:37,243
SYNERGY BETWEEN ANTIBODY AND

4734
02:59:37,243 --> 02:59:37,676
T-CELL.

4735
02:59:37,676 --> 02:59:40,312
SO THE REAL QUESTION IS, CAN WE

4736
02:59:40,312 --> 02:59:42,815
GENERATE TISSUE TARGETED

4737
02:59:42,815 --> 02:59:44,884
CD8 T-CELL MEDIATED

4738
02:59:44,884 --> 02:59:46,085
ANTIRESERVOIR EFFECT BY

4739
02:59:46,085 --> 02:59:49,155
VACCINATING THE ANIMALS IN THIS

4740
02:59:49,155 --> 02:59:53,659
SAME WAY FOR CD8 CELLS PRIOR TO

4741
02:59:53,659 --> 02:59:55,427
SIEVE INFECTION, CAN WE GENERATE

4742
02:59:55,427 --> 02:59:58,697
A TISSUE TARGETED CD8 T-CELL

4743
02:59:58,697 --> 03:00:01,667
MEDIATED ANTIRESERVOIR EFFECT

4744
03:00:01,667 --> 03:00:04,170
VACCINATING UNDER ART AND IF WE

4745
03:00:04,170 --> 03:00:05,504
COMBINE THESE TOGETHER, CAN WE

4746
03:00:05,504 --> 03:00:07,406
REDUCE THE SIZE OF THE RESERVOIR

4747
03:00:07,406 --> 03:00:11,277
AND GENERATE A CD8 T-CELL

4748
03:00:11,277 --> 03:00:13,045
MEDIATED LONG TERM VIRAL

4749
03:00:13,045 --> 03:00:13,479
SUPPRESSION?

4750
03:00:13,479 --> 03:00:17,516
THIS JUST SHOWS THE DESIGN.

4751
03:00:17,516 --> 03:00:19,818
ONE GROUP, GROUP TWO, WILL BE

4752
03:00:19,818 --> 03:00:21,253
VACCINATED USING AGAIN THE

4753
03:00:21,253 --> 03:00:23,556
HETEROLOGOUS VECTORS PRIOR TO

4754
03:00:23,556 --> 03:00:26,325
PUTTING THE -- PRIOR TO

4755
03:00:26,325 --> 03:00:27,459
INFECTION AND PUTTING THE

4756
03:00:27,459 --> 03:00:28,227
ANIMALS ON ART.

4757
03:00:28,227 --> 03:00:30,196
ANOTHER GROUP, GROUP ONE, WILL

4758
03:00:30,196 --> 03:00:32,598
BE PUT ON ART AND THEN

4759
03:00:32,598 --> 03:00:33,933
VACCINATED AGAIN TO SEE WHETHER

4760
03:00:33,933 --> 03:00:37,002
WE CAN GET THE SAME LEVEL OF

4761
03:00:37,002 --> 03:00:41,140
TISSUE LOCALIZED CD8 CELLS.

4762
03:00:41,140 --> 03:00:43,776
GROUP THREE IS A STANDARD ART,

4763
03:00:43,776 --> 03:00:46,278
AND GROUP FOUR WILL BE

4764
03:00:46,278 --> 03:00:50,783
VACCINATED AS IN GROUP 2 BUT

4765
03:00:50,783 --> 03:00:53,052
WILL BE BOOSTED DURING ART TO

4766
03:00:53,052 --> 03:00:54,253
SEE WHETHER DURING -- WITH THAT

4767
03:00:54,253 --> 03:00:57,089
BOOST, WE CAN REDUCE THE VIRAL

4768
03:00:57,089 --> 03:00:59,425
RESERVOIR.

4769
03:00:59,425 --> 03:01:05,197
WE DON'T HAVE A COMMUNITY PART

4770
03:01:05,197 --> 03:01:06,966
OF OUR PROGRAM, BUT JUST FOR

4771
03:01:06,966 --> 03:01:10,569
THOSE IN THE COMMUNITY, WHAT THE

4772
03:01:10,569 --> 03:01:12,504
NHP EXPERIMENTS ALLOW US TO DO

4773
03:01:12,504 --> 03:01:15,140
IS USE INTERVENTIONS THAT ARE

4774
03:01:15,140 --> 03:01:19,545
IMPOSSIBLE AT THIS POINT TO DO

4775
03:01:19,545 --> 03:01:24,450
IN HUMANS, BUT ALLOW US TO TEST

4776
03:01:24,450 --> 03:01:25,884
HYPOTHESES THAT MAY BE VERY

4777
03:01:25,884 --> 03:01:27,853
USEFUL IN FUTURE STUDIES IN

4778
03:01:27,853 --> 03:01:29,388
HUMANS.

4779
03:01:29,388 --> 03:01:31,657
AND THAT INCLUDES THE USE OF NEW

4780
03:01:31,657 --> 03:01:36,795
LRAs, IT INCLUDES THE USE OF

4781
03:01:36,795 --> 03:01:38,430
CD8 DEPLETION, AS WELL AS

4782
03:01:38,430 --> 03:01:39,965
VACCINATION, AND WE ARE HOPEFUL

4783
03:01:39,965 --> 03:01:41,066
THAT IT WILL CONTRIBUTE TO THE

4784
03:01:41,066 --> 03:01:42,101
CURE EFFORT IN A SIGNIFICANT

4785
03:01:42,101 --> 03:01:44,036
WAY.

4786
03:01:44,036 --> 03:01:45,437
I WOULD LIKE TO JUST POINT OUT,

4787
03:01:45,437 --> 03:01:50,476
THIS TYPE OF WORK TAKES A

4788
03:01:50,476 --> 03:01:52,344
VILLAGE, AND WE'D LIKE TO THANK

4789
03:01:52,344 --> 03:01:54,446
ALL OF OUR COLLABORATORS.

4790
03:01:54,446 --> 03:01:54,980
THANK YOU.

4791
03:01:54,980 --> 03:02:00,786
[APPLAUSE]

4792
03:02:00,786 --> 03:02:02,988
AND I GUESS GUIDO IS GOING TO

4793
03:02:02,988 --> 03:02:10,396
FOLLOW ME.

4794
03:02:10,396 --> 03:02:12,564
>> THANK YOU, ERIC, AND
THANK

4795
03:02:12,564 --> 03:02:18,604
YOU FOR EXHIBIT DU FOR INTRODUCT

4796
03:02:18,604 --> 03:02:23,509
OF THE CIAVCR WHICH SEEMS LIKE A

4797
03:02:23,509 --> 03:02:25,678
GOOD SERIES FOR A TV SHOW,

4798
03:02:25,678 --> 03:02:26,445
COMBINING SCIENCE AND SPY

4799
03:02:26,445 --> 03:02:31,183
FICTION.

4800
03:02:31,183 --> 03:02:37,589
WE ARE -- I'M THE CO-PI WITH DRR

4801
03:02:37,589 --> 03:02:37,956
CONSORTIA.

4802
03:02:37,956 --> 03:02:44,430
AND WE ARE VERY FORTUNATE TO

4803
03:02:44,430 --> 03:02:46,398
HAVE SO MANY COLLABORATORS THAT

4804
03:02:46,398 --> 03:02:47,599
ARE WELL ESTABLISHED IN THE

4805
03:02:47,599 --> 03:02:50,002
FIELD, DESIGNING VACCINE,

4806
03:02:50,002 --> 03:02:51,437
IDENTIFYING MONOCLONAL

4807
03:02:51,437 --> 03:02:53,405
ANTIBODIES, IDENTIFYING LATENCY

4808
03:02:53,405 --> 03:02:54,907
REVERSING AGENTS, AND DEFINING

4809
03:02:54,907 --> 03:02:59,311
WHAT IS THE PROFILE OF THE

4810
03:02:59,311 --> 03:03:00,512
TRANSCRIPTOMIC OF THE CELLS THAT

4811
03:03:00,512 --> 03:03:02,581
ARE INFECTED AND RESPONSIBLE FOR

4812
03:03:02,581 --> 03:03:05,484
THE RESERVOIR, BUT I WANT TO

4813
03:03:05,484 --> 03:03:09,054
POINT OUT THAT WE'RE ALL HONORED

4814
03:03:09,054 --> 03:03:17,563
TO HAVE DREW WISEMAN AMONG OUR

4815
03:03:17,563 --> 03:03:18,330
COLLABORATORS AND WHAT THEY'VE

4816
03:03:18,330 --> 03:03:18,764
DONE FOR US.

4817
03:03:18,764 --> 03:03:20,999
SO I WANTED TO TAKE THIS

4818
03:03:20,999 --> 03:03:22,368
OPPORTUNITY.

4819
03:03:22,368 --> 03:03:23,569
AND ALONG WITH THE

4820
03:03:23,569 --> 03:03:31,210
COLLABORATORS, WE HAVE A VERY

4821
03:03:31,210 --> 03:03:33,011
INSPIRING AND DEVOTED MEMBER OF

4822
03:03:33,011 --> 03:03:34,713
THE SCIENTIFIC ADVISORY BOARD,

4823
03:03:34,713 --> 03:03:39,852
AS WELL AS OUR PROJECT OFFICERS.

4824
03:03:39,852 --> 03:03:46,792
AS ERIC MENTIONED, WE HAVE TO --

4825
03:03:46,792 --> 03:03:47,493
IN THE PROGRAM.

4826
03:03:47,493 --> 03:03:49,128
ONE IS MEANT TO BE PREVENTION,

4827
03:03:49,128 --> 03:03:50,996
ONE IS MEANT TO BE ERADICATION

4828
03:03:50,996 --> 03:03:52,364
OF INFECTION.

4829
03:03:52,364 --> 03:03:55,501
THE FIRST IS LED BY

4830
03:03:55,501 --> 03:04:00,305
DR. WILLIAMS, AND THE SECOND BY

4831
03:04:00,305 --> 03:04:00,973
DR. BETTS AND MYSELF.

4832
03:04:00,973 --> 03:04:02,341
WE ALSO HAVE A CENTRALIZED

4833
03:04:02,341 --> 03:04:11,350
RESOURCE DIRECTED BY.

4834
03:04:11,350 --> 03:04:13,585
TODAY I WILL REALLY FOCUS ON

4835
03:04:13,585 --> 03:04:17,356
THESE TWO PARTS OF OUR FOCI.

4836
03:04:17,356 --> 03:04:23,695
EVERYTHING IS BASED ON NHP.

4837
03:04:23,695 --> 03:04:30,669
SO ERADICATION STRATEGY IN

4838
03:04:30,669 --> 03:04:31,904
CD8 T-CELL RESPONSES WOULD BE

4839
03:04:31,904 --> 03:04:34,940
THE OPTIMAL REGIMEN TO ERADICATE

4840
03:04:34,940 --> 03:04:36,942
HIV INFECTION.

4841
03:04:36,942 --> 03:04:43,916
THE GOAL IS TO EXPLORE MRNA

4842
03:04:43,916 --> 03:04:45,918
CONSTRUCT THAT CAN DELIVER

4843
03:04:45,918 --> 03:04:47,019
THERAPEUTIC B AND T-CELL

4844
03:04:47,019 --> 03:04:48,220
RESPONSES.

4845
03:04:48,220 --> 03:04:52,791
OUR WORK REALLY STEMS FROM THE

4846
03:04:52,791 --> 03:04:54,860
VACCINE STRATEGY THAT WAS

4847
03:04:54,860 --> 03:05:00,833
REPORTED BY DR. SANDERS WHO

4848
03:05:00,833 --> 03:05:04,236
OBSERVED THE TRANSMITTED FOUNDER

4849
03:05:04,236 --> 03:05:06,939
SOSIP TRIMER ELICITED PROTECTIVE

4850
03:05:06,939 --> 03:05:08,607
AUTOLOGOUS TIER 2 NEUTRALIZING

4851
03:05:08,607 --> 03:05:10,542
ANTIBODIES IN RHESUS MACAQUES.

4852
03:05:10,542 --> 03:05:14,813
AS INDICATED IN THE CURVE BY THE

4853
03:05:14,813 --> 03:05:16,548
BLUE LINE REPRESENTING THE

4854
03:05:16,548 --> 03:05:18,750
ANIMALS WITH HIGHEST

4855
03:05:18,750 --> 03:05:20,819
NEUTRALIZING ANTIBODY TITERS.

4856
03:05:20,819 --> 03:05:22,921
THIS VACCINE STRATEGY WILL BE

4857
03:05:22,921 --> 03:05:27,192
TESTED ALSO IN THE ACT

4858
03:05:27,192 --> 03:05:31,096
ACTG5422 CLINICAL TRIALS, AND WE

4859
03:05:31,096 --> 03:05:33,398
THINK THAT OUR PROGRAM WILL HAVE

4860
03:05:33,398 --> 03:05:36,368
A RELEVANT IMPACT IN DEFINING

4861
03:05:36,368 --> 03:05:41,273
SOME OF THE MECHANISTIC ASPECT

4862
03:05:41,273 --> 03:05:42,808
OF THE IMPACT OF THIS VACCINE IN

4863
03:05:42,808 --> 03:05:44,243
THE CLINIC AND BE TRANSLATIONAL

4864
03:05:44,243 --> 03:05:44,977
TO THAT POINT.

4865
03:05:44,977 --> 03:05:48,480
JUST AS A REMINDER, THE FACT

4866
03:05:48,480 --> 03:05:51,550
THAT THE SOSIP, ESTABLISHED

4867
03:05:51,550 --> 03:05:54,219
SOSIP TRIMER IS BASED ON THE

4868
03:05:54,219 --> 03:05:56,488
CONCEPT THAT A BOND BETWEEN THE

4869
03:05:56,488 --> 03:06:01,059
GP130 AND GP41 WITH PROLINE

4870
03:06:01,059 --> 03:06:04,696
ADDITION IN 558 STABILIZED THE

4871
03:06:04,696 --> 03:06:08,367
TRIMER AND MAINTAIN THE

4872
03:06:08,367 --> 03:06:10,135
CONFORMATION OF THE ENVELOPE AS

4873
03:06:10,135 --> 03:06:12,104
INDICATED IN THE

4874
03:06:12,104 --> 03:06:13,438
ELECTROMICROSCOPY ON THE RIGHT

4875
03:06:13,438 --> 03:06:15,407
COMPARED TO THE NON-STABILIZED

4876
03:06:15,407 --> 03:06:20,879
ON THE LEFT.

4877
03:06:20,879 --> 03:06:23,815
THE NEW VACCINE IMMUNOGENS ARE

4878
03:06:23,815 --> 03:06:25,951
WHAT WE'RE AIMING AT IN FOCUS

4879
03:06:25,951 --> 03:06:27,419
ONE AND THEY WILL FEED FOCUS TWO

4880
03:06:27,419 --> 03:06:28,954
AS WE MOVE ALONG.

4881
03:06:28,954 --> 03:06:32,791
SO THIS IS A HIGHLY ITERATIVE

4882
03:06:32,791 --> 03:06:36,061
PROCESS BETWEEN PREVENTING AND

4883
03:06:36,061 --> 03:06:39,565
ERADICATING THE INFECTION.

4884
03:06:39,565 --> 03:06:42,301
THE PARADIGM THAT WE WILL TEST

4885
03:06:42,301 --> 03:06:44,169
IS BASED ESSENTIALLY ON THE

4886
03:06:44,169 --> 03:06:47,105
ABILITY OF REACTIVATING THE

4887
03:06:47,105 --> 03:06:49,308
LATENT RESERVOIR TO MAKE THE

4888
03:06:49,308 --> 03:06:53,579
CELLS RECOGNIZABLE BY THE

4889
03:06:53,579 --> 03:06:54,246
IMMUNOTHERAPY INTERVENTION THAT

4890
03:06:54,246 --> 03:06:58,183
ARE BASED ON VACCINE AND

4891
03:06:58,183 --> 03:06:59,585
MONOCLONAL ANTIBODY MOLECULES.

4892
03:06:59,585 --> 03:07:01,119
LET'S TALK FOR A SECOND ABOUT

4893
03:07:01,119 --> 03:07:03,522
THE MONOCLONAL ANTIBODY BASED

4894
03:07:03,522 --> 03:07:06,658
MOLECULES TO FOLLOW UP WITH SOME

4895
03:07:06,658 --> 03:07:08,093
OF THE DISCUSSION THAT I BROUGHT

4896
03:07:08,093 --> 03:07:12,931
IN TO THIS AUDIENCE THIS MORNING

4897
03:07:12,931 --> 03:07:15,867
ABOUT HLA-E RECOGNITION OF THE

4898
03:07:15,867 --> 03:07:16,368
INFECTED CELLS.

4899
03:07:16,368 --> 03:07:18,604
IN THIS PROGRAM WE WILL TEST

4900
03:07:18,604 --> 03:07:21,907
ANTIBODIES TO THE

4901
03:07:21,907 --> 03:07:22,774
MAMU-E/VL9 COMPLEXES THAT CAN

4902
03:07:22,774 --> 03:07:24,743
BLOCK THE INHIBITORY SIGNAL OF

4903
03:07:24,743 --> 03:07:27,679
THE LIVER TO THE NK CELLS AND

4904
03:07:27,679 --> 03:07:30,549
PREVENT THE NK CELLS FROM

4905
03:07:30,549 --> 03:07:32,417
RECOGNIZING THE INFECTED CELLS,

4906
03:07:32,417 --> 03:07:34,353
AS WELL AS FOR THE CD8.

4907
03:07:34,353 --> 03:07:36,989
BUT WE'RE ALSO TRYING TO DEVELOP

4908
03:07:36,989 --> 03:07:43,095
ANTIBODIES TO THE MAMU-E/GAG RLE

4909
03:07:43,095 --> 03:07:49,101
INFECTED CELLS.

4910
03:07:49,101 --> 03:07:51,536
SO WHERE DOES THE RESEARCH

4911
03:07:51,536 --> 03:07:54,773
RESOURCE COMING IN WITH THE BAR

4912
03:07:54,773 --> 03:07:55,607
IN THE CENTER?

4913
03:07:55,607 --> 03:07:56,875
THEY ARE COMING IN BECAUSE IT

4914
03:07:56,875 --> 03:07:58,777
WILL PROVIDE US WITH THE

4915
03:07:58,777 --> 03:08:00,479
BARCODED SHIV, WHICH ESSENTIALLY

4916
03:08:00,479 --> 03:08:02,981
MOST OF YOU KNOW BUT THANKS TO

4917
03:08:02,981 --> 03:08:08,286
THE INSERTION OF A 34 BASED

4918
03:08:08,286 --> 03:08:13,291
CASSETTE WITH A 10 RANDOM BASES

4919
03:08:13,291 --> 03:08:15,494
BETWEEN THE VPX AND VPR

4920
03:08:15,494 --> 03:08:18,130
CONSTRUCT, WE CAN HAVE MORE THAN

4921
03:08:18,130 --> 03:08:19,665
10,000 VARIANTS IN OUR STOCK,

4922
03:08:19,665 --> 03:08:24,236
AND UP WI 1,000 UNIQUE INFECTION

4923
03:08:24,236 --> 03:08:26,972
EVENTS FOR EACH IV CHALLENGE.

4924
03:08:26,972 --> 03:08:30,676
AND WE KNOW THAT THIS INSERTION

4925
03:08:30,676 --> 03:08:32,411
DOESN'T AFFECT THE INFECTIVITY

4926
03:08:32,411 --> 03:08:34,746
OF THE VIRUS.

4927
03:08:34,746 --> 03:08:36,381
WHAT THIS ALLOWS US TO DO IS

4928
03:08:36,381 --> 03:08:37,916
THAT WE CAN FOLLOW THE PROGENY

4929
03:08:37,916 --> 03:08:40,552
OF THESE VIRUSES DURING THE

4930
03:08:40,552 --> 03:08:43,055
ACUTE PHASE OF THE TIME THAT WE

4931
03:08:43,055 --> 03:08:45,023
START ART AND FOLLOW UP IN THE

4932
03:08:45,023 --> 03:08:53,098
LEVEL OF THE TISSUE WHERE THESE

4933
03:08:53,098 --> 03:08:54,199
CLONOESTABLISHED LATE CEASE AND

4934
03:08:54,199 --> 03:08:58,136
IDLATENCY ANDIDENTIFY WHAT IS T.

4935
03:08:58,136 --> 03:09:00,338
IN ORDER TO ACHIEVE THE

4936
03:09:00,338 --> 03:09:01,506
ERADICATION WE'VE BEEN THINKING

4937
03:09:01,506 --> 03:09:02,307
ABOUT TWO POSSIBLE STRATEGY.

4938
03:09:02,307 --> 03:09:06,144
ONE IS THE STRATEGY WHERE THE

4939
03:09:06,144 --> 03:09:08,080
IMMUNOTHERAPY WILL START AT TIME

4940
03:09:08,080 --> 03:09:09,981
OF UNDETECTABLE VIREMIA AFTER

4941
03:09:09,981 --> 03:09:11,817
ART INITIATION.

4942
03:09:11,817 --> 03:09:13,251
AND IN ORDER TO DO THIS, THE

4943
03:09:13,251 --> 03:09:16,421
GOAL IS TO DEFINE THE MECHANISM

4944
03:09:16,421 --> 03:09:21,560
EFFECTS OF VACCINE INDUCED

4945
03:09:21,560 --> 03:09:23,195
RESPONSES ON RESERVOIR AFTER

4946
03:09:23,195 --> 03:09:26,031
VIREMIA IS UNDETECTABLE.

4947
03:09:26,031 --> 03:09:28,867
HERE IS THE DESIGN OF OUR STUDY.

4948
03:09:28,867 --> 03:09:31,770
AS WE SAID, WE ARE THE YOUNG KID

4949
03:09:31,770 --> 03:09:33,672
ON THE BLOCK, WE JUST STARTED

4950
03:09:33,672 --> 03:09:35,674
LAST YEAR, THIS IS ALL IN THE

4951
03:09:35,674 --> 03:09:36,108
PROCESS.

4952
03:09:36,108 --> 03:09:40,378
WE WILL USE THE BARCODE SHIV TO

4953
03:09:40,378 --> 03:09:45,283
INFECT THE AN MALTS ANIMALS ANDL

4954
03:09:45,283 --> 03:09:46,985
START ANTIRETROVIRAL THERAPY.

4955
03:09:46,985 --> 03:09:48,787
AS SOON AS DETECTABLE, WE WILL

4956
03:09:48,787 --> 03:09:49,755
DETERMINE WHAT IS THE SIZE OF

4957
03:09:49,755 --> 03:09:51,089
THE RESERVOIR AND WE WILL

4958
03:09:51,089 --> 03:09:53,492
IMMUNIZE THE ANIMALS WITH THE

4959
03:09:53,492 --> 03:09:57,629
MRNA EXPRESSING THE ASSOCIATE

4960
03:09:57,629 --> 03:09:58,096
TRIMER.

4961
03:09:58,096 --> 03:09:59,498
DURING THE ROUNDS OF

4962
03:09:59,498 --> 03:10:00,599
IMMUNIZATION, WE WILL ALSO

4963
03:10:00,599 --> 03:10:02,334
ADMINISTER A COCKTAIL OF LATENCY

4964
03:10:02,334 --> 03:10:03,201
REVERSING AGENT SO THAT WE'RE

4965
03:10:03,201 --> 03:10:06,304
TRYING TO DEFINE AT THE MOMENT,

4966
03:10:06,304 --> 03:10:08,774
AND IN ORDER TO MAKE SURE THAT

4967
03:10:08,774 --> 03:10:10,842
WE CAN REACTIVATE THE RESERVOIR

4968
03:10:10,842 --> 03:10:13,211
AT THE TIME THAT WE'RE INDUCING

4969
03:10:13,211 --> 03:10:14,079
THE IMMUNE RESPONSES.

4970
03:10:14,079 --> 03:10:18,884
AT THIS POINT, WE WILL EVALUATE

4971
03:10:18,884 --> 03:10:20,218
THE IMMUNE RESPONSES AND THE

4972
03:10:20,218 --> 03:10:22,988
SIZE OF THE RESERVOIR AT THE END

4973
03:10:22,988 --> 03:10:24,456
OF THE IMMUNIZATION AND COMPARE

4974
03:10:24,456 --> 03:10:26,124
THAT TO THE TWO CONTROL GROUPS,

4975
03:10:26,124 --> 03:10:28,727
ONE OF WHICH WILL RECEIVE

4976
03:10:28,727 --> 03:10:31,129
POLYCLONAL AGG AND MONOCLONAL

4977
03:10:31,129 --> 03:10:32,364
ANTIBODIES THAT WERE DERIVED

4978
03:10:32,364 --> 03:10:35,734
FROM THE PROTECTED ANIMALS.

4979
03:10:35,734 --> 03:10:37,702
WHAT IS THE SIZE OF THE

4980
03:10:37,702 --> 03:10:39,204
RESERVOIR ACROSS THESE THREE

4981
03:10:39,204 --> 03:10:40,972
GROUPS WILL TELL US HOW

4982
03:10:40,972 --> 03:10:43,074
SUCCESSFUL THIS STRATEGY WAS, AS

4983
03:10:43,074 --> 03:10:45,210
WELL AS WHAT IS THE TIME OF

4984
03:10:45,210 --> 03:10:46,578
REBOUND AND THE COMPOSITION OF

4985
03:10:46,578 --> 03:10:48,947
THE RESERVOIR IN THESE ANIMALS.

4986
03:10:48,947 --> 03:10:52,684
THERE IS ALSO ANOTHER STRATEGY,

4987
03:10:52,684 --> 03:10:55,854
ANOTHER GOAL THAT WE WANT TO

4988
03:10:55,854 --> 03:10:57,155
ACHIEVE, AND THIS IS TO TEST THE

4989
03:10:57,155 --> 03:10:58,490
POSSIBILITY THAT AFTER

4990
03:10:58,490 --> 03:11:01,526
DELIVERING THE VACCINE, CAN WE

4991
03:11:01,526 --> 03:11:03,295
ALSO DELIVER A COCKTAIL OF

4992
03:11:03,295 --> 03:11:05,363
MONOCLONAL ANTIBODIES AND

4993
03:11:05,363 --> 03:11:08,567
IDENTIFY WHAT CAN BE THE --

4994
03:11:08,567 --> 03:11:10,202
EFFECT OF MONOCLONAL ANTIBODY

4995
03:11:10,202 --> 03:11:11,837
AND VACCINE IN SEQUENCE.

4996
03:11:11,837 --> 03:11:13,371
AND I'M NOT GOING TO SHOW THE

4997
03:11:13,371 --> 03:11:18,076
DESIGN OF THIS AT THIS POINT,

4998
03:11:18,076 --> 03:11:20,579
BUT IN TERMS OF

4999
03:11:20,579 --> 03:11:24,749
IMMUNOMONITORRING, WE WILL

5000
03:11:24,749 --> 03:11:26,117
CHECK -- RESPONSES, THESE ARE

5001
03:11:26,117 --> 03:11:27,919
ALL INVOLVED IN THE SIZE OF THE

5002
03:11:27,919 --> 03:11:28,787
RESERVOIR AS WELL AS WHERE THE

5003
03:11:28,787 --> 03:11:31,723
VIRUS IS INSERTED IN

5004
03:11:31,723 --> 03:11:32,824
TRANSCRIPTOMIC PROFILE.

5005
03:11:32,824 --> 03:11:35,994
THE EXPECTED OUTCOME IS THAT

5006
03:11:35,994 --> 03:11:37,863
THIS STRATEGY WILL ALLOW US TO

5007
03:11:37,863 --> 03:11:38,730
DETERMINE THE INDIVIDUAL AND

5008
03:11:38,730 --> 03:11:40,932
SEQUENTIAL IMPACT OF A

5009
03:11:40,932 --> 03:11:46,504
THERAPEUTIC VACCINE, INFUSION,

5010
03:11:46,504 --> 03:11:48,006
IN TIME TO REBOUND.

5011
03:11:48,006 --> 03:11:53,211
BUT WE KNOW WE CAN HEARD A LOT

5012
03:11:53,211 --> 03:11:55,146
TODAY ABOUT WHAT CAN WE DO AT

5013
03:11:55,146 --> 03:12:01,052
TIME OF ART INITIATION.

5014
03:12:01,052 --> 03:12:02,787
THIS THE STRATEGY WE WANT TO

5015
03:12:02,787 --> 03:12:05,423
PURSUE IN THIS PROGRAM, TO START

5016
03:12:05,423 --> 03:12:06,291
OUR IMMUNOTHERAPY AT THE TIME WE

5017
03:12:06,291 --> 03:12:06,725
START ART.

5018
03:12:06,725 --> 03:12:09,527
SO THIS IS OUR SECOND STRATEGY.

5019
03:12:09,527 --> 03:12:11,363
AND TO FIND WHAT THE MECHANISM

5020
03:12:11,363 --> 03:12:16,334
THAT CAN BE ABLE TO ERADICATE

5021
03:12:16,334 --> 03:12:17,435
THE RESERVOIR.

5022
03:12:17,435 --> 03:12:21,606
AND HERE IS ESSENTIALLY ALL THE

5023
03:12:21,606 --> 03:12:24,242
ARROWS, THE ART STARTS BUT THE

5024
03:12:24,242 --> 03:12:26,111
VACCINE IS DELIVERED AT THE SAME

5025
03:12:26,111 --> 03:12:27,279
TIME, WE WILL CHECK THE

5026
03:12:27,279 --> 03:12:28,613
RESERVOIR AND THEN WE WILL GO IN

5027
03:12:28,613 --> 03:12:30,916
WITH THE SECOND ROUND OF THE

5028
03:12:30,916 --> 03:12:33,952
VACCINE BOOST, AND MONOCLONAL

5029
03:12:33,952 --> 03:12:35,387
ANTIBODY INFUSION.

5030
03:12:35,387 --> 03:12:41,293
THIS IS THE DESIGN, IS AFTER

5031
03:12:41,293 --> 03:12:44,062
INFECTION WITH THE VIRUS, WE

5032
03:12:44,062 --> 03:12:46,531
WILL DELIVER ART AND VACCINE

5033
03:12:46,531 --> 03:12:47,632
WITH ONE CAVEAT.

5034
03:12:47,632 --> 03:12:49,167
THE VACCINE WILL NOT JUST BE

5035
03:12:49,167 --> 03:12:50,702
DESIGNED ON ONE SEQUENCE.

5036
03:12:50,702 --> 03:12:52,437
THE VACCINE WILL BE DESIGNED

5037
03:12:52,437 --> 03:12:56,808
BASED ON WHAT WE LEARN ABOUT THE

5038
03:12:56,808 --> 03:13:00,545
BREAKTHROUGH INFECTION IN FOCUS

5039
03:13:00,545 --> 03:13:03,281
ONE FOR -- RESERVOIR IN FOCUS

5040
03:13:03,281 --> 03:13:05,283
TWO, WHAT ARE THE VARIANCE OF

5041
03:13:05,283 --> 03:13:06,985
THE ENVELOPE, CAN WE USE THEM.

5042
03:13:06,985 --> 03:13:09,487
MOREOVER, WE WILL ALSO INCLUDE

5043
03:13:09,487 --> 03:13:12,657
MRNA THAT CAN DELIVER TARGET FOR

5044
03:13:12,657 --> 03:13:14,292
CD8 RESPONSES.

5045
03:13:14,292 --> 03:13:17,462
AT THIS POINT, WE WILL LET THE

5046
03:13:17,462 --> 03:13:19,564
SYSTEM REST, AND WE WILL GO IN

5047
03:13:19,564 --> 03:13:21,299
WITH AN ADDITIONAL BOOST THAT

5048
03:13:21,299 --> 03:13:25,236
WILL BE FOLLOWED WITH THE

5049
03:13:25,236 --> 03:13:29,074
INFUSION OF LRAs, AND

5050
03:13:29,074 --> 03:13:30,375
SUBSEQUENTLY, MONOCLONAL

5051
03:13:30,375 --> 03:13:33,778
ANTIBODIES.

5052
03:13:33,778 --> 03:13:35,747
WE HAVE -- THE SIZE OF THE

5053
03:13:35,747 --> 03:13:36,848
RESERVOIR WILL BE EVALUATED AT

5054
03:13:36,848 --> 03:13:38,717
THE END AND COMPARED TO OUR

5055
03:13:38,717 --> 03:13:38,950
CONTROL.

5056
03:13:38,950 --> 03:13:42,320
AT THE END, WE WILL STILL GO

5057
03:13:42,320 --> 03:13:44,889
INTO OUR INTERRUPTION, TIME TO

5058
03:13:44,889 --> 03:13:50,161
REA BOUND,REBOUND, AND COMPOSITE

5059
03:13:50,161 --> 03:13:51,396
RESERVOIR.

5060
03:13:51,396 --> 03:13:53,465
SO THE EXPECTED OUTCOMES ARE TO

5061
03:13:53,465 --> 03:13:55,100
EXPAND THE BREADTH OF THE

5062
03:13:55,100 --> 03:13:56,901
RESPONSES AND PUT THE IMMUNE

5063
03:13:56,901 --> 03:14:08,046
SYSTEM AHEAD OF THE INSUR JENS H

5064
03:14:10,482 --> 03:14:14,152
THE ADDITION OF NEUTRALIZING

5065
03:14:14,152 --> 03:14:18,289
ANTIBODY IN HLA-E ANTIBODY

5066
03:14:18,289 --> 03:14:20,258
COMPLEXES COMBINATION.

5067
03:14:20,258 --> 03:14:21,359
WHAT ARE THE KEY QUESTIONS THAT

5068
03:14:21,359 --> 03:14:23,762
WE'RE GOING TO TRY TO ADDRESS IN

5069
03:14:23,762 --> 03:14:25,296
THE UPCOMING YEARS.

5070
03:14:25,296 --> 03:14:28,366
CAN WE USE MRNA BASED VACCINE TO

5071
03:14:28,366 --> 03:14:30,435
INDUCE HIGHLY EFFECTIVE

5072
03:14:30,435 --> 03:14:31,836
ANTIBODIES CAPABLE OF PREVENTING

5073
03:14:31,836 --> 03:14:33,938
THE INFECTION OF OUR CELLS ALONG

5074
03:14:33,938 --> 03:14:35,774
WITH CELLULAR RESPONSES TO

5075
03:14:35,774 --> 03:14:37,208
ELIMINATE THE CELLS WHERE THE

5076
03:14:37,208 --> 03:14:39,511
VIRUS IS HIDING?

5077
03:14:39,511 --> 03:14:42,147
AND CAN WE COMBINE THE

5078
03:14:42,147 --> 03:14:44,015
VACCINATION WITH THE INFUSION OF

5079
03:14:44,015 --> 03:14:45,116
ANTIBODY BASED MOLECULES SUCH

5080
03:14:45,116 --> 03:14:46,851
THAT THE KILLER CELLS OF OUR

5081
03:14:46,851 --> 03:14:48,820
IMMUNE SYSTEM CAN RECOGNIZE THE

5082
03:14:48,820 --> 03:14:51,322
INFECTED CELLS IN A WAY THAT IS

5083
03:14:51,322 --> 03:14:53,291
UNIVERSAL AND NOT RESTRICTED BY

5084
03:14:53,291 --> 03:14:55,460
THE GENETIC-BASED DIFFERENCES IN

5085
03:14:55,460 --> 03:14:58,763
EACH INDIVIDUAL'S IMMUNE CELLS?

5086
03:14:58,763 --> 03:15:00,732
THE OUTCOME IS THAT WE WANT THE

5087
03:15:00,732 --> 03:15:01,933
STUDIES CONDUCTED IN ANIMAL

5088
03:15:01,933 --> 03:15:04,235
MODELS TO BE HIGHLY APPLICABLE

5089
03:15:04,235 --> 03:15:07,305
TO THE CLINICAL SETTINGS.

5090
03:15:07,305 --> 03:15:08,840
AND WHAT ARE THE NEXT STEPS?

5091
03:15:08,840 --> 03:15:14,646
WELL, WE JUST STARTED.

5092
03:15:14,646 --> 03:15:16,514
AND AGAIN, THANKS TO ALL THE

5093
03:15:16,514 --> 03:15:17,182
COLLABORATORS, AND HAPPY TO

5094
03:15:17,182 --> 03:15:17,749
ANSWER QUESTIONS.

5095
03:15:17,749 --> 03:15:28,093
[APPLAUSE]

5096
03:15:28,093 --> 03:15:29,294
>> SO WE HAVE TIME FOR

5097
03:15:29,294 --> 03:15:39,471
QUESTIONS.

5098
03:15:43,575 --> 03:15:53,685
GO AHEAD.

5099
03:16:09,834 --> 03:16:11,069
 -- ARE YOU THINKING ABOUT DOING

5100
03:16:11,069 --> 03:16:12,837
IM OR IV INJECTION, WHAT'S THE

5101
03:16:12,837 --> 03:16:13,037
PLAN?

5102
03:16:13,037 --> 03:16:14,906
>> RIGHT NOW THE MRNA WILL
BE

5103
03:16:14,906 --> 03:16:16,341
DELIVERED IN THE SAME WAY THAT

5104
03:16:16,341 --> 03:16:18,209
WE ARE DELIVERING THE COVID

5105
03:16:18,209 --> 03:16:19,310
VACCINE MRNA.

5106
03:16:19,310 --> 03:16:22,013
THIS IS OUR FORMULATION.

5107
03:16:22,013 --> 03:16:25,216
THE LATEST ONE HAS A NUMBER 315,

5108
03:16:25,216 --> 03:16:28,953
AND THIS IS WHAT IS GOING TO BE

5109
03:16:28,953 --> 03:16:30,855
IN THE CLINIC, AND THIS IS WHAT

5110
03:16:30,855 --> 03:16:34,826
WE'RE WORKING ON WITH THE TEST

5111
03:16:34,826 --> 03:16:38,863
TO ENCAPSULATE THE MRNA.

5112
03:16:38,863 --> 03:16:41,332
>> AND IM, I'M ASSUMING?

5113
03:16:41,332 --> 03:16:46,838
>> YES.

5114
03:16:46,838 --> 03:16:49,674
>> SO SINCE NO ONE ELSE
WILL ASK

5115
03:16:49,674 --> 03:16:53,945
THIS, I WILL ASK THOSE WERE

5116
03:16:53,945 --> 03:16:54,646
CADI-CODED VIRUSES?

5117
03:16:54,646 --> 03:16:56,114
>> YES.

5118
03:16:56,114 --> 03:16:57,815
>> KT BARCODED.

5119
03:16:57,815 --> 03:16:59,617
>> I KNOW, I KNOW.

5120
03:16:59,617 --> 03:17:00,952
>> BUT YOU DON'T WANT TO
POINT

5121
03:17:00,952 --> 03:17:03,054
IT OUT BECAUSE YOU'RE ONLY GOING

5122
03:17:03,054 --> 03:17:04,455
TO FEED HIM AND HE'S GOING TO

5123
03:17:04,455 --> 03:17:05,456
GET WORSE.

5124
03:17:05,456 --> 03:17:06,891
>> THAT'S A HARD QUESTION
TO

5125
03:17:06,891 --> 03:17:10,995
FOLLOW, BUT I'LL TRY.

5126
03:17:10,995 --> 03:17:14,399
QEE DOUGUIDO, CAN YOU TALK ABOUE

5127
03:17:14,399 --> 03:17:16,267
RATIONALE FOR HOW YOU CHOSE THE

5128
03:17:16,267 --> 03:17:17,702
TIMING OF VACCINATION, WE'RE

5129
03:17:17,702 --> 03:17:20,538
WAITING FOR ART SUPPRESSION,

5130
03:17:20,538 --> 03:17:22,173
PRESUMABLY BECAUSE OF IMMUNE

5131
03:17:22,173 --> 03:17:23,808
ACTIVATION BUT WERE THERE OTHER

5132
03:17:23,808 --> 03:17:24,809
FACTORS IN THINKING ABOUT THE

5133
03:17:24,809 --> 03:17:25,043
TIMING?

5134
03:17:25,043 --> 03:17:31,416
>> SO THE FACT IS THAT I
CAN

5135
03:17:31,416 --> 03:17:33,651
MAKE A CLINICAL REMARK THAT WE

5136
03:17:33,651 --> 03:17:34,719
HAVE 39 MILLION PEOPLE LIVING

5137
03:17:34,719 --> 03:17:36,187
WITH HIV WHO HAVE BEEN ON ART

5138
03:17:36,187 --> 03:17:37,255
FOREVER AND THEY'RE WAITING FOR

5139
03:17:37,255 --> 03:17:42,093
A STRATEGY THAT CAN REALLY BE

5140
03:17:42,093 --> 03:17:42,493
IMPLEMENTED.

5141
03:17:42,493 --> 03:17:47,232
SO YES, WE CAN DO FOR EARLIER

5142
03:17:47,232 --> 03:17:48,199
IMMUNIZATION, AND THIS IS WHAT

5143
03:17:48,199 --> 03:17:50,501
WE'RE TRYING DO IN STRATEGY TWO.

5144
03:17:50,501 --> 03:17:56,641
WE'RE LOOKING FORWARD FOR

5145
03:17:56,641 --> 03:17:58,176
UNFORTUNATELY THE NEXT ROUND OF

5146
03:17:58,176 --> 03:17:59,677
INFECTIONS WE HAVE TO DEAL WITH,

5147
03:17:59,677 --> 03:18:02,313
BUT WE STILL HAVE TO THINK ABOUT

5148
03:18:02,313 --> 03:18:06,251
HOW WE IMPACTED THE RESERVOIR IN

5149
03:18:06,251 --> 03:18:07,919
THOSE PEOPLE LIVING WITH HIV.

5150
03:18:07,919 --> 03:18:12,056
AND THAT'S WHY WE TRIED TO LET

5151
03:18:12,056 --> 03:18:13,691
THE IMMUNE SYSTEM REST AS MUCH

5152
03:18:13,691 --> 03:18:16,094
AS POSSIBLE, AND THIS, WE THINK,

5153
03:18:16,094 --> 03:18:18,062
IS ALSO GOING TO BE A

5154
03:18:18,062 --> 03:18:20,164
TRANSLATIONAL ASPECT AS I SAID

5155
03:18:20,164 --> 03:18:22,233
WITH THE ACTG TRIAL THAT IS

5156
03:18:22,233 --> 03:18:22,767
COMING UP.

5157
03:18:22,767 --> 03:18:23,868
DOES THAT MAKE SENSE?

5158
03:18:23,868 --> 03:18:25,103
>> IT DOES, THANKS.

5159
03:18:25,103 --> 03:18:31,209
[APPLAUSE]

5160
03:18:31,209 --> 03:18:32,510
>> WE HAVE ONE MORE
QUESTION.

5161
03:18:32,510 --> 03:18:33,811
>> I JUST WANTED TO ASK,
WHAT'S

5162
03:18:33,811 --> 03:18:35,580
THE RATIONALE FOR USING THE

5163
03:18:35,580 --> 03:18:38,316
MONOCLONAL ANTIBODIES DURING

5164
03:18:38,316 --> 03:18:39,417
ART, TREATMENT WITH --

5165
03:18:39,417 --> 03:18:41,819
>> SO THE MONOCLONAL
ANTIBODY,

5166
03:18:41,819 --> 03:18:45,290
MAYBE I WASN'T CLEAR, I'M SORRY,

5167
03:18:45,290 --> 03:18:48,493
BUT WE WILL ADMINISTER THEM

5168
03:18:48,493 --> 03:18:51,429
WHILE WE ARE ALSO ADMINISTERING

5169
03:18:51,429 --> 03:18:53,931
LATENCY REVERSING AGENTS.

5170
03:18:53,931 --> 03:18:58,536
IF YOU -- SORRY, DIDN'T POINT

5171
03:18:58,536 --> 03:19:00,171
OUT SPECIFIC DETAILS BUT IF YOU

5172
03:19:00,171 --> 03:19:03,441
LOOK THE MONOCLONAL ANTIBODIES

5173
03:19:03,441 --> 03:19:04,676
ARE ALWAYS DELIVERED IN

5174
03:19:04,676 --> 03:19:05,410
COMBINATION BECAUSE WE THINK

5175
03:19:05,410 --> 03:19:07,712
THAT THERE IS A BETTER WAY TO --

5176
03:19:07,712 --> 03:19:10,748
FOR THEM TO WORK IF THE ANTIGENS

5177
03:19:10,748 --> 03:19:13,618
ARE EXPRESSED RATHER THAN TO

5178
03:19:13,618 --> 03:19:15,586
WAIT FOR NATURAL REACTIVATION

5179
03:19:15,586 --> 03:19:17,689
THAT COULD OCCUR DURING THE

5180
03:19:17,689 --> 03:19:21,693
PLIPS THABLIPS THAT WE KNOW.

5181
03:19:21,693 --> 03:19:23,261
>> I ACTUALLY ALSO HAVE A

5182
03:19:23,261 --> 03:19:24,996
QUESTION BOTH FOR ERIC AND

5183
03:19:24,996 --> 03:19:25,229
GUIDO.

5184
03:19:25,229 --> 03:19:28,399
YOU KNOW WHEN YOU LOOK AT YOUR

5185
03:19:28,399 --> 03:19:33,204
PROPHYLACTIC VACCI VACCINE PARTD

5186
03:19:33,204 --> 03:19:35,073
THERAPEUTIC PART, DO YOU USE THE

5187
03:19:35,073 --> 03:19:37,141
SAME VACCINE OR DO YOU

5188
03:19:37,141 --> 03:19:38,776
REFORMULATE OR CHANGE THE DOSING

5189
03:19:38,776 --> 03:19:41,179
SCHEDULE OR HOW DO YOU APPROACH

5190
03:19:41,179 --> 03:19:43,481
THESE TWO PARTS OF THE

5191
03:19:43,481 --> 03:19:47,652
CONSORTIUM?

5192
03:19:47,652 --> 03:19:50,722
>> SO FOR THE EMORY
CONSULTING,

5193
03:19:50,722 --> 03:19:53,658
WE ARE USING THE SAME VACCINE

5194
03:19:53,658 --> 03:19:55,293
APPROACH BECAUSE IT'S A

5195
03:19:55,293 --> 03:19:57,261
HETEROLOGOUS VIRAL VECTOR

5196
03:19:57,261 --> 03:19:57,929
APPROACH.

5197
03:19:57,929 --> 03:20:02,300
SO THE VECTORS ARE NOT

5198
03:20:02,300 --> 03:20:04,602
INTERFERING WITH ONE ANOTHER.

5199
03:20:04,602 --> 03:20:06,871
BY ANTIVECTOR RESPONSES.

5200
03:20:06,871 --> 03:20:08,639
AND WE'RE PLANNING TO USE

5201
03:20:08,639 --> 03:20:12,577
EXACTLY THE SAME SCHEDULE OF

5202
03:20:12,577 --> 03:20:15,113
VACCINATION AS WE DID IN OUR

5203
03:20:15,113 --> 03:20:16,147
PROPHYLACTIC VACCINE APPROACH

5204
03:20:16,147 --> 03:20:20,051
THAT WAS PROTECTIVE.

5205
03:20:20,051 --> 03:20:22,887
WHERE WE ARE GOING TO BE

5206
03:20:22,887 --> 03:20:26,391
VACCINATING BEFORE ART AND THEN

5207
03:20:26,391 --> 03:20:28,126
BOOSTING DURING ART, WE WILL USE

5208
03:20:28,126 --> 03:20:31,295
A DIFFERENT VECTOR SET, AND

5209
03:20:31,295 --> 03:20:32,730
WE'RE STILL DETERMINING WHAT THE

5210
03:20:32,730 --> 03:20:33,831
OPTIMAL VECTORS WILL BE FOR

5211
03:20:33,831 --> 03:20:35,900
THAT, BUT THEN TO AVOID

5212
03:20:35,900 --> 03:20:39,303
ANTIVECTOR RESPONSES BEING --

5213
03:20:39,303 --> 03:20:44,876
INTERFERING WITH THE BOOST.

5214
03:20:44,876 --> 03:20:46,844
>> GUIDO?

5215
03:20:46,844 --> 03:20:48,579
>> DID YOU WANT TO SAY
SOMETHING

5216
03:20:48,579 --> 03:20:49,247
AS WELL?

5217
03:20:49,247 --> 03:20:51,549
>> GUIDO, IF YOU'RE
WATCHING, WE

5218
03:20:51,549 --> 03:20:52,550
HAVEN'T TALKED TO YOU ABOUT THIS

5219
03:20:52,550 --> 03:20:56,254
YET.

5220
03:20:56,254 --> 03:20:57,955
GUIDO SYLVESTRI.

5221
03:20:57,955 --> 03:20:59,757
>> WE WILL DO IT THE SAME
WAY,

5222
03:20:59,757 --> 03:21:00,958
THE SAME VACCINE, THERE WILL BE

5223
03:21:00,958 --> 03:21:02,593
A LITTLE DISCONNECT, WE'RE GOING

5224
03:21:02,593 --> 03:21:05,296
TO USE THE SAME VACCINE IN FOCUS

5225
03:21:05,296 --> 03:21:07,064
TWO AS IN FOCUS ONE.

5226
03:21:07,064 --> 03:21:10,668
AND WE WILL DEVELOP A FOCUS TWO

5227
03:21:10,668 --> 03:21:12,003
BASED ON THE RESULTS.

5228
03:21:12,003 --> 03:21:14,839
ANY INDUCTION OF ANTIBODY

5229
03:21:14,839 --> 03:21:18,776
RESPONSES IN FOCUS ONE, SO FOCUS

5230
03:21:18,776 --> 03:21:22,280
TWO FOLLOWS IN THEIR -- WILL

5231
03:21:22,280 --> 03:21:25,249
FEED FROM FOCUS ONE.

5232
03:21:25,249 --> 03:21:26,584
>> WILTON, DO YOU HAVE
ANYTHING

5233
03:21:26,584 --> 03:21:28,653
TO ADD?

5234
03:21:28,653 --> 03:21:30,254
>> VERY EXCITED TO BE PART
OF

5235
03:21:30,254 --> 03:21:31,789
THE CONSORTIUM AND JOIN THE CURE

5236
03:21:31,789 --> 03:21:33,324
BECAUSE I'VE ALWAYS BEEN ON THE

5237
03:21:33,324 --> 03:21:34,525
VACCINE SIDE OF THINGS.

5238
03:21:34,525 --> 03:21:36,894
>> THANK YOU VERY MUCH FOR
TWO

5239
03:21:36,894 --> 03:21:38,996
EXCELLENT PRESENTATIONS.

5240
03:21:38,996 --> 03:21:40,531
AND WE MOVE ON TO THE NEXT

5241
03:21:40,531 --> 03:21:40,865
COLLABORATORY.

5242
03:21:40,865 --> 03:21:51,042
[APPLAUSE]

5243
03:22:08,960 --> 03:22:10,161
>> HELLO AGAIN.

5244
03:22:10,161 --> 03:22:15,433
I AMELIEI AM LEIA NOVACK.

5245
03:22:15,433 --> 03:22:17,401
IT IS MY PLEASURE TO INTRODUCE

5246
03:22:17,401 --> 03:22:23,074
THE BEAT-HIV COLLABORATORY.

5247
03:22:23,074 --> 03:22:27,111
BASED AT THE WISTART INSTITUTE,

5248
03:22:27,111 --> 03:22:31,282
LED BY THREE PRINCIPAL

5249
03:22:31,282 --> 03:22:32,483
INVESTIGATORS, LUIS MONTANER,

5250
03:22:32,483 --> 03:22:35,019
JIM RILEY FROM THE UNIVERSITY OF

5251
03:22:35,019 --> 03:22:37,522
PENNSYLVANIA AND ALSO BOB

5252
03:22:37,522 --> 03:22:37,788
SILICANO.

5253
03:22:37,788 --> 03:22:39,590
WITH THAT, I WILL HAND IT OVER

5254
03:22:39,590 --> 03:22:42,260
TO LUIS TO GET STARTED.

5255
03:22:42,260 --> 03:22:45,296
>> THANK YOU FOR THE
OPPORTUNITY

5256
03:22:45,296 --> 03:22:46,697
TO REPRESENT THE TEAM.

5257
03:22:46,697 --> 03:22:50,868
I'M BASICALLY THE WARMUP TO FOUR

5258
03:22:50,868 --> 03:22:52,837
STORIES THAT YOU'RE GOING TO

5259
03:22:52,837 --> 03:22:55,373
HEAR ABOUT, MOSTLY UNPUBLISHED.

5260
03:22:55,373 --> 03:22:58,776
LASTLY FEATURING A COMMUNITY

5261
03:22:58,776 --> 03:22:59,877
FOCUSED SOCIAL SCIENCE AGENDA

5262
03:22:59,877 --> 03:23:01,812
WHICH HAS BEEN REALLY PRODUCTIVE

5263
03:23:01,812 --> 03:23:02,146
AS WELL.

5264
03:23:02,146 --> 03:23:03,347
I WOULD LIKE TO GIVE YOU AN

5265
03:23:03,347 --> 03:23:06,083
OVERVIEW OF OUR TEAM AND SOME

5266
03:23:06,083 --> 03:23:07,752
HIGHLIGHTS OF WHERE WE'RE HEADED

5267
03:23:07,752 --> 03:23:10,788
REGARDING STRATEGIES AND ONGOING

5268
03:23:10,788 --> 03:23:11,889
WORK THAT'S DEFINING THIS YEAR

5269
03:23:11,889 --> 03:23:16,160
AND THE NEXT COMPLETION OF THE

5270
03:23:16,160 --> 03:23:16,494
AWARD.

5271
03:23:16,494 --> 03:23:17,695
I THINK WE'VE BEEN REALLY

5272
03:23:17,695 --> 03:23:19,230
FORTUNATE TO RECRUIT AND RETAIN

5273
03:23:19,230 --> 03:23:21,299
A LARGE NUMBER OF INVESTIGATORS

5274
03:23:21,299 --> 03:23:23,367
THROUGHOUT OUR TENURE AND THIS

5275
03:23:23,367 --> 03:23:24,569
CONTINUES.

5276
03:23:24,569 --> 03:23:28,205
AND OUR WEBINAR SERIES ARE OPEN

5277
03:23:28,205 --> 03:23:29,440
TO ANYONE, SO IF YOU WANT TO BE

5278
03:23:29,440 --> 03:23:30,708
PART OF IT, PLEASE REACH OUT.

5279
03:23:30,708 --> 03:23:33,444
MANY OF THE COLLABORATORIES

5280
03:23:33,444 --> 03:23:35,947
PARTICIPATE ON THE -- THAT WE

5281
03:23:35,947 --> 03:23:36,180
SPONSOR.

5282
03:23:36,180 --> 03:23:37,281
PART OF THE OBJECTIVE IS TO

5283
03:23:37,281 --> 03:23:38,249
HIGHLIGHT THE INITIATIVES THAT

5284
03:23:38,249 --> 03:23:39,917
WE CAN COLLABORATE WITH, AND WE

5285
03:23:39,917 --> 03:23:41,085
HAVE BEEN VERY ACTIVE IN THAT

5286
03:23:41,085 --> 03:23:42,420
REGARD IN CONNECTING PEOPLE AND

5287
03:23:42,420 --> 03:23:45,022
WE CAN REFLECT THAT IN THE

5288
03:23:45,022 --> 03:23:46,591
RECORDS OR PUBLICATIONS THAT

5289
03:23:46,591 --> 03:23:47,792
INCLUDE TWO, THREE OR MORE OF

5290
03:23:47,792 --> 03:23:49,527
OUR INVESTIGATORS IN THE SAME

5291
03:23:49,527 --> 03:23:49,860
PUBLICATION.

5292
03:23:49,860 --> 03:23:51,262
I JUST HIGHLIGHTED FOUR EXAMPLES

5293
03:23:51,262 --> 03:23:53,464
IN RED ARE THE COLLABORATORY

5294
03:23:53,464 --> 03:23:55,967
MEMBERS, JUST TO HIGHLIGHT THAT

5295
03:23:55,967 --> 03:23:57,301
ONE OF THE MISSIONS THAT WE WANT

5296
03:23:57,301 --> 03:23:58,603
TO PROMOTE IS COLLABORATION AND

5297
03:23:58,603 --> 03:24:02,106
THAT RELATES TO PUBLICATIONS.

5298
03:24:02,106 --> 03:24:03,741
ONE OF THE SUCCESSES THIS YEAR

5299
03:24:03,741 --> 03:24:05,276
IS REALLY THE MOVEMENT OF SOME

5300
03:24:05,276 --> 03:24:07,478
OF OUR INITIATIVES, PARTICULARLY

5301
03:24:07,478 --> 03:24:11,182
BEING LED BY JEANNE RILEY AND

5302
03:24:11,182 --> 03:24:14,352
UPON BLOW TAVAS ON THE GENE

5303
03:24:14,352 --> 03:24:15,553
THERAPY APPROACHES THAT COULD

5304
03:24:15,553 --> 03:24:16,654
ACTUALLY BE IMPLEMENTED IN THE

5305
03:24:16,654 --> 03:24:17,021
CLINIC.

5306
03:24:17,021 --> 03:24:17,989
WE WERE VERY FORTUNATE TO HAVE

5307
03:24:17,989 --> 03:24:19,423
THE OPPORTUNITY TO TAKE

5308
03:24:19,423 --> 03:24:21,592
ADVANTAGE OF THE NEW ACTG SMALL

5309
03:24:21,592 --> 03:24:22,393
CLINICAL TRIALS INITIATIVE TO

5310
03:24:22,393 --> 03:24:25,329
MOVE A NEW SORT OF STRATEGY

5311
03:24:25,329 --> 03:24:27,498
UNDER JIM AND PABLO, AND

5312
03:24:27,498 --> 03:24:29,700
BASICALLY THE STRATEGY IS TRYING

5313
03:24:29,700 --> 03:24:32,036
TO ENHANCE THE FREQUENCY OF

5314
03:24:32,036 --> 03:24:34,071
CAR-T CELLS BY GIVING

5315
03:24:34,071 --> 03:24:35,272
VACCINATIONS DURING THE PERIOD

5316
03:24:35,272 --> 03:24:40,745
OF ART WHEN THE CARs ARE

5317
03:24:40,745 --> 03:24:42,713
PRESENT, DOING SO WITH THE

5318
03:24:42,713 --> 03:24:44,048
CONSTRUCTS WITHIN THE CAR

5319
03:24:44,048 --> 03:24:45,549
ITSELF, THAT HAVE ALREADY BEEN

5320
03:24:45,549 --> 03:24:48,619
NOTED TO PROTECT AND ALSO TARGET

5321
03:24:48,619 --> 03:24:52,156
HIV INFECTED CELLS THROUGH CD4.

5322
03:24:52,156 --> 03:24:55,192
AND THE DNA ENCODED VACCINE IS

5323
03:24:55,192 --> 03:24:59,497
ALSO ANOTHER CONNECTION TO THE

5324
03:24:59,497 --> 03:25:00,564
BEAT THROUGH DAVID WEINER.

5325
03:25:00,564 --> 03:25:03,100
WE ALSO INITIATED A MORE FORMAL

5326
03:25:03,100 --> 03:25:04,001
WORKING GROUP AND THIS INCLUDES

5327
03:25:04,001 --> 03:25:09,440
THE HLA-E, THE GENE MODIFIED IN

5328
03:25:09,440 --> 03:25:11,509
CASE, THE BITES INITIATIVE AND

5329
03:25:11,509 --> 03:25:13,177
ALSO CLINICAL DEVELOPMENT IDEAS,

5330
03:25:13,177 --> 03:25:14,478
SO THIS HAS BEEN TSH AND YOU'RE

5331
03:25:14,478 --> 03:25:21,852
GOING TO HEAR A DISCUSSION ABOUT

5332
03:25:21,852 --> 03:25:23,854
ECD 4-IG AND THERE'S A COUPLE

5333
03:25:23,854 --> 03:25:25,256
POSTERS THAT ALSO RELATE TO THIS

5334
03:25:25,256 --> 03:25:25,790
AGENDA.

5335
03:25:25,790 --> 03:25:28,626
I THINK ON GOING, WE CONTINUE TO

5336
03:25:28,626 --> 03:25:31,062
BE FOCUSED ON TRANSLATIONAL

5337
03:25:31,062 --> 03:25:31,362
INITIATIVES.

5338
03:25:31,362 --> 03:25:35,533
YOU'RE GOING TO HEAR WITHDREW

5339
03:25:35,533 --> 03:25:36,634
WIESSMAN THAT TED IS GOING TO

5340
03:25:36,634 --> 03:25:37,168
PRESENT.

5341
03:25:37,168 --> 03:25:42,306
ALSO THERE'S A POSTER ON

5342
03:25:42,306 --> 03:25:44,375
NOVEL -- USED BY NATURAL HEALERS

5343
03:25:44,375 --> 03:25:45,910
WE'RE TRYING TO MOVE INTO

5344
03:25:45,910 --> 03:25:47,144
CLINICAL DEVELOPMENT.

5345
03:25:47,144 --> 03:25:48,879
AS FAR AS EFFECTOR STRATEGIES, I

5346
03:25:48,879 --> 03:25:51,415
LIST HERE SIX OF WHICH POSTERS

5347
03:25:51,415 --> 03:25:56,020
AND TALKS WOULD AGRES THE STORY

5348
03:25:56,020 --> 03:25:57,321
AND THE SOCIAL SCIENCE WHICH IS

5349
03:25:57,321 --> 03:25:59,056
PART OF OUR COMMUNITY

5350
03:25:59,056 --> 03:26:00,391
ENGAGEMENT, THERE'S THREE

5351
03:26:00,391 --> 03:26:02,693
POSTERS OUT ON THAT INITIATIVE

5352
03:26:02,693 --> 03:26:03,861
OUTSIDE, AND IN ADDITION TO

5353
03:26:03,861 --> 03:26:06,263
THAT, WE HAVE NOW BASICALLY

5354
03:26:06,263 --> 03:26:08,199
COMPLETED A VERY LARGE EFFORT ON

5355
03:26:08,199 --> 03:26:11,769
AT HOME VIRAL LOAD COLLECTION OF

5356
03:26:11,769 --> 03:26:13,070
DEVICES, OVER 5500 OF THESE,

5357
03:26:13,070 --> 03:26:16,173
WHICH WE HOPE TO REPORT AT QUOA

5358
03:26:16,173 --> 03:26:17,575
NEXT YEAR IF THE POSTERS

5359
03:26:17,575 --> 03:26:19,210
OBVIOUSLY GET ACCEPTED.

5360
03:26:19,210 --> 03:26:22,313
AND THEN WE ALSO ARE STARTING AN

5361
03:26:22,313 --> 03:26:24,815
INITIATIVE ON THE CURE IN SOUTH

5362
03:26:24,815 --> 03:26:25,783
AFRICA.

5363
03:26:25,783 --> 03:26:29,520
SO REGARDING THE BIOLOGY, I

5364
03:26:29,520 --> 03:26:30,921
THINK WE STILL CONTINUE TO MOVE

5365
03:26:30,921 --> 03:26:32,156
UNDER THE PARADIGM OF

5366
03:26:32,156 --> 03:26:34,558
UNDERSTANDING THE RESERVOIR WITH

5367
03:26:34,558 --> 03:26:35,993
MORE RESOLUTION, AND WE'VE GONE

5368
03:26:35,993 --> 03:26:37,428
FROM OBVIOUSLY INTACT TO

5369
03:26:37,428 --> 03:26:39,396
DEEIVETTIVE TO GENOMIC,

5370
03:26:39,396 --> 03:26:40,164
NON-GENOMIC, REPRESSED, AND

5371
03:26:40,164 --> 03:26:42,466
WE'RE NOW IN THE EPIGENETICS

5372
03:26:42,466 --> 03:26:44,335
TISSUE MICROENVIRONMENT AND THE

5373
03:26:44,335 --> 03:26:45,603
DYNAMIC BETWEEN REPLICATION

5374
03:26:45,603 --> 03:26:47,805
COMPETENT AND IMMUNE RESPONSES,

5375
03:26:47,805 --> 03:26:49,707
AND THERE'S A POSTER OUTSIDE ON

5376
03:26:49,707 --> 03:26:53,077
THE KINETICS ON SIV THAT

5377
03:26:53,077 --> 03:26:53,944
BASICALLY SUGGEST WE NEED TO

5378
03:26:53,944 --> 03:26:55,946
WAIT A PERIOD OF UP TO TWO YEARS

5379
03:26:55,946 --> 03:26:57,581
TO SEE ADEQUATE DECAY, SO I

5380
03:26:57,581 --> 03:26:59,450
WOULD ACTUALLY ENCOURAGE YOU TO

5381
03:26:59,450 --> 03:27:00,217
LOOK OUT FOR THAT.

5382
03:27:00,217 --> 03:27:04,822
THERE'S A DISCUSSION FROM YACHI

5383
03:27:04,822 --> 03:27:07,458
HO ON WHERE THE RESERVOIR SITS

5384
03:27:07,458 --> 03:27:09,093
AND WE HAVE SEVERAL

5385
03:27:09,093 --> 03:27:09,860
INVESTIGATORS LOOKING INTO THAT.

5386
03:27:09,860 --> 03:27:11,629
IN ADDITION TO THE WORK WITH TOM

5387
03:27:11,629 --> 03:27:14,231
AND YACHI ON RETENTION OF

5388
03:27:14,231 --> 03:27:15,366
RESERVOIR BETWEEN BLOOD AND

5389
03:27:15,366 --> 03:27:16,567
TISSUE, THAT'S ALSO A VERY

5390
03:27:16,567 --> 03:27:18,536
ACTIVE AREA WITHIN OUR GROUP.

5391
03:27:18,536 --> 03:27:21,505
AND THE SILICANO INITIATIVE ON

5392
03:27:21,505 --> 03:27:25,442
HOST FACTORS AND ANTIBODY, I

5393
03:27:25,442 --> 03:27:26,544
THINK WE'LL TALK ABOUT THAT BUT

5394
03:27:26,544 --> 03:27:27,745
WE'VE ALSO CONTRIBUTED TO THAT.

5395
03:27:27,745 --> 03:27:30,147
SO WITH THAT, I NEED TO THANK

5396
03:27:30,147 --> 03:27:31,582
ALL OUR RESEARCH PARTICIPANTS

5397
03:27:31,582 --> 03:27:32,683
FOR THE CONTRIBUTION OF ALL OF

5398
03:27:32,683 --> 03:27:34,418
THESE STUDIES, AND I WANT TO

5399
03:27:34,418 --> 03:27:35,853
HIGHLIGHT THAT WE ALSO JUST

5400
03:27:35,853 --> 03:27:37,521
REDID OUR WEBSITE, SO PLEASE

5401
03:27:37,521 --> 03:27:39,056
VISIT IT, IT HAS A LOT MORE

5402
03:27:39,056 --> 03:27:40,691
COMMUNITY FEATURES AND VIDEOS,

5403
03:27:40,691 --> 03:27:42,993
AND PART OF OUR MISSION OF

5404
03:27:42,993 --> 03:27:44,195
EDUCATING THE COMMUNITY ALSO

5405
03:27:44,195 --> 03:27:45,496
INCLUDES EDUCATING OUR PROVIDERS

5406
03:27:45,496 --> 03:27:47,832
WHICH ARE REALLY THE GATEKEEPERS

5407
03:27:47,832 --> 03:27:49,266
FOR RECRUITMENT TO SOME OF OUR

5408
03:27:49,266 --> 03:27:50,234
TRIALS.

5409
03:27:50,234 --> 03:27:52,203
AND WE'RE FORTUNATE ENOUGH TO

5410
03:27:52,203 --> 03:27:55,039
FEATURE A VIDEO THAT HIGHLIGHTS

5411
03:27:55,039 --> 03:27:57,908
THE BEAT-HIV PROGRAM 7 MINUTES

5412
03:27:57,908 --> 03:28:01,612
AND IF YOU -- TODAY IS WHEN ID

5413
03:28:01,612 --> 03:28:03,547
WEEK, THE LARGEST INFECTIOUS

5414
03:28:03,547 --> 03:28:04,381
DISEASE MEETING STARTS IN

5415
03:28:04,381 --> 03:28:04,615
BOSTON.

5416
03:28:04,615 --> 03:28:06,784
IF YOU GO TO THEIR WEBSITE AND

5417
03:28:06,784 --> 03:28:09,053
GO UNDER ID TV, YOU'LL SEE THAT

5418
03:28:09,053 --> 03:28:11,488
THE BEAT-HIV HAS A VIDEO THERE

5419
03:28:11,488 --> 03:28:15,526
INSTRUCTING THE PROGRAM ABOUT

5420
03:28:15,526 --> 03:28:17,294
WHAT THE MARCHING DELANEY

5421
03:28:17,294 --> 03:28:18,062
PROGRAM IS AND WHY IT'S

5422
03:28:18,062 --> 03:28:19,263
IMPORTANT TO MOVE FORWARD.

5423
03:28:19,263 --> 03:28:22,333
SO WITH THAT, I WANT TO THANK

5424
03:28:22,333 --> 03:28:25,636
OBVIOUSLY THE TEAM, THIS IS THE

5425
03:28:25,636 --> 03:28:28,038
GROUP THAT FINALLY MET AFTER

5426
03:28:28,038 --> 03:28:30,541
COVID, AND ALL OF THE SUPPORT

5427
03:28:30,541 --> 03:28:32,076
AND DIVISION OF NIH, AND WITH

5428
03:28:32,076 --> 03:28:34,945
THAT, I WILL HAND IT OVER TO

5429
03:28:34,945 --> 03:28:36,146
YA-CHI, WHO WILL START THE

5430
03:28:36,146 --> 03:28:37,081
DISCUSSIONS ON THE RESEARCH.

5431
03:28:37,081 --> 03:28:38,015
THANK YOU.

5432
03:28:38,015 --> 03:28:43,220
[APPLAUSE]

5433
03:28:43,220 --> 03:28:44,722
>> THANK YOU, LEWIS.

5434
03:28:44,722 --> 03:28:46,690
THANKS TO THE ORGANIZERS FOR THE

5435
03:28:46,690 --> 03:28:47,791
OPPORTUNITY TO PRESENT OUR WORK.

5436
03:28:47,791 --> 03:28:48,559
TODAY I'M GOING TO SHARE SOME

5437
03:28:48,559 --> 03:28:50,794
WORK FROM OUR LAB INCLUDING

5438
03:28:50,794 --> 03:28:51,829
THREE VERY TALENTED YOUNG

5439
03:28:51,829 --> 03:28:54,598
STUDENTS AND POSTDOCS.

5440
03:28:54,598 --> 03:28:56,467
DESPITE YEARS OF RESEARCH,

5441
03:28:56,467 --> 03:28:58,369
WHAT'S STILL PUZZLING IS THAT

5442
03:28:58,369 --> 03:29:01,805
HOW MUCH HAVE WE LEARNED ABOUT

5443
03:29:01,805 --> 03:29:03,140
LATENT RESERVOIR?

5444
03:29:03,140 --> 03:29:05,009
SUPPOSE AFTER REVERSAL ALL THESE

5445
03:29:05,009 --> 03:29:09,179
ARE EXPRESSING PROTEINS --

5446
03:29:09,179 --> 03:29:11,982
SOMETIMES THEY DON'T.

5447
03:29:11,982 --> 03:29:15,719
THE SECOND, SOMETIMES THEY

5448
03:29:15,719 --> 03:29:16,620
DON'T, WHY?

5449
03:29:16,620 --> 03:29:17,688
THIRD, NOT ONLY JUST SIT THERE

5450
03:29:17,688 --> 03:29:19,657
OVER TIME, THEY PROLIFERATE FROM

5451
03:29:19,657 --> 03:29:21,325
ONE INTO MANY, MANY.

5452
03:29:21,325 --> 03:29:23,093
AND FOURTH, THESE HIV INFECTED

5453
03:29:23,093 --> 03:29:24,762
CELLS ARE HIGHLY HETEROGENEOUS.

5454
03:29:24,762 --> 03:29:26,263
IMAGINE THAT IF WE STUDY THESE

5455
03:29:26,263 --> 03:29:28,666
CANCER MUTATIONS THROUGH

5456
03:29:28,666 --> 03:29:30,434
DESIGNED SPECIFIC TREATMENT,

5457
03:29:30,434 --> 03:29:33,070
HAVE WE KNOWN ENOUGH ABOUT THE

5458
03:29:33,070 --> 03:29:34,838
HETEROGENEITY OF HIV-INFECTED

5459
03:29:34,838 --> 03:29:35,172
CELLS?

5460
03:29:35,172 --> 03:29:37,241
SO BASICALLY WE HAVE THIS ONE

5461
03:29:37,241 --> 03:29:39,076
IMMEDIATE PROBLEM THAT ONLY

5462
03:29:39,076 --> 03:29:40,978
ONE -- CONTINUES INFECTIOUS HIV

5463
03:29:40,978 --> 03:29:43,380
SO IT LIKE A NEEDLE IN THE

5464
03:29:43,380 --> 03:29:46,216
HAYSTACK OR NEEDLE IN THE

5465
03:29:46,216 --> 03:29:47,451
NEEDLESTACK PROBLEM BECAUSE WE

5466
03:29:47,451 --> 03:29:48,185
DON'T UNDERSTAND WHERE TO FIND

5467
03:29:48,185 --> 03:29:52,122
THEM AND WHAT THEY LOOK LIKE.

5468
03:29:52,122 --> 03:29:55,960
T-CELLS -- FOR US TO TRY TO

5469
03:29:55,960 --> 03:29:57,394
UNDERSTAND HIV RESERVOIR IS HARD

5470
03:29:57,394 --> 03:29:58,829
AS TRYING TO FIND THESE BLACK

5471
03:29:58,829 --> 03:29:59,830
HOLES IN THE MIDDLE OF THE

5472
03:29:59,830 --> 03:30:00,064
GALAXY.

5473
03:30:00,064 --> 03:30:01,899
AND THIS IS WHY WE LIKE TO TAKE

5474
03:30:01,899 --> 03:30:04,001
A SINGLE CELL APPROACH BASICALLY

5475
03:30:04,001 --> 03:30:07,071
TO TALLY DOWN THE -- FOR T-CELLS

5476
03:30:07,071 --> 03:30:10,107
AND FIND THOSE RARE HIV INFECTED

5477
03:30:10,107 --> 03:30:13,410
CELLS INSTEAD WHICH BASICALLY

5478
03:30:13,410 --> 03:30:15,179
PROFILES 99.9% OF UNINFECTED

5479
03:30:15,179 --> 03:30:16,246
CELLS.

5480
03:30:16,246 --> 03:30:17,915
USING GENOME WIDE PROFILING, WE

5481
03:30:17,915 --> 03:30:20,751
HOPE TO HAVE A MORE -- OF THESE

5482
03:30:20,751 --> 03:30:23,053
CELLS INSTEAD OF TARGETED

5483
03:30:23,053 --> 03:30:24,254
PROFILINGLY WILL NEED TO BE

5484
03:30:24,254 --> 03:30:25,456
BASED ON EXISTING KNOWLEDGE.

5485
03:30:25,456 --> 03:30:27,324
THIS HAS BEEN A VERY EXCITING

5486
03:30:27,324 --> 03:30:31,328
YEAR.

5487
03:30:31,328 --> 03:30:35,366
FIND A GROUP OF HIV-POSITIVE

5488
03:30:35,366 --> 03:30:40,404
CELLS FOR PROFILING.

5489
03:30:40,404 --> 03:30:45,743
THEY USED -- TO RECONSTRUCT THE

5490
03:30:45,743 --> 03:30:46,944
PROVIDER GENOME WITH COUPLED AND

5491
03:30:46,944 --> 03:30:48,946
SINGLE CELL PROTEIN EXPRESSION

5492
03:30:48,946 --> 03:30:51,148
PROFILES.

5493
03:30:51,148 --> 03:30:54,952
VINCENT U AND MICHAEL BETTS

5494
03:30:54,952 --> 03:30:58,489
USED -- TO USE A TRANS POE ACE

5495
03:30:58,489 --> 03:31:00,424
TO DETECT HIV DNA COUPLED WITH

5496
03:31:00,424 --> 03:31:05,162
SINK EL CELL PROTEIN PROFILES.

5497
03:31:05,162 --> 03:31:07,231
EXCISE SEQ AND DOGMA SEQ TRYING

5498
03:31:07,231 --> 03:31:10,067
TO UNDERSTAND HIV INFECTED CELLS

5499
03:31:10,067 --> 03:31:14,238
THROUGH -- BASICALLY FROM DNA,

5500
03:31:14,238 --> 03:31:15,906
RNA, AND PROTEIN EXPRESSION.

5501
03:31:15,906 --> 03:31:18,008
SO WE FIRST STARTED WITH TRYING

5502
03:31:18,008 --> 03:31:20,077
TO UNDERSTAND THESE HIV RNA

5503
03:31:20,077 --> 03:31:22,046
POSITIVE CELLS THAT ARE

5504
03:31:22,046 --> 03:31:22,813
TRANSCRIPTIONALLY ACTIVE.

5505
03:31:22,813 --> 03:31:26,884
WE COLLABORATED WITH FRED HUTCH,

5506
03:31:26,884 --> 03:31:28,485
BASICALLY WE TOOK BLOOD SAMPLES

5507
03:31:28,485 --> 03:31:32,589
FROM PEOPLE HAVING HIV HAVING

5508
03:31:32,589 --> 03:31:34,191
VIREMIA AFTER VIRAL SUPPRESSION

5509
03:31:34,191 --> 03:31:36,193
TO SEE WHAT HAPPENED THROUGHOUTT

5510
03:31:36,193 --> 03:31:38,028
TIME.

5511
03:31:38,028 --> 03:31:39,596
IT'S LIKE -- USING THESE

5512
03:31:39,596 --> 03:31:41,865
COUPLING OF BARCODES, YOUR CELL

5513
03:31:41,865 --> 03:31:43,534
AND REAGENTS, NOW WE CAN SEE ALL

5514
03:31:43,534 --> 03:31:44,568
THESE DIFFERENT MODALITIES

5515
03:31:44,568 --> 03:31:45,936
WITHIN THE SAME SINGLE CELL.

5516
03:31:45,936 --> 03:31:48,472
FOR EXAMPLE, USING

5517
03:31:48,472 --> 03:31:49,540
TRANSCRIPTIONAL ANALYSIS, WE CAN

5518
03:31:49,540 --> 03:31:53,610
LOOK AT THESE T-CELL PROFILES.

5519
03:31:53,610 --> 03:31:56,046
USING SURFACE PROTEIN STAINING,

5520
03:31:56,046 --> 03:32:00,284
YOU CAN SEE WHICH ARE NAIVE

5521
03:32:00,284 --> 03:32:02,419
VERSUS CENTRAL MEMORY.

5522
03:32:02,419 --> 03:32:07,558
WE CAN SEE WHICH CELLS ARE

5523
03:32:07,558 --> 03:32:08,759
HIV-POSITIVE, AND T-CELL

5524
03:32:08,759 --> 03:32:09,793
RECEPTOR SEQUENCE, WE CAN SEE

5525
03:32:09,793 --> 03:32:11,061
WHICH ARE THE CELLS THAT

5526
03:32:11,061 --> 03:32:13,797
PROLIFERATED MOST IN THE BODY.

5527
03:32:13,797 --> 03:32:15,099
DARK BLUE REGION, THESE ARE THE

5528
03:32:15,099 --> 03:32:16,900
MANY CELLS HAVING THE SAME

5529
03:32:16,900 --> 03:32:19,169
T-CELL RECEPTOR SEQUENCE, THESE

5530
03:32:19,169 --> 03:32:20,838
ARE THE CELLS THAT REALLY

5531
03:32:20,838 --> 03:32:21,839
PROLIFERATED INTO MANY, MANY.

5532
03:32:21,839 --> 03:32:24,575
BY TRACKING THESE CELLS THAT

5533
03:32:24,575 --> 03:32:27,845
PRIF LATE TO MANY, BACK TO THE

5534
03:32:27,845 --> 03:32:28,846
TRANSCRIPTOME, WITH YOU KNOW IT

5535
03:32:28,846 --> 03:32:34,651
IS A SITE OF TOXO -- MOST IN THE

5536
03:32:34,651 --> 03:32:35,085
BODY.

5537
03:32:35,085 --> 03:32:37,488
TRYING TO CARE HIV RNA POSITIVE

5538
03:32:37,488 --> 03:32:39,389
CELLS VERSUS UNINFECTED CELLS,

5539
03:32:39,389 --> 03:32:41,992
THEN WE CAN SEE IN ADDITION TO

5540
03:32:41,992 --> 03:32:44,294
ACTIVATION MARKERS AND --

5541
03:32:44,294 --> 03:32:45,362
MARKERS THAT PEOPLE HAVE

5542
03:32:45,362 --> 03:32:46,463
IDENTIFIED IN THE FIELD AS

5543
03:32:46,463 --> 03:32:48,332
MARKERS FOR HIV INFECTED CELLS,

5544
03:32:48,332 --> 03:32:50,100
WE FOUND THAT HIV INFECTED CELLS

5545
03:32:50,100 --> 03:32:59,643
ARE ENRICHED IN CYTOTOXIC CD4 --

5546
03:32:59,643 --> 03:33:03,680
THIS STUDY HAS BEEN

5547
03:33:03,680 --> 03:33:09,186
RECAPITULATED -- B S THESE ARE S

5548
03:33:09,186 --> 03:33:11,121
THAT PROLIFERATED SO WELL, AND

5549
03:33:11,121 --> 03:33:14,024
SECOND, THEIR NATURAL JOB -- TO

5550
03:33:14,024 --> 03:33:16,760
KILL THE TARGET CELLS, BUT TO

5551
03:33:16,760 --> 03:33:19,163
PREVENT SELF INFLICTED INJURY,

5552
03:33:19,163 --> 03:33:22,199
THESE CELLS WOULD ALSO MAKE THIS

5553
03:33:22,199 --> 03:33:23,233
SPER PIN B9.

5554
03:33:23,233 --> 03:33:26,303
THE PROBLEM IS WHEN HIV INFECTS

5555
03:33:26,303 --> 03:33:31,341
IT, THE CD8 T-CELLS WANT TO KILL

5556
03:33:31,341 --> 03:33:37,514
THTHE INFECT -- T-CELL KILLING

5557
03:33:37,514 --> 03:33:39,483
WHEN CHRONIC INTERSTIMULATION

5558
03:33:39,483 --> 03:33:40,250
CONTINUES THESE CELLS MAY

5559
03:33:40,250 --> 03:33:41,652
CONTINUE TO PROLIFERATE.

5560
03:33:41,652 --> 03:33:43,554
USING HIV RNA MAPPING WE

5561
03:33:43,554 --> 03:33:49,259
IDENTIFY TRANSCRIPTIONAL --

5562
03:33:49,259 --> 03:33:50,994
HOWEVER -- WHICH DO NOT EXPRESS

5563
03:33:50,994 --> 03:33:52,829
VIRAL RNA CANNOT BE CAPTURED

5564
03:33:52,829 --> 03:33:55,499
THIS WAY, SO USING THE SAME

5565
03:33:55,499 --> 03:33:58,235
COALITION, WE USE A DIFFERENT

5566
03:33:58,235 --> 03:34:00,237
APPROACH, DONE BY A VERY TALENT

5567
03:34:00,237 --> 03:34:04,174
THED POSTDOC AT ULONG.

5568
03:34:04,174 --> 03:34:08,212
YOU CAN USE ATAC SEQ, RNA SEQ

5569
03:34:08,212 --> 03:34:09,112
AND PRO FILING ALL TOGETHER

5570
03:34:09,112 --> 03:34:11,415
WITHIN THE SAME SINGLE CELL.

5571
03:34:11,415 --> 03:34:14,751
BY MAPPING IN THE TRANSCRIPTOME,

5572
03:34:14,751 --> 03:34:17,454
NOW WE CAN SEE THESE INFECTED

5573
03:34:17,454 --> 03:34:19,656
CELLS WITH THEIR ATAC

5574
03:34:19,656 --> 03:34:21,491
TRANSCRIPTOME AND PROTEIN

5575
03:34:21,491 --> 03:34:23,160
EXPRESSION PROFILE, IN EVERY

5576
03:34:23,160 --> 03:34:24,928
SINGLE DOT THAT YOU SEE ON THIS

5577
03:34:24,928 --> 03:34:25,262
FILE.

5578
03:34:25,262 --> 03:34:28,765
WE CAN ALSO SEE HIV DNA AND HIV

5579
03:34:28,765 --> 03:34:30,133
RNA INSIDE THESE CELLS.

5580
03:34:30,133 --> 03:34:32,970
SO TAKING THEM ALL TOGETHER, NOW

5581
03:34:32,970 --> 03:34:35,906
WE CAN IDENTIFY THOSE HIV

5582
03:34:35,906 --> 03:34:37,107
LATENTLY AFFECTED CELLS WHICH

5583
03:34:37,107 --> 03:34:44,381
ARE POSITIVE HIV DL DNA BUT MAYE

5584
03:34:44,381 --> 03:34:50,053
STILL EXPRESSED BUT BELOW THE

5585
03:34:50,053 --> 03:34:51,388
DE -- THIS IS THE FIRST TIME

5586
03:34:51,388 --> 03:34:54,258
WE'RE ABLE TO IDENTIFY THE

5587
03:34:54,258 --> 03:34:56,193
SINGLE CELL PROFILE OF LATENTLY

5588
03:34:56,193 --> 03:34:56,793
AFFECTED CELLS.

5589
03:34:56,793 --> 03:34:59,997
WE CAPTURE THEM BOTH DURING

5590
03:34:59,997 --> 03:35:01,431
VIREMIA AND AFTER VIRAL

5591
03:35:01,431 --> 03:35:01,865
SUPPRESSION.

5592
03:35:01,865 --> 03:35:03,734
SO NOW WE CAN LOOK AT THE

5593
03:35:03,734 --> 03:35:04,635
SELLING ENVIRONMENT IN DIFFERENT

5594
03:35:04,635 --> 03:35:05,168
WAYS.

5595
03:35:05,168 --> 03:35:13,810
FIRST USING ATACSEQ --

5596
03:35:13,810 --> 03:35:15,479
DIFFERENTIATION WHILE THE

5597
03:35:15,479 --> 03:35:20,851
ACTIVELY INFECTED CELLS --

5598
03:35:20,851 --> 03:35:22,486
ACTIVITY.

5599
03:35:22,486 --> 03:35:25,322
WHEN I LOOK -- I THOUGHT IT WAS

5600
03:35:25,322 --> 03:35:26,356
EXACTLY THE SAME BECAUSE THEY

5601
03:35:26,356 --> 03:35:27,124
WERE LATENT.

5602
03:35:27,124 --> 03:35:28,959
NOW WE FOUND THERE'S STILL SOME

5603
03:35:28,959 --> 03:35:30,727
DIFFERENCE, THAT THERE ARE

5604
03:35:30,727 --> 03:35:32,496
DIFFERENCES IN GENE EXPRESSION

5605
03:35:32,496 --> 03:35:34,831
THAT WE COULD TELL THESE APART,

5606
03:35:34,831 --> 03:35:40,637
ESPECIALLY FOR THE -- ACCURATELY

5607
03:35:40,637 --> 03:35:42,806
DESCRIBED CELLS.

5608
03:35:42,806 --> 03:35:45,909
 -- T-CELL RESPONSES,

5609
03:35:45,909 --> 03:35:47,077
L2 PRODUCTION, ALPHA 4 WHICH HAS

5610
03:35:47,077 --> 03:35:49,513
BEEN PREVIOUSLY REPORTED AS A

5611
03:35:49,513 --> 03:35:55,585
MARKER FOR IMMUNE INFECTED CEL 

5612
03:35:55,585 --> 03:35:58,088
CELLS.

5613
03:35:58,088 --> 03:36:02,326
KNOWN TO TEACH INDUCING B CELL

5614
03:36:02,326 --> 03:36:04,761
TWO EXPRESSION, INTO THIS GENE,

5615
03:36:04,761 --> 03:36:06,129
HAS BEEN PREVIOUSLY REPORTED IN

5616
03:36:06,129 --> 03:36:07,731
DIFFERENT STUDIES.

5617
03:36:07,731 --> 03:36:09,599
IN GENE IS AMAZING BECAUSE WHEN

5618
03:36:09,599 --> 03:36:13,470
WE TRIED TO FIGURE OUT WHY --

5619
03:36:13,470 --> 03:36:15,405
DON'T DIE OF CYTOPATHIC EFFECTS.

5620
03:36:15,405 --> 03:36:16,840
THEY SHOULD DIE, THEY DIDN'T.

5621
03:36:16,840 --> 03:36:19,076
SO WE IDENTIFIED THIS

5622
03:36:19,076 --> 03:36:19,943
PROLIFERATION SURVIVAL PROGRAM

5623
03:36:19,943 --> 03:36:23,647
THAT THERE ARE GENES COEXPRESSED

5624
03:36:23,647 --> 03:36:28,352
WITH PROLIFERATIVE MARKER.

5625
03:36:28,352 --> 03:36:30,787
THESE -- AND IKC OF 3,

5626
03:36:30,787 --> 03:36:37,127
SUGGESTING THAT ICZ OF THREE

5627
03:36:37,127 --> 03:36:42,499
WHWHEN WE INFECT T-CELLS WITH

5628
03:36:42,499 --> 03:36:45,602
DIFFERENT VIRUSES, THESE WERE

5629
03:36:45,602 --> 03:36:47,237
INCREASE -- EXPRESSION AND THESE

5630
03:36:47,237 --> 03:36:54,711
HIGHER LEVELS, IKZF3 -- MAY

5631
03:36:54,711 --> 03:36:55,779
INDUCE -- AND HELP

5632
03:36:55,779 --> 03:36:57,114
PROLIFERATION.

5633
03:36:57,114 --> 03:37:01,284
FINALLY, THE PROTEIN MARKERS ORE

5634
03:37:01,284 --> 03:37:04,688
SIMILAR TO -- WE SEE SOME T

5635
03:37:04,688 --> 03:37:06,857
MARKERS FOR THESE LATENTLY

5636
03:37:06,857 --> 03:37:07,991
AFFECTED CELLS.

5637
03:37:07,991 --> 03:37:11,395
BY THE END, ALL OF THESE

5638
03:37:11,395 --> 03:37:12,796
TRANSCRIPTOME DATA PUTTING THE

5639
03:37:12,796 --> 03:37:15,465
TOGETHER, WE NOW SEE THE PICTURE

5640
03:37:15,465 --> 03:37:18,301
OF THESE HIV INFECTED CELLS, BUT

5641
03:37:18,301 --> 03:37:19,636
ALL OF THEM TOGETHER WE FOUND

5642
03:37:19,636 --> 03:37:22,906
THEY ARE RETROGENUS, YES, BUT

5643
03:37:22,906 --> 03:37:26,743
THEY ARE SELF -- DICTATING THE

5644
03:37:26,743 --> 03:37:30,147
FATE OF THESE CELLS.

5645
03:37:30,147 --> 03:37:31,815
 -- WILL ACTIVATE SELF

5646
03:37:31,815 --> 03:37:32,916
PROLIFERATION AND ACTIVATION

5647
03:37:32,916 --> 03:37:34,217
MARKERS.

5648
03:37:34,217 --> 03:37:40,690
SOME CELL WILL DIE OF VIRAL

5649
03:37:40,690 --> 03:37:44,861
CYTOTOXIC -- SOME CELLS UNDER

5650
03:37:44,861 --> 03:37:47,831
AP1 DRIVEN TRANSCRIPT ACTIVATION

5651
03:37:47,831 --> 03:37:52,736
OF TNF ALPHA -- THIS HELPS A

5652
03:37:52,736 --> 03:37:54,304
LOT -- BUT WHAT DO WE DO WITH

5653
03:37:54,304 --> 03:37:54,971
THE DISH EU?

5654
03:37:54,971 --> 03:37:59,810
WE CA CAN DO A SINGLE CELL ANASS

5655
03:37:59,810 --> 03:38:04,181
THE PROBLEM IS WE MISSED THE

5656
03:38:04,181 --> 03:38:05,615
INTERACTION PART BETWEEN CELLS.

5657
03:38:05,615 --> 03:38:08,985
TRY TO PROFILE THESE INFECTED

5658
03:38:08,985 --> 03:38:11,521
CELLS AND THEY'RE AT RESOLUTION

5659
03:38:11,521 --> 03:38:18,862
WHICH IS THE MIXTURE OF CELLS,

5660
03:38:18,862 --> 03:38:21,498
10-MICRON RESOLUTION USING

5661
03:38:21,498 --> 03:38:24,568
SPATIAL -- WITH THAT TAKING CLAB

5662
03:38:24,568 --> 03:38:31,174
RAYTIVE SAMPLES FROM TOM

5663
03:38:31,174 --> 03:38:34,144
HAUPT -- DURING THE EARLY

5664
03:38:34,144 --> 03:38:36,646
REBOUND PHASE FOUR DAYS AFTER

5665
03:38:36,646 --> 03:38:37,681
TREATMENT INTERRUPTION SO WE CAN

5666
03:38:37,681 --> 03:38:39,983
EXTEND OUR SCOPE FROM BLOOD INTO

5667
03:38:39,983 --> 03:38:41,184
TISSUE AT THE SPATIAL LEVEL.

5668
03:38:41,184 --> 03:38:44,254
SO SUMMARY FOR THE EXEUNT.

5669
03:38:44,254 --> 03:38:45,589
THE KEY QUESTION IS HOW DO WE

5670
03:38:45,589 --> 03:38:47,090
ADVANCE THE HIV CURE FIELD?

5671
03:38:47,090 --> 03:38:50,393
IT TOOK US 13 YEARS TO FIND THE

5672
03:38:50,393 --> 03:38:52,596
RESERVOIR, 22 YEARS TO DEFINE

5673
03:38:52,596 --> 03:38:53,930
THE QUANTITY OF THEM.

5674
03:38:53,930 --> 03:38:55,999
NOW THAT WE'RE NOT SATISFIED

5675
03:38:55,999 --> 03:38:58,068
WITH HOW MANY AND WHAT ARE THEY,

5676
03:38:58,068 --> 03:39:00,403
WE WANT TO UNDERSTAND WHY AND

5677
03:39:00,403 --> 03:39:02,372
HOW HIV PERSISTS.

5678
03:39:02,372 --> 03:39:05,842
SO BEYOND HIV OR RNA SEQUENCING,

5679
03:39:05,842 --> 03:39:07,511
DNA SEQUENCING, WE CAN NOW LOOK

5680
03:39:07,511 --> 03:39:10,180
AT THE CIVIL LANDSCAPE CH THESE

5681
03:39:10,180 --> 03:39:13,350
HIV INFECTED CELLS.

5682
03:39:13,350 --> 03:39:14,317
IDENTIFIED MARKERS IN TARGETS

5683
03:39:14,317 --> 03:39:17,988
THAT CAN BE -- HELPING PROVISION

5684
03:39:17,988 --> 03:39:21,925
OF HIV INFECTED CELLS -- TO BE

5685
03:39:21,925 --> 03:39:25,695
KILLED BY THE IMMUNE SYSTEM,

5686
03:39:25,695 --> 03:39:27,731
BOTH CAN BE TARGETED BY DRUGS

5687
03:39:27,731 --> 03:39:29,199
USED IN THE CANCER FIELD.

5688
03:39:29,199 --> 03:39:30,500
FINALLY, WE ARE BUILDING A MAP,

5689
03:39:30,500 --> 03:39:33,370
A HIGH RESOLUTION GENOME-WIDE

5690
03:39:33,370 --> 03:39:34,337
SINGLE CELL MAP FOR US TO

5691
03:39:34,337 --> 03:39:37,874
UNDERSTAND BETTER ABOUT THE

5692
03:39:37,874 --> 03:39:38,975
HETEROGENEOUS HIV RESERVOIR, AND

5693
03:39:38,975 --> 03:39:41,044
WE'RE HOPING TO USE THIS TO

5694
03:39:41,044 --> 03:39:41,378
GUIDE.

5695
03:39:41,378 --> 03:39:43,046
WITH THAT I'D LIKE TO THANK THE

5696
03:39:43,046 --> 03:39:46,116
STUDY PARTICIPANT IN OUR LAB AND

5697
03:39:46,116 --> 03:39:46,783
THE FUNDING SOURCES.

5698
03:39:46,783 --> 03:39:47,350
THANK YOU.

5699
03:39:47,350 --> 03:39:57,527
[APPLAUSE]

5700
03:40:01,531 --> 03:40:03,567
>> GOOD AFTERNOON,
EVERYONE.

5701
03:40:03,567 --> 03:40:06,403
I'M VERY HAPPY TO BE HERE TO

5702
03:40:06,403 --> 03:40:11,908
INTRODUCE OUR WORK FOR DNA ECD

5703
03:40:11,908 --> 03:40:14,444
4IG TO DECREASE THE HIV-1

5704
03:40:14,444 --> 03:40:16,079
RESERVOIR AND ALSO TO DELAY THE

5705
03:40:16,079 --> 03:40:19,849
VIRAL REBOUND THROUGH IL15

5706
03:40:19,849 --> 03:40:20,817
TRANSGENIC BLT MICE.

5707
03:40:20,817 --> 03:40:23,320
THE KEY QUESTION WE WANT TO ASK

5708
03:40:23,320 --> 03:40:25,722
IS, CAN DNA DELIVERED THERAPY

5709
03:40:25,722 --> 03:40:28,925
ACT TO DETECT OR PLAN TO KILL

5710
03:40:28,925 --> 03:40:30,694
HIV INFECTED RESERVOIR CELLS

5711
03:40:30,694 --> 03:40:31,995
DURING ART SUPPRESSION, AND ALSO

5712
03:40:31,995 --> 03:40:34,431
DELAY VIRAL REBOUND IF

5713
03:40:34,431 --> 03:40:34,998
ADMINISTERED?

5714
03:40:34,998 --> 03:40:37,968
AND WE FIND USING HUMANIZED

5715
03:40:37,968 --> 03:40:40,604
MICE, DNA DELIVERY TOGETHER WITH

5716
03:40:40,604 --> 03:40:43,273
ENZYMES THAT OPTIMIZE ITS

5717
03:40:43,273 --> 03:40:45,008
EXPRESSION REDUCE RESERVOIR ART

5718
03:40:45,008 --> 03:40:47,544
AND DELAY THE VIRAL REBOUND BY

5719
03:40:47,544 --> 03:40:51,381
PROVIDING KILLER CELLS BY USING

5720
03:40:51,381 --> 03:41:01,791
A SPECIFIC PART OF ECD 4IG.

5721
03:41:01,791 --> 03:41:04,194
DATA SUPPORTS A NOVEL TREATMENT

5722
03:41:04,194 --> 03:41:05,562
STRATEGY THAT COULD BE EXTENDED

5723
03:41:05,562 --> 03:41:07,530
TO HUMAN TESTING ALONE, OR AS

5724
03:41:07,530 --> 03:41:11,801
PART OF AN ERADICATION STRATEGY.

5725
03:41:11,801 --> 03:41:16,072
ECD 4-I GWAS INVENTED BY --

5726
03:41:16,072 --> 03:41:17,741
GROUP AND INCLUDES ONE PART OF

5727
03:41:17,741 --> 03:41:23,680
THE CD4 D1-D2 DOMAIN FOR BINDING

5728
03:41:23,680 --> 03:41:27,083
SITE AND THE CCR5 MIMETIC

5729
03:41:27,083 --> 03:41:33,990
PEPTIDE TO BIND WITH THE CD

5730
03:41:33,990 --> 03:41:36,059
CDR5 BINDING POINT.

5731
03:41:36,059 --> 03:41:37,060
UNAVOIDABLE ON THE ENVELOPE AND

5732
03:41:37,060 --> 03:41:38,628
WITH A HIGH POTENCY.

5733
03:41:38,628 --> 03:41:41,698
IT IS HARD TO BE ESCAPED.

5734
03:41:41,698 --> 03:41:43,533
AND WITH THIS, SEVERAL

5735
03:41:43,533 --> 03:41:47,103
PUBLICATIONS USE AAV EXPRESS THE

5736
03:41:47,103 --> 03:41:49,172
ECD IG TO SHOW THE DURABLE

5737
03:41:49,172 --> 03:41:50,907
PROTECTION THROUGH THE MULTIPLE

5738
03:41:50,907 --> 03:41:53,343
SIV OR SHIV CHALLENGE IN THE

5739
03:41:53,343 --> 03:41:57,313
RHESUS MACAQUE MODEL.

5740
03:41:57,313 --> 03:42:00,483
ALSO THERE IS WORK SHOWING THE

5741
03:42:00,483 --> 03:42:03,520
ECD-IG PROMOTES ACTIVITY THROUGH

5742
03:42:03,520 --> 03:42:06,656
BINDING TO THE RECEPTOR OF --

5743
03:42:06,656 --> 03:42:10,260
CELLS AND OUR PREVIOUS WORK SHOW

5744
03:42:10,260 --> 03:42:13,997
THE -- TO MEDIATE SULFATION IN

5745
03:42:13,997 --> 03:42:15,965
FURTHERING ENHANCE THE POTENCY

5746
03:42:15,965 --> 03:42:16,633
BY THREE FOLD.

5747
03:42:16,633 --> 03:42:19,803
WITH ALL OF THIS INFORMATION,

5748
03:42:19,803 --> 03:42:22,472
WE'VE HI HYPOTHESIZED IF WE

5749
03:42:22,472 --> 03:42:26,743
CODELIVER AND THE D2, WE MAY

5750
03:42:26,743 --> 03:42:28,378
REDUCE THE REGULAR SIZE AND

5751
03:42:28,378 --> 03:42:30,613
DELAY THE REBOUND IN VIVO.

5752
03:42:30,613 --> 03:42:32,582
WITH THIS HYPOTHESIS, WE START

5753
03:42:32,582 --> 03:42:37,220
OUR IN-HOUSE NSG HUMANIZED MICE

5754
03:42:37,220 --> 03:42:39,489
AND THE CHALLENGE ANIMALS WITH

5755
03:42:39,489 --> 03:42:42,659
HIV FOLLOWED BY THE VIREMIA AND

5756
03:42:42,659 --> 03:42:43,660
THE ART SUPPRESSION.

5757
03:42:43,660 --> 03:42:46,096
AND THEN WE GAVE THREE TIMES OF

5758
03:42:46,096 --> 03:42:49,499
THE INTRAMUSCULAR DELIVERY OF

5759
03:42:49,499 --> 03:42:54,404
THE EC5G AND -- DNA AND WE USE A

5760
03:42:54,404 --> 03:42:57,607
P VAX ANTIVECTOR AS A CONTROL.

5761
03:42:57,607 --> 03:42:59,042
AFTER THREE TIMES OF THE

5762
03:42:59,042 --> 03:43:01,111
TREATMENT, WE CANNOT FIND ANY

5763
03:43:01,111 --> 03:43:02,612
OBVIOUS DECLINE OF THE BODY

5764
03:43:02,612 --> 03:43:05,548
WEIGHT AND ALL OF THE MICE ARE

5765
03:43:05,548 --> 03:43:08,718
HEALTHY, BUT IN THE -- DERIVE

5766
03:43:08,718 --> 03:43:10,954
THE -- MICE, THE NK FREQUENCY IS

5767
03:43:10,954 --> 03:43:11,588
RELATIVELY LOW.

5768
03:43:11,588 --> 03:43:15,325
AND WE ONLY FIND A LONG ONE-WEEK

5769
03:43:15,325 --> 03:43:16,626
DELAY AND NOT TOO MUCH DELAY

5770
03:43:16,626 --> 03:43:20,196
COMPARED TO THE EMPTY CONTROL.

5771
03:43:20,196 --> 03:43:22,599
THEN WE FURTHER WANT TO IMPROVE

5772
03:43:22,599 --> 03:43:25,668
OUR SYSTEM AND WE USE

5773
03:43:25,668 --> 03:43:30,406
INTERLEUKIN 15 TRANSGENIC NSG

5774
03:43:30,406 --> 03:43:33,243
BLT DERIVED MICE SO SEE IF WE

5775
03:43:33,243 --> 03:43:38,248
CAN HAVE MORE -- THIS IS FROM

5776
03:43:38,248 --> 03:43:45,989
THE SPLENOCYTES OF BOTH MODELS.

5777
03:43:45,989 --> 03:43:47,791
THE NK CELL IS COLOR-CODED IN

5778
03:43:47,791 --> 03:43:50,059
PINK AND WE CAN SEE THE

5779
03:43:50,059 --> 03:43:51,494
INTERLEUKIN 15 TRANSGENIC BLT

5780
03:43:51,494 --> 03:43:54,130
MICE HAVE MORE ROBUST

5781
03:43:54,130 --> 03:43:58,434
ENVIRONMENT THAN NSG BLT MICE.

5782
03:43:58,434 --> 03:44:00,403
WITH THIS TRANSGENIC BLT MICE

5783
03:44:00,403 --> 03:44:02,639
WITH HIGHER NK FREQUENCY, WE

5784
03:44:02,639 --> 03:44:04,274
REPEATED WHAT WE THOUGHT IN

5785
03:44:04,274 --> 03:44:07,110
THOSE WILD TYPE NSG MICE.

5786
03:44:07,110 --> 03:44:10,446
AND EXCITINGLY WE FIND THAT THIS

5787
03:44:10,446 --> 03:44:13,283
MODEL WHICH HAVE THE MORE NK

5788
03:44:13,283 --> 03:44:16,219
FREQUENCY, THE ECD 4-IG TREATED

5789
03:44:16,219 --> 03:44:17,821
ANIMAL CAN DELAY THE REBOUND UP

5790
03:44:17,821 --> 03:44:20,223
TO SIX WEEKS COMPARED TO THE

5791
03:44:20,223 --> 03:44:24,727
EMPTY CONTROL.

5792
03:44:24,727 --> 03:44:26,930
THEN WE START TO THINK ABOUT

5793
03:44:26,930 --> 03:44:28,464
WHAT'S THE MECHANISM BEHIND THIS

5794
03:44:28,464 --> 03:44:31,768
BECAUSE AFTER WE START TO

5795
03:44:31,768 --> 03:44:33,636
INCREASE NK CELLS WE FIND THE

5796
03:44:33,636 --> 03:44:35,972
REBOUND IS FURTHER DELAYED.

5797
03:44:35,972 --> 03:44:37,473
THE HYPOTHESIS IS THIS WILL BE

5798
03:44:37,473 --> 03:44:40,243
AN FC MEDIATED REGION PROCESS.

5799
03:44:40,243 --> 03:44:44,514
WE USE A MUTATION VERSION OF

5800
03:44:44,514 --> 03:44:46,182
THE -- OTHER ARM AND REPEAT WHAT

5801
03:44:46,182 --> 03:44:49,018
WE HAVE DONE, AND THIS MUTATION

5802
03:44:49,018 --> 03:44:53,423
CAN PREVENT THE FC BINDING WITH

5803
03:44:53,423 --> 03:44:54,657
THE EFFECTOR CELLS.

5804
03:44:54,657 --> 03:44:57,694
FROM THE SURVIVAL CURVE, AND WE

5805
03:44:57,694 --> 03:45:01,698
CAN'T SEE THE -- CAN DELAY THE

5806
03:45:01,698 --> 03:45:03,566
REA BOUND UP TO SIX WEEKS, BUT

5807
03:45:03,566 --> 03:45:05,735
TO THE -- MUTATION DIMINISHED TO

5808
03:45:05,735 --> 03:45:09,806
THIS EFFECT, AND THE OUTCOME

5809
03:45:09,806 --> 03:45:13,443
COMPARABLE TO THE EMPTY VECTOR.

5810
03:45:13,443 --> 03:45:16,279
THEN FROM THE FLOW DATA, WE FIND

5811
03:45:16,279 --> 03:45:18,181
INTERESTINGLY THE CD4 -- THE

5812
03:45:18,181 --> 03:45:20,049
UPPER PANEL IS THE

5813
03:45:20,049 --> 03:45:21,351
CD4 DEPLETION, AND WE CAN FIND

5814
03:45:21,351 --> 03:45:24,787
THE COLOR-CODED OF THE ECD 4IG

5815
03:45:24,787 --> 03:45:28,291
ANIMAL TREATED IN RED AND THE

5816
03:45:28,291 --> 03:45:30,126
ECD 4 TREATED ANIMALS HAVE

5817
03:45:30,126 --> 03:45:33,696
PRETTY GOOD CD -- BECAUSE OF THE

5818
03:45:33,696 --> 03:45:34,764
REBOUND DELAY.

5819
03:45:34,764 --> 03:45:36,599
AND THE FURTHER WE FIND THAT ALL

5820
03:45:36,599 --> 03:45:40,403
OF THE ECD4IG TREATED ANIMALS,

5821
03:45:40,403 --> 03:45:42,805
THEY HAVE THE INCREASED NK

5822
03:45:42,805 --> 03:45:45,642
FREQUENCY, AND COMPARED TO THE

5823
03:45:45,642 --> 03:45:49,545
LA LA LA OR THE VECTOR CONTROL.

5824
03:45:49,545 --> 03:45:52,715
THEN WE WANT TO CONFIRM OUR

5825
03:45:52,715 --> 03:45:54,317
TREATMENT IN VIVO CAN PROMOTE

5826
03:45:54,317 --> 03:45:56,619
THE ADCC ACTIVITY THROUGH THE

5827
03:45:56,619 --> 03:45:59,222
BINDING TO FC RECEPTOR -- K

5828
03:45:59,222 --> 03:45:59,889
CELLS.

5829
03:45:59,889 --> 03:46:05,495
THE PANEL F, IT IS -- INSIDE OF

5830
03:46:05,495 --> 03:46:10,199
HUMANIZED MICE SERUM AND WE CAN

5831
03:46:10,199 --> 03:46:16,039
FIND CONCENTRATION -- ROUND YO 

5832
03:46:16,039 --> 03:46:17,507
YOUR -- WHICH IS CONSISTENT TO

5833
03:46:17,507 --> 03:46:19,475
THE PANEL G IN THE ELI IS A DATA

5834
03:46:19,475 --> 03:46:22,879
AFTER EACH OF THE DNA TREATMENT,

5835
03:46:22,879 --> 03:46:24,881
THE PEAK OF THE EXPRESSION ALSO

5836
03:46:24,881 --> 03:46:32,522
AROUND THE 4 TO 6.

5837
03:46:32,522 --> 03:46:34,324
WE CAN FIND ONLY THE INTACT --

5838
03:46:34,324 --> 03:46:36,960
CAN GIVE OUT TO THE STRONG ADCC,

5839
03:46:36,960 --> 03:46:40,563
BUT THERE IS VERY MINIMUM ADCC

5840
03:46:40,563 --> 03:46:44,634
FROM THE CD8 T-CELLS OR FROM THE

5841
03:46:44,634 --> 03:46:48,905
LALEMIEUX TAITION OF THE ECD FOR

5842
03:46:48,905 --> 03:46:49,472
G.

5843
03:46:49,472 --> 03:46:50,773
FURTHER WE WANT TO INVESTIGATE

5844
03:46:50,773 --> 03:46:54,344
WHETHER OUR TREATMENT CAN REDUCE

5845
03:46:54,344 --> 03:46:57,513
THE INTACT VIRAL DNA AND THIS

5846
03:46:57,513 --> 03:46:59,148
INTERLEUKIN 15 TRANSGENIC MODEL,

5847
03:46:59,148 --> 03:47:01,818
AND WE DESIGNED EXPERIMENT TO

5848
03:47:01,818 --> 03:47:04,120
THE -- AND TO PREVENT GENERATE

5849
03:47:04,120 --> 03:47:07,890
MORE CLONES AND WE USE IPD ASSAY

5850
03:47:07,890 --> 03:47:10,827
IN THE MU HANNIZED MICE

5851
03:47:10,827 --> 03:47:12,895
SPLENOCYTES AND EXCITINGLY WE

5852
03:47:12,895 --> 03:47:14,130
FIND THE TREATED ANIMALS, THEY

5853
03:47:14,130 --> 03:47:17,100
HAVE THE SIGNIFICANTLY LOWER PRO

5854
03:47:17,100 --> 03:47:19,002
VIRAL DNA SIZE COMPARED TO THE

5855
03:47:19,002 --> 03:47:21,504
LALA AND THE VECTOR TREATED

5856
03:47:21,504 --> 03:47:22,572
MODEL.

5857
03:47:22,572 --> 03:47:24,607
ESPECIALLY THE INTACT PRO VIRUS.

5858
03:47:24,607 --> 03:47:27,577
AND THIS DNA ASSAY DOWN BY THE

5859
03:47:27,577 --> 03:47:31,514
NASCENT BOARD FROM BOB'S GROUP.

5860
03:47:31,514 --> 03:47:35,952
THEN WE WANT TO RECONFIRM WHAT

5861
03:47:35,952 --> 03:47:38,454
WE FOUND IN OTHER ASSAYS IN THE

5862
03:47:38,454 --> 03:47:40,223
TISSUE MEASURES FROM THE HUMAN

5863
03:47:40,223 --> 03:47:47,030
ICED MICEHUMANIZED MICE LYMPH N.

5864
03:47:47,030 --> 03:47:49,632
IN THE HUMANIZED MICE WE USED IN

5865
03:47:49,632 --> 03:47:52,235
THE STUDY, AND FROM THE

5866
03:47:52,235 --> 03:47:54,704
COLOR-CODED RESULT OF THE

5867
03:47:54,704 --> 03:47:56,339
CD4 IN -- AND THE HIV DNA

5868
03:47:56,339 --> 03:47:58,875
COLORED IN RED, AND WE MANUALLY

5869
03:47:58,875 --> 03:48:02,078
COUNT MORE THAN 1,500 CELLS PER

5870
03:48:02,078 --> 03:48:03,846
SLIDE, AND NORMALIZE THE RESULT

5871
03:48:03,846 --> 03:48:06,082
OF THE HIV-POSITIVE HARBORING

5872
03:48:06,082 --> 03:48:08,785
CELLS PER MILLION CD4 T-CELLS.

5873
03:48:08,785 --> 03:48:13,523
AND EXCITINGLY, CONSISTENTLY, WE

5874
03:48:13,523 --> 03:48:16,159
FIND THE ECD 4-IG TREATED

5875
03:48:16,159 --> 03:48:17,927
ANIMALS HAVE SIGNIFICANTLY LOWER

5876
03:48:17,927 --> 03:48:22,198
HIV HARBORING CELLS PER MILLION

5877
03:48:22,198 --> 03:48:24,400
CD4 T-CELLS.

5878
03:48:24,400 --> 03:48:31,107
CONCLUSION, THE -- THE DELAY OF

5879
03:48:31,107 --> 03:48:33,976
THE VIRAL REBOUND IN THE HIV

5880
03:48:33,976 --> 03:48:36,479
INFECTED INTERLEUKIN 15

5881
03:48:36,479 --> 03:48:38,381
TRANSGENIC BLT MICE AND OUR

5882
03:48:38,381 --> 03:48:40,016
TREATMENT ALSO DECREASED THE

5883
03:48:40,016 --> 03:48:43,219
TISSUE HIV PRO VIRAL DNA,

5884
03:48:43,219 --> 03:48:45,288
ESPECIALLY THE -- AND THE

5885
03:48:45,288 --> 03:48:49,826
MECHANISMS OF THIS ACTION, IT

5886
03:48:49,826 --> 03:48:51,027
IS -- TO THE PROCESS BECAUSE A

5887
03:48:51,027 --> 03:48:53,463
LOT OF MUCATIONS DIMINISH THIS

5888
03:48:53,463 --> 03:48:56,466
PROCESS AND ALSO OUR TREATMENT

5889
03:48:56,466 --> 03:48:59,502
PRO PLOATS ADCC ACTIVITIES

5890
03:48:59,502 --> 03:49:01,804
THROUGH -- FC RECEPTOR OF NK

5891
03:49:01,804 --> 03:49:04,941
CELLS RATHER THAN CD8 T-CELLS.

5892
03:49:04,941 --> 03:49:05,641
FURTHER INVESTIGATION REQUIRED

5893
03:49:05,641 --> 03:49:06,676
TO DETERMINE THE POTENTIAL OF

5894
03:49:06,676 --> 03:49:09,545
OUR TREATMENT TO CONTROL AND

5895
03:49:09,545 --> 03:49:12,982
CONTRIBUTE TO ERADICATION WHEN

5896
03:49:12,982 --> 03:49:14,517
USED ON AND AFTER ART

5897
03:49:14,517 --> 03:49:15,818
INTERRUPTION.

5898
03:49:15,818 --> 03:49:18,121
THANKS TO OUR CO-AUTHORS,

5899
03:49:18,121 --> 03:49:18,521
COLLABORATORS.

5900
03:49:18,521 --> 03:49:19,388
THANKS FOR YOUR ATTENTION.

5901
03:49:19,388 --> 03:49:29,565
[APPLAUSE]

5902
03:49:33,236 --> 03:49:34,470
>> HI.

5903
03:49:34,470 --> 03:49:37,106
MY NAME IS TIM KREIDER.

5904
03:49:37,106 --> 03:49:39,142
I'LL BE TELLING YOU TODAY ABOUT

5905
03:49:39,142 --> 03:49:40,643
CD4 TARGETED DELIVERY OF TAT

5906
03:49:40,643 --> 03:49:44,280
MRNA FOR REVERSING HIV LATENCY.

5907
03:49:44,280 --> 03:49:48,484
FOR OUR PLAIN IN ENGLISH SUMMAR,

5908
03:49:48,484 --> 03:49:49,685
THE KE QUESTION, CAN WE UNCOVER

5909
03:49:49,685 --> 03:49:51,420
THE HIDDEN VIRUSES WITHOUT

5910
03:49:51,420 --> 03:49:52,588
HARMING A PERSON OR THEIR CELLS.

5911
03:49:52,588 --> 03:49:53,823
WHAT WE ACCOMPLISHED IS, WE

5912
03:49:53,823 --> 03:49:55,391
COULD UNCOVER SOME HIDDEN

5913
03:49:55,391 --> 03:49:57,260
VIRUSES USING A TARGETED MRNA

5914
03:49:57,260 --> 03:49:58,995
GENE THERAPY.

5915
03:49:58,995 --> 03:50:01,130
AND THIS RELATES TO THE CARE

5916
03:50:01,130 --> 03:50:02,465
AGENDA BECAUSE LATENT VIRUSES

5917
03:50:02,465 --> 03:50:04,300
ARE HIDDEN FROM THE IMMUNE

5918
03:50:04,300 --> 03:50:05,701
SYSTEM AND OUR THERAPIES, SO WE

5919
03:50:05,701 --> 03:50:07,170
NEED NEW METHODS FOR UNCOVERING

5920
03:50:07,170 --> 03:50:09,272
THEM THAT ARE NOT TOXIC, AND

5921
03:50:09,272 --> 03:50:11,140
THIS IS IMPORTANT BECAUSE THIS

5922
03:50:11,140 --> 03:50:12,308
TYPE OF INTERVENTION COULD BE

5923
03:50:12,308 --> 03:50:15,578
PART OF A CURE STRATEGY AND MAY

5924
03:50:15,578 --> 03:50:16,812
TEACH US IMPORTANT LESSONS OF

5925
03:50:16,812 --> 03:50:18,281
HOW VIRUSES HIDE AND FLY UNDER

5926
03:50:18,281 --> 03:50:19,348
THE RADAR.

5927
03:50:19,348 --> 03:50:21,984
AS AN EXAMPLE, I'M SHOWING A

5928
03:50:21,984 --> 03:50:23,419
PICTURE OF TWO HOUSES WHERE A

5929
03:50:23,419 --> 03:50:24,253
VIRUS IS HIDING.

5930
03:50:24,253 --> 03:50:27,089
WE DON'T WANT TO DISORGANIZE THE

5931
03:50:27,089 --> 03:50:28,724
WHOLE HOUSE, TRYING TO FIND THE

5932
03:50:28,724 --> 03:50:29,325
VIRUS.

5933
03:50:29,325 --> 03:50:30,226
INSTEAD, WE WANT TO GO RIGHT

5934
03:50:30,226 --> 03:50:33,162
WHERE THE VIRUS IS, AND UNCOVER

5935
03:50:33,162 --> 03:50:34,697
IT.

5936
03:50:34,697 --> 03:50:36,098
SO AS SOME BACKGROUND, THIS

5937
03:50:36,098 --> 03:50:38,034
CROWD KNOWS THAT HIV CAN PERSIST

5938
03:50:38,034 --> 03:50:40,236
WITHIN PEOPLE LIVING WITH HIV AS

5939
03:50:40,236 --> 03:50:43,539
A LATENT PRO VIRUS DESPITE

5940
03:50:43,539 --> 03:50:45,074
COMBINATION ANTIRETROVIRALS.

5941
03:50:45,074 --> 03:50:46,409
LATENCY REVERSALS MAY BE A

5942
03:50:46,409 --> 03:50:48,044
NECESSARY ASPECT OF A DRUG-FREE

5943
03:50:48,044 --> 03:50:49,779
HIV CURE.

5944
03:50:49,779 --> 03:50:52,114
IN PREVIOUSLY USED LATENCY

5945
03:50:52,114 --> 03:50:53,516
REVERSING AGENTS EMPLOY MULTIPLE

5946
03:50:53,516 --> 03:50:54,550
MECHANISMS THAT LARGELY TARGET

5947
03:50:54,550 --> 03:50:54,917
THE HOST.

5948
03:50:54,917 --> 03:50:57,620
THIS INCLUDES OPENING UP

5949
03:50:57,620 --> 03:50:58,521
CHROMATIN, SIGNALING THROUGH

5950
03:50:58,521 --> 03:51:02,992
HOST PATHWAYS THAT DRIVE

5951
03:51:02,992 --> 03:51:05,561
TRANSCRIPTION, CHECKPOINT

5952
03:51:05,561 --> 03:51:06,529
INHIBITION, CD8 DEPLETION AND

5953
03:51:06,529 --> 03:51:06,963
MORE.

5954
03:51:06,963 --> 03:51:08,064
THE QUESTION WE TRIED TO ANSWER

5955
03:51:08,064 --> 03:51:10,099
ARE THERE VIRUS-SPECIFIC WAYS OF

5956
03:51:10,099 --> 03:51:10,766
REVERSING LATENCY?

5957
03:51:10,766 --> 03:51:11,634
TO ADDRESS THIS QUESTION, WE

5958
03:51:11,634 --> 03:51:14,470
RETURNED TO THE REGULATION OF

5959
03:51:14,470 --> 03:51:15,771
VIRAL TRANSCRIPTION.

5960
03:51:15,771 --> 03:51:17,173
DEPICTED HERE IS A GENOMIC MAP

5961
03:51:17,173 --> 03:51:22,812
OF AN INTERGREATE INTEGRATED VID

5962
03:51:22,812 --> 03:51:27,750
BY TWO -- THE 5 PRIME LTR, THE

5963
03:51:27,750 --> 03:51:29,452
TATA BOX IS INDICATED IN GREEN

5964
03:51:29,452 --> 03:51:32,388
AND IN FALL COLORS I HAVE A

5965
03:51:32,388 --> 03:51:34,190
COUPLE TRANSCRIPTION FACTOR

5966
03:51:34,190 --> 03:51:36,626
BINDING SITES KNOWN TO DRIVE

5967
03:51:36,626 --> 03:51:39,362
TRANSCRIPTION.

5968
03:51:39,362 --> 03:51:40,329
IT'S LARGELY REGULATED BY THE

5969
03:51:40,329 --> 03:51:41,764
PLENS OR ABSENCE OF A VIRAL

5970
03:51:41,764 --> 03:51:42,898
PROTEIN CALLED TAT.

5971
03:51:42,898 --> 03:51:44,867
IN THE ABSENCE OF TAT, THERE

5972
03:51:44,867 --> 03:51:46,636
ACTUALLY IS TRANSCRIPTION

5973
03:51:46,636 --> 03:51:47,937
INITIATION WITH THE

5974
03:51:47,937 --> 03:51:49,972
TRANSCRIPTION OF THE FIRST

5975
03:51:49,972 --> 03:51:51,507
APPROXIMATELY 16 NUCLEOTIDES OF

5976
03:51:51,507 --> 03:51:52,908
THE HIV GENOME.

5977
03:51:52,908 --> 03:51:55,111
THIS IS CALLED THE TAR STEM LOOP

5978
03:51:55,111 --> 03:51:56,479
AND IT FORMS A VERY TIGHT

5979
03:51:56,479 --> 03:51:57,346
HAIRPIN.

5980
03:51:57,346 --> 03:51:58,147
HOWEVER, TRANSCRIPTION

5981
03:51:58,147 --> 03:51:59,448
ELONGATION IS ARRESTED, AND THIS

5982
03:51:59,448 --> 03:52:03,653
LEADS TO THE ACCUMULATION OF

5983
03:52:03,653 --> 03:52:04,654
ABORTIVE TRANSCRIPTS WITHIN A

5984
03:52:04,654 --> 03:52:06,622
SELL.

5985
03:52:06,622 --> 03:52:09,558
CELL.

5986
03:52:09,558 --> 03:52:11,727
THIS LEADS TO MASSIVE CHANGES TO

5987
03:52:11,727 --> 03:52:12,995
TRANSCRIPTION WITHIN THE CELL,

5988
03:52:12,995 --> 03:52:14,330
WITH RELEASE OF THE

5989
03:52:14,330 --> 03:52:15,298
TRANSCRIPTIONAL COMPLEX FROM

5990
03:52:15,298 --> 03:52:17,133
NEGATIVE REGULATORS,

5991
03:52:17,133 --> 03:52:22,805
HYPERPHOSPHORYLATION OF RNA POL.

5992
03:52:22,805 --> 03:52:24,307
THE ULTIMATE RESULT IS A MASSIVE

5993
03:52:24,307 --> 03:52:26,042
ELONGATION OF TAR STEM LOOPS.

5994
03:52:26,042 --> 03:52:27,677
THIS RESULTS IN RNA

5995
03:52:27,677 --> 03:52:29,979
TRANSCRIPTION AND PROTEIN

5996
03:52:29,979 --> 03:52:30,880
EXPRESSION.

5997
03:52:30,880 --> 03:52:32,882
THIS HAS ACTUALLY BEEN SHOWN IN

5998
03:52:32,882 --> 03:52:35,518
SAMPLES FROM PEOPLE LIVING WITH

5999
03:52:35,518 --> 03:52:36,919
HIV TO BE AN IMPORTANT BLOCK IN

6000
03:52:36,919 --> 03:52:38,754
THE REVERSAL OF LATENCY AND I'LL

6001
03:52:38,754 --> 03:52:41,057
SHOW DATA FROM THE 2018 PAPER IN

6002
03:52:41,057 --> 03:52:42,591
WHICH THEY LOOKED AT A WIDE

6003
03:52:42,591 --> 03:52:44,593
VARIETY OF PEOPLE LIVING WITH

6004
03:52:44,593 --> 03:52:46,529
HIV AND QUANTIFIED THE DIFFERENT

6005
03:52:46,529 --> 03:52:48,531
RNA SPECIES WITHIN THEIR CELL.

6006
03:52:48,531 --> 03:52:49,198
EACH DIFFERENT COLOR IS A

6007
03:52:49,198 --> 03:52:51,600
DIFFERENT PERSON.

6008
03:52:51,600 --> 03:52:53,869
ON THE Y AXIS IS THE AMOUNT OF

6009
03:52:53,869 --> 03:52:55,271
RNA FOUND IN THAT CELL.

6010
03:52:55,271 --> 03:52:57,707
THE X AXIS IS DIFFERENT TYPES OF

6011
03:52:57,707 --> 03:52:58,374
RNA SPECIES.

6012
03:52:58,374 --> 03:53:00,376
YOU CAN SEE BY FAR THE MOST

6013
03:53:00,376 --> 03:53:02,345
ABUNDANT RNA SPECIES ARE TAR

6014
03:53:02,345 --> 03:53:03,546
STEM LOOPS, THOSE LITTLE

6015
03:53:03,546 --> 03:53:04,814
HAIRPINS I SHOWED YOU ON THE

6016
03:53:04,814 --> 03:53:05,281
LAST SLIDE.

6017
03:53:05,281 --> 03:53:06,482
WHEN THEY QUANTIFIED THIS,

6018
03:53:06,482 --> 03:53:08,050
NORMALIZING TO THE AMOUNT OF DNA

6019
03:53:08,050 --> 03:53:09,685
INTEGRATED IN THESE CELLS, THEY

6020
03:53:09,685 --> 03:53:11,754
ESTIMATED BETWEEN 89 AND 100% OF

6021
03:53:11,754 --> 03:53:13,089
CELLS MAKE THESE ABORTIVE

6022
03:53:13,089 --> 03:53:16,092
TRANSCRIPTS.

6023
03:53:16,092 --> 03:53:20,696
SO CAN WE SUPPLY EXOGENOUS TAT,

6024
03:53:20,696 --> 03:53:22,331
WE'VE GOT A COUPLE OF PROBLEMS

6025
03:53:22,331 --> 03:53:23,332
WITH THIS STRATEGY.

6026
03:53:23,332 --> 03:53:25,134
ONE, TAT IS POLYFUNCTIONAL, AND

6027
03:53:25,134 --> 03:53:27,737
TWO, IT KILLS CELLS.

6028
03:53:27,737 --> 03:53:29,739
SO SHOWN HERE IS A STRUCTURE OF

6029
03:53:29,739 --> 03:53:30,673
TAT.

6030
03:53:30,673 --> 03:53:32,074
IT'S ENCODED BY TWO EXONS WITH A

6031
03:53:32,074 --> 03:53:33,743
NUMBER OF FUNCTIONAL DOMAINS

6032
03:53:33,743 --> 03:53:35,745
THAT HAVE BEEN STUDIED OVER

6033
03:53:35,745 --> 03:53:36,545
DECADES OF RESEARCH.

6034
03:53:36,545 --> 03:53:38,914
I'M GOING TO SHOW YOU DATA

6035
03:53:38,914 --> 03:53:40,649
SHOWING ONE WILD TYPE TAT AND A

6036
03:53:40,649 --> 03:53:43,018
SECOND VARIANT THAT'S 86 AMINO

6037
03:53:43,018 --> 03:53:45,621
ACIDS IN LENGTH CALLED THE R5M4.

6038
03:53:45,621 --> 03:53:48,991
THE REASON R5 M4 WAS CHOSEN IS

6039
03:53:48,991 --> 03:53:50,426
BASED ON THIS 2016 PAPER IN

6040
03:53:50,426 --> 03:53:52,561
WHICH THIS VARIANT WAS FIRST

6041
03:53:52,561 --> 03:53:52,928
DESCRIBED.

6042
03:53:52,928 --> 03:53:54,563
THEY INCORPORATED A SERIES OF

6043
03:53:54,563 --> 03:53:55,431
ALANINE MUTATIONS IN THE

6044
03:53:55,431 --> 03:53:56,799
SEQUENCE OF TAT AND FOUND THAT

6045
03:53:56,799 --> 03:53:58,968
IT COMPLETELY ATTENUATED THE

6046
03:53:58,968 --> 03:54:02,371
CYTOTOXIC ASPECT OF THIS PROT 

6047
03:54:02,371 --> 03:54:03,472
PROTEIN.

6048
03:54:03,472 --> 03:54:04,740
SHOWN HERE ARE PRIMARY CD4s

6049
03:54:04,740 --> 03:54:05,941
THAT THEY TREATED WITH EITHER

6050
03:54:05,941 --> 03:54:08,911
THE WILD VERSION OF TAT OR R5

6051
03:54:08,911 --> 03:54:09,078
M4.

6052
03:54:09,078 --> 03:54:10,913
AS YOU SEE THEY INCREASED THE

6053
03:54:10,913 --> 03:54:13,015
TYPE OF WILD TYPE TAT THEY PUT

6054
03:54:13,015 --> 03:54:14,717
ON THESE CELLS, THESE CELLS ARE

6055
03:54:14,717 --> 03:54:17,019
LESS VIABLE.

6056
03:54:17,019 --> 03:54:19,755
HOWEVER THE R5M4 SHOWED NO

6057
03:54:19,755 --> 03:54:20,956
IMPACT ON CELL VIABILITY.

6058
03:54:20,956 --> 03:54:24,994
SO WE TESTED THESE AT MRNAs IN

6059
03:54:24,994 --> 03:54:27,163
A CELL LINE THAT EXPRESSES --

6060
03:54:27,163 --> 03:54:29,231
UNDER THE CONTROL OF THE HIV

6061
03:54:29,231 --> 03:54:29,865
PROMOTER.

6062
03:54:29,865 --> 03:54:36,605
RNA EXPRESSING EITHER JR CSF, 

6063
03:54:36,605 --> 03:54:39,508
R -- I INCLUDED A RNA ENCODING

6064
03:54:39,508 --> 03:54:40,576
OF FLUORESCENT PRO TEEFNLT ON

6065
03:54:40,576 --> 03:54:42,711
THE Y AXIS, I HAVE LUCIFERASE

6066
03:54:42,711 --> 03:54:46,382
SIGNAL AND ON THE X AXIS THE

6067
03:54:46,382 --> 03:54:46,682
DOSE.

6068
03:54:46,682 --> 03:54:50,419
CAN YOU SEE BOTH THE JRC --

6069
03:54:50,419 --> 03:54:51,720
POTENTLY TRANS ACTIVATE

6070
03:54:51,720 --> 03:54:52,988
EXPRESSION FROM THE HIV

6071
03:54:52,988 --> 03:54:53,556
PROMOTER.

6072
03:54:53,556 --> 03:54:55,825
AND THUS THESE CHANGES THAT ARE

6073
03:54:55,825 --> 03:54:58,160
SUPPOSED TO ATTENUATE

6074
03:54:58,160 --> 03:55:00,396
CYTOTOXICITY DO NOT IMPACT TRANS

6075
03:55:00,396 --> 03:55:01,063
ACTIVATION FUNCTION.

6076
03:55:01,063 --> 03:55:03,999
WE ALSO TESTED THIS IN THE JLA

6077
03:55:03,999 --> 03:55:05,167
T10 .6 MODEL OF LATENCY AND I

6078
03:55:05,167 --> 03:55:06,268
WON'T GO THROUGH ALL THE DATA

6079
03:55:06,268 --> 03:55:08,237
BUT SHOW YOU A SUMMARY OF A

6080
03:55:08,237 --> 03:55:10,706
DOSE-RESPONSE CURVE IN WHICH WE

6081
03:55:10,706 --> 03:55:12,675
PUT INCREASING AMOUNTS OF TAT

6082
03:55:12,675 --> 03:55:20,516
MRNA LRPs ON JLATS.

6083
03:55:20,516 --> 03:55:22,451
AS COMPARED TO THE NEGATIVE

6084
03:55:22,451 --> 03:55:23,886
CONTROL LUCIFERASE YOU SEE THAT

6085
03:55:23,886 --> 03:55:26,922
THERE IS A SIGMOID D AS L CURVE

6086
03:55:26,922 --> 03:55:28,324
WITH INCREASING DOSES OF TAT

6087
03:55:28,324 --> 03:55:29,758
LEADING TO MORE REACTIVATION OF

6088
03:55:29,758 --> 03:55:37,266
LAY TEBT HIV IN STLATENT HIV IN.

6089
03:55:37,266 --> 03:55:39,935
WE TOOK THE DOSE IN WHICH WE HAD

6090
03:55:39,935 --> 03:55:42,238
ABOUT 60% GFP POSITIVE CELLS AND

6091
03:55:42,238 --> 03:55:43,539
PERFORMED MULTIPLE PARAMETER

6092
03:55:43,539 --> 03:55:47,009
PROFILING ON THIS USING ATAC SEQ

6093
03:55:47,009 --> 03:55:48,544
AND SINGLE CELL RNA SEQ.

6094
03:55:48,544 --> 03:55:53,883
SHOWN HERE IS A PRINCIPAL

6095
03:55:53,883 --> 03:55:54,950
COMPONENT ANALYSIS RNA SEEK

6096
03:55:54,950 --> 03:55:55,718
COMPARING FOUR CONDITIONS.

6097
03:55:55,718 --> 03:55:58,721
IN PURPLE WE HAVE CELLS TREATED

6098
03:55:58,721 --> 03:56:02,024
WITH INCREDIBLY ACTIVATED -- AND

6099
03:56:02,024 --> 03:56:03,692
IN THE THREE OTHER COLORS WE HAD

6100
03:56:03,692 --> 03:56:06,328
EITHER CELLS TREATED WITH TAT

6101
03:56:06,328 --> 03:56:08,731
MRNA TWO DAYS PRIOR, LMPs

6102
03:56:08,731 --> 03:56:10,666
THREE DAYS PRIOR OR LUCIFERASE

6103
03:56:10,666 --> 03:56:12,968
MRNA LMPs THREE DAYS PRIOR.

6104
03:56:12,968 --> 03:56:15,471
WHAT I HOPE YOU TAKE FROM THIS

6105
03:56:15,471 --> 03:56:17,306
SLIDE IS THAT SHOWN IN PURPLE IS

6106
03:56:17,306 --> 03:56:18,741
COMPLETELY DIFFERENT

6107
03:56:18,741 --> 03:56:19,441
TRANSCRIPTIONALLY THAN ALL THREE

6108
03:56:19,441 --> 03:56:20,142
OTHER CONDITIONS.

6109
03:56:20,142 --> 03:56:21,777
AND THUS THE INCLUSION OF TAT

6110
03:56:21,777 --> 03:56:24,380
DOES NOT SEEM TO HAVE GLOBAL

6111
03:56:24,380 --> 03:56:25,848
IMPACT ON THE TRANSCRIPTIONAL

6112
03:56:25,848 --> 03:56:32,555
PROFILE OF JLAT 10.6 CELLS.

6113
03:56:32,555 --> 03:56:34,223
WHAT ARE THE DIFFERENT

6114
03:56:34,223 --> 03:56:35,624
TRANSCRIPTS THAT SHOW

6115
03:56:35,624 --> 03:56:36,725
SIGNIFICANT CHANGES COMPARING

6116
03:56:36,725 --> 03:56:37,560
LUCIFERASE TO TAT?

6117
03:56:37,560 --> 03:56:40,529
WE FOUND ONLY FOUR.

6118
03:56:40,529 --> 03:56:41,397
THOSE FOUR ARE SHOWN HERE.

6119
03:56:41,397 --> 03:56:43,499
THE FIRST ONE IS A MITOCHONDRIAL

6120
03:56:43,499 --> 03:56:43,999
PROTEIN.

6121
03:56:43,999 --> 03:56:45,200
THE SECOND A RIBOSOMAL

6122
03:56:45,200 --> 03:56:46,969
COMPONENT, AND THE LAST ONE, A

6123
03:56:46,969 --> 03:56:48,604
LONG NON-CODING RNA WITH NO

6124
03:56:48,604 --> 03:56:50,539
DESCRIBED FUNCTION.

6125
03:56:50,539 --> 03:56:52,508
AND IMPORTANTLY, HIV GENOME

6126
03:56:52,508 --> 03:56:53,375
TRANSCRIPTION CAME OUT OF THIS,

6127
03:56:53,375 --> 03:56:55,578
WHICH WAS GOOD.

6128
03:56:55,578 --> 03:56:57,513
THESE DATA SUGGESTED TO US THAT

6129
03:56:57,513 --> 03:56:59,381
THIS IS A RELATIVELY SPECIFIC

6130
03:56:59,381 --> 03:57:02,217
WAY OF MODIFYING RNA EXPRESSION

6131
03:57:02,217 --> 03:57:04,820
OF SPECIFICALLY THE HIV GENOME.

6132
03:57:04,820 --> 03:57:06,021
AND IN FACT, IN DATA THAT I

6133
03:57:06,021 --> 03:57:07,790
DON'T HAVE TIME TO SHOW TODAY,

6134
03:57:07,790 --> 03:57:13,762
WE'VE LOOKED AT TAT MRNA  LNP

6135
03:57:13,762 --> 03:57:15,531
T-CELLS AND FOUND NO EVIDENCE OF

6136
03:57:15,531 --> 03:57:16,699
APOPTOSIS OR ACTIVATION OF THOSE

6137
03:57:16,699 --> 03:57:17,866
CELLS, SUGGESTING THAT WE ARE

6138
03:57:17,866 --> 03:57:20,269
NOT GLOBALLY AFFECTING THE CELLS

6139
03:57:20,269 --> 03:57:22,137
WITH OUR TREATMENT.

6140
03:57:22,137 --> 03:57:23,806
HOWEVER, CD4 T-CELLS ARE

6141
03:57:23,806 --> 03:57:25,841
DIFFICULT TO TRANSVECT AND

6142
03:57:25,841 --> 03:57:28,143
ACTUALLY DO NOT TAKE UP MRNA

6143
03:57:28,143 --> 03:57:30,546
LIPID NANOPARTICLES USUALLY.

6144
03:57:30,546 --> 03:57:32,047
AND SO WE'VE DEVELOPED A METHOD

6145
03:57:32,047 --> 03:57:35,517
IN THE LAB TO CHEMICALLY CON JEW

6146
03:57:35,517 --> 03:57:37,720
GATE LIPID PARTICLES SUCH THAT

6147
03:57:37,720 --> 03:57:39,455
THEY EXPRESS AN ANTIBODY ON

6148
03:57:39,455 --> 03:57:40,222
THEIR EXTERIOR SURFACE.

6149
03:57:40,222 --> 03:57:45,461
THIS TAKES A LNP THAT WHEN

6150
03:57:45,461 --> 03:57:49,565
INJECTED INTRAVENOUSLY REDIRECTS

6151
03:57:49,565 --> 03:57:51,333
THE MRNA TO ANOTHER CELL TYPE.

6152
03:57:51,333 --> 03:57:55,571
I USE THE FDA APPROVED

6153
03:57:55,571 --> 03:57:57,673
MONOCLONAL ANTIBODY THAT IS

6154
03:57:57,673 --> 03:57:59,408
RAPIDLY INTERNALIZED IN CELLS.

6155
03:57:59,408 --> 03:58:00,676
IN PREVIOUS WORK IN THE LAB HAS

6156
03:58:00,676 --> 03:58:02,778
SHOWN THAT CD4 TARGETING CAN

6157
03:58:02,778 --> 03:58:05,280
REDIRECT LNPs TO CD4 POSITIVE

6158
03:58:05,280 --> 03:58:07,883
T-CELLS INCLUDING RESTING CELLS

6159
03:58:07,883 --> 03:58:09,084
AND SHOWS EVIDENCE OF DELIVERY

6160
03:58:09,084 --> 03:58:12,688
OF MRNA TO LYMPHOID RESOIDING

6161
03:58:12,688 --> 03:58:13,355
CELLS.

6162
03:58:13,355 --> 03:58:15,724
ON THIS NEXT SLIDE I'M SHOWING

6163
03:58:15,724 --> 03:58:17,993
YOU DATA DEMONSTRATING THAT

6164
03:58:17,993 --> 03:58:20,763
IEBLIZUMAB TARGETING

6165
03:58:20,763 --> 03:58:23,699
EFFICIENTLY -- THE T-CELLS.

6166
03:58:23,699 --> 03:58:27,603
THESE WERE TREATED WITH

6167
03:58:27,603 --> 03:58:30,773
TARGETED -- I'M PLOTTING GFP

6168
03:58:30,773 --> 03:58:33,208
INTENSITY VERSUS FREAK Z THE

6169
03:58:33,208 --> 03:58:34,143
CONTROLS SHOWN HERE, NO

6170
03:58:34,143 --> 03:58:35,010
TREATMENT IS SHOWN IN BLACK WITH

6171
03:58:35,010 --> 03:58:38,280
A GREY FILL.

6172
03:58:38,280 --> 03:58:40,449
THE NON-TARGETED LNPs SHOWN IN

6173
03:58:40,449 --> 03:58:41,850
PINK ONLY IN THE RHESUS

6174
03:58:41,850 --> 03:58:44,687
CONDITION SHOW COMPLETE OVERLAP

6175
03:58:44,687 --> 03:58:45,921
DEMONSTRATING THAT CONJUGATION

6176
03:58:45,921 --> 03:58:51,226
OF THIS ANTIBODY IS NECESSARY

6177
03:58:51,226 --> 03:58:55,297
FOR MRNA -- DID NOT RESULT IN

6178
03:58:55,297 --> 03:58:55,931
FLUORESCENT SIGNAL.

6179
03:58:55,931 --> 03:58:57,766
HOWEVER, WHEN WE DELIVERED GFP

6180
03:58:57,766 --> 03:58:59,735
USING THIS METHOD, WE SEE

6181
03:58:59,735 --> 03:59:02,037
EFFICIENT DELIVERY TO

6182
03:59:02,037 --> 03:59:03,639
CD4 T-CELLS IN THIS MIXED

6183
03:59:03,639 --> 03:59:06,275
POPULATION TAKEN FROM SOMEONE

6184
03:59:06,275 --> 03:59:10,512
WITHOUT ACTIVATION.

6185
03:59:10,512 --> 03:59:12,181
FINALLY WE TOOK THIS INTO CELLS

6186
03:59:12,181 --> 03:59:13,682
FROM PEOPLE LIVING WITH HIV IN

6187
03:59:13,682 --> 03:59:14,983
WHICH WE TESTED THE ABILITY OF

6188
03:59:14,983 --> 03:59:17,286
THIS INTERVENTION TO REACTIVATE

6189
03:59:17,286 --> 03:59:18,420
BIOPROTEIN EXPRESSION.

6190
03:59:18,420 --> 03:59:19,421
IN THREE SUBJECTS, WE WERE ABLE

6191
03:59:19,421 --> 03:59:21,523
TO IDENTIFY P24 EXPRESSION IN

6192
03:59:21,523 --> 03:59:26,795
BOTH CELLULAR PELLET AND

6193
03:59:26,795 --> 03:59:27,830
SUPERNATENT AS SHOWN HERE,

6194
03:59:27,830 --> 03:59:30,332
COMPARED TO NO TREATMENT,

6195
03:59:30,332 --> 03:59:33,368
ANTICD -- TREATMENT, ANTICD4 TAT

6196
03:59:33,368 --> 03:59:36,205
MRNA LNP AND THEN A SHAM.

6197
03:59:36,205 --> 03:59:37,506
IN EACH CASE YOU WITH SEE

6198
03:59:37,506 --> 03:59:39,341
DETECTION OF P24 IN BOTH

6199
03:59:39,341 --> 03:59:42,211
COMPARTMENTS.

6200
03:59:42,211 --> 03:59:44,379
SO IN CONCLUSION, WE THINK THESE

6201
03:59:44,379 --> 03:59:45,481
DATA DEMONSTRATE THAT

6202
03:59:45,481 --> 03:59:46,849
TRANSCRIPTIONAL PROGRAMS

6203
03:59:46,849 --> 03:59:49,384
INCLUDING HIV-1 LATENCY CAN BE

6204
03:59:49,384 --> 03:59:51,019
PRECISELY MODIFIED USING MRNA

6205
03:59:51,019 --> 03:59:52,454
GENE THERAPY.

6206
03:59:52,454 --> 03:59:53,822
AND I THINK THIS PRINCIPLE CAN

6207
03:59:53,822 --> 03:59:56,125
BE APPLIED TO OTHER SYSTEMS,

6208
03:59:56,125 --> 03:59:58,227
INFECTIOUS OR OTHERWISE, BUT WE

6209
03:59:58,227 --> 04:00:00,162
SPECIFICALLY HAVE BEEN STUDYING

6210
04:00:00,162 --> 04:00:02,364
HIV, AND I THINK THAT

6211
04:00:02,364 --> 04:00:06,034
CD4 TARGETED TAT MRNA LNPs

6212
04:00:06,034 --> 04:00:08,337
OFFER SOME BENEFITS OVER OTHER

6213
04:00:08,337 --> 04:00:10,773
LATENCY APPROACHINGS.

6214
04:00:10,773 --> 04:00:12,407
FIRST THIS IS TRANSIENT, MRNA

6215
04:00:12,407 --> 04:00:13,675
WILL DEGRADE OVER TIME AND A YOU

6216
04:00:13,675 --> 04:00:17,479
WYOUWILL HAVE LOSS OF ECK PRETIF

6217
04:00:17,479 --> 04:00:18,347
THE GENE.

6218
04:00:18,347 --> 04:00:19,548
THIS IS A SELF-DIRECTED TYPE

6219
04:00:19,548 --> 04:00:20,749
METHOD IN WHICH WE CAN GET THE

6220
04:00:20,749 --> 04:00:21,950
CARGO TO THE TISSUES AND THE

6221
04:00:21,950 --> 04:00:23,585
CELLS WHERE IT NEEDS TO BE.

6222
04:00:23,585 --> 04:00:25,788
IN ADDITION, WE THINK WE'VE

6223
04:00:25,788 --> 04:00:27,289
DEVELOPED SOMETHING THAT'S

6224
04:00:27,289 --> 04:00:27,956
VIRUS-SPECIFIC.

6225
04:00:27,956 --> 04:00:29,992
AND THERE'S OPTIONS TO EXTEND

6226
04:00:29,992 --> 04:00:32,194
THIS APPROACH TO INCLUDE

6227
04:00:32,194 --> 04:00:33,729
HOST-SPECIFIC INTERVENTIONS.

6228
04:00:33,729 --> 04:00:35,030
HOWEVER, THIS WILL HOPEFULLY

6229
04:00:35,030 --> 04:00:38,634
ALLOW US TO DECREASE TOXICITY.

6230
04:00:38,634 --> 04:00:39,835
IN ADDITION, I DIDN'T HAVE TIME

6231
04:00:39,835 --> 04:00:44,506
TO SHOW YOU, WE WERE ABLE TO

6232
04:00:44,506 --> 04:00:45,374
DEMONSTRATE THAT MEMBRANE

6233
04:00:45,374 --> 04:00:46,909
PERMEATION OF THIS TAT VARIANT

6234
04:00:46,909 --> 04:00:51,847
WAS RETAINED.

6235
04:00:51,847 --> 04:00:53,148
AND THIS WAS INCREDIBLY POTENT.

6236
04:00:53,148 --> 04:00:54,883
I JUST REALIZED THIS, IS ONE

6237
04:00:54,883 --> 04:00:55,717
BEHIND EVERYTHING.

6238
04:00:55,717 --> 04:00:57,019
I APOLOGIZE IF MY ANIMATIONS

6239
04:00:57,019 --> 04:00:58,887
WERE OFF.

6240
04:00:58,887 --> 04:01:01,423
SO THIS IS A LARGE GROUP ERTMENT

6241
04:01:01,423 --> 04:01:05,561
EFFORT.I APOLOGIZE IF IT WAS DIT

6242
04:01:05,561 --> 04:01:06,228
TO TELL WHAT I WAS TALKING

6243
04:01:06,228 --> 04:01:07,462
ABOUT.

6244
04:01:07,462 --> 04:01:17,639
[APPLAUSE]

6245
04:01:26,348 --> 04:01:27,549
>> HI, EVERYONE.

6246
04:01:27,549 --> 04:01:28,217
GOOD AFTERNOON.

6247
04:01:28,217 --> 04:01:31,153
I'D LIKE TO THANK THE LEADERSHIP

6248
04:01:31,153 --> 04:01:32,921
FOR THIS INVITATION TO DISCUSS

6249
04:01:32,921 --> 04:01:35,090
THE COMMUNITY ENGAGEMENT GROUP

6250
04:01:35,090 --> 04:01:44,700
OR CEG MODEL.

6251
04:01:44,700 --> 04:01:47,102
WE'LL DISCUSS THE CAB, EXAMPLES

6252
04:01:47,102 --> 04:01:48,570
OF COMMUNITY ENGAGED PROJECTS

6253
04:01:48,570 --> 04:01:53,308
AND THE SOCIAL BEHAVIORAL ETHICS

6254
04:01:53,308 --> 04:01:55,177
WORKING GROUP.

6255
04:01:55,177 --> 04:01:56,845
THIS INTEGRATES BASIC AND

6256
04:01:56,845 --> 04:01:58,547
CLINICAL BIOMEDICAL SCIENTISTS,

6257
04:01:58,547 --> 04:02:00,649
THE CAB AND AN ESTABLISHED

6258
04:02:00,649 --> 04:02:01,950
COMMUNITY-BASED ORGANIZATION,

6259
04:02:01,950 --> 04:02:04,253
PHILADELPHIA FIGHT.

6260
04:02:04,253 --> 04:02:06,188
THE CEG ALSO INCLUDES A WORKING

6261
04:02:06,188 --> 04:02:07,623
GROUP WHICH HELPS INTEGRATE THE

6262
04:02:07,623 --> 04:02:08,490
VARIOUS ELEMENTS.

6263
04:02:08,490 --> 04:02:09,958
THE CAB FOCUSES ON PROVIDING

6264
04:02:09,958 --> 04:02:12,427
INPUT INTO THE RESEARCH PROCESS,

6265
04:02:12,427 --> 04:02:13,629
ACTS AS A SOUNDING BOARD AND

6266
04:02:13,629 --> 04:02:15,364
ALSO ENGAGES IN COMMUNITY

6267
04:02:15,364 --> 04:02:16,665
EDUCATION, AND MEMBERS CAN

6268
04:02:16,665 --> 04:02:18,433
PARTICIPATE IN DESIGNING SOCIAL

6269
04:02:18,433 --> 04:02:20,502
BEHAVIORAL RESEARCH PROJECTS.

6270
04:02:20,502 --> 04:02:21,904
PHILADELPHIA FIGHT PROVIDES THE

6271
04:02:21,904 --> 04:02:23,238
HISTORICAL PARTNERSHIP AND

6272
04:02:23,238 --> 04:02:24,406
KNOWLEDGE OF THE PATIENT

6273
04:02:24,406 --> 04:02:26,375
PARTICIPANT POPULATION, AND ALSO

6274
04:02:26,375 --> 04:02:28,577
PROVIDES EXPERTISE IN COMMUNITY

6275
04:02:28,577 --> 04:02:30,846
OUTREACH AND HELPS BRIDGE HIV

6276
04:02:30,846 --> 04:02:31,847
PREVENTION, TREATMENT AND CARE.

6277
04:02:31,847 --> 04:02:34,583
IT'S ALSO A CLINICAL RESEARCH

6278
04:02:34,583 --> 04:02:35,117
SITE.

6279
04:02:35,117 --> 04:02:36,618
SOME OF OUR OPERATING PRINCIPLES

6280
04:02:36,618 --> 04:02:38,720
ARE LISTED ON THIS SLIDE.

6281
04:02:38,720 --> 04:02:41,757
SINCE THE INCEPTION OF BEAT-HIV

6282
04:02:41,757 --> 04:02:43,926
COLLABORATORY IN 2016, THE CEG

6283
04:02:43,926 --> 04:02:46,762
HAS DOCUMENTED ITS LESSONS

6284
04:02:46,762 --> 04:02:47,863
LEARNED.

6285
04:02:47,863 --> 04:02:49,164
POTENTIAL STRENGTHS INCLUDE

6286
04:02:49,164 --> 04:02:50,032
SYNERGIES BETWEEN THE DIFFERENT

6287
04:02:50,032 --> 04:02:51,133
COMPONENTS, GREATER AWARENESS OF

6288
04:02:51,133 --> 04:02:52,467
HOW WE CAN WORK TOGETHER AND

6289
04:02:52,467 --> 04:02:53,502
HELPING OVERCOME THE

6290
04:02:53,502 --> 04:02:54,736
SHORTCOMINGS OF A TRADITIONAL

6291
04:02:54,736 --> 04:02:56,605
CAB SCIENTIST-ONLY MODEL.

6292
04:02:56,605 --> 04:02:58,240
CHALLENGES HAVE INCLUDED

6293
04:02:58,240 --> 04:02:59,541
DIFFERENTIAL TIME COMMITMENTS,

6294
04:02:59,541 --> 04:03:01,510
DETERMINING LEAD ARE SHIP FOR

6295
04:03:01,510 --> 04:03:03,345
PROJECTS, AND ENSURING COMMUNITY

6296
04:03:03,345 --> 04:03:04,379
RECOMMENDATIONS GET INTEGRATED

6297
04:03:04,379 --> 04:03:05,514
INTO ALL STAGES OF RESEARCH

6298
04:03:05,514 --> 04:03:05,847
DESIGNS.

6299
04:03:05,847 --> 04:03:08,717
AND THERE ARE WAYS TO EVALUATE

6300
04:03:08,717 --> 04:03:10,752
COMMUNITY ENGAGEMENT USING

6301
04:03:10,752 --> 04:03:12,387
REALIST FRAME WORKS.

6302
04:03:12,387 --> 04:03:14,056
THE BEAT-HIV CAB MEETS EVERY

6303
04:03:14,056 --> 04:03:15,457
MONTH AND THERE ARE ALSO

6304
04:03:15,457 --> 04:03:16,458
DIFFERENT COMMITTEES.

6305
04:03:16,458 --> 04:03:17,759
THE VISION AND MISSION STATEMENT

6306
04:03:17,759 --> 04:03:19,695
ARE LISTED HERE AND THEY'RE READ

6307
04:03:19,695 --> 04:03:21,563
AT THE START OF EVERY MEETING.

6308
04:03:21,563 --> 04:03:23,932
THIS SLIDE SHOWS CURRENT

6309
04:03:23,932 --> 04:03:26,134
BEAT-HIV CAB MEMBERS.

6310
04:03:26,134 --> 04:03:30,839
WILL CARTER IS THE CHAIR, OUR

6311
04:03:30,839 --> 04:03:34,743
COURAGEOUS AND HIGHLY EFFECTIVE

6312
04:03:34,743 --> 04:03:36,178
COORDINATOR, AND DAVE METZGER

6313
04:03:36,178 --> 04:03:44,586
ALSO PROVIDES LEADERSHIP FROM

6314
04:03:44,586 --> 04:03:45,854
U-PENN.

6315
04:03:45,854 --> 04:03:48,557
HOME BASED VIRAL LOAD

6316
04:03:48,557 --> 04:03:50,792
ACCEPTABILITY STUDY, A SURVEY OF

6317
04:03:50,792 --> 04:03:54,896
PEOPLE WITH HIV IN PHILADELPHIA

6318
04:03:54,896 --> 04:03:56,298
AND A PROVIDER SURVEY AND THAT

6319
04:03:56,298 --> 04:03:57,933
IS POSTER 50.

6320
04:03:57,933 --> 04:04:00,102
THERE'S ALSO AN ACTIVE SOCIAL

6321
04:04:00,102 --> 04:04:01,737
BEHAVIOR SCIENCES AND ETHICS

6322
04:04:01,737 --> 04:04:05,040
WORKING GROUP, GOALS TO

6323
04:04:05,040 --> 04:04:06,441
ASSESS -- GENERATE ETHICAL

6324
04:04:06,441 --> 04:04:07,542
CONSIDERATIONS, SET REALISTIC

6325
04:04:07,542 --> 04:04:09,845
EX-PIEXPECTATIONS, PROVIDE

6326
04:04:09,845 --> 04:04:10,812
INFORMATION TO COMMUNITIES OF

6327
04:04:10,812 --> 04:04:13,749
INTEREST AND ALSO SUPPORT THE

6328
04:04:13,749 --> 04:04:14,316
INCLUSIVE ENGAGEMENT OF

6329
04:04:14,316 --> 04:04:14,616
COMMUNITIES.

6330
04:04:14,616 --> 04:04:16,518
ONE OF THE RECENTLY COMPLETED

6331
04:04:16,518 --> 04:04:18,186
HIV SOCIAL BEHAVIORAL RESEARCH

6332
04:04:18,186 --> 04:04:19,855
PROJECT HAS BEEN A CAB-DRIVEN

6333
04:04:19,855 --> 04:04:23,025
PARTICIPANT EXPERIENCES STUDY AS

6334
04:04:23,025 --> 04:04:25,327
PART OF THE BEAT-HIV TRIAL IN

6335
04:04:25,327 --> 04:04:29,231
CONNECTION WITH THE U-PENN --

6336
04:04:29,231 --> 04:04:31,266
ONE IS CURRENTLY IN PRESS IN HIV

6337
04:04:31,266 --> 04:04:32,200
RESEARCH AND CLINICAL PRACTICE

6338
04:04:32,200 --> 04:04:34,803
AS SEPAR PART OF A SPECIAL ISSU.

6339
04:04:34,803 --> 04:04:36,338
ANOTHER PROJECT HAS BEEN THE CEG

6340
04:04:36,338 --> 04:04:37,672
DRIVEN ACCEPTABILITY STUDY OF A

6341
04:04:37,672 --> 04:04:40,275
HOME BASED DEVICE FOR TESTING

6342
04:04:40,275 --> 04:04:43,345
AND HIV CURE TRIALS WITH ATI.

6343
04:04:43,345 --> 04:04:44,546
THIS WAS ALSO IN COLLABORATION

6344
04:04:44,546 --> 04:04:46,581
WITH MEMBERS OF THE AIDS

6345
04:04:46,581 --> 04:04:48,016
TREATMENT ACTIVIST COALITION.

6346
04:04:48,016 --> 04:04:48,884
THERE'S A LOT OF INTEREST IN

6347
04:04:48,884 --> 04:04:51,920
THIS ACTIVITY TO HELP REDUCE

6348
04:04:51,920 --> 04:04:53,688
PARTICIPANT BURDEN DURING

6349
04:04:53,688 --> 04:04:53,889
ATIs.

6350
04:04:53,889 --> 04:04:55,757
IN THE LAST YEAR WE'VE CONTINUED

6351
04:04:55,757 --> 04:04:57,159
ADVOCACY ON THE TOPIC OF PARTNER

6352
04:04:57,159 --> 04:04:58,794
PROTECTIONS TO HELP REDUCE THE

6353
04:04:58,794 --> 04:05:01,329
RISK OF UNINVENTED HIV RISK

6354
04:05:01,329 --> 04:05:03,398
DURING TREATMENT INTERRUPTIONS.

6355
04:05:03,398 --> 04:05:04,699
THERE'S ALSO A POSTER AT THIS

6356
04:05:04,699 --> 04:05:05,567
MEETING, NUMBER 77.

6357
04:05:05,567 --> 04:05:06,768
TOGETHER WITH THE CAB, WE'VE

6358
04:05:06,768 --> 04:05:08,303
BEEN ADVOCATING FOR INCREASING

6359
04:05:08,303 --> 04:05:13,108
DIVERSITY BY SEX AND GENDER,

6360
04:05:13,108 --> 04:05:15,844
RACE/ETHNICITY.

6361
04:05:15,844 --> 04:05:18,180
DEVELOPMENTOF A CHAPTER ON WOMEN

6362
04:05:18,180 --> 04:05:19,481
AND CURE RESEARCH, AND WE'VE

6363
04:05:19,481 --> 04:05:20,882
ALSO RECENTLY PUBLISHED A

6364
04:05:20,882 --> 04:05:22,484
MANUSCRIPT ON INCREASING THE

6365
04:05:22,484 --> 04:05:23,819
MEANINGFUL INVOLVEMENT OF WOMEN

6366
04:05:23,819 --> 04:05:24,920
IN HIV CURE RESEARCH IN

6367
04:05:24,920 --> 04:05:26,354
COLLABORATION WITH OTHER CABs.

6368
04:05:26,354 --> 04:05:29,091
THESE HAVE INCLUDED DARE, RID

6369
04:05:29,091 --> 04:05:31,259
HIV, HOPE, AND ERASE HIV.

6370
04:05:31,259 --> 04:05:34,196
A NEW AREA OF RESEARCH HAS BEEN

6371
04:05:34,196 --> 04:05:35,297
UTILIZING -- TO HELP INFORM HOW

6372
04:05:35,297 --> 04:05:38,700
TO MOVE HIV CURE RELATED TRIALS

6373
04:05:38,700 --> 04:05:39,901
TO RESOURCE LIMITED PARTS OF THE

6374
04:05:39,901 --> 04:05:41,203
WORLD OR THE MAJORITY WORLD.

6375
04:05:41,203 --> 04:05:44,706
WE NOW HAVE COLLABORATION

6376
04:05:44,706 --> 04:05:47,409
WITH -- IN DURBIN, SOUTH AFRICA.

6377
04:05:47,409 --> 04:05:53,215
AND THE UNIVERSITY, AND WE ARE

6378
04:05:53,215 --> 04:05:54,449
INTEGRATING RESEARCH CONCEPTS

6379
04:05:54,449 --> 04:05:55,517
INTO TRIAL DESIGN.

6380
04:05:55,517 --> 04:05:57,886
AND WE NEED TO KEEP DEVELOPING

6381
04:05:57,886 --> 04:05:59,020
THE PSYCHOSOCIAL SUPPORT AND

6382
04:05:59,020 --> 04:06:00,322
RESEARCH INFRASTRUCTURE.

6383
04:06:00,322 --> 04:06:02,491
SO HERE IS OUR COMMUNITY SLIDE.

6384
04:06:02,491 --> 04:06:04,493
OUR KEY QUESTION IS, HOW CAN WE

6385
04:06:04,493 --> 04:06:07,529
MAKE HIV CURE SCIENCE MORE SIBL

6386
04:06:07,529 --> 04:06:09,664
AND ETHICAL TO COMMUNITIES OF

6387
04:06:09,664 --> 04:06:13,034
INTEREST TO FACILITATE EVENTUAL

6388
04:06:13,034 --> 04:06:13,768
UPTAKE?

6389
04:06:13,768 --> 04:06:15,637
IT HELPS BRIDGE BASIC AND

6390
04:06:15,637 --> 04:06:16,738
BIOMEDICAL RESEARCH WITH

6391
04:06:16,738 --> 04:06:17,839
COMMUNITY PRIORITIES.

6392
04:06:17,839 --> 04:06:20,775
WHAT'S BEING ACCOMPLISHED?

6393
04:06:20,775 --> 04:06:22,477
AND WHY IS THIS IMPORTANT?

6394
04:06:22,477 --> 04:06:23,745
AT THE END OF THE DAY WE NEED TO

6395
04:06:23,745 --> 04:06:26,114
MAKE SURE THAT ANY HIV CURE

6396
04:06:26,114 --> 04:06:27,215
STRATEGY THAT'S DEVELOPED IS

6397
04:06:27,215 --> 04:06:28,984
GOING TO BE MEANINGFUL TO PEOPLE

6398
04:06:28,984 --> 04:06:30,051
WITH HIV.

6399
04:06:30,051 --> 04:06:31,920
AND ONCE AGAIN, IT TAKES A

6400
04:06:31,920 --> 04:06:32,154
VILLAGE.

6401
04:06:32,154 --> 04:06:32,921
THANK YOU SO MUCH.

6402
04:06:32,921 --> 04:06:38,693
[APPLAUSE]

6403
04:06:38,693 --> 04:06:39,995
>> WONDERFUL, THANK YOU.

6404
04:06:39,995 --> 04:06:41,496
WE'D LIKE TO GO AHEAD AND TAKE

6405
04:06:41,496 --> 04:06:42,731
SOME QUESTIONS NOW, SO FEEL FREE

6406
04:06:42,731 --> 04:06:48,537
TO COME UP TO THE MICROPHONE.

6407
04:06:48,537 --> 04:06:53,308
WHILE WE'RE WAITING, I SAW SOME

6408
04:06:53,308 --> 04:06:56,278
OF THE DATA IN YOUR TRANSGENIC

6409
04:06:56,278 --> 04:06:58,013
MICE, YOUR TREATMENT ALSO SEEMED

6410
04:06:58,013 --> 04:07:00,515
TO REDUCE SOME OF THE DEFECTIVE

6411
04:07:00,515 --> 04:07:00,815
RESERVOIRS.

6412
04:07:00,815 --> 04:07:01,283
WAS THAT TRUE?

6413
04:07:01,283 --> 04:07:03,818
>> SORRY, CAN YOU REPEAT
THAT?

6414
04:07:03,818 --> 04:07:06,021
THE ECD 4-IG IN THE MICE, I

6415
04:07:06,021 --> 04:07:07,656
THINK I SAW ON SOME OF YOUR DATA

6416
04:07:07,656 --> 04:07:09,724
SLIDES THAT INTACT PRO VIRUS WAS

6417
04:07:09,724 --> 04:07:11,826
REDUCED BUT ALSO IT LOOKED LIKE

6418
04:07:11,826 --> 04:07:12,260
SOME OF THE --

6419
04:07:12,260 --> 04:07:15,864
>> YES, THE DEFECTIVE
ONES, WE

6420
04:07:15,864 --> 04:07:17,365
ALSO FIND THE REDUCTION AND THIS

6421
04:07:17,365 --> 04:07:20,235
ONE WE ALSO DISCUSSED WITH

6422
04:07:20,235 --> 04:07:22,537
UPON'S GROUP AND CURRENTLY WE

6423
04:07:22,537 --> 04:07:24,272
THINK THAT THE DEFECT ONES, THEY

6424
04:07:24,272 --> 04:07:28,577
ALSO MAY HAVE THE ENVELOPE

6425
04:07:28,577 --> 04:07:29,544
EXPRESSION ON CELL SURFACE.

6426
04:07:29,544 --> 04:07:30,545
>> THAT'S WHAT I WAS
CURIOUS

6427
04:07:30,545 --> 04:07:30,979
ABOUT.

6428
04:07:30,979 --> 04:07:31,279
OKAY.

6429
04:07:31,279 --> 04:07:31,613
INTERESTING.

6430
04:07:31,613 --> 04:07:32,380
GO AHEAD.

6431
04:07:32,380 --> 04:07:32,581
>> HI.

6432
04:07:32,581 --> 04:07:34,683
I HAVE A QUESTION FOR TED.

6433
04:07:34,683 --> 04:07:38,720
THE TAT LMP STUFF, THAT'S

6434
04:07:38,720 --> 04:07:39,688
TANTALIZING, FOR SPECIFICITY.

6435
04:07:39,688 --> 04:07:42,591
I COULDN'T SEE, DID YOU HAVE ANY

6436
04:07:42,591 --> 04:07:43,425
SORT OF POSITIVE CONTROL?

6437
04:07:43,425 --> 04:07:47,896
I MEAN, HOW MUCH OF THE LATENT

6438
04:07:47,896 --> 04:07:49,231
RESERVOIR WERE YOU REACTIVATING?

6439
04:07:49,231 --> 04:07:51,399
DO YOU HAVE A SORT OF CLUE, WERE

6440
04:07:51,399 --> 04:07:53,735
YOU GETTING 1%, 10%, 50%?

6441
04:07:53,735 --> 04:07:58,073
>> FIRST OFF I APOLOGIZE,
I DID

6442
04:07:58,073 --> 04:07:59,040
NOT REALIZE I USED THE WORD

6443
04:07:59,040 --> 04:08:01,142
SUBJECT AND I DID NOT MEAN TO.

6444
04:08:01,142 --> 04:08:02,344
I APOLOGIZE TO ALL MEMBERS OF

6445
04:08:02,344 --> 04:08:03,078
THE AUDIENCE.

6446
04:08:03,078 --> 04:08:05,814
I MEANT TO SAY PARTICIPANT.

6447
04:08:05,814 --> 04:08:08,683
AND I -- I APOLOGIZE.

6448
04:08:08,683 --> 04:08:10,218
TO GET AT YOUR QUESTION, SO WE

6449
04:08:10,218 --> 04:08:12,187
HAVE LOOKED AT VARIOUS IN VITRO

6450
04:08:12,187 --> 04:08:13,588
MODELS.

6451
04:08:13,588 --> 04:08:17,425
SO WE DO SEE POTENT REACTIVATION

6452
04:08:17,425 --> 04:08:21,463
IN TZMBM CELLS, JLAT CELLS, WE

6453
04:08:21,463 --> 04:08:25,066
CAN HIT ABOUT 90 TO 95% OF JLA

6454
04:08:25,066 --> 04:08:28,770
T-CELLS, WE NEVER HIT 100% USING

6455
04:08:28,770 --> 04:08:30,205
LNP TRANS FEX.

6456
04:08:30,205 --> 04:08:31,273
JLATS ARE NOT PARTICULARLY

6457
04:08:31,273 --> 04:08:31,539
COMPETENT.

6458
04:08:31,539 --> 04:08:32,607
BUT WERE YOU TALKING ABOUT A

6459
04:08:32,607 --> 04:08:33,108
DIFFERENT TYPE OF --

6460
04:08:33,108 --> 04:08:34,542
>> I THOUGHT YOU SHOWED
SOME

6461
04:08:34,542 --> 04:08:38,280
DATA MAYBE IN CELLS FROM PEOPLE

6462
04:08:38,280 --> 04:08:39,481
LIVING WITH HIV --

6463
04:08:39,481 --> 04:08:41,082
>> OH, I APOLOGIZE.

6464
04:08:41,082 --> 04:08:42,517
I MISUNDERSTOOD.

6465
04:08:42,517 --> 04:08:44,719
SO THOSE SUBJECTS DO HAVE

6466
04:08:44,719 --> 04:08:46,454
PARTICULARLY LARGE RESERVOIRS,

6467
04:08:46,454 --> 04:08:48,189
SO WE'RE IN THE PROCESS OF

6468
04:08:48,189 --> 04:08:49,090
QUANTIFYING ALL OF THE

6469
04:08:49,090 --> 04:08:51,059
RESERVOIRS IN ORDER TO DO A MORE

6470
04:08:51,059 --> 04:08:52,060
SYSTEMATIC ANALYSIS, BUT THEY

6471
04:08:52,060 --> 04:08:54,763
HAVE IPDA VALUES GREATER THAN

6472
04:08:54,763 --> 04:08:56,197
100 PER MILLION.

6473
04:08:56,197 --> 04:08:58,500
AND WE DO NOT HAVE THE EXACT

6474
04:08:58,500 --> 04:09:00,235
QUANTITATION OF WHAT PERCENT OF

6475
04:09:00,235 --> 04:09:02,103
CELLS REACTIVATED AMONG THOSE,

6476
04:09:02,103 --> 04:09:03,305
BECAUSE THESE ARE BULK

6477
04:09:03,305 --> 04:09:04,406
MEASUREMENTS.

6478
04:09:04,406 --> 04:09:05,607
SORRY ABOUT THAT.

6479
04:09:05,607 --> 04:09:06,708
SORRY I MISUNDERSTOOD THE

6480
04:09:06,708 --> 04:09:08,476
QUESTION.

6481
04:09:08,476 --> 04:09:08,877
>> HI.

6482
04:09:08,877 --> 04:09:10,211
I HAVE A QUESTION FOR THE

6483
04:09:10,211 --> 04:09:14,349
GENTLEMAN WHO PRESENTED THE ECD

6484
04:09:14,349 --> 04:09:15,216
4IG DATA.

6485
04:09:15,216 --> 04:09:16,551
THINK YOU SHOWED A PANEL WHERE

6486
04:09:16,551 --> 04:09:19,154
LEVELS WERE DECAYING AFTER EACH.

6487
04:09:19,154 --> 04:09:20,388
WHAT'S MEDIATING THAT DECAY?

6488
04:09:20,388 --> 04:09:23,224
ARE THE CELLS DYING, IS IT

6489
04:09:23,224 --> 04:09:24,893
SILENCING OF THE PLASMID?

6490
04:09:24,893 --> 04:09:30,432
>> SO THE ECD 4IG, THE

6491
04:09:30,432 --> 04:09:32,834
EXPRESSION LEVEL THEY DECAY,

6492
04:09:32,834 --> 04:09:33,034
RIGHT?

6493
04:09:33,034 --> 04:09:33,935
>> THAT'S WHAT I MEAN.

6494
04:09:33,935 --> 04:09:35,570
I THINK I SAW A PRESENTATION

6495
04:09:35,570 --> 04:09:37,639
WHERE THE LEVELS FROZE AND THEN

6496
04:09:37,639 --> 04:09:38,506
DECAYED OVER TIME.

6497
04:09:38,506 --> 04:09:41,209
>> THAT DECAY, BECAUSE THE

6498
04:09:41,209 --> 04:09:47,048
KINETICS I SHOW THE ELI IS A  IR

6499
04:09:47,048 --> 04:09:48,383
THE EXPRESSION, WE DID ANOTHER

6500
04:09:48,383 --> 04:09:50,985
BATCH OF THE ANIMAL AND THE --

6501
04:09:50,985 --> 04:09:52,187
TIME IS LONGER THAN WE HAVE IN

6502
04:09:52,187 --> 04:09:53,588
THE EXPERIMENT.

6503
04:09:53,588 --> 04:09:56,491
AND IN THE EXPERIMENT, WE GAVE

6504
04:09:56,491 --> 04:10:00,595
THE EC4IG TREATMENT EVERY TWO

6505
04:10:00,595 --> 04:10:02,797
WEEKS BUT IN THAT ELI IS A DATA,

6506
04:10:02,797 --> 04:10:04,432
WE HAVE THE ELONGATED AND WE

6507
04:10:04,432 --> 04:10:05,867
WANTED TO SEE HOW LONG IT CAN

6508
04:10:05,867 --> 04:10:09,471
LAST AND HOW BAD THE DECAY.

6509
04:10:09,471 --> 04:10:12,173
SO WE ELONGATED IN TURBO TIME.

6510
04:10:12,173 --> 04:10:12,607
>> RIGHT.

6511
04:10:12,607 --> 04:10:15,043
DO YOU HAVE ANY IDEA WHY IT'S

6512
04:10:15,043 --> 04:10:16,778
DECAYING?

6513
04:10:16,778 --> 04:10:18,413
ARE THE TRANSFECTED CELLS DYING

6514
04:10:18,413 --> 04:10:19,647
OR IS IT SOMETHING TO DO WITH

6515
04:10:19,647 --> 04:10:20,982
THE PLASMA BEING SILENCED?

6516
04:10:20,982 --> 04:10:24,753
>> BECAUSE WE DELIVER THE
ECD 4

6517
04:10:24,753 --> 04:10:28,923
IG NOT THROUGH THE AV, WE USE A

6518
04:10:28,923 --> 04:10:30,892
DNA DELIVERY, WE ONLY CAN HAVE

6519
04:10:30,892 --> 04:10:32,761
SEVERAL WEEKS OF THE EXPRESSION.

6520
04:10:32,761 --> 04:10:35,797
AND AFTER THAT, THAT EXPRESSION

6521
04:10:35,797 --> 04:10:36,698
IS LOWER AND LOWER.

6522
04:10:36,698 --> 04:10:38,133
>> THANK YOU.

6523
04:10:38,133 --> 04:10:38,967
>> MICHAEL?

6524
04:10:38,967 --> 04:10:39,467
>> HI.

6525
04:10:39,467 --> 04:10:40,335
MY NAME IS MICHAEL.

6526
04:10:40,335 --> 04:10:41,436
I'M WITH THE DARE CAB.

6527
04:10:41,436 --> 04:10:42,971
I HAVE A QUESTION, WE HAVE THIS

6528
04:10:42,971 --> 04:10:43,938
BASIC SCIENCE GOING ON AND WE

6529
04:10:43,938 --> 04:10:46,775
HAVE ALL THIS COMMUNITY-LED

6530
04:10:46,775 --> 04:10:48,743
SOCIAL SCIENCE WORK GOING ON.

6531
04:10:48,743 --> 04:10:50,378
WHAT'S THE ADVANTAGE OF HAVING

6532
04:10:50,378 --> 04:10:51,813
THESE TWO THINGS TOGETHER?

6533
04:10:51,813 --> 04:10:53,348
COULD YOU EACH THINK OF TELLING

6534
04:10:53,348 --> 04:10:55,417
ME LIKE HOW DOES THE SOCIAL

6535
04:10:55,417 --> 04:10:57,652
SCIENCE WORK HELP YOUR

6536
04:10:57,652 --> 04:10:59,254
INDIVIDUAL RFs DO WHAT THEY

6537
04:10:59,254 --> 04:11:00,989
WANT TO DO AND HOW -- I KNOW HOW

6538
04:11:00,989 --> 04:11:02,857
YOU GUYS ARE PROBABLY HELPING

6539
04:11:02,857 --> 04:11:03,525
COMMUNITY SCIENCE.

6540
04:11:03,525 --> 04:11:04,826
I'M JUST WONDERING HOW IT WORKS

6541
04:11:04,826 --> 04:11:06,661
TOGETHER AND WHAT VALUE YOU FEEL

6542
04:11:06,661 --> 04:11:10,432
YOU'RE GETTING FROM HAVING

6543
04:11:10,432 --> 04:11:11,399
COMMUNITY-LED SCIENCE ALONG WITH

6544
04:11:11,399 --> 04:11:12,400
YOUR BASIC SCIENCE THAT YOU'RE

6545
04:11:12,400 --> 04:11:12,867
GOING THROUGH.

6546
04:11:12,867 --> 04:11:14,235
>> THANK YOU.

6547
04:11:14,235 --> 04:11:17,338
SO I THINK IT'S REALLY

6548
04:11:17,338 --> 04:11:18,339
COMPLEMENTARY BECAUSE LIKE FOR

6549
04:11:18,339 --> 04:11:21,843
EXAMPLE, WHEN WE WERE DEFINING

6550
04:11:21,843 --> 04:11:23,378
OUR CLINICAL TRIAL DESIGNS, WE

6551
04:11:23,378 --> 04:11:25,547
NEVER REALLY TOOK INTO ACCOUNT

6552
04:11:25,547 --> 04:11:28,283
THE STRESS ASSOCIATED WITH THE

6553
04:11:28,283 --> 04:11:30,919
REBOUND IN TRYING TO ACTUALLY

6554
04:11:30,919 --> 04:11:32,353
INTENTIONALLY TARGET THAT PERIOD

6555
04:11:32,353 --> 04:11:34,522
FOR SUPPORT OF PARTICIPANTS.

6556
04:11:34,522 --> 04:11:35,623
DURING THE SOCIAL SCIENCE

6557
04:11:35,623 --> 04:11:37,926
EVALUATION OF WHAT WAS THE

6558
04:11:37,926 --> 04:11:39,027
EXPERIENCE OF INDIVIDUALS IN THE

6559
04:11:39,027 --> 04:11:40,228
TRIAL, WE LEARNED THAT PERIOD

6560
04:11:40,228 --> 04:11:42,030
WAS ACTUALLY QUITE A STRESSFUL

6561
04:11:42,030 --> 04:11:42,397
PERIOD.

6562
04:11:42,397 --> 04:11:43,598
BUT YET WE DIDN'T KNOW THAT WHEN

6563
04:11:43,598 --> 04:11:45,700
WE WERE DESIGNING AT THE

6564
04:11:45,700 --> 04:11:46,134
BEGINNING.

6565
04:11:46,134 --> 04:11:48,303
THE SAME THING FOR THE

6566
04:11:48,303 --> 04:11:49,504
PARTICIPANT STUDIES ABOUT HOME

6567
04:11:49,504 --> 04:11:49,938
DEVICES.

6568
04:11:49,938 --> 04:11:52,040
WE DID NOT KNOW EXACTLY TO WHAT

6569
04:11:52,040 --> 04:11:53,441
EXTENT THAT WOULD BE ACCEPTED IN

6570
04:11:53,441 --> 04:11:54,242
THE COMMUNITY, SHOULD WE

6571
04:11:54,242 --> 04:11:56,077
ACTUALLY DEVELOP THIS WITH A

6572
04:11:56,077 --> 04:11:57,278
COMMERCIAL PARTNER LIKE MERCK

6573
04:11:57,278 --> 04:11:58,780
THAT HAS BEEN REALLY SUPPORTIVE,

6574
04:11:58,780 --> 04:12:00,582
AND WE DID THREE DIFFERENT

6575
04:12:00,582 --> 04:12:01,983
STUDIES ON A NATIONAL SURVEY, ON

6576
04:12:01,983 --> 04:12:04,419
A LOCAL SURVEY, AND IN A WORKING

6577
04:12:04,419 --> 04:12:05,053
GROUP TO DETERMINE IS THIS

6578
04:12:05,053 --> 04:12:06,721
SOMETHING THAT WE SHOULD INVEST

6579
04:12:06,721 --> 04:12:08,256
IN FOR DEVELOPMENT.

6580
04:12:08,256 --> 04:12:09,958
AND ALL OF THOSE STUDIES SHOWED

6581
04:12:09,958 --> 04:12:10,825
THAT THERE WAS AN INCREDIBLE

6582
04:12:10,825 --> 04:12:13,161
AMOUNT OF INTEREST AND HOW TO

6583
04:12:13,161 --> 04:12:14,562
COMMUNICATE FOR PEOPLE TO

6584
04:12:14,562 --> 04:12:15,663
ACTUALLY ENGAGE IN THESE TYPES

6585
04:12:15,663 --> 04:12:16,431
OF STRATEGIES.

6586
04:12:16,431 --> 04:12:18,266
SO I THINK THAT WE CAN TALK

6587
04:12:18,266 --> 04:12:19,701
ABOUT THE SCIENCE BUT IF THERE'S

6588
04:12:19,701 --> 04:12:21,336
NOT ACCEPTABILITY, IF THERE'S

6589
04:12:21,336 --> 04:12:23,771
NOT UNDERSTANDING AND WE DON'T

6590
04:12:23,771 --> 04:12:25,106
KNOW THE DYNAMICS OF HOW THIS IS

6591
04:12:25,106 --> 04:12:26,741
GOING TO IMPACT THE LIFE OF

6592
04:12:26,741 --> 04:12:28,810
SOMEBODY LIVING WITH HIV, I

6593
04:12:28,810 --> 04:12:30,678
THINK THAT WE WOULD BE

6594
04:12:30,678 --> 04:12:30,979
UNINFORMED.

6595
04:12:30,979 --> 04:12:33,948
SO I THINK THE SOCIAL SCIENCE

6596
04:12:33,948 --> 04:12:35,717
STUDIES REALLY COMPLEMENT THE

6597
04:12:35,717 --> 04:12:39,120
BASIC RESEARCH AGENDA.

6598
04:12:39,120 --> 04:12:44,492
[APPLAUSE]

6599
04:12:44,492 --> 04:12:45,126
>> HELLO.

6600
04:12:45,126 --> 04:12:48,263
I HAVE A QUESTION FOR TED ABOUT

6601
04:12:48,263 --> 04:12:52,333
THE TARGETING OF THE LMPs.

6602
04:12:52,333 --> 04:12:54,202
IN VITRO, YOU CAN GET THEM TO GO

6603
04:12:54,202 --> 04:12:57,138
TO A CD4 T-CELL RATHER THAN A

6604
04:12:57,138 --> 04:12:58,473
HEMATOPOIETIC STEM CELL, BUT IN

6605
04:12:58,473 --> 04:12:59,774
VIVO, IN AN ACTUAL BODY, IF

6606
04:12:59,774 --> 04:13:01,175
YOU'RE GOING TO DEPLOY THESE

6607
04:13:01,175 --> 04:13:02,277
THINGS INTO THE BLOODSTREAM, HOW

6608
04:13:02,277 --> 04:13:03,311
ARE YOU GOING TO MAKE SURE IT

6609
04:13:03,311 --> 04:13:05,480
ALSO GETS TO THE TISSUE RESIDENT

6610
04:13:05,480 --> 04:13:05,914
T-CELLS?

6611
04:13:05,914 --> 04:13:06,814
LIKE WHAT WOULD YOUR SUCCESS

6612
04:13:06,814 --> 04:13:09,417
RATE BE TO GETTING COVERAGE OF

6613
04:13:09,417 --> 04:13:10,418
INFECTED CELLS?

6614
04:13:10,418 --> 04:13:12,921
>> IT'S A FANTASTIC
QUESTION.

6615
04:13:12,921 --> 04:13:15,757
SO THIS HAS BEEN BEST WORKED OUT

6616
04:13:15,757 --> 04:13:18,393
IN MURINE MODELS, SO

6617
04:13:18,393 --> 04:13:20,161
CD4 DELIVERY IN MURINE MODELS

6618
04:13:20,161 --> 04:13:21,563
ACTUALLY DOES DELIVER TO

6619
04:13:21,563 --> 04:13:23,231
RESIDENT CD4s IN TISSUES, BUT

6620
04:13:23,231 --> 04:13:24,999
IT IS NOT 100%.

6621
04:13:24,999 --> 04:13:26,968
SO THAT IS AN ISSUE THAT WE ARE

6622
04:13:26,968 --> 04:13:30,338
GOING TO HAVE TO OVERCOME FOR

6623
04:13:30,338 --> 04:13:31,673
INTERVENTIONS THAT REQUIRE 100%

6624
04:13:31,673 --> 04:13:34,075
DELIVERY TO EVERY SINGLE CELL.

6625
04:13:34,075 --> 04:13:34,943
ONE OF THE THINGS THAT I DIDN'T

6626
04:13:34,943 --> 04:13:36,277
HAVE TIME TO GO INTO IS I THINK

6627
04:13:36,277 --> 04:13:38,146
THAT THIS INTERVENTION, BECAUSE

6628
04:13:38,146 --> 04:13:41,349
TAT IS ABLE TO SECRETE AND GO

6629
04:13:41,349 --> 04:13:42,650
INTO NEIGHBORING CELLS, YOU

6630
04:13:42,650 --> 04:13:45,820
DON'T HAVE TO HIT 100%, SO AS

6631
04:13:45,820 --> 04:13:47,021
LONG AS YOU'RE GETTING TO ALL OF

6632
04:13:47,021 --> 04:13:48,122
THE ANATOMIC LOCATIONS THAT YOU

6633
04:13:48,122 --> 04:13:52,293
NEED TO, YOU MAY BE ABLE TO HAVE

6634
04:13:52,293 --> 04:13:53,061
TAT 50 ELSEWHERE.

6635
04:13:53,061 --> 04:13:55,797
AND OTHERS HAVE ASKED ME ABOUT

6636
04:13:55,797 --> 04:13:57,765
IS IT ONLY CD4 T-CELLS?

6637
04:13:57,765 --> 04:13:59,968
NO, IT WILL NOT BE ONLY

6638
04:13:59,968 --> 04:14:01,169
CD4 T-CELLS BUT I AGAIN VIEW

6639
04:14:01,169 --> 04:14:02,136
THAT AS A POSSIBLE BENEFIT

6640
04:14:02,136 --> 04:14:03,905
BECAUSE THEY COULD BE PRODUCER

6641
04:14:03,905 --> 04:14:06,307
CELLS WITHIN WHATEVER TISSUES

6642
04:14:06,307 --> 04:14:07,742
THEY RESIDE AND GIVE OUT.

6643
04:14:07,742 --> 04:14:09,611
SO IT IS A HURDLE FOR THE

6644
04:14:09,611 --> 04:14:12,380
DELIVERY SYSTEM.

6645
04:14:12,380 --> 04:14:13,448
BUT THANKFULLY FOR THIS

6646
04:14:13,448 --> 04:14:14,315
APPLICATION, I DON'T THINK IT

6647
04:14:14,315 --> 04:14:16,284
WILL BE AS LARGE OF A HURDLE,

6648
04:14:16,284 --> 04:14:18,486
BUT AN IMPORTANT ONE.

6649
04:14:18,486 --> 04:14:19,621
>> THAT'S REALLY EXCITING.

6650
04:14:19,621 --> 04:14:19,988
THANK YOU.

6651
04:14:19,988 --> 04:14:21,322
>> WE'LL TAKE THE LAST
QUESTION

6652
04:14:21,322 --> 04:14:24,425
FROM CHRIS AND THEN THE BREAK.

6653
04:14:24,425 --> 04:14:25,827
>> FOLLOWING UP ON THAT

6654
04:14:25,827 --> 04:14:27,028
QUESTION, HAVE YOU LOOKED AT

6655
04:14:27,028 --> 04:14:28,796
OTHER DELIVERY METHODS FOR

6656
04:14:28,796 --> 04:14:30,565
TISSUE, LIKE INTRAMURAL,

6657
04:14:30,565 --> 04:14:33,401
INTRANODAL OR OTHER WAYS TO GET

6658
04:14:33,401 --> 04:14:35,269
YOUR LNPs INTO --

6659
04:14:35,269 --> 04:14:36,237
>> OTHER SITES OF
INJECTION?

6660
04:14:36,237 --> 04:14:36,571
>> YEAH.

6661
04:14:36,571 --> 04:14:37,805
>> I HAVE NOT PERSONALLY.

6662
04:14:37,805 --> 04:14:40,308
I CAN SAY MANY PEOPLE HAVE.

6663
04:14:40,308 --> 04:14:43,711
PEOPLE HAVE INJECTED LNPs INTO

6664
04:14:43,711 --> 04:14:44,712
THE BONE MARROW, PEOPLE HAVE

6665
04:14:44,712 --> 04:14:46,347
DONE A LOT OF THINGS.

6666
04:14:46,347 --> 04:14:48,516
SO I'M NOT AWARE OF EVERYTHING

6667
04:14:48,516 --> 04:14:48,983
OUT THERE.

6668
04:14:48,983 --> 04:14:50,952
I THINK GETTING INTO LYMPHOID

6669
04:14:50,952 --> 04:14:53,454
TISH SUE IS PARTICULARLY HARD

6670
04:14:53,454 --> 04:14:54,355
BECAUSE LYMPHOID TISSUE IS

6671
04:14:54,355 --> 04:14:55,690
THROUGHOUT THE BODY, SO THERE

6672
04:14:55,690 --> 04:14:57,425
WON'T BE AN ANATOMIC LOCATION

6673
04:14:57,425 --> 04:15:00,695
THAT I CAN THINK OF ON THE SPOT

6674
04:15:00,695 --> 04:15:02,130
THAT WOULD BE GOOD FOR THAT.

6675
04:15:02,130 --> 04:15:05,199
BUT YES, FOR OTHER APPROACHES,

6676
04:15:05,199 --> 04:15:07,935
PEOPLE HAVE DONE DIRECT

6677
04:15:07,935 --> 04:15:09,470
ANATOMIC, DELIVER THE LNPs

6678
04:15:09,470 --> 04:15:10,104
RIGHT TO THE SITE.

6679
04:15:10,104 --> 04:15:15,067
THANK YOU.

6680
04:15:15,067 --> 04:15:16,268
I'M DIANE LAWRENCE, WELCOME

6681
04:15:16,268 --> 04:15:20,739
AGAIN, AND I'M HERE TO INTRODUCE

6682
04:15:20,739 --> 04:15:21,740
THE DARE COLLABORATORY.

6683
04:15:21,740 --> 04:15:24,009
THIS IS THE THIRD ITERATION OF

6684
04:15:24,009 --> 04:15:28,046
THE DARE GROUP, AND ONE JUST

6685
04:15:28,046 --> 04:15:29,381
REALLY QUICK ANNOUNCEMENT FOR

6686
04:15:29,381 --> 04:15:32,351
THOSE WATCHING ONLINE, THERE IS

6687
04:15:32,351 --> 04:15:34,086
A SEND LIVE FEEDBACK BUTTON AT

6688
04:15:34,086 --> 04:15:36,255
THE BOTTOM, SO IF YOU HAVE ANY

6689
04:15:36,255 --> 04:15:37,289
QUESTIONS, THAT WILL GET TO US

6690
04:15:37,289 --> 04:15:39,558
AND WE CAN SHARE YOUR QUESTIONS

6691
04:15:39,558 --> 04:15:40,993
LIVE HERE IN THE ROOM.

6692
04:15:40,993 --> 04:15:43,395
SO FEEL FREE TO DO THAT.

6693
04:15:43,395 --> 04:15:44,029
GREAT.

6694
04:15:44,029 --> 04:15:50,068
SO I'M HAPPY TO INTRODUCE THE

6695
04:15:50,068 --> 04:15:50,802
DARE COLLABORATORY.

6696
04:15:50,802 --> 04:15:53,005
FIRST STARTING US OFF IS ONE OF

6697
04:15:53,005 --> 04:15:57,376
THE PRINCIPAL INVESTIGATORS, DR.

6698
04:15:57,376 --> 04:15:59,811
STEVE?

6699
04:15:59,811 --> 04:16:03,315
>> THANK YOU, DIANE.

6700
04:16:03,315 --> 04:16:04,950
SO ON BEHALF OF THE DARE

6701
04:16:04,950 --> 04:16:06,251
COLLABORATORY, I WAS GOING TO DO

6702
04:16:06,251 --> 04:16:08,020
JUST A VERY BRIEF INTRODUCTION

6703
04:16:08,020 --> 04:16:10,188
AS TO WHO WE ARE, AND THEN WE

6704
04:16:10,188 --> 04:16:11,723
CAN JUMP INTO THE SCIENTIFIC

6705
04:16:11,723 --> 04:16:12,924
PRESENTATIONS.

6706
04:16:12,924 --> 04:16:14,760
AS DIANE SAID, THIS IS OUR THIRD

6707
04:16:14,760 --> 04:16:15,427
TIME AROUND.

6708
04:16:15,427 --> 04:16:20,032
SINCE DAY ONE, THE GROUP, WHICH

6709
04:16:20,032 --> 04:16:21,566
HAS SORT OF EVOLVED IN TERMS OF

6710
04:16:21,566 --> 04:16:23,302
ITS MEMBERSHIP, HAS ALWAYS

6711
04:16:23,302 --> 04:16:25,604
REALLY BEEN FOCUSED ON

6712
04:16:25,604 --> 04:16:27,906
DEVELOPING IMMUNOTHERAPIES

6713
04:16:27,906 --> 04:16:30,409
ESSENTIALLY LARGELY TO CONTROL

6714
04:16:30,409 --> 04:16:32,411
SIV AND HIV IN THE ABSENCE OF

6715
04:16:32,411 --> 04:16:33,912
THERAPY, AND THIS TIME AROUND

6716
04:16:33,912 --> 04:16:35,447
WE'RE ALSO MAKING AN INVESTMENT

6717
04:16:35,447 --> 04:16:36,782
IN HOW WE CAN MODIFY THE IMMUNE

6718
04:16:36,782 --> 04:16:39,184
RESPONSE TO CLEAR THE RESERVOIR.

6719
04:16:39,184 --> 04:16:40,819
SO WE'RE PRIMARILY CLINICIANS

6720
04:16:40,819 --> 04:16:41,820
AND IMMUNOLOGISTS BUT KE

6721
04:16:41,820 --> 04:16:43,455
CERTAINLY HAVE OUR FOCUS ON THE

6722
04:16:43,455 --> 04:16:46,291
VIROLOGY AS WELL.

6723
04:16:46,291 --> 04:16:49,695
THERE ARE THREE RFs, BUT THE

6724
04:16:49,695 --> 04:16:51,330
FIRST, THE BASIC SCIENCE ONE, WE

6725
04:16:51,330 --> 04:16:53,832
HAVE BASICALLY TWO GROUPS.

6726
04:16:53,832 --> 04:16:57,369
WE HAVE FOCUSING ON THE ACTIVE

6727
04:16:57,369 --> 04:16:58,337
RESERVOIR, THOSE CELLS THAT ARE

6728
04:16:58,337 --> 04:17:01,940
ACTUALLY PRODUCING RNA AND

6729
04:17:01,940 --> 04:17:03,175
PROTEINS, AND WHILE WE'RE DOING

6730
04:17:03,175 --> 04:17:05,811
THIS, HOW BIG IS IT, WHAT'S THE

6731
04:17:05,811 --> 04:17:07,112
MECHANISM OF IT, WHAT'S THE

6732
04:17:07,112 --> 04:17:09,514
CONSEQUENCES OF IT, THE

6733
04:17:09,514 --> 04:17:11,616
IMPLICATIONS FOR CLONAL PRO LIVE

6734
04:17:11,616 --> 04:17:12,250
PROLIFERATION, THAT KIND OF

6735
04:17:12,250 --> 04:17:14,453
THING, AND WE HAVE A SECOND DI

6736
04:17:14,453 --> 04:17:15,787
VIEWS AND VERY LARGE GROUP

6737
04:17:15,787 --> 04:17:19,157
LOOKING AT MECHANISMS OF IN

6738
04:17:19,157 --> 04:17:21,059
PEOPLE OF POST TREATMENT

6739
04:17:21,059 --> 04:17:22,127
CONTROL, POST INTERVENTION

6740
04:17:22,127 --> 04:17:23,895
CONTROL LARGELY USING SAMPLES

6741
04:17:23,895 --> 04:17:24,663
FROM CLINICAL TRIALS AND

6742
04:17:24,663 --> 04:17:25,530
CLINICAL COHORTS.

6743
04:17:25,530 --> 04:17:29,801
AND WE'LL HEAR FROM MAURO GARCIA

6744
04:17:29,801 --> 04:17:31,136
ON SOME OF THE EARLY DATA COMING

6745
04:17:31,136 --> 04:17:33,739
OUT FROM THAT PARTICULAR WORKING

6746
04:17:33,739 --> 04:17:34,740
GROUP.

6747
04:17:34,740 --> 04:17:36,475
RF 2 IS LEVERAGING THE NON-HUMAN

6748
04:17:36,475 --> 04:17:38,343
PRIMATE MODEL TO DEVELOP NEW

6749
04:17:38,343 --> 04:17:40,078
IMMUNOTHERAPIES TO CONTROL SIV

6750
04:17:40,078 --> 04:17:43,715
IN THE ABSENCE OF ART.

6751
04:17:43,715 --> 04:17:46,118
AND RF THREE, SORT OF A NEW

6752
04:17:46,118 --> 04:17:49,187
INITIATIVE FOR US, LED BY SHARON

6753
04:17:49,187 --> 04:17:52,391
AND FOCUSING ON AGAIN SORT OF

6754
04:17:52,391 --> 04:17:53,925
MODIFYING INTERCELLULAR PATHWAYS

6755
04:17:53,925 --> 04:17:55,527
TO ELIMINATE THE RESERVOIR

6756
04:17:55,527 --> 04:17:56,695
PARTICULARLY THOSE THAT ARE

6757
04:17:56,695 --> 04:18:01,066
FOCUSED ON CELL SURVIVAL.

6758
04:18:01,066 --> 04:18:02,601
SO RATHER THAN GOING INTO OUR

6759
04:18:02,601 --> 04:18:04,903
GREATEST HITS, I'D RATHER TAKE

6760
04:18:04,903 --> 04:18:06,204
THE NEXT COUPLE MINUTES AND

6761
04:18:06,204 --> 04:18:07,205
DESCRIBE HOW WE COLLABORATE.

6762
04:18:07,205 --> 04:18:10,175
I THINK WE REALLY ARE A SOLID

6763
04:18:10,175 --> 04:18:12,043
GROUP OF INVESTIGATORS BEEN

6764
04:18:12,043 --> 04:18:14,446
WORKING TOGETHER FOR A WHILE WHO

6765
04:18:14,446 --> 04:18:15,514
COLLABORATE NATURALLY ON VARIOUS

6766
04:18:15,514 --> 04:18:16,281
DIFFERENT PROGRAMS.

6767
04:18:16,281 --> 04:18:17,416
THERE ARE JUST THREE SORT OF

6768
04:18:17,416 --> 04:18:19,684
STORY LINES THAT I WANT TO

6769
04:18:19,684 --> 04:18:21,453
MENTION.

6770
04:18:21,453 --> 04:18:23,321
 THAT GO ACROSS THE RFs

6771
04:18:23,321 --> 04:18:24,756
THAT INVOLVE MULTIPLE

6772
04:18:24,756 --> 04:18:25,290
INSTITUTIONS, MULTIPLE

6773
04:18:25,290 --> 04:18:25,624
INVESTIGATORS.

6774
04:18:25,624 --> 04:18:28,260
FOR EXAMPLE, AS I SAID, WE HAVE

6775
04:18:28,260 --> 04:18:31,530
THIS VERY INTENSE GROUP OF

6776
04:18:31,530 --> 04:18:32,431
VIROLOGISTS, IMMUNOLOGISTS

6777
04:18:32,431 --> 04:18:34,933
LOOKING AT THE ACTIVE RESERVOIR.

6778
04:18:34,933 --> 04:18:37,235
AND WE'RE DOING THIS IN PART

6779
04:18:37,235 --> 04:18:39,004
BECAUSE THE IMMUNOTHERAPIES THAT

6780
04:18:39,004 --> 04:18:44,910
ARE BEING DEVELOPED BY THE OTHER

6781
04:18:44,910 --> 04:18:51,016
RFs ACTUALLY TARGET BASICALLY

6782
04:18:51,016 --> 04:18:53,552
THE RESERVOIR, CELLS THAT MAKE

6783
04:18:53,552 --> 04:18:59,257
PROTEIN, SOME OF THE WORK THAT

6784
04:18:59,257 --> 04:19:00,225
LOUIS WILL DISCUSS AND THIS

6785
04:19:00,225 --> 04:19:02,761
LARGE GROUP OF INVESTIGATORS,

6786
04:19:02,761 --> 04:19:03,628
PATHWAYS ASSOCIATED WITH CELL

6787
04:19:03,628 --> 04:19:05,297
DEATH GENERALLY REQUIRE THAT THE

6788
04:19:05,297 --> 04:19:05,931
RESERVOIR BE ACTIVE.

6789
04:19:05,931 --> 04:19:07,466
SO THERE'S A LOT OF CROSSTALK

6790
04:19:07,466 --> 04:19:08,900
BETWEEN THESE GROUPS IN TERMS OF

6791
04:19:08,900 --> 04:19:11,970
THESE DIFFERENT PATHWAYS, AND WE

6792
04:19:11,970 --> 04:19:13,405
MOVE FROM SORT OF THE BASIC

6793
04:19:13,405 --> 04:19:15,707
BIOLOGY TO THE MORE

6794
04:19:15,707 --> 04:19:17,976
TRANSLATIONAL WORK INTO ANIMALS

6795
04:19:17,976 --> 04:19:19,878
AND OF COURSE OUR ULTIMATE GOAL

6796
04:19:19,878 --> 04:19:21,513
AND WE'VE BEEN QUITE SUCCESSFUL

6797
04:19:21,513 --> 04:19:22,380
IN DOING THIS IS MOVING THIS

6798
04:19:22,380 --> 04:19:24,916
INTO THE CLINICAL ARENA, AND WE

6799
04:19:24,916 --> 04:19:28,854
ACTUALLY HAVE AN ONGOING STUDY

6800
04:19:28,854 --> 04:19:31,656
ON THE BCL2 INHIBITOR BASED ON

6801
04:19:31,656 --> 04:19:32,924
THIS WORK.

6802
04:19:32,924 --> 04:19:34,125
WE'RE ALSO INTERESTED IN POST

6803
04:19:34,125 --> 04:19:35,861
TREATMENT CONTROL AND

6804
04:19:35,861 --> 04:19:37,028
INCREASINGLY POST INTERVENTIONAL

6805
04:19:37,028 --> 04:19:38,196
CONTROL IN THE AREA OF CLINICAL

6806
04:19:38,196 --> 04:19:42,701
MEDICINE, KIND OF GLOBALLY THERE

6807
04:19:42,701 --> 04:19:44,636
ARE POPPING UP ALL OVER THE

6808
04:19:44,636 --> 04:19:46,938
PLACE THESE INDIVIDUALS

6809
04:19:46,938 --> 04:19:47,939
CONTROLLING HIV AS A CONSEQUENCE

6810
04:19:47,939 --> 04:19:50,008
OF AN INTERVENTION, USUALLY

6811
04:19:50,008 --> 04:19:52,110
BROADLY NEWT LICED ANTIBO DEAS,

6812
04:19:52,110 --> 04:19:54,379
VACCINES, SO WE'RE ASSEMBLING

6813
04:19:54,379 --> 04:19:57,249
THESE CASES, THE STUDY POST

6814
04:19:57,249 --> 04:19:58,250
INTERVENTIONAL CONTROL IN

6815
04:19:58,250 --> 04:20:01,186
PEOPLE, WE'RE DOING A VARIETY OF

6816
04:20:01,186 --> 04:20:02,621
DIFFERENT INTERVENTIONS IN THE

6817
04:20:02,621 --> 04:20:04,256
MONKEY MODEL.

6818
04:20:04,256 --> 04:20:05,824
AS I SAID, WE'RE LOOKING AT

6819
04:20:05,824 --> 04:20:06,925
THESE POST INTERVENTIONAL

6820
04:20:06,925 --> 04:20:07,893
CONTROLS FROM THE CLINICAL

6821
04:20:07,893 --> 04:20:09,861
TRIALS, FROM THE COHORTS,

6822
04:20:09,861 --> 04:20:10,962
COLLECTING THESE SAMPLES, AND

6823
04:20:10,962 --> 04:20:11,963
USING THIS COMBINED KNOWLEDGE TO

6824
04:20:11,963 --> 04:20:15,367
DO THE NEXT GENERATION OF

6825
04:20:15,367 --> 04:20:15,834
IMMUNOTHERAPIES.

6826
04:20:15,834 --> 04:20:17,002
THIS TIME AROUND, WE'RE VERY

6827
04:20:17,002 --> 04:20:19,004
INTERESTED IN THE CONCEPT OF THE

6828
04:20:19,004 --> 04:20:19,304
INTERCEPT.

6829
04:20:19,304 --> 04:20:24,242
THIS IS WHAT'S HAPPENING IN THE

6830
04:20:24,242 --> 04:20:27,846
RESERVOIR POST ART, PREREBOUND.

6831
04:20:27,846 --> 04:20:30,815
BASED ON WORK FROM LYDDIE

6832
04:20:30,815 --> 04:20:31,950
TRAWTMAN, MAJOR INVESTIGATOR IN

6833
04:20:31,950 --> 04:20:35,520
THE GROUP, SHE HAD A PUBLICATION

6834
04:20:35,520 --> 04:20:37,489
THAT WILL FORM THE BASE I OF A

6835
04:20:37,489 --> 04:20:39,291
LOT OF WHAT WE'RE DOING IN DARE.

6836
04:20:39,291 --> 04:20:40,458
WHEN WE'RE PUTTING THE GRANT

6837
04:20:40,458 --> 04:20:44,996
TOGETHER WHERE SHE OBSERVED THAT

6838
04:20:44,996 --> 04:20:47,666
THE ANTIGEN CELL, DENDRITIC

6839
04:20:47,666 --> 04:20:48,533
RESPONSE TO THE VIRUS DURING

6840
04:20:48,533 --> 04:20:51,603
THIS VERY VULNERABLE PERIOD

6841
04:20:51,603 --> 04:20:52,904
ACTUALLY COULD HAVE A BIG IMPACT

6842
04:20:52,904 --> 04:20:54,239
ON WHAT HAPPENS SUBSEQUENTLY, SO

6843
04:20:54,239 --> 04:20:57,976
WE HAVE BUILT A CLINICAL COHORT

6844
04:20:57,976 --> 04:21:00,478
AND NON-HUMAN PRIMATE MODELS

6845
04:21:00,478 --> 04:21:03,014
AROUND DOING DEEP INVESTIGATION

6846
04:21:03,014 --> 04:21:04,883
OF WHAT MIGHT BE HAPPENING.

6847
04:21:04,883 --> 04:21:06,851
AS SOON AS THAT VIRUS BEGINS TO

6848
04:21:06,851 --> 04:21:09,721
REBOUND AROUND DAY 10.

6849
04:21:09,721 --> 04:21:10,956
LOUIS HAS REFERRED TO THIS AS

6850
04:21:10,956 --> 04:21:12,490
LOCAL REBOUND, ALSO THE

6851
04:21:12,490 --> 04:21:13,458
INTERCEPT, WHEN THE VIRUS AND

6852
04:21:13,458 --> 04:21:16,595
THE HOST FIRST INTERACT.

6853
04:21:16,595 --> 04:21:18,630
SO WE HAVE WORK GOING ON IN

6854
04:21:18,630 --> 04:21:20,065
VITRO.

6855
04:21:20,065 --> 04:21:21,266
LOUIS'S TEAM IS LOOKING AT

6856
04:21:21,266 --> 04:21:22,901
WHAT'S HAPPENING IN THE IN VIVO

6857
04:21:22,901 --> 04:21:25,303
MODEL WITH PD-1 BLOCKADE AS JUST

6858
04:21:25,303 --> 04:21:25,770
ONE EXAMPLE.

6859
04:21:25,770 --> 04:21:27,405
THERE'S BEEN A NUMBER OF

6860
04:21:27,405 --> 04:21:30,475
DIFFERENT INTERVENTIONS, AND

6861
04:21:30,475 --> 04:21:38,116
THERE'S A POSTER HERE BY DEMI

6862
04:21:38,116 --> 04:21:38,984
SINDELL I'D ENCOURAGE YOU TO

6863
04:21:38,984 --> 04:21:39,451
SEE.

6864
04:21:39,451 --> 04:21:41,653
A HANDFUL OF THE DARE POSTERS

6865
04:21:41,653 --> 04:21:43,388
ARE KIND OF IN THE BACK

6866
04:21:43,388 --> 04:21:44,723
UPSTAIRS, YOU HAVE TO LOOK FOR

6867
04:21:44,723 --> 04:21:45,824
IT, WE'VE BEEN LEVERAGING A

6868
04:21:45,824 --> 04:21:48,259
STUDY THAT REALLY DEEPLY, DEEPLY

6869
04:21:48,259 --> 04:21:51,429
INVESTIGATES THIS INTERCEPT, AND

6870
04:21:51,429 --> 04:21:54,366
SHE'S GOT SOME FASCINATING DATA,

6871
04:21:54,366 --> 04:21:55,367
I'D ENCOURAGE YOU GO TO HER

6872
04:21:55,367 --> 04:21:55,700
POSTER.

6873
04:21:55,700 --> 04:21:57,235
BUT EACH OF THESE THREE STORY

6874
04:21:57,235 --> 04:21:58,770
LINES BASICALLY INVOLVES

6875
04:21:58,770 --> 04:22:01,172
MULTIPLE INS TUESDAY TEUTIONS,

6876
04:22:01,172 --> 04:22:06,478
INSTITUTIONS, WE THINKTHE TEAM E

6877
04:22:06,478 --> 04:22:06,778
WELL.

6878
04:22:06,778 --> 04:22:07,846
NOW LET'S GET INTO SOME OF THE

6879
04:22:07,846 --> 04:22:08,113
SCIENCE.

6880
04:22:08,113 --> 04:22:09,547
I'M GOING TO TURN IT OVER TO

6881
04:22:09,547 --> 04:22:10,315
MAURO.

6882
04:22:10,315 --> 04:22:18,757
[APPLAUSE]

6883
04:22:18,757 --> 04:22:19,958
>> THANK YOU FOR THE
OPPORTUNITY

6884
04:22:19,958 --> 04:22:20,925
TO PRESENT OUR LAB'S WORK HERE

6885
04:22:20,925 --> 04:22:21,493
TODAY.

6886
04:22:21,493 --> 04:22:26,531
MY NAME IS MAURO GARCIA, I'M A

6887
04:22:26,531 --> 04:22:28,299
GRADUATE STUDENT IN BOB AND

6888
04:22:28,299 --> 04:22:30,602
JANET SILICANO'S LAB.

6889
04:22:30,602 --> 04:22:32,671
THE FRACTION OF HIV VARIANTS

6890
04:22:32,671 --> 04:22:35,640
READILY NEUTRALIZE BY YOU AUTOLS

6891
04:22:35,640 --> 04:22:37,942
IGG ANTIBODIES PRIOR TO AN ATI,

6892
04:22:37,942 --> 04:22:38,943
CORRELATES WITH THE TIME TO

6893
04:22:38,943 --> 04:22:44,215
VIRAL REBOUND.

6894
04:22:44,215 --> 04:22:45,083
ANTIRETROVIRAL THERAPY

6895
04:22:45,083 --> 04:22:46,384
SUPPRESSES VIREMIA TO BELOW THE

6896
04:22:46,384 --> 04:22:47,852
LIMIT OF DETECTION.

6897
04:22:47,852 --> 04:22:49,821
HOWEVER, ART IS NOT CURATIVE.

6898
04:22:49,821 --> 04:22:51,356
FOLLOWING TREATMENT

6899
04:22:51,356 --> 04:22:52,991
INTERRUPTION, THERE'S RAPID AND

6900
04:22:52,991 --> 04:22:54,759
EXPONENTIAL VIRAL REBOUND THAT

6901
04:22:54,759 --> 04:22:57,328
OCCURS, AND THIS IS DUE TO A

6902
04:22:57,328 --> 04:22:58,663
POPULATION OF LATENTLY INFECTED

6903
04:22:58,663 --> 04:23:01,633
CELLS WITH A VERY LONG HALF-LIFE

6904
04:23:01,633 --> 04:23:03,702
THAT HARBOR INDUCIBLE

6905
04:23:03,702 --> 04:23:09,841
REPLICATIINDUCIBLE REPLY --PRINE

6906
04:23:09,841 --> 04:23:11,476
RESEARCH.

6907
04:23:11,476 --> 04:23:14,345
AND WE CAN ASSESS THE INDUCIBLE

6908
04:23:14,345 --> 04:23:15,447
REPLICATION COMPETENT RESERVOIR

6909
04:23:15,447 --> 04:23:19,718
IN PEOPLE WITH HIV USING THE

6910
04:23:19,718 --> 04:23:20,919
QUANTITATIVE ASSAY IN WHICH WE

6911
04:23:20,919 --> 04:23:23,354
PURIFY RESTING CD4 POSITIVE

6912
04:23:23,354 --> 04:23:25,757
T-CELLS WHICH ARE NOT PRODUCING

6913
04:23:25,757 --> 04:23:28,393
VIRUS, ACTIVATE THE CELLS WITH

6914
04:23:28,393 --> 04:23:31,162
THE MITOGEN AND FROM AN

6915
04:23:31,162 --> 04:23:32,297
INDIVIDUAL LATENTLY INFECTED

6916
04:23:32,297 --> 04:23:35,734
CELL WE CAN PRODUCE ENOUGH VIRUS

6917
04:23:35,734 --> 04:23:38,470
WITH A RELATIVELY SENSITIVE ELI

6918
04:23:38,470 --> 04:23:39,938
IS A TWO WEEKS LATER.

6919
04:23:39,938 --> 04:23:41,239
THIS REQUIRES EXPONENTIAL

6920
04:23:41,239 --> 04:23:41,706
REPLICATION.

6921
04:23:41,706 --> 04:23:46,311
AND THE QVOA PROVIDES AN

6922
04:23:46,311 --> 04:23:53,084
ESTIMATE OF THE -- THEY USED THE

6923
04:23:53,084 --> 04:23:55,820
QVOR TO INDICATE THE RESERVOIR

6924
04:23:55,820 --> 04:23:57,922
DECAYS VERY SLOWLY IN THE FIRST

6925
04:23:57,922 --> 04:23:59,023
SEVEN YEARS ON ART WITH THE

6926
04:23:59,023 --> 04:24:00,458
HALF-LIFE OF 44 MONTHS.

6927
04:24:00,458 --> 04:24:02,460
THIS RATE IS SLOW ENOUGH TO

6928
04:24:02,460 --> 04:24:04,529
GUARANTEE LIFE-LONG PERSISTENCE

6929
04:24:04,529 --> 04:24:06,064
OF HIV EVEN WITHOUT IN INFECTION

6930
04:24:06,064 --> 04:24:09,134
EVENTS.

6931
04:24:09,134 --> 04:24:10,902
NANCY ARCHIN REPEATED THIS STUDY

6932
04:24:10,902 --> 04:24:13,071
WITH INDIVIDUALS ON NEWER

6933
04:24:13,071 --> 04:24:15,373
REGIMENS AND GOT THE SAME

6934
04:24:15,373 --> 04:24:16,508
HALF-LIFE.

6935
04:24:16,508 --> 04:24:19,677
SO THESE ARE DATA FROM JANET'S

6936
04:24:19,677 --> 04:24:21,980
2003 QVOA STUDY AND WE CAN ASK

6937
04:24:21,980 --> 04:24:23,114
WHETHER THE RESERVOIR CONTINUES

6938
04:24:23,114 --> 04:24:25,517
TO DECAY AT THE SAME RATE ON

6939
04:24:25,517 --> 04:24:27,051
LONG-TERM ART, AND WHAT EFFECT

6940
04:24:27,051 --> 04:24:29,454
THE CHANGES IN THE INTEGRATION

6941
04:24:29,454 --> 04:24:30,889
SITE LANDSCAPE HAVE HAD AS

6942
04:24:30,889 --> 04:24:35,260
DESCRIBED IN THE ELEGANT WORK.

6943
04:24:35,260 --> 04:24:39,497
JANET PREVIOUSLY SHOWED THAT

6944
04:24:39,497 --> 04:24:41,065
PERSISTENT HIV PRO VIRUSES ARE

6945
04:24:41,065 --> 04:24:41,966
PRIMARILY INTEGRATED INTO

6946
04:24:41,966 --> 04:24:45,336
ACTIVELY TRANSCRIBED HOST GENES.

6947
04:24:45,336 --> 04:24:46,304
HOWEVER, OVER TIME, THERE SEEMS

6948
04:24:46,304 --> 04:24:48,206
TO BE A SELECTION PROCESS IN

6949
04:24:48,206 --> 04:24:50,942
WHICH INTACT HIV GENOMES ARE

6950
04:24:50,942 --> 04:24:56,548
PRIMARILY FOUND IN NON-GENIC AND

6951
04:24:56,548 --> 04:24:58,616
CENTROMERIC REGIONS FOR PRO

6952
04:24:58,616 --> 04:24:59,150
VIRAL INDUCTION.

6953
04:24:59,150 --> 04:25:02,253
SO WE ASKED WOULD INDUCIBLE

6954
04:25:02,253 --> 04:25:03,588
REPLICATION COMPETENT PRO VIRUS

6955
04:25:03,588 --> 04:25:04,656
BECOME EVEN LESS FREQUENT WITH

6956
04:25:04,656 --> 04:25:07,058
TIME ON ART?

6957
04:25:07,058 --> 04:25:10,061
WITH THE HELP OF R REBECCA HO AD

6958
04:25:10,061 --> 04:25:13,565
STEVE DEEKS, WE RECRUITED

6959
04:25:13,565 --> 04:25:15,433
42 PEOPLE WITH HIV ON LONG TERM

6960
04:25:15,433 --> 04:25:17,602
SUPPRESSIVE ART FOR AN AVERAGE

6961
04:25:17,602 --> 04:25:20,371
OF 22 YEARS, AND SOME

6962
04:25:20,371 --> 04:25:24,509
PARTICIPANTS FROM JANET'S 2003

6963
04:25:24,509 --> 04:25:26,845
STUDY WERE STILL ON SUPPRESSIVE

6964
04:25:26,845 --> 04:25:29,347
ART REGIMENTS, AND THEY HAD NO

6965
04:25:29,347 --> 04:25:32,116
LONG-TERM DECAY IN THE INDUCIBLE

6966
04:25:32,116 --> 04:25:32,984
REPLICATION-COMPETENT RESERVOIR.

6967
04:25:32,984 --> 04:25:34,419
AND HERE ARE THE OTHER

6968
04:25:34,419 --> 04:25:37,488
PARTICIPANTS IN THE STUDY.

6969
04:25:37,488 --> 04:25:39,357
AND IN THE BEST FIT MODEL, THERE

6970
04:25:39,357 --> 04:25:41,893
IS INITIAL DECAY AND THEN

6971
04:25:41,893 --> 04:25:43,194
INFLECTION AT SEVEN YEARS AND

6972
04:25:43,194 --> 04:25:45,363
THE RESERVOIR SEEMS TO INCREASE

6973
04:25:45,363 --> 04:25:48,032
SLIGHTLY OVER TIME.

6974
04:25:48,032 --> 04:25:49,567
WHICH WE CAN DESCRIBE WITH A

6975
04:25:49,567 --> 04:25:52,737
DOUBLING TIME OF 23 YEARS.

6976
04:25:52,737 --> 04:25:55,573
SO OVERALL, THERE'S NO NET DECAY

6977
04:25:55,573 --> 04:25:57,909
IN THE FREQUENCY OF RESTING

6978
04:25:57,909 --> 04:25:59,544
CD4 POSITIVE T-CELLS WITH

6979
04:25:59,544 --> 04:26:01,446
INDUCIBLE REPLICATION-COMPETENT

6980
04:26:01,446 --> 04:26:05,817
PRO VIRUSES OVER TIME.

6981
04:26:05,817 --> 04:26:07,352
AND MOST PRO VIRUSES DETECTED

6982
04:26:07,352 --> 04:26:08,553
APPEAR TO BE DERIVED FROM THE

6983
04:26:08,553 --> 04:26:10,321
CLONAL EXPANSION OF PREVIOUSLY

6984
04:26:10,321 --> 04:26:11,956
INFECTED CELLS BECAUSE THE

6985
04:26:11,956 --> 04:26:15,260
ISOLATES ARE OFTEN IDENTICAL.

6986
04:26:15,260 --> 04:26:16,494
AND THESE EXPANDED CLONES HAVE

6987
04:26:16,494 --> 04:26:17,495
THE POTENTIAL TO CAUSE REBOUND

6988
04:26:17,495 --> 04:26:20,198
BUT INTERESTINGLY, IN SOME

6989
04:26:20,198 --> 04:26:22,433
PEOPLE, RAPID AND EXPONENTIAL

6990
04:26:22,433 --> 04:26:23,735
VIRAL REBOUND FOLLOWING

6991
04:26:23,735 --> 04:26:26,371
TREATMENT INTERRUPTION COMES

6992
04:26:26,371 --> 04:26:28,106
FROM PHYLOGENETICALLY DISTINCT

6993
04:26:28,106 --> 04:26:29,574
MINOR VARIANTS THAT WERE NOT

6994
04:26:29,574 --> 04:26:30,975
PREVIOUSLY DETECTED IN THE ASSAY

6995
04:26:30,975 --> 04:26:33,444
PRIOR TO AN ANALYTICAL TREATMENT

6996
04:26:33,444 --> 04:26:33,945
INTERRUPTION.

6997
04:26:33,945 --> 04:26:38,016
AND THIS WAS FIRST SHOWN BY

6998
04:26:38,016 --> 04:26:40,184
MICHELLE -- AND KATIE BARR.

6999
04:26:40,184 --> 04:26:41,185
SEVERAL EXPLANATIONS WERE

7000
04:26:41,185 --> 04:26:43,187
OFFERED FOR THESE FINDINGS BUT

7001
04:26:43,187 --> 04:26:44,722
WE HIGH POTASSIUM SEISE THE

7002
04:26:44,722 --> 04:26:47,225
VIRUS RELEASED FROM LEASE LARGE

7003
04:26:47,225 --> 04:26:49,227
CLONES ARE READILY NEUTRALIZED

7004
04:26:49,227 --> 04:26:50,862
BY AUTOLOGOUS NEUTRALIZING

7005
04:26:50,862 --> 04:26:52,063
ANTIBODIES.

7006
04:26:52,063 --> 04:26:55,133
SO CLASSIC STUDIES DEMONSTRATED

7007
04:26:55,133 --> 04:26:57,602
THAT DURING UNTREATED INFECTION,

7008
04:26:57,602 --> 04:27:01,072
NEUTRALIZING ANTIBODIES ARISE,

7009
04:27:01,072 --> 04:27:03,408
BUT VIRAL EVOLUTION ALLOWS FOR

7010
04:27:03,408 --> 04:27:04,509
CONTINUAL ESCAPE FROM THE

7011
04:27:04,509 --> 04:27:06,277
ANTIBODY RESPONSE, ALLOWING FOR

7012
04:27:06,277 --> 04:27:07,045
LITTLE CONTEMPORANEOUS

7013
04:27:07,045 --> 04:27:07,478
NEUTRALIZATION.

7014
04:27:07,478 --> 04:27:09,247
AND FOR THIS REASON, THE

7015
04:27:09,247 --> 04:27:11,115
AUTOLOGOUS NEUTRALIZING ANTIBODY

7016
04:27:11,115 --> 04:27:11,983
RESPONSE HAS BEEN PAID LITTLE

7017
04:27:11,983 --> 04:27:13,851
ATTENTION TO.

7018
04:27:13,851 --> 04:27:15,653
AND SO IF VIRUSES ARE DEPOSITED

7019
04:27:15,653 --> 04:27:17,355
IN THE RESERVOIR THROUGHOUT

7020
04:27:17,355 --> 04:27:20,191
UNTREATED INFECTION, AND AT THE

7021
04:27:20,191 --> 04:27:21,759
TIME OF ART INITIATION, THEN

7022
04:27:21,759 --> 04:27:23,728
SOME RESERVOIR ISOLATES SHOULD

7023
04:27:23,728 --> 04:27:24,729
BE SENSITIVE WHEREAS OTHERS

7024
04:27:24,729 --> 04:27:27,598
MIGHT BE RESISTANT TO AUTOLOGOUS

7025
04:27:27,598 --> 04:27:29,901
NEUTRALIZING ANTIBODIES.

7026
04:27:29,901 --> 04:27:31,436
THEREFORE, ISOLATES THAT ARE

7027
04:27:31,436 --> 04:27:34,973
RESISTANT TO THE CO CONTEMPORANS

7028
04:27:34,973 --> 04:27:36,374
ANAB RESPONSE MAY REBOUND IF ART

7029
04:27:36,374 --> 04:27:39,644
IS STOPPED.

7030
04:27:39,644 --> 04:27:41,179
TO SEE IF THIS WAS THE CAUSE IN

7031
04:27:41,179 --> 04:27:43,748
INDIVIDUALS WITH HIV, A STUDY

7032
04:27:43,748 --> 04:27:51,289
LED BY LYNN BERTAGNOLLI INCLU

7033
04:27:51,289 --> 04:27:52,523
INCLUDED -- AND ASKED IF

7034
04:27:52,523 --> 04:27:54,926
AUTOLOGOUS NEUTRALIZING

7035
04:27:54,926 --> 04:27:56,361
ANTIBODIES COULD BLOCK SOME BUT

7036
04:27:56,361 --> 04:27:58,029
NOT ALL RESERVOIR VIRUSES AND

7037
04:27:58,029 --> 04:28:00,331
PLATED THESE CELLS IN THE

7038
04:28:00,331 --> 04:28:02,867
MODIFIED QVOA IN WHICH THERE

7039
04:28:02,867 --> 04:28:07,839
WERE THREE ARMS, WITHOUT AND

7040
04:28:07,839 --> 04:28:10,675
ANTIBODY, NEGATIVE DONOR AND

7041
04:28:10,675 --> 04:28:12,343
AUTOLOGOUS IGG ANTIBODIES AND

7042
04:28:12,343 --> 04:28:15,079
LACKED FOR A REDUCTION MEDIATED

7043
04:28:15,079 --> 04:28:16,814
BY AUTOLOGOUS NEUTRALIZATION.

7044
04:28:16,814 --> 04:28:17,949
HERE'S A REPRESENTATIVE

7045
04:28:17,949 --> 04:28:19,584
PARTICIPANT FROM THE STUDY

7046
04:28:19,584 --> 04:28:21,753
SHOWING THE AUTOLOGOUS IGG

7047
04:28:21,753 --> 04:28:24,088
ANTIBODIES INDEED WERE ABLE TO

7048
04:28:24,088 --> 04:28:26,858
BLOCK SOME BUT NOT ALL ISOLATES.

7049
04:28:26,858 --> 04:28:28,393
AND PHYLOGENETIC ANALYSES

7050
04:28:28,393 --> 04:28:29,627
REVEALED THAT ONLY A SMALL

7051
04:28:29,627 --> 04:28:31,696
SUBSET OF RESERVOIR ISOLATES

7052
04:28:31,696 --> 04:28:33,765
SHOWN IN RED WERE ABLE TO GROW

7053
04:28:33,765 --> 04:28:35,199
OUT IN THE QVOA IN THE PRESENCE

7054
04:28:35,199 --> 04:28:37,335
OF LOW CONCENTRATIONS OF

7055
04:28:37,335 --> 04:28:38,970
AUTOLOGOUS IGG ANTIBODIES, AND

7056
04:28:38,970 --> 04:28:43,708
THESE ISOLATES HAD MUTATIONS IN

7057
04:28:43,708 --> 04:28:45,243
THE VARIABLE LOOPS OF ENVELOPE

7058
04:28:45,243 --> 04:28:48,513
CONSISTENT WITH ANTIBODY ESCAPE.

7059
04:28:48,513 --> 04:28:50,081
THESE ISOLATES WERE HIGHLY

7060
04:28:50,081 --> 04:28:53,818
RESISTANT TO AUTOLOGOUS IGG

7061
04:28:53,818 --> 04:28:54,786
ANTIBODIES WHEREAS THESE TWO

7062
04:28:54,786 --> 04:28:56,154
LARGE CLONES WERE HIGHLY

7063
04:28:56,154 --> 04:28:56,487
SENSITIVE.

7064
04:28:56,487 --> 04:28:58,022
THESE RESULTS EXPLAIN WHY SOME

7065
04:28:58,022 --> 04:29:00,992
LARGE CLONES DETECTED IN QVOAs

7066
04:29:00,992 --> 04:29:04,162
DON'T CAUSE REBOUNDS.

7067
04:29:04,162 --> 04:29:05,396
AND OUR LAB HAS GONE ON TO

7068
04:29:05,396 --> 04:29:07,031
ESTABLISH THE PHYLOGENETIC

7069
04:29:07,031 --> 04:29:08,332
RELATIONSHIP OF VIRUSES GROWING

7070
04:29:08,332 --> 04:29:09,934
OUT IN THE PRESENCE OF

7071
04:29:09,934 --> 04:29:12,437
AUTOLOGOUS IGG IN VIRUSES

7072
04:29:12,437 --> 04:29:13,404
CAUSING REPOUND IN VIVO.

7073
04:29:13,404 --> 04:29:15,440
SO BASED ON THIS DATA I'VE

7074
04:29:15,440 --> 04:29:16,407
PRESENTED, REBOUND IS A

7075
04:29:16,407 --> 04:29:17,408
SELECTION PROCESS.

7076
04:29:17,408 --> 04:29:19,143
ANTIGENS CONTINUOUSLY ACTIVATE

7077
04:29:19,143 --> 04:29:20,845
CELLS COMPRISING THE LATENT

7078
04:29:20,845 --> 04:29:24,782
RESERVOIR, LEADING TO RESIDUAL

7079
04:29:24,782 --> 04:29:25,216
VIREMIA.

7080
04:29:25,216 --> 04:29:27,118
SOME VIRUSES RELEASED FROM THE

7081
04:29:27,118 --> 04:29:27,985
RESERVOIR ARE READILY

7082
04:29:27,985 --> 04:29:31,255
NEUTRALIZED BY YOU AUTOLOGOUS

7083
04:29:31,255 --> 04:29:32,156
ANALYZING ANTIBODIES.

7084
04:29:32,156 --> 04:29:33,825
HOWEVER, SOME VIRUSES MAY BE

7085
04:29:33,825 --> 04:29:35,026
RESISTANT AND IF ART IS STOPPED

7086
04:29:35,026 --> 04:29:38,629
MAY CONTRIBUTE TO VIRAL REBOUND.

7087
04:29:38,629 --> 04:29:40,765
AND IN PREVIOUS ATI STUDIES, WE

7088
04:29:40,765 --> 04:29:42,300
KNOW THAT THERE'S HETEROGENEITY

7089
04:29:42,300 --> 04:29:43,734
IN THE TIME TO VIRAL REBOUND

7090
04:29:43,734 --> 04:29:45,636
THAT'S DIFFICULT TO DESCRIBE AND

7091
04:29:45,636 --> 04:29:46,704
PINPOINT.

7092
04:29:46,704 --> 04:29:48,573
AND IN STUDIES WHERE VERY EARLY

7093
04:29:48,573 --> 04:29:51,776
ART WAS INITIATED AND RESTRICTED

7094
04:29:51,776 --> 04:29:52,877
RESERVOIR SIZE, WE ALSO SEE

7095
04:29:52,877 --> 04:29:54,979
DELAYED TIMES TO VIRAL REBOUND.

7096
04:29:54,979 --> 04:29:57,381
AND THIS WAS A STUDY SHOWN BY

7097
04:29:57,381 --> 04:29:59,050
DEBORAH PERSAUD.

7098
04:29:59,050 --> 04:30:00,918
SO THERE'S VARIOUS FACTORS THAT

7099
04:30:00,918 --> 04:30:02,353
MAY INFLUENCE VIRAL REBOUND

7100
04:30:02,353 --> 04:30:04,021
DYNAMICS FOLLOWING TREATMENT

7101
04:30:04,021 --> 04:30:04,789
INTERRUPTION.

7102
04:30:04,789 --> 04:30:08,192
AND SO WE ASKED, DO AUTOLOGOUS

7103
04:30:08,192 --> 04:30:09,494
NEUTRALIZING ANTIBODIES

7104
04:30:09,494 --> 04:30:10,528
INFLUENCE THE TIME TO VIRAL

7105
04:30:10,528 --> 04:30:11,863
REBOUND?

7106
04:30:11,863 --> 04:30:15,566
SO FOR THIS STUDY, WE COLLECTED

7107
04:30:15,566 --> 04:30:17,902
CELLS, RESTING CD4 POSITIVE

7108
04:30:17,902 --> 04:30:20,638
T-CELLS AND CONTEMPORANEOUS

7109
04:30:20,638 --> 04:30:21,973
AUTOLOGOUS IGG FROM PARTICIPANTS

7110
04:30:21,973 --> 04:30:24,075
PRIOR TO AN ATI, AND CONDUCTED

7111
04:30:24,075 --> 04:30:26,944
THESE MODIFIED QVOAs.

7112
04:30:26,944 --> 04:30:29,514
AND WE USED THE SCOPE ATI COHORT

7113
04:30:29,514 --> 04:30:31,349
WHICH RECEIVED NO INTERVENTION

7114
04:30:31,349 --> 04:30:34,418
TO DIRECTLY ASSESS TIME TO

7115
04:30:34,418 --> 04:30:36,787
REBOUND IN THE CONTEXT OF

7116
04:30:36,787 --> 04:30:37,421
AUTOLOGOUS NEUTRALIZING

7117
04:30:37,421 --> 04:30:43,327
ANTIBODIES.

7118
04:30:43,327 --> 04:30:45,396
HERE WE SHOW A STATISTICALLY

7119
04:30:45,396 --> 04:30:46,030
SIGNIFICANT CORRELATION BETWEEN

7120
04:30:46,030 --> 04:30:47,331
THE TIME TO REBOUND AND THE

7121
04:30:47,331 --> 04:30:49,267
PERCENTAGE OF INDUCIBLE

7122
04:30:49,267 --> 04:30:50,701
REPLICATION COMPETENT RESERVOIR

7123
04:30:50,701 --> 04:30:52,837
ISOLATES THAT ARE NEUTRALIZED BY

7124
04:30:52,837 --> 04:30:54,138
AUTOLOGOUS NEUTRALIZING

7125
04:30:54,138 --> 04:31:00,478
ANTIBODIES PRIOR TO THE ATI.

7126
04:31:00,478 --> 04:31:02,280
IN SOME OF THESE ATI

7127
04:31:02,280 --> 04:31:03,681
PARTICIPANTS, WE'VE IDENTIFIED

7128
04:31:03,681 --> 04:31:05,783
LARGE ANAB RESISTANT CLONES

7129
04:31:05,783 --> 04:31:09,554
PRIOR TO THE ATI, USING THE

7130
04:31:09,554 --> 04:31:11,656
MODIFIED QVOA, AND WE

7131
04:31:11,656 --> 04:31:12,757
HYPOTHESIZE THAT THESE ISOLATES

7132
04:31:12,757 --> 04:31:14,525
MAY BE IDENTICAL OR GENETICALLY

7133
04:31:14,525 --> 04:31:17,929
SIMILAR TO THE VIRUS THAT CAUSES

7134
04:31:17,929 --> 04:31:19,297
REBOUND IN VIVO ONCE ART IS

7135
04:31:19,297 --> 04:31:19,630
STOPPED.

7136
04:31:19,630 --> 04:31:21,832
AND WE'RE CURRENTLY WORKING WITH

7137
04:31:21,832 --> 04:31:24,135
LILLIAN COHEN AND ANNA SHURMAN

7138
04:31:24,135 --> 04:31:24,902
TO INVESTIGATE THIS FURTHER.

7139
04:31:24,902 --> 04:31:28,039
SO IN CONCLUSION, THE INDUCIBLE

7140
04:31:28,039 --> 04:31:30,641
REPLICATION COMPETENT RESERVOIR

7141
04:31:30,641 --> 04:31:32,944
DOES NOT CONTINUE TO DECAY IN

7142
04:31:32,944 --> 04:31:36,280
PEOPLE ON LONG TERM ART.

7143
04:31:36,280 --> 04:31:37,715
AUTOLOGOUS NAUGHT KNUTEIZEING

7144
04:31:37,715 --> 04:31:39,016
ANTIBODIES PREVENT OUTGROWTH OF

7145
04:31:39,016 --> 04:31:41,485
SOME BUT NOT ALL INDUCIBLE

7146
04:31:41,485 --> 04:31:42,386
REPLICATION COMPETENT ISOLATES

7147
04:31:42,386 --> 04:31:45,856
AND THE DEGREE OF NEUTRALIZATION

7148
04:31:45,856 --> 04:31:46,857
VARIES AMONG PARTICIPANTS.

7149
04:31:46,857 --> 04:31:48,960
THE FRACTION OF ANAB -- SORRY

7150
04:31:48,960 --> 04:31:51,128
THE FRACTION OF ANAB SENSITIVE

7151
04:31:51,128 --> 04:31:52,096
VIRUSES IN THE RESERVOIR

7152
04:31:52,096 --> 04:31:53,064
STRONGLY CORRELATES WITH THE

7153
04:31:53,064 --> 04:31:55,600
TIME TO VIRAL REBOUND, AND

7154
04:31:55,600 --> 04:31:57,902
LASTLY, ATI STUDIES USING TIME

7155
04:31:57,902 --> 04:31:59,670
TO REBOUND AS AN OUTCOME

7156
04:31:59,670 --> 04:32:01,072
MEASUREMENT SHOULD CONSIDER THE

7157
04:32:01,072 --> 04:32:03,241
AUTOLOGOUS NEUTRALIZING ANTIBODY

7158
04:32:03,241 --> 04:32:03,507
RESPONSE.

7159
04:32:03,507 --> 04:32:05,743
AND WE'D LIKE TO THANK OUR

7160
04:32:05,743 --> 04:32:07,278
COLLABORATORS, LILLIAN COHEN,

7161
04:32:07,278 --> 04:32:13,684
ANNA SHURMAN, L LUIS MONTANER, Y

7162
04:32:13,684 --> 04:32:19,590
FELLOW LAB MATES, AND MY PIs,

7163
04:32:19,590 --> 04:32:21,192
AS WELL AS OUR FUNDING SOURCES

7164
04:32:21,192 --> 04:32:24,595
AND THE STUDY PARTICIPANT.

7165
04:32:24,595 --> 04:32:27,965
AND NOW I'LL HAND IT OVER TO

7166
04:32:27,965 --> 04:32:28,432
LOUIS PICKER.

7167
04:32:28,432 --> 04:32:33,337
[APPLAUSE]

7168
04:32:33,337 --> 04:32:35,072
>> THOSE WERE REALLY
BEAUTIFUL

7169
04:32:35,072 --> 04:32:36,274
SLIDES AND A BEAUTIFUL STORY IF

7170
04:32:36,274 --> 04:32:38,376
I SAY SO MYSELF.

7171
04:32:38,376 --> 04:32:39,176
WELL, BEFORE I START, I JUST

7172
04:32:39,176 --> 04:32:44,215
WANTED TO ADDRESS

7173
04:32:44,215 --> 04:32:46,984
>> I HAVE BEEN QUOTED
SAYING

7174
04:32:46,984 --> 04:32:47,885
ANTIBODIES ARE SOMETHING YOU BUY

7175
04:32:47,885 --> 04:32:48,986
TO STUDY T-CELLS.

7176
04:32:48,986 --> 04:32:50,655
HERE YOU SEE THAT I'M ON AN

7177
04:32:50,655 --> 04:32:52,189
ABSTRACT OR A TALK WHERE

7178
04:32:52,189 --> 04:32:53,291
ANTIBODY IS IN THE TITLE.

7179
04:32:53,291 --> 04:32:54,558
BUT I JUST WANT TO TELL YOU

7180
04:32:54,558 --> 04:32:55,693
THIS, IS REALLY ABOUT IT. CELLS

7181
04:32:55,693 --> 04:32:59,230
THIS TALK, EVEN THOUGH

7182
04:32:59,230 --> 04:33:00,331
NEUTRALIZING ANTIBODIES ARE IN

7183
04:33:00,331 --> 04:33:00,865
THE TITLE.

7184
04:33:00,865 --> 04:33:02,466
I ALSO WANT TO MAKE SURE I GIVE

7185
04:33:02,466 --> 04:33:03,668
APPROPRIATE CREDIT TO THE PEOPLE

7186
04:33:03,668 --> 04:33:05,970
THAT ACTUALLY DID THE WORK WHICH

7187
04:33:05,970 --> 04:33:08,472
IS THE GROUP AT OHSU.

7188
04:33:08,472 --> 04:33:10,274
I AM ONE OF THE OLDER STATEMEN

7189
04:33:10,274 --> 04:33:12,743
THAT KEEPS AN EYE ON THINGS, BUT

7190
04:33:12,743 --> 04:33:13,611
THE ACTUAL PERSON OUT IN THE

7191
04:33:13,611 --> 04:33:15,846
FIELD DOING THE WORK IS HE AND

7192
04:33:15,846 --> 04:33:17,281
HIS GROUP.

7193
04:33:17,281 --> 04:33:19,483
AND ALL THE REST OF THE NHP

7194
04:33:19,483 --> 04:33:20,818
PEOPLE IN OUR GROUP ARE LISTED

7195
04:33:20,818 --> 04:33:24,021
ON HERE.

7196
04:33:24,021 --> 04:33:26,324
SO PREVIOUS WORK OVER MANY YEARS

7197
04:33:26,324 --> 04:33:29,460
BY OUR GROUP AND MANY OTHERS HAS

7198
04:33:29,460 --> 04:33:31,295
SHOWN THAT PERHAPS THE MOST

7199
04:33:31,295 --> 04:33:33,264
FUNDAMENTAL REASON THAT THE

7200
04:33:33,264 --> 04:33:35,666
IMMUNE SYSTEM OR THE CELLULAR

7201
04:33:35,666 --> 04:33:37,635
IMMUNE SYSTEM CAN CONTROL HIV OR

7202
04:33:37,635 --> 04:33:39,837
SIV IS THE DYNAMIC MISMATCH

7203
04:33:39,837 --> 04:33:40,971
BETWEEN EXPONENTIAL VIRAL

7204
04:33:40,971 --> 04:33:42,740
REPLICATION AND THE LAGGING

7205
04:33:42,740 --> 04:33:45,309
EITHER PRIMARY OR AMNESTIC

7206
04:33:45,309 --> 04:33:47,044
CD8 T-CELL RESPONSE THAT OCCURS

7207
04:33:47,044 --> 04:33:48,379
DURING -- IN THIS PARTICULAR

7208
04:33:48,379 --> 04:33:51,115
CASE, AFTER YOU DISCONTINUE ART.

7209
04:33:51,115 --> 04:33:52,817
THE COIN TOO LITTLE, TOO LATE

7210
04:33:52,817 --> 04:33:54,151
WAS FIRST COINED FOR PRIMARY

7211
04:33:54,151 --> 04:33:55,419
INFECTION BUT IT'S EENGLY

7212
04:33:55,419 --> 04:33:57,088
APPLICABLE TO POST ART, ALTHOUGH

7213
04:33:57,088 --> 04:33:58,456
IT'S A LITTLE BIT FASTER BECAUSE

7214
04:33:58,456 --> 04:34:00,191
YOU HAVE A PREVIOUSLY

7215
04:34:00,191 --> 04:34:02,159
ESTABLISHED IMMUNE RESPONSE IN

7216
04:34:02,159 --> 04:34:03,327
ANIMALS THAT WERE TREATED WITH

7217
04:34:03,327 --> 04:34:04,962
ART.

7218
04:34:04,962 --> 04:34:08,366
BUT WHEN THE IMMUNE EVASIVE

7219
04:34:08,366 --> 04:34:09,800
VIRUS SUCH AS HIV, IT'S REALLY

7220
04:34:09,800 --> 04:34:11,035
HARD IF NOT IMPOSSIBLE UNLESS

7221
04:34:11,035 --> 04:34:12,803
YOU HAVE VERY SPECIAL

7222
04:34:12,803 --> 04:34:14,205
CIRCUMSTANCES LIKE HIGHLY

7223
04:34:14,205 --> 04:34:16,774
PROTECTIVE ALLELES FOR THE

7224
04:34:16,774 --> 04:34:18,008
C8 T-CELL SYSTEM TO CONTROL AN

7225
04:34:18,008 --> 04:34:19,443
INFECTION THAT IT FOLLOWS RATHER

7226
04:34:19,443 --> 04:34:21,479
THAN PRECEDES.

7227
04:34:21,479 --> 04:34:25,616
SO ONE OF OUR HYPOTHESES IN

7228
04:34:25,616 --> 04:34:27,451
RF2 AND INDEED IN THE DARE

7229
04:34:27,451 --> 04:34:29,653
COLLABORATORY IS REALLY TO FOCUS

7230
04:34:29,653 --> 04:34:32,456
ON IMMUNE INTERVENTIONS THAT

7231
04:34:32,456 --> 04:34:34,625
INVOLVE IMMUNE STIMULATION IN

7232
04:34:34,625 --> 04:34:35,860
THE PERIARTERY LEASE PERIOD.

7233
04:34:35,860 --> 04:34:37,495
THE IDEA IS TO GET -- IS TO

7234
04:34:37,495 --> 04:34:39,964
CHANGE THE TIMING AND CHANGE THE

7235
04:34:39,964 --> 04:34:42,266
DYNAMICS OF WHAT WE HAVE COINED

7236
04:34:42,266 --> 04:34:43,567
AS THE INTERCEPT.

7237
04:34:43,567 --> 04:34:45,436
TO ACTUALLY HAVE THE T-CELL

7238
04:34:45,436 --> 04:34:46,904
RESPONSE PEAK RIGHT AS THE VIRUS

7239
04:34:46,904 --> 04:34:49,106
IS COMING OUT OF AND BEGINNING

7240
04:34:49,106 --> 04:34:51,208
TO SPREAD IN LOCAL REBOUND

7241
04:34:51,208 --> 04:34:52,743
RATHER THAN FOLLOWING THAT LOCAL

7242
04:34:52,743 --> 04:34:53,778
REBOUND.

7243
04:34:53,778 --> 04:34:57,047
AND SO THE HYPOTHESIS IS THE

7244
04:34:57,047 --> 04:34:58,916
SOONER AND BIGGER MIGHT EQUAL

7245
04:34:58,916 --> 04:35:00,284
BETTER.

7246
04:35:00,284 --> 04:35:01,152
HOWEVER, THERE ARE CAVEATS TO

7247
04:35:01,152 --> 04:35:02,353
THIS, AND THIS IS JUST AN

7248
04:35:02,353 --> 04:35:04,422
EXAMPLE TO SHOW A CAVEAT OF A

7249
04:35:04,422 --> 04:35:07,892
STUDY THAT WE DID A WHILE BACK,

7250
04:35:07,892 --> 04:35:09,226
STILL HAVEN'T PUBLISHED IT YET,

7251
04:35:09,226 --> 04:35:12,062
BUT BASICALLY WHERE WE'RE USING

7252
04:35:12,062 --> 04:35:14,965
N820, WHICH IS A COMBINATION

7253
04:35:14,965 --> 04:35:19,003
ANTICD20 AND IL15 SUPERAGONIST,

7254
04:35:19,003 --> 04:35:21,038
AND BASICALLY WHAT WE SHOWED IS

7255
04:35:21,038 --> 04:35:22,373
THAT MORE ISN'T ALWAYS BETTER,

7256
04:35:22,373 --> 04:35:23,774
IF YOU GIVE A REALLY POTENT

7257
04:35:23,774 --> 04:35:25,309
IMMUNE STIMULATION AT THE TIME

7258
04:35:25,309 --> 04:35:28,212
OF ART RELEASE AS SHOWN IN THE

7259
04:35:28,212 --> 04:35:30,181
RED, YOU CAN GET HUGE

7260
04:35:30,181 --> 04:35:32,650
PROLIFERATIVE INCREASES IN

7261
04:35:32,650 --> 04:35:34,985
C4 T-CELLS WHICH RESPONDS AS AIN

7262
04:35:34,985 --> 04:35:36,387
CREASE IN VIRAL REPLICATION POST

7263
04:35:36,387 --> 04:35:37,254
ART RATHER THAN A DECREASE.

7264
04:35:37,254 --> 04:35:39,757
SO THESE DATA SUGGEST TO US THAT

7265
04:35:39,757 --> 04:35:41,158
PERHAPS A MORE SUBTLE T-CELL

7266
04:35:41,158 --> 04:35:43,127
STIMULATION MIGHT BE INFECTIVE,

7267
04:35:43,127 --> 04:35:45,362
PARTICULARLY ONE THAT MIGHT ALSO

7268
04:35:45,362 --> 04:35:46,297
INDEPENDENTLY SUPPRESS VIRAL

7269
04:35:46,297 --> 04:35:46,697
SPREAD.

7270
04:35:46,697 --> 04:35:48,332
AND THAT COMES -- IS WHERE WE

7271
04:35:48,332 --> 04:35:50,367
CAME INTO ANTIBODIES, BECAUSE IT

7272
04:35:50,367 --> 04:35:51,502
HAS BEEN PROPOSED THROUGH A

7273
04:35:51,502 --> 04:35:53,437
NUMBER OF STUDIES, INITIALLY IN

7274
04:35:53,437 --> 04:35:55,940
RHESUS MACAQUE, BUT MORE

7275
04:35:55,940 --> 04:35:59,210
RECENTLY IN HUMANS, OF THE

7276
04:35:59,210 --> 04:36:01,078
SO-CALLED VACCINEAL EFFECT, THE

7277
04:36:01,078 --> 04:36:02,580
POTENTIAL FOR NEUTRALIZING, THAT

7278
04:36:02,580 --> 04:36:07,051
IS ABLE TO BIND THE ACTUAL VIRUS

7279
04:36:07,051 --> 04:36:08,686
NEUTRALIZING ANTIBODIES TO FORM

7280
04:36:08,686 --> 04:36:11,589
IMMUNE COMPLEXES THAT POTENTIATE

7281
04:36:11,589 --> 04:36:12,323
CD8 T-CELL RESPONSES.

7282
04:36:12,323 --> 04:36:13,424
THERE ARE PAPERS IN THE

7283
04:36:13,424 --> 04:36:16,026
LITERATURE SHOWN ON TOP SHOWING

7284
04:36:16,026 --> 04:36:18,896
THAT THIS CAN INCREASE RESPONSES

7285
04:36:18,896 --> 04:36:21,165
AND THERE ARE STUDIES IN HUMAN

7286
04:36:21,165 --> 04:36:23,033
IN THE SHORT AND LOWER PANEL IN

7287
04:36:23,033 --> 04:36:25,736
WHICH PEOPLE MAINTAIN VIRAL

7288
04:36:25,736 --> 04:36:28,806
CONTROL AFTER THE INITIALIZING

7289
04:36:28,806 --> 04:36:29,974
ANTIBODY BASICALLY DECAYED THAT

7290
04:36:29,974 --> 04:36:31,275
SUGGESTED THAT THIS MIGHT BE THE

7291
04:36:31,275 --> 04:36:33,577
MECHANISM OF THAT PROLONGED

7292
04:36:33,577 --> 04:36:34,778
SUPPRESSION IN THE ABSENCE OF

7293
04:36:34,778 --> 04:36:36,514
ANY MORE ACTIVE ANTIBODY.

7294
04:36:36,514 --> 04:36:40,217
SO WE SET OUT TO ASK THE

7295
04:36:40,217 --> 04:36:45,122
QUESTION, CAN WE USE VISUALIZING

7296
04:36:45,122 --> 04:36:46,790
ANTIBODIES IN THE -- 9 SYSTEM TO

7297
04:36:46,790 --> 04:36:48,158
CHANGE THE DYNAMICS POST ARTERY

7298
04:36:48,158 --> 04:36:48,392
LEASE.

7299
04:36:48,392 --> 04:36:51,795
AND THAT IS, TO SIMULTANEOUSLY

7300
04:36:51,795 --> 04:36:53,864
SUPPRESS VIRUS WITH THE

7301
04:36:53,864 --> 04:36:54,698
ANTIBODY, MAYBE ALLOWING A

7302
04:36:54,698 --> 04:36:56,567
LITTLE BIT TO COME UP TO BE ABLE

7303
04:36:56,567 --> 04:36:58,736
TO INHIBIT -- TO STIMULATE THE

7304
04:36:58,736 --> 04:37:00,905
IMMUNE SYSTEM, HAVE A SOONER,

7305
04:37:00,905 --> 04:37:02,973
QUICKER, BIGGER IMMUNE RESPONSE

7306
04:37:02,973 --> 04:37:06,644
THAT COMES BEFORE THAT GROWTH

7307
04:37:06,644 --> 04:37:07,912
AND SYSTEMIZATION OF THE VIRUS,

7308
04:37:07,912 --> 04:37:09,213
AND THEREFORE HAS A BETTER

7309
04:37:09,213 --> 04:37:12,716
CHANCE OF SUPPRESSING IT.

7310
04:37:12,716 --> 04:37:15,419
AND THAT'S THE BASIC CONCEPT.

7311
04:37:15,419 --> 04:37:23,460
NOW, IN RECENT YEARS, AT LEAST

7312
04:37:23,460 --> 04:37:25,029
TWO POTENT INITIALIZING

7313
04:37:25,029 --> 04:37:25,896
ANTIBODIES HAVE BEEN DEVELOPED

7314
04:37:25,896 --> 04:37:30,200
FOR THIS VIRUS.

7315
04:37:30,200 --> 04:37:34,905
THERE'S THE ITS SUN 03.01 BY

7316
04:37:34,905 --> 04:37:39,710
MARIO ROEDERER AND THE K11 BY

7317
04:37:39,710 --> 04:37:41,211
DENNIS BURTON, BOTH HAVE

7318
04:37:41,211 --> 04:37:42,413
DOCUMENTED ADCC ACTIVITY AND

7319
04:37:42,413 --> 04:37:43,914
THEREFORE I THINK ALLOW US TO

7320
04:37:43,914 --> 04:37:47,851
TEST THIS HYPOTHESIS.

7321
04:37:47,851 --> 04:37:49,386
AND I WOULD ALSO ADD THAT IN

7322
04:37:49,386 --> 04:37:50,554
PILOT STUDIES THAT I DON'T HAVE

7323
04:37:50,554 --> 04:37:51,655
TIME TO SHOW YOU THE COMBINATION

7324
04:37:51,655 --> 04:37:54,291
OF THESE ANTIBODIES, WE'RE ABLE

7325
04:37:54,291 --> 04:37:57,294
TO POTENTLY SUPPRESS ACTIVE

7326
04:37:57,294 --> 04:37:59,063
VIREMIA IN INFECTED ANIMALS WHEN

7327
04:37:59,063 --> 04:38:05,703
THE NEUTRALIZATION TIGHT TITER S

7328
04:38:05,703 --> 04:38:09,640
ABOVE  1 TO 500.

7329
04:38:09,640 --> 04:38:11,809
STUDY 1, THESE ANIMALS WERE PUT

7330
04:38:11,809 --> 04:38:13,877
ON ART AT DAY 9, THE DAY THEY

7331
04:38:13,877 --> 04:38:15,646
HAVE WHAT WE DESCRIBE AS A FULL

7332
04:38:15,646 --> 04:38:17,481
RESERVOIR, AND THEY WERE

7333
04:38:17,481 --> 04:38:19,550
SUPPRESSED BY A POTENT

7334
04:38:19,550 --> 04:38:20,651
ANTIRETROVIRAL THERAPY FOR

7335
04:38:20,651 --> 04:38:20,985
72 WEEKS.

7336
04:38:20,985 --> 04:38:26,624
AS SHOWN IN THE TOP MIDDLE.

7337
04:38:26,624 --> 04:38:28,359
THREE DAYS AFTER THE LAST DOSE

7338
04:38:28,359 --> 04:38:30,894
OF ART, THEY WERE EITHER GIVEN A

7339
04:38:30,894 --> 04:38:32,830
CONTROL ANTI ANTIBODY OR THEY WE

7340
04:38:32,830 --> 04:38:35,232
GIVEN A COMBINATION OF THE TWO

7341
04:38:35,232 --> 04:38:36,333
NEUTRALIZING ANTIBODIES I

7342
04:38:36,333 --> 04:38:40,004
MENTIONED AT 20 MGS PER KG AND

7343
04:38:40,004 --> 04:38:41,005
THEN THEY WERE FOLLOWED

7344
04:38:41,005 --> 04:38:41,305
CAREFULLY.

7345
04:38:41,305 --> 04:38:43,073
AS WE HAVE EXPECTED, THERE WAS A

7346
04:38:43,073 --> 04:38:47,711
HUGE DELAY IN VIRAL REBOUND,

7347
04:38:47,711 --> 04:38:49,813
THAT IN THIS PARTICULAR CASE WAS

7348
04:38:49,813 --> 04:38:51,215
LIKE 10 WEEKS OR 12 WEEKS.

7349
04:38:51,215 --> 04:38:54,318
I CAN'T SEE WELL ENOUGH TO SEE

7350
04:38:54,318 --> 04:38:54,785
WHAT IT IS.

7351
04:38:54,785 --> 04:38:55,886
THAT'S A LONG TIMEMENT VERY

7352
04:38:55,886 --> 04:38:56,320
SIGNIFICANT.

7353
04:38:56,320 --> 04:38:57,721
BASICALLY ALL THE ANIMALS

7354
04:38:57,721 --> 04:39:00,024
REBOUNDED WHEN THE NEUTRALIZING

7355
04:39:00,024 --> 04:39:04,261
ANTIBODY TITERS REACHED BELOW

7356
04:39:04,261 --> 04:39:07,197
1 TO 500, IN THIS CASE 1 TO 330.

7357
04:39:07,197 --> 04:39:08,632
HOWEVER, WHEN WE LOOKED AT --

7358
04:39:08,632 --> 04:39:10,167
WHEN WE NORMALIZED ALL THESE

7359
04:39:10,167 --> 04:39:12,102
ANIMALS TO REBOUND AND ASKED THE

7360
04:39:12,102 --> 04:39:13,070
QUESTION WHAT HAPPENED WITH POST

7361
04:39:13,070 --> 04:39:14,838
ART CONTROL, WE SAW NOTHING.

7362
04:39:14,838 --> 04:39:17,174
SO LOOKING AT THE VIRAL LOAD

7363
04:39:17,174 --> 04:39:18,842
PROFILES IN THE LOWER LEFT OR

7364
04:39:18,842 --> 04:39:22,379
THE SUMMATION OF THE VIRAL SET

7365
04:39:22,379 --> 04:39:23,447
POINT ON THE RIGHT GRAPH, THERE

7366
04:39:23,447 --> 04:39:25,482
WAS NO DIFFERENCE IN POST ART

7367
04:39:25,482 --> 04:39:26,884
VIRAL SET POINTS.

7368
04:39:26,884 --> 04:39:29,853
SO WE DID NOT SEE ANYTHING IN

7369
04:39:29,853 --> 04:39:33,323
THIS RESEMBLING A VACCINAL

7370
04:39:33,323 --> 04:39:34,625
EFFECTIVE EXPERIMENT SO WE SAID

7371
04:39:34,625 --> 04:39:35,826
LET'S PUT OUR FINGER ON THE

7372
04:39:35,826 --> 04:39:36,927
SCALE HERE AND SEE IF WE CAN

7373
04:39:36,927 --> 04:39:38,195
HELP THE IMMUNE RESPONSE.

7374
04:39:38,195 --> 04:39:39,863
INSTEAD OF PUTTING ANIMALS ON

7375
04:39:39,863 --> 04:39:42,466
ART AT DAY NINE, LET'S PUT THEM

7376
04:39:42,466 --> 04:39:44,835
ON AT DAY 35, LET'S ASK THE

7377
04:39:44,835 --> 04:39:46,236
QUESTION WHETHER THIS GIVES THEM

7378
04:39:46,236 --> 04:39:47,271
A MORE POE AT THE PRESENT TIME

7379
04:39:47,271 --> 04:39:48,872
RESPONSE BY MAKING SURE THAT ALL

7380
04:39:48,872 --> 04:39:51,942
THE ANIMALS IS BOTH GROUPS HAD

7381
04:39:51,942 --> 04:39:54,011
PROTECTIVE MHC1 ALLELES AND

7382
04:39:54,011 --> 04:39:54,778
ASKED THE SAME QUESTION.

7383
04:39:54,778 --> 04:39:56,613
AND AGAIN WE REPEATED THE

7384
04:39:56,613 --> 04:39:58,048
EXPERIMENT, AS SHOWN IN THE

7385
04:39:58,048 --> 04:39:59,783
LOWER LEFT, THE NEUTRALIZING

7386
04:39:59,783 --> 04:40:02,686
ANTIBODIES HAD THE SAME PROFOUND

7387
04:40:02,686 --> 04:40:05,656
DELAY IN VIRAL REBOUND.

7388
04:40:05,656 --> 04:40:07,191
BUT AGAIN THERE WAS NO CHANGE IN

7389
04:40:07,191 --> 04:40:09,693
THE SET POINT VIREMIA AFTER

7390
04:40:09,693 --> 04:40:10,794
REBOUND, AND IN FACT IN THE

7391
04:40:10,794 --> 04:40:12,196
LOWER RIGHT, YOU CAN SEE THAT

7392
04:40:12,196 --> 04:40:13,931
THE CD8 T-CELL RESPONSES TO

7393
04:40:13,931 --> 04:40:15,432
REBOUND WERE OVERLAPPING.

7394
04:40:15,432 --> 04:40:20,137
SO THERE WAS NO APPARENT

7395
04:40:20,137 --> 04:40:20,904
VACCINAL EFFECT IN THIS

7396
04:40:20,904 --> 04:40:22,239
EXPERIMENT EITHER.

7397
04:40:22,239 --> 04:40:23,407
ONE LAST EXPERIMENT WE ALSO

7398
04:40:23,407 --> 04:40:24,742
ASKED THE QUESTION, WOULD

7399
04:40:24,742 --> 04:40:26,777
NEUTRALIZING ANTIBODIES

7400
04:40:26,777 --> 04:40:28,445
POTENTIATE ANOTHER

7401
04:40:28,445 --> 04:40:30,380
IMMUNOTHERAPY, IN THIS CASE,

7402
04:40:30,380 --> 04:40:31,548
ANTIPD-1 BLOCKADE.

7403
04:40:31,548 --> 04:40:33,417
STEVE SHOWED YOU AND IT'S SHOWN

7404
04:40:33,417 --> 04:40:35,185
IN THE TOP PANEL HERE, WE HAVE

7405
04:40:35,185 --> 04:40:36,587
PREVIOUSLY SHOWN THAT JUST

7406
04:40:36,587 --> 04:40:38,889
GIVING ANTIPD-1 IN THE

7407
04:40:38,889 --> 04:40:48,065
PERIARTERY LEASE PERIODPERIARTRT

7408
04:40:48,065 --> 04:40:49,533
DEPRESSION OF THE VIRAL SET

7409
04:40:49,533 --> 04:40:51,502
POINT AT LEAST WHILE THE

7410
04:40:51,502 --> 04:40:51,902
ANTIBODY IS THERE.

7411
04:40:51,902 --> 04:40:53,170
WE REPEATED THE EXPERIMENT IN

7412
04:40:53,170 --> 04:40:55,906
ANIMALS THAT WERE GIVEN THE

7413
04:40:55,906 --> 04:40:57,941
NEUTRALIZING ANTIBODIES, AND AS

7414
04:40:57,941 --> 04:40:59,042
SHOWN IN THE FAR RIGHT, EVEN

7415
04:40:59,042 --> 04:41:00,711
THOUGH THE REBOUND WAS DELAYED

7416
04:41:00,711 --> 04:41:03,313
BY WEEKS IN THESE ANIMALS, THE

7417
04:41:03,313 --> 04:41:05,582
END RESULT, THE EFFECT OF THE

7418
04:41:05,582 --> 04:41:07,217
PD-1 WAS EXACTLY THE SAME, SO

7419
04:41:07,217 --> 04:41:09,286
THERE'S NO POTENTIATION OF THAT

7420
04:41:09,286 --> 04:41:09,887
EFFECT.

7421
04:41:09,887 --> 04:41:11,655
SO IN TERMS OF SUMMARY, AND THIS

7422
04:41:11,655 --> 04:41:14,291
IS A VERY LAY LANGUAGE SUMMARY

7423
04:41:14,291 --> 04:41:17,995
OR CLEAR ENGLISH SUMMARY.

7424
04:41:17,995 --> 04:41:18,595
NEUTRALIZING ANTIBODIES AT THE

7425
04:41:18,595 --> 04:41:23,467
TIME OF ARTERY LEAF

7426
04:41:23,467 --> 04:41:25,769
SIGNIFICANTLY DELAYS TIME TO SIV

7427
04:41:25,769 --> 04:41:27,137
REBOUND.

7428
04:41:27,137 --> 04:41:28,906
THIS WAS NICE TO SEE -- HOWEVER,

7429
04:41:28,906 --> 04:41:30,207
THE APPLICATION OF THESE

7430
04:41:30,207 --> 04:41:31,074
NEUTRALIZING ANTIBODIES DID NOT

7431
04:41:31,074 --> 04:41:32,576
PROVIDE FOR ANY ENHANCED POST

7432
04:41:32,576 --> 04:41:33,243
ART CONTROL.

7433
04:41:33,243 --> 04:41:34,778
THERE'S NO EVIDENCE OF A

7434
04:41:34,778 --> 04:41:37,181
FUNCTIONAL VACCINAL EFFECT OR

7435
04:41:37,181 --> 04:41:38,849
ANY BENEFICIAL MODIFICATION OF

7436
04:41:38,849 --> 04:41:42,152
THE T-CELL VIRAL INTERCEPT.

7437
04:41:42,152 --> 04:41:43,821
SIV REBOUND DYNAMICS WERE

7438
04:41:43,821 --> 04:41:45,422
ASSOCIATED WITH DECAY IN

7439
04:41:45,422 --> 04:41:47,157
NEUTRALIZING ANTIBODY TITERS

7440
04:41:47,157 --> 04:41:49,259
INDICATING AT FULLY SUPPRESSIVE

7441
04:41:49,259 --> 04:41:51,962
LEVELS, NEUTRALIZING ANTIBODIES

7442
04:41:51,962 --> 04:41:52,930
EFFECTIVELY LIMIT VIRAL SPREAD.

7443
04:41:52,930 --> 04:41:56,900
TO US THEY LOOKED LIKE

7444
04:41:56,900 --> 04:41:58,202
NEUTRALIZING ANTIBODY ART.

7445
04:41:58,202 --> 04:42:01,772
THE COMBINATION OF NABS WITH

7446
04:42:01,772 --> 04:42:05,375
ANTIPD-1 DID NOT SHOW ENHANCED

7447
04:42:05,375 --> 04:42:09,079
POST ART ANTIVIRAL CONTROL.

7448
04:42:09,079 --> 04:42:10,914
IT'S POSSIBLE THAT NO LONGER NAB

7449
04:42:10,914 --> 04:42:12,983
SUPPRESSION OR DIFFERENT NABS

7450
04:42:12,983 --> 04:42:15,252
WOULD REVEAL PAIR PEW TICK

7451
04:42:15,252 --> 04:42:16,019
BENEFIT OR NOT.

7452
04:42:16,019 --> 04:42:17,454
TOTAL OF THREE EXPERIMENTS WHICH

7453
04:42:17,454 --> 04:42:18,655
I SHOWED YOU.

7454
04:42:18,655 --> 04:42:19,323
OKAY, AND THAT'S IT.

7455
04:42:19,323 --> 04:42:28,265
[APPLAUSE]

7456
04:42:28,265 --> 04:42:28,632
>> THANK YOU.

7457
04:42:28,632 --> 04:42:31,134
I'M GOING TO SPEAK WITH RESEARCH

7458
04:42:31,134 --> 04:42:33,003
FOCUS THREE ON BEHALF OF MYSELF

7459
04:42:33,003 --> 04:42:34,504
AND JAKE ESTES.

7460
04:42:34,504 --> 04:42:36,240
THIS IS THE TEAM INVOLVED IN

7461
04:42:36,240 --> 04:42:37,441
RF3.

7462
04:42:37,441 --> 04:42:39,376
WE COLLABORATE WITH A NUMBER OF

7463
04:42:39,376 --> 04:42:44,181
PHARMACEUTICAL COMPANIES, AND

7464
04:42:44,181 --> 04:42:47,484
THE MAIN GOAL OF RF3 IN DARE IS

7465
04:42:47,484 --> 04:42:51,188
TO IDENTIFY NOVEL STRATEGIES TO

7466
04:42:51,188 --> 04:42:53,023
ENHANCE CELL DEATH OF INFECTED

7467
04:42:53,023 --> 04:42:57,728
CELLS THAT PERSIST ON ART USING

7468
04:42:57,728 --> 04:43:02,432
IAP ANTAGONISTS, OR

7469
04:43:02,432 --> 04:43:03,166
BCL2 ANTAGONISTS TO

7470
04:43:03,166 --> 04:43:05,135
SIGNIFICANTLY REDUCE THE

7471
04:43:05,135 --> 04:43:05,569
RESERVOIR.

7472
04:43:05,569 --> 04:43:06,970
I'M GOING TO SPEAK TO YOU MAINLY

7473
04:43:06,970 --> 04:43:09,473
ON OUR WORK THAT WAS RECENTLY

7474
04:43:09,473 --> 04:43:12,643
PUBLISHED ON VENETOCLAX IN

7475
04:43:12,643 --> 04:43:17,547
COMBINATION WITH ANOVA

7476
04:43:17,547 --> 04:43:20,083
ANTISURVIVAL PROTEIN IN EX VIVO

7477
04:43:20,083 --> 04:43:25,789
SAMPLES OF HUMANIZED MICE.

7478
04:43:25,789 --> 04:43:29,793
MIMETIC WORK MAINLY FOCUSING ON

7479
04:43:29,793 --> 04:43:31,561
MONOVALENT SMACK MIMETICS SO I

7480
04:43:31,561 --> 04:43:33,063
ENCOURAGE YOU TO GO SEE THE

7481
04:43:33,063 --> 04:43:33,297
POSTER.

7482
04:43:33,297 --> 04:43:35,565
SO AS WE HEARD EARLIER TODAY,

7483
04:43:35,565 --> 04:43:37,434
GREAT OVERVIEW FROM ANDREW

7484
04:43:37,434 --> 04:43:41,004
BADLEY, BCL2 IS IMPORTANT FOR

7485
04:43:41,004 --> 04:43:43,173
THE SURVIVAL OF LATENTLY

7486
04:43:43,173 --> 04:43:43,941
INFECTED CELLS.

7487
04:43:43,941 --> 04:43:46,009
MANY GROUPS IS SHOWN THAT

7488
04:43:46,009 --> 04:43:47,344
LATENTLY INFECTED CELLS

7489
04:43:47,344 --> 04:43:50,047
OVEREXPRESS THE PROTEIN BCL2,

7490
04:43:50,047 --> 04:43:53,450
TIPPING THE PRO AND

7491
04:43:53,450 --> 04:43:54,351
ANTI-APOPTOTIC MACHINERY OF

7492
04:43:54,351 --> 04:43:57,454
EVERY CELL IN FAVOR OF SURVIVAL.

7493
04:43:57,454 --> 04:43:58,889
AND THEREFORE INHIBITING THAT

7494
04:43:58,889 --> 04:44:01,792
PROTEIN WITH A DRUG SUCH AS

7495
04:44:01,792 --> 04:44:03,894
VENETOCLAX COULD POTENTIALLY TIP

7496
04:44:03,894 --> 04:44:06,964
THE CELL INTO APOPTOSIS.

7497
04:44:06,964 --> 04:44:08,598
AS YOU HEARD EARLIER, VENETOCLAX

7498
04:44:08,598 --> 04:44:11,535
IS A BCL2 ANTAGONIST LICENSED

7499
04:44:11,535 --> 04:44:13,704
FOR THE TREATMENT OF CHRONIC

7500
04:44:13,704 --> 04:44:16,473
LYMPHOCYTIC LEUKEMIA -- CLINICAL

7501
04:44:16,473 --> 04:44:17,975
EXPERIENCE WITH USING THIS DRUG.

7502
04:44:17,975 --> 04:44:20,243
EX VIVO, A NUMBER OF GROUPS HAVE

7503
04:44:20,243 --> 04:44:21,745
SHOWN THAT VENETOCLAX LEADS TO

7504
04:44:21,745 --> 04:44:24,047
THE SELECTIVE DEATH OF LATENTLY

7505
04:44:24,047 --> 04:44:25,148
INFECTED CELLS, PRESUMABLY

7506
04:44:25,148 --> 04:44:26,383
BECAUSE OF THIS OVEREXPRESSION

7507
04:44:26,383 --> 04:44:28,518
AND DEPENDENCE ON BCL2 FOR

7508
04:44:28,518 --> 04:44:29,052
SURVIVAL.

7509
04:44:29,052 --> 04:44:30,687
AND OTHERS HAVE SHOWN THAT THE

7510
04:44:30,687 --> 04:44:33,323
EFFECTS ARE ENHANCED IN THE

7511
04:44:33,323 --> 04:44:35,359
PRESENCE OF CD8 T-CELLS, MAKING

7512
04:44:35,359 --> 04:44:38,195
THEM MORE AMENABLE TO TOXICITY

7513
04:44:38,195 --> 04:44:39,429
AND ALSO WE'VE SHOWN THAT IN THE

7514
04:44:39,429 --> 04:44:42,766
PRESENCE OF HRV PROTEINS OR

7515
04:44:42,766 --> 04:44:43,867
LATENCY APPROACHING AGENTS THIS

7516
04:44:43,867 --> 04:44:45,335
EFFECT IS ENHANCED.

7517
04:44:45,335 --> 04:44:49,873
SO TOGETHER WITH MARK PILLIGRINI

7518
04:44:49,873 --> 04:44:52,109
WHERE VENETOCLAX WAS DISCOVERED,

7519
04:44:52,109 --> 04:44:54,378
MARK TESTED VENETOCLAX IN A

7520
04:44:54,378 --> 04:44:56,113
HUMANIZED MOUSE MODEL.

7521
04:44:56,113 --> 04:44:58,648
HE TOOK HUMANIZED MOUSE MODEL

7522
04:44:58,648 --> 04:45:01,685
INFECTED WITH HIV, PLACED THOSE

7523
04:45:01,685 --> 04:45:03,987
ANIMALS ON ART AND GAVE

7524
04:45:03,987 --> 04:45:05,822
DIFFERENT DURATION OF

7525
04:45:05,822 --> 04:45:06,923
VENETOCLAX.

7526
04:45:06,923 --> 04:45:08,358
INITIALLY FIVE DAYS, WHICH

7527
04:45:08,358 --> 04:45:10,861
SHOWED LIMITED IMPACT ON TIME TO

7528
04:45:10,861 --> 04:45:12,496
VIRAL REBOUND, AND THEN GAVE

7529
04:45:12,496 --> 04:45:17,067
REPEATED DOSING, SIX COURSES OF

7530
04:45:17,067 --> 04:45:18,535
VENETOCLAX, EACH OF FIVE DAYS

7531
04:45:18,535 --> 04:45:20,470
WITH A TWO-DAYBREAK IN BETWEEN

7532
04:45:20,470 --> 04:45:22,506
EACH COURSE.

7533
04:45:22,506 --> 04:45:25,475
AND WHAT MARK SHOWED WAS INDEED

7534
04:45:25,475 --> 04:45:26,343
THAT THIS TREATMENT OF

7535
04:45:26,343 --> 04:45:29,413
VENETOCLAX COMPARED TO A VEHICLE

7536
04:45:29,413 --> 04:45:30,947
CONTROL LED TO A SIGNIFICANT

7537
04:45:30,947 --> 04:45:35,385
DELAY IN VIRAL REBOUND.

7538
04:45:35,385 --> 04:45:36,486
HE THEN ASKED WHETHER THIS

7539
04:45:36,486 --> 04:45:39,990
EFFECT COULD BE ENHAN ENHANCED Y

7540
04:45:39,990 --> 04:45:43,794
BROCKBLOCKING OVER BCL2 PROTEIN.

7541
04:45:43,794 --> 04:45:45,262
IT SHOWS A RANGE OF PROTEINS

7542
04:45:45,262 --> 04:45:47,197
THAT SIT IN THE BCL2 FAMILY.

7543
04:45:47,197 --> 04:45:55,906
YOU CAN SEE BCL2, BCLXL, BCLW,

7544
04:45:55,906 --> 04:45:56,239
MCL1 AND.

7545
04:45:56,239 --> 04:45:56,473
1.

7546
04:45:56,473 --> 04:45:57,674
THERE ARE OTHER COMPOUNDS THAT

7547
04:45:57,674 --> 04:46:00,277
BLOCK THESE OTHER PRO SURVIVAL

7548
04:46:00,277 --> 04:46:00,544
PROTEINS.

7549
04:46:00,544 --> 04:46:07,017
ONE OF THOSE BEING SX3845 AND

7550
04:46:07,017 --> 04:46:09,352
MCL1 INHIBITOR NOT YET LICENSED.

7551
04:46:09,352 --> 04:46:12,722
SO MARK GAVE THIS COMBINATION TO

7552
04:46:12,722 --> 04:46:15,225
HUMANIZED MICE, THIS TIME WITH A

7553
04:46:15,225 --> 04:46:16,860
REDUCED DOSE OF VENETOCLAX, JUST

7554
04:46:16,860 --> 04:46:20,464
THREE CYCLES TOGETHER WITH THE

7555
04:46:20,464 --> 04:46:21,231
MCL-1 INHIBITOR, AND AGAIN

7556
04:46:21,231 --> 04:46:23,767
SHOWED DELAYED TIME TO VIRAL

7557
04:46:23,767 --> 04:46:26,169
REBOUND.

7558
04:46:26,169 --> 04:46:29,673
WE THEN WORKED WITH MARK TO

7559
04:46:29,673 --> 04:46:30,540
DECIDE WHAT VENETOCLAX WAS DOING

7560
04:46:30,540 --> 04:46:31,942
TO CELLS THAT CAME FROM

7561
04:46:31,942 --> 04:46:34,377
PARTICIPANTS LIVING WITH HIV ON

7562
04:46:34,377 --> 04:46:35,011
ANTIRETROVIRAL THERAPY.

7563
04:46:35,011 --> 04:46:38,381
THEY UNDERWENT LEUKOPHORESIS AND

7564
04:46:38,381 --> 04:46:39,249
TREATMENT EX VIVO WITH

7565
04:46:39,249 --> 04:46:40,250
VENETOCLAX, AND WE COULD SHOW

7566
04:46:40,250 --> 04:46:42,085
THAT ON THE LEFT, THERE WAS A

7567
04:46:42,085 --> 04:46:45,789
DOSE DEPENDENT REDUCTION IN

7568
04:46:45,789 --> 04:46:47,958
INTEGRATED DNA AND ON THE RIGHT,

7569
04:46:47,958 --> 04:46:51,261
A DOSE DEPENDENT REDUCTION IN

7570
04:46:51,261 --> 04:46:55,065
INTACT DNA MEASURED BY THE IPDA

7571
04:46:55,065 --> 04:46:55,398
ASSAY.

7572
04:46:55,398 --> 04:46:57,801
AND THERE WAS NO EFFECT ON

7573
04:46:57,801 --> 04:47:00,670
DEFECTIVE VIRUS.

7574
04:47:00,670 --> 04:47:02,339
WE USED DIFFERENT CONCENTRATIONS

7575
04:47:02,339 --> 04:47:05,742
OF VENETOCLAX EX VIVO, 5, 10 AND

7576
04:47:05,742 --> 04:47:07,110
100 NANOMOLAR.

7577
04:47:07,110 --> 04:47:08,712
JUST TO NOTE THAT 1,000

7578
04:47:08,712 --> 04:47:10,313
NANOMOLAR HAS NOT BEEN USED, IT

7579
04:47:10,313 --> 04:47:11,581
HAS BEEN USED IN OTHER

7580
04:47:11,581 --> 04:47:12,816
PUBLICATIONS, IT LED TO

7581
04:47:12,816 --> 04:47:14,184
SIGNIFICANT GENERALIZED CELLULAR

7582
04:47:14,184 --> 04:47:16,486
TOXICITY.

7583
04:47:16,486 --> 04:47:18,388
SO THE NEXT QUESTION WAS WHY AND

7584
04:47:18,388 --> 04:47:20,290
WHAT WAS VENETOCLAX DOING TO

7585
04:47:20,290 --> 04:47:20,857
THESE CELLS.

7586
04:47:20,857 --> 04:47:24,361
AND WE ADDRESSED THIS BY TAKING

7587
04:47:24,361 --> 04:47:27,430
CD4 T-CELLS IN PEOPLE WITH HIV

7588
04:47:27,430 --> 04:47:30,033
ON ANTIRETROVIRAL THERAPY,

7589
04:47:30,033 --> 04:47:31,434
TREATED EX VIVO WITH VENETOCLAX

7590
04:47:31,434 --> 04:47:35,839
AND LOOKED AT THE SELECTIVE

7591
04:47:35,839 --> 04:47:37,674
IMPACT OF DEATH OF T-CELL

7592
04:47:37,674 --> 04:47:38,875
SUBSETS AND ALSO PERFORMED RNA

7593
04:47:38,875 --> 04:47:40,243
SEQ.

7594
04:47:40,243 --> 04:47:42,279
SO THIS JUST SHOWS YOU THE

7595
04:47:42,279 --> 04:47:44,347
PERCENTAGE OF CELLS THAT WERE

7596
04:47:44,347 --> 04:47:47,951
DYING AMONGST CENTRAL MEMORY,

7597
04:47:47,951 --> 04:47:50,353
TRANSITIONAL MEMORY, EFFECTIVE

7598
04:47:50,353 --> 04:47:52,455
MEMORY AND DIFFERENTIATED

7599
04:47:52,455 --> 04:47:54,157
T-CELLS AT FIVE DIFFERENT DOSES

7600
04:47:54,157 --> 04:47:57,027
OF VENETOCLAX, 5, 10 AND 100

7601
04:47:57,027 --> 04:47:58,662
NANOMOLAR, THE INTENSITY OF THE

7602
04:47:58,662 --> 04:48:01,031
BLUE SHOWS YOU MORE DEATH WITH A

7603
04:48:01,031 --> 04:48:01,464
DEEPER BLUE.

7604
04:48:01,464 --> 04:48:02,999
SO YOU CAN SEE HERE THAT REALLY

7605
04:48:02,999 --> 04:48:07,571
AT THE LOWER DOSES, THERE'S

7606
04:48:07,571 --> 04:48:08,905
SIMILAR DEATH AMONGST THE T-CELL

7607
04:48:08,905 --> 04:48:10,307
SUBSETS BUT MORE DEATH IN

7608
04:48:10,307 --> 04:48:11,841
EFFECTOR MEMORY AND NAIVE

7609
04:48:11,841 --> 04:48:14,010
T-CELLS AND THAT'S CLEARLY

7610
04:48:14,010 --> 04:48:15,011
ENHANCED AT THE HIGHER DOSE.

7611
04:48:15,011 --> 04:48:18,615
WE THEN DID RNA SEQ AND LOOKED

7612
04:48:18,615 --> 04:48:24,054
AT THE EXPRESSION OF RNA OF PRO

7613
04:48:24,054 --> 04:48:26,489
DEATH PROTEINS, AND PRO SURVIVAL

7614
04:48:26,489 --> 04:48:27,390
PROTEINS.

7615
04:48:27,390 --> 04:48:30,460
SO IF VENETOCLAX IS TIPPING, IF

7616
04:48:30,460 --> 04:48:35,699
YOU'VE REDUCED THE PROTEIN BCL2,

7617
04:48:35,699 --> 04:48:37,200
THE DIES THAT ARE DYING EXPRESS

7618
04:48:37,200 --> 04:48:38,301
THE PRO DEATH MARKER.

7619
04:48:38,301 --> 04:48:40,270
SO YOU CAN SEE THIS IS EXACTLY

7620
04:48:40,270 --> 04:48:41,771
WHAT WE SAW, THAT THE CELLS THAT

7621
04:48:41,771 --> 04:48:43,640
WERE PICKED OFF BY VENETOCLAX

7622
04:48:43,640 --> 04:48:46,610
WERE ONES THAT WERE

7623
04:48:46,610 --> 04:48:48,044
OVEREXPRESSING PRO DEATH

7624
04:48:48,044 --> 04:48:48,345
TRANSCRIPTS.

7625
04:48:48,345 --> 04:48:49,679
AND YOU CAN SEE THAT THIS

7626
04:48:49,679 --> 04:48:51,548
SIGNIFICANTLY DECLINED WITH

7627
04:48:51,548 --> 04:48:53,383
VENETOCLAX, WHILE THE

7628
04:48:53,383 --> 04:48:55,352
PRO-SURVIVAL TRANSCRIPTS WERE

7629
04:48:55,352 --> 04:48:57,087
UNCHANGED, MEANING THAT THOSE

7630
04:48:57,087 --> 04:49:00,824
CELLS WERE NOT TIPPED TOWARDS

7631
04:49:00,824 --> 04:49:02,425
DYING.

7632
04:49:02,425 --> 04:49:04,861
SO THE OVERALL MODEL WE HAVE IS

7633
04:49:04,861 --> 04:49:06,496
THAT AMONGST LATENTLY INFECTED

7634
04:49:06,496 --> 04:49:07,797
CELLS, THERE'S INCREASED

7635
04:49:07,797 --> 04:49:09,866
EXPRESSION OF WHAT'S CALLED

7636
04:49:09,866 --> 04:49:12,802
BH3 ONLY PROTEINS THAT FAVOR

7637
04:49:12,802 --> 04:49:14,437
CELL DEATH IN THE PRESENCE OF

7638
04:49:14,437 --> 04:49:17,073
VENETOCLAX OR OTHER DRUGS THAT

7639
04:49:17,073 --> 04:49:19,042
BLOCK PRO-SURVIVAL PROTEINS.

7640
04:49:19,042 --> 04:49:20,343
THE INFECTED CELLS ARE MORE

7641
04:49:20,343 --> 04:49:23,179
LIKELY TO DIE, AND THAT'S WHY WE

7642
04:49:23,179 --> 04:49:24,481
GET SELECTIVE DEATH OF INFECTED

7643
04:49:24,481 --> 04:49:25,348
CELLS.

7644
04:49:25,348 --> 04:49:29,753
SO WHAT ARE THE NEXT STEPS?

7645
04:49:29,753 --> 04:49:31,054
WE'RE NOW GOING TO MOVE THIS

7646
04:49:31,054 --> 04:49:31,921
INTO MONKEYS.

7647
04:49:31,921 --> 04:49:33,657
WE'RE LOOKING AT STARTING

7648
04:49:33,657 --> 04:49:35,825
VENETOCLAX INTRAMUSCULARLY IN

7649
04:49:35,825 --> 04:49:38,662
NON-HUMAN PRIMATES.

7650
04:49:38,662 --> 04:49:40,330
DOSING HAS BEEN VERY KINDLY

7651
04:49:40,330 --> 04:49:44,234
INFORMED BY THE ARRAYS TEAM,

7652
04:49:44,234 --> 04:49:50,674
MA.IT SEEMS TO BE BEST DONE IM,

7653
04:49:50,674 --> 04:49:52,876
10 MILLIGRAMS PER KILOGRAM.

7654
04:49:52,876 --> 04:49:54,611
WE'RE FIRST GOING TO DO THIS IN

7655
04:49:54,611 --> 04:49:57,447
THE SETTING OF OTHERWISE

7656
04:49:57,447 --> 04:49:59,649
HEALTHY -- IN MONKEYS THAT ARE

7657
04:49:59,649 --> 04:50:00,817
VIE REMIBG AND THEN IN MONKEYS

7658
04:50:00,817 --> 04:50:03,887
THAT ARE ON ART AND UNDERGOING A

7659
04:50:03,887 --> 04:50:04,654
TREATMENT INTERRUPTION, AND THEN

7660
04:50:04,654 --> 04:50:07,257
THE GOAL WILL BE TO COMBINE

7661
04:50:07,257 --> 04:50:08,258
VENETOCLAX WITH OTHER AGENTS

7662
04:50:08,258 --> 04:50:11,194
THAT WE SHOW SYNERGY WITH EX

7663
04:50:11,194 --> 04:50:11,528
VIVO.

7664
04:50:11,528 --> 04:50:13,063
AT THE SAME TIME, WE'RE

7665
04:50:13,063 --> 04:50:14,831
SEPARATELY ABOUT TO START A

7666
04:50:14,831 --> 04:50:16,733
CLINICAL TRIAL OF VENETOCLAX

7667
04:50:16,733 --> 04:50:18,868
CALLED THE AMBA STUDY.

7668
04:50:18,868 --> 04:50:21,805
THIS IS LED BY THOMAS RASMUSSEN

7669
04:50:21,805 --> 04:50:22,439
IN DENMARK.

7670
04:50:22,439 --> 04:50:26,176
AND THIS STUDY HAS TWO PHASES.

7671
04:50:26,176 --> 04:50:30,080
THERE'S A DOSE ESCALATION PHASE,

7672
04:50:30,080 --> 04:50:30,947
200, 400 AND 800 MILLIGRAMS OF

7673
04:50:30,947 --> 04:50:32,582
VENETOCLAX WHICH IS BEING DOSED

7674
04:50:32,582 --> 04:50:35,652
AT OVER TWO WEEKS, AND THEN A

7675
04:50:35,652 --> 04:50:37,287
TWO-WEEK BREAK AND TWO WEEKS

7676
04:50:37,287 --> 04:50:37,487
AGAIN.

7677
04:50:37,487 --> 04:50:38,521
WE EXPECT THAT THIS IS GOING TO

7678
04:50:38,521 --> 04:50:41,224
BE SAFE, GIVEN WHAT WE KNOW FROM

7679
04:50:41,224 --> 04:50:44,294
OTHER CLINICAL TRIALS.

7680
04:50:44,294 --> 04:50:46,162
AND THEN AT THE FOURTH COHORT,

7681
04:50:46,162 --> 04:50:47,831
COHORT D WILL BE A PLACEBO

7682
04:50:47,831 --> 04:50:50,166
CONTROL STUDY OF VENETOCLAX, NO

7683
04:50:50,166 --> 04:50:51,201
TREATMENT INTERRUPTION, BUT TO

7684
04:50:51,201 --> 04:50:52,736
SEE THE EFFECT ON THE RESERVOIR.

7685
04:50:52,736 --> 04:50:54,237
THE MAIN GOAL BEING SAFETY AND

7686
04:50:54,237 --> 04:50:55,705
THEN, OF COURSE, UNDERSTAND THE

7687
04:50:55,705 --> 04:50:58,308
EFFECT OF THE RESERVOIR.

7688
04:50:58,308 --> 04:51:00,043
SO IN MY PLAIN ENGLISH SUMMARY,

7689
04:51:00,043 --> 04:51:01,044
WHAT ARE WE DOING?

7690
04:51:01,044 --> 04:51:03,646
WE ASKED WHETHER THE LICENSED

7691
04:51:03,646 --> 04:51:06,616
ANTICANCER DRUG VENETOCLAX COULD

7692
04:51:06,616 --> 04:51:08,051
INDUCE SELECTIVE DEATH OF THE

7693
04:51:08,051 --> 04:51:10,787
VIRAL RESERVOIR THROUGH

7694
04:51:10,787 --> 04:51:13,289
INHIBITING THE PROS OF OUR

7695
04:51:13,289 --> 04:51:14,157
PROTEIN BCL2.

7696
04:51:14,157 --> 04:51:15,592
WHAT DID WE FIND?

7697
04:51:15,592 --> 04:51:18,762
WE FOUND IN A HUMANIZED MOUSE

7698
04:51:18,762 --> 04:51:21,297
MODEL THIS DID INDEED LED TO

7699
04:51:21,297 --> 04:51:25,001
SIGNIFICANT DELAY OF REBOUND.

7700
04:51:25,001 --> 04:51:27,270
COULD BE REDUCED WHEN GIVEN WITH

7701
04:51:27,270 --> 04:51:31,541
ANOTHER PRO APOPTOTIC DRUG AND

7702
04:51:31,541 --> 04:51:35,145
ANTE MCL-1 INHIBITOR AND DOSE --

7703
04:51:35,145 --> 04:51:39,315
SEEN IN CELLS WITH PEOPLE HIV

7704
04:51:39,315 --> 04:51:41,184
TREATED WITH VENETOCLAX EX-VEE

7705
04:51:41,184 --> 04:51:41,918
RE VO.

7706
04:51:41,918 --> 04:51:43,553
IT'S LICENSED, IT'S SAFE, IN THE

7707
04:51:43,553 --> 04:51:45,422
ABSENCE OF CANCER, AND IT COULD

7708
04:51:45,422 --> 04:51:46,423
INDUCE SELECTIVE DEATH OF THE

7709
04:51:46,423 --> 04:51:47,624
RESERVOIR.

7710
04:51:47,624 --> 04:51:50,760
SO IN OUR TESTING ALONE AND IN

7711
04:51:50,760 --> 04:51:52,328
COMBINATION IN MACAQUES AND A

7712
04:51:52,328 --> 04:51:53,663
DOSE ESCALATION CLINICAL TRIAL

7713
04:51:53,663 --> 04:51:56,266
OF VENETOCLAX IS SOON TO START

7714
04:51:56,266 --> 04:51:58,768
WHICH I THINK WILL TELL US A LOT

7715
04:51:58,768 --> 04:52:00,837
NOT JUST ONLY IN THE

7716
04:52:00,837 --> 04:52:01,638
QUANTITATIVE CHANGE IN THE

7717
04:52:01,638 --> 04:52:02,939
RESERVOIR BUT WE PLAN TO LOOK

7718
04:52:02,939 --> 04:52:04,507
VERY DEEPLY AT THE QUALITATIVE

7719
04:52:04,507 --> 04:52:05,241
CHANGES IN THE RESERVOIR.

7720
04:52:05,241 --> 04:52:09,712
AND JUST WHAT  WANT TO ABLG KNOE

7721
04:52:09,712 --> 04:52:17,053
ACKNOWLEDGE ALLTHE PEOPLE WHO D.

7722
04:52:17,053 --> 04:52:19,222
PARTICULARLY MARK AND PHIL, WHO

7723
04:52:19,222 --> 04:52:20,757
LED THE MOUSE STUDIES, AND I'LL

7724
04:52:20,757 --> 04:52:21,191
STOP THERE.

7725
04:52:21,191 --> 04:52:25,829
THANKS VERY MUCH.

7726
04:52:25,829 --> 04:52:33,036
[APPLAUSE]

7727
04:52:33,036 --> 04:52:34,270
>> HI, EVERYBODY.

7728
04:52:34,270 --> 04:52:35,638
THANKS FOR HANGING IN TO ALMOST

7729
04:52:35,638 --> 04:52:37,173
THE BITTER END.

7730
04:52:37,173 --> 04:52:39,042
SO I AM THE DARE COMMUNITY

7731
04:52:39,042 --> 04:52:40,009
ENGAGEMENT COORDINATOR, AND I'M

7732
04:52:40,009 --> 04:52:42,545
GOING TO TELL YOU ABOUT WHAT WE

7733
04:52:42,545 --> 04:52:43,847
DID IN THE FIRST YEAR AND WHAT

7734
04:52:43,847 --> 04:52:45,682
WE LEARNED, WHAT WE'RE DOING

7735
04:52:45,682 --> 04:52:48,251
THIS YEAR, AND WHAT WE PLAN TO

7736
04:52:48,251 --> 04:52:50,220
DO.

7737
04:52:50,220 --> 04:52:52,956
LAST YEAR WE HAD A CELL AND GENE

7738
04:52:52,956 --> 04:52:54,057
THERAPY WEBINAR SERIES.

7739
04:52:54,057 --> 04:52:56,259
I'M A BIG BELIEVER IN STRUCTURE

7740
04:52:56,259 --> 04:52:56,793
AND REPETITION.

7741
04:52:56,793 --> 04:52:59,262
AND SO WHAT WE DID WAS, MONTHLY,

7742
04:52:59,262 --> 04:53:03,032
WE HAD THESE MEETINGS WITH

7743
04:53:03,032 --> 04:53:05,101
REALLY GREAT SCIENTISTS AND

7744
04:53:05,101 --> 04:53:07,303
COMMUNITY PEOPLE FROM AROUND THE

7745
04:53:07,303 --> 04:53:07,837
COUNTRY.

7746
04:53:07,837 --> 04:53:10,440
WE'RE A U.S.-BASED CAB SO OUR

7747
04:53:10,440 --> 04:53:11,875
COMMUNITY PEOPLE ARE PRETTY MUCH

7748
04:53:11,875 --> 04:53:13,943
FROM THE UNITED STATES.

7749
04:53:13,943 --> 04:53:16,246
ANYWAY, WE LEARNED A LOT HERE, I

7750
04:53:16,246 --> 04:53:18,548
MEAN, WE HAD THE RESEARCHERS

7751
04:53:18,548 --> 04:53:21,384
INTERACT WITH COMMUNITY PEOPLE,

7752
04:53:21,384 --> 04:53:24,854
AND WHAT WE LEARNED WAS THAT WE

7753
04:53:24,854 --> 04:53:25,788
WANTED TO TRY AND DO IT

7754
04:53:25,788 --> 04:53:26,222
DIFFERENTLY.

7755
04:53:26,222 --> 04:53:29,926
SO THIS YEAR WE'VE BEEN DEALING

7756
04:53:29,926 --> 04:53:35,865
WITH IF-50-PLUS PEOPLE, LONG TEM

7757
04:53:35,865 --> 04:53:40,570
SURVIVORS, PEOPLE WITH HIV, AND

7758
04:53:40,570 --> 04:53:43,840
WE PILOTED THIS TO SEE HOW IT

7759
04:53:43,840 --> 04:53:44,941
WOULD GO OVER WITH PEOPLE OF

7760
04:53:44,941 --> 04:53:46,809
COLOR AND WITH OLDER PEOPLE,

7761
04:53:46,809 --> 04:53:48,778
ACTUALLY WENT VERY WELL AND WAS

7762
04:53:48,778 --> 04:53:51,948
COVERED BY POSITIVELY AWARE, A

7763
04:53:51,948 --> 04:53:54,350
GREAT HIV-POSITIVE NEWSLETTER.

7764
04:53:54,350 --> 04:53:58,054
ANYWAY, SO WHAT WE DID WITH THIS

7765
04:53:58,054 --> 04:53:59,923
NEW SERIES, WHICH IS AGAIN SEVEN

7766
04:53:59,923 --> 04:54:03,426
WEEKS FOR SEVEN MONTHS -- EXCUSE

7767
04:54:03,426 --> 04:54:05,728
ME, SEVEN MONTHS OF SERIES.

7768
04:54:05,728 --> 04:54:08,331
ANYWAY, WITH LONG TERM

7769
04:54:08,331 --> 04:54:09,432
SURVIVORS, COLLABORATORS, WHICH

7770
04:54:09,432 --> 04:54:12,068
WE BELIEVE IN ALSO, DARE, RID

7771
04:54:12,068 --> 04:54:15,138
HIV, CRISPR FOR CURE, WE BELIEVE

7772
04:54:15,138 --> 04:54:16,773
THERE'S A LOT OF SYNERGY IN

7773
04:54:16,773 --> 04:54:18,541
WORKING TOGETHER ON THESE

7774
04:54:18,541 --> 04:54:18,841
THINGS.

7775
04:54:18,841 --> 04:54:20,076
IF YOU'LL SEE ON THE BOTTOM,

7776
04:54:20,076 --> 04:54:22,011
THERE ARE 18 DIFFERENT

7777
04:54:22,011 --> 04:54:22,912
ORGANIZATIONS THAT WERE

7778
04:54:22,912 --> 04:54:23,446
SPONSORED.

7779
04:54:23,446 --> 04:54:25,949
AND SO THIS TIME INSTEAD OF

7780
04:54:25,949 --> 04:54:29,786
PUTTING ONE PERSON ON A PANEL

7781
04:54:29,786 --> 04:54:32,255
WITH AN INVESTIGATOR, WE PUT TWO

7782
04:54:32,255 --> 04:54:34,757
OR THREE AND 16 OF THESE 18

7783
04:54:34,757 --> 04:54:36,025
ORGANIZATIONS WERE INCLUDED IN

7784
04:54:36,025 --> 04:54:37,560
THOSE PANELS.

7785
04:54:37,560 --> 04:54:39,095
HERE'S THE FIRST, WE GET AN

7786
04:54:39,095 --> 04:54:42,265
INTRO TO AGING, INTRO TO CURE

7787
04:54:42,265 --> 04:54:45,735
RESEARCH, A SESSION ON ATIs,

7788
04:54:45,735 --> 04:54:49,372
WOMEN WITH HIV, AND LIFETIME

7789
04:54:49,372 --> 04:54:50,406
SURVIVORS.

7790
04:54:50,406 --> 04:54:51,374
THOSE TWO SESSIONS WERE REALLY

7791
04:54:51,374 --> 04:54:51,641
WONDERFUL.

7792
04:54:51,641 --> 04:54:54,677
WE LEARNED SO MUCH AND SO MUCH

7793
04:54:54,677 --> 04:54:56,112
NEW INFORMATION FROM PEOPLE THAT

7794
04:54:56,112 --> 04:54:59,382
ARE USUALLY NOT INCLUDED.

7795
04:54:59,382 --> 04:55:00,483
I'LL JUST PUT IT THAT WAY.

7796
04:55:00,483 --> 04:55:01,784
THE LAST TWO SESSIONS ARE GOING

7797
04:55:01,784 --> 04:55:03,753
TO BE JUST COMMUNITY PEOPLE.

7798
04:55:03,753 --> 04:55:05,955
TRIAL PARTICIPANTS, GIVEN THEIR

7799
04:55:05,955 --> 04:55:06,255
EXPERIENCES.

7800
04:55:06,255 --> 04:55:10,526
AND WHERE DO WE GO FROM HERE.

7801
04:55:10,526 --> 04:55:12,161
AND WE WERE PLEASANTLY

7802
04:55:12,161 --> 04:55:12,962
SURPRISED, BECAUSE WHAT HAPPENS

7803
04:55:12,962 --> 04:55:13,363
WITH THIS?

7804
04:55:13,363 --> 04:55:17,333
WHAT HAPPENED WITH THIS IS WITH

7805
04:55:17,333 --> 04:55:18,267
THAT STRUCTURE AND REPETITION

7806
04:55:18,267 --> 04:55:19,402
AND WITH INCLUDING ALL OF THESE

7807
04:55:19,402 --> 04:55:20,803
OTHER ORGANIZATIONS, IT HAS LIKE

7808
04:55:20,803 --> 04:55:23,973
A RIPPLE EFFECT.

7809
04:55:23,973 --> 04:55:24,641
SO THE KNOWLEDGE WE LEARN FROM

7810
04:55:24,641 --> 04:55:26,275
THE INVESTIGATORS COMES DOWN TO

7811
04:55:26,275 --> 04:55:27,810
THE COMMUNITY AND COMMUNITY

7812
04:55:27,810 --> 04:55:29,612
LEADERS AND THEN THEY TAKE TO

7813
04:55:29,612 --> 04:55:31,114
THEIR COMMUNITIES AND IT REALLY

7814
04:55:31,114 --> 04:55:32,749
ENDS UP -- WE HAVE OUR OWN

7815
04:55:32,749 --> 04:55:34,484
LITTLE COHORT, YOU KNOW, OUR

7816
04:55:34,484 --> 04:55:36,452
U.S. COHORT OF PEOPLE THAT

7817
04:55:36,452 --> 04:55:38,321
ATTEND OUR MEETINGS PRETTY

7818
04:55:38,321 --> 04:55:38,955
REGULARLY.

7819
04:55:38,955 --> 04:55:42,358
AND WE HAD ALMOST THREE TIMES

7820
04:55:42,358 --> 04:55:43,893
THE NUMBER OF PEOPLE AT THESE

7821
04:55:43,893 --> 04:55:45,194
SESSIONS THAN WE DID LAST YEAR,

7822
04:55:45,194 --> 04:55:47,730
SO YOU CAN SEE THE TOTAL CALL,

7823
04:55:47,730 --> 04:55:48,898
THIS IS FOR FIVE MONTHS.

7824
04:55:48,898 --> 04:55:50,233
WE'VE GOT TWO MORE SESSIONS TO

7825
04:55:50,233 --> 04:55:51,200
GO.

7826
04:55:51,200 --> 04:55:54,504
OVER 700 PEOPLE, 2618 FOR

7827
04:55:54,504 --> 04:55:56,806
YOUTUBE AND 600 ON FACEBOOK.

7828
04:55:56,806 --> 04:56:00,510
THANK YOU, MICHAEL LUELLA, FOR

7829
04:56:00,510 --> 04:56:01,611
EXAP TOURING ALL THAT.

7830
04:56:01,611 --> 04:56:04,147
AND YOU KNOW, WE ACTUALLY

7831
04:56:04,147 --> 04:56:05,581
EXTENDED THE SESSIONS TO AN HOUR

7832
04:56:05,581 --> 04:56:06,983
AND A HALF TO GIVE THE COMMUNITY

7833
04:56:06,983 --> 04:56:10,820
PEOPLE TIME TO EXPRESS WHAT THEY

7834
04:56:10,820 --> 04:56:12,355
WERE GOING TO SAY OR WANTED TO

7835
04:56:12,355 --> 04:56:13,723
SAY AND OUR EVALUATION SCORES

7836
04:56:13,723 --> 04:56:14,891
WERE LIKE 80%.

7837
04:56:14,891 --> 04:56:18,161
SO WE ARE DOING A OVER 60

7838
04:56:18,161 --> 04:56:19,128
BEHAVIORAL RESEARCH STUDY, YOU

7839
04:56:19,128 --> 04:56:20,630
CAN SEE WHAT THE FIGURES --

7840
04:56:20,630 --> 04:56:23,066
EXCUSE ME -- WHAT THE QUESTIONS

7841
04:56:23,066 --> 04:56:25,601
WILL BE, THAT'S A STUDY KARINA

7842
04:56:25,601 --> 04:56:28,638
IS DOING WITH CRISPR GRID AND

7843
04:56:28,638 --> 04:56:29,639
DARE.

7844
04:56:29,639 --> 04:56:32,141
WE'VE DONE TWO PAPERS WITH

7845
04:56:32,141 --> 04:56:34,544
KARINE THIS YEAR, WOMEN IN HIV,

7846
04:56:34,544 --> 04:56:35,745
WOMEN IN CURE RESEARCH AND

7847
04:56:35,745 --> 04:56:37,613
PARTNER PROTECTIONS DURING

7848
04:56:37,613 --> 04:56:39,582
ATIs, WE'VE DONE A LOT OF

7849
04:56:39,582 --> 04:56:39,916
ADVOCACY.

7850
04:56:39,916 --> 04:56:41,217
YOU CAN SEE ALL THE DIFFERENT

7851
04:56:41,217 --> 04:56:42,885
PLACES, BUT THE MOST IMPORTANT I

7852
04:56:42,885 --> 04:56:44,287
THINK ARE WITH THE FDA.

7853
04:56:44,287 --> 04:56:45,822
WE'VE INVITED -- WE INVITED ALL

7854
04:56:45,822 --> 04:56:47,223
THE COLLABORATORIES TO THAT.

7855
04:56:47,223 --> 04:56:51,728
WE'VE HAD A MEETING WITH CBER IN

7856
04:56:51,728 --> 04:56:53,463
FEBRUARY AND A REALLY LARGE

7857
04:56:53,463 --> 04:56:55,031
MEETING WITH CDR THAT INCLUDED

7858
04:56:55,031 --> 04:56:56,099
MORE THAN THE DARE CAB.

7859
04:56:56,099 --> 04:56:59,068
AND WE'RE HAVING ANOTHER MEETING

7860
04:56:59,068 --> 04:57:00,369
IN DECEMBER.

7861
04:57:00,369 --> 04:57:04,207
SO FOR FUTURE, WE'RE GOING TO DO

7862
04:57:04,207 --> 04:57:07,176
SOMETHING WITH THE LAST -- IN

7863
04:57:07,176 --> 04:57:08,911
JANUARY AND OUR LAST SERIES IS

7864
04:57:08,911 --> 04:57:10,680
GOING TO BE ON VIRAL RESERVOIRS.

7865
04:57:10,680 --> 04:57:12,448
WE'RE GOING TO CONTINUE TO WORK

7866
04:57:12,448 --> 04:57:15,051
WITH COMMUNITY PARTNERS,

7867
04:57:15,051 --> 04:57:18,454
SAN FRANCISCO AIDS FOUNDATION,

7868
04:57:18,454 --> 04:57:19,756
LGBT CENTER AND WE'RE GOING TO

7869
04:57:19,756 --> 04:57:22,291
TRY TO WORK WITH OAKLAND AGAIN.

7870
04:57:22,291 --> 04:57:23,826
WE THANK THE INVESTIGATORS FOR

7871
04:57:23,826 --> 04:57:27,530
BEING SO COLLEGIAL AND

7872
04:57:27,530 --> 04:57:28,831
SUPPORTIVE, AND TO THE DARE CAB,

7873
04:57:28,831 --> 04:57:31,267
WE'VE GOT EBONY, KARINE, I KNOW

7874
04:57:31,267 --> 04:57:32,668
DERRICK IS HERE AND MICHAEL,

7875
04:57:32,668 --> 04:57:33,803
WOULD YOU STAND UP, PLEASE?

7876
04:57:33,803 --> 04:57:35,538
THEY'RE ON THE CAB, AND BRIGITTE

7877
04:57:35,538 --> 04:57:37,306
IS ONE OF OUR COLLABORATORS.

7878
04:57:37,306 --> 04:57:38,508
SO GIVE THEM A HAND TOO.

7879
04:57:38,508 --> 04:57:44,046
[APPLAUSE]

7880
04:57:44,046 --> 04:57:51,187
>> THANK YOU FOR
LISTENING.

7881
04:57:51,187 --> 04:57:52,155
>> WE HAVE SEVERAL MINUTES
BE

7882
04:57:52,155 --> 04:57:53,890
FOR QUESTIONS.

7883
04:57:53,890 --> 04:57:54,891
>> WE ENDED ON TIME.

7884
04:57:54,891 --> 04:57:56,325
ANY QUESTIONS?

7885
04:57:56,325 --> 04:57:57,627
>> STEVE, YOU MENTIONED

7886
04:57:57,627 --> 04:57:58,828
SOMETHING ABOUT BACK ROOMS IN

7887
04:57:58,828 --> 04:58:00,296
THE POSTER SESSION.

7888
04:58:00,296 --> 04:58:00,830
WHERE IS THIS PLACE?

7889
04:58:00,830 --> 04:58:03,166
>> I DIDN'T SEE IT AT THE
END

7890
04:58:03,166 --> 04:58:05,868
BUT ABOVE US, ON THE SIDE IN THE

7891
04:58:05,868 --> 04:58:08,337
BALCONY, THERE'S SORT OF A

7892
04:58:08,337 --> 04:58:09,505
DARKROOM.

7893
04:58:09,505 --> 04:58:10,873
>> I SAID I DIDN'T GO
THERE

7894
04:58:10,873 --> 04:58:12,241
TODAY SO I JUST WANTED TO KNOW.

7895
04:58:12,241 --> 04:58:12,475
THANKS.

7896
04:58:12,475 --> 04:58:15,211
>> OKAY.

7897
04:58:15,211 --> 04:58:16,712
>> QUESTION FOR LOUIS.

7898
04:58:16,712 --> 04:58:18,014
SO FIRST I WAS REALLY HAPPY TO

7899
04:58:18,014 --> 04:58:20,650
SEE YOUR DATA, BECAUSE WE HAD

7900
04:58:20,650 --> 04:58:23,486
TALKED ABOUT THESE THINGS BEF 

7901
04:58:23,486 --> 04:58:25,254
BEFORE.

7902
04:58:25,254 --> 04:58:26,823
SO IF I SAW YOUR SLIDES

7903
04:58:26,823 --> 04:58:28,558
CORRECTLY, YOU SHOW THAT WITH OR

7904
04:58:28,558 --> 04:58:31,627
WITHOUT THE BNABs IN THE EARLY

7905
04:58:31,627 --> 04:58:35,231
PART AND THE MAGNITUDE AND THE

7906
04:58:35,231 --> 04:58:39,535
PROFILE VIREMIA ONCE YOU GET

7907
04:58:39,535 --> 04:58:40,503
REBOUND THE SAME SO YOU

7908
04:58:40,503 --> 04:58:41,604
CONCLUDED IN YOUR EXPERIMENT AT

7909
04:58:41,604 --> 04:58:43,472
LEAST THERE WAS NO VAXAL EFFECT.

7910
04:58:43,472 --> 04:58:45,141
DID YOU ACTUALLY MEASURE THE

7911
04:58:45,141 --> 04:58:46,976
T-CELL RESPONSES EXPLICITLY IN

7912
04:58:46,976 --> 04:58:49,545
THE PERIPHERY AND THE LYMPH

7913
04:58:49,545 --> 04:58:50,346
NODES?

7914
04:58:50,346 --> 04:58:52,048
>> YEAH, I MEAN, I SHOWED
ONE

7915
04:58:52,048 --> 04:58:52,949
SLIDE OF THAT.

7916
04:58:52,949 --> 04:58:54,584
THE BIGGEST RESPONSE WE GET IS

7917
04:58:54,584 --> 04:58:56,752
ACTUALLY LOOKING IN THE BOWEL

7918
04:58:56,752 --> 04:58:57,653
BECAUSE THAT'S AN EFFECTOR SITE

7919
04:58:57,653 --> 04:58:59,956
THAT REALLY CHANGES  A LOT WITH

7920
04:58:59,956 --> 04:59:01,591
REBOUND AND ALL THREE

7921
04:59:01,591 --> 04:59:03,259
EXPERIMENTS, WE DIDN'T SEE ANY

7922
04:59:03,259 --> 04:59:05,728
DIFFERENCE IN THE RESPONSE TO

7923
04:59:05,728 --> 04:59:07,697
REBOUND.

7924
04:59:07,697 --> 04:59:09,999
SO IN PERIPHERAL BLOOD, IT'S

7925
04:59:09,999 --> 04:59:11,868
SIMILAR, THE CHANGES WEREN'T AS

7926
04:59:11,868 --> 04:59:12,869
DRAMATIC.

7927
04:59:12,869 --> 04:59:14,604
>> SO HOW DO YOU INTERPRET
YOUR

7928
04:59:14,604 --> 04:59:16,172
DATA ALONGSIDE THE PREVIOUS

7929
04:59:16,172 --> 04:59:17,707
STUDIES THAT AT LEAST HAD

7930
04:59:17,707 --> 04:59:22,178
CONCLUDED THAT THERE WAS A

7931
04:59:22,178 --> 04:59:22,745
VACCINAL EFFECT?

7932
04:59:22,745 --> 04:59:25,681
>> WELL, YOU KNOW,
DIFFERENT

7933
04:59:25,681 --> 04:59:27,116
ANTIBODIES, DIFFERENT

7934
04:59:27,116 --> 04:59:27,416
SITUATIONS.

7935
04:59:27,416 --> 04:59:29,185
IT MAY BE THAT THESE ANTIBODIES

7936
04:59:29,185 --> 04:59:31,387
WERE TOO GOOD.

7937
04:59:31,387 --> 04:59:33,256
THAT THEY ACTUALLY ACTED JUST

7938
04:59:33,256 --> 04:59:33,689
LIKE ART.

7939
04:59:33,689 --> 04:59:35,524
THEY DIDN'T ALLOW ENOUGH ANTIGEN

7940
04:59:35,524 --> 04:59:36,859
OR IMMUNE COMPLEX GENERATION TO

7941
04:59:36,859 --> 04:59:41,130
BE ABLE TO STIMULATE THE T-CELL

7942
04:59:41,130 --> 04:59:42,498
RESPONSE IN A PARTICULARLY

7943
04:59:42,498 --> 04:59:43,532
POTENT WAY.

7944
04:59:43,532 --> 04:59:45,067
MAYBE THE ONES THAT HAVE SHOWN

7945
04:59:45,067 --> 04:59:48,037
THE EFFECT ARE ANTIBODIES OR

7946
04:59:48,037 --> 04:59:49,138
VIRUS COMBINATIONS WHERE IT'S

7947
04:59:49,138 --> 04:59:51,874
NOT AS GOOD.

7948
04:59:51,874 --> 04:59:54,377
THERE'S LOTS OF POTENTIAL

7949
04:59:54,377 --> 04:59:55,278
DIFFERENCES.

7950
04:59:55,278 --> 04:59:56,712
I NEVER REALLY FELT -- I MEAN,

7951
04:59:56,712 --> 04:59:58,447
WE'RE ACTUALLY WORKING WITH

7952
04:59:58,447 --> 05:00:05,788
T-CELL VACCINES AT THE PAI PERIT

7953
05:00:05,788 --> 05:00:07,089
PERIOD WHICH HAVE A HUGE EFFECT

7954
05:00:07,089 --> 05:00:08,758
ON T-CELL RESPONSES AND DATA ARE

7955
05:00:08,758 --> 05:00:10,493
GOING TO SHOW BY THE NEXT

7956
05:00:10,493 --> 05:00:12,695
MEETING DO SEEM TO DELAY REBOUND

7957
05:00:12,695 --> 05:00:15,965
AND MEDIATE SOME POST ART

7958
05:00:15,965 --> 05:00:16,632
CONTROL.

7959
05:00:16,632 --> 05:00:19,268
BUT THIS IS A RELATIVELY WEAK

7960
05:00:19,268 --> 05:00:20,603
EFFECT, BUT IF IT WAS USEFUL, WE

7961
05:00:20,603 --> 05:00:24,407
WOULD HAVE LIKED TO HAVE USED IT

7962
05:00:24,407 --> 05:00:28,477
OOAND BUILT UPON IT WITH OTHER

7963
05:00:28,477 --> 05:00:30,346
IMMUNOTHERAPIES BUT SO FAR WE

7964
05:00:30,346 --> 05:00:31,314
HAVEN'T SEEN MUCH REASON TO

7965
05:00:31,314 --> 05:00:33,316
CONTINUE AT LEAST WITH THESE TWO

7966
05:00:33,316 --> 05:00:34,617
ANTIBODIES IN THE MACK 239

7967
05:00:34,617 --> 05:00:34,850
SYSTEM.

7968
05:00:34,850 --> 05:00:35,384
>> THANKS.

7969
05:00:35,384 --> 05:00:37,153
>> CAN I JUMP IN HERE,
LOUIS?

7970
05:00:37,153 --> 05:00:37,386
>> YEAH.

7971
05:00:37,386 --> 05:00:39,689
>> BECAUSE IF YOU LOOK,
DAN, I

7972
05:00:39,689 --> 05:00:40,790
MEAN, I KNOW YOU GUYS WERE

7973
05:00:40,790 --> 05:00:42,091
TALKING ABOUT THE MONKEY DATA,

7974
05:00:42,091 --> 05:00:43,759
BUT IF YOU LOOK IN THE HUMAN

7975
05:00:43,759 --> 05:00:45,394
DATA, THERE'S TWO PHENOMENA.

7976
05:00:45,394 --> 05:00:48,898
SOMETIMES WITH SOME OF THESE

7977
05:00:48,898 --> 05:00:50,766
ANTIBODIES, WHEN 101074 WAS USED

7978
05:00:50,766 --> 05:00:54,270
BY ITSELF, THE VIRUS IS SIMPLY

7979
05:00:54,270 --> 05:00:56,138
SHOT STRAIGHT UP LIKE IN LEWIS'

7980
05:00:56,138 --> 05:00:56,372
MONKEYS.

7981
05:00:56,372 --> 05:00:58,641
BUT WHEN YOU USE OTHER

7982
05:00:58,641 --> 05:01:00,076
ANTIBODIES, CD4 BINDING SITE

7983
05:01:00,076 --> 05:01:01,077
ANTIBODY, YOU'VE GOT THAT

7984
05:01:01,077 --> 05:01:02,044
INITIAL DELAY IN THE UPSLOPE.

7985
05:01:02,044 --> 05:01:03,813
THOSE ARE THE INDIVIDUALS, AT

7986
05:01:03,813 --> 05:01:06,449
LEAST IN THE CLINICAL TRIALS,

7987
05:01:06,449 --> 05:01:07,984
FOR WHOM YOU ENDED UP HAVING A

7988
05:01:07,984 --> 05:01:09,085
CHANCE OF POST TREATMENT

7989
05:01:09,085 --> 05:01:10,486
CONTROL.

7990
05:01:10,486 --> 05:01:12,421
THAT'S MY GESTALT TO THE DATA.

7991
05:01:12,421 --> 05:01:15,024
I WONDER IF SIV -- TOO FAST.

7992
05:01:15,024 --> 05:01:16,993
>> IS JUST TOO FAST,
RIGHT?

7993
05:01:16,993 --> 05:01:18,427
BECAUSE THE VACCINAL EFFECT WAS

7994
05:01:18,427 --> 05:01:19,662
INITIALLY WITH SHIV, WHERE IT

7995
05:01:19,662 --> 05:01:21,163
WAS SEEN PRETTY EASILY, THEN

7996
05:01:21,163 --> 05:01:24,133
WITH HIV, WHERE IT'S SEEN

7997
05:01:24,133 --> 05:01:25,301
SOMETIMES, CERTAIN ANTIBODIES,

7998
05:01:25,301 --> 05:01:27,737
BUT THEN YOU'RE NOT SEEING WITH

7999
05:01:27,737 --> 05:01:29,171
SIV, WHICH IS A REALLY ROBUST

8000
05:01:29,171 --> 05:01:30,706
VIRUS THAT I THINK IS JUST TOO

8001
05:01:30,706 --> 05:01:32,041
POWERFUL FOR THESE ANTIBODIES.

8002
05:01:32,041 --> 05:01:34,010
>> IN OUR STUDIES WITH
SHIV, WE

8003
05:01:34,010 --> 05:01:36,545
ALSO DID NOT SEE EVIDENCE OF THE

8004
05:01:36,545 --> 05:01:39,148
VACCINAL EFFECT WITH A VARIETY

8005
05:01:39,148 --> 05:01:41,250
OF ANTIBODIES ALSO.

8006
05:01:41,250 --> 05:01:48,157
THAT'S A SLOWER VIRUS ALSO.

8007
05:01:48,157 --> 05:01:50,059
>> MAURO, THAT WAS
BEAUTIFUL

8008
05:01:50,059 --> 05:01:50,426
DATA.

8009
05:01:50,426 --> 05:01:52,628
I WAS CURIOUS, WHEN YOU SEE THE

8010
05:01:52,628 --> 05:01:56,032
INCREASE IN TOTAL NUMBERS OF I

8011
05:01:56,032 --> 05:01:57,933
IUPM OVER TIME, IF YOU EXPRESS

8012
05:01:57,933 --> 05:02:00,336
THAT AS A TOTAL AMOUNT OF HIV

8013
05:02:00,336 --> 05:02:02,838
DNA IN THE SAMPLES, IS THE TOTAL

8014
05:02:02,838 --> 05:02:04,373
AMOUNT OF HIV DNA GOING UP AS

8015
05:02:04,373 --> 05:02:05,508
WELL?

8016
05:02:05,508 --> 05:02:08,878
>> I HAVEN'T LOOKED AT
THAT YET,

8017
05:02:08,878 --> 05:02:10,613
BUT I KNOW PREVIOUS DATA HAVE

8018
05:02:10,613 --> 05:02:14,116
CORRELATED TOTAL DNA AND RNA

8019
05:02:14,116 --> 05:02:16,986
WITH TIME TO REBOUND.

8020
05:02:16,986 --> 05:02:18,387
BUT WE HAVEN'T ASSESSED THAT.

8021
05:02:18,387 --> 05:02:20,056
MAINLY BECAUSE IT INCLUDES

8022
05:02:20,056 --> 05:02:21,791
TRANSCRIPTS FROM DEFECTIVE PRO

8023
05:02:21,791 --> 05:02:23,025
VIRUSES THAT WOULDN'T CONTRIBUTE

8024
05:02:23,025 --> 05:02:23,559
TO REBOUND.

8025
05:02:23,559 --> 05:02:24,326
BUT THAT'S SOMETHING WE COULD

8026
05:02:24,326 --> 05:02:24,927
LOOK AT.

8027
05:02:24,927 --> 05:02:26,962
>> RIGHT.

8028
05:02:26,962 --> 05:02:28,297
PRESUMABLY IT MAY BE DUE TO

8029
05:02:28,297 --> 05:02:30,666
CLONAL EXPANSION OF REPLICATION

8030
05:02:30,666 --> 05:02:31,700
COMPETENT PRO VIRUSES.

8031
05:02:31,700 --> 05:02:34,637
IT WOULD BE INTERESTING TO KNOW,

8032
05:02:34,637 --> 05:02:36,705
THAT SOME OF THOSE PRO VIRUSES

8033
05:02:36,705 --> 05:02:38,240
OVER TIME MAY DELETE, BECOME

8034
05:02:38,240 --> 05:02:42,845
SOLO LTR, SO USING A DEA DENOMIR

8035
05:02:42,845 --> 05:02:44,847
THAT ACTUALLY CAPTURES LTRs,

8036
05:02:44,847 --> 05:02:46,282
WHICH I GUESS SOME OF THE ASSAYS

8037
05:02:46,282 --> 05:02:48,684
DO AND SOME DON'T, MIGHT BE VERY

8038
05:02:48,684 --> 05:02:48,918
USEFUL.

8039
05:02:48,918 --> 05:02:50,419
>> THANK YOU FOR THE
SUGGESTION.

8040
05:02:50,419 --> 05:02:51,353
THANK YOU.

8041
05:02:51,353 --> 05:02:53,289
>> HI.

8042
05:02:53,289 --> 05:02:54,490
THIS IS FOR SHARON.

8043
05:02:54,490 --> 05:02:54,924
BEAUTIFUL DATA.

8044
05:02:54,924 --> 05:02:56,292
SO IT SEEMS THAT AT LEAST FOR

8045
05:02:56,292 --> 05:02:59,128
THE DATA THAT YOU SHOWED WITH

8046
05:02:59,128 --> 05:03:02,498
VENETOCLAX, -- ON EFFECTOR

8047
05:03:02,498 --> 05:03:04,500
MEMORY ARE REALLY SENSITIVE BUT

8048
05:03:04,500 --> 05:03:06,135
CENTRAL MEMORY AND TRANSITIONAL

8049
05:03:06,135 --> 05:03:07,803
MEMORY DON'T SEEM TO BE AS

8050
05:03:07,803 --> 05:03:10,639
EFFECTIVE TO THE ANTI-APOPTOSIS

8051
05:03:10,639 --> 05:03:10,973
INDUCING.

8052
05:03:10,973 --> 05:03:13,042
SO DO YOU THINK THAT -- DO YOU

8053
05:03:13,042 --> 05:03:15,678
THINK THAT THAT WOULD BE A

8054
05:03:15,678 --> 05:03:17,213
PROBLEM YOU TRY TO REDUCE THE

8055
05:03:17,213 --> 05:03:18,314
RESERVOIR BECAUSE CENTRAL MEMORY

8056
05:03:18,314 --> 05:03:20,082
ARE GOING TO HAVE A BIG PORTION

8057
05:03:20,082 --> 05:03:26,856
OF THE LATENT RESERVOIR?

8058
05:03:26,856 --> 05:03:29,391
>> VENETOCLAX WILL DEPLETE
ALL

8059
05:03:29,391 --> 05:03:32,895
T-CELLS, IT'S A MATTER OF ITS

8060
05:03:32,895 --> 05:03:35,097
DEPENDENCY ON BCL2 AND WHAT WE

8061
05:03:35,097 --> 05:03:36,866
SAW, THERE WAS GREATER

8062
05:03:36,866 --> 05:03:41,337
DEPENDENCY OF NAIVE AND EFFECTOR

8063
05:03:41,337 --> 05:03:41,904
MEMORY T-CELLS.

8064
05:03:41,904 --> 05:03:43,205
IF YOU LOOK AT THE INTACT DNA,

8065
05:03:43,205 --> 05:03:44,673
IT WAS ABOUT A 50% REDUCTION.

8066
05:03:44,673 --> 05:03:47,309
SO THERE ARE CELLS THAT SURVIVE

8067
05:03:47,309 --> 05:03:50,613
VENETOCLAX, EITHER BECAUSE IT'S

8068
05:03:50,613 --> 05:03:52,248
IN T-CELL SUBSETS THAT ARE

8069
05:03:52,248 --> 05:03:53,249
RELATIVELY RESISTANT, OR THERE

8070
05:03:53,249 --> 05:03:55,317
ARE OTHER FACTORS AS WE HEARD

8071
05:03:55,317 --> 05:03:56,085
EARLIER THIS MORNING, YOU KNOW,

8072
05:03:56,085 --> 05:03:57,853
HOST FACTORS THAT LEAD TO

8073
05:03:57,853 --> 05:04:02,658
SURVIVAL OF SOME CELLS.

8074
05:04:02,658 --> 05:04:04,860
BUT WE THOUGHT IT MIGHT BE --

8075
05:04:04,860 --> 05:04:05,961
BECAUSE YOU'RE SELECTIVELY

8076
05:04:05,961 --> 05:04:07,930
REMOVING MORE NAIVE AND EFFECTOR

8077
05:04:07,930 --> 05:04:09,265
MEMORY CELLS AND, THEREFORE,

8078
05:04:09,265 --> 05:04:10,366
MORE LIKELY TO GET MORE OF THE

8079
05:04:10,366 --> 05:04:13,536
RESERVOIR, BUT WE DIDN'T SORT

8080
05:04:13,536 --> 05:04:16,038
INTO DIFFERENT T-CELL SUBSETS TO

8081
05:04:16,038 --> 05:04:16,972
ANSWER THAT SPECIFIC QUESTION.

8082
05:04:16,972 --> 05:04:19,975
>> THANKS.

8083
05:04:19,975 --> 05:04:22,111
>> JEFF BARRY, CRISPR FOR
CURE

8084
05:04:22,111 --> 05:04:23,479
AND THE REUNION PROJECT.

8085
05:04:23,479 --> 05:04:24,980
I WANT TO THANK ALL THE

8086
05:04:24,980 --> 05:04:28,017
PRESENTERS FOR A VERY CLEAR

8087
05:04:28,017 --> 05:04:29,251
PRESENTATION BUT PARTICULARLY

8088
05:04:29,251 --> 05:04:30,352
MAURO, I THINK AS SOMEONE FROM

8089
05:04:30,352 --> 05:04:31,687
THE COMMUNITY WHO DOESN'T

8090
05:04:31,687 --> 05:04:33,189
NECESSARILY HAVE A SCIENTIFIC

8091
05:04:33,189 --> 05:04:34,523
BACKGROUND, IT WAS REALLY

8092
05:04:34,523 --> 05:04:35,824
CONCISE AND CLEAR AND

8093
05:04:35,824 --> 05:04:37,493
UNDERSTANDABLE, SO THANK YOU.

8094
05:04:37,493 --> 05:04:40,663
I KNOW YOUR STUDY DIDN'T INVOLVE

8095
05:04:40,663 --> 05:04:41,597
ANALYTICAL TREATMENT

8096
05:04:41,597 --> 05:04:43,399
INTERRUPTION BUT I WONDERED IF

8097
05:04:43,399 --> 05:04:44,500
YOU OR STEVE WANTED TO COMMENT

8098
05:04:44,500 --> 05:04:47,036
ON ANALYTICAL TREATMENT --

8099
05:04:47,036 --> 05:04:50,139
ATIs IN LONG TERM SURVIVORS.

8100
05:04:50,139 --> 05:04:51,140
YOU ALLUDED TO SOME OF THAT

8101
05:04:51,140 --> 05:04:53,409
YESTERDAY IN YOUR TALK, STEVE.

8102
05:04:53,409 --> 05:04:55,377
>> HEY, JEFF.

8103
05:04:55,377 --> 05:04:57,112
MAURO, DO YOU WANT TO TAKE THAT?

8104
05:04:57,112 --> 05:04:58,447
>> SURE.

8105
05:04:58,447 --> 05:05:01,517
SO IN PARTICIPANTS ON LONG TERM

8106
05:05:01,517 --> 05:05:02,985
ART, IT WAS DATA THAT I DIDN'T

8107
05:05:02,985 --> 05:05:05,154
SHARE TODAY BUT THESE

8108
05:05:05,154 --> 05:05:07,223
PARTICIPANTS, I SHOWED THAT THE

8109
05:05:07,223 --> 05:05:09,325
RESERVOIR MIGHT BE INCREASING

8110
05:05:09,325 --> 05:05:13,062
AND THESE CLONES ARE RESISTANT

8111
05:05:13,062 --> 05:05:17,299
TO YO AUTOLOGOUS NEUTRALIZING

8112
05:05:17,299 --> 05:05:21,170
ANTIBEES MOANTIBODIES SO IF ARTE

8113
05:05:21,170 --> 05:05:23,906
STOPPED THEN, THESE LARGE CLONES

8114
05:05:23,906 --> 05:05:26,508
THAT MIGHT BE ANAB RESISTANT

8115
05:05:26,508 --> 05:05:27,643
MIGHT CONTRIBUTE TO REBOUND.

8116
05:05:27,643 --> 05:05:28,477
IN THREE OF THE PARTICIPANTS

8117
05:05:28,477 --> 05:05:30,212
THAT I SHOWED ON THE CORRELATION

8118
05:05:30,212 --> 05:05:31,280
GRAPH, TWO OF THEM ACTUALLY

8119
05:05:31,280 --> 05:05:34,149
REBOUNDED THE FASTEST, WHEREAS

8120
05:05:34,149 --> 05:05:36,318
ONE REBOUNDED -- THEY HAD THE

8121
05:05:36,318 --> 05:05:41,056
LONGEST TIME TO VIRAL REBOUND,

8122
05:05:41,056 --> 05:05:43,359
SO I'LL LET STEVE TAKE OVER.

8123
05:05:43,359 --> 05:05:44,660
>> SO THOSE ARE GOOD
POINTS.

8124
05:05:44,660 --> 05:05:47,329
I THINK JEFF WAS ALSO CURIOUS, I

8125
05:05:47,329 --> 05:05:48,530
BELIEVE FOLLOW-UP ON DISCUSSION

8126
05:05:48,530 --> 05:05:50,833
FROM YESTERDAY WHERE WE WERE

8127
05:05:50,833 --> 05:05:52,268
DISCUSSING ABOUT THE CHALLENGE

8128
05:05:52,268 --> 05:05:53,902
AND THE ETHICS OF DOING THESE

8129
05:05:53,902 --> 05:05:55,437
TREATMENT INTERRUPTIONS AND LONG

8130
05:05:55,437 --> 05:05:56,438
TERM SURVIVORS.

8131
05:05:56,438 --> 05:06:01,176
THERE'S ACTUALLY A REALLY A REAY

8132
05:06:01,176 --> 05:06:02,378
INTERESTING QUESTIONS THAT CAN

8133
05:06:02,378 --> 05:06:06,448
BE ASKED TO PEOPLE ON

8134
05:06:06,448 --> 05:06:07,383
ANTIRETROVIRAL THERAPY FOR 20,

8135
05:06:07,383 --> 05:06:09,718
30 YEARS, BY DEFINITION THOSE

8136
05:06:09,718 --> 05:06:11,253
PEOPLE ARE 25, 30 YEARS OLDER

8137
05:06:11,253 --> 05:06:12,554
THAN MOST PEOPLE, SO THEY'RE NOW

8138
05:06:12,554 --> 05:06:14,456
IN THEIR 60s AND 70s AND

8139
05:06:14,456 --> 05:06:16,425
THERE TRADITIONALLY HAS BEEN

8140
05:06:16,425 --> 05:06:17,726
PUSHBACK ABOUT DOING THESE TYPES

8141
05:06:17,726 --> 05:06:18,961
OF STUDIES ON PEOPLE OF THAT

8142
05:06:18,961 --> 05:06:20,296
AGE, BUT THERE'S A BIG

8143
05:06:20,296 --> 05:06:21,196
POPULATION OF PEOPLE WHO REALLY

8144
05:06:21,196 --> 05:06:23,065
WANT TO ENGAGE IN THIS WORK.

8145
05:06:23,065 --> 05:06:24,266
WE'RE VERY ALTRUISTIC.

8146
05:06:24,266 --> 05:06:25,901
WE WANT TO GIVE BACK TO THE

8147
05:06:25,901 --> 05:06:27,036
COMMUNITY, WHO HAVE THE TIME,

8148
05:06:27,036 --> 05:06:29,438
AND NOW THEY' THERE ARE REALLY

8149
05:06:29,438 --> 05:06:30,406
INTERESTING QUESTIONS.

8150
05:06:30,406 --> 05:06:32,308
SO THERE HAS BEEN A DISCUSSION

8151
05:06:32,308 --> 05:06:33,776
AND DEBATE, NOT DEBATE ACTUALLY,

8152
05:06:33,776 --> 05:06:35,377
A REALLY HEALTHY QUESTION WITH

8153
05:06:35,377 --> 05:06:36,278
SCIENTISTS AND COMMUNITY ABOUT

8154
05:06:36,278 --> 05:06:37,680
WHETHER OR NOT THE QUESTION

8155
05:06:37,680 --> 05:06:40,783
BEING ASKED IS APPROPRIATE.

8156
05:06:40,783 --> 05:06:41,984
I THINK IT IS, I THINK JEFF

8157
05:06:41,984 --> 05:06:43,519
THINKS IT, AND WHETHER WE CAN DO

8158
05:06:43,519 --> 05:06:45,087
IT CAREFULLY AND SAFELY, AND I

8159
05:06:45,087 --> 05:06:46,388
DO THINK HE WITH CAN.

8160
05:06:46,388 --> 05:06:47,589
SO THERE'S A PROCESS WHERE I

8161
05:06:47,589 --> 05:06:48,791
THINK WE'LL BEGIN TO DO SOME OF

8162
05:06:48,791 --> 05:06:50,459
THESE STUDIES IN LONG TERM

8163
05:06:50,459 --> 05:06:51,660
SURVIVORS WHO HAVE GENERALLY

8164
05:06:51,660 --> 05:06:53,195
BEEN EXCLUDED FROM THESE CURE

8165
05:06:53,195 --> 05:06:54,363
STUDIES, AND I THINK THAT'S A

8166
05:06:54,363 --> 05:06:54,997
GOOD THING.

8167
05:06:54,997 --> 05:06:56,365
BUT IT'S AN ONGOING DISCUSSION.

8168
05:06:56,365 --> 05:06:57,966
>> THANK YOU.

8169
05:06:57,966 --> 05:06:59,568
>> HI.

8170
05:06:59,568 --> 05:07:05,774
OLIVIA COUNCIL FROM UNC.

8171
05:07:05,774 --> 05:07:07,943
>> ONE OF ARE OUR AGENDA
ITEMS

8172
05:07:07,943 --> 05:07:09,511
IS ACTUALLY -- THE KARINE WE'RE

8173
05:07:09,511 --> 05:07:11,146
DOING THAT STUDY WITH KARINE

8174
05:07:11,146 --> 05:07:13,215
ABOUT PEOPLE OVER 65 WITH HIV IS

8175
05:07:13,215 --> 05:07:14,917
SO WE CAN INCLUDE THEM AS SOON

8176
05:07:14,917 --> 05:07:15,217
AS POSSIBLE.

8177
05:07:15,217 --> 05:07:17,519
WE'VE NEVER REALLY REALLY

8178
05:07:17,519 --> 05:07:19,488
SURVEYED THEM ABOUT WHAT WORKS

8179
05:07:19,488 --> 05:07:21,690
FOR THEM, WHAT DOESN'T,

8180
05:07:21,690 --> 05:07:23,025
THEIR DEGREE OF WILLINGNESS TO

8181
05:07:23,025 --> 05:07:24,860
DO ATIs, DIFFERENT STRATEGIES

8182
05:07:24,860 --> 05:07:26,428
AND THAT SORT OF THING.

8183
05:07:26,428 --> 05:07:29,164
SO WE'VE ACTUALLY TALKED TO THE

8184
05:07:29,164 --> 05:07:33,135
FDA ABOUT PEOPLE OVER 65 AND

8185
05:07:33,135 --> 05:07:34,670
THEY ABSOLUTELY MENTIONED THE

8186
05:07:34,670 --> 05:07:35,571
RISKINESS OF TRIALS AT THIS

8187
05:07:35,571 --> 05:07:37,106
POINT, BUT THEY HAVE NO

8188
05:07:37,106 --> 05:07:39,408
OBJECTION TO IT ESSENTIALLY IF

8189
05:07:39,408 --> 05:07:41,944
PEOPLE FIT WITHIN THE

8190
05:07:41,944 --> 05:07:42,711
INCLUSION/EXCLUSION CRITERIA.

8191
05:07:42,711 --> 05:07:44,913
AND INTERESTINGLY, LAST THING,

8192
05:07:44,913 --> 05:07:47,649
WE HAD SOMEBODY ON ONE OF OUR

8193
05:07:47,649 --> 05:07:49,418
CALLS, ACTUALLY THE FDA CALL,

8194
05:07:49,418 --> 05:07:52,588
AND HE DID A REVIEW OF ALL

8195
05:07:52,588 --> 05:07:53,922
PROTOCOLS FOR -- I DON'T KNOW

8196
05:07:53,922 --> 05:07:55,557
FOR HOW MANY YEARS, IT WAS AT

8197
05:07:55,557 --> 05:07:56,558
THE CRO IN NEW YORK.

8198
05:07:56,558 --> 05:07:58,327
THE BOTTOM LINE IS THE PEOPLE

8199
05:07:58,327 --> 05:08:00,362
JUST CUT AND PASTE IN 65 YEARS,

8200
05:08:00,362 --> 05:08:01,230
AND SO MANY OTHER THINGS.

8201
05:08:01,230 --> 05:08:03,198
SO IT'S JUST REALLY TIME TO LOOK

8202
05:08:03,198 --> 05:08:04,633
AT THAT DIFFERENTLY.

8203
05:08:04,633 --> 05:08:05,734
THANKS.

8204
05:08:05,734 --> 05:08:05,934
SORRY.

8205
05:08:05,934 --> 05:08:06,869
>> JEFF, THAT WAS A GREAT

8206
05:08:06,869 --> 05:08:08,170
QUESTION, BUT IT TOOK UP WAY TOO

8207
05:08:08,170 --> 05:08:10,305
MUCH TIME SO WE HAVE TO STOP.

8208
05:08:10,305 --> 05:08:10,639
I'M SORRY.

8209
05:08:10,639 --> 05:08:11,273
>> THAT'S FINE.

8210
05:08:11,273 --> 05:08:11,840
NOT A PROBLEM.

8211
05:08:11,840 --> 05:08:12,741
>> OKAY.

8212
05:08:12,741 --> 05:08:14,009
>> THANKS VERY MUCH TO THE
DARE

8213
05:08:14,009 --> 05:08:15,110
TEAM.

8214
05:08:15,110 --> 05:08:16,645
[APPLAUSE]

8215
05:08:16,645 --> 05:08:20,682
WE'LL MOVE ON.

8216
05:08:20,682 --> 05:08:25,220
OUR FINAL SESSION OF THE DAY.

8217
05:08:25,220 --> 05:08:26,488
>> SO NOW WE'RE GOING TO
HAVE

8218
05:08:26,488 --> 05:08:26,922
SOME FUN.

8219
05:08:26,922 --> 05:08:29,825
WE'RE GOING TO HAVE AN OPEN

8220
05:08:29,825 --> 05:08:30,259
DISCUSSION.

8221
05:08:30,259 --> 05:08:32,127
SO MOST OF THE WORK, AND I'LL

8222
05:08:32,127 --> 05:08:35,931
ASK THE PANELISTS TO COME ON UP.

8223
05:08:35,931 --> 05:08:38,367
MOST EVERYTHING THAT'S BEING

8224
05:08:38,367 --> 05:08:40,402
PRESENTED TODAY AND TOMORROW

8225
05:08:40,402 --> 05:08:44,273
INVOLVE KIND OF BLUNT INSTRUMENT

8226
05:08:44,273 --> 05:08:45,040
INTERVENTIONS THAT WE'RE HOPING

8227
05:08:45,040 --> 05:08:47,376
ARE GOING TO HAVE EFFECTIVENESS

8228
05:08:47,376 --> 05:08:48,577
AGAINST THE BROADER POPULATION

8229
05:08:48,577 --> 05:08:51,213
OF INDIVIDUALS.

8230
05:08:51,213 --> 05:08:52,981
AND WE WANTED TO ASK THE

8231
05:08:52,981 --> 05:08:55,117
QUESTION, YOU KNOW, SOMETIMES IN

8232
05:08:55,117 --> 05:08:56,418
THESE SMALL TRIALS OR SMALL

8233
05:08:56,418 --> 05:08:58,187
MONKEY STUDIES, YOU'LL SEE AN

8234
05:08:58,187 --> 05:08:59,755
EFFECT IN SOME INDIVIDUALS AND

8235
05:08:59,755 --> 05:09:00,522
NOT IN OTHERS.

8236
05:09:00,522 --> 05:09:01,623
WE WANT TO ASK THE QUESTION, ARE

8237
05:09:01,623 --> 05:09:04,226
WE GETTING TO THE POINT WHERE WE

8238
05:09:04,226 --> 05:09:10,199
COULD POTENTIALLY TAILOR

8239
05:09:10,199 --> 05:09:10,933
INTERVENTIONS SPECIFICALLY TO

8240
05:09:10,933 --> 05:09:13,502
THE VIROLOGIC AND IMMUNOLOGIC

8241
05:09:13,502 --> 05:09:14,136
BACKGROUND OF THE PARTICIPANTS.

8242
05:09:14,136 --> 05:09:15,370
AND SO THAT'S WHAT WE'VE ASKED

8243
05:09:15,370 --> 05:09:19,741
THE PANEL TO COMMENT ON TODAY,

8244
05:09:19,741 --> 05:09:21,743
AND DR. RICHARD D'AQUILA IS OUR

8245
05:09:21,743 --> 05:09:26,215
MODERATOR.

8246
05:09:26,215 --> 05:09:27,649
>> THANK YOU, KARL.

8247
05:09:27,649 --> 05:09:29,051
IT'S A PRIVILEGE TO BE HERE WITH

8248
05:09:29,051 --> 05:09:32,287
THIS GROUP, AND YOU KNOW, THE

8249
05:09:32,287 --> 05:09:36,859
BACKGROUND IS UP ON THE SLIDE,

8250
05:09:36,859 --> 05:09:40,362
AND LEIA AND HER COLLEAGUES AT

8251
05:09:40,362 --> 05:09:42,564
DAIDS DEVELOPED THIS CONCEPT.

8252
05:09:42,564 --> 05:09:45,234
THE GOAL IS NOT, AND I WANT TO

8253
05:09:45,234 --> 05:09:46,768
EMPHASIZE, NOT TO TRY TO

8254
05:09:46,768 --> 05:09:49,938
PERSONALIZE A CURE APPROACH FOR

8255
05:09:49,938 --> 05:09:53,242
EVERY INDIVIDUAL, BUT THE GOAL

8256
05:09:53,242 --> 05:09:55,010
IS TO SEE IF WE CAN TEST THE

8257
05:09:55,010 --> 05:09:57,746
HYPOTHESIS THAT IF YOU HAVE AN

8258
05:09:57,746 --> 05:10:04,186
OPTIMAL SITUATION, A CURATIVE

8259
05:10:04,186 --> 05:10:05,654
INTERVENTION CAN ACTUALLY WORK.

8260
05:10:05,654 --> 05:10:08,390
SO THE IDEA IS TO TAILOR TO WHAT

8261
05:10:08,390 --> 05:10:09,825
WE THINK IS A BEST CASE

8262
05:10:09,825 --> 05:10:11,460
SCENARIO.

8263
05:10:11,460 --> 05:10:15,764
AND THEN PROVE THE CONCEPT THAT

8264
05:10:15,764 --> 05:10:17,399
CURE CAN BE DONE IN THAT BEST

8265
05:10:17,399 --> 05:10:18,534
CASE SCENARIO AND LEARN LESSONS

8266
05:10:18,534 --> 05:10:21,036
FROM THAT.

8267
05:10:21,036 --> 05:10:22,237
THIS CONCEPT HAS BEEN APPROVED,

8268
05:10:22,237 --> 05:10:25,741
AS YOU SEE ON THE BOTTOM OF THE

8269
05:10:25,741 --> 05:10:26,909
SLIDE, SO IT'S POSSIBLE THERE

8270
05:10:26,909 --> 05:10:28,944
WILL BE A NOTICE OF FUNDING

8271
05:10:28,944 --> 05:10:30,612
OPPORTUNITY IN THE FUTURE, AND

8272
05:10:30,612 --> 05:10:35,751
DAIDS IS VERY INTERESTED TODAY

8273
05:10:35,751 --> 05:10:37,052
IN HEARING A DISCUSSION ABOUT

8274
05:10:37,052 --> 05:10:38,420
HOW FEASIBLE SUCH APPROACHES

8275
05:10:38,420 --> 05:10:38,954
MIGHT BE.

8276
05:10:38,954 --> 05:10:43,025
SO WE HAVE A GREAT PANEL WHO ARE

8277
05:10:43,025 --> 05:10:44,993
EACH GOING TO GET ABOUT FIVE

8278
05:10:44,993 --> 05:10:47,763
MINUTES TO TELL US IF THEY THINK

8279
05:10:47,763 --> 05:10:50,365
THIS IS FEASIBLE, AND HOW SUCH

8280
05:10:50,365 --> 05:10:55,504
AN APPROACH MIGHT BE DONE.

8281
05:10:55,504 --> 05:10:57,573
I'LL ASK EACH PANELIST TO GIVE A

8282
05:10:57,573 --> 05:10:58,574
BRIEF INTRODUCTION OF YOURSELF,

8283
05:10:58,574 --> 05:10:59,775
YOUR NAME AND YOUR INSTITUTION,

8284
05:10:59,775 --> 05:11:00,842
AND WE'LL HAVE TIME FOR

8285
05:11:00,842 --> 05:11:01,810
DISCUSSION AFTER THE PANELISTS

8286
05:11:01,810 --> 05:11:11,987
ARE DONE.

8287
05:11:18,493 --> 05:11:20,128
>> MY NAME IS GAURUV
GAIHA.

8288
05:11:20,128 --> 05:11:23,131
I'M A PHYSICIAN SCIENTIST IN MY

8289
05:11:23,131 --> 05:11:24,199
LAB AT THE REAGAN INSTITUTE.

8290
05:11:24,199 --> 05:11:28,503
>> I'M MARC WAGNER WITH
THE I4C

8291
05:11:28,503 --> 05:11:30,472
COMMUNITY ADVISORY BOARD.

8292
05:11:30,472 --> 05:11:31,907
>> I'M MATHIAS
LICHTERFELD.

8293
05:11:31,907 --> 05:11:33,241
I'M AN INFECTIOUS DISEASE

8294
05:11:33,241 --> 05:11:37,279
PHYSICIAN AT BRIGHAM AND MGH IN

8295
05:11:37,279 --> 05:11:37,512
BOSTON.

8296
05:11:37,512 --> 05:11:43,919
>> I'M MORGANE ROLLAND,
U.S.

8297
05:11:43,919 --> 05:11:44,720
MILITARY HIV RESEARCH PROGRAM.

8298
05:11:44,720 --> 05:11:50,993
>> HI, MY NAME IS NILU

8299
05:11:50,993 --> 05:11:52,628
GOONETILEKE, I'M AT UNC.

8300
05:11:52,628 --> 05:11:54,129
>> I GUESS I'LL GET
STARTED.

8301
05:11:54,129 --> 05:11:56,298
SO I'M PLANNING TO SPEAK ABOUT A

8302
05:11:56,298 --> 05:11:57,399
BIT ABOUT OUR FOCUS ON

8303
05:11:57,399 --> 05:11:59,067
PARTICULARLY T-CELL RESPONSES

8304
05:11:59,067 --> 05:12:01,903
AND OPTIMIZING T-CELL VACCINES.

8305
05:12:01,903 --> 05:12:03,238
SO TO THE SPECIFIC QUESTION OF

8306
05:12:03,238 --> 05:12:04,706
WHETHER WE THINK THIS IS A PROOF

8307
05:12:04,706 --> 05:12:06,441
OF CONCEPT APPROACH THAT IS

8308
05:12:06,441 --> 05:12:08,210
FEASIBLE, I THINK MY KIND OF

8309
05:12:08,210 --> 05:12:09,544
ANSWER FROM THE OUTSIDE IS

8310
05:12:09,544 --> 05:12:09,911
ABSOLUTELY YES.

8311
05:12:09,911 --> 05:12:11,546
I THINK THAT IN THE DESIGN OF

8312
05:12:11,546 --> 05:12:12,981
T-CELL VACCINES, THERE REALLY

8313
05:12:12,981 --> 05:12:14,549
HAVE BEEN KIND OF A FEW

8314
05:12:14,549 --> 05:12:17,085
APPROACHES THAT HAVE BEEN TAKTA,

8315
05:12:17,085 --> 05:12:18,153
INCORPORATED INTO KIND OF FULL

8316
05:12:18,153 --> 05:12:20,589
LENGTH PROTEINS AS PART OF A

8317
05:12:20,589 --> 05:12:21,690
T-CELL VACCINE CONCEPT OR TRYING

8318
05:12:21,690 --> 05:12:22,891
TO INCLUDE CERTAIN REGIONS

8319
05:12:22,891 --> 05:12:26,294
ACROSS THE HIV PROTEOME THAT MAY

8320
05:12:26,294 --> 05:12:27,629
BE CONSERVED OR RESISTANT TO

8321
05:12:27,629 --> 05:12:28,130
MUTATION.

8322
05:12:28,130 --> 05:12:29,498
I THINK IN DESIGNING THOSE

8323
05:12:29,498 --> 05:12:31,466
PARTICULAR VACCINES, THERE'S

8324
05:12:31,466 --> 05:12:34,603
EFFORT TO REALLY TRY TO HAVE

8325
05:12:34,603 --> 05:12:35,470
BROAD COVERAGE TO BASICALLY

8326
05:12:35,470 --> 05:12:36,705
COVER AS MANY PEOPLE AS POSSIBLE

8327
05:12:36,705 --> 05:12:37,739
BUT I THINK THERE ARE

8328
05:12:37,739 --> 05:12:38,807
LIMITATIONS WHEN TRYING TO DO

8329
05:12:38,807 --> 05:12:41,643
THAT IN TERMS OF OPTIMIZING

8330
05:12:41,643 --> 05:12:42,310
CONSENTS FOR INDIVIDUAL

8331
05:12:42,310 --> 05:12:42,644
PARTICIPANTS.

8332
05:12:42,644 --> 05:12:44,946
I THINK THAT DOES IN SOME WAYS

8333
05:12:44,946 --> 05:12:46,181
LIMIT SOME OF THESE PROOF OF

8334
05:12:46,181 --> 05:12:47,149
CONCEPT STUDIES.

8335
05:12:47,149 --> 05:12:49,618
SO I THINK A TAILORING APPROACH

8336
05:12:49,618 --> 05:12:50,752
TO INDIVIDUALS, I THINK THE

8337
05:12:50,752 --> 05:12:51,653
FIRST MAJOR ADVANTAGE WE HAVE

8338
05:12:51,653 --> 05:12:53,021
FROM THE T-CELL PERSPECTIVE IS

8339
05:12:53,021 --> 05:12:56,625
TO HAVE AN HLA GENOTYPING

8340
05:12:56,625 --> 05:12:57,259
SPECIFICALLY OF THE INDIVIDUAL

8341
05:12:57,259 --> 05:12:58,393
WHICH IS QUITE FEASIBLE TO DO,

8342
05:12:58,393 --> 05:13:01,930
AND THEN REALLY OP OPTIMIZING

8343
05:13:01,930 --> 05:13:03,265
T-CELL VACCINES WHERE WE SELECT

8344
05:13:03,265 --> 05:13:04,900
SPECIFIC EPITOPE THAT REALLY

8345
05:13:04,900 --> 05:13:05,667
MATCH THE ALEALS OF

8346
05:13:05,667 --> 05:13:06,768
PARTICIPANTS.

8347
05:13:06,768 --> 05:13:12,374
KNOWING THE HLA GE GENOTYPES --

8348
05:13:12,374 --> 05:13:13,909
HIGHLY MUTATION-CONSTRAINED, WE

8349
05:13:13,909 --> 05:13:15,777
CAN THEN ALSO OPTIMIZE CASSETTES

8350
05:13:15,777 --> 05:13:18,213
IN TERMS OF IMMUNODOMINANCE

8351
05:13:18,213 --> 05:13:20,248
HIERARCHIES TO REALLY TRY TO GET

8352
05:13:20,248 --> 05:13:21,883
AS BROAD T-CELL RESPONSES TO

8353
05:13:21,883 --> 05:13:22,617
THIS INDIVIDUAL TARGET, SO

8354
05:13:22,617 --> 05:13:23,518
RATHER THAN TRYING TO USE THIS

8355
05:13:23,518 --> 05:13:25,520
OFF THE SHELF VACCINE, AND

8356
05:13:25,520 --> 05:13:29,257
REALLY TRYING TO HAVE THAT BE

8357
05:13:29,257 --> 05:13:31,326
USED FOR INDIVIDUALS FOR A

8358
05:13:31,326 --> 05:13:33,795
PERSONAL APPROACH -- EPITOPE

8359
05:13:33,795 --> 05:13:34,996
SELECTION TO MATCH THEIR

8360
05:13:34,996 --> 05:13:35,430
GENOTYPE.

8361
05:13:35,430 --> 05:13:38,166
I THINK SECONDLY, WE'LL TALK

8362
05:13:38,166 --> 05:13:41,937
BHOR SEQUENCING THE COMPETENT

8363
05:13:41,937 --> 05:13:43,438
RESERVOIR, THE UNDERLYING

8364
05:13:43,438 --> 05:13:45,307
RESERVOIR WE'RE TRYING TO

8365
05:13:45,307 --> 05:13:46,308
SUPPRESS AND KNOWING THE

8366
05:13:46,308 --> 05:13:48,310
SEQUENCES OF THOSE PARTICULAR

8367
05:13:48,310 --> 05:13:49,544
EPITOPE TARGET THAT'S GOING TO

8368
05:13:49,544 --> 05:13:50,712
FURTHER FACILITATE THE SELECTION

8369
05:13:50,712 --> 05:13:52,948
OF EPITOPES IN THE DESIGN OF

8370
05:13:52,948 --> 05:13:54,049
VACCINES, WE CLEARLY CAN

8371
05:13:54,049 --> 05:13:56,384
INCORPORATE THOSE EPITOPES IN

8372
05:13:56,384 --> 05:13:57,919
POLYMORPHISMS IN ORDER TO HAVE

8373
05:13:57,919 --> 05:13:59,387
STRONG SUPPRESSION OF THE VIRUS.

8374
05:13:59,387 --> 05:14:01,223
SO I THINK THAT GIVES US A

8375
05:14:01,223 --> 05:14:03,859
FURTHER OPTIMIZATION AND ABILITY

8376
05:14:03,859 --> 05:14:05,761
TO REALLY SELECT WHAT EPITOPES

8377
05:14:05,761 --> 05:14:06,661
AND THE SEQUENCES TO INCLUDE

8378
05:14:06,661 --> 05:14:07,796
THAT WILL MATCH THE RESERVOIR

8379
05:14:07,796 --> 05:14:09,397
AND HELP US UNDERSTAND FROM A

8380
05:14:09,397 --> 05:14:11,099
PROOF OF CONCEPT PERSPECTIVE IF

8381
05:14:11,099 --> 05:14:12,501
WE HAVE THE RIGHT T-CELL

8382
05:14:12,501 --> 05:14:13,568
RESPONSE DIRECTED TO THE RIGHT

8383
05:14:13,568 --> 05:14:15,003
TARGETS AND EPITOPES THAT MATCH

8384
05:14:15,003 --> 05:14:16,705
SEQUENCE OR THAT ACTUALLY HAVE

8385
05:14:16,705 --> 05:14:18,306
SOME IMPACT ON POST ART

8386
05:14:18,306 --> 05:14:19,307
SUPPRESSION.

8387
05:14:19,307 --> 05:14:22,611
I THINK THIS WILL ALSO JUST

8388
05:14:22,611 --> 05:14:23,979
GENERALLY FACILITATE VACCINE

8389
05:14:23,979 --> 05:14:26,782
DESIGN, MAKING THESE LARGE

8390
05:14:26,782 --> 05:14:28,550
CONSTRUCTS CAN BE QUITE

8391
05:14:28,550 --> 05:14:29,985
CUMBERSOME, HAVING MORE FOCUSED

8392
05:14:29,985 --> 05:14:30,919
CASSETTES FOR INDIVIDUALS I

8393
05:14:30,919 --> 05:14:33,121
THINK WILL JUST BE MUCH EASIER.

8394
05:14:33,121 --> 05:14:34,322
THE LAST THING I'D LIKE TO SAY,

8395
05:14:34,322 --> 05:14:36,792
WITH THE ADVENT OF THESE NUCLEIC

8396
05:14:36,792 --> 05:14:38,193
ACID VACCINE APPROACHES, CLEARLY

8397
05:14:38,193 --> 05:14:39,528
FROM OUR EXPERIENCE WITH

8398
05:14:39,528 --> 05:14:41,329
COVID-19, PARTICULARLY NUCLEIC

8399
05:14:41,329 --> 05:14:42,964
ACID, THE RNA VACCINES, THERE'S

8400
05:14:42,964 --> 05:14:44,599
A CLEAR PRECEDENT FOR USING

8401
05:14:44,599 --> 05:14:46,501
THESE NUCLEIC ACID BASED

8402
05:14:46,501 --> 05:14:47,269
APPROACHES IN PERSONALIZED

8403
05:14:47,269 --> 05:14:48,370
CANCER THERAPY.

8404
05:14:48,370 --> 05:14:50,639
I THINK ACTUALLY MAKING GMP

8405
05:14:50,639 --> 05:14:52,007
PRODUCT IN A REASONABLE TIME

8406
05:14:52,007 --> 05:14:54,442
FRAME THAT CAN BE UTILIZED FOR

8407
05:14:54,442 --> 05:14:55,343
SPECIFIC INDIVIDUALS CAN REALLY

8408
05:14:55,343 --> 05:14:56,912
BE DONE IN A MUCH MORE

8409
05:14:56,912 --> 05:14:57,579
FACILITATED MANNER NOW.

8410
05:14:57,579 --> 05:15:00,415
SO I THINK IN TERMS OF EPITOPE

8411
05:15:00,415 --> 05:15:02,317
SELECTION FROM AN HLA

8412
05:15:02,317 --> 05:15:02,984
STANDPOINT, IN TERMS OF MATCHING

8413
05:15:02,984 --> 05:15:04,719
THE VACCINE TO THE UNDERLYING

8414
05:15:04,719 --> 05:15:05,754
RESERVOIR IN INDIVIDUALS AND

8415
05:15:05,754 --> 05:15:07,622
ACTUALLY GENERATING THE VACCINE

8416
05:15:07,622 --> 05:15:09,591
MATERIAL ITSELF IN THE

8417
05:15:09,591 --> 05:15:10,792
APPROPRIATE DESIGN, I THINK ALL

8418
05:15:10,792 --> 05:15:13,195
OF THESE COMPONENTS ARE QUITE

8419
05:15:13,195 --> 05:15:15,430
FEASIBLE AND REALLY MAKE A -- DO

8420
05:15:15,430 --> 05:15:17,666
A PROOF OF CONCEPT STUDY WHEN WE

8421
05:15:17,666 --> 05:15:19,167
LOOK AT THE ROLE PERHAPS OF

8422
05:15:19,167 --> 05:15:21,536
T-CELL IMMUNITY THAT'S OPTIMIZED

8423
05:15:21,536 --> 05:15:22,504
FOR INDIVIDUALS ON POTENTIAL

8424
05:15:22,504 --> 05:15:23,505
SUPPRESSION.

8425
05:15:23,505 --> 05:15:24,806
SO I THINK THE ANSWER IS A

8426
05:15:24,806 --> 05:15:29,611
DECIDED YES.

8427
05:15:29,611 --> 05:15:31,346
>> I'M MARC WAGNER, A
COMMUNITY

8428
05:15:31,346 --> 05:15:33,615
MEMBER BUT I ALSO DO SCIENCE.

8429
05:15:33,615 --> 05:15:36,685
BUT YOU KNOW, WE'RE MORE THAN 40

8430
05:15:36,685 --> 05:15:39,554
YEARS INTO THE PANDEMIC, AND

8431
05:15:39,554 --> 05:15:41,323
39-PLUS YEARS OF THAT, I'VE BEEN

8432
05:15:41,323 --> 05:15:44,593
LIVING WITH HIV.

8433
05:15:44,593 --> 05:15:49,798
I THINK THAT REALLY SHOWS US THE

8434
05:15:49,798 --> 05:15:52,200
CHALLENGE THIS VIRUS POSES TO

8435
05:15:52,200 --> 05:15:55,904
ALL CURE STRATEGIES.

8436
05:15:55,904 --> 05:15:58,039
EVEN WITH THAT IN PLACE, I HAVE

8437
05:15:58,039 --> 05:16:00,675
HOPE AND I DARE TO BELIEVE THAT

8438
05:16:00,675 --> 05:16:05,914
WE CAN BEAT THIS CONDITION AND

8439
05:16:05,914 --> 05:16:12,120
RID THE BODY OF THIS VIRUS.

8440
05:16:12,120 --> 05:16:13,989
IT'S MORE THAN IMMUNOTHERAPY FOR

8441
05:16:13,989 --> 05:16:15,390
CURE WHICH IS THE CAB I SIT ON

8442
05:16:15,390 --> 05:16:17,726
BUT THE I4C IS A VISION AND I

8443
05:16:17,726 --> 05:16:22,898
THINK IT'S A VISION ALL OF US

8444
05:16:22,898 --> 05:16:24,299
SHARE ACROSS ALL THE

8445
05:16:24,299 --> 05:16:25,433
COLLABORATORIES, THE VISION OF

8446
05:16:25,433 --> 05:16:29,905
REACHING A CURE.

8447
05:16:29,905 --> 05:16:31,773
DURING YESTERDAY'S RAVE,

8448
05:16:31,773 --> 05:16:34,209
DR. DEEKS BROUGHT UP ABOUT SOME

8449
05:16:34,209 --> 05:16:38,079
OF THE LEGACY EFFECTS OF SOME OF

8450
05:16:38,079 --> 05:16:42,317
THE OLDER MEDICATIONS, D4T BEING

8451
05:16:42,317 --> 05:16:45,553
ONE OF THEM WI BUT MANY MORE AS.

8452
05:16:45,553 --> 05:16:46,888
I THINK THESE THINGS NEED TO BE

8453
05:16:46,888 --> 05:16:47,856
CONSIDERED FOR THEIR IMPACT ON

8454
05:16:47,856 --> 05:16:48,723
CURE RESEARCH.

8455
05:16:48,723 --> 05:16:50,492
BUT I THINK WE ALSO NEED TO

8456
05:16:50,492 --> 05:16:51,693
THINK ABOUT WHAT THERAPIES

8457
05:16:51,693 --> 05:16:57,432
PEOPLE ARE ON CURRENTLY FOR HIV.

8458
05:16:57,432 --> 05:17:05,473
JUST FOR EXAMPLE,  ABACAVIR, TO

8459
05:17:05,473 --> 05:17:08,209
MOP VEER, TUSCOVI ALL HAVE

8460
05:17:08,209 --> 05:17:09,577
COMPOUNDS IN THEM THAT HAVE

8461
05:17:09,577 --> 05:17:10,912
PURINES IN THEIR CHEMICAL

8462
05:17:10,912 --> 05:17:11,446
STRUCTURES.

8463
05:17:11,446 --> 05:17:16,084
AND THESE PURINES ARE SIMILAR TO

8464
05:17:16,084 --> 05:17:16,985
ADENOSINE.

8465
05:17:16,985 --> 05:17:18,887
SO IF THEY WERE ABLE TO BIND TO

8466
05:17:18,887 --> 05:17:22,924
THE ADENOSINE RECEPTORS ON

8467
05:17:22,924 --> 05:17:24,759
IMMUNE CELLS, ONE WOULD IMAGINE

8468
05:17:24,759 --> 05:17:26,962
THAT THEY WOULD NOT ONLY

8469
05:17:26,962 --> 05:17:29,130
DECREASE INFLAMMATION BUT THEY

8470
05:17:29,130 --> 05:17:32,300
WOULD ALSO HAVE A SUPPRESSIVE

8471
05:17:32,300 --> 05:17:32,534
EFFECT.

8472
05:17:32,534 --> 05:17:35,370
SO I THINK WE NEED TO UNDERSTAND

8473
05:17:35,370 --> 05:17:37,339
WHAT THE MEDICATIONS MAY BE

8474
05:17:37,339 --> 05:17:41,142
PLAYING IN ON THE OVERALL

8475
05:17:41,142 --> 05:17:41,476
STRATEGIES.

8476
05:17:41,476 --> 05:17:43,078
I THINK THIS IS A GOOD CONCEPT.

8477
05:17:43,078 --> 05:17:44,713
IT SHOULD MOVE FORWARD.

8478
05:17:44,713 --> 05:17:48,216
I THINK WE DON'T KNOW WHAT IS

8479
05:17:48,216 --> 05:17:50,151
THE OPTIMAL, BUT WE NEED TO

8480
05:17:50,151 --> 05:17:53,421
START SOMEWHERE AND I APPRECIATE

8481
05:17:53,421 --> 05:17:54,723
THE FACT THAT NIH AND EVERYBODY

8482
05:17:54,723 --> 05:17:57,792
IN THIS ROOM IS PUTTING FORTH

8483
05:17:57,792 --> 05:18:00,161
THE EFFORT TO CHANGE THE FUTURE

8484
05:18:00,161 --> 05:18:03,431
FOR ALL OF US, EVEN IF IT TAKES

8485
05:18:03,431 --> 05:18:04,966
10, 20 OR 30 MORE YEARS.

8486
05:18:04,966 --> 05:18:11,306
THANK YOU.

8487
05:18:11,306 --> 05:18:17,912
[APPLAUSE]

8488
05:18:17,912 --> 05:18:19,714
>> FROM MY PERSPECTIVE, I

8489
05:18:19,714 --> 05:18:20,348
BELIEVE FIRST OF ALL IT'S GREAT

8490
05:18:20,348 --> 05:18:21,349
WE'RE HAVING THIS DISCUSSION.

8491
05:18:21,349 --> 05:18:23,151
I BELIEVE IT'S IN A WAY

8492
05:18:23,151 --> 05:18:24,519
REFLECTING IMPORTANT ADVANCES

8493
05:18:24,519 --> 05:18:25,987
THAT WE HAVE MADE IN OUR

8494
05:18:25,987 --> 05:18:27,188
COMMUNITY IN THE LAST COUPLE OF

8495
05:18:27,188 --> 05:18:30,392
YEARS THAT WE CAN NOW SORT OF

8496
05:18:30,392 --> 05:18:32,961
RAISE QUESTIONS OF HOW TO

8497
05:18:32,961 --> 05:18:33,828
POTENTIALLY TAILOR CURE

8498
05:18:33,828 --> 05:18:34,262
STRATEGIES.

8499
05:18:34,262 --> 05:18:36,064
IT'S REFLECTING FROM MY

8500
05:18:36,064 --> 05:18:36,965
PERSPECTIVE THAT THERE HAVE A

8501
05:18:36,965 --> 05:18:38,466
LOT MORE DATA AVAILABLE NOW ON

8502
05:18:38,466 --> 05:18:40,235
THE RESERVOIR.

8503
05:18:40,235 --> 05:18:41,936
LARGELY DRIVEN BY TECHNOLOGY

8504
05:18:41,936 --> 05:18:43,905
DEVELOPMENT THAT BECAME

8505
05:18:43,905 --> 05:18:44,672
AVAILABLE IN THE LAST COUPLE OF

8506
05:18:44,672 --> 05:18:45,206
YEARS.

8507
05:18:45,206 --> 05:18:47,876
AND WE CAN IN A WAY COLLECT A

8508
05:18:47,876 --> 05:18:49,444
LOT OF PIECES OF INFORMATION

8509
05:18:49,444 --> 05:18:50,412
ABOUT THE RESERVOIR CELLS FROM

8510
05:18:50,412 --> 05:18:51,713
THESE TYPES OF TECHNOLOGIES.

8511
05:18:51,713 --> 05:18:54,783
WE KNOW A LOT ABOUT THE VIRUS,

8512
05:18:54,783 --> 05:19:00,755
THAT'S WHAT GAURUV TALKED ABOUT

8513
05:19:00,755 --> 05:19:03,525
BUT WE CAN ALSO TALK ABOUT THE

8514
05:19:03,525 --> 05:19:05,994
INFECTED CELL, THEIR

8515
05:19:05,994 --> 05:19:06,728
SUSCEPTIBILITIES, POTENTIAL

8516
05:19:06,728 --> 05:19:07,462
VULNERABILITIES AND ALL THIS

8517
05:19:07,462 --> 05:19:08,063
INFORMATION IS USEFUL.

8518
05:19:08,063 --> 05:19:09,597
AT THE SAME TIME, I ALSO BELIEVE

8519
05:19:09,597 --> 05:19:11,833
WE ARE FAR AWAY FROM KNOWING ALL

8520
05:19:11,833 --> 05:19:14,135
THAT WE NEED TO KNOW IN A WAY.

8521
05:19:14,135 --> 05:19:15,336
THERE'S A LOT OF UNCERTAINTIES

8522
05:19:15,336 --> 05:19:17,272
AND A LOT OF THINGS THAT WE

8523
05:19:17,272 --> 05:19:18,239
JUST -- THAT THE TECHNOLOGIES

8524
05:19:18,239 --> 05:19:20,442
ARE NOT GOOD ENOUGH AT THE

8525
05:19:20,442 --> 05:19:22,077
CURRENT STAGE TO KNOW ABOUT.

8526
05:19:22,077 --> 05:19:24,379
THE SEQUENCING TECHNOLOGIES THAT

8527
05:19:24,379 --> 05:19:27,749
OUR GROUP HAS USED, AND WE ARE

8528
05:19:27,749 --> 05:19:28,716
FULLY RECOGNIZING WE'RE GETTING

8529
05:19:28,716 --> 05:19:30,819
A VERY SMALL PROPORTION OF THE

8530
05:19:30,819 --> 05:19:32,020
RESERVOIR, AND IT'S HARD TO

8531
05:19:32,020 --> 05:19:34,489
CONCLUDE BASED ON THAT TYPE OF

8532
05:19:34,489 --> 05:19:35,957
ANALYSIS WHAT THE OVERALL POOL

8533
05:19:35,957 --> 05:19:38,526
OF RESERVOIR CELLS ARE DOING, SO

8534
05:19:38,526 --> 05:19:40,195
THERE'S LOTS OF OPPORTUNITIES

8535
05:19:40,195 --> 05:19:42,797
FOR IMPROVEMENT, I BELIEVE, AND

8536
05:19:42,797 --> 05:19:44,032
THESE LIMITATIONS, WE NEED TO

8537
05:19:44,032 --> 05:19:45,600
SORT OF KEEP IN MIND AS WE MOVE

8538
05:19:45,600 --> 05:19:47,802
FORWARD WITH THIS PARTICULAR

8539
05:19:47,802 --> 05:19:48,903
AGENDA.

8540
05:19:48,903 --> 05:19:50,271
ALSO, WHAT'S SORT OF A BLACK BOX

8541
05:19:50,271 --> 05:19:52,440
TO A LARGE EXTENT IS THE TISSUE,

8542
05:19:52,440 --> 05:19:53,675
IT'S VERY HARD TO CHARACTERIZE

8543
05:19:53,675 --> 05:19:55,376
AND TO ANALYZE, SO WHAT'S GOING

8544
05:19:55,376 --> 05:19:59,948
ON IN THE TISSUES, WE DON'T KNOW

8545
05:19:59,948 --> 05:20:02,250
TO A LARGE EXTENT AND THAT

8546
05:20:02,250 --> 05:20:03,084
COMPLICATES THIS FURTHER.

8547
05:20:03,084 --> 05:20:04,652
SO FROM MY PERSPECTIVE, AGAIN AS

8548
05:20:04,652 --> 05:20:05,820
I SAID I BELIEVE IT'S A GREAT

8549
05:20:05,820 --> 05:20:07,522
QUESTION TO TALK ABOUT AND TO A

8550
05:20:07,522 --> 05:20:08,623
LARGE EXTENT, NEW TECHNOLOGIES

8551
05:20:08,623 --> 05:20:10,358
WILL BE HELPFUL IN DRIVING THIS

8552
05:20:10,358 --> 05:20:11,392
FURTHER AND GETTING US TO A

8553
05:20:11,392 --> 05:20:12,393
POINT THAT WE CAN ASK THESE

8554
05:20:12,393 --> 05:20:15,430
TYPES OF QUESTIONS EVEN MORE

8555
05:20:15,430 --> 05:20:15,697
PRECISELY.

8556
05:20:15,697 --> 05:20:18,967
THANKS.

8557
05:20:18,967 --> 05:20:20,168
>> THANKS.

8558
05:20:20,168 --> 05:20:23,838
SO I THINK IT'S TO ADDRESS THE

8559
05:20:23,838 --> 05:20:25,340
QUESTION, I THINK IT'S CURRENTLY

8560
05:20:25,340 --> 05:20:27,775
FEASIBLE, BUT THE EXTENT

8561
05:20:27,775 --> 05:20:29,477
PROBABLY DEPENDS SO ON THE STUDY

8562
05:20:29,477 --> 05:20:30,245
CONDITIONS.

8563
05:20:30,245 --> 05:20:33,414
AND MAYBE I'LL TALK ABOUT OUR

8564
05:20:33,414 --> 05:20:36,284
STUDY, A STUDY THAT WAS

8565
05:20:36,284 --> 05:20:38,219
CONDUCTED AT MHRP.

8566
05:20:38,219 --> 05:20:44,659
THE FIRST STUDY ON BNAB INFUS 

8567
05:20:44,659 --> 05:20:46,961
INFUSIONS ON ATI -- IN THE END

8568
05:20:46,961 --> 05:20:48,997
IT'S A SMALL GROUP OF

8569
05:20:48,997 --> 05:20:51,733
PARTICIPANTS, AND WHEN PEOPLE

8570
05:20:51,733 --> 05:20:53,368
REBOUNDED, WE FOUND THAT THE

8571
05:20:53,368 --> 05:20:55,436
PEOPLE THAT REBOUNDED THE

8572
05:20:55,436 --> 05:20:57,405
FASTEST HAD VIRUSES THAT WERE

8573
05:20:57,405 --> 05:20:59,908
RESISTANT TO VRCON.

8574
05:20:59,908 --> 05:21:03,745
OF COURSE THAT WAS A -- AND I

8575
05:21:03,745 --> 05:21:05,547
THINK SINCE WE'RE ENROLLING

8576
05:21:05,547 --> 05:21:08,183
PARTICIPANTS IN STUDIES WHO HAVE

8577
05:21:08,183 --> 05:21:10,785
BEEN ON ART FOR A LONG TIME, WE

8578
05:21:10,785 --> 05:21:13,588
HAVE AN OPPORTUNITY TO

8579
05:21:13,588 --> 05:21:16,124
CHARACTERIZE THEIR VIRUS IN

8580
05:21:16,124 --> 05:21:18,059
ADVANCE BEFORE THEY'RE ACTUALLY

8581
05:21:18,059 --> 05:21:23,598
ENROLLED, AND SO FOR FUTURE

8582
05:21:23,598 --> 05:21:24,599
STUDIES, THAT'S WHAT WE'RE

8583
05:21:24,599 --> 05:21:24,933
DOING.

8584
05:21:24,933 --> 05:21:27,101
WE'RE GOING TO ENROLL

8585
05:21:27,101 --> 05:21:30,572
PARTICIPANTS, ONE OF THE

8586
05:21:30,572 --> 05:21:31,306
ELIGIBILITY CRITERIA WILL BE

8587
05:21:31,306 --> 05:21:32,874
THAT THEY HAVE VIRUSES THAT WE

8588
05:21:32,874 --> 05:21:36,644
THINK ARE SENSITIVE TO THE BNABS

8589
05:21:36,644 --> 05:21:38,479
THAT WILL BE USED IN THE ATI.

8590
05:21:38,479 --> 05:21:41,449
AND HERE, I GUESS IT ALSO REALLY

8591
05:21:41,449 --> 05:21:45,453
VERY MUCH DEPENDS ON THE STUDY

8592
05:21:45,453 --> 05:21:47,622
CONSIDERATIONS, BECAUSE WE'RE

8593
05:21:47,622 --> 05:21:49,724
WORKING WITH A COHORT IN

8594
05:21:49,724 --> 05:21:52,961
BANGKOK, IN THAILAND, 254

8595
05:21:52,961 --> 05:21:53,194
COHORT.

8596
05:21:53,194 --> 05:21:54,596
IT'S A COHORT OF PEOPLE WHO

8597
05:21:54,596 --> 05:21:56,431
STARTED TREATMENT IN ACUTE

8598
05:21:56,431 --> 05:21:57,232
INFECTION.

8599
05:21:57,232 --> 05:22:00,335
SO IT'S MUCH EASIER TO KNOW WHAT

8600
05:22:00,335 --> 05:22:02,103
VIRUSES THEY HAVE, BECAUSE

8601
05:22:02,103 --> 05:22:04,372
THERE'S VERY LITTLE DIVERSITY IN

8602
05:22:04,372 --> 05:22:06,975
THEIR VIRUSES, SO TYPICALLY WE

8603
05:22:06,975 --> 05:22:08,710
HAVE A CLONAL VIRAL POPULATION

8604
05:22:08,710 --> 05:22:11,446
SO WE'RE NOT WORRIED AS MUCH

8605
05:22:11,446 --> 05:22:16,484
ABOUT HAVING THE RESISTANT

8606
05:22:16,484 --> 05:22:20,688
VARIETY OF VIRUSES THAT CAN BE

8607
05:22:20,688 --> 05:22:21,889
RESISTANT AT DIFFERENT LEVELS

8608
05:22:21,889 --> 05:22:24,859
DUE TO VIRAL EVOLUTION.

8609
05:22:24,859 --> 05:22:27,562
SO IN TERMS OF THINKING THAT IT

8610
05:22:27,562 --> 05:22:32,233
IS FEASIBLE, THERE ARE LOTS OF

8611
05:22:32,233 --> 05:22:35,637
LIMITATIONS THAT ARE DUE TO --

8612
05:22:35,637 --> 05:22:39,007
AND OF COURSE WE CAN ALSO TRY TO

8613
05:22:39,007 --> 05:22:41,075
IDENTIFY CONDITIONS THAT WOULD

8614
05:22:41,075 --> 05:22:44,812
BE BETTER AND MAKE US HAVE SORT

8615
05:22:44,812 --> 05:22:46,614
OF OPTIMAL -- AN OPTIMAL -- WE

8616
05:22:46,614 --> 05:22:48,483
NEED TO FIND OPTIMAL CONDITIONS

8617
05:22:48,483 --> 05:22:51,019
THAT ARE BETTER FOR THE

8618
05:22:51,019 --> 05:22:53,621
PARTICIPANTS, AND CONSIDERING

8619
05:22:53,621 --> 05:22:56,324
THE LIMITATIONS THAT WE HAVE

8620
05:22:56,324 --> 05:22:59,093
ALSO TECHNOLOGICALLY.

8621
05:22:59,093 --> 05:23:01,396
>> YES, MY SHORT ANSWER IS
YES

8622
05:23:01,396 --> 05:23:03,898
TO DEVELOP A RESEARCH PLATFORM.

8623
05:23:03,898 --> 05:23:06,801
JUST TO FRAME THE DISCUSSION

8624
05:23:06,801 --> 05:23:09,203
FROM MY MIND, AT LEAST, IN THE

8625
05:23:09,203 --> 05:23:12,273
ABSENCE OF TRANSPLANTATION IN

8626
05:23:12,273 --> 05:23:13,875
CURATIVE STUDIES, POST TREATMENT

8627
05:23:13,875 --> 05:23:21,215
CONTROL IS STILL PHENOMENONICAL.

8628
05:23:21,215 --> 05:23:22,950
WE SEE TO TAKE IT A PART.

8629
05:23:22,950 --> 05:23:24,719
SO TO ME THIS IS COMING AT IT

8630
05:23:24,719 --> 05:23:26,654
FROM THE OTHER END AND

8631
05:23:26,654 --> 05:23:29,691
RECOGNIZING THAT EVERYBODY'S HIV

8632
05:23:29,691 --> 05:23:31,959
INFECTION AND SUBSEQUENT DISEASE

8633
05:23:31,959 --> 05:23:34,162
COURSE IS UNIQUE.

8634
05:23:34,162 --> 05:23:35,263
EVERY INDIVIDUAL IS INFECTED

8635
05:23:35,263 --> 05:23:37,098
WITH A DIFFERENT VIRUS BECAUSE

8636
05:23:37,098 --> 05:23:40,368
OF HLA DIVERSITY, THE SUBSEQUENT

8637
05:23:40,368 --> 05:23:42,103
EVOLUTION WITHIN THAT PERSON IS

8638
05:23:42,103 --> 05:23:43,871
DISTINCT AND, THEREFORE, THE

8639
05:23:43,871 --> 05:23:45,940
T-CELL RESPONSE TO THAT PATHOGEN

8640
05:23:45,940 --> 05:23:48,109
IS DISTINCT.

8641
05:23:48,109 --> 05:23:50,345
THAT THEN IMPACTS THE ANTIBODY

8642
05:23:50,345 --> 05:23:51,179
RESPONSE WITHIN THAT PERSON

8643
05:23:51,179 --> 05:23:52,180
BECAUSE YOU HAVE DIFFERENT

8644
05:23:52,180 --> 05:23:54,048
LEVELS OF EVOLUTION,

8645
05:23:54,048 --> 05:23:55,717
RECOMBINATION THAT ARE

8646
05:23:55,717 --> 05:23:56,284
OCCURRING.

8647
05:23:56,284 --> 05:23:59,020
THAT LEVEL OF EVOLUTION IS

8648
05:23:59,020 --> 05:24:00,521
DEPENDENT ON HOW LONG THAT

8649
05:24:00,521 --> 05:24:03,057
INDIVIDUAL IS UNTREATED.

8650
05:24:03,057 --> 05:24:06,227
SO TREATMENT IN ADE ACUTE VERSUS

8651
05:24:06,227 --> 05:24:07,095
CHRONIC, WHICH WE'RE ALREADY

8652
05:24:07,095 --> 05:24:07,562
DOING.

8653
05:24:07,562 --> 05:24:08,930
WE'RE ALREADY DOING TALENT

8654
05:24:08,930 --> 05:24:10,798
STUDIES BECAUSE WE'RE PICKING OR

8655
05:24:10,798 --> 05:24:13,634
IDENTIFYING STUDY PARTICIPANTS

8656
05:24:13,634 --> 05:24:14,569
DEPENDENT ON WHEN THEY'RE

8657
05:24:14,569 --> 05:24:15,036
TREATED.

8658
05:24:15,036 --> 05:24:16,437
SUBSEQUENTLY ONCE WE INITIATE

8659
05:24:16,437 --> 05:24:19,707
ART THERAPY, THE TIME OF ART

8660
05:24:19,707 --> 05:24:21,342
TREATMENT IS VERY RELEVANT

8661
05:24:21,342 --> 05:24:23,311
BECAUSE WE HAVE TO ALLOW IMMUNE

8662
05:24:23,311 --> 05:24:24,178
RESTORATION FOR THOSE

8663
05:24:24,178 --> 05:24:25,847
INDIVIDUALS WHO REMAIN UNTREATED

8664
05:24:25,847 --> 05:24:28,282
FOR MANY, MANY YEARS.

8665
05:24:28,282 --> 05:24:30,385
SO IN TERMS OF CAN WE STUDY IT,

8666
05:24:30,385 --> 05:24:31,919
I THINK WE HAVE A LOT OF THE

8667
05:24:31,919 --> 05:24:33,121
TOOLS.

8668
05:24:33,121 --> 05:24:34,389
OF COURSE A LOT MORE NEEDS TO BE

8669
05:24:34,389 --> 05:24:34,822
DONE.

8670
05:24:34,822 --> 05:24:36,924
WE CAN RECOVER REPLICATION

8671
05:24:36,924 --> 05:24:38,760
COMPETENT VIRUS LIMITING

8672
05:24:38,760 --> 05:24:41,362
DELUSION, WE CAN SEQUENCE IT, WE

8673
05:24:41,362 --> 05:24:44,332
CAN THEN LOOK TO SEE IF IT IS

8674
05:24:44,332 --> 05:24:45,833
SUSCEPTIBLE TO THE CIRCULATING

8675
05:24:45,833 --> 05:24:47,568
T-CELL RESPONSES, THE

8676
05:24:47,568 --> 05:24:49,837
CIRCULATING ANAB RESPONSES,

8677
05:24:49,837 --> 05:24:50,705
YOU'VE HEARD ABOUT ALL OF THAT

8678
05:24:50,705 --> 05:24:53,040
THIS WEEK.

8679
05:24:53,040 --> 05:24:54,709
WE CAN THEN IDENTIFY PERHAPS IF

8680
05:24:54,709 --> 05:24:57,211
WE HAVE A SUITE, LET'S SAY, OF

8681
05:24:57,211 --> 05:25:02,083
10 BNABs THAT ARE AVAILABLE,

8682
05:25:02,083 --> 05:25:03,551
WHICH THREE OF THAT PARTICULAR

8683
05:25:03,551 --> 05:25:04,218
INDIVIDUAL'S RESERVOIR VIRUS TO

8684
05:25:04,218 --> 05:25:07,955
THE EXTENT THAT WE SEE IT CAN BE

8685
05:25:07,955 --> 05:25:08,656
SUSCEPTIBLE TO.

8686
05:25:08,656 --> 05:25:10,358
SO IN SOME WAYS I THINK WE'RE

8687
05:25:10,358 --> 05:25:11,559
ALREADY MOVING TOWARDS IT, BUT

8688
05:25:11,559 --> 05:25:14,429
PERHAPS ONE OF THE THINGS WE CAN

8689
05:25:14,429 --> 05:25:16,264
AIM FOR IS RECOGNIZING JUST LIKE

8690
05:25:16,264 --> 05:25:19,200
CANCER, WE MAY NOT BE ABLE TO

8691
05:25:19,200 --> 05:25:20,935
CURE OR FUNCTIONAL LIQUEUR 100%

8692
05:25:20,935 --> 05:25:22,603
OF PEOPLE, BUT MAYBE IN THE

8693
05:25:22,603 --> 05:25:24,105
FIRST INSTANCE, 10% IS GOOD.

8694
05:25:24,105 --> 05:25:26,407
BUT VERY IMPORTANTLY, KNOWING

8695
05:25:26,407 --> 05:25:29,777
WHY WE ACHIEVED POST TREATMENT

8696
05:25:29,777 --> 05:25:31,712
CONTROL IN THAT 10% TO ME IS A

8697
05:25:31,712 --> 05:25:34,415
STEP FORWARD, TO MOVE AWAY FROM

8698
05:25:34,415 --> 05:25:35,216
IF HE PHENOMENA.

8699
05:25:35,216 --> 05:25:37,018
>> THANK YOU ALL.

8700
05:25:37,018 --> 05:25:38,786
I WANTED TO MAKE AN OBSERVATION,

8701
05:25:38,786 --> 05:25:41,856
BUT WE HAVE A VERY PATIENT

8702
05:25:41,856 --> 05:25:42,223
GENTLEMAN HERE.

8703
05:25:42,223 --> 05:25:44,091
>> I JUST WAS -- SO I
DON'T

8704
05:25:44,091 --> 05:25:45,293
UNDERSTAND WHAT IT MEANS THAT

8705
05:25:45,293 --> 05:25:46,828
WE'RE TALKING ABOUT, WHAT YOU'RE

8706
05:25:46,828 --> 05:25:51,098
TALKING ABOUT IS THIS CON ACCEPT

8707
05:25:51,098 --> 05:25:52,166
THAT'S BEEN APPROVED, IS THIS

8708
05:25:52,166 --> 05:25:54,569
NOW RESEARCH, IS THIS A WAY LIKE

8709
05:25:54,569 --> 05:25:56,337
HOW SCHOOLHOUSE ROCK DIDN'T

8710
05:25:56,337 --> 05:25:57,371
TEACH ME WHAT COMES WITH THE

8711
05:25:57,371 --> 05:25:59,807
CONCEPT THAT'S APPROVED, WHAT'S

8712
05:25:59,807 --> 05:26:00,875
IT BECOMING AND I DON'T KNOW

8713
05:26:00,875 --> 05:26:01,809
WHAT WE'RE TALKING ABOUT.

8714
05:26:01,809 --> 05:26:03,411
SO IT'S LIKE HOW AM I SUPPOSED

8715
05:26:03,411 --> 05:26:05,213
TO FEEL ABOUT IT?

8716
05:26:05,213 --> 05:26:06,914
SO I WOULD LOVE TO KNOW WHAT

8717
05:26:06,914 --> 05:26:09,784
THIS IS GOING ON, I DON'T

8718
05:26:09,784 --> 05:26:10,551
UNDERSTAND WHAT YOU GUYS ARE

8719
05:26:10,551 --> 05:26:10,852
DISCUSSING.

8720
05:26:10,852 --> 05:26:12,720
>> I'M SORRY, I DIDN'T DO
A GOOD

8721
05:26:12,720 --> 05:26:14,021
JOB WITH MY PLAIN ENGLISH

8722
05:26:14,021 --> 05:26:15,223
SUMMARY.

8723
05:26:15,223 --> 05:26:18,192
SO A CONCEPT MEANS THAT IN THE

8724
05:26:18,192 --> 05:26:21,529
NEXT YEAR OR SO, IT MAY TURN

8725
05:26:21,529 --> 05:26:23,731
INTO A REQUEST FOR PROPOSAL,

8726
05:26:23,731 --> 05:26:24,131
SOME SORT OF --

8727
05:26:24,131 --> 05:26:24,899
>> OH, COOL.

8728
05:26:24,899 --> 05:26:27,535
>>  -- NOTICE OF FUNDING

8729
05:26:27,535 --> 05:26:28,402
OPPORTUNITY.

8730
05:26:28,402 --> 05:26:33,307
AND YOU KNOW, THIS WAS APPROVED

8731
05:26:33,307 --> 05:26:35,510
BY THE NIAID COUNCIL IN JUNE,

8732
05:26:35,510 --> 05:26:38,112
AND I THINK DAIDS TODAY IS

8733
05:26:38,112 --> 05:26:41,048
LOOKING FOR THIS KIND OF

8734
05:26:41,048 --> 05:26:41,916
SCIENTIFIC CONVERSATION WITH A

8735
05:26:41,916 --> 05:26:44,986
BROADER AUDIENCE, INCLUDING

8736
05:26:44,986 --> 05:26:48,022
COMMUNITY, TO SEE DOES THIS

8737
05:26:48,022 --> 05:26:49,257
REALLY MAKE SENSE.

8738
05:26:49,257 --> 05:26:51,526
I WAS ON THE AIDS RESEARCH

8739
05:26:51,526 --> 05:26:52,393
ADVISORY COMMITTEE THAT

8740
05:26:52,393 --> 05:26:54,028
DISCUSSED THIS AT THE COUNCIL

8741
05:26:54,028 --> 05:26:56,197
MEETING, AND THAT COMMITTEE, AS

8742
05:26:56,197 --> 05:26:58,165
YOU'VE HEARD FROM THIS PANEL,

8743
05:26:58,165 --> 05:26:59,400
WAS STRONGLY SUPPORTIVE.

8744
05:26:59,400 --> 05:27:00,735
>> RIGHT.

8745
05:27:00,735 --> 05:27:01,536
IT HELPS A LOT KNOWING WHAT WE

8746
05:27:01,536 --> 05:27:02,937
WERE TALKING ABOUT BECAUSE NOW

8747
05:27:02,937 --> 05:27:05,306
I'M LIKE, AH, NOW I GET IT.

8748
05:27:05,306 --> 05:27:07,174
BUT I UNDERSTAND THE VISION, I

8749
05:27:07,174 --> 05:27:08,175
LOVE THE DEFINITION AND THE

8750
05:27:08,175 --> 05:27:09,510
CONCERNS, BUT NOT KNOWING WHAT I

8751
05:27:09,510 --> 05:27:10,645
WAS TALKING ABOUT OR WHAT YOU

8752
05:27:10,645 --> 05:27:12,413
WERE TALKING ABOUT, THAT'S WHY I

8753
05:27:12,413 --> 05:27:13,814
STOOD UP HERE ALL THIS TIME

8754
05:27:13,814 --> 05:27:15,516
BECAUSE I WAS LIKE WAIT, WHAT

8755
05:27:15,516 --> 05:27:16,050
ARE YOU TALKING ABOUT, YOU

8756
05:27:16,050 --> 05:27:16,417
DIDN'T TELL US.

8757
05:27:16,417 --> 05:27:16,851
THANK YOU SO MUCH.

8758
05:27:16,851 --> 05:27:18,219
>> YOU'RE WELCOME.

8759
05:27:18,219 --> 05:27:22,089
>> I JUST WANT TO MAKE ONE

8760
05:27:22,089 --> 05:27:23,524
OBSERVATION, THAT I AGREE WITH

8761
05:27:23,524 --> 05:27:25,359
EVERYTHING THAT EACH OF THE

8762
05:27:25,359 --> 05:27:29,297
PANELISTS SAID, AND EACH OF

8763
05:27:29,297 --> 05:27:31,799
THE -- AND I THINK WE NEED THIS

8764
05:27:31,799 --> 05:27:33,000
KIND OF OPPORTUNITY IN ORDER TO

8765
05:27:33,000 --> 05:27:36,170
DO WHAT YOU'RE ALL THINKING

8766
05:27:36,170 --> 05:27:38,906
ABOUT AND POTENTIALLY PROPOSING,

8767
05:27:38,906 --> 05:27:42,143
BECAUSE IT ALL TAKES A LONG TIME

8768
05:27:42,143 --> 05:27:46,314
TO CHARACTERIZE HLA ALLELES, THE

8769
05:27:46,314 --> 05:27:49,884
VIRAL EPITOPES, THE INTEGRATION

8770
05:27:49,884 --> 05:27:51,852
SITE, THE PRO VIRUS, WHETHER

8771
05:27:51,852 --> 05:27:53,588
THERE'S AUTOLOGOUS NEUTRALIZING

8772
05:27:53,588 --> 05:27:54,889
ANTIBODIES MAYBE IS ANOTHER

8773
05:27:54,889 --> 05:27:56,090
FACTOR.

8774
05:27:56,090 --> 05:27:58,392
BUT I DO THINK THERE ARE MAYBE

8775
05:27:58,392 --> 05:28:02,229
QUICKER THINGS THAT WE COULD

8776
05:28:02,229 --> 05:28:04,365
CHARACTERIZE THAT MAYBE COULD BE

8777
05:28:04,365 --> 05:28:08,336
DONE EVEN WITHOUT A SPECIFIC

8778
05:28:08,336 --> 05:28:11,272
NOFO ON THIS, LIKE

8779
05:28:11,272 --> 05:28:13,674
CHARACTERIZING INFLAMMATION

8780
05:28:13,674 --> 05:28:15,843
PRIOR TO AN ATI.

8781
05:28:15,843 --> 05:28:18,045
ESPECIALLY IF WE'RE USING LRAs

8782
05:28:18,045 --> 05:28:21,949
THAT ARE ACTIVATING CELLULAR

8783
05:28:21,949 --> 05:28:22,850
PROMOTERS, WHAT'S THAT DOING TO

8784
05:28:22,850 --> 05:28:23,384
INFLAMMATION?

8785
05:28:23,384 --> 05:28:25,353
I THINK IT'S VERY PERTINENT IF

8786
05:28:25,353 --> 05:28:26,988
WE'RE TALKING ABOUT MAKING MORE

8787
05:28:26,988 --> 05:28:30,124
OPPORTUNITIES TO INCLUDE OLDER

8788
05:28:30,124 --> 05:28:33,094
LONG TERM SURVIVORS IN CURE

8789
05:28:33,094 --> 05:28:35,196
RESEARCH.

8790
05:28:35,196 --> 05:28:36,597
OBVIOUSLY IT DOESN'T APPLY TO

8791
05:28:36,597 --> 05:28:38,065
EVERY INTERVENTION FOR CURE, BUT

8792
05:28:38,065 --> 05:28:41,168
IT MIGHT TO SOME, AND THE

8793
05:28:41,168 --> 05:28:42,269
HISTORY OF ART IS VERY IMPORTANT

8794
05:28:42,269 --> 05:28:43,571
BECAUSE IT ALSO INDICATES HOW

8795
05:28:43,571 --> 05:28:44,939
WELL SUPPRESSED SOMEONE HAS

8796
05:28:44,939 --> 05:28:49,010
BEEN, I THINK, AND WHEN IT COMES

8797
05:28:49,010 --> 05:28:51,312
TO TISSUE RESERVOIRS, IMAGING IS

8798
05:28:51,312 --> 05:28:52,647
ANOTHER THING WE SHOULD CONTINUE

8799
05:28:52,647 --> 05:28:56,117
TO BE PUSHING THE FRONTIER AND

8800
05:28:56,117 --> 05:28:56,350
DEVELOP.

8801
05:28:56,350 --> 05:28:57,652
SO I THINK SOME OF THOSE THINGS,

8802
05:28:57,652 --> 05:28:59,787
WE COULD KIND OF COLLECT THE

8803
05:28:59,787 --> 05:29:03,924
DATA PROSPECTIVELY, AND THEN

8804
05:29:03,924 --> 05:29:04,825
RETROSPECTIVELY ANALYZE WHICH

8805
05:29:04,825 --> 05:29:06,093
FACTORS ARE ASSOCIATED WITH A

8806
05:29:06,093 --> 05:29:08,062
BETTER RESPONSE.

8807
05:29:08,062 --> 05:29:09,597
OKAY, I'LL GET OFF MY SOAP BOX

8808
05:29:09,597 --> 05:29:11,032
AND OPEN UP THE --

8809
05:29:11,032 --> 05:29:11,565
>> HI.

8810
05:29:11,565 --> 05:29:13,534
THANK YOU ALL SO MUCH FOR

8811
05:29:13,534 --> 05:29:13,768
SHARING.

8812
05:29:13,768 --> 05:29:15,736
I HAD A QUESTION, WHEN THINKING

8813
05:29:15,736 --> 05:29:20,641
ABOUT THESE APPROACHES, WE ARE

8814
05:29:20,641 --> 05:29:22,276
TENDING TO ASSUME THAT THESE

8815
05:29:22,276 --> 05:29:24,779
APPLICATIONS CAN BE APPLIED SO

8816
05:29:24,779 --> 05:29:27,848
HAVING SEQUENCING DONE REQUIRES

8817
05:29:27,848 --> 05:29:28,949
AN INSTITUTION THAT HAS ACCESS

8818
05:29:28,949 --> 05:29:31,452
TO SEQUENCERS, AND HAVING AN

8819
05:29:31,452 --> 05:29:34,121
INDIVIDUAL HLA TYPED REQUIRES,

8820
05:29:34,121 --> 05:29:36,757
YOU KNOW, A RESEARCH INSTITUTION

8821
05:29:36,757 --> 05:29:40,661
OR SOME SORT OF MORE ADVANCED,

8822
05:29:40,661 --> 05:29:43,764
YOU KNOW, MEDICAL SITE THAT

8823
05:29:43,764 --> 05:29:46,200
AREN'T NECESSARILY AVAILABLE IN

8824
05:29:46,200 --> 05:29:48,469
EVERY COMMUNITY, AND SO I THINK

8825
05:29:48,469 --> 05:29:51,405
THAT HOW WOULD THIS APPLY TO THE

8826
05:29:51,405 --> 05:29:53,808
BROADER FIELD AND NOT JUST

8827
05:29:53,808 --> 05:29:55,543
HAVING THESE OPPORTUNITIES

8828
05:29:55,543 --> 05:29:57,244
AVAILABLE TO INDIVIDUALS WHO

8829
05:29:57,244 --> 05:30:00,915
LIVE IN VERY ADVANCED BIOMEDICAL

8830
05:30:00,915 --> 05:30:03,651
RESEARCH, I GUESS FOCUSED CITIES

8831
05:30:03,651 --> 05:30:05,753
AND REGIONS?

8832
05:30:05,753 --> 05:30:07,888
>> THAT'S A VERY GOOD
POINT, AND

8833
05:30:07,888 --> 05:30:11,392
I ACTUALLY BROUGHT THAT UP WITH

8834
05:30:11,392 --> 05:30:13,360
NIH BEFORE, THAT THERE SHOULD BE

8835
05:30:13,360 --> 05:30:15,429
CENTRALIZED TESTING FOR

8836
05:30:15,429 --> 05:30:20,034
ESPECIALLY HLA AND KERR TYPING

8837
05:30:20,034 --> 05:30:23,738
BECAUSE TH THESE ARE MORE

8838
05:30:23,738 --> 05:30:24,939
CHALLENGING THINGS TO BE DONE,

8839
05:30:24,939 --> 05:30:27,575
AND I THINK IF NIH WOULD INVEST

8840
05:30:27,575 --> 05:30:30,177
IN THAT, THEN RESEARCHERS THAT

8841
05:30:30,177 --> 05:30:33,114
ARE FUNDED THROUGH NIH COULD

8842
05:30:33,114 --> 05:30:35,316
THEN MAKE USE OF THAT.

8843
05:30:35,316 --> 05:30:37,251
IT WOULD BE STANDARDIZED, IT

8844
05:30:37,251 --> 05:30:38,252
WOULD BE DONE WELL, TAKE THE

8845
05:30:38,252 --> 05:30:39,520
BURDEN OFF OF THE INDIVIDUAL

8846
05:30:39,520 --> 05:30:41,522
SITES TO BE ABLE TO DO SOME OF

8847
05:30:41,522 --> 05:30:42,490
THOSE THINGS.

8848
05:30:42,490 --> 05:30:43,357
MY UNDERSTANDING, YOU CAN TELL

8849
05:30:43,357 --> 05:30:45,659
ME IF I'M WRONG, I BELIEVE

8850
05:30:45,659 --> 05:30:48,195
IPDAs ARE ALSO AVAILABLE

8851
05:30:48,195 --> 05:30:48,863
THROUGH NIH.

8852
05:30:48,863 --> 05:30:58,539
IS THAT CORRECT, KARL?

8853
05:30:58,539 --> 05:31:02,810
SO THAT'S ONE THING, BUT I THINK

8854
05:31:02,810 --> 05:31:04,011
OTHERS DEFINITELY NEED TO BE

8855
05:31:04,011 --> 05:31:04,612
ADDRESSED.

8856
05:31:04,612 --> 05:31:06,080
AND I'LL LET ANYONE ELSE ANSWER.

8857
05:31:06,080 --> 05:31:07,715
>> WELL, I'LL JUST MAKE
ONE

8858
05:31:07,715 --> 05:31:08,582
QUICK OBSERVATION THAT I THINK

8859
05:31:08,582 --> 05:31:12,219
THE DELANEY COLLABORATORIES ARE

8860
05:31:12,219 --> 05:31:14,488
A GOOD EXAMPLE OF HOW GROUPS OF

8861
05:31:14,488 --> 05:31:16,090
RESEARCHERS CAN WORK TOGETHER

8862
05:31:16,090 --> 05:31:19,426
AND KIND OF SPREAD ACCESS TO

8863
05:31:19,426 --> 05:31:22,997
RESOURCES, INCLUDING TO PLACES

8864
05:31:22,997 --> 05:31:25,332
THAT, YOU KNOW, PARTICIPANTS MAY

8865
05:31:25,332 --> 05:31:27,701
HAVE THEIR SPECIMENS SHIPPED

8866
05:31:27,701 --> 05:31:31,472
ELSEWHERE FOR ANALYSIS.

8867
05:31:31,472 --> 05:31:33,507
>> I WOULD JUST ADD THAT I
THINK

8868
05:31:33,507 --> 05:31:35,176
THAT THE UTILITY OF THIS IS

8869
05:31:35,176 --> 05:31:36,577
REALLY TO TRY TO UNDERSTAND

8870
05:31:36,577 --> 05:31:38,212
SCIENTIFIC CONCEPTS, SO I THINK

8871
05:31:38,212 --> 05:31:40,281
THAT PERHAPS IF WE SEE THIS AS

8872
05:31:40,281 --> 05:31:44,218
AN OPPORTUNITY TO -- OPTIMAL

8873
05:31:44,218 --> 05:31:45,085
CONDITIONS, UNDERSTAND WHAT CAN

8874
05:31:45,085 --> 05:31:46,487
WORK, MAYBE THAT CAN HELP INFORM

8875
05:31:46,487 --> 05:31:50,524
BROADER STRATEGIES.

8876
05:31:50,524 --> 05:31:53,127
SO RATHER THAN THIS NECESSARILY

8877
05:31:53,127 --> 05:31:54,028
BE THE APPROACH WE TRY TO APPLY

8878
05:31:54,028 --> 05:31:55,763
BUT REALLY FOCUS ON A FEW

8879
05:31:55,763 --> 05:31:56,997
PARTICIPANTS FROM A STUDY

8880
05:31:56,997 --> 05:31:58,799
PERSPECTIVE TO REALLY KNOWING

8881
05:31:58,799 --> 05:31:59,667
WITH OPTIMAL CONDITION WHAT CAN

8882
05:31:59,667 --> 05:32:01,101
AND CANNOT WORK IS WHERE THE

8883
05:32:01,101 --> 05:32:03,337
UTILITY REALLY IS.

8884
05:32:03,337 --> 05:32:04,238
>> THANK YOU.

8885
05:32:04,238 --> 05:32:06,674
AND I WOULD AGREE THAT I THINK

8886
05:32:06,674 --> 05:32:07,341
IT'S BABY STEPS.

8887
05:32:07,341 --> 05:32:11,712
IF WE CAN ACTUALLY CONFIDENTLY

8888
05:32:11,712 --> 05:32:13,113
PREDICT WHY 10% MAY ACTUALLY

8889
05:32:13,113 --> 05:32:15,416
RESPOND TO TREATMENT, AT THAT

8890
05:32:15,416 --> 05:32:17,351
JUNCTURE, YOU'RE LOOKING FOR

8891
05:32:17,351 --> 05:32:18,252
BIOMARKERS TO SCREEN THE

8892
05:32:18,252 --> 05:32:22,857
POPULATION FOR THAT 10%.

8893
05:32:22,857 --> 05:32:24,792
>> LET'S GO OVER TO THIS
SIDE.

8894
05:32:24,792 --> 05:32:26,660
>> ANDY FROM NIAID.

8895
05:32:26,660 --> 05:32:27,728
SO ONE THING AS A COMMENT AND

8896
05:32:27,728 --> 05:32:32,666
THEN A QUESTION IS, ONE OF THE

8897
05:32:32,666 --> 05:32:33,868
THINGS ABOUT TAILORING A CURE

8898
05:32:33,868 --> 05:32:35,502
FOR INDIVIDUALS IS WE NEED TO

8899
05:32:35,502 --> 05:32:36,303
KNOW MORE ABOUT DIFFERENT

8900
05:32:36,303 --> 05:32:36,704
INDIVIDUALS.

8901
05:32:36,704 --> 05:32:38,739
WE'RE STARTING TO SEE IT A

8902
05:32:38,739 --> 05:32:39,740
LITTLE MORE WHERE SO MUCH OF

8903
05:32:39,740 --> 05:32:41,208
CURE WORK WAS ONLY DONE IN THE

8904
05:32:41,208 --> 05:32:43,110
UNITED STATES, USUALLY DONE IN

8905
05:32:43,110 --> 05:32:44,745
MOSTLY MALE POPULATIONS, AND I

8906
05:32:44,745 --> 05:32:48,249
THINK IF WE STUDY MORE DIVERSE

8907
05:32:48,249 --> 05:32:49,550
POPULATIONS IN AFRICA AS WELL AS

8908
05:32:49,550 --> 05:32:55,990
MALE AND FEMALE, AGAIN, OLDER

8909
05:32:55,990 --> 05:32:56,857
INDIVIDUALS, ACUTE, CHRONIC, ET

8910
05:32:56,857 --> 05:32:57,858
CETERA, I THINK WE'RE GOING TO

8911
05:32:57,858 --> 05:32:59,894
LEARN MORE, WHICH WILL HELP MAKE

8912
05:32:59,894 --> 05:33:00,561
THIS A REALITY, RIGHT?

8913
05:33:00,561 --> 05:33:02,863
IF WE ONLY STUDY PEOPLE WHO ARE

8914
05:33:02,863 --> 05:33:04,732
TREATED DURING ACUTE INFECTION

8915
05:33:04,732 --> 05:33:07,234
AND ONLY MALES, WE'RE MISSING A

8916
05:33:07,234 --> 05:33:09,036
HUGE AMOUNT OF INFORMATION.

8917
05:33:09,036 --> 05:33:11,372
BUT IT NICE TO SEE MORE OF THAT

8918
05:33:11,372 --> 05:33:15,209
BEING INCLUDED IN -- THE

8919
05:33:15,209 --> 05:33:16,176
DELANEYS ARE JUST RESEARCH IN

8920
05:33:16,176 --> 05:33:16,510
GENERAL.

8921
05:33:16,510 --> 05:33:18,812
BUT THE SECOND COMMENT IS -- ON

8922
05:33:18,812 --> 05:33:22,716
THIS IS SOME WORK BY MELISSA

8923
05:33:22,716 --> 05:33:24,018
SMITH THAT JUST CAME OUT IN

8924
05:33:24,018 --> 05:33:24,919
NATURE COMMUNICATIONS THAT

8925
05:33:24,919 --> 05:33:27,288
SHOWED THAT THERE'S A LOT MORE

8926
05:33:27,288 --> 05:33:29,390
DIVERSITY IN THINGS LIKE THE VDJ

8927
05:33:29,390 --> 05:33:30,791
RECOMBINANT REGIONS OF OUR

8928
05:33:30,791 --> 05:33:31,258
ANTIBODIES.

8929
05:33:31,258 --> 05:33:33,627
AND SO HOW DO YOU GUYS THINK, AS

8930
05:33:33,627 --> 05:33:35,930
WE DRILL DEEPER INTO EACH

8931
05:33:35,930 --> 05:33:37,898
INDIVIDUAL, THE COMPLEXITY GETS

8932
05:33:37,898 --> 05:33:41,835
THAT MUCH MORE COMPLEEX?

8933
05:33:41,835 --> 05:33:45,773
AND LIKE WE REALLY CAN'T CURE

8934
05:33:45,773 --> 05:33:46,941
ANYBODY WITH PERFECT SITUATIONS

8935
05:33:46,941 --> 05:33:48,275
NOW, LIKE AS IT GETS MORE AND

8936
05:33:48,275 --> 05:33:49,877
MORE COMPLEX, HOW DO YOU GUYS

8937
05:33:49,877 --> 05:33:52,179
THINK WE'LL DEAL WITH THAT LEVEL

8938
05:33:52,179 --> 05:33:58,986
OF COMPLEXITY?

8939
05:33:58,986 --> 05:34:00,487
>> JUST A BRIEF COMMENT ON
THAT.

8940
05:34:00,487 --> 05:34:01,889
SO I BELIEVE WHAT IS REALLY

8941
05:34:01,889 --> 05:34:02,990
HELPFUL AT THE CURRENT STAGE OF

8942
05:34:02,990 --> 05:34:04,959
DEVELOPMENT ARE THESE SORT OF N

8943
05:34:04,959 --> 05:34:07,628
EQUALS 1 STUDY, SO GOING DEEP ON

8944
05:34:07,628 --> 05:34:08,896
ONE PARTICULAR PERSON WHO HAS A

8945
05:34:08,896 --> 05:34:11,732
VERY ATYPICAL RESERVOIR OR A

8946
05:34:11,732 --> 05:34:14,435
VERY ATYPICAL DISEASE COURSE

8947
05:34:14,435 --> 05:34:15,769
AFTER TREATMENT INTERRUPTION.

8948
05:34:15,769 --> 05:34:18,706
THAT BY ITSELF CAN BE INCREDIBLY

8949
05:34:18,706 --> 05:34:21,041
INFORMATIVE, AND USING THAT FULL

8950
05:34:21,041 --> 05:34:22,343
PIPELINE OF TECHNOLOGIES THAT IS

8951
05:34:22,343 --> 05:34:23,644
AVAILABLE AT THE CURRENT TIME

8952
05:34:23,644 --> 05:34:25,946
CAN BE A SORT OF REVEALING

8953
05:34:25,946 --> 05:34:27,915
PATTERNS AND MECHANISMS AND

8954
05:34:27,915 --> 05:34:29,450
BIOLOGY THAT WAS JUST NOT

8955
05:34:29,450 --> 05:34:30,317
OBVIOUS BEFORE.

8956
05:34:30,317 --> 05:34:34,054
SO I BELIEVE ZOOMING IN ON

8957
05:34:34,054 --> 05:34:35,322
INDIVIDUAL PERSONS IS AN

8958
05:34:35,322 --> 05:34:36,323
IMPORTANT ASPECT OF IT, AS YOU

8959
05:34:36,323 --> 05:34:38,959
SAID, AND ALSO DIVERSITY IS

8960
05:34:38,959 --> 05:34:39,626
INCREDIBLY IMPORTANT.

8961
05:34:39,626 --> 05:34:40,794
JUST THAT DIFFERENCE THAT YOU

8962
05:34:40,794 --> 05:34:41,795
MENTIONED BETWEEN MALE AND

8963
05:34:41,795 --> 05:34:43,297
FEMALE, I BELIEVE HAS A

8964
05:34:43,297 --> 05:34:44,298
FUNDAMENTAL IMPACT ON WHAT THE

8965
05:34:44,298 --> 05:34:46,667
IMMUNE SYSTEM CAN DO AGAINST THE

8966
05:34:46,667 --> 05:34:48,002
RESERVOIR, AND IT'S GREAT THAT

8967
05:34:48,002 --> 05:34:49,236
THERE'S NOW MORE RECOGNITION FOR

8968
05:34:49,236 --> 05:34:51,005
THAT.

8969
05:34:51,005 --> 05:34:56,510
>> IN I CO IF I COULD MAKE
AN EL

8970
05:34:56,510 --> 05:34:57,378
COMMENT, MATHIAS.

8971
05:34:57,378 --> 05:34:59,013
I'VE HAD CONVERSATIONS WITH

8972
05:34:59,013 --> 05:35:00,981
STATISTICIANS WHO RAISE CONCERNS

8973
05:35:00,981 --> 05:35:02,950
ABOUT N EQUALS 1 STUDIES BECAUSE

8974
05:35:02,950 --> 05:35:04,251
YOU CAN'T COMPARE, RIGHT?

8975
05:35:04,251 --> 05:35:06,320
SO YOU'RE NEVER REALLY SURE.

8976
05:35:06,320 --> 05:35:07,755
SO I THINK THAT'S AN AREA WHERE

8977
05:35:07,755 --> 05:35:09,156
WE WANT STUDY DESIGNS WHERE

8978
05:35:09,156 --> 05:35:11,091
THERE CAN BE LIKE A CROSSOVER,

8979
05:35:11,091 --> 05:35:13,327
YOU KNOW, SO YOU EVALUATE

8980
05:35:13,327 --> 05:35:16,363
SOMETHING BEFORE AND AFTER AN

8981
05:35:16,363 --> 05:35:18,098
INTERVENTION, OR YOU KNOW, SOME

8982
05:35:18,098 --> 05:35:19,199
WAY WITHIN THE INDIVIDUAL TO

8983
05:35:19,199 --> 05:35:26,607
HAVE A COMPARISON.

8984
05:35:26,607 --> 05:35:28,342
>> YOU ALL HAVE DONE A
REALLY

8985
05:35:28,342 --> 05:35:29,877
GREAT JOB EXPLAINING HOW WE

8986
05:35:29,877 --> 05:35:32,679
COULD TAILOR HIV CURE STRATEGIES

8987
05:35:32,679 --> 05:35:34,348
TO THE INDIVIDUAL PARTICIPANT

8988
05:35:34,348 --> 05:35:36,216
FROM A VIROLOGICAL AND

8989
05:35:36,216 --> 05:35:36,984
IMMUNOLOGICAL STAND POINTS.

8990
05:35:36,984 --> 05:35:39,153
HAVE YOU ALSO CONSIDERED

8991
05:35:39,153 --> 05:35:40,687
INTEGRATING PSYCHOSOCIAL MARKERS

8992
05:35:40,687 --> 05:35:42,423
AND ACCEPTABILITY MARKERS TO

8993
05:35:42,423 --> 05:35:44,725
MAKE SURE THAT THESE STRATEGIES

8994
05:35:44,725 --> 05:35:45,926
REMAIN ACCEPTABLE TO

8995
05:35:45,926 --> 05:35:46,693
PARTICIPANT?

8996
05:35:46,693 --> 05:35:49,196
WE KNOW ATIs ARE ASSOCIATED

8997
05:35:49,196 --> 05:35:50,664
WITH VIREMIA RELATED WORRY AND

8998
05:35:50,664 --> 05:35:51,632
PEOPLE HAVE DIFFERENT TOLERANCE

8999
05:35:51,632 --> 05:35:53,133
FOR RISK SO IT SEEMS LIKE WE

9000
05:35:53,133 --> 05:35:54,535
COULD LEARN A LOT ABOUT THE

9001
05:35:54,535 --> 05:35:55,736
ACCEPTABILITY OF THESE DIFFERENT

9002
05:35:55,736 --> 05:35:56,070
MODALITIES.

9003
05:35:56,070 --> 05:35:57,805
AND ALSO ARE YOU INTEGRATING

9004
05:35:57,805 --> 05:36:00,340
ETHICAL CONSIDERATIONS FOR

9005
05:36:00,340 --> 05:36:01,308
PERSONALIZED CURE?

9006
05:36:01,308 --> 05:36:03,944
IT SEEMS LIKE WE WANT TO PREVENT

9007
05:36:03,944 --> 05:36:05,479
INCREASING DISPARITIES WITH

9008
05:36:05,479 --> 05:36:09,183
THESE STRATEGIES.

9009
05:36:09,183 --> 05:36:10,818
>> DOES ANYBODY WANT TO
COMMENT

9010
05:36:10,818 --> 05:36:16,523
ON THAT?

9011
05:36:16,523 --> 05:36:17,925
>> I I BELIEVE YOU SHOULD
BE

9012
05:36:17,925 --> 05:36:18,992
SITTING UP HERE TO TALK ABOUT

9013
05:36:18,992 --> 05:36:19,226
THIS.

9014
05:36:19,226 --> 05:36:20,127
THESE ARE VERY IMPORTANT PARTS

9015
05:36:20,127 --> 05:36:22,062
OF IT, RIGHT, AND IT NEEDS TO BE

9016
05:36:22,062 --> 05:36:23,163
TAKEN INTO CONSIDERATION AS MUCH

9017
05:36:23,163 --> 05:36:25,532
AS ALL THE OTHER THINGS AS THE

9018
05:36:25,532 --> 05:36:27,301
BROADLY NEUTRALIZING ANTIBODIES,

9019
05:36:27,301 --> 05:36:29,036
THE T-CELLS, SO IT SHOULD BE

9020
05:36:29,036 --> 05:36:31,004
HAVING -- IT SHOULD BE

9021
05:36:31,004 --> 05:36:32,005
INCORPORATED INTO ALL THESE

9022
05:36:32,005 --> 05:36:33,073
DISCUSSIONS.

9023
05:36:33,073 --> 05:36:35,909
SO I'M HAPPY TO LEARN FROM YOU,

9024
05:36:35,909 --> 05:36:37,211
IT SOUNDS LIKE YOU HAVE A LOT OF

9025
05:36:37,211 --> 05:36:38,512
THINGS TO CONTRIBUTE WHEN IT

9026
05:36:38,512 --> 05:36:40,247
COMES TO THESE QUESTIONS.

9027
05:36:40,247 --> 05:36:41,915
>> KARINE, I GUESS MY

9028
05:36:41,915 --> 05:36:42,516
UNDERSTANDING OF THE QUESTION

9029
05:36:42,516 --> 05:36:44,084
IS, I DON'T THINK WE'RE TRYING

9030
05:36:44,084 --> 05:36:48,021
TO PUSH  ATI, I THINK WE'RE

9031
05:36:48,021 --> 05:36:49,123
ACTUALLY TRYING TO LEARN A LOT

9032
05:36:49,123 --> 05:36:50,824
MORE BEFORE AND THEN SELECTIVELY

9033
05:36:50,824 --> 05:36:52,826
IDENTIFY THE BEST CHANCES FOR AN

9034
05:36:52,826 --> 05:36:53,060
ATI.

9035
05:36:53,060 --> 05:36:54,128
SO I THINK WE'RE MOVING THE

9036
05:36:54,128 --> 05:36:56,196
OTHER WAY, PERSONALLY, FROM MY

9037
05:36:56,196 --> 05:36:57,631
PERSPECTIVE.

9038
05:36:57,631 --> 05:36:59,900
>> I THINK IT'S ACTUALLY
-- I

9039
05:36:59,900 --> 05:37:02,202
MEAN, A LOT OF THIS IS TRYING TO

9040
05:37:02,202 --> 05:37:05,939
MAKE -- TO OPTIMIZE CONDITIONS

9041
05:37:05,939 --> 05:37:07,241
SO FOR THE PARTICIPANTS IT'S

9042
05:37:07,241 --> 05:37:08,208
BETTER.

9043
05:37:08,208 --> 05:37:09,076
>> LYNDA?

9044
05:37:09,076 --> 05:37:10,944
>> YEAH, SO YOU SAID THAT
MAYBE

9045
05:37:10,944 --> 05:37:13,881
IN A YEAR OR SO, THERE MIGHT BE

9046
05:37:13,881 --> 05:37:14,381
SOME SORT OF REQUEST FOR

9047
05:37:14,381 --> 05:37:16,083
PROPOSAL ON THIS, AND I JUST

9048
05:37:16,083 --> 05:37:18,352
WONDER, I MEAN, IT SOUNDS

9049
05:37:18,352 --> 05:37:19,453
FABULOUS, BUT THERE ARE

9050
05:37:19,453 --> 05:37:21,288
CONTROVERSIES ABOUT PRO VIRUS,

9051
05:37:21,288 --> 05:37:23,490
AND WHAT IMMUNOLOGIC PROFILE ARE

9052
05:37:23,490 --> 05:37:24,658
WE LOOKING AT?

9053
05:37:24,658 --> 05:37:25,659
LOU I I LOVE THIS, ALWAYS LIKES

9054
05:37:25,659 --> 05:37:28,328
TO SAY, IT'S ALL ONE SYSTEM AND

9055
05:37:28,328 --> 05:37:30,797
ONE PIECE, YOU KNOW, AFFECTS THE

9056
05:37:30,797 --> 05:37:33,500
OTHER PIECES.

9057
05:37:33,500 --> 05:37:34,902
YOU KNOW, IT'S A WHOLE MOVING

9058
05:37:34,902 --> 05:37:37,771
THING INSTEAD OF JUST ONE LITTLE

9059
05:37:37,771 --> 05:37:39,740
CD4 OR CD8, THAT SORT OF THING.

9060
05:37:39,740 --> 05:37:41,575
SO WHAT WOULD THE IMMUNOLOGIC

9061
05:37:41,575 --> 05:37:42,009
PROFILE BE?

9062
05:37:42,009 --> 05:37:43,877
I THINK WE'RE KIND OF -- MAYBE

9063
05:37:43,877 --> 05:37:44,311
THREE YEARS?

9064
05:37:44,311 --> 05:37:48,482
I DON'T KNOW ABOUT NEXT YEAR.

9065
05:37:48,482 --> 05:37:50,784
I BELIEVE IN FORWARD PLANNING,

9066
05:37:50,784 --> 05:37:50,984
BUT --

9067
05:37:50,984 --> 05:37:53,220
>> I WOULD JUST ADD THAT,
AND

9068
05:37:53,220 --> 05:37:54,321
LYNDA, I THINK FROM THE LESSONS

9069
05:37:54,321 --> 05:37:55,489
WE'VE LEARNED FROM ALL THESE

9070
05:37:55,489 --> 05:37:58,992
COHORT STUDY, ACROSS ALL THESE

9071
05:37:58,992 --> 05:37:59,960
COLLABORATORIES, I THINK THERE'S

9072
05:37:59,960 --> 05:38:03,363
SOME GENERAL THOUGHT THAT A

9073
05:38:03,363 --> 05:38:05,632
POTENT CD -- RESPONSE COULD

9074
05:38:05,632 --> 05:38:06,533
POTENTIALLY HAVE AN IMPACT.

9075
05:38:06,533 --> 05:38:08,268
I THINK CLEARLY THE BNABS, IF

9076
05:38:08,268 --> 05:38:15,475
THEY'RE HITTING SENSITIVE RE --

9077
05:38:15,475 --> 05:38:17,344
TAKE PATIENTS OFF TREATMENT,

9078
05:38:17,344 --> 05:38:19,313
CLEARLY AUTOLOGOUS TO

9079
05:38:19,313 --> 05:38:19,913
ANTIBODIES, EMERGING SOME OF

9080
05:38:19,913 --> 05:38:21,181
THESE INNATE IMMUNE FACTORS.

9081
05:38:21,181 --> 05:38:22,616
I THINK THE IDEA IS WE KIND OF

9082
05:38:22,616 --> 05:38:24,284
TAKE THAT COLLECTIVE KNOWLEDGE

9083
05:38:24,284 --> 05:38:25,786
AND IF WE ARE GOING TO TRY TO

9084
05:38:25,786 --> 05:38:28,188
TAILOR A STRATEGY, HOW CAN WE

9085
05:38:28,188 --> 05:38:29,389
OPTIMIZE ALL THOSE COLLECTIVE

9086
05:38:29,389 --> 05:38:30,257
COMPONENTS FOR A GIVEN

9087
05:38:30,257 --> 05:38:31,358
INDIVIDUAL BEFORE WE CONSIDER?

9088
05:38:31,358 --> 05:38:32,993
AND IF WE DO OPTIMIZE CERTAIN

9089
05:38:32,993 --> 05:38:34,494
COMPONENTS VERSUS OTHERS, OR

9090
05:38:34,494 --> 05:38:35,729
SOME KIND OF COMBINATION

9091
05:38:35,729 --> 05:38:36,930
THEREOF, WHAT EFFECT DOES THAT

9092
05:38:36,930 --> 05:38:37,364
HAVE?

9093
05:38:37,364 --> 05:38:39,666
I THINK THAT'S WHERE THE REAL

9094
05:38:39,666 --> 05:38:41,301
POSSIBILITY FOR LEARNINGS CAN

9095
05:38:41,301 --> 05:38:41,602
TAKE PLACE.

9096
05:38:41,602 --> 05:38:43,303
SO WHAT HAPPENS WHEN THINGS ARE

9097
05:38:43,303 --> 05:38:46,039
OPTIMIZED, WHAT'S THE OUTCOME

9098
05:38:46,039 --> 05:38:46,373
SUBSEQUENTLY.

9099
05:38:46,373 --> 05:38:47,441
>> ISN'T THAT BETTER IN A
BIG

9100
05:38:47,441 --> 05:38:48,742
GROUP THAN TRYING TO DO THAT

9101
05:38:48,742 --> 05:38:49,743
PATIENT BY PATIENT, THOUGH?

9102
05:38:49,743 --> 05:38:51,812
IS IT IN EACH PARTICIPANT?

9103
05:38:51,812 --> 05:38:53,413
>> THAT'S THE IDEA.

9104
05:38:53,413 --> 05:38:55,115
>> GOOD LUCK.

9105
05:38:55,115 --> 05:38:57,017
[LAUGHTER]

9106
05:38:57,017 --> 05:39:02,122
>> HI.

9107
05:39:02,122 --> 05:39:03,991
I WOULD LIKE TO BRING YOUR

9108
05:39:03,991 --> 05:39:05,626
ATTENTION BACK TO THE TISSUE

9109
05:39:05,626 --> 05:39:06,927
LEVEL.

9110
05:39:06,927 --> 05:39:09,029
SO I KIND OF AGREE THAT A TISSUE

9111
05:39:09,029 --> 05:39:10,197
LEVEL IS KIND OF LIKE A BLACK

9112
05:39:10,197 --> 05:39:12,199
BOX RIGHT NOW.

9113
05:39:12,199 --> 05:39:16,670
SO I JUST WISH TO THINK ABOUT

9114
05:39:16,670 --> 05:39:19,606
WHEN WE STARTED THE TISSUE --

9115
05:39:19,606 --> 05:39:22,676
THE STILL LIKE IT'S A BABY AND

9116
05:39:22,676 --> 05:39:25,312
THE -- GET FROM THE T-CELL.

9117
05:39:25,312 --> 05:39:28,715
SO I THINK PROBABLY IT'S A

9118
05:39:28,715 --> 05:39:30,617
LITTLE MORE -- IT'S SO DIFFICULT

9119
05:39:30,617 --> 05:39:34,421
TO STUDY, AND SHOULD IT BE MORE

9120
05:39:34,421 --> 05:39:36,290
ENCOURAGED FOR THIS.

9121
05:39:36,290 --> 05:39:40,961
THANK YOU.

9122
05:39:40,961 --> 05:39:45,799
SO FOR THE -- WE JUST MENTIONED

9123
05:39:45,799 --> 05:39:56,276
ABOUT THE -- -- THE TISSUES.

9124
05:39:56,476 --> 05:40:02,516
SO I -- WE JUST WANT TO GET MORE

9125
05:40:02,516 --> 05:40:03,750
ENCOURAGING IN THIS FIELD AND

9126
05:40:03,750 --> 05:40:08,221
MORE PROGRESS IN THIS FIELD.

9127
05:40:08,221 --> 05:40:09,523
>> I BELIEVE IT'S GREAT
THAT

9128
05:40:09,523 --> 05:40:11,825
YOU'RE BRINGING IT UP, AND IN MY

9129
05:40:11,825 --> 05:40:12,893
EXPERIENCE, I CAN ONLY SAY WE

9130
05:40:12,893 --> 05:40:14,895
DID A RECENT STUDY WHERE WE

9131
05:40:14,895 --> 05:40:16,963
LOOKED AT THE PHENOTYPE OF

9132
05:40:16,963 --> 05:40:18,699
RESERVOIR CELLS IN TISSUES

9133
05:40:18,699 --> 05:40:20,000
VERSUS BLOOD AND IT LOOKS VERY

9134
05:40:20,000 --> 05:40:20,267
DIFFERENT.

9135
05:40:20,267 --> 05:40:22,436
>> THAT'S EXACTLY WHAT I
WANT TO

9136
05:40:22,436 --> 05:40:23,070
SAY.

9137
05:40:23,070 --> 05:40:27,240
SO WHAT WE SEE IS SO DIFFERENT

9138
05:40:27,240 --> 05:40:30,844
BETWEEN THE -- THE T-CELL, SO

9139
05:40:30,844 --> 05:40:33,046
WHAT -- OR I DON'T -- IT'S SO

9140
05:40:33,046 --> 05:40:34,915
DIFFERENT.

9141
05:40:34,915 --> 05:40:36,316
>> IT'S A CHALLENGE FOR
ALL OF

9142
05:40:36,316 --> 05:40:38,618
US, I BELIEVE, IN THIS

9143
05:40:38,618 --> 05:40:40,354
COMMUNITY, AND THE ANIMAL STUDY

9144
05:40:40,354 --> 05:40:43,123
KS HELP TO SOME EXTENT, AND THE

9145
05:40:43,123 --> 05:40:44,591
TISSUES USING AUTOPSY MATERIAL

9146
05:40:44,591 --> 05:40:48,729
THAT YOU ARE DOING, BUT IT'S

9147
05:40:48,729 --> 05:40:49,896
GOOD TO HAVE A BIGGER DISCUSSION

9148
05:40:49,896 --> 05:40:51,098
ABOUT HOW WE ARE ADDRESSING

9149
05:40:51,098 --> 05:40:51,298
THAT.

9150
05:40:51,298 --> 05:40:52,866
>> THANK YOU.

9151
05:40:52,866 --> 05:40:55,402
>> HI.

9152
05:40:55,402 --> 05:40:59,339
I THINK IT'S A REALLY VERY

9153
05:40:59,339 --> 05:41:06,012
WELL -- THIS APPROACH, I THINK

9154
05:41:06,012 --> 05:41:07,848
THE ADVENT OF SYSTEM BIOLOGY IS

9155
05:41:07,848 --> 05:41:10,050
WHEN WE CAN REALLY RE-TAILOR

9156
05:41:10,050 --> 05:41:11,585
PERSONALIZED MEDICINE.

9157
05:41:11,585 --> 05:41:14,988
 -- AND MYSELF, WE WORK FOR 15

9158
05:41:14,988 --> 05:41:16,089
YEARS ON PERSONALIZED APPROACHES

9159
05:41:16,089 --> 05:41:18,392
TO VACCINATION, AND WE SHOWED

9160
05:41:18,392 --> 05:41:21,895
CLEARLY THERE ARE PROFILES THAT

9161
05:41:21,895 --> 05:41:24,297
CAN PREDICT -- RESPOND TO

9162
05:41:24,297 --> 05:41:24,731
VACCINES.

9163
05:41:24,731 --> 05:41:27,801
I THINK WE HAVE NOW THE SAME

9164
05:41:27,801 --> 05:41:33,573
DATA, -- HAS IDENTIFIED WHERE WE

9165
05:41:33,573 --> 05:41:37,144
SEE ABOUT FIVE -- AVAILABLE, IS

9166
05:41:37,144 --> 05:41:39,613
ALMOST WHAT YOU EAT.

9167
05:41:39,613 --> 05:41:42,449
IT'S THE -- AND MICROBES THAT

9168
05:41:42,449 --> 05:41:45,752
SHAPE THE -- AND SHAPE THE AREAS

9169
05:41:45,752 --> 05:41:46,820
THAT CONTROL THE VIRUS.

9170
05:41:46,820 --> 05:41:50,991
SO THIS APPROACH, THIS STRATEGY,

9171
05:41:50,991 --> 05:41:55,595
I THINK NOT ONLY CAN BE FOCUSED

9172
05:41:55,595 --> 05:41:57,330
ON -- FACTORS WHICH I'M SURE ARE

9173
05:41:57,330 --> 05:42:02,436
THERE, HOST IMMUNE FACTORS, WE

9174
05:42:02,436 --> 05:42:04,037
CHOSE -- AND -- THE GROUP TO

9175
05:42:04,037 --> 05:42:06,873
THINK OUTSIDE OF THE BOX, AND

9176
05:42:06,873 --> 05:42:08,642
THINK WHAT IN FACT IS REALLY

9177
05:42:08,642 --> 05:42:10,377
WHAT DICTATES THE SHAPE OF

9178
05:42:10,377 --> 05:42:11,711
IMMUNE RESPONSE EVERY DAY.

9179
05:42:11,711 --> 05:42:13,213
THAT HAS CLEARLY BEEN SHOWN IN

9180
05:42:13,213 --> 05:42:13,447
CANCER.

9181
05:42:13,447 --> 05:42:15,749
THERE WAS A MEETING OF --

9182
05:42:15,749 --> 05:42:18,151
MICROBE AND METABALOME FOR TWO

9183
05:42:18,151 --> 05:42:22,756
DAYS AND ALL I HEARD IS YOU MAY

9184
05:42:22,756 --> 05:42:27,127
EAT HIGH FIBER, LOW FIBER DIET,

9185
05:42:27,127 --> 05:42:29,529
THERAPIES TO CANCER, PANCREATIC

9186
05:42:29,529 --> 05:42:31,932
CANCER, SO THAT REALLY HAS TO GO

9187
05:42:31,932 --> 05:42:32,332
INTO OUR MIND.

9188
05:42:32,332 --> 05:42:34,868
MAYBE WHAT YOU EAT CAN BE

9189
05:42:34,868 --> 05:42:38,038
EXTREMELY GENERIC, BUT YOU

9190
05:42:38,038 --> 05:42:42,542
WHATEVER INTAKE WE TAKE, THAT

9191
05:42:42,542 --> 05:42:45,045
NOW WE CAN HAVE VERY IMPORTANT

9192
05:42:45,045 --> 05:42:46,580
EFFECTS ON THE RESPONSE AND

9193
05:42:46,580 --> 05:42:52,252
POTENTIAL VIRAL -- BECAUSE -- OF

9194
05:42:52,252 --> 05:42:54,321
COURSE -- CAN CONTROL VIRAL

9195
05:42:54,321 --> 05:42:58,725
LATENCY SO I REALLY URGE THE

9196
05:42:58,725 --> 05:42:59,559
GROUP --

9197
05:42:59,559 --> 05:43:03,463
>> THANK YOU.

9198
05:43:03,463 --> 05:43:06,600
>> HI.

9199
05:43:06,600 --> 05:43:07,901
JULIE, HRP.

9200
05:43:07,901 --> 05:43:09,002
REALLY GREAT TO HEAR ALL OF THE

9201
05:43:09,002 --> 05:43:11,204
COMMENTS SO FAR IN THIS SESSION.

9202
05:43:11,204 --> 05:43:13,607
AND TO REALLY ACKNOWLEDGE THAT I

9203
05:43:13,607 --> 05:43:15,408
THINK, YOU KNOW, TOOLS AND

9204
05:43:15,408 --> 05:43:19,446
COHORTS ARE RAPIDLY DEVELOPING,

9205
05:43:19,446 --> 05:43:20,213
ARE HERE.

9206
05:43:20,213 --> 05:43:21,648
RESEARCH PLATFORMS ARE VERY

9207
05:43:21,648 --> 05:43:22,315
FEASIBLE.

9208
05:43:22,315 --> 05:43:25,252
YOU KNOW, THE CH CHALLENGE, OFT,

9209
05:43:25,252 --> 05:43:26,152
IS THE MANUFACTURING.

9210
05:43:26,152 --> 05:43:27,754
I THINK IT'S VERY EASY TO THINK

9211
05:43:27,754 --> 05:43:29,623
ABOUT HOW THIS SHOULD BE SO MUCH

9212
05:43:29,623 --> 05:43:32,125
BETTER WITH MRNA, BUT THE FACT

9213
05:43:32,125 --> 05:43:33,560
OF THE MATTER IS FOR MOST

9214
05:43:33,560 --> 05:43:34,995
GROUPS, THERE'S NO EASY BUTTON

9215
05:43:34,995 --> 05:43:35,762
FOR MRNA.

9216
05:43:35,762 --> 05:43:37,731
THERE'S ONLY A VERY, VERY HARD

9217
05:43:37,731 --> 05:43:40,600
BUTTON FOR MRNA, RIGHT NEXT TO A

9218
05:43:40,600 --> 05:43:42,869
SPEND A LOT OF TIME WITH YOUR

9219
05:43:42,869 --> 05:43:46,740
LAWYER BUTTON BECAUSE OF ALL OF

9220
05:43:46,740 --> 05:43:52,312
THE VERY INTENSE THINGS LIKE

9221
05:43:52,312 --> 05:43:53,380
LIPID ENCAPSULATION.

9222
05:43:53,380 --> 05:43:55,582
THAT I THINK IS THE BIGGEST

9223
05:43:55,582 --> 05:44:01,154
CHALLENGE, HAVING -- THAT WE CAN

9224
05:44:01,154 --> 05:44:02,122
ACTUALLY FULFILL THE PROMISE.

9225
05:44:02,122 --> 05:44:04,524
I KNOW THAT WE HAVE COLLEAGUES

9226
05:44:04,524 --> 05:44:05,859
AT THE DIVISION OF AIDS THAT

9227
05:44:05,859 --> 05:44:06,826
REALLY THINKING ABOUT THIS, NOT

9228
05:44:06,826 --> 05:44:09,696
JUST IN THIS SETTING, BUT ACROSS

9229
05:44:09,696 --> 05:44:12,566
THE HIV PROARL.

9230
05:44:12,566 --> 05:44:12,999
 PORTFOLIO.

9231
05:44:12,999 --> 05:44:14,634
I'D BE REALLY INTERESTED TO HEAR

9232
05:44:14,634 --> 05:44:18,004
WHAT PEOPLE'S THOUGHTS ARE ON

9233
05:44:18,004 --> 05:44:19,439
THAT.

9234
05:44:19,439 --> 05:44:21,274
>> THAT'S A REALLY GOOD
POINT.

9235
05:44:21,274 --> 05:44:22,375
IN TERMS OF THE MANUFACTURING TO

9236
05:44:22,375 --> 05:44:27,547
MAKE THIS A REALITY, THAT'S A

9237
05:44:27,547 --> 05:44:27,981
BIPG.

9238
05:44:27,981 --> 05:44:28,949
ONE QUESTION THAT MAYBE SHOULD

9239
05:44:28,949 --> 05:44:32,185
BE CONSIDERED IS SHOULD THERE BE

9240
05:44:32,185 --> 05:44:35,922
SOME KIND OF PUBLIC PRIVATE

9241
05:44:35,922 --> 05:44:37,023
PARTNERSHIP, WHO DOES THIS IN

9242
05:44:37,023 --> 05:44:39,059
THE PERSONALIZED CANCER VACCINE

9243
05:44:39,059 --> 05:44:41,161
SPACE, AND THAT WOULD JUST

9244
05:44:41,161 --> 05:44:42,729
FURTHER FACILITATE ADVANCES IN

9245
05:44:42,729 --> 05:44:44,097
MORE RAPID FASHION OR IS THERE

9246
05:44:44,097 --> 05:44:46,733
WAY TO GET ACCESS OF SOME KIND

9247
05:44:46,733 --> 05:44:49,336
OF STANDARDIZED MRNA PRODUCTION

9248
05:44:49,336 --> 05:44:51,571
FACILITY TO PROVIDE THIS

9249
05:44:51,571 --> 05:44:52,872
SPECIFICALLY FOR THIS PROGRAM.

9250
05:44:52,872 --> 05:44:59,312
BUT I THINK THE PUBLI

9251
05:44:59,312 --> 05:44:59,713
PUBLIC/PRIVATE --

9252
05:44:59,713 --> 05:45:01,748
>> CAN I SUGGEST A HAPPY
MEDIUM,

9253
05:45:01,748 --> 05:45:04,584
SOMETHING MORE LIKE THE CANCER,

9254
05:45:04,584 --> 05:45:07,454
THERAPY FOR EVERY INDIVIDUAL BUT

9255
05:45:07,454 --> 05:45:09,723
OPTIMIZED COMBINATION FOR

9256
05:45:09,723 --> 05:45:12,926
INDIVIDUALS.

9257
05:45:12,926 --> 05:45:15,295
SO IF YOU HAVE THE SUITE OF --

9258
05:45:15,295 --> 05:45:18,598
IF YOU HAVE A CHOICE OF GMP-MADE

9259
05:45:18,598 --> 05:45:20,967
VACCINES FOR T-CELLS DEPENDING

9260
05:45:20,967 --> 05:45:23,770
ON THE SEQUENCE PRE-EXISTING

9261
05:45:23,770 --> 05:45:26,706
ESCAPE, PRE-EXISTING RESPONSE

9262
05:45:26,706 --> 05:45:29,442
WHICH INDIVIDUAL WILL RESPOND TO

9263
05:45:29,442 --> 05:45:34,714
WHICH VACCINE AND CHOOSE THOSE.

9264
05:45:34,714 --> 05:45:38,118
AGAIN, RFIQ TALKED ABOUT PD-1

9265
05:45:38,118 --> 05:45:39,319
SUSCEPTIBILITY.

9266
05:45:39,319 --> 05:45:40,520
CANCER THERAPY CHOOSES PATIENTS

9267
05:45:40,520 --> 05:45:41,354
NOW, RESPONSIVENESS.

9268
05:45:41,354 --> 05:45:43,456
SO I WOULD GO WITH THAT TO SORT

9269
05:45:43,456 --> 05:45:45,859
OF THE INTERMEDIATE, AND THEN

9270
05:45:45,859 --> 05:45:46,960
THAT MAKES IT MORE EQUITABLE,

9271
05:45:46,960 --> 05:45:47,994
RIGHT?

9272
05:45:47,994 --> 05:45:51,064
OTHERWISE PERSONALIZED, ONLY IT

9273
05:45:51,064 --> 05:45:51,931
WILL HAPPEN IN AMERICA AND

9274
05:45:51,931 --> 05:45:52,399
EUROPE.

9275
05:45:52,399 --> 05:45:53,633
>>  REALLY EXCELLENT
POINTS.

9276
05:45:53,633 --> 05:45:54,534
THANKS.

9277
05:45:54,534 --> 05:45:56,469
>> IF I COULD JUST ADD,
WE'VE

9278
05:45:56,469 --> 05:45:57,837
HEARD ALREADY TODAY, AND I'M

9279
05:45:57,837 --> 05:45:58,471
SURE WE'RE GOING TO HEAR MORE

9280
05:45:58,471 --> 05:46:00,974
TOMORROW ABOUT A VERY BROAD

9281
05:46:00,974 --> 05:46:05,478
RANGE OF DIFFERENT THINGS IN THE

9282
05:46:05,478 --> 05:46:06,780
TOOLBOXES OF ALL THE

9283
05:46:06,780 --> 05:46:07,347
COLLABORATORIES AND THEIR

9284
05:46:07,347 --> 05:46:10,717
PARTNERS INCLUDING PRIVATE

9285
05:46:10,717 --> 05:46:11,818
ENTERPRISE PARTNERS.

9286
05:46:11,818 --> 05:46:15,655
SO YOU KNOW, I'M HOPEFUL THAT

9287
05:46:15,655 --> 05:46:16,956
LARGE CONSORTIA CAN BE PUT

9288
05:46:16,956 --> 05:46:20,026
TOGETHER THAT CAN ADDRESS THESE

9289
05:46:20,026 --> 05:46:23,329
CHALLENGING IDEAS.

9290
05:46:23,329 --> 05:46:24,831
>> I JUST WANTED TO ASK
THE

9291
05:46:24,831 --> 05:46:26,199
PANEL MAYBE TO COMMENT ON

9292
05:46:26,199 --> 05:46:26,733
MODELS.

9293
05:46:26,733 --> 05:46:28,034
MY UNDERSTANDING IS THAT THIS

9294
05:46:28,034 --> 05:46:29,135
CONCEPT WILL NOT INCLUDE

9295
05:46:29,135 --> 05:46:32,639
CLINICLINICAL TRIALS IN HUMANS,T

9296
05:46:32,639 --> 05:46:34,374
WILL BE EITHER PRIMARILY METHOD

9297
05:46:34,374 --> 05:46:35,942
DEVELOPMENT OR ANIMAL MODEL

9298
05:46:35,942 --> 05:46:36,142
WORK.

9299
05:46:36,142 --> 05:46:37,410
AND WHEN WE GET TO THE ANIMAL

9300
05:46:37,410 --> 05:46:38,912
MODEL WORK, THERE'S A DISCUSSION

9301
05:46:38,912 --> 05:46:40,980
FOR EXAMPLE IN NON-HUMAN PRIMATE

9302
05:46:40,980 --> 05:46:42,549
ABOUT HOW LONG WE NEED TO KEEP

9303
05:46:42,549 --> 05:46:44,517
ANIMALS ON ART BEFORE THEY TRULY

9304
05:46:44,517 --> 05:46:46,720
GET TO A LOW RESERVOIR, WHICH

9305
05:46:46,720 --> 05:46:49,022
THE DISCUSSION IS ANYWHERE

9306
05:46:49,022 --> 05:46:49,989
BETWEEN SIX MONTHS TO TWO YEARS.

9307
05:46:49,989 --> 05:46:51,224
SO BY THE TIME YOU GET THE

9308
05:46:51,224 --> 05:46:53,393
ANIMALS, YOU PUT THEM ON ARKTS

9309
05:46:53,393 --> 05:46:55,261
YOU WAIT, YOU'RE BASICALLY IN

9310
05:46:55,261 --> 05:46:56,396
THE LAST BASICALLY YEAR AND A

9311
05:46:56,396 --> 05:46:58,832
HALF TO TWO OF THE FIVE-YEAR

9312
05:46:58,832 --> 05:47:00,734
CYCLE.

9313
05:47:00,734 --> 05:47:05,205
IF WE GO TO HUMANIZED MICE, THEN

9314
05:47:05,205 --> 05:47:06,306
THERE ARE SHORT TERM ANSWERS TO

9315
05:47:06,306 --> 05:47:07,974
SPECIFIC QUESTIONS BUT LONGEVITY

9316
05:47:07,974 --> 05:47:11,711
AND IMPACT OF STRATEGY LONG TERM

9317
05:47:11,711 --> 05:47:13,446
IS REALLY HARD TO EVALUATE

9318
05:47:13,446 --> 05:47:15,181
BECAUSE OF THE LYMPHOID

9319
05:47:15,181 --> 05:47:16,449
TRAFFICKING LIMITATIONS AND B

9320
05:47:16,449 --> 05:47:20,019
CELL RESPONSE LIMITATIONS.

9321
05:47:20,019 --> 05:47:22,622
SO CAN MAYBE YOU COMMENT ON WHAT

9322
05:47:22,622 --> 05:47:26,459
TYPES OF -- HOW DO WE DEAL WITH

9323
05:47:26,459 --> 05:47:27,794
THAT, HOW DO WE DEAL TO

9324
05:47:27,794 --> 05:47:29,429
PERSONALIZED APPROACH WITHOUT

9325
05:47:29,429 --> 05:47:31,097
HUMAN TRIAL DEPENDENT ON MODELS

9326
05:47:31,097 --> 05:47:36,136
OR METHOD DEVELOPMENT?

9327
05:47:36,136 --> 05:47:38,304
>> I'M GOING TO GO OUT ON
A LIMB

9328
05:47:38,304 --> 05:47:39,639
FIRST AND JUST SAY THERE COULD

9329
05:47:39,639 --> 05:47:41,374
BE HUMAN RESEARCH WITHOUT A

9330
05:47:41,374 --> 05:47:43,710
CLINICAL TRIAL, AND YOU CAN

9331
05:47:43,710 --> 05:47:47,313
COLLECT A LOT OF DATA AND MAKE

9332
05:47:47,313 --> 05:47:49,949
ASSOCIATIONS.

9333
05:47:49,949 --> 05:47:51,785
>> I BELIEVE THAT'S A VERY

9334
05:47:51,785 --> 05:47:52,552
IMPORTANT POINT THAT YOU'RE

9335
05:47:52,552 --> 05:47:53,319
BRINGING UP.

9336
05:47:53,319 --> 05:47:56,322
WHAT I WOULD EMPHASIZE FROM MY

9337
05:47:56,322 --> 05:47:58,057
PERSPECTIVE IS THAT IT DOESN'T

9338
05:47:58,057 --> 05:47:58,925
NECESSARILY HAVE TO BE MODEL

9339
05:47:58,925 --> 05:47:59,259
SYSTEMS.

9340
05:47:59,259 --> 05:48:00,894
YOU COULD ALSO DO A TISSUE

9341
05:48:00,894 --> 05:48:02,228
CULTURE SYSTEM AND MAYBE GET A

9342
05:48:02,228 --> 05:48:03,630
LOT OF INFORMATION IN THAT

9343
05:48:03,630 --> 05:48:04,631
SETTING.

9344
05:48:04,631 --> 05:48:06,733
SO FOR EXAMPLE, WHAT TYPE OF PRO

9345
05:48:06,733 --> 05:48:08,902
VIRUSES RESPOND TO WHAT TYPE OF

9346
05:48:08,902 --> 05:48:10,336
LATENCY REVERSING AGENT.

9347
05:48:10,336 --> 05:48:11,638
THAT'S SORT OF BROADLY FITTING

9348
05:48:11,638 --> 05:48:12,539
INTO THIS IDEA, AND THAT CAN BE

9349
05:48:12,539 --> 05:48:14,174
ADDRESSED IN A TISSUE CULTURE

9350
05:48:14,174 --> 05:48:15,508
SYSTEM, FOR EXAMPLE, OR WHAT'S

9351
05:48:15,508 --> 05:48:16,709
THE PHENOTYPE OF THE RESERVOIR

9352
05:48:16,709 --> 05:48:19,846
CELLS AND HOW IT DOES TARGETING

9353
05:48:19,846 --> 05:48:21,281
OF ONE PARTICULAR MARKER THAT'S

9354
05:48:21,281 --> 05:48:23,049
EXPRESSED ON A RESERVOIR CELL,

9355
05:48:23,049 --> 05:48:25,118
HOW DOES THAT INFLUENCE THE

9356
05:48:25,118 --> 05:48:27,253
FREQUENCY OF THE RESERVOIR IN AN

9357
05:48:27,253 --> 05:48:28,087
IN VITRO SYSTEM.

9358
05:48:28,087 --> 05:48:31,057
I MEAN, AS A FIRST STEP, I

9359
05:48:31,057 --> 05:48:32,358
BELIEVE THOSE ARE RELATIVELY

9360
05:48:32,358 --> 05:48:33,560
SIMPLE TYPES OF ASSAYS AND

9361
05:48:33,560 --> 05:48:35,128
EXPERIMENTS COULD ALSO BE

9362
05:48:35,128 --> 05:48:39,399
INFORMATIVE.

9363
05:48:39,399 --> 05:48:42,135
>> YOU WOULD ADD THE
CONCEPT OF

9364
05:48:42,135 --> 05:48:44,003
HLA DIVERSITY CLEARLY AN ISSUE

9365
05:48:44,003 --> 05:48:45,638
FOR THE T-CELL-BASED APPROACHES.

9366
05:48:45,638 --> 05:48:47,073
YOU CAN LOOK AT DIFFERENT KIND

9367
05:48:47,073 --> 05:48:49,175
OF OPTIMIZED CASSETTE DESIGN

9368
05:48:49,175 --> 05:48:53,213
WITHIN HLA TRANS GEGENIC AND

9369
05:48:53,213 --> 05:48:56,516
KNOCK-IN MICE, WHAT ARE

9370
05:48:56,516 --> 05:48:58,084
POTENTIALLY -- TO SOME DEGREE AS

9371
05:48:58,084 --> 05:48:59,719
WELL WHERE YOU HAVE THE EXTENT

9372
05:48:59,719 --> 05:49:03,022
OF MHC DIVERSITY IN HUMANS AS

9373
05:49:03,022 --> 05:49:04,224
NON-HUMAN PRIMATE BUT IT STILL

9374
05:49:04,224 --> 05:49:05,258
EXISTS AND THERE'S WAYS OF

9375
05:49:05,258 --> 05:49:07,293
ACTUALLY TESTING OPTIMIZED

9376
05:49:07,293 --> 05:49:08,494
T-CELL APPROACHES IN THAT

9377
05:49:08,494 --> 05:49:08,895
SETTING AS WELL.

9378
05:49:08,895 --> 05:49:10,897
I THINK YOU PROBABLY IN SOME

9379
05:49:10,897 --> 05:49:14,200
WAYS GET BNAB SENSITIVITY THAT

9380
05:49:14,200 --> 05:49:15,635
WOULD VARY ACROSS AFFECTED

9381
05:49:15,635 --> 05:49:15,969
ANIMALS.

9382
05:49:15,969 --> 05:49:17,370
SO I THINK THERE ARE WAYS WHERE

9383
05:49:17,370 --> 05:49:18,972
THE MODEL SYSTEMS CAN PROVE TO

9384
05:49:18,972 --> 05:49:21,341
BE VERY INFORMATIVE FROM A KIND

9385
05:49:21,341 --> 05:49:31,117
OF TAILORED APPROACH.

9386
05:49:31,117 --> 05:49:32,085
ANY OTHER COMMENTS?

9387
05:49:32,085 --> 05:49:33,286
THANK YOU ALL FOR GREAT

9388
05:49:33,286 --> 05:49:37,257
QUESTIONS.

9389
05:49:37,257 --> 05:49:39,058
THANKS TO ALL OUR
PANELISTS

9390
05:49:39,058 --> 05:49:43,396
FOR A GREAT DISCUSSION.

9391
05:49:43,396 --> 05:49:45,064
WE DO HAVE ANOTHER PANEL JUST

9392
05:49:45,064 --> 05:49:46,699
LIKE THR AT THE END OF

9393
05:49:46,699 --> 05:49:48,668
TOMORROW'S SESSION THAT'S

9394
05:49:48,668 --> 05:49:50,003
SPECIFICALLY FOCUSED ON

9395
05:49:50,003 --> 05:49:51,371
EXPANDING HIF CURE RESEARCH

9396
05:49:51,371 --> 05:49:52,839
GLOBALLY AND IN DIFFERENT

9397
05:49:52,839 --> 05:49:54,040
POPULATIONS, SO PLEASE STICK

9398
05:49:54,040 --> 05:49:55,241
AROUND TOMORROW FOR THAT.

9399
05:49:55,241 --> 05:49:57,343
I HAVE A COUPLE OTHER

9400
05:49:57,343 --> 05:49:59,879
ANNOUNCEMENTS, THE MDC CAB, ALL

9401
05:49:59,879 --> 05:50:03,049
THE 10 NPC CABS ARE SPONSORING

9402
05:50:03,049 --> 05:50:04,717
COMMUNITY EVENT TONIGHT FROM

9403
05:50:04,717 --> 05:50:05,919
6:30 TO 8:00 P.M. AT BUS BOYS

9404
05:50:05,919 --> 05:50:08,955
AND POETS IN ANACOSTIA IN

9405
05:50:08,955 --> 05:50:10,423
SOUTHEAST D.C.  ENTITLED

9406
05:50:10,423 --> 05:50:12,392
INTRODUCTION TO HIV CURE

9407
05:50:12,392 --> 05:50:13,459
RESEARCH, AND THERE ARE FREE

9408
05:50:13,459 --> 05:50:14,560
FOOD AND DRINKS PROVIDED.

9409
05:50:14,560 --> 05:50:17,363
SO EVERYONE IS WELCOME TO ATTEND

9410
05:50:17,363 --> 05:50:18,431
THAT.

9411
05:50:18,431 --> 05:50:20,433
ALSO FOR THE REACH SPEAKERS,

9412
05:50:20,433 --> 05:50:21,768
YOU'RE UP FIRST TOMORROW SO GET

9413
05:50:21,768 --> 05:50:24,037
A GOOD NIGHT'S SLEEP, TRY TO GET

9414
05:50:24,037 --> 05:50:25,038
THROUGH SECURITY EARLY SO THAT

9415
05:50:25,038 --> 05:50:26,673
OUR SPEAKERS ARE HERE.

9416
05:50:26,673 --> 05:50:29,008
WE WILL START SHARPLY ON TIME AT

9417
05:50:29,008 --> 05:50:29,976
8:30 A.M., AND AGAIN, THANKS TO

9418
05:50:29,976 --> 05:50:31,411
ALL OUR SPEAKERS, EVERYONE THAT

9419
05:50:31,411 --> 05:50:32,178
ASKED QUESTIONS.

9420
05:50:32,178 --> 05:50:32,745
IT WAS A GREAT DAY.

9421
05:50:32,745 --> 05:50:33,212
THANK YOU.

9422
05:50:33,212 --> 05:50:43,389
[APPLAUSE]