OKAY, GOOD MORNING, EVERYONE,
AND WELCOME TO THE SIXTH
BIENNIAL STRATEGIES FOR AN HIV
CURE MEETING.
THIS MEETING BEGAN IN 2012, AS
AN ATTEMPT TO BRING TOGETHER
RESEARCHERS AND THE COMMUNITY
WITH A SHARED INTEREST IN HIV
CURE RESEARCH, WHICH AT THAT
TIME WAS A RATHER NASCENT FIELD.
IT QUICKLY GREW TO BECOME THE
LARGEST SCIENTIFIC MEETING
DEDICATED SOLELY TO HIV CURE
RESEARCH.
AND IT NOW SERVES AS THE JOINT
MEETING OF THE NIH MARTIN
DELANEY COLLABORATORIES FOR HIV
CURE RESEARCH PROGRAM.
TO GET US STARTED THIS MORNING,
IT'S MY PLEASURE TO INTRODUCE
OUR NEW DIRECTOR AT NIAID,
DR. JEANNE MARRAZZO.
THIS IS HER THIRD WEEK ON THE
JOB, SO SHE'S STILL VERY FRESH
TO THE JOB.
DR. MARRAZZO EARNED HER
BACHELOR'S AT HARVARD AND MD
FROM THOMAS JEFFERSON
UNIVERSITY.
HER MPH IN EPIDEMIOLOGY FROM
WASHINGTON UNIVERSITY.
SHE THEN COMPLETED RESIDENCY AND
CHIEF RESIDENCY IN INTERNAL
MEDICINE AT YALE AND PRIOR TO
JOINING NIAID, SHE WAS DIRECTOR
OF THE DIVISION OF INFECTIOUS
DISEASES AT THE UNIVERSITY OF
ALABAMA AT BIRMINGHAM.
SO WITH THAT, WELCOME,
DR. MARRAZZO.
THANK YOU FOR GETTING US
STARTED.
>> THANKS, KARL.
CAN YOU ALL HEAR ME OKAY?
I'M GOING TO ASSUME THAT'S A
YES.
WELL, I AM THRILLED TO BE HERE
VIRTUALLY.
I APOLL JAIZ FOR APOLOGIZE FOR E
VIRTUALLY.
AS YOU CAN SEE, I AM IN THE
THROES OF MOVING LITERALLY, I'M
HOPING TO BE UP IN MARYLAND THIS
WEEKEND, BUT I REALLY COULDN'T
TURN DOWN THE OPPORTUNITY TO
ACTUALLY HAVE MY VERY FIRST
OFFICIAL WELCOME BE FOR THIS
GROUP.
AS YOU CAN SEE FROM THE FIRST
SLIDE AND AS I THINK EVERYBODY
IN THIS ROOM IS SUPER DEDICATED
TO DEVELOPING AN APPROACH FOR
THE TREATMENT AND CURE OF HIV
INFECTIONS, IT'S REALLY ONE OF
THE TOP PRIORITIES FOR NIAID,
AND IT'S ESPECIALLY IMPORTANT
BECAUSE IT'S AN THAT HAS
REQUIRED VERY CLOSE
COLLABORATION WITH THE
COMMUNITY, BOTH THE SCIENTIFIC
AND COMMUNITY STAKEHOLDERS.
I THINK THAT EVERYONE IN THIS
AUDIENCE IS EXTREMELY AWARE OF
THE NEED FOR A CURE.
DON'T NEED TO REITERATE THESE
STATISTICS, I THINK, FOR THIS
GROUP, BUT HAVING LIVED FOR THE
LAST SEVEN YEARS IN A PART OF
THE WORLD THAT IN THE U.S. HAS
OVER 50% OF NEW INFECTIONS, I'M
EXQUISITELY AWARE OF THE NEED TO
REALLY FUNDAMENTALLY ADDRESS
CURE.
THE EXISTING INTERVENTIONS WE
HAVE ARE FANTASTIC, BUT THEY ARE
SIMPLY NOT GOING TO GET US WHERE
WE NEED TO BE, AND WHEN YOU LOOK
AT THAT NEED GLOBALLY, THE NEED
FOR CURE IS EVEN MORE INTENSE.
IT LOOKS LIKE YOU'VE MOVED ME
ALONG TO THE THIRD SLIDE.
THAT'S OKAY.
YOU CAN GO AHEAD, BECAUSE THE
REAL MEAT OF THIS IS JUST TO
THANK YOU ALL FOR YOUR WORK AS
PART OF THE MARTY DELANEY
COLLABORATORIES, REALLY AN
INCREDIBLE PARTNERSHIP WITH
COFUNDING ACROSS SEVERAL
INSTITUTES AT NIH, AND THIS
REALLY IS THE FLAGSHIP PROGRAM
FOR CURE RESEARCH, AND IT'S
IMPORTANT PARTICULARLY BECAUSE
IT SPANS TRANSLATIONAL RESEARCH
SINCE 2011.
THIS IS JUST TO ACKNOWLEDGE THE
CRITICAL ROLE THAT MARTY DELANEY
PLAYED AS AN ACTIVIST IN THIS
AREA, WAS INCREDIBLY IMPORTANT
IN FAST TRACKING REVIEWS OF AIDS
DRUGS, FAIR PRICING, AND, OF
COURSE, AN AVID ADVOCATE FOR
COMMUNITY EDUCATION BEFORE HIS
UNTIMELY DEATH IN 2009.
SO A HUGE MOVER AND SHAKER THAT
WE HAVE TO THANK FOR WHAT'S
HAPPENING TODAY.
I JUST WANT TO POINT OUT THAT
NIH'S INVESTMENT IN THE CURE
PROGRAM HAS GROWN STEADILY WITH
EACH FIVE-YEAR ITERATION,
STARTING WITH THREE
COLLABORATORY AWARDS IN 2011 AND
GROWING AS KARL MENTIONED TO A
TOTAL OF 10 IN THE CURRENT
ITERATION.
AND YOU CAN SEE THE TOTAL
FUNDING IS NOW ALMOST
$270 MILLION.
BUT GIVEN THAT, WE STILL HAVE A
WAYS TO GO.
WHEN YOU LOOK AT HIV CURE
RESEARCH RELATIVE TO THE OTHER
BUCKETS THAT WE ARE CURRENTLY
FUNDING, INCLUDING CO-OCCURRING
CONDITIONS, CROSS-CUTTING
RESEARCH, NEXT GEN THERAPIES AND
REDUCTION OF INCIDENCE, I.E.,
PRIMARY PREVENTION, WE ARE STILL
NOT ALLOCATING, I THINK, A
PROPORTIONATE AMOUNT OF FUNDS TO
THIS AREA.
SO RIGHT NOW HIV CURE RESEARCH
TAKES UP ABOUT 7% OF THE TOTAL
HIV/AIDS BUDGET.
SO THAT CLEARLY NEEDS TO BE
FOREFRONT, I THINK, IN OUR
DISCUSSIONS WHEN WE THINK STA TK
STRATEGICALLY ABOUT MOVING
FORWARD.
SO THIS IS JUST A SLIDE TO SHOW
YOU WHERE THESE COLLABORATORIES
ARE.
AGAIN I KNOW YOU'RE ALL THERE
TODAY, AND I'M REALLY SORRY I
CAN'T BE THERE TO HEAR ABOUT THE
PROGRESS.
I'M REALLY IMPRESSED AT THE WORK
THAT THIS GROUP HAS DONE.
AND I HOPE THAT YOU HAVE GREAT
MEETING, AND I LOOK FORWARD TO
SEEING YOU ALL IN PERSON VERY
SOON.
WITH THAT, I'LL TURN IT BACK TO
KARL, AND WISH YOU A REALLY
GREAT DAY.
AND THANKS FOR GIVING ME THE
OPPORTUNITY TO SAY WELCOME.
[APPLAUSE]
>> THANK YOU SO MUCH,
DR. MARRAZZO.
SO NOW WE'LL MOVE ON TO THE
PRESENTATIONS FROM THE
INDIVIDUAL MARTIN DELANEY
COLLABORATORIES.
AS YOU'LL NOTICE IN THE PROGRAM,
THESE ARE ALL STRUCTURED AROUND
THE SAME RESEARCH FOCI, SO
RESEARCH FOCUS ONE IS FOCUSED ON
BASIC RESEARCH AND UNDERSTANDING
POST TREATMENT CONTROL, RESEARCH
FOCUS TWO IS DEVELOPING STRAT
STRATEGIES FOR A DURABLE CONTROL
OF VIRAL REBOUND IN THE ABSENCE
OF ANTIRETROVIRAL DRUGS, AND
THEN RESEARCH FOCUS THREE IS
DEDICATED TO REDUCING THE SIZE
OF THE RESERVOIR TOWARDS THE
ULTIMATE GOAL OF EVENTUALLY
ERADICATING HIV FROM THE BODY.
SO WITH THAT, I INTRODUCE DIANE
LAWRENCE, THE PROGRAM OFFICER
FOR THE FIRST COLLABORATORY.
>> GOOD MORNING, EVERYONE.
DIANE LAWRENCE, I'M A PROGRAM
OFFICER IN THE BASIC SCIENCE
PROGRAM, DIVISION OF AIDS AT
NIAID, AND I'M VERY PLEASED TO
INTRODUCE OUR FIRST
COLLABORATORY GROUP
PRESENTATIONS THIS MORNING.
THE CARE COLLABORATORY IS
CURRENTLY IN ITS THIRD CYCLE
WITH OUR MARTIN DELANEY PROGRAM.
AND SO LEADING US OFF IS THE
PRINCIPAL INVESTIGATOR,
DR. DAVID MARGOLIS FROM THE
UNIVERSITY OF NORTH CAROLINA
CHAPEL HILL.
DAVID?
WELCOME.
>> THANK YOU, DIANE.
SO I'LL JUST GIVE A QUICK
OVERVIEW FOLLOWED BY THE
SCIENTIFIC PRESENTATION.
SO FIRST, THANKS TO ALL THE
PEOPLE INVOLVED, A FEW OF WHOM
ARE PICTURED HERE.
OUR MANY INVESTIGATORS,
TRAINEES, STUDENTS, INDUSTRY
COLLABORATORS, AND MEMBERS OF
THE COMMUNITY THAT HELP US DO
ALL OF THIS IMPORTANT WORK,
THANKS VERY MUCH.
SO THE FUNDAMENTAL IDEA THAT
UNDERPINS OUR WORK TO EITHER
ERADICATE OR CONTROL HIV
INFECTION COMES FROM THIS
PARADIGM, WHICH IS A PARADIGM
WHICH HAS SORT OF UNDERLAID THE
FIELD FOR QUITE A NUMBER OF
YEARS.
I WOULD JUST WANT TO SAY THAT
THIS HAS BEEN A DIFFICULT PATH
FORWARD, BUT I THINK THAT IF YOU
LOOK CAREFULLY, I THINK WE'RE
MAKING SIGNIFICANT BUT
INCREMENTAL PROGRESS AND
HOPEFULLY WE WILL GET TO THE
DESIRED OUTCOME.
THE ADVANCES IN THE FIELD OVER
THE LAST YEARS HAVE LED TO A
NUMBER OF TRIALS GIVING LATENCY
REVERSAL AGENTS AND
IMMUNOTHERAPIES TOGETHER.
NONE OF THOSE TRIALS, AT LEAST
TO MY KNOWLEDGE OR OPINION, HAVE
RESULTED IN A REALLY SUBSTANTIAL
DEPLETION OF PERSISTENT
INFECTION, WHICH IS, I THINK, AN
IMPORTANT GOAL SHOWING THAT WE
HAVE MADE THE NEXT STEP FORWARD.
CERTAINLY THE TRIALS HAVE SHOWN
THAT LATENCY REVERSALS WITH THE
AGENCY WE CURRENTLY HAVE
MEASURED WITH THE ASSAYS NEW AND
OLD CAN BE GIVEN SAFELY AND
EFFECTIVELY AND MONITORED.
IMMUNOTHERAPIES CAN BE GIVEN AND
IN SAIR J VARIOUS TRIALS SIGNIFT
ALTERATIONS IN THE IMMUNE
RESPONSE WERE DEMONSTRATED BY
THESE THERAPIES BUT SO FAR THE
COMBINATION OF THOSE TWO EVENTS
HAVE NOT LED TO DEPLETION OF
PERSISTENT INFECTION, AND THAT'S
REALLY WHERE I THINK WE NEED TO
GET NEXT.
A BIT AGO, STARTING IN THE LAST
CYCLE OF THIS FUNDING MECHANISM,
A REALLY COLLABORATIVE EFFORT
ACROSS INDUSTRY AND ACADEMIA
DISCOVERED OR RE-DISCOVERED THE
USE OF THE NON-CANONICAL NF KB
SIGNALING CIRCUIT, THE ABILITY
TO REVERSE LATENCY IN AN
EFFECTIVE WAY IN BOTH THE
HUMANIZED MOUSE AND THE PRIMATE
MODEL AND INDUCE VERY WIDESPREAD
LATENCY REVERSAL WITHIN TISSUES
AS WELL.
AND SO THIS PARTICULAR DRUG IS
NOW BEING WIDELY USED IN THE
FIELD AS A TOOL MOLECULE, BUT
WE'VE NOT YET BEEN ABLE TO MOVE
THIS APPROACH INTO HUMAN
STUDIES.
SO THE FIRST EFFORTS ARE AROUND
THE BIOLOGY OF LATENCY.
WE HAVE A NUMBER OF EFFORTS
ONGOING, AND I'LL JUST HIGHLIGHT
SOME THAT WILL BE DISCUSSED AT
THE MEETING.
MIKE LIMMERMAN'S GROUP DID A
VERY NOVEL SCREEN USING CRISPR
TECHNOLOGY TO DISCOVER A NUMBER
OF NEW LATENCY REVERSAL TARGETS.
UNFORTUNATELY MICHAEL IS
STRUGGLING WITH ANOTHER VIRUS AT
HOME, AND SO TODAY ED BROWNE
WILL TALK ABOUT HIS WORK THAT
FOLLOWS THAT, TAKING MICHAEL'S
WORK AND MOVING IT FORWARD INTO
A NEW SCREEN TO DISCOVER AND
VALIDATE OTHER TARGETS.
IN THE POSTER SESSION, WHICH I
HOPE YOU'LL ALL BE ABLE TO
PARTICIPATE IN, I THINK PROBABLY
THE MOST IMPORTANT PART OF THIS
MEETING, WE HAVE A NUMBER OF
EFFORTS LOOKING AT DIFFERENT
KINDS OF EPIGENETIC
MODIFICATION, VALIDATING SOME
NEW TARGETS THAT HAVE BEEN
DISCOVERED, AND TRYING TO
UNDERSTAND SOME BASIC MECHANISMS
OF LATENCY REGULATION.
ANOTHER SUBSTANTIAL EFFORT IS TO
UNDERSTAND PERSISTENCE IN A VERY
DETAILED WAY WITHIN TISSUES
USING SOME OF THE LATEST
ADVANCES IN TECHNOLOGY.
RECENTLY ONE OF THOSE EFFORTS
LED BY DR. TANG AND DR. JANG
SHOWED BRAIN MICROGLIA ARE A
PERSISTENT RESERVOIR OF
INFECTION IN DURABLY TREATED
PATIENTS.
THIS WAS A UNIQUE COLLABORATION
WITH THE LAST COHORT IN UCSD
WHICH WE'RE VERY GRATEFUL FOR.
I THINK THIS WAS AN IMPORTANT
DESCRIPTION OF A NEW TARGET.
AT THE MEETING, SEVERAL
INVESTIGATORS WILL SHOW SOME OF
THEIR EARLY WORK LOOKING AT
TISSUE RESERVOIRS IN THE G.I.
TRACT, IN LYMPH NODES, AND
DIFFERENCES IN INFECTION BETWEEN
MEN AND WOMEN.
ANOTHER PRINCIPLE THAT WE --
THAT HAS BEEN DISCOVERED
RECENTLY IS THE IDEA OF WHEN THE
LATENCY IS -- WHEN THE LATENT
RESERVOIR IS FORMED FROM WHICH
VIRUSES.
THIS ORIGINALLY CAME OUT OF
OBSERVATIONS IN A COLLABORATION
WITH THE CAPRISA COHORT.
AND YOU CAN SEE HERE THAT THE
PINK RESERVOIR VIRUSES IN MOST
PATIENTS, MOST PEOPLE, COME FROM
VIRUSES THAT WERE CIRCULATING
NEAR THE TIME OF THERAPY
INITIATION.
AND THIS GAVE US SORT OF A NEW
WAY OF LOOKING AT THE POPULATION
OF VIRUSES IN THE LATENT
RESERVOIR.
MOST OF THEM ORIGINATED IN BLUE
FROM TIMES CLOSE TO THE
INITIATION OF THERAPY, GIVING US
A NEW WAY TO INTERVENE INSTEAD
OF GIVING LATENCY REVERSAL
AGENTS OR IN ADDITION TO SOME
DAY GIVING LATENCY REVERSAL
AGENTS ONCE VIREMIA HAS BEEN
WELL SUPPRESSED.
WE ALSO HAVE THE OPPORTUNITY TO
UNDERSTAND HOW LATENCY IS
FOUNDED AND HOW THAT BIOLOGICAL
PROCESS CAN BE INHIBITED AND WE
COULD PREVENT THE FOUNDATION OF
LATENCY IN THE FIRST PLACE.
THE OTHER PIECE OF INFORMATION
THAT'S NOT KNOWN IS THE TIMING
OF ENTRY OF VIRUSES INTO THE
RESERVOIR OVER THE TIME OF
VIREMIA, AND SO SOME EARLY DATA
WILL BE SHOWN BY OLIVIA COUNSELL
HERE IN THE POSTER SESSION ABOUT
THAT.
THE SECOND GOAL HAS TO DO WITH
CONTROLLING VIRAL REBOUND,
POTENTIALLY ALSO CLEARING THE
RESERVOIR.
GUIDO FERRARI WILL SHORTLY TALK
ABOUT NUMBER OF YEARS OF WORK
LOOKING AT TARGETING SELLS USING
THE HLA-E ACCESS, AND SOME
IMPORTANT EARLY DATA IN AN IN
VIVO MODEL FROM VICTOR GARCIA
ABOUT THAT.
ADDITIONALLY, WE'RE WORKING WITH
MICHAEL FORSIAN AS WELL AS
WORKING WITH SEVERAL OF THE
OTHER COLLABORATORY GROUPS ON AN
ECE4 APPROACH TO SUPPRESS
VIREMIA.
RECENTLY MICHAEL HAS BEEN
ADVANCING B CELL EDITING AS A
WAY TO MAKE IMPROVED ANTIBODIES
AND AT THIS MEETING IN MATT
GARDENER'S LAB, THEY WILL
PRESENT SOME DATA ABOUT SOME NEW
APPROACHES TO DELIVER THESE
MOLECULES WITHIN AAV VECTOR.
FINALLY STUDYING LATENCY AND
PERSISTENCE.
IN IN VIVO MODELS, WE'VE
CONTINUED TO ITERATIVELY USE
PRIMATE AND MOUSE MODELS AND
I'LL TALK ABOUT SOME OF THE WORK
THAT GEE COWAS GOING TO PRESENT
IN THE PRIMATE MODEL LATER.
SO LET ME NOW ASK ED TO COME UP
AND TALK HIS WORK.
ABOUT HIS WORK.
>> GOOD MORNING.
THANK YOU FOR THE OPPORTUNITY TO
PRESENT.
WE ARE INTERESTED IN IDENTIFYING
NEW FACTORS THAT REGULATE HIV
LATENCY.
HIV IS ABLE TO PERSIST DURING
THERAPY TO ENTER A STATE OF
VIRAL LATENCY, THESE CELLS CAN
REACTIVATE, WHICH IS KIND OF THE
DEFINITION OF LATENCY.
THIS CAN HAPPEN SPORADICALLY OR
IT CAN OCCUR UNDER THE INFLUENCE
OF LATENCY REVERSING AGENTS.
BUT THUS FAR OUR CURRENT TOOLBOX
FOR LATENCY REVERSING AGENTS IS
INSUFFICIENT TO BROAD
REACTIVATION OF THE LATENT
RESERVOIR.
SO OUR HYPOTHESIS IS THAT BY
UNDERSTANDING THE BASIC BIOLOGY
OF HIV TRANSCRIPTION AND
EXPRESSION, WE COULD POTENTIALLY
IDENTIFY NEW FACTORS THAT
REGULATE HIV LATENCY THAT CAN BE
TARGETED TO IMPROVE THE BREADTH
OF OUR ABILITY TO TARGET THE
LATENT RESERVOIR.
SO TO DO THIS, WE'VE BEEN
RELYING HEAVILY ON A MODEL
SYSTEM OF LATENCY.
WE HAVE A PRIMARY CD4 MODEL, WE
CAN MAKE LATENTLY INFECTED CELLS
IN OUR LAB IN LARGE NUMBERS AND
WE CAN USE THIS SYSTEM TO DO A
BUNCH OF DIFFERENT THINGS.
WE CAN DO OBSERVATIONAL STUDIES
LIKE SINGLE CELL OMICS, WHAT
THESE CELLS LOOK LIKE, WHAT'S
GOING ON INSIDE THEM.
WE CAN LOOK AT HISTONE MARKS AND
FUNCTIONAL STUDIES SO QUITE
EFFICIENT CRISPR KNOCKOUT IN
THESE PRIMARY CELLS, TAKE OUT
SPECIFIC GENES AND ASK QUESTIONS
ABOUT WHAT THEY DO, AND WE CAN
ALSO DO CHEMICAL SCREENS, SEE
WHAT CAUSES THINGS TO HAPPEN TO
THE LATENTLY AFFECTED CELLS.
THIS IS OUR APPROACH STARTING
WITH OBSERVATIONAL STUDY, THEN
USING FUNCTIONAL STUDIES TO KIND
OF VALIDATE WHAT WE SEE.
THE MAIN EXPERIMENT WE'VE DONE
IN THE LAST COUPLE YEARS, WE
TOOK A POPULATION OF LATENTLY
INFECTED CELLS, ABOUT 100,000
CELLS AND STIMULATED WITH THREE
DIFFERENT LATENCY REVERSING
AGENTS TO INDUCE VIRAL
TRANSCRIPTION.
AND THEN WE PROFILED ALL THESE
CELLS USING A COMBINED
MULTI-OMICS APPROACH.
WE DID COMBINE SINGLE CELL RNA
SEQ AND ATAC SEQ, DYNAMIC
CHROMATIN PEAKS WHICH ALLOWS US
TO INFER THE ACTIVITY OF
DIFFERENT TRANSCRIPTION FACTORS
IN EACH CELL.
FAIRLY SIMPLE MINOR APPROACH TO
TAKE ALL THIS DATA AND A
CORRELATE IT WITH HIV EXPRESSION
ACROSS THIS POPULATION OF CELLS,
LEADING US TO ABOUT 300
DIFFERENT CELLULAR FACTORS THAT
WERE TO SOME DEGREE CORRELATED
WITH HIV EXPRESSION.
THESE ARE TRANSCRIPTS OR
TRANSCRIPTION FACTORS.
SO SINCE DOING THAT, WE HAVE
TURNED THIS INTO A TARGETED
CRISPR LAB SO WE CAN KNOCK OUT
ALL THESE LATENCY CORRELATED
FACTORS -- SORRY -- HIV
CORRELATED FACTORS IN PARALLEL.
THIS IS THE PART WE DID IN
COLLABORATION WITH MIKE'S LAB, A
VERY COOL STRATEGY FOR DOING
CRISPR SCREENS WHERE THEY HAVE A
LENGTHY GUIDE RNA VECTOR FOR THE
CRISPR THAT HAS A PACKAGING
SIGNAL SO THAT WHEN YOU
INACTIVATE A LATENCY MAINTENANCE
FACTOR YOU GET RELEASE OF VIRAL
PARTICLES THAT CONTAIN -- FOR
THE RNA SEQ SO YOU CAN SEQUENCE
THE SUPER NAY TE -- TO FIND OUT
WHAT'S DOING THINGS.
WE DID THIS IN TWO DIFFERENT
J-LAT LINES.
WE DID THIS SCREEN IN
COMBINATION WITH DIFFERENT
LRAs TO TRY TO FIND
SYNERGISTIC COMBINATIONS OF
KNOCKOUTS AND LRAs THAT COULD
COMBINE TOGETHER TO GET BETTER
REACTIVATION.
TO CUT A LONG STORY SHORT WE
HAVE A BUNCH OF INTERESTING HITS
THAT CAME OUT OF THIS.
DOWN TO ABOUT 20 DIFFERENT
TARGETS OF INTEREST THAT WE
THINK ARE INTERESTING TO FOLLOW
UP FOR VALIDATION STUDIES.
I DON'T HAVE TIME TO GO THROUGH
ALL THE DIFFERENT TARGETS BUT
I'LL TALK TO YOU ABOUT JUST A
HANDFUL OF THESE THINGS WE'RE
DOING OUR FOLLOW-UP STUDIES ON.
SO THESE ARE CTCF, RAD 21, CDK6,
ETS1.
SO CTCF RAD 21 -- THESE THINGS
ALL CAME OUT OF THE SCREEN AND
PART OF THE SAME COMPLEX.
THIS IS A MACROMOLECULAR
STRUCTURE WHICH IS INVOLVED IN
FORMING LONG RANGE DNA LOOPS, SO
WE THINK THAT THIS STRUCTURE IS
SOMEHOW IMPORTANT IN MAINTAINING
LATENCY IN SOME CELLS.
WE DON'T KNOW EXACTLY HOW.
PREVIOUS WORK IN MY LAB HAS
SHOWN THAT WHEN YOU KNOCK OUT
CTCF, YOU CAN REACTIVATE HIV
FROM LATENCY.
ANOTHER HIT WITH CDK6, THIS IS A
CELL CYCLE ASSOCIATED KINASE
ABUNDANTLY EXPRESSIONED IN
ACTIVATED T-CELLS.
WHEN WE KNOCK IT OUT, WE GET
POTENT EXPRESSION.
THIS WAS DONE BY A STUDENT IN MY
LAB.
SHOWED THAT THIS INHIBITOR WAS
ABLE TO PREVENT REACTIVATION SO
I THINK CDK6 IS IMPORTANT FOR
EXPRESSION OF HIV IN ACTIVELY
INFECTED CELLS AND ALSO
REACTIVATION FROM LATENCY.
ANOTHER HIT WAS ETS1,
TRANSCRIPTION FACTOR THAT'S
WIDELY EXPRESSED IN T-CELLS.
WE CAN KNOCK IT OUT VERY
EFFICIENTLY AS SEEN BY THIS
WESTERN BLOT IN CRISPR IN
PRIMARY CELLS.
WE SEE A SIGNIFICANT BOOST TO
HIV EXPRESSION IN CELLS THAT ARE
IN A RESTING STATE.
THIS IS A NEW REPRESSOR WE THINK
OF HIV THAT'S POTENTIALLY
IMPORTANT.
SO IN ADDITION TO DOING ALL
THESE CRISPR KNOCKOUT, WE'VE
TAKEN THIS MULTI-OMICS DATA, SO
THE TASK WE GAVE TO THIS
BOOSTING BASED ALGORITHM, CAN WE
PREDICT FROM MULTI-OMIC DATA
WHETHER OR NOT THE CELLS IN THE
TOP 10% OF HIV EXPRESSING CELLS
WITHIN THE POPULATION, AND THIS
WAS REASONABLY SUCCESSFUL.
THESE TELLS YOU HOW WELL THIS
MODEL WORKS.
SO THE MODEL THAT WE DEVELOPED
WAS ABLE TO PREDICT TO 75 TO
80% -- FROM THE ATAC SEQ DATA.
THIS MO EL DID PREDICTED NICELY
ACROSS DONORS, STILL PREDICTS ON
A SECOND DONOR.
SO LASTLY, CHEMICAL SCREEN.
SO WE'RE INTERESTED IN NEW
COMPOUNDS THAT CAN DO THINGS TO
LATENCY.
SO WE COLLABORATED WITH LINDSAY
JAMES AT UNC, A BIOLOGICAL
CHEMIST, AND THIS EXPERIMENT
DONE BY SAM BURGOS, TARGETING
CHROMATIN REGULATING ENZYMES.
SO SAM EFFECTED SON CELLS IN THE
PRESENCE OF THESE COMPOUNDS AND
PROFILED THESE CELLS WITH FLOW
CYTOMETRY TO LOOK AT THE LATENT
AND ACTIVE POPULATIONS.
THIS IS A DUAL COLOR REPORTER
VIRUS.
SO TWO DRUGS THAT HAVE COME OUT
OF THIS APPROACH WE THINK ARE
INTERESTING.
BAY299, TAF1 IS A COMPONENT OF
THE TF2D GENERAL TRANSCRIPTION
FACTOR COMPLEX THAT'S IMPORTANT
FOR INITIATING TRANSCRIPTION.
SAM KNOCKED OUT TAF1 AND BID1 IN
A MODEL OF LATENCY AND SHOWED
REACTIVATION OF TAF1 WAS
SUFFICIENT TO REACTIVATE HIV
FROM LATENCY.
I THINK THIS IS IMPORTANT FOR
REPRESSING HIV IN SOME CELLS AT
LEAST.
SO LASTLY, UNC9153, THIS IS A
TRANS PHRASE THAT ASSOCIATES
WITH ACTIVELY TRANSCRIBING
RNA -- 2.
TO THE GENE BODIES OF ACTIVELY
EXPRESSED GENES, INHIBITED BY
UNC9153.
SO WE CAN INHIBIT THIS ENZYME
AND ALSO KNOCK OUT WITH CRISPR
IN THIS CASE, WHEN YOU DO THAT
YOU CAN SEE A SIGNIFICANT
REDUCTION IN HIV EXPRESSION SO
SETD2 WE THINK IS REQUIRED TO
SUSTAIN ACTIVELY LEVELS OF HIV
EXPRESSION.
SO PUTTING IT ALL TOGETHER INTO
OUR MODEL, SO THE APPROACH OF
TAKING AN OBSERVATIONAL APPROACH
FOLLOWED BY FUNCTIONAL STUDIES I
THINK WAS REASONABLY SUCCESSFUL.
WE'VE GOT NEW THINGS TO PLAY
WITH TO LOOK AT IN TERMS OF --
SO SET -- WE THINK ARE REQUIRED
FOR HIV EXPRESSION AND ACTIVELY
TRANSCRIBING CELLS.
THESE COULD BE LIMITING FACTORS
FOR EXAMPLE IN LATENTLY AFFECTED
CELLS THAT WE CAN OVEREXPRESS OR
DELIVER.
NEW THINGS WE THINK ARE
REPRESSING HIV, SO TAF1,
ETS1 AND THE COHESION COMPLEX.
WE ARE FOLLOWING UP ON ALL THESE
HITS FIGURING OUT
MECHANISTICALLY HOW DO THEY
WORK, WHAT ARE THEY DOING, IN TE
CLINICAL RESERVOIR WOULD BE THE
NEXT STEP.
TAKE-HOME MESSAGE FOR THE
COMMUNITY, THE QUESTION WE'RE
TRYING TO ADDRESS IS WHY DOES
HIV SHUT DOWN IN SOME CELLS, HAY
I THINGS IN THE ENVIRONMENT
REGULATING THAT.
WE FOUND NEW THINGS THAT
REGULATE HIV ACTIVITY IN
LATENTLY AFFECTED CELLS.
OUR NEXT STEP IS TO FIND DRUGS
THAT COULD TARGET THESE GENES TO
HELP CLEAR HIV INFECTED CELLS.
SPECIAL THANKS TO MY LAB,
SPECIAL SHOUT OUT TO JACKSON,
THESIS MONDAY, WAY TO GO, JACK
JACKSON.
THANKS TO EVERYBODY ELSE, ALL
OUR FUNDERS AND COLLABORATORS
HERE.
[APPLAUSE]
>> ALL RIGHT.
THANK YOU FOR THIS.
WE'RE A PART OF -- AS YOU HEARD
THE RESEARCH FOCUS STRATEGY IS
TO ELIMINATE THE RESERVOIR.
WHY ARE WE INTERESTED IN HLA-E?
THE GERMINAL OBSERVATIONS WERE
REPORTED BY DR. SPEAKER'S GROUP
WHO EVALUATED IMMUNOGENICITY --
OF THE SIV GAG AND REPEAT LID
DEMONSTRATED THAT IT COULD
ELIMINATE INFECTION IN 60% OF
THE VACCINATED RHESUS MACAQUES.
THE PROTECTION WAS CORRELATED
WITH THE CD8 T-CELLS TO
RECOGNIZE SIV GAG PEPTIDES IN
THE CONTEXT OF THE HLA-E
MOLECULES.
AS A REMINDER, IMMUNE RESPONSES
INVOLVING HLA-E, ITS RELATED
FUNCTIONS CAN BE DIVIDED IN
MAJOR AND MINOR.
THE MAJOR ARE REALLY RELATED TO
THE PRESENTATION OF ENDOGENOUS
VL9 PEPTIDES THAT ARE RECOGNIZED
BY RECEPTORS AND REGULATE THE NK
FUNCTION.
THE MINOR ARE RELATED TO THE
GENERATION OF NON-VL9 PEPTIDES
THAT DERIVE FROM THE PROCESSING
OF THE ANTIGENS OF SEVERAL
DIFFERENT PATHOGENS, AND THEY
CAN BE RECOGNIZED BY THE
CD8 T-CELLS AND ELIMINATE THE
CELLS.
THESE MECHANISM ESSENTIALLY
COUNTERBALANCE THE INHIBITORY
EFFECT OF THE PATHOGENS THAT ARE
TRYING TO INCREASE THE HLA-E
EXPRESSION OF THE INFECTED CELLS
AND INHIBIT THE NK CELLS'
ACTIVITY.
SO WE AIM AT ANSWERING THE
QUESTION, CAN HUMAN MAKE HLA-E
RESTRICTED T-CELLS RESPONSES TO
HIV?
WE WERE ABLE TO ISOLAT ISOLATEDT
CAN BE PRESENTED IN THE CONTEXT
OF THE HLA MOLECULES.
T-CELLS WERE PRIMED IN VITRO
HUGHESING HLA-E PEPTIDES BY
CULTURING THEM WITH DENDRITIC
CELLS IN PRESENCE OF EXCESS
PEPTIDES.
AND T-CELL CLONES WERE SORTED
USING SPECIFIC TETRAMERS.
WE WERE ABLE TO ISOLATE 45
EPITOPE RELATED TO IL9 AND 15
AJV GAG EPITOPE RL9 T-CELL
CLONES.
THE NEXT QUESTION WAS, CAN HLA-E
RESTRICTED -- THE APPROACH WAS
TO INFECT THE CELLS IN VITRO
USING THE NL4 -- 3 ISOLATE, ADD
THE T-CELL CLONE IN THE
RAVIL9 CLONES, CULTURE FOR FIVE
DAYS AND THEN IDENTIFY THE
REMAINING INFECTED CELLS, THE
INTRACELLULAR P24 STAINING.
AS YOU CAN SEE IN THIS PANEL, IN
THE CONTROL YOU HAVE A
POPULATION OF POSITIVE P24
INFECTED CELLS.
WHEN YOU ADD THE CLONES, THESE
POPULATION ARE REDUCED AND THEY
ARE DEFINITELY REDUCED COMPARED
TO WHEN YOU ADD THE CLONES THAT
ARE SARS-COV-2 OR IRRELEVANT TO
AJV.
DR. YANG DEMONSTRATED THAT WHEN
YOU LOOK AT ALL THE CLONES IN
GENERAL, THE AVERAGE OF
INHIBITION OBSERVED IS
SIGNIFICANTLY HIGHER THAN WHAT
YOU OBSERVE USING THE KNOWN
RELEVANT SARS-COV-2 CLONES.
THE OTHER ASPECT WAS
INVESTIGATED BY DR. RAY WHO
SEQUENCED THE T-CELL RECEPTOR OF
THE RL9 CLONES, IDENTIFY THE PCR
CHAIN, SYNTHESIZE THE FULL
CONCERT AND TRANSDUCE THEM INTO
THE CD8 T-CELLS.
THESE CLONES REPORT IN THE BARS
HERE -- SIGNIFICANT INHIBITION
OF THE VIRUS REPLICATION
COMPARED TO WHAT OBSERVED BY THE
HLA-E B27 RESTRICTED KK10
CLONES.
AND YOU CAN SEE THE DIFFERENCE
BETWEEN -- IN THE GREEN BARS
THAT IF YOU ARE HLA-E B27
POSITIVE, YOU CAN OBSERVE
REDUCTION IN THE INFECTION,
WHEREAS IF YOU ARE B27 NEGATIVE,
YOU CANNOT.
THIS IS NOT THE CASE WHEN YOU'RE
USING THE HLA-E CLONES, IT'S
IRRELEVANT TO YOUR HLA-B27
STATUS.
CAN SPECIFIC T-CELL CLONES
CONTROL IN VIVO.
THIS WAS WORK CONDUCTED IN
DR. GARCIA'S LAB WITH HIS
COLLABORATION, BLT MICE WERE
USED TO GENERATE THE HLA-E TRANS
DUCK TANT CD8 T-CELLS.
THE MICE WERE INFUSED WITH THESE
TRANS DUCTANT CLONES, AND 24
HOURS LATER INFECTED WITH THE
HIV.
ONE WEEK LATER, THERE WAS A
SECOND INFUSION, AT THE END OF
THE STUDY, THE ORGANS WERE
COLLECTED.
WHAT WAS OBSERVED IS THAT IN THE
LONGITUDAL SAMPLES, THE PLASMA
VIREMIA STARTED TO DECLINE, AND
IT REACHED SIGNIFICANT
DIFFERENCE IN THE LOWER LEVEL
AFTER 28 DAYS OF POST INFUSION.
WHEN WE LACK AT THE DISTRIBUTION
OF THESE TRANSDUCTANT CLONES
INTO THE TISSUES, YOU CAN SEE
THAT THE CLONES SPECIFIC FOR HIV
WERE HIGHLY AND SIGNIFICANTLY
ACCUMULATING IN THE BONE MARROW
AND IN THE LYMPH NODE.
WHAT HAPPENED ABOUT THE VIRAL
RNA WAS OVERALL ACROSS ALL THE
TISSUE A SIGNIFICANTLY LOWER
LEVEL OF VIRAL RNA IN THE
ANIMALS WHO WERE TRANSDUCED WITH
THE CLONES, AND SPECIFICALLY
LYMPH NODE AND LIVER PRESENTED
LESS VIRUS LOAD.
WITHOUT REACHING SIGNIFICANCE,
LOWER VIRAL RNA WAS OBSERVED IN
ALL THE OTHER TISSUES.
SO I THINK THESE DATA
DEMONSTRATE THAT THE HLA-E
RESTRICTED T-CELLS CAN EXIST AND
CAN BE PRIMED AND CLONED.
THEY CAN SUPPRESS BOTH IN VIVO
AND IN VITRO VIRUS REPLICATION.
AND THESE FUNCTIONAL ASSAYS ARE
RELEVANT TO OUR GOALS.
WHERE WE'RE GOING FROM HERE IS
THERE'S ALREADY THE OBSERVATION
BY DR. PICKERS OF THE IMPORTANCE
FOR VACCINES.
WE KNOW THAT THESE HLA-E CLONES
CAN OVERCOME THE RESTRICTION
SPECIFIC FOR HLA-E -- AND IT CAN
BE A UNIVERSAL METHOD.
IT'S DOWN REGULATED IF NOTHING
ELSE IS UPREGULATED DURING
INFECTION AND WE CAN EXPLOIT
BOTH NK AND T-CELL RESPONSES.
SO FOR US, THIS IS IMPORTANT
BECAUSE WE ANSWER THE KEY
QUESTION, CAN WE USE
ANTIBODY-BASED MOLECULES THAT
CAN ALLOW KILLER CELLS OF OUR
IMMUNE SYSTEM TO RECOGNIZE THE
INFECTED CELLS IN A WAY THAT IS
UNIVERSAL AND NOT RESTRICTED BY
THE GENETIC-BASED DIFFERENCE IN
EACH INDIVIDUAL'S IMMUNE CELLS?
THE FINDINGS, REPORTED RESULTS
OBTAINED BY EXPERIMENTS
CONDUCTED USING HUMAN CELLS IN
THE LABORATORY AND IN MOUSE
MODEL IN VIVO INDICATED THAT
THIS APPROACH CAN BE SUCCESSFUL.
AND WE STILL HAVE WORK TO DO,
BOTH IN THE SMALL HUMAN ANIMAL
MODEL AND THEN MOVING THIS INTO
THE NON-HUMAN PRIMATE TO
UNDERSTAND HOW WE CAN BETTER
EXPLOIT ALL OF THIS.
AND I WANT TO ACKNOWLEDGE ALL
OUR COLLABORATORS.
[APPLAUSE]
>> SO THANKS.
NOW I'LL TALK A BIT ABOUT SOME
OF THE STUDIES DONE IN NON-HUMAN
PRIMATES.
THE GROUP HAS BASICALLY LOOKED
AT PERSISTENCE AND CONTROL OF
PERSISTENT INFECTION IN TWO
SETTINGS.
THE FIRST, THE SORT OF -- OR THE
SECOND, THE MORE TRADITIONAL
ONE, THAT'S NUMBER TWO, WHERE
ANIMALS ARE INFECTED, SUPPRESSED
ON THERAPY AND THEN AN
INTERVENTION IS DONE WITH A
DISTAL READOUT.
THE NEWER WAY IS TO TRY TO
INTERVENE EARLY, THAT'S NUMBER
ONE HERE.
WHERE ANIMALS ARE INFECTED, AN
INTERVENTION IS DONE CLOSE AFTER
ART IS INITIATED, AND THEN A
READOUT IS DONE AT THE END OF
THE STUDY.
SO I'M SORRY, I GUESS I MISSED A
NUMBER OF THESE.
SO THE FIRST THING I'LL TALK
ABOUT IS NUMBER TWO.
THIS IS THE STUDY THAT WE
ALLUDED TO EARLIER USING THE
NON-CANONICAL APPROACH.
THIS WAS PUBLISHED BY A BROAD
GROUP OF INVESTIGATORS SHOWN
HERE, AND HAS BEEN A SIGNIFICANT
ADVANCE IN LATENCY REVERSAL
THAT'S BEING USED ACROSS MANY IN
VIVO MODELS CURRENTLY.
BUT THE GROUP WANTED TO GO
BEYOND THIS AND ADD TO THIS.
IN THIS REGARD, THEY USED THE
SUPER AGONIST APPROACH.
SOMETHING THAT'S ALREADY BEEN
TESTED IN CLINICAL TRIALS, HAS
BROAD EFFECTS ON THE IMMUNE
SYSTEM, AND COULD ACT AS AN LRA
IN VITRO.
AND IN ANOTHER PREVIOUS STUDY,
IN THE CONTEXT OF CD8 DEPLETION
IN THE USE OF N-803, MCBRIEN --
WE WANTED TO GO OUT AND TRY
ANOTHER IMMUNOTHERAPY, BASICALLY
THE BEST THAT WE COULD FIND TO
TEST IN THE PRIMATE MODEL AT THE
TIME, AND HERE WE WERE HELPED
GREATLY BY THE WORK OF THE NIH
AND THE FREMONT GROUP THAT
PRODUCED THESE ANTIBODIES.
THEY SELECTED FOUR SPECIFICALLY
MONOCLONALS THAT HAD BROAD
EFFECTS IN POTENCY AND
NEUTRALIZATION, IN NOT JUST
NEUTRALIZATION BUT IN ANTIVIRAL
EFFECT IN ADCC.
AND THESE SELECTED ANTIBODIES
ARE SHOWN HERE.
ITS08 TO 113.
SO IN THIS STUDY, THEY INFECTED
ANIMALS, SUPPRESSED THEM
DURABLY, AND THEN GAVE THIS
INTERVENTION, EITHER ART ALONE,
ART PLUS AZD, OR N-803.
SO WE LOOKED AT THE COMBINATION
OF THESE EFFECTS.
WITH THE USE OF ANTIBODIES.
THE ANTIBODY INFUSIONS ARE IN
GREY.
YOU CAN SEE THEM GIVEN TWICE IN
THE LATENCY REVERSAL
INTERVENTIONS ARE IN RED AND
PURPLE.
SO GOING TO THE KEY RESULT,
BECAUSE EACH ANIMAL -- BECAUSE
WE NEEDED TO LOOK AT ANIMALS AS
A GROUP.
WE SAW THAT BEFORE THE
INTERVENTION, AS A GROUP THE
DIFFERENT GROUPS WERE THE SAME,
THAT'S UP IN THE TOP THERE AS
FAR AS DNA LEVELS IN THE VARIOUS
TISSUES.
SO THEY WERE STARTING IN THE
SAME PLACE.
THEN AT THE END, AFTER
INTERVENTION, EITHER LOOKING AT
RECOVERY OF REPLICATION
COMPETENT SIV BY AN IUPM OR CUVO
ASSAY, WE SAW A SIGNIFICANT
DECREASE OF REPLICATION
COMPETENT VIRUS IN THE LYMPH
NODES ON THE RIGHT, AND LOOKING
AT DNA, WE SAW SIGNIFICANT
DECREASES IN SIV DNA ACROSS
SEVERAL VARIOUS TISSUES.
SO THE OTHER STUDY THAT WE HAVE
DONE LOOKS AT THE OTHER MODALITY
INTERVENING EARLY IN THE CONTEXT
OF RECENT ART, TRYING TO
DECREASE THE SIZE OF THE
RESERVOIR IN THAT MODALITY.
AND HERE, WE STUDIED THE IMPACT
OF AZD AGAIN IN COMBINATION WITH
AN IL-15 ACCESS, HERE USING THE
HETEROAMERICA IL-15 MOLECULE IN
COMBINATION.
THIS STUDY HAS REALLY JUST BEGUN
AND SO WE'RE JUST SORT OF GIVING
YOU -- AT FUTURE MEETINGS WE
HOPE TO SEE WHETHER THE EFFECTS
THESE COMBINED INTERVENTIONS
REDUCES THE LIFESPAN OF INFECTED
CELLS.
SO FAR WE SEE GOOD VIRAL
SUPPRESSION IN ALL THE ANIMALS.
PERHAPS WITH SOME EVIDENCE THAT
THERE IS SOME -- THERE'S SOME
DIFFERENCES, LET'S JUST SAY,
BETWEEN THE ARMS AT THIS POINT,
ALTHOUGH A SUPPRESSION APPEARS
TO BE QUITE EFFECTIVE.
SO THIS IS REALLY EARLY DATA,
AND HOPEFULLY PERHAPS AT THE
BEGINNING OF NEXT YEAR, WE'LL
HAVE MORE DEFINITIVE RESULTS
ABOUT THESE OUTCOMES.
SO OVERALL, OUR KEY QUESTION
WAS, COULD WE REDUCE EITHER THE
ESTABLISHMENT OR THE PERSISTENCE
OF THE VIRAL RESERVOIR, AND HERE
WE'RE ABLE TO USE PRIMATE MODEL
AS WE HAVE USED HUMANIZED MOUSE
MODEL AS YOU SAW IN GUIDO'S TALK
TO TEST THESE CONCEPTS.
SO AGAIN THIS IS REALLY A BROAD
GROUP INVOLVING MANY PEOPLE WHO
I NEED TO SHARE.
I'M SORRY, I'M GETTING SOMETHING
FLASHING AT ME ON THE SCREEN.
I'M TRYING TO GO TO THE NEXT
PRESENTATION.
HERE WE ARE.
OKAY.
SO NOW I'D LIKE TO INTRODUCE
TONYA DEL SOLDATA WHO LEADS OUR
COMMUNITY ENGAGEMENT GROUP, AND
SHE'LL TELL YOU ABOUT THEIR
ACTIVITIES.
[APPLAUSE]
>> HI, EVERYONE.
HOW ARE YOU DOING?
GOOD MORNING.
MY NAME IS TO TONYA DEL SODA TT.
I'VE BEEN WORKING IN THE HIV
FIELD FOR OVER 25 YEARS AND I
CHOSE THIS FIELD WHEN I WAS AN
INFECTIOUS DISEASE CLASS FOR MY
BIOLOGY DEGREE, AND WAS SHOCKED
WITH THE STIGMA AND THE
DISCRIMINATION AGAINST PEOPLE
LIVING WITH HIV AND AIDS.
SO THEN I WANTED TO MAKE A
CHANGE AND I'M STILL HERE.
THIS IS A WHEEL THAT I CREATED
TO ENGAGE THE THE COMMUNITY, AND
FOR EDUCATION.
IT'S A TOOL TO TEACH HIV 101.
IT ASKS BASIC QUESTIONS TO TEST
HIV 101, THEIR KNOWLEDGE, IN
EDUCATING THE COMMUNITY IS
ABSOLUTELY NEEDED.
I BELIEVE EDUCATION REDUCES
STIGMA, AND IT ALSO REDUCES OR
COULD LEAD TO PREVENTION.
FOR SURE.
SO THE WAY THAT WE DO EDUCATION
THROUGHOUT TO REACH A BROADER
COMMUNITY IS WE CREATED
PARTNERSHIPS.
WE HAVE THREE PARTNERSHIPS
THROUGHOUT RALEIGH-DURHAM CHAPEL
HILL AREA OF NORTH CAROLINA, AND
IT'S NORTH CAROLINA AIDS ACTION
NETWORK.
AND WE TALKED TO THE GENERAL
ASSEMBLY TO CHANGE POLICIES THAT
AFFECT PEOPLE LIVING WITH HIV.
SECOND ONE IS ALLIANCE OF AIDS.
IT'S A COMMUNITY-BASED
ORGANIZATION, AND EL CENTRO IS
ALSO ANOTHER COMMUNITY-BASED
ORGANIZATION FOR THE HISPANIC
COMMUNITY.
THIS IS HIV SPEAKS ON JONES
STREET PUT ON BY THE NORTH
CAROLINA AIDS ACTION NETWORK,
AND IT'S ON JONES STREET BECAUSE
THAT'S WHERE THE LEGISLATIVE
BUILDING IS AND GENERAL
ASSEMBLY.
THIS WAS EXTRA AMAZING THIS YEAR
BECAUSE I DID GET TO MEET HAROLD
J. PHILLIPS, WHICH IS THE
DIRECTOR OF THE WHITE HOUSE
OFFICE OF THE NATIONAL AIDS
POLICY.
THAT WAS COOL.
SO THIS IS A SLIDE OF WHEN WE
DID A PRESENTATION FOR EL
CENTRO.
THIS WAS PUT ON BY MARIA ABAD, A
RESEARCHER WITH CARE, SO TO MEET
EVERYONE WHERE THEY ARE IS
EXTREMELY IMPORTANT.
JUST LAST WEEK, WE PUT ON A
LUNCH AND LEARN MEETING FOR THE
COMMUNITY.
IT WAS ON OCTOBER 5TH.
THIS WAS OUR FLYER, AND IT'S TO
ENGAGE THE COMMUNITY.
SO WE DID USE THE WHEEL I SPOKE
ABOUT TO ENGAGE THE COMMUNITY.
YOU USE THAT TO TEST KNOWLEDGE,
BREAK THE ICE, AND THEY GET SOME
CARE SWAG THAT YOU SEE ON THE
TABLE.
AND GET FED.
EDUCATION IS VITAL BECAUSE THERE
IS A BASIC LACK OF INFORMATION
IN THE COMMUNITY FOR HIV.
AND THERE IS DR. MARGOLIS
EXPLAINING THE RESEARCH FOR THE
CURE FOR HIV.
THIS IS ME DOING ANOTHER OU
OUTREACH ENGAGING THE COMMUNITY.
THIS WAS AT RALEIGH PRIDE.
AND RIGHT HERE IS ANOTHER
ENGAGEMENT TOOL THAT YOU MIGHT
HAVE NOTICED.
ON THE TABLE RIGHT BEHIND ME.
IT SAYS, "WHAT WOULD A CURE MEAN
TO YOU?"
THIS IS FOR THE COMMUNITY TO --
IT'S ANOTHER ENGAGEMENT TOOL.
AND A FEW OF THEM WAS THAT WHAT
DOES A CURE MEAN TO THEM IS
HAPPINESS.
NO MORE TAKING MEDS.
REDUCING -- NO MORE STIGMA.
AND FREEDOM.
AND A CHANCE TO SMILE AGAIN.
SO THERE YOU ARE, RESEARCHERS.
THIS IS WHAT IT MEANS, AND THIS
IS WHAT YOUR WORK IS GOING FOR.
SO THANK YOU ALL SO MUCH.
AND THANKS.
[APPLAUSE]
>> THANKS VERY MUCH.
WE NOW HAVE ABOUT 10 MINUTES FOR
Q & A FOR THE CARE
COLLABORATORY.
SO I'LL ASK DR. MARGOLIS TO
MODERATE, AND IF ANYONE HAS ANY
QUESTIONS, WE HAVE STAND
MICROPHONES, AND IF YOU HAVE
TROUBLE GETTING OUT OF YOUR ROW,
JUST STAND UP OR RAISE YOUR HAND
AND WE CAN GET THE MICROPHONE TO
YOU.
WE ALSO IF YOU'RE WATCHING
ONLINE, THERE'S A Q & A BUTTON
AT THE BOTTOM OF THE SCREEN, SO
PLEASE FEEL FREE TO SUBMIT
QUESTIONS AND AS TIME ALLOWS,
WE'LL DO OUR BEST TO GET TO YOUR
QUESTIONS.
OKAY, DR. MARGOLIS.
>> SO WE HAVE TO PRESS THE
BUTTON BEFORE WE TALK, AND IF
YOU'D LIKE TO ASK US SOMETHING,
WAVE, BECAUSE THE LIGHT IS RIGHT
IN OUR EYES AND I CAN HARDLY
SEE, BUT I THINK THAT'S
PROBABLY --
>> IT'S BRAD.
>> BRAD, YEAH.
GO AHEAD.
>> I HAVE A QUESTION FOR GUIDO.
SO BEAUTIFUL WORK.
KUDOS ON PULLING UP 45 CTL
CLONES, THAT'S A LOT OF WORK.
SO WHEN YOU GIVE THOSE HLA-E
RESTRICTED CLONES, YOU KILL 80%
OF THE INFECTED CELLS.
I'M INTERESTED IN THOSE 20% OR
SO THAT SURVIVE.
EVEN THOUGH YOU HAVE ABOUT A
5 TO 1 RATIO OF CTL TO TARGET.
SO IF WE USE CONVENTIONAL CTL,
ONE OF THE THINGS WE SEE IS THAT
SURVIVORS ARE SELECTED FOR THOSE
THAT ARE MHC1 LOW BECAUSE OF THE
ACTIONS OF NEF.
PRESUMABLY YOU WOULDN'T SEE THAT
WITH YOUR HLA-E RESTRICTED
CELLS, SO ARE THEY SELECTED FOR
LOWER LEVELS OF HLA-E OR DO YOU
KNOW ANYTHING ABOUT THOSE
SURVIVORS?
>> IT'S A VERY GOOD QUESTION.
I DON'T THINK THAT WE HAVE
LOOKED AT THE LEVEL OF HLA-E IN
THE TARGET THAT ARE SURVIVING.
THIS IS WORK THAT IS IN
PROGRESS.
I ALSO WONDER, THESE ARE 5 TO 28
DAYS ASSAYS.
WHAT I THINK NEEDS TO BE DONE
THAT IS IN THE PIPELINE IS A
LOOK AT THE FUNCTIONALITY OF
THESE CLONES OVER TIME.
I THINK THESE ARE ALL THE BIG --
YOU KNOW, MOVING FORWARD THE
QUESTIONS THAT WE NEED TO HAVE.
THERE IS DEFINITELY AN ACUTE
EFFECT, AS YOU CAN SEE.
NOW WE NEED TO UNDERSTAND WHAT
IS GOING TO HAPPEN AFTER.
AND I THINK THAT ALSO SOME OF
THIS MODELING WILL HAVE TO FEED
IN WHAT IS DONE IN CANCER WITH
THESE CELLS.
>> AND HAVE YOU EVER TRIED
COMBINING AN HLA-E RESTRICTED
CLONE WITH A CONVENTIONAL CLONE
TO SEE IF THEY SYNERGIZE?
>> YEAH, SO THE CONVENTIONAL
CLONES WERE ALL THE SARS-COV-2
CLOSARS-COV-2CLONES I SHOWED ATD
YOU CAN SEE THOSE, BUT IT WOULD
BE NICE TO SEE FOR THOSE CELLS
WHAT ARE THE DIFFERENCE, IF THIS
IS WHAT YOU MEAN, ABSOLUTELY
RIGHT.
>> THANKS.
>> VERY EXCITING WORK WITH THE
HLA-E ANGLE AS WELL.
I'M OVER HERE.
SO SIMPLE QUESTION, HAVE YOU
EVER SEEN EVIDENCE FOR SCAPE IN
THE HLA-E RESTRICTED EPITOPES?
>> NO.
WE HAVEN'T DONE THAT YET.
>> OKAY.
AND WHAT ABOUT THE MONOCLONAL
ANTIBODY THAT CAN RECOGNIZE THE
HLA-E PEPTIDE COMPLEX, HOW IS
THAT GOING?
>> YES.
SO THAT IS PART OF MY SECOND
TALK THIS AFTERNOON, BUT IT IS
IN THE PIPELINE WITH DR. --
>> EXCITING.
>> YES.
>> STEWART SHAPIRO, DIVISION OF
AIDS.
SO I HAVE ANOTHER QUESTION FOR
GUIDO.
SORRY TO THE REST OF YOU, BUT SO
WE HAD A WORKSHOP IN AUGUST ON
T-CELL B CELL SYNERGY IN HIV
PREVENTION VACCINES, AND A POINT
WAS MADE BY CLAUSE FRUE, WHO
WORKS WITH LEWIS PICKER ON THE
HLA-E, THE CYTOMEGLOVIRUS
VACCINE, THAT IT SEEMED TO BE
PREVENTING THE ESTABLISHMENT OF
LATENCY.
AND THAT WAS ONE OF THE KEY
FACTORS ON HOW IT WORKED, IN
ADDITION TO KILLING HIV INFECTED
CELLS.
AND SO I'M WONDERING IF IN YOUR
STUDIES, YOU LOOK AT -- YOU
COMPARE THE HLA-E KILLING WITH
CD8 KILLING MEDIATED BY MHC1 TO
SEE IF THERE ARE DIFFERENCES IN
HOW CELLS ARE KILLED THAT MIGHT
ILLUMINATE DIFFERENCES IN
NORMALLY INFECTED CELLS AS
OPPOSED TO LATENTLY -- THE
LATENT RESERVOIR AND WHERE ITS
LOCATION IS AND OTHER THINGS
LIKE THAT.
>> STEWART, I THINK THOSE ARE
THE OTHER SECTION OF ANALYSIS
FROM THE BLT MODEL, THAT VICTOR
AND THE GROUPS ARE DOING.
I ONLY PRESENTED HERE THE VIRUS
RNA AS PROOF OF CONCEPT OF THE
ELIMINATION OF THE CELLS.
THERE IS ALL THE OTHER PART OF
UNDERSTANDING, THE SEATING OF
THE RESERVOIR.
IN THAT MODEL AS YOU NOTICED,
THERE WAS AN INFUSION OF THE
TRANSDUCTANT.
-- INFECTION IN A SECOND
INFUSION.
SO THE QUESTION IS REALLY HOW
WAS THE PREEXISTENCE PRESENCE OF
THESE CLONES IMPACTING THE EARLY
RESERVOIR.
SO IT'S IN THE LINE IN WHAT HAS
TO BE DONE NEXT.
>> YOU HAVE A GREAT TOOL HERE
FOR ILLUMINATING THE
ESTABLISHMENT OF LATENCY, WHICH
IS REALLY IMPORTANT.
>> I THINK -- I WANT TO TRY TO
GET IN THESE LAST THREE PEOPLE
REALLY QUICKLY.
>> THANK YOU.
I ACTUALLY HAD ONE QUESTION FOR
GUIDO AND ONE QUESTION FOR
EDWARD.
GUIDO, FOLLOWING UP ON WHAT BRAD
SAID ABOUT THE DOWN REGULATED
HLA-E ON THE SURVIVORS, DO YOU
THINK IN AN ANIMAL MODEL THAT
WOULD HAVE WELL CONSTITUTED NK
CELLS THAT YOU WOULD SEE
EXPANSION OF THE NKD2A
POPULATION BECAUSE YOU BASICALLY
LOSE THAT INHIBITORY SIGNAL?
I'M NOT SURE WITH VICTOR'S B █LT
MODEL HOW GOOD THE NK CELLS ARE
BUT MAYBE IN AN NHP MODEL YOU'D
BE ABLE TO SEE SOMETHING LIKE
THAT?
>> THAT'S A GOOD POINT.
I THINK IT HAS TO BE EVALUATED.
>> THE NK CELLS ARE FUNCTIONAL
IN THE -- MOUSE MODEL AS WELL.
>> RIGHT, BUT THE POINT WITH THE
IL15 MODEL FOR THE MOUSE MODEL
WILL PROBABLY SOLVE THE BETTER.
FOR THE NK, WHAT I WAS PRESENTED
HERE ARE TRA TRANSDUCTANT TO CDO
WE WERE LOOKING AT -- IF YOU
REMEMBER THE MAJOR AND MINOR, WE
WERE FOCUSING ON THE MINOR POINT
OF THE HLA-E EFFECT.
SO IF WE WANT TO EXPLORE BOTH AS
MENTIONING THE LAST SLIDE, THE
IL15 CONCEPT COMES ALONG VERY
WELL.
>> PERFECT.
THANK YOU.
AND EDWARD JUST ASKED -- SORRY,
ONE QUICK QUESTION.
YOUR VOLCANO PLOTS ARE REALLY
INTERESTING AND CLEARLY YOU HAD
A SET OF GENES YOU WERE GOING
AFTER FOR VALIDATION, BUT IN THE
REST OF THE GENES, WE SAW SOME
VERY INTERESTING HITS KIND OF
RELATED TO SOME OF THE HITS WE
SEE IN SURVIVORS FROM NK CELL
KILLING, SO DO YOU KNOW IF ANY
OF THOSE OTHER HITS ARE RELATED
TO TNF SIGNALING OR INTERFERON
SIGNALING?
>> -- INTERFERON SIGNALING?
>> LIKE INTERFERON SIGNATURES AT
ALL.
>> OH.
NO, WE HAVEN'T SEEN ANY
INTERFERON SIGNATURES IN THE
HITS SO FAR, AT LEAST I DON'T
THINK SO.
WHAT WAS THE OTHER THING YOU
MENTIONED?
>> IT WAS TNF OR NF KAPPA BY
SIGNALING.
>> -- 20 BASICALLY WHICH IS FOR
THE FEEDBACK, THAT DEFINITELY
REACTIVATES IN -- IT SOMETIMES
WORKS IN PRIMARY CELLS BUT
THAT'S ONE THAT CAME OUT OF IT,
THAT IS A SIGNALING PATHWAY.
>> THANK YOU.
I'D ENCOURAGE YOU TO GO SEE
POSTER?
70.
>> ONE LAST QUESTION REALLY
QUICKLY.
>> QUESTION FOR ED I'M
INTERESTED IN YOUR SET D2 STORY
THERE.
WE IDENTIFIED -- AS A METHYL
TRANS PHRASE ALSO TARGETING --
WE DID NOT FIND AN EFFECTIVE
HK336 TRI-METHYL ON THE PROMOTER
PARTICULARLY IN CONTROLLING
LATENCY.
I WANTED TO SEE IF YOU FOUND OR
HAVE ANY EVIDENCE FOR THIS.
>> SO WE HAVE LOOKED AT THAT, SO
WE'RE WORKING ON THE MECHANISMS.
WE DEFINITELY SEE REDUCTION OF
THE PROTEIN LEVEL FOR HIV
EXPRESSION WHEN YOU AT A SET
D2 INHIBITOR.
IT SEEMS TO BE ALL POST
TRANSCRIPTIONAL.
TRANSCRIPTION IS NOT CHANGED AT
ALL.
SO WE STILL ARE TRYING TO FIGURE
OUT EXACTLY HOW IT WORKS.
OUR BEST GUESS IS IT'S PROBABLY
TO DO WITH SPLICING OR TO DO
WITH SOMETHING LIKE RNA
METHYLATION SO WE'RE TRYING TO
FOLLOW UP ON THOSE TWO LEADS SO
YES, I THINK IT'S POST
TRANSCRIPTIONAL.
>> OKAY, THANKS.
>> ONE MORE QUESTION.
>> HI, I WANT TO MAKE A COMMENT
TO ANSWER SOME OF THE PREVIOUS
QUESTIONS ABOUT MHC RESTRICTED
T-CELLS IN THE MON K MONKEY MOD.
GUIDO, NICE DATA, BUT PART OF
THE ISSUE IS NOT NECESSARILY
THAT THEY'RE MHCU RESTRICTED BUT
IT'S ALSO THE TIMING.
SO THE FACT THAT THE INTERCEPT
AND REPLICATION ARREST OCCURS
BEFORE THE RESERVOIR IS SET
MATCHES WHAT WE SEE WITH EARLY
ART, AND THE LOSS OF CELLS AND
THE CLEARANCE OF INFECTION HAS
THE SAME TIMING AS IF YOU PUT
THE ANIMALS ON EARLY ART.
SO WHAT WE THINK IS HAPPENING,
WHEN MHC RESTRICTED T-CELLS IN
VIVO IN THE CNV MODEL IS THERE'S
REPLICATION ARREST WHICH IS NOT
NECESSARILY KILLING THE CELLS
BUT STOPPING VIRAL SPREAD, AND
THAT OCCURS BEFORE THE LONG
LIVED RESERVOIR.
AND THAT'S WHY WE SEE WHAT WE
SEE.
WE LOOK CAREFULLY FOR ESCAPE IN
THE NON-PROTECTED ANIMALS.
THERE'S NO EVIDENCE OF
MUTATIONAL ESCAPE, AND THAT'S
AGAIN BECAUSE OF THE EARLY
INTERCEPT THAT OCCURS PROBABLY
IN THE FIRST SEVEN DAYS.
IT EITHER STOPS IT OR IT
DOESN'T, AND THAT TENDS TO BE A
FUNCTION MORE OF THE PROGRAMMING
OF THE CELLS BY THE INNATE
IMMUNE RESPONSE AS OPPOSED TO --
SO THERE'S NO EVIDENCE OF
MUTATIONAL ESCAPE.
>> I GUESS I WOULD JUST SAY SORT
OF ORTHOGONALLY, PLEASE LOOK AT
THIS EXPERIMENT THAT WAS
PRESENTED AS A PRELIMINARY
EXPERIMENT SHOWING SOME KIND OF
ANTIVIRAL ACTIVITY, WHICH WAS
REALLY ALL THAT IT SHOWED.
ALL OF THE MECHANISM QUESTIONS
THAT WERE ASKED, VERY IMPORTANT,
BUT REQUIRE FURTHER STUDY.
THIS WAS ACUTE INFECTION AND
JUST HAVING THE CELLS THERE
DURING ACUTE VIREMIA, AND THERE
WAS AN ANTIVIRAL EFFECT.
SO EXACTLY WHAT'S GOING ON, HOW
THAT CAN BE USED, IS SOMETHING
THAT REQUIRES A LOT MORE WORK.
>> ABSOLUTELY.
AND WE'VE ALSO SEEN SIMILAR IN
VITRO ACTIVITY.
[APPLAUSE]
>> ENTERPRISE FOR RESEARCH AND
ADVOCACY TO STOP AND ERADICATE
HIV.
I'M HAPPY TO INTRODUCE THE
CONTACT PI, DR. MIRKO PAIARDINI.
HE'S A PROFESSOR AT EMMY EMORY
UNIVERSITY AND IT ALSO HAPPENS
TO BE HIS BIRTHDAY TODAY.
IF YOUR TEAM FINISHES EARLY, WE
COULD ALSO SING HAPPY BIRTHDAY.
TAKE IT AWAY.
>> THAT'S A GOOD EXCUSE, THANK
YOU FOR THAT INTRODUCTION IN
PRESENTING.
THESE SLIDES ARE JUST TO SHOW
YOU OUR THEME IS COMPOSED OF 14
DIFFERENT PATTERNS, AT LEAST IN
THIS MAP, AND FROM FIVE
DIFFERENT COUNTRIES AND TO
HIGHLIGHT OUR INDUSTRY AND
COMMUNITY.
I WANT TO ALSO SHOW AND THANK
THE MEMBERS OF THE ADVISORY
BOARD AND THE MEMBER THAT IS IN
THE AUDIENCE FOR THIS MEETING.
SO WE ARE A NEWLY FUNDED
COLLABORATORY SINCE 2 1/2 YEARS
NOW, AND I BELIEVE WE'VE BEEN
QUITE PRODUCTIVE.
ERASE HIV -- MEMBERS OF THE TEAM
HAVE BEEN PRESENTING AT
CONFERENCE AND ACADEMIC
INSTITUTION IN MORE THAN 100
LOCATION AND WE HAVE 36
PUBLISHED PAPERS, 17 OF THEM
WITH TWO OR MORE MEMBERS OF THE
COLLABORATORY, AND THESE ARE
PAPERS NOT ONLY FUNDED BY ERASE
HIV BUT REALLY SUMMARIZED IN
SOME OF THESE MANUSCRIPT ON THE
SLIDE FOCUS ON THE KEY GOAL OF
THE ERASE HIV COLLABORATORY.
AND TO SPEAK ABOUT THE KEY GOAL,
WE ARE REALLY FOCUSED ON TRYING
TO UNDERSTAND TWO VERY IMPORTANT
QUESTIONS FOR HIV PERSISTENCE,
WHAT ARE THE MECHANISM --
PERSISTENCE, FAVOR THE SURVIVAL
DESPITE THEY'RE INFECTED AND
WHAT ARE THE MECHANISMS LIMITING
THE CAPACITY OF THE SYSTEM TO
INTERCEPT AND ELIMINATE THESE
CELLS.
AND WE ARE ABLY FOCUSED ALSO AT
PERFORMING IMMUNOSTUDY IN IMMUNE
BASED INTERVENTIONS WHEN WE TRY
TO UNDERSTAND THESE MECHANISMS
WITH INTERVENTION TO HOPEFULLY
BE ABLE TO CONTROL HIV.
AND TODAY'S PRESENTATION IS
GOING TO BE FOCUSED ON THIS KEY
GOAL OF THE ERASE COLLABORATORY
AND I APOLOGIZE FOR SOME LAST
MINUTE CHANGES, SO RESEARCH
FOCUS ONE IS GOING TO PRESENT ON
MECHANISM OF CD8 CYTOLYTIC
FUNCTION BUT ALSO PRO LATENCY
ACTIVITY, AND DEANNA KULPA WAS
SUPPOSED TO PRESENT BUT DEANNA
JUST TESTED POSITIVE FOR COVID,
SO BRAD WILL TAKE IT OVER FOR
THE ENTIRE RF1.
RF2 IS GOING TO BE MYSELF AND
PRITI KUMAR, TO TRY TO INTERCEPT
THE REBOUNDING OF THE VIRUS.
AND THE RESEARCH FOCUS THREE IS
GOING TO BE FOCUSED ON THE
MECHANISM THAT FAVOR THE
SURVIVAL OF -- PARTICULARLY THE
EXPRESSION OF B CE BCL-2 AND HOE
CAN TARGET THAT PATHWAY.
TTHOMAS CANNOT MAKE IT SO ANDREW
WILL TAKE OVER FOR HIM.
FINALLY WE'LL FINISH WITH PRITI
BHANDARI SPEAKING ABOUT OUR
COMMUNITY WORK.
ALL THIS WORK WE ARE DOING IN
THE 2 1/2 YEARS OF THE ERASE HIV
COLLABORATORY IS FOCUSED TO
SELECT THE MOST EFFECTIVE IMMUNE
BASED INTERVEX THA INTERVENTIONE
PERFORMED AS DR. MARGOLIS WAS
HIGHLIGHTING BEFORE TO REDUCE
THE ESTABLISHMENT OF THE
RESERVOIR, AND THEN TO BE
PERFORMED -- WHICH ALREADY
REDUCE -- AND FURTHER IMPROVE TO
NOW CONTROL THE REBOUNDING
VIRUS.
AND WITH THAT, I WILL HAVE BRAD
START WITH RF1.
>> THANK YOU, MIRKO.
I'M GOING TO TELL YOU ABOUT IT.
AZEMETOSTA, A -- SO OUR GOAL ISO
TEST A MO VEL THERAPEUTIC
APPROACH -- WE'VE LEARNED THAT
IN CELL CULTURE, THIS APPROVED
DRUG HELPS EXPOSE HIV INFECTED
CELLS TO CD8 CELLS RESULTING IN
MORE KILLING AND MOUSE
EXPERIMENTS ARE STILL ONGOING
BUT THERE'S SOME EARLY
SUGGESTION IT MAY EMPOWER
CD8 CELLS TO BETTER CONTROL
VIRAL REPLICATION IN VIVO.
IT'S AN APPROVED DRUG THAT CAN
BE CONSIDERED FOR CLINICAL
TRIALS IN PEOPLE LIVING WITH HIV
TO ENHANCE CD8 T-CELLS.
WE'RE REALLY INTERESTED IN THE
INFECTED CELLS THAT SURVIVE
KILLING ONCE YOU EXPOSE TO
CONDITIONS IN VITRO, THERE'S
ALWAYS SOME SURVIVORS.
WE SAW THAT ALSO IN THE TALK
EARLIER.
WE'VE BEEN PROFILING THESE CELLS
AND SEEN A NUMBER OF DIFFERENT
HITS.
SO THERE'S GOING TO BE
PRESENTATIONS LATER ABOUT
BCL2 AND BCL2 FAMILY MEMBERS.
THIS IS BCLXL.
WHEN WE EXPOSE TO CTL, WE SEE
THE INFECTED CELLS THAT SURVIVE
HAVE BEEN SELECTED FOR THOSE
THAT ARE BCL2 HIGH.
EZH2 AS WELL IS ONE OF THESE
THAT'S OVEREXPRESSED IN THESE
CELLS THAT SURVIVE KILLING.
WHEN YOU EXPOSE TO CTL KILLING,
IT'S UP IN THE SURVIVORS.
SO WHAT IS EZH2?
IT'S PART OF THE POLY -- RE PRE
SIEVE COMPLEX AND IT ACTS BY
METHYLATING HISTONE 3 AT LYSINE
27.
SO THIS HAS A LOT OF EFFECTS ON
THE CELL, BUT ONE OF THE THINGS
THAT IT DOES IS REPRESS
EXPRESSION OF NLRC5, WHICH IS
IMPORTANT IN DRIVING
MHC1 UPREGULATION IN RESPONSE TO
INTERFERON GAMMA.
SO IT'S KNOWN IN VARIOUS TUMORS
THAT SOME TUMORS OVEREXPRESS
EZH2.
THIS PREVENTS MHC1 UPREGULATION
AND THIS IS A MECHANISM OF
IMMUNOINVASION SO IS SOMETHING
HAPPENING IN THE CONTEXT OF HIV.
FIRST WASN'T TODAY ASK ARE THE Y
DEFICIENT IN SURFACE MHC1.
IF THAT'S THE CASE MAYBE WE DO
SOMETHING ABOUT IT BY
INTERFERING WITH EZH2.
THESE ARE THE RESULTS OF A
KILLING ASSAY WITH THE CTL
CLONE.
WE CAN SEE THAT WITHOUT APPLYING
THE CLONE, THE INFECTED CELLS
HAVE A SMEAR TOWARDS BEING
MHC1 LOW THROUGH THE ACTIONS OF
NEF BUT IF WE KILL WITH THE CTL
CLONE WE CUT OFF THIS PART OF
THE CURVE, WE SELECT FOR KURNS
WHICH ARE MORE MHC1 LOW, LESS
ABLE TO BE SEEN BY THE IMMUNE
SYSTEM.
SO CAN WE DO SOMETHING ABOUT
THIS BY UPREGULATING MHC1.
WE TEST THIS IN AN IN VITRO CTL
KILLING ASSAY.
INFECTED CDR -- EXPOSED TO
CYTOTOXIC T-CELL CLONE AND WE'RE
LOOKING AT THE DEGREE OF KILLING
OF THESE INFECTED CELLS.
THESE ARE VERY SIMILAR PLOTS TO
WHAT GUIDO SHOWED EARLIER.
SO CD4 T-CELLS ALONE WE CAN SEE
THIS PORTION OF INFECTED CELLS.
WE ADD THE CTL CLONE AND WE KILL
THE MAJORITY OF THESE CELLS, BUT
WE NEVER KILL ALL OF THEM.
THERE'S ALWAYS THESE SURVIVORS
IN THESE KILLING ASSAYS.
THESE ARE THE SAME RESULTS, IT'S
PROJECTING A LITTLE BIT ODDLY
HERE, BUT WHERE WE PRE-TREAT
WITH TAZEMETOSTAT, AND NOW YOU
CAN SEE WE'VE CUT DEEPER INTO
THESE CELLS, SO A PROPORTION OF
THE CELLS THAT WOULD HAVE
SURVIVED ARE KILLED OFF WHEN WE
TREAT WITH TAZEMETOSTAT, AND
THIS IS ASSOCIATED WITH, INDEED,
A CONSISTENT UPREGULATION OF
MHC1 WE SEE IN
TAZEMETOSTAT-TREATED CELLS.
IT'S JUST PUSHING MHC1 LEVELS UP
ON EVERYTHING, SO THAT THE
MHC1 DOWN REGULATED INFECTED
CELLS CAN BE SEEN BETTER BY THE
CTL.
SO HERE'S DIFFERENT EFFECT
EFFECTOR-TARGET RATIOS.
SORRY THIS IS PROJECTING PRETTY
STRANGELY HERE BUT EACH DOT IS A
DIFFERENT BIOLOGICAL REPLICATE.
WE LOOK AT THE PROPORTION THAT
SURVIVE UPON CTL EXPOSURE IF
THEY'VE BEEN TREATED WITH
TAZEMETOSTAT OR NOT, SO WE KILL
OFF AN EXTRA ABOUT 50% OF THE
WOULD-BE SURVIVORS IN THESE IN
VITRO ASSAYS.
SO WE'VE DONE MANY VERSIONS OF
THIS ASSAY AND SEEN VERY
CONSISTENT RESULTS.
SO THEN WE WANT TO MOVE THIS IN
VIVO.
SO TO DO THIS, WE USE WHAT WE
CALL OUR PA PARTICIPANT DERIVED
MOUSE MODEL, ENGRAFTED WITH
CD4 T-CELLS FROM A PERSON LIVING
WITH HIV.
THEN WE CAN COME IN WITH
CD8 T-CELLS FROM THE SAME
INDIVIDUAL AND TEST THE
ANTIVIRAL ACTIVITY OF THAT
PARTICIPANT'S CD8 T-CELLS IN A
MOUSE MODEL.
WHAT I CAN TELL YOU VERY CLEARLY
SO FAR IS THAT IF YOU TREAT
THESE MICE WITH TAZEMETOSTAT,
YOU SEE NICE UPREGULATION OF
MHC1 ON THEIR CD4 T-CELLS.
SO THIS IMPORTANT IMPACT THAT
WE'RE SEEING IN VITRO IS CLEARLY
RECAPITULATED IN THIS MOUSE
MODEL.
THESE RESULTS I WOULD FLAG AS A
LITTLE BIT MORE PRELIMINARY
BECAUSE WE NEED TO REPEAT THE
EXPERIMENT, BUT ALSO VERY
TANTALIZING.
SO HERE'S THE VIRAL LOAD
TRAJECTORIES IN MICE.
THESE TWO GROUPS HAVE RECEIVED
CD8 T-CELLS, SO JUST BY
RECEIVING CD8 T-CELLS FROM THIS
PERSON LIVING WITH HIV, WE HAVE
A NICE IMPACT ON THE VIRAL LOAD.
WE SUPPRESS ON ANTIRETROVIRAL
THERAPY FOR A BRIEF TIME IN THIS
THERAPY AND TREAT OR NOT WITH
TAZEMETOSTAT AND THE QUESTION IS
WHAT HAPPENS TO VIRAL REBOUND.
YOU CAN SEE THERE'S SOMEWHAT
CURVED REBOUND IN THE MIGHT
TREATED WITH CD8 T-CELLS BUT THE
MICE THAT RECEIVED TAZEMETOSTAT,
WE SEE MORE OF A REDUCTION IN
THIS VARIABLE REBOUND.
SO TANTALIZING DATA, BUT AGAIN,
THIS PART IS SOMETHING THAT
NEEDS TO BE FOLLOWED UP ON.
SO I WANT TO ACKNOWLEDGE ANDREA
WHO'S BEEN DRIVING THIS WORK IN
OUR LAB AS WELL AS ALI.
HERE'S █ANOTHER SIDE OF THE COI,
THE MACH BRIEN PAPER MENTIONED
EARLIER SHOWS CD8 T-CELLS CAN
ALSO POTENTIALLY INDUCE LATENCY
IN CD4 T-CELLS.
THIS WAS SEEN IN MICE THAT
RECEIVED THE IL15 SUPERAGONIST,
YOU SAW MUCH GREATER LATENCY
REVERSAL.
SO WE WANT TO KNOW WHY
CD8 T-CELLS CAN HAVE THIS
POTENTIALLY DETRIMENTAL EFFECT
AND BLOCK THAT, SO THAT WE CAN
HARNESS THEIR POSITIVE EFFECT OF
KILLING CELLS.
SO BRIEFLY THAT'S WHAT WE'RE
LOOKING AT, WHY DO SOME
CD8 T-CELLS PROMOTE LATENCY, IF
WE IDENTIFY THIS PATHWAY, CAN WE
BLOCK THIS PATHWAY AND THEN
IMPROVE LATENCY REVERSAL.
SO ERASE PUBLISHED THIS PAPER IN
IMMUNITY EARLIER THIS YEAR
LOOKING AT THE MECHANISMS BY
WHICH CD8 CELLS CAN PROMOTE
LATENCY.
THIS USES THIS IN VITRO ASSAY.
IF YOU USE JUST X VEE VO
CD8 T-CELLS IN PEOPLE WITHOUT
HIV, SO THESE DON'T HAVE
HIV-SPECIFIC CTLs IN THEM,
WHAT WE SEE IS THIS CO-CULTURE
DOES SEE A REDUCTION IN THE
PERCENTAGE OF CELLS THAT EXPRESS
GAG BUT NOT A REDUCTION IN THE
FREQUENCY OF INTEGRATED HIV DNA.
SUGGESTING THAT INSTEAD OF
KILLING CELLS, THERE'S SOME
SUPPRESSION OF GAG EXPRESSION.
SO IN THIS STUDY, DEANNA AND HER
TEAM WENT ON TO LOOK AT THE
PROFILE OF THESE CELLS, THE
CD4 CELLS FOLLOWING CO-CULTURE
WITH CD8 T-CELLS.
WHAT THEY SAUL WAS QUIESCENCE
AND MEMORY PATHWAYS WERE
UPREGULATED IN THESE
CD4 T-CELLS, AND SO THESE ARE
SOME PATHWAYS WE MIGHT BE ABLE
TO INTERFERE WITH TO PREVENT
KRCHT D8 T-CELLS FROM -- LATE
LATENCY.
BCL2, WHICH YOU'RE GOING TO HEAR
ABOUT LATER -- PRO SURVIVAL
PATHWAYS IN CD4 T-CELLS.
AND THERE'S SOME NICE
INTERSECTIONS HERE WITH OTHER
INVESTIGATORS IN ERASE BECAUSE
WE DO SEE -- OF -- SWELS
UPREGULATION OF IL10 WHICH IS
BEING BLOCKED IN NON-HUMAN
PRIMATE STUDIES IN OTHER ASPECTS
OF THE ERASE COLLABORATORY.
SO WITH THAT, I'LL WRAP UP FOR
RF1, AND HERE'S DEANNA'S
ACKNOWLEDGMENTS.
AND THANK YOU FOR YOUR
ATTENTION.
[APPLAUSE]
>> THANK YOU, BRAD.
NOW STARTING WITH RF2, IMMUNE
BASED INTERVENTION.
MANY MANUSCRIPTS INCLUDING --
AND SOME FROM OUR GROUP HAVE
SHOWN THAT CD4 T-CELLS THAT
EXPRESS -- INCLUDING PD-1 AND
CTL4 COULD CONTRIBUTE TO THE
PERSISTENCE OF THE VIRUS
INCLUDING ANTIRETROVIRAL
THERAPY.
A FEW YEARS AGO WE COMPLETED A
BLOCKADE AND PROVED THERE WAS
SUPERIOR -- COMPARED TO -- ON
ANTIRETROVIRAL THERAPY REDUCING
SEVERE ACTIVATION BUT WAS NOT
SUFFICIENT TO CONTROL VIRAL
REBOUND AFTER -- INTERRUPTION.
WE PROPOSE THE BLOCKADE MAY BE
MORE BENEFICIAL DURING --
TREATMENT INTERRUPTION SO WHEN
YOU CAN -- REBOUNDING VIRUS AND
PROPOSE THERE MAY BE MORE
BENEFITS WITH THERAPEUTIC
VACCINE OR -- BLOCK CADE.
THE REASON WE'RE INTERESTED WITH
IL10 IS -- HIV INVESTIGATOR
SHOWED LAST YEAR -- CONTRIBUTE
TO ESTABLISHMENT AND PERSISTENCE
IN SIV INFECTED MACAQUES -- IN
HUMAN WITH HIV.
YOU CAN SEE ON THE RIGHT OF THIS
SLIDE PUBLISHED SHOWING THAT --
IS ACTUALLY VERY IMPORTANT FOR
THE -- OF THE SILENT AND ACTIVE
RESERVOIR.
SO TOGETHER THIS DATA REALLY
PROVIDE THE RATIONALE TO
TARGET IL10 SIGNALING IN
COMBINATION WITH THE --
BLOCKADE.
THIS IS WHAT WE DID IN THIS
STUDY CO-LED WITH -- AND
COLLABORATOR MERCK WHERE WE
INFECTED 28 RHESUS MACAQUES
WITH -- STARTED ANTIRETROVIRAL
THERAPY SIX WEEKS AFTER
INFECTION AND KEEP THE ANIMAL
ALIVE FOR 14 MONTHS BEFORE
STARTING INTERVENTION.
SO THE CONTROL IN BLACK -- AND
RECEIVE -- YOU CAN SEE WE
CONTINUE TO TREAT AFTER
INTERRUPTION UP TO 14 WEEKS.
AND I'M GOING TO SHOW ONLY ONE
RESULT BUT WHAT WE FOUND IS
THAT -- BLOCKADE IN BLUE HAVE
IMPORTANT CONTROL OF SEVERE
REPLICATION AFTER INTERRUPTION
WITH 90% OF THE ANIMAL HAVING AT
LEAST ONE BUT LARGELY MULTIPLE
TIME POINT -- A THOUSAND COPY.
THERE WAS NO EXPANSION OF THE
VIRAL RESERVOIR NEITHER IN THE
LYMPH NODE NOR THE BLOOD SO THE
CONTROL INCREASE -- AND IL10
BLOCKADE, THERE WAS NO
EXPANSION.
SO WE BELIEVE THESE ARE EXCITING
DATA, PROOF OF CONCEPT WE CAN --
TO CONTROL AT LEAST FOR SOME
TIME THESE REBOUNDING VIRUS
WHERE WE HAVE IMPORTANT
CHALLENGE WE TRY TO NOW SOLVE AS
PART OF THE NEXT -- SO ONE IS
SAFETY.
WE DO SEE SOME TOXICITY BY
BLOCKING THESE TWO IMPORTANT
REGULATOR OF THE IMMUNE SYSTEM,
SO WE NEED TO TRY TO REDUCE THE
SIDE EFFECTS.
AND A VERY IMPORTANT POINT OF
THE LONGEVITY OF THE RESPONSE.
SO THE DATA THAT I SHOWED UNTIL
NOW WAS UNTIL WEEK 24 --
INDICATED BY THESE BLACK LINE IN
THIS GRAPH.
SO WHEN THE DEPLETING --
BLOCKING -- WAS STILL IN THE
SYSTEM.
WE FOLLOWED THIS ANIMAL FOR MANY
MORE WEEKS AND AS YOU CAN SEE,
WE HAVE SOME ANIMALS THAT ROMAN
CATHRETURNTO A NORMAL SET POINTE
VIRAL LOAD GO BACK.
WE HAVE THREE ANIMAL --
REBOUNDED BUT MAINTAINING LOWER
VIREMIA AROUND A THOUSAND COPY
AND WE HAVE TWO ANIMALS THAT
FULLY CONTROL LESS THAN 15 COPY
DESPITE ONE YEAR OF --
INTERRUPTION.
INTERESTINGLY WE DECIDE TO
RETREAT THESE THREE ANIMALS THAT
WE ARE MAINTAINING LOW LEVEL OF
VIRAL LOAD FOR SIX MONTHS AND
WITH THE -- THREE DOSES -- AFTER
THE FIRST DOSE, 10 MONTHS AFTER
INTERRUPTION WE'RE STILL ABLE TO
COMPLETELY BLOCK VIRAL
REPLICATION LESS THAN 15 COPY.
SO ALL TOGETHER, THIS SHOWS WE
ARE ABLE TO TIP THE BALANCE
TOWARD IMMUNE CONTROL EVEN AFTER
ALMOST ONE YEAR OF INTERRUPTION,
BUT AGAIN AS YOU SEE, THOSE
ANIMALS REBOUND WHEN ANTIBODY --
SO WE NEED TO IMPROVE SAFETY AND
IMPROVE THE LONGEVITY OF THE
RESPONSE THAT IS CONTROLLING THE
VIRUS.
AND ONE WAY WE'RE TRYING TO DO
THIS IN THE NEXT GENERATIONAL
STUDY IS TO USE IL-21.
SO MY GROUP -- HAS BEEN SHOWN
THAT IL10 T1 IS ABLE TO REDUCE
INFLAMMATION BY IMPROVING --
INTEGRITY, SO THIS MAY BE
IMPORTANT AFTER INTERRUPTION AND
THOSE -- IMPORTANT TO EXPAND NK
CELLS THAT IS -- IL21 IS HIGHLY
SYNERGISTIC WITH -- BLOCKADE AND
ACTUALLY THE MECHANISM SEEMS TO
BE -- FAVOR THE LONG TERM
MAINTENANCE OF -- CELLS SO BASED
ON THIS DATA, THIS IS THE
ONGOING STUDY.
WE HAVE 32 ANIMALS DIVIDED IN
FOUR EXPERIMENTAL ARMS, 8 IN
EACH ARM, SO ONE GROUP IS ONLY
CONTROL WITH ANTIRETROVIRAL
THERAPY, ONE GROUP IS MIMICKING
THE PREVIOUS STUDY WITH IL10 AND
PD-1.
IN ONE GROUP WE ARE ALSO NOW
ADDING IL -- GENERATED BY THE
BLO A CADEBLOCKADE MAKING IT LOG
AND ONE GROUP TO TRY TO REDUCE
TOXICITY WE ARE ELIMINATING IL10
AND -- COMBINATION AND WE'RE
ALSO HAVING A QR AFTER
INTERRUPTION AND TREATMENT WITH
THE HOPE THAT IN THE SECOND
INTERRUPTION START WITH LOWER
RESERVOIR IMMUNE BASED
INTERVENTION MAY BE EVEN MORE
EFFECTIVE.
SO THE CONCLUSION AND COMMUNITY
SUMMARY, WE BELIEVE THAT CONTROL
OF HIV WILL REQUIRE COMBINED
APPROACH THAT TAKES INTO ACCOUNT
THE LARGE COMPLEXITY OF THE
PERSISTENT RESERVOIR, AND THAT
SIGNALING FOR NEGATIVE
REGULATOR, DATA FROM MANY IN
THIS AUDIENCE WHO WILL SPEAK AND
MANY OTHERS, CONTRIBUTE TO HIV
PERSISTENCE AND IN PARTICULAR
PD-1 AND IL-10 AND WE BRIEF THIE
THIS STUDY BY BLOCKING THESE
RECEPTORS WE CAN -- ABLE TO
CONTROL SIV.
AND AGAIN AS THINGS WE NEED TO
IMPROVE, LIMITING THE SIDE
EFFECTS AND INCREASING THE
LONGEVITY OF THE RESPONSE, AND
ANOTHER DIRECTION WE'RE
INVESTIGATING AS BRAD JUST
SHOWED IN DEANNA'S WORK, IL-10
ALSO SEEMS TO BE PART OF THE PRO
LATENCY MECHANISM OF CD8 T-CELLS
SO -- IMPROVING THE CD8 T-CELL
FUNCTION BUT ALSO REDUCING THE
PRO LATENCY ACTIVITY TO USE TO
OUR ADVANTAGE.
SO WITH THAT, I WOULD LIKE TO
THANK ALL THE KEY MEMBERS AND
COLLABORATORS OF THIS STUDY
LISTED ON THIS SLIDE.
I DON'T HAVE TIME TO GO OVER ALL
OF THEM BUT I WANT TO REALLY
HIGHLIGHT RAFIC, SUSAN, AND ALL
THE MEMBERS OF MY LAB AND CLAB
COLLABORATORS.
THANK YOU.
>> I CONTINUE WITH INTERVENTIONS
THAT MAY BE USED TO REDUCE
THE -- VIRAL REBOUND.
I STARTED WITH ACKNOWLEDGMENT TO
COCOLLABORATORS AS WELL AS
PEOPLE IN THE LAB THAT HAVE
CONTRIBUTED TO THE WORK THAT I'M
GOING TO BE SHOWING.
TO VERY BRIEFLY SUM UP THE
COMMUNITY SLIDE, WE ARE TESTING
IF WE ARE LOOKING AT A NEW MORE
IMPORTANT MOLECULE WHICH HAS THE
ABILITY TO SENSITIZE HIV
INFECTED CELLS TO KILLING BY
WEEK -- MOST PEOPLE WITH HIV.
WE HAVE TESTED THIS MOLECULE IN
HUMANIZED MOUSE STUDY AND FIND
IT REDUCES THE RESERVOIR.
-- CLOSED OR -- INACCESSIBLE TO
ANTIBODIES THAT BIND TO THE
CLUSTER A DOMAIN OF THE
CORECEPTOR-BINDING SITE.
EXPOSURE OF THIS GP120 TO SMALL
MOLECULES -- OPENS UP THE
ENVELOPE TO CONFIRMATION THAT
CAN ENABLE BINDING TO THESE
ANTIBODIES BY EXPOSING THESE
EPITOPES.
THESE ANTIBODIES WHICH ARE ALSO
CALLED CD4 INDUCED ANTI ANTIBODS
CAN NOW ELICIT IMMUNE CELLS --
THAT LEAD TO TARGETED
DESTRUCTION OF THE INFECTED
CELL.
SO IN RECENTLY PUBLISHED STUDY,
OUR GROUP HAS REPORTED THE
DEVELOPMENT OF NOVEL AND MORE
POTENT CD4 -- LONGING TO THE --
COMPOUNDS, COMPARED TO THE LEAD
COMPOUND OF THE PREVIOUS CLASS,
REFERRING TO CJF IN MY TALK WAS
FOUND TO BE MORE POTENT AND HAS
BROAD -- AGAINST VARIETY OF HIV
VIRUS STRAINS BELONGING TO
SEVERAL CLADES, AND ALSO COULD
MEDIATE UTILIZATION -- 117.
SO IN VITRO DATA WHICH IS SHOWN
IN BLUE HERE, THE CGF3 ALONG
WITH -- COULD VERY EASILY ELICIT
KILLING OF INFECTED CD4 T-CELLS
IN THE PLASMA FROM HIV INFECTED
INDIVIDUALS AND DID THIS MUCH
BETTER THAN BNM-III170 SHOWN IN
PURPLE.
INTERESTINGLY IT COULD MEDIATE
WITH THE HELP OF ONLY ONE CLASS
OF ANTIBODIES WITH THE
CORECEPTOR-BINDING SITE.
SO -- HUMANIZED MICE -- STRAIN
THAT ENABLES EFFECTOR FUNCTIONS,
THE IDEA WAS TO TREAT THESE MICE
WHICH WERE WILDLY SUPPRESSED
WITH ANTIRETROVIRAL THERAPY, AT
THE TIME -- OR AT THE TIME OF
INITIATION OF ART, AND LOOK AT
VIRUS REBOUND WITH TIME UNDER
THE IMPRESSION -- UNDER THE
ASSUMPTION THAT TIME TO -- IS
CORRELATED WITH THE SIZE OF THE
VIRAL RESERVOIR.
THE DATA I'M GOING TO SHOW YOU
IN THE NEXT FEW SLIDES ARE
PRELIMINARY AND ARE CURRENTLY
BEING EXPANDED ON IN EXPERIMENTS
IN THE LAB.
THIS IS THE DATA WITH MICE
TREATED AT THE TIME OF
ANTIRETROVIRAL WITHDRAWAL, FOUND
THAT THE VIRUS REBOUNDS IN THESE
MICE BY ABOUT THREE TO FIVE DAYS
POST TREATMENT AND THESE ARE
CONTROLLED COHORTS.
WHEN MICE WERE TREATED WITH
CJF-III IN COMBINATION WE FOUND
THE TIME TO REBOUND COULD BE
DELAYED BY ABOUT THREE WEEKS
POST ANTIRETROVIRAL WITHDRAWAL
INDICATING THERE WAS AN EFFECT
ON THE RESERVOIR.
WE THEN PERFORMED THE EXPERIMENT
IN MICE THAT WERE TREATED AT THE
TIME OF ANTIRETROVIRAL THERAPY.
WHILE THIS DID NOT AFFECT THE
REBOUND KINETICS IN CONTROL MICE
EITHER MOCK TREATED OR TREATED
WITH CJF-III, WE FOUND
INTERESTING DIFFERENCES IN MICE
TREATED WITH CJF AND THE
COMBINATION OF ANTIBODIES.
I SHOW HERE THE DATA IN THREE
INDEPENDENT MICE.
IN MOUSE NUMBER ONE ON YOUR
EXTREME LEVEL PANEL, DELAYED
VIRAL REBOUND BY ABOUT
1.5 MONTHS POST ANTIRETROVIRAL
WITHDRAWAL.
AND IN THE OTHER MICE, WE COULD
SEE THAT VIRAL REBOUND WAS
DURABLY SUPPRESSED FOR UP TO
FOUR MONTHS POST ART WITHDRAWAL
DESPITE THE APPEARANCE OF BLIPS,
AND -- FOUR MONTHS POST
WITHDRAWAL BUT THERE WAS
EXTENDED DELAY IN THE VIRAL
REBOUND EVEN IN TERMS OF BLIPS.
-- FIVE DAYS POST WITHDRAWAL WE
FOUND VIRAL DNA LEVELS WERE
HUGELY REDUCED IN MOST OF THE
TISSUES.
WHEN WE LOOK AT TIME TO REBOUND,
WE ALSO CONDUCTED THIS
EXPERIMENT WITH CJF -- WITH THE
MICE TREATED WITH CJF AND ONLY
THE -- ANTIBODY.
THIS IS SHOWN IN MAGENTA.
EVEN THIS ALLOWED DELAY IN VIER
REBOUND BUT OUR BEST EFFECTS
WERE SEEP WITH CJF IN
COMBINATION WITH TWO ANTIBODIES.
SO ESSENTIALLY TIME TO REBOUND,
WE CONCLUDE TIME TO REBOUND IS
DEPENDENT ON TREATMENT -- IS
BETTER WHEN TREATED AT
INITIATION OF ART AND WITH THE
COMBINATION OF ANTIBODIES.
SO SUMMARY -- SIGNIFICANTLY
DELAYS VIRAL REBOUND.
CJF CAN EXERT THESE EFFECTS WITH
ONLY -- AND TREATMENT WITH
CJF-THREE-288/CD4I ANTIBODIES
SIGNIFICANTLY REDUCES THE
RESERVOIR SIZE.
SO THIS IS MY ACKNOWLEDGMENT
SLIDE AND THANK YOU FOR YOUR
ATTENTION.
[APPLAUSE]
>>
>> IN THE NEXT 10 MINUTES OR SO,
I'M GOING TO TALK ABOUT THE BCLN
IN MY LAB AND IN MIRKO'S LAB
WITH TOMAS.
BCL2 INHIBITORS HAVE SHOWN
PROMISE TOWARDS REDUCING
RESERVOIR SIZE AND WE ASK WHAT'S
ITS INFECT IN VITRO MODELS AND
WHAT ARE REASONS WHY IT MIGHT
NOT WORK.
SO THIS WORK BEGINS ALMOST 20
YEARS AGO WHEN WE STARTED WITH
THE OBSERVATION THAT HIV
PROTEASE WHEN EXPRESSED IN ANY
CELL KILLS THAT CELL.
AND WE THOUGHT THAT WAS AN
IMPORTANT LEAD SO WE DECIDED TO
TRACK DOWN THE PATHWAY.
WE FOUND OUT THAT IF YOU KNOCK
OUT CASPASE 8, THEREFORE LIKELY
A TARGET AND WE FOUND OUT THE
CLEAVAGE SITE WITHIN CASPASE
8 THAT LEADS TO THE CLEAVAGE
WHICH RESULTS IN A FRAGMENT
CALLED CASP8P41.
IT DOES NOT CONTAIN A CATALYTIC
CYSTINE DOMAIN BUT IT STILL
KILLS THE CELL, SO WE MAPPED
WHAT ARE THE PROTEINS THAT IT
ASSOCIATES WITH TO RESULT IN
CELL DEATH AND WE FOUND OUT THAT
THE PROTEIN IT BINDS TO TO CAUSE
CELL DEATH IS CALLED BAC.
WE WORK WOULD WITH SOME
STRUCTURAL BIOLOGISTS TO FIND
HOW THIS IS POSSIBLE AND THEY
SHOWED THE ALPHA HELICAL DOMAIN
IS FORMED WITHIN THE CLEAVE
PROTEIN, NOT THE FULL LENGTH
PROTEIN AND THAT BINDS AND
ACTIVATES BAK WHICH IS A PRO
APOPTOTIC BCL2 FAMILY MEMBER
THAT CAUSES POOR FORMATION AND
SUBSEQUENTLY CELL DEATH.
SO THEN WE ASKED WHY IS IT THE
CASPASE 8P41 DOESN'T KILL ALL
CELLS?
IT CAN ALSO BIND TO OTHER
PROTEINS WHICH HAVE THE GROOVE
THAT BINDS, THAT'S CALLED THE
BH3 GROOVE.
THOSE INCLUDE THE ANTIA POP TO
TICK PROTEINS.
SO THIS ALLOWED US TO PROPOSE
THE MODEL THAT WHETHER YOU
REACTIVATE OR REP TI KATE HIV
YOU CREATE PROTEASE, A CLEAVES,
BINDS TO ONE OF TWO TARGETS,
EITHER BCL2 IN WHICH CASE THE
CELL SURVIVES, OR BAK IN WHICH
CASE THE CELL DIES.
THIS GIVES THE POTENTIAL FOR
INTERVENTION.
THE FIRST INTERVENTION IS YOU
COULD BLOCK THE ABILITY OF
CASPASE 8P41 TO BIND TO, THE
OTHER POSSIBILITY IS YOU CAN
CAUSE CASPASE 8P41 LEVELS -- NOW
ENTERING PHASE TWO CLINICAL
TRIALS WITH ATCG.
SHOWN ON THE RIGHT IS RESULTS --
IN THE MIDDLE PANEL YOU SEE IF
YOU TRANSFECT A CELL IN THE
PRESENCE, ROUGHLY 50% OF THE
CELLS DIE.
WHEREAS IF YOU TRANS EFFECT
CELLS WITH GFP CASPASE 8P41 IN
THE PRESENCE, NOW ABOUT 80% OF
THE CELLS DIE.
SO IT AUGMENTS THE ABILITY OF
CASPASE 8P41 TO KILL CELLS.
WE THEN WENT ON AND OUR GROUP
AND OTHER GROUPS HAVE LOOKED AT
THE EFFECT ON CELL KILLING IN A
VARIETY OF MODELS.
THIS IS IN AN ACUTE INFECTION
MODEL, THIS IS IN A HOMEOSTATIC
PROLIFERATION MODEL AND THIS IS
IN AN IN VIVO HUME HUGH HUMANIZE
MODEL.
IN THIS INCIDENCE, VENETOC LAX
INCREASES THE NUMBER OF MICE
WITH UNDETECTABLE RESERVOIR SI
SIZE.
TOMAS IN MIRKO'S LAST WENT ON TO
DO THIS STUDY IN THE LAST
ITERATION OF THE ERASE WHERE WE
DID AN S AN SID STUDY WHERE MICE
TREATED WITH EARLY ART, EARLY
ART PLUS VENETOC LAX OR
CD8 DEPLETION.
THE RATIONALE FOR THE
CD8 DEPLETION WAS MENTIONED BY
DAVE MARGOLIS IN HIS
PRESENTATION IN THAT IT ACTS AS
AN LRA EFFECT.
WHAT WAS SHOWN IN THIS STUDY IS
THE VENATOCLAX ALONE ALTERS THE
DECAY RATE OF VIRAL PLASMA LOAD.
THERE'S A MINIMAL DIFFERENCE
BETWEEN VENATOCLAX PLUS CD8 IN
THAT THERE ARE TWO POSSIBILITIES
AS TO WHY THIS DECAY RATE IS
DIFFERENT.
ONE OF WHICH IS THAT THERE'S
DELAYED ESTABLISHMENT OF THE HIV
RESERVOIR SIZE.
SO THE GROUP WENT ON TO ANALYZE
HIV RESERVOIR SIZE BY IPDA
MEASUREMENT, AND WHAT YOU CAN
SEE IS THAT IPDA MESH MANAGEMENT
RESULTS IN LOWER RESERVOIR SIZE
IN THE VENATOCLAX-TREATED GROUP,
EXPRESSES TOTAL NUMBER OF
COPIES, OR AS EXPRESSED BY PER
ML OF BLOOD.
SO NOW WE'VE SEEN IN A VARIETY
OF MODELS THAT VENATOCLAX HAS A
BENEFICIAL EFFECT, AND BY SHEER
COINCIDENCE, THE GROUP OUT OF
AUSTRALIA WITH SHARON LUEN AND
OTHERS JUST PUBLISHED A PAPER
LOOKING AT THE EFFECT IN CHRONIC
INFECTION ALONG WITH ART IN A
HUMANIZED MODEL WHERE THEY
SHOWED CONCEPTUALLY SIMILAR
EFFECTS, DELAYED VIRAL REBOUND
AS A RESULT OF VENATOCLAX
TREATMENT FOMMINGTREATMENT FOLLL
REBOUND.
WE THEN HAD THE INTEREST OF
LOOKING -- SUGGESTS THAT
FOLLOWING REACTIVATION FROM
LATENCY OF THE CASPASE 8P41
PATHWAY SHOULD BE INVOKED SO WE
WENT ON AND TESTED THAT AND WE
DID, IN FACT, SHOW THAT CASPASE
8P41 IS EXPRESSED IN A LATENT
CELL POPULATION FOLLOWING
REACTIVATION FROM LATENCY, AND
THEN WE WANTED TO TEST
VENATOCLAX IN THAT MODEL.
WE FIRST DID THIS SOME NUMBER OF
YEARS AGO USING BULK PRIMARY
PVMCs OF HIV INFECTED SUBJECTS
AND WE WERE ABLE TO SHOW IN THE
MAJORITY OF PATIENTS RESERVOIR
SIDE WAS INDUCED.
BRAD AND HIS TEAM DID A SIMILAR
STUDY USING CD4s WITH AND
WITHOUT CTLs AND SHOWED THAT
WITH CTLs AND VENATOCLAX,
RESERVOIR SEI SIZE IS REDUCED.
AND TRAIL MEDIATED PATHWAYS.
SO VENETOCLAX HAS BEEN USED
EXTENSIVELY IN HEMATOLOGIC
MALIGNANCIES, MOST NOTABLY CLL.
THERE ARE PATIENTS WHO HAVE BEEN
TREATED FOR 8-PLUS YEARS AND
THEY DO WONDERFULLY WITH IT AND
IN THE MAJORITY OF CASES, IT
WORKS.
BUT IN THE MINORITY OF CASES, IT
DOES NOT WORK, AND SO A LOT OF
INTEREST HAS GONE INTO WHY
DOESN'T IT WORK, AND WHAT WE
KNOW IS THAT THERE CAN BE
SOMATIC MUTATION THAT CAUSES
MUTATIONS WITHIN BCL2 BUT ALSO
THERE CAN BE PHOSPHORYLATION
EVENTS WITHIN BCL2.
IF YOU LOOK AT IT
MECHANISTICALLY, THIS IS A
RIBBON STRUCK TOOR OF CASPASE
8P41 BINDING TO BCL2, THIS IS
VENETOCLAX BINDING TO BCL2 AND
THEY BIND TO THE SAME REGION.
SO WE -- DOES THAT ALTER THE
ABILITY OF VENETOCLAX TO WORK
AND DOES IT ALTER THE ABILITY OF
CASP8P41 TO WORK?
WE TOOK -- WITH CELLS THAT
EXPRESS PHOSPHOMIMICS OF BCL2,
SO WHEN YOU DO A SERINE THAT
MIMICS PHOSPHORYLATION EVENT, IF
YOU DO A SERINE E2 THAT CREATES
A PHOSPHORESISTANT FORM.
SO SHOWN HERE IS A KNOCKOUT IS
MISSING BCL-2.
THESE ARE ALL THE OTHER
PHOSPHORYLATION EVENTS.
CAN YOU SEE A SLIGHT SHIFT
UPWARD CONSISTENT WITH THE
PHOSPHORYLATION EVENT AND WE
ASKED WHAT EFFECT DOES THIS HAVE
ON THE NUMBER OF INFECTED CELLS,
IN THIS CASE MEASURED BY THE
NUMBER OF GREEN CELLS.
NORMALLY WHEN YOU INFECT A
JURKAT CELL YOU GET A CERTAIN
EFFECT OF VENETOCLAX.
HERE IF YOU USE THE S70A
MUTATION, YOU CAN SEE THAT THE
EFFECT OF VENETOCLAX IS GROSSLY
REDUCED.
SO THIS CAUSES RESISTANCE TO
VENETOCLAX IN THE HIV MODEL.
WE'VE ALSO LOOKED AT DOES IT
ALTER THE BINDING TO BCL2?
WHAT WE CAN SEE IS THAT HERE
WE'VE MADE A PHOSPHORYLATED BCLE
ACTIVITIES.
WE'VE SHOWN THAT IT'S
PHOSPHORYLATED ON SERINE 70, AND
WHAT WE SHOW IS THAT CASPASE
8P41 BINDING TO PHOSPHORYLATED
BCL2 IS MUCH MORE AVID AND MUCH
HIGHER THAN BINDING TO WILD TYPE
BCL2.
SO WE'VE GONE ON AND LOOKED AT
THE EFFECT OF DIFFERENT
BCL2 PHOSPHOFORMS ON HIV INDUCED
KILLING VERSUS VENETOCLAX
EFFECT.
WE HAVEN'T COMPLETED ALL THIS
WORK, IT'S A LOT OF WORK, A LOT
OF CELL LINES, BUT S70A CAUSES
AN INCREASED NUMBER OF INFECTED
CELLS, WHEREAS T69E CAUSES
REDUCED NUMBER OF INFECTED CELLS
AND THE DIFFERENCE IS QUITE
DRAMATIC.
AND AS MENTIONED, HERE'S THE
BCL2 WILD TYPE EFFECT.
THE S70A REDUCES THAT EFFECT BUT
INTERESTINGLY, THE T69A MUTATION
INCREASES THAT EFFECT.
SO WE THINK THIS IS AN IMPORTANT
AVENUE TO PURSUE.
WE'VE SHOWN -- WE AND OTHERS
HAVE SHOWN THAT VENETOCLAX IS
EFFECTIVE IN A VARIETY OF
DIFFERENT MODELS AND SHORT OF A
CLINICAL TRIAL, I THINK WE HAVE
PRETTY ROBUST DATA VENETOCLAX
HAS AN EFFECT.
WE'RE LOOKING INTO WHERE BCL2 IS
PHOSPHORYLATED IN VITRO.
PART OF THIS IS LIMITED BY THE
AVAILABILITY OF PHOSPHO-SPECIFIC
ANTIBODIES, SO THIS HAS TO BE
DONE WITH A MASS SPEC APPROACH,
SO IF PEOPLE HAVE MASS SPEC
CAPABILITIES, WE'D LOVE TO
PARTNER WITH YOU.
WE'RE LOOKING AT THE EFFECT OF
DIFFERENT PHOSPHO FORMS ON
KILLING AND RESERVOIR EFFECT,
AND WE PLAN TO GO ON AND LOOK AT
THE BINDING BY CASPASE 8P41 TO
THE DIFFERENT PHOSPHOSM FORMS.
PHOSPHO FORMS.
WE WANT TO FIND OUT WHICH
KINASES ARE RESPONSIBLE FOR
THESE EVENTS AND HOW CAN WE
INHIBIT THEM.
PHOSPHATASES TO NEGATE THE
EFFECTS AND OF COURSE WE'RE
INTERESTED IN PURSUING OUR WORK
WITH VENETOCLAX WITH DIFFERENT
LATENCY REVERSAL AGENTS.
SO WITH THAT, WE'LL MOVE IT ON
TO OUR NEXT SPEAKER.
[APPLAUSE]
>> THANK YOU.
OUR LAST SPEAKER IS PRITI WITH
OUR WORK FROM THE COMMUNITY.
>> HI, EVERYONE.
I'M THE COMMUNITY ENGAGEMENT
COORDINATOR FORRESTER LOVE.
WHO IS THE COMMUNITY PARTNER FOR
ERASE HIV.
JUST A BRIEF OVERVIEW OF WHO WE
ARE.
OUR MISSION IS TO ERADICATE THE
ADVERSE IMPACTS OF HIV AND
SEXUAL AND REPRODUCTIVE HEALTH
INJUSTICE CHALLENGES THAT IMPACT
WOMEN AND THEIR FAMILIES THROUGH
A MULTIPRONGED APPROACH OF
EDUCATION, PREVENTION, SUPPORT,
RESEARCH AND ADVOCACY, AND WE DO
THIS BOTH LOCALLY IN ATLANTA, AS
WELL AS GLOBALLY.
SO THESE ARE SOME OF OUR TEAM
MEMBERS, OUR P.I., OUR RESEARCH
PROGRAM MANAGER AND MYSELF, THE
COMMUNITY ENGAGEMENT
COORDINATOR.
SOME YEAR TWO MILESTONES FOR US
WERE WE HELD INSTAGRAM LIVE
SESSIONS WHERE WE DISCUSSED
TOPICS SURROUNDING HIV CURE AND
PREVENTION AND WE TITLED THESE
CURE CONVERSATIONS.
WE DEVELOPED A COMMUNITY SURVEY
TO GAUGE THE COMMUNITY'S
KNOWLEDGE SURROUNDING HIV CURE.
SISTER LOVE ACTUALLY LAUNCHED A
MOBILE TESTING UNIT AS WELL ON
WORLD AIDS DAY CALLED THE
HEALTHY LOVE BUS THAT OFFERS
FREE HIV TESTING AROUND ATLANTA.
WE HELD OUR ANNUAL COMMUNITY
CURE COOKOUT EVENT WHERE WE
FOSTERED ENGAGEMENT BETWEEN OUR
RESEARCHERS AND OUR COMMUNITY.
WE HELD AB EVENT TITLED STAGES
TO HIGHLIGHT COMMUNITY STORIES
THROUGH ART MEDIUMS.
THIS WAS HELD IN NOVEMBER WITH A
SPECIFIC FOCUS ON VISUAL ART,
WHERE WE IT THREE ARTISTS SHARE
THEIR STORIES ABOUT REPRODUCTIVE
JUSTICE.
FINALLY WE PARTICIPATED IN EMORY
UNIVERSITY'S ART EVENT WHERE WE
TABLED SHARED INFORMATION ABOUT
ERASE HIV AS WELL AS WAYS TO GET
INVOLVED.
WITH HIRED A NEW COMMUNITY-BASED
RESEARCH MANAGER.
WE HELD A COMMUNITY CURE
COOKOUT.
THIS WAS HOSTED AT THE
MOTHERHOUSE, WHICH IS THE HOUSE
WE ALL WORK OUT OF AND THERE'S A
LOT OF HISTORY ATTACHED TO IT SO
WE WERE ABLE TO OFFER TOURS OF
THAT AS WELL.
WE HIRED THE NEW CEC, MYSELF,
AND JOINED ERASE HIV'S TEAM FOR
THE ATLANTA AIDS WALK.
AND FINALLY COLLABORATED WITH
RID HIV AND THE HIV AGING AND
RESEARCH PROJECT PALM SPRINGS
FOR THEIR CURE RESEARCH EVENT
HAPPENING IN ATLANTA NEXT WEEK.
THESE ARE SOME PICTURES FROM OUR
COMMUNITY CURE COOKOUT IN JUNE.
AND HERE ARE SOME PICTURES LAST
MONTH FROM THE AIDS WALK.
IN ATLANTA.
AND AS FAR AS OUR PLAN GOING
FORWARD, WE PLAN TO WORK ON
REVISING OUR MISSION STATEMENT
AS WELL AS THE RESPONSIBILITIES.
WE HELP TO FOSTER COLLABORATION
AND ENGAGEMENT BETWEEN OUR
RESEARCHERS AND OUR COMMUNITIES
AS WELL AS COORDINATE OUR NEXT
COMMUNITY CURE COOKOUT EVENT.
THANK YOU.
[APPLAUSE]
>> ANY QUESTIONS?
I'M JUST LOOKING ONLINE IF THERE
ARE ANY QUESTIONS.
>> SO BRAD, I HAVE ONE FOR YOU
AND ONE FOR YOU, ANDREW.
SO ECH2 IS -- COMPLEX THAT YOU
MENTIONED, AND PR C 2 IS VERY
MUCH INVOLVED IN REDUCING HIV
LATENCY.
SO IN YOUR EXPERIMENTS, CAN
YOU -- THE EFFECT YOU'RE SEEING
IS NOT ONLY DONE ON
MHC1 EXPRESSION BUT ALSO ON HIV
ACTIVATION?
>> YEAH, SO THANK YOU FOR THE
QUESTION.
I THINK THAT THE EFFECT WE'VE
SEEN SO FAR, WE CAN RULE OUT
THAT IT'S BEING IMPACTED BY
LATENCY REVERSAL BECAUSE WE'RE
JUST DOG DOING A VERY SHORT
OVERNIGHT KILLING -- BUT TO YOUR
POINT I THINK WHAT WE SHOULD DO
IS ASK THE QUESTION IF WE'RE
TARGETING EVEN MORE INFECTED
CELLS THAT WOULD HAVE BEEN
LATENT BECAUSE WE'RE ALSO
REVERSING LATENCY AT THE SAME
TIME WE'RE DRIVING
MHC1 UPREGULATION.
SO I THINK THE LATENCY -- IS
REALLY AN IMPORTANT COMPONENT.
WE'VE REALLY FOCUSED ON THE CTL
RESISTANCE ASPECT, BUT WE SHOULD
LOOK IN THAT DIRECTION AS WELL.
>> TO GET BACK TO THE STUDY THAT
MIRKO PRESENTED, OUR JOINT WORK
IS, IL10 BOOSTS -- EHC
INHIBITORS DOWNSTREAM OF IL10 TO
TRY TO SYNERGIZE THE EFFECT OF
ANTIIL10 -- INHIBITORS, SO I'M
NOT INTERESTED IN CD8 T-CELLS, I
WORK MOSTLY ON CD4s, SO --
MIGHT WANT TO DO TOGETHER.
>> INTERESTING.
THANK YOU.
>> SO FOR ANDREW, SO TO ME, IT'S
VERY OBVIOUS THAT ONE OF THE
KINASES THAT ARE INVOLVED IN
BCL2 MIGHT BE -- KINASE.
YOU KNOW THERE'S -- KINASE
INHIBITORS IN CLINICAL TRIALS,
HAVE YOU LOOKED AT THOSE?
IT'S VERY OBVIOUS TO ME.
>> YEAH, SO GREAT QUESTION.
SO THERE'S A NUMBER OF KINASES
REPORTED PHOSPHORYLATE BCL2 OF
WHICH KINASES ARE ABSOLUTELY
ONE.
YES, WE'RE LOOKING AT THOSE.
PART OF IT HAS TO DO WITH THE
CUMULATIVE TOXICITY, WITH IS OUR
CONCERN, SO WE'RE TRYING TO WORK
THROUGH THAT FIRST, BUT I THINK
IT'S AN OBVIOUS STRATEGY TO USE
SELECTED KINASE INHIBITORS AT
THE RIGHT DOSE, PLUS
BCL2 ANTAGONISTS.
>> THE COMPLEXITY OF THE --
KINASE INHIBITOR, IT CAN DOWN
REGULATE STAT5 EXPRESSION SO THE
PROMOTION OF BCL2 EXPRESSION BUT
OF COURSE IT WILL HAVE AN
EFFECT -- THAT THE KINASE -- THE
KINASE ACTIVITY.
>> AGREE.
>> HI THERE.
-- FROM WESTERN UNIVERSITY.
I HAVE A QUESTION ABOUT THE PD-1
WILL ANTAGONISM EXPERIMENTS IN
THE RHESUS MACAQUE.
I'M WONDERING, WE SAW ALSO
SIMILAR CORRELATIONS BETWEEN
PD-1 EXPRESSION AND RESERVOIR
SIZE MEASURED BY THE -- IN OUR
COHORT IN UGANDA.
BUT WHEN WE STRATIFIED BY SEX,
WE DIDN'T SEE THAT CORRELATION
AMONG FEMALES.
IT WAS VERY STRONG IN OUR MALE
PARTICIPANTS AND NOTHING IN THE
FEMALES.
I'M WONDERING, DO YOU HAVE BOTH
FEMALE AND MALE ANIMALS IN YOUR
STUDY AND HAVE YOU DISAGGREGATED
BY SEX?
>> THANK YOU FOR THAT QUESTION.
WE HAVE BOTH, THE NUMBER ARE LOW
BECAUSE WE HAVE 10 ANIMALS FOR
EACH EXPERIMENT SO IT DIFFICULT
TO MAKE A CONCLUSION.
IN TERMS OF THE IMPACT OF THE
INTERVENTION WAS AGAIN -- DURING
THE ANTIBODY PHASE IN 90% OF THE
ANIMAL SO BOTH FEMALE AND MALE
BUT AGAIN, THE NUMBER ARE LOWER.
AND IN TERMS OF THE SIZE OF THE
RESERVOIR, AS I SAID THERE WAS
NO EXPANSION, SO REMAIN STABLE,
BUT OVERALL IN THE NUMBER OF --
THERE WAS NO REDUCTION.
THERE IS A SUBSET OF ANIMALS IN
WHICH THERE WAS A SIGNIFICANT
REDUCTION AND -- WE'RE WORKING
ON UNDERSTANDING THE MECHANISM,
BUT OVERALL IT WAS SIMILAR
BETWEEN MALE AND FEMALE BUT
AGAIN WITH VERY LOW NUMBERS IT'S
DIFFICULT TO CONCLUDE.
>> THANKS.
>> HI.
COULD YOU GO INTO A BIT MORE
DETAIL ABOUT THE ACTUAL CELLULAR
CHANGES THAT THE ANTIIL10 AND
PD-1 INCURRED IN THE MONKEYS?
WAS THERE DECREASES IN T REG
CELLS, INCREASED ACTUAL
FUNCTIONALITY OF CD8s, AND WAS
THAT TEMPORARILY RELATED TO THE
HALF-LIFE OF THE ANTIBODY IN THE
MONKEYS?
AND DID IT GO BACK TO NORM
AFTER?
>> SO I DIDN'T HAVE TIME TO
PRESENT THAT AND AGAIN THAT'S
WORK IN COLLABORATION WITH
RAFICK AND SUSAN.
I MAKE A SHORT RESPONSE OF A
LONG -- SO THERE IS MULTIPLE
MECHANISMS THAT WE ARE SEEING,
SO ONE IS IMPROVING THE CD4 --.
THERE IS EVEN -- BUT INNATE INMU
KNOW RESPONSE WE ARE PROPOSING
TO TARGET -- COLLABORATORY.
AND THERE IS A BETTER C
CD8 RESPONSE.
AND INTERESTINGLY, YOU HAVE
EFFECT RIGHT AWAY SO THIS SEEMS
TO BE PRO -- TOO EARLY, BUT WE
TRY TO -- SINCE -- CD8 EFFECTOR
CELLS THAT ARE ACTUALLY ALREADY
PRONE AND ABLE TO RECENT THE
REBOUNDING VIRUS.
AND INTERESTINGLY IF YOU LOOK
LATER ON, WITH THE -- VIRAL LOAD
IS VERY DIFFERENT BUT THE
CD8 REMAIN MORE STEM CELL LIKE,
FOR EXAMPLE THE LEVEL OF --
1 AND THAT IS ASSOCIATED WITH
THE LOWER VIRAL LOAD AND THERE'S
MECHANISM POTENTIAL T REG AS
IL10.
>> SO NO LIFT.
>> -- CD4 T-CELLS --
INTERRUPTIONS STILL ON ART WAS
LOWER WHEN YOU BROUGHT I LI. 10
AND CONSISTENT WITH -- BLC2.
>> I WANTED TO THANK YOU ALL FOR
HAVING THAT COMMUNITY SUMMARY
SLIDE THAT PUTS THINGS INTO
CONTEXT FOR US WITH SIMPLE
QUESTIONS, SIMPLE ANSWERS AND
THEN PUTTING IT INTO THE CONTEXT
HOW IT RELATES TO CURE FOR US.
ONE THING THAT I WANTED TO GIVE
AS A NOTE, THIS IS FOR EVERYBODY
IN THE ROOM, IS THAT SOMETIMES
PEOPLE THINK THAT THE USE OF
COMMUNITY IS BELITTLING SAYING
THAT THE COMMUNITY IS STUPID,
CAN'T UNDERSTAND THE SCIENCE AS
WELL, NEED SPECIAL HELP.
SO CALLING IT A PLAIN LANGUAGE
SUMMARY SLIDE IS A WAY AROUND
THAT SO YOU DON'T
UNINTENTIONALLY STIGMATIZE
ANYONE FOR NEEDING SOME HELP
BECAUSE IT IS OUR JOB AS SCIENCE
EXEUN KAY TORES TO COMMUNICATE
EFFECTIVELY SO THAT'S WHAT IT'S
FOR.
BUT I WANT TO THANK YOU ALL FOR
HAVING THEM BECAUSE IT REALLY
HELPS WITH THE HIRE GLISKS AND
THE THROAT SINGING THAT
SOMETIMES SCIENCE SOUNDS LIKE TO
ME SO THANK YOU VERY MUCH.
[APPLAUSE]
>> QUESTION FOR BRAD.
BRAD, WHAT ARE YOUR THOUGHTS
ABOUT THE DECREASE OF -- CLASS M
MORE SENSITIVE FOR NK KILLING?
BECAUSE YOU DON'T HAVE ANY NKs
ON YOUR SYSTEM, SO HOW DO YOU
BALANCE THAT RELATIONSHIP
BETWEEN GOING TOWARDS NK
SUSCEPTIBILITY FOR KILLING
VERSUS THE CD8 INCREASING WITH
THE DRUG?
>> IT'S A GREAT QUESTION.
WE THOUGHT THE SAME THING, THAT
IT WOULD BE A TRADEOFF, THEN WE
WERE PLEASANT RI SURPRISED WHEN
WE DID NK CELL KILLING ASSAYS
AND FOUND THAT TAZEMETOSTAT
ACTUALLY SENSITIZES THE CELLS TO
BETTER NK CELL KILLING.
WE'RE NOT -- WE HAVEN'T
PINPOINTED THE MECHANISM YET BUT
THERE IS UPREGULATION OF SOME
STRESS LIGANDS AS WELL ON
EZH2 TREATMENT AND ALSO BASED ON
PROTEOMICS, IT LOOKS LIKE THREAR
UPREGULATION OF ICAM1 WHICH
HELPS WITH ADHESION OF THE NK
CELLS TO THE TARGET CELLS, SO IT
LOOKS LIKE THAT'S NOT ACTUALLY
THE TRADEOFF THAT WE THOUGHT.
WE ENHANCE NK CELL KILLING AND
CD8 KILLING AT LEAST IN VITRO.
>> I HAVE A QUESTION FOR THE CD
MODEL.
IT'S VERY GOOD TO -- REBOUND, SO
AT THAT TIME DO YOU THINK THE
ANTIBODY OR SMALL MOLECULE PK
ISSUE OR HOW TO EXPLAIN THIS
PHENOMENON?
>> SO THE TREATMENT WAS
PERFORMED ONLY FOR ONE WEEK
DURING ART SUPPRESSION AND
FALLING UPON VIRAL REBOUND.
SO OBVIOUSLY THE MIMETIC AND THE
ANTIBODY DON'T STICK AROUND THAT
LONG, SO WE ARE HOPING OUR -- WE
HAVE TO DO EXPERIMENTS WHERE WE
CAN GIVE IT FOR A LONGER PERIOD
OF TIME AND THEN SEE IF IT WOULD
FURTHER DELAY.
THIS WAS ONLY AFTER A VERY, VERY
SHORT EXPOSURE TO THE COMPOUND.
IT WAS JUST DURING A PERIOD OF
ONE WEEK.
>> JUST A QUICK QUESTION FOR DRO
CONTROL VIE REAM NA TO 15
COPIES.
I WAS WONDERING WHAT WAS SPECIAL
ABOUT THAT MONKEY AS COMPARED TO
OTHERS.
>> SO WE HAVE TWO OF THOSE
ANIMALS WE SACRIFICE ONE YEAR
AFTER INTERRUPTION, THEY WERE
STILL UNDETECTABLE.
SO AS I SAID BEFORE IF YOU LOOK
ALL THE GROUP, THERE IS NO
REDUCTION -- A CONTROL OF
REBOUNDING VIRUS.
BUT AS WAS MENTIONED, THERE ARE
FOUR OF THE 10 ANIMALS WHICH IS
ACTUALLY A SIGNIFICANT
REDUCTION -- AND THOSE TWO
ANIMAL ARE TWO OF THOSE FOUR IN
WHICH THE TREATMENT WAS
ASSOCIATED WITH REDUCTION OF
THE -- RESERVOIR AND THEN BETTER
CONTROL OF THE REBOUND.
THAT IS THE MAIN ASSOCIATION,
THERE'S BEEN A LOT OF WORK
ONGOING ON THAT -- AND OTHER
MECHANISMS.
ONE THING I FORGOT TO MENTION IS
THAT SINCE THE INTERVENTION
STARTED TO LATE, WE INFECTED THE
ANIMAL, KEEP THEM ALIVE FOR MORE
THAN ONE YEAR, WE WERE ABLE TO
STRATIFY THE ANIMAL TO BE -- SO
WE COMPARED THE ANIMAL TO BE NOT
ONLY ON THE SAME -- HAVING THE
SAME VIRAL LOAD BEFORE STARTING
ANTIRETROVIRAL THERAPY BUT HOW
QUICKLY THEY BECAME UNDETECTABLE
AND MAIN OT MANY OTHER PARAMETE.
THE -- POSITIVE OR NOT, ET
CETERA.
SO THOSE ARE NOT PARAMETERS THAT
ARE IMPORTANT FOR THE CONTROL.
OKAY, THANK YOU.
[APPLAUSE]
THANKS A LOT.
SO I THINK WE WILL GET
STARTED.
I AM LEIA NOVACK, A PROGRAM
OFFICER IN THE PATHOGENESIS AND
BASIC RESEARCH BRANCH IN THE
BASIC SCIENCES PROGRAM IN THE
DIVISION OF AIDS AT NIAID.
I AM HAPPY TO PRESENT OUR NEXT
SET OF COLLABORATORY, THE HOPE
COLLABORATORY BASED AT THE
GLADSTONE INSTITUTES.
EXOWP HOPE IS AN ACRONYM FOR HIV
OBSTRUCTION BY PROGRAMMED
EPIGENETICS LED BY THREE
PRINCIPAL INVESTIGATORS.
MELANIE OTT AT GLADSTONE, LISH
LOVU AND SUSANA VALENTE.
I'LL HAND IT OVER TO MELANIE TO
GET STARTED ON THE OVERVIEW.
>> THANK YOU, LE.
IA.
THANK YOU VERY MUCH.
WELCOME TO HOPE.
AS LEIA SAID, I'M MELANIE OTT,
TOGETHER WITH MY CO-PIs, WE
CO-LEAD THE HOPE COLLABORATORY.
HOPE TOGETHER HAS 20 PIs,
ABOUT 150 MEMBERS AND IS LOCATED
IN SIX COUNTRIES, INCLUDING
BRAZIL, UGANDA, THAILAND AND
GERMANY.
THE PROGRAM IS BASED ON A BLOCK,
LOCK AND STOP AGENDA, BLOCK
MEANS INHIBITING HIV
TRANSCRIPTION, LOCK MEANS
KEEPING THE VIRUS BLOCKED
WITHOUT THERAPY, AND STOP MEANS
INACTIVATING PRO VIRAL DNA IN
THE GENOME.
TOGETHER WE'RE USING BOTH
CHEMICAL AND GENE THERAPY
APPROACHES TO PERMANENTLY
INACTIVATE HIV.
WE ARE ALSO A NEW COLLABORATORY
IN OUR THIRD YEAR, AND JUST IN
THE LAST YEAR -- SORRY, I WANTED
TO SAY THAT WE THINK THAT THIS
BLOCK, LOCK AND STOP AGENDA IS
VERY RELEVANT BASED ON OUR NEW
KNOWLEDGE THAT TRANSCRIPTIONALLY
ACTIVE CELLS PERSIST DESPITE ART
AND THIS IS DONE IN MANY PAPERS
AND MANY OF THE AUTHORS ARE HERE
IN THE AUDIENCE.
THIS REALLY IN THE LAST TWO
YEARS HAS SHOWN WE HAVE A
GLARING LOOPHOLE IN OUR ART
REGIMEN CURRENTLY BECAUSE WE ARE
NOT INCLUDING ANY DRUGS
TARGETING TRANSCRIPTION.
AND I THINK THIS ALLOWS THESE
TRANSCRIPTIONALLY ACTIVE CELLS
TO PERSIST AND TO PROLIFERATE,
AND WE ARE POISED TO AND ARE
AIMING TO CLOSE THIS LOOPHOLE.
TRANSCRIPTION -- HIV
TRANSCRIPTION IS REALLY BASED ON
THREE FACTORS.
THE VIRALLY ENCODED -- PROTEIN,
THE TAR STEM LOOP RNA, AND THE
HOST SUPER ELONGATION COMPLEX
ALSO CALLED SEC, THAT TOGETHER
REALLY ALLOW THE PRO L POLYMERA-
WE HAD HOPED WE'RE TARGETING
BOTH THE VIRUS AND THE HOST.
WITH A PIPELINE OF MODALITIES
THAT RANGE FROM FDA-APPROVED
DRUGS LIKE SPEAR K SPIRONOLACTO,
CDK-9, BUT WE ALSO HAVE
DEVELOPED SEVERAL MODALITIES
THAT ARE CRISPR BASED, THAT ARE
TARGETING EITHER CORECEPTORS OR
THE SUPERELONGATION COMPLEX.
TARGETING THE VI VIRUS, WE HAVEA
LONG-STANDING EFFORT IN
DEVELOPING TAT INHIBITORS BASED
ON SUSANA'S EFFORTS THAT REALLY
RANGE FROM CONTINUOUS SCREENING
THAT WE'RE CURRENTLY DOING TO
PRE-CLINICAL TRIALS IN HUMANIZED
MICE AND NHPs.
AGAIN, WE'RE USING BASE EDITING
CRISPR-BASED BASE EDITING TO
TARGET SEQUENCES IN HIV TO
INACTIVATE HIV, AND WE'RE ALSO
WORKING WITH A RECOMBINATION
CALLED BREC1 THAT DOESN'T
REQUIRE ANY GUIDE RNA AND
DIRECTLY IS TRAINED TO RECOGNIZE
THE HIV PRO VIRUS, EITHER AS
A -- OF THE ACTIVE FORM FOR
EXCISION OR AS A CATALYTICALLY
INACTIVE FORM FOR TARGETING.
AS I SAID WE'RE A NEW
COLLABORATORY, IN OUR THIRD
YEAR, BUT WE HAVE BEEN QUITE
PRODUCTIVE JUST IN THE LAST
YEAR, WE HAD ABOUT
21 PUBLICATIONS.
AN INTERESTING STUDY IN NATURE
THAT REALLY TOLD US A LOT MORE
ABOUT THE BIOPHYSICS OF THE TAR
ELEMENT THAT WE'RE USING, BUT
ALSO A VERY INTERESTING STUDY
USING CHROMATIN AFFINITY
PURIFICATION AND MASS
SPECTROMETRY TO REALLY IDENTIFY
NEW FACTORS AT THE HIV PROMOTER
THAT IS RELEVANT FOR LATENCY OR
ACTIVATION.
IN 2023, WE HAVE LEARNED FROM
ENDOGENOUS RETROVIRUSES ABOUT
HIV SILENCING WITH NEW
COMPUTATIONAL MOLECULES AT BULK
AND SINGLE CELL RESOLUTION.
WE HAVE BLOCKED HIV
TRANSCRIPTION WITH
SPIRONOLACTONE ALONE OR IN
COMBINATION WITH HUMAN ICED
MIETION, NHPs AND IN PEOPLE.
THIS WILL BE PRESENTED BY SUSANA
VALENTE FOR RF2.
WE HAVE RENDERED HUMAN CELLS
RESISTANT TO HIV TRANSCRIPTION
THROUGH PRIME EDITING OF THE
CYCLIN T1 GENE, AND WE HAVE
REACHED MORE THAN EIGHT'
THOUSAND PEOPLE IN COMMUNITY
EVENTS IN THE U.S., CANADA,
UGANDA AND BRAZIL AND ON SOCIAL
MEDIA, AND THIS WILL SH
PRESENTED BY PATRICIA
DEFECHEREUX FOR THE COMMUNITY
ENGAGEMENT.
WE HAVE BROUGHT SIX YOUNG, VERY
TALENTED YOUNG INVESTIGATORS
FROM HOPE TO THIS MEETING, AND I
HOPE YOU WILL ALL MEET THEM AT
THE POSTER SESSION.
WE ALSO JUST HAD OUR SECOND
ANNUAL MEETING AT THE BUC
INSTITUTE IN MARIN.
WE HAD VERY SPECIAL GUESTS IN
THE AUDIENCE.
WE HAD THE VERY SPECIAL GUESTS
JOINING US.
ONE IS PAUL EDMONDS AND I KNOW
THAT HE'S HERE IN THE AUDIENCE,
AND THE OTHER ONE WAS MARK, BOTH
CURED FROM HIV AND IT WAS VERY
INSPIRING TO HAVE THEM WITH US.
APART FROM GREAT SCIENCE, WE
ALSO DID A COMMUNITY ARTS
INTEGRATED RESEARCH EVENT WHERE
WE ACTUALLY DANCED THE BLOCK,
LOCK AND STOP AGENDA.
PRITI AND I ARE COORGANIZING A
KEYSTONE MEETING NEXT APRIL IN
HANOVER, AND WE HOPE THAT WE SEE
A LOT OF YOU THERE.
WE HAVE A GREAT WEBSITE IF YOU
WANT TO LEARN MORE ABOUT OUR
RESEARCH OR FOLLOW US ON X, AND
WITHOUT FURTHER ADO, I THANK YOU
FOR YOUR ATTENTION.
THE NIH FOR THEIR SUPPORT, AND I
HAND OVER TO DOUG FOR RF1.
[APPLAUSE]
>> THANKS, MELANIE.
MY NAME IS DOUGLAS NIXON.
I AM GOING TO GIVE THE OVERVIEW
FOR RF1.
AND THIS YEAR WE'RE GOING TO
FOCUS IN ON ONE OF THE ELEMENTS
OF RF1, AND IT'S ABOUT
HARNESSING HUMAN ENDOGENOUS
RETROVIRUSES AND KRAB ZINC
FINGER PROTEINS TO LOCK HIV.
SO
YOU'VE ALREADY HEARD FROM
MELANIE ABOUT THE OVERARCHING
GOALS OF THE HOPE SCIENTIFIC
PROGRAM TO BLOCK, LOCK AND STOP
VIRUS.
AND FOR THE PRESENTATION TODAY,
WE'RE GOING TO BE FOCUSED ON THE
LOCK COMPONENT.
RF1 HAS SOME GREAT MEMBERS,
CO-DIRECTORS WITH SUSANA VALENTE
WHO IS PRESENTING FOR RF2, AND I
THINK ONE OF THE STRENGTHS OF
HOPE IS THE WAY THAT THE RFs
INTERACT WITH EACH OTHER AND
SHARE MEMBERS.
THIS IS THE BASIC SCIENCE
COMPONENT, THE HYPOTHESIS THAT
HIV TRANSCRIPTION AND STRUCTURE
OF UNIQUE TARGETS FOR SILENCING.
WE HAVE FOUR GOALS.
FIRST TO IDENTIFY HOST REGULA
REGULATORS, HOW WE POTENTIALLY
COULD SILENCE HIV, TO DEFINE THE
ROLE OF TAT IN HIV SILENCING AND
TO USE ADVANCED OMIC TECHNIQUES
TO CHARACTERIZE HOW SILENCING
CAN OCCUR.
THERE HAS BEEN PUBLICATIONS IN
ALL OF THESE AREAS WI BUT WE HAE
CHOSEN TO FOCUS ON ONE STORY
TODAY FROM GOAL TWO.
FOR THE PLAIN LANGUAGE SLIDE,
WHAT'S THE KEY QUESTION?
ANCIENT VIRUSES WITHIN
EVERYONE'S DNA IN THIS ROOM THAT
HAVE BEEN NATURALLY CONTROLLED.
WE ALSO HAVE THIS ARMY OF KRAB
ZINC FINGER PROTEINS, WHICH
REPRESS ENDOGENOUS RETROVIRUS,
SO THE QUESTION WE WANT TO KNOW
IS, CAN WE LEARN FROM THESE
ELEMENTS HOW TO POTENTIALLY
CONTROL THE HIV VIRUSES THAT ARE
INFECTING HUMAN CELLS.
KEY TALK HOME MESSAGE, IMMUNE
CELLS INFECTED WITH HIV APPEAR
TO HAVE IMMUNE MECHANISMS
REGULATING THE ACTIVITY OF
HERVs, AND IMMUNE CELLS U.S.
SEPTEMBER IBLG TO INFECTION BY
HIV ALREADY KNOW HOW TO CONTROL
THESE VIRUS.
EXCITINGLY SOME KRAB ZINC FINGER
PROTEINS CAN DIRECTLY REPRESS
HIV.
SO WE MIGHT BE ABLE TO USE THESE
SAME CELLULAR MECHANISMS THAT
CONTROL OUR NATURAL ENDOGENOUS
RETROVIRUSES TO CONTROL HIV PRO
VIRUSES AND WHY SHOULD WE BE
EXCITED IN WOULDN'T IT BE COOL
IF THE WAY OUR CELLS DEFEATED
THESE ANCIENT VIRUSES COULD LEAD
TO A NOVEL WAY TO GET RID OF
HIV.
ONE OF THE SHOCKS WHEN THE HUMAN
GENOME WAS SEQUENCED WAS HOW
SMALL A FRACTION OF THIS PIZZA
PIE IS FOR CODING GENES, AND A
LARGE COMPONENT OF THE GENOME
HAS TRANSPOSABLE ELEMENTS, OF
WHICH A LARGE COMPONENT ARE
RETRO ELEMENTS.
WE'RE GOING TO FOCUS ON THE 8%
OF THE GENOME, ALL OF OUR
GENOMES THAT ARE HUMAN
ENDOGENOUS RETROVIRUSES, THESE
REPRESENT PAST INFECTIOUS RETRO
VIE RETROVIRUSES WHICH INFECTED
GERMLINE CELLS AND HAVE GOT
PASSED FROM PARENT TO OFFSPRING
OVER TIME AND HAVE BECOME
FIXATED, OFTEN DELETED, OFTEN
MUTATED, AND NOW WE HAVE ABOUT
400,000 OF THESE FRAGMENTS IN
OUR GENOME, SCATTERED THROUGHOUT
THE CHROMOSOMAL MAP, OF WHICH
3,000 ARE STILL FULL LENGTH PRO
VIRUSES.
THERE ARE HUNDREDS OF FAMILIES,
EACH A DISTINCT RETROVIRUS.
WE KNOW THAT THERE'S SENSITIVE
MARKERS OF CELL TYPES AND CELL
STATES, AND THEY'RE REALLY
TIGHTLY REGULATED.
NICK IN MY LAB PRODUCED THIS
SIMPLIFIED DIAGRAM TO SHARE THE
MANY TRANSCRIPTIONAL WAYS THAT
HERVS ARE NORMALLY REPRESSED,
BOTH PRE AND POST
TRANSCRIPTIONALLY, AND TODAY I'M
GOING TO TALK ABOUT WORK FROM
CEDRIC'S LAB FOR KRAB ZINC
FINGER PROTEINS WHICH HAVE
CO-EVOLVES TO SILENCE HUMAN
ENDOGENOUS RETROVIRUSES.
WE THINK THAT'S ONE OF THE MAJOR
ROLES OF THESE KRAB ZINC FINGER
PROTEINS.
THERE'S AROUND 400 OF THEM IN
THE HUMAN GENOME.
MOST BIND SPECIFIC HERV
FAMILIES.
AND THEY'RE HIGHLY REGULATED IN
HUMAN DEVELOPMENT, BUT THEY
HAVEN'T BEEN REALLY WELL STUDIED
IN IMMUNITY AND INFECTION,
ALTHOUGH THERE'S SOME POSTERS,
FOR EXAMPLE, FR THAT I WOULD
ENCOURAGE YOU TO LOOK AT WHICH
ALSO GO INTO KRAB ZINC FINGER
PROTEIN.
WHAT DOES THE BATTLEFIELD LOOK
LIKE IN T-CELLS DURING HIV
INFECTION.
SO SABRINA LEDI REALIZED THAT IN
THE LITERATURE, THERE WAS SOME
RNA SEQ DATA THAT SHE COULD MINE
FROM A PAPER IN EMBO JOURNAL
WHICH HAD USED PRIMARY CELLS TO
INFECT WITH HIV AFTER
ACTIVATION, AND THEN WERE TAKEN
AT DIFFERENT TIME POINTS.
AND WE SAW THAT THERE WERE BOTH
UPREGULATED AND DOWN DIAGNOSE DD
ENDOGENOUS RETROVIRUSES AS WELL
AS KRAB ZINC FINGERS.
SOME OF THESE LOOK QUITE
FAMILIAR TO CEDRIC.
BECAUSE THESE HE HAD PREVIOUSLY
SHOWN TO BE INTIMATELY RELATED
TO BE SHOWN TO INNATE IMMUNITY.
MANY PAIRS WERE ANTICORRELATED
IN EXPRESSION DURING THE HIV
INFECTION TIME COURSE.
SO IN OTHER WORDS, IF YOU LOOK
AT ONE OF THESE, THE LTR12C
ENDOGENOUS RETROVIRUS AND THE
ZINC F2, THAT THEY DIVERGE OVER
THE COURSE OF THE DAYS POST
INFECTION.
AND SABRINA WENT ON TO CONFIRM
THIS BINDING PROFILE.
SO THERE'S A DYNAMIC INTERPLAY
BETWEEN HERV AND KRAB ZINC
FINGER CONTROL ARE DURING HIV
INFECTION AND THIS CAN MODULATE
THE IMMUNE RESPONSE TO HIV.
SO HERVs MAY HAVE EFFECTS ON
ANTIVIRAL GENES NEARBY, AND THEN
THIS REPRESSIVE COMPLEX TO
KAP1 OR -- 28 CAN HAVE AN
IMPORTANT REPRESSION AND CAN IN
ESSENCE CONTROL INNATE IMMUNE
RESPONSES.
SO THE NEXT QUESTION WAS, COULD
THESE KRAB ZINC FINGER PROTEINS
DIRECTLY BIND TO AND REPRESS
HIV.
SO AS WE ALL KNOW IN THIS FIELD,
LIKE MANY INTERESTING IDEAS,
OTHER PEOPLE WORK ON IT AND WE
FOUND THAT A GREAT PAPER
SUDDENLY APPEARED IN OUR
MAILBOXES, EMAIL BOXES, AND THEY
HAD DONE THE EXPERIMENT THAT WE
WERE INTERESTED IN DOG.
IDOING.IT'S A GREAT PAPER.
THEY SHOWED THAT MULTIPLE KRAB
ZINC FINGER PROTEINS COULD
REPRESS HIV BY BINDING TO THE
LYSINE IN THE PRIMARY BINDING
SITE.
THEY FOLLOWED THIS UP BY SHOWING
IF YOU DID A KNOCKOUT
EXPERIMENT, YOU COULD PROMOTE
HIV ACTIVATION, SO SABRINA IN
CEDRIC'S GROUP LOOKED TO SEE
WHETHER THERE WAS A RELATIONSHIP
IN HIV LATENCY BETWEEN KRAB ZINC
FINGER PROTEINS AND HIV
REPRESSION AND SHE IDENTIFIED A
NUMBER OF KRAB ZINC FINGERS
WHICH APPEARED TO BE ABLE TO
REPRESS HIV AND THOSE WERE
UPREGULATED IN THE CONTEXT OF
THE LATENCY MODEL.
ZETRON LI WAS ALSO INVESTIGATING
DIFFERENT ZINC FINGER PROTEINS,
3, 4 AND 10, AND THEY COULD
DIRECTLY REPRESS HIV DIRECTLY IN
A CELL MODEL, AND INDEED UPON
HIV INFECTION, ONE OF THESE ZINC
FINGERS, 304, WAS DOWNREGULATED.
SO HAVING ESTABLISHED THAT
THERE'S THIS INTERESTING
RELATIONSHIP BETWEEN FAMILIES OF
ENDOGENOUS RETROVIRUSES AND ZINC
FINGER PROTEIN CONTROL, WE THEN
WANTED TO TRY AND UNDERSTAND
MORE ABOUT DIFFERENTIAL
EXPRESSION OF ENDOGENOUS
RETROVIRUSES IN HIV INFECTED
CELLS.
AND THEY LOOKED AT DIFFERENT
POPULATIONS OF RESERVOIR
POTENTIAL CELL TYPES,
CD4 T-CELLS, MONOCYTES,
MICROGLIA, AND USED A
COMPUTATIONAL PROGRAM THAT
MATTHEW BEND AL IN THE LAB USED
WHICH ALLOWS YOU TO LOOK AT EGGS
PRETION OF RETROVIRUSES FROM
BULK RNA SEQ DATA AND FOUND THAT
INDEED, THESE DIFFERENT CELL
TYPES COULD BE MARKED BY
DIFFERENT DIFFERENTIAL
EXPRESSION OF ENDOGENOUS
RETROVIRUSES, IN OTHER WORDS,
HERV O TYPING, YOU CAN IDENTIFY
CELLS BASED UPON THE COMPLEXITY
OF DIFFERENTIALLY EXPRESSED
ENDOGENOUS RETROVIRUS.
THEN LOOKING AT THE FAMILY
LEVEL, DOES THIS ENDOGENOUS
RETROVIRUS TRANSCRIPTIONAL
ACTIVITY ALLOW YOU TO
INVESTIGATE DIFFERENT CELL TYPES
AND INDEED IT DOES.
YOU CAN FIND INDIVIDUAL FAMILIES
WHICH ARE ONLY EXPRESSED IN
CD4 T-CELLS OR PREDOMINANTLY
EXPRESSED IN MONOCYTES, AND THEN
YOU CAN ALSO FIND ENDOGENOUS
RETROVIRUS FAMILIES EXPRESSED
BOTH IN MONOCYTES AND
CD4 T-CELLS.
SO HAVING IDENTIFIED THAT WE
COULD HERV TYPE CELLS AT THE
FAMILY LEVEL, WE WANTED TO ASK
WITH KECAN WE DO THIS AT THE SIE
CELL RNA LEVEL.
IT ALLOWS TO YOU DISCOVER
HETEROGENEITY, IT ALLOWS YOU TO
IDENTIFY CELL-CELL INTERACTIONS
AND -- COULD WE DETECT WITH
SINGLE CELL RNA SEQ AND WE WENT
TO A 10X SET FROM ONE HEALTHY
FEMALE, AND THEY RAN STARSOLO.
THEY THEN RAN THEIR NEW PROGRAM
STELLARSCOPE AND THEY COMPLETED
CELL TYPE ASSIGNMENTS WITH
AZIMUTH AND PBMC REFERENCES.
THEY FOUND THAT INDEED YOU COULD
IDENTIFY A SINGLE CELL LEVEL
EXPRESSIONS OF ENDOGENOUS
RETROVIRUSES.
IT APPEARS THAT DENDRITIC CELLS
HAVE THE HIGHEST PROPORTION OF
ENDOGENOUS RETROVIRUS EXPRESSION
IN THE LEUKOCYTE POPULATIONS AND
THAT'S DRIVEN BY THE HIGHEST
EXPRESSION OF PLASMA S -- DIFFET
AMOUNTS IN DIFFERENT CELL
SUBTYPES.
THE ADVANTAGE OF THE SINGLE CELL
ALLOWS US TO PUT A
LOCUS-SPECIFIC RESOLUTION ON
THIS.
IF WE WERE JUST LOOKING AT THE
FAMILY LEVEL AND WE PICKED ONE
OF THESE ENDOGENOUS
RETROVIRUSES, THE HARLEQUIN
FAMILY WE WOULD SEE EXPRESSION
PREDOMINANTLY IN THE PDCs,
THAT'S AN INTERESTING STORY FOR
ANOTHER TIME, AND ALSO IN B
CELLS AND T-CELLS.
BUT IF YOU LOOK AT INDIVIDUAL
LOCUS-SPECIFIC ENDOGENOUS RETRO
RETROVIRUSES, YOU CAN SEE THAT
THE 1Q321 HALEQUIN RETROVIRUS IS
OVEREXPRESSED IN SOME, THAT
17Q12 IS OVEREXPRESSED IN
T-CELLS AND MONOCYTES HAVE THEIR
OWN COMPLEMENT.
SO THE TAKE-HOME IS THERE'S A
DYNAMIC INTERPLAY BETWEEN KRAB
ZINC FINGER PROTEINS AND
HERVs, WHICH MIGHT HAVE DIRECT
OR INDIRECT EFFECTS ON HIV
REPLICATION.
SEVERAL CRAP ZINC FINGER
PROTEINS MIGHT DIRECTLY BIND AND
REPRESS HIV, AND HAVE EXPRESSION
USEFUL FOR CHARACTERIZING SINGLE
CELLS AND SUBSETS.
WE THINK THAT LOCUS SPECIFICITY
OF HER SCRAN SCRIP TOE MIX IS A
GATEWAY TO STUDYING HERV
REGULATION, AND THIS NEW PROGRAM
STELLAR SCOPE WILL ALLOW THE
ACCURATE LOCUS SPECIFIC HERV
EXPRESSION IN SINGLE CELLS.
FROM THE PERSPECTIVE OF MOVING
FORWARD IN THE HOPE PROGRAM, WE
THINK THAT KRAB ZINC FINGER
PROTEINS MIGHT HOLD IMPORTANT
KEYS TO STRATEGIES TO LOCK HIV,
AND WE'VE GOT A NUMBER OF
SYNERGIES WITHIN THE HOPE GROUP
THAT WE ARE WORKING ON OVER THE
COURSE OF THE NEXT YEAR TO LEAD
TOWARDS THE POTENTIAL FOR
COMBINING KRAB ZINC FINGER
PROTEINS WITH OTHER REPRESSORS
FOR A SYNERGISTIC LOCK OF HIV.
SO ALL OF THIS WORK, OF COURSE,
DOESN'T TAKE PLACE IN A VACUUM,
THE LARGE NUMBER OF PEOPLE.
HOPE HAS GOT INTERNATIONAL
SITES, DOMESTIC SITE, AND THIS
WAS A VERY CLOSE COLLABORATION
BETWEEN A NUMBER OF DIFFERENT
GROUPS.
SO THANKS, I'LL HAND OVER TO
SUSANA.
[APPLAUSE]
>> HI, EVERYONE.
I WAS TASKED TO GIVING YOU AN
UPDATE OF THE EFFICACY OF
SPIRONOLACTONE AGAINST HIV IN
SEVERAL MODELS.
THIS IS A SUMMARY SLIDE.
THE QUESTION WE'RE TRYING TO ASK
IS WHETHER SPIRONOLACTONE WHICH
IS AN FDA-APPROVED DRUG BLOCKS
EXPRESSION IN MULTIPLE MODELS OF
HIV INFECTION AND WHETHER
THERE'S BENEFIT IN USING IN
COMBINATION TO BLOCK HIV
REACTIVATION.
THE KEY FINDINGS WAS THAT
LONG-ACTING PELLETS OF
SPIRONOLACTONE ACCELERATE HIV
DECAY IN HIV INFECTED MICE
UNDERGOING ART SUPPRESSION.
IN RHESUS MACAQUE, SP REDUCES
THE TARGET PROTEIN XPB WHICH
PAVES THE WAY TO EFFICACY IN
THIS MODEL.
WE HAVE ALREADY ASSEMBLED ASSAYS
AND NETWORK TO START
INVESTIGATING ACTIVITY OF SP IN
PEOPLE LIVING WITH HIV.
FINALLY, WE FOUND OUT TWO DRUGS
TOGETHER IS BETTER THAN ONE AT
BLOCKING HIV.
THIS IS EXCITING FOR THE CURE
BECAUSE FOR A NEW DRUG THAT IS
FDA-APPROVED THAT PUTS -- TO
SLEEP AND CAN ACCELERATE DRUG
REPURPOSING.
THIS IS THE FIRST TIME WE
DEMONSTRATE WHEN ADDED TO ART
THIS FIRST MECHANISM OF ACTION
CAN ACTUALLY ACCELERATE VIRAL
SUPPRESSION.
SUPPRESSED WITH SILENCING
PROMOTING AGENTS, WE CALL THEM
SPAs, AFTER ART IS
INTERRUPTED.
THE FIRST GOAL OF THIS RF2 IS TO
DETERMINE THE EFFECTS IN VIVO,
THE SECOND GOAL IS TO DEVELOP
NOVEL SPAS AND FINALLY THE THIRD
GOAL IS TO APPLY
SEQUENCE-SPECIFIC SPAs IN VIVO
IDENTIFIED IN RF1.
SO THIS IS THE GROUP OF PEOPLE
THAT PARTICIPATE IN RF2.
THISO AS YOU KNOW, HOPE
COLLABORATORY IS FOCUSED ON
LOCKING HIV TRANSCRIPTION AND IN
THE PAST WE'VE PUT A LOT OF
EFFORTS IN USING AT THAT TIME
INHIBITORS TO DO SO.
TODAY I'M GOING TO BE TALKING TO
YOU ABOUT SPIRONOLACTONE WHICH
BLOCKS HIV TRANSCRIPTIONAL
INITIATION.
SO SPIRONOLACTONE IS AN
FDA-APPROVED DRUG.
IT WAS -- IT'S BEEN APPROVED
SINCE 1959 TO TREAT HIGH BLOOD
PRESSURE, HEART FAILURE, STROKES
AND KIDNEY DISEASE.
THE BRTHE THE MECHANISM OF ACTIS
THAT IT COMPETES FOR THE
MINERALCORTICOID
RECEPTOR-BINDING.
IT DEGRADES THE XPB SUBUNIT OF
THE TFIIH COMPLEX.
WHICH SOMEHOW GOT BLOCKED OUT
THERE, IT'S RESPONSIBLE FOR THIS
PHOSPHORYLATION EVENT THAT
HAPPENS AT RNA POLYMERASE THAT
STARTS TRANSCRIPTIONAL
INITIATION.
SO BY LIMITING XPB, WE CAN
INHIBIT THIS STEP.
A PLEUR ON IS ANOTHER MINERAL
CORTICOID RECEPTOR, THIS DOES
NOT HAVE THE SOFT TARGET EFFECT
ON XPB.
SO THE WAY THIS WORKS, SO THE
WAY THIS WORKS, EXOWR WE TREAT
THESE CELLS WITH COMBINATION OF
THREE DRUGS, ART PLUS -- OR ART
AND EPL IN THE LIGHT BLUE, YOU
HAVE NO DIFFERENCE IN
TRANSCRIPTION.
NOW, IF YOU ADD SPIRONOLACTONE,
YOU HAVE THIS VERY NICE
INHIBITION OF RRL TRANSCRIPTION.
YOU SEE THERE'S THIS NICE DOSE
DEPENDENT DEGRADATION OF XPB.
WE HAVE SHOWN THAT -- IS
ASSOCIATED SPECIFICALLY WITH XPB
DEPLETION IF WE KNOCK DOWN XPB
USING -- RNAs IN GREEN YOU SEE
THAT YOU OBTAIN THE SAME EFFECT
AS ON HIV RNA TRANSCRIPTION AS
YOU DO WITH SPIRONOLACTONE.
FURTHERMORE, IF WE LOOK WITH RNA
SEQ STUDIES, WE SEE THAT THERE'S
A VERY POTENT EFFECT ON HIV
TRANSCRIPTION WITH ONLY MODEST
EFFECTS ON CELLULAR GENES.
SO WE WONDERED WHETHER THIS DRUG
COULD BE EFFECTIVE IN AN IN VIVO
MODEL OF HIV INFECTION.
WE WORKED WITH VETO GARCIA FOR
THESE STUDIES SMG T.
WE USED 12 ANIMALS, WE INFECTED
THEM WITH HIV AND TWO WEEKS
LATER, WE TREATED SEVEN OF THEM
WITH ART, A COCKTAIL OF THREE
DRUGS, AND FIVE OF THEM, THEY
RECEIVED ART PLUS THEY WERE
IMPLANTED IN THE BACKS OF THE
MICE WITH A LONG-ACTING PELLET
OF 200 MILLIGRAMS OF SP.
WE FOLLOWED VIRAL TRANSCRIPTION
FOR THE NEXT 35 DAYS.
SO THE FIRST GRAPH IN THE BOTTOM
LEFT SHOWS THE PLASMA
CONCENTRATION OF SP IN THESE
ANIMALS WITH THIS IMPLANTED
PELLET, AND THE DRUGS ARE NOT
VERY HYUN FORTUNATELY, THAT
LOOKS MORE LIKE IN THE --
NANOGRAMS PER ML.
BUT FORTUNATELY THESE
CONCENTRATIONS WERE SUFFICIENT
TO SEE SOME LEVEL OF DEGRADATION
OF XPB.
YOU CAN SEE IN THE WESTERN PLOT
IN THE UPPER RIGHT THERE'S
DEGRADATION OF XPB, THIS IS THE
LUNG TISSUE AND IN THE BOTTOM,
WE HAVE SEVERAL DIFFERENT
TISSUES.
THE DIFFERENCE IS NOT
STATISTICAL SIGNIFICANCE BUT
THERE WAS THIS -- IMPORTANTLY
EVEN WITH THESE LOW DOSES WHEN
WE LOOK AT VIRAL LOADS WE'RE
VERY SURPRISED TO SEE THERE WAS
A VERY STRONG EFFECT ALREADY ON
LIMITING HIV TRANSCRIPTION, AND
SEVEN DAYS POST IMPLANTATION OF
THE PELLET WE ALREADY SAW A
DIFFERENCE IN TWO LOGS IN VIRAL
LOADS IN THE PLASMA OF THESE
INFECTED MICE.
AND YOU SAW AN ACCELERATION
BELOW DETECTION LIMITS OF OVER A
WEEK IN THE ANIMALS THAT
RECEIVED SP.
SO THESE ANIMALS WERE SAC'D AND
DAY 35, WES LOOKED AT VIRAL RNA
TISSUES.
THIS IS TISSUES FROM LIVER,
LUNG, LYMPH NODES AND SPLEEN.
THERE'S A STATISTICAL
SIGNIFICANCE DIFFERENCE BETWEEN
THE LEVELS OF RNA IN THESE
TISSUES.
WHEN WE LOOKED AT CELLS
ASSOCIATED -- WE DIDN'T SEE ANY
DIFFERENCE, AND THIS IS EXPECTED
FROM TRANSCRIPTIONAL INHIBITOR.
SO WE WERE VERY INTERESTED IN
DETERMINING WHETHER THIS
ACCELERATION OF VIRAL
SUPPRESSION WAS ALSO CORRELATED
WITH LOWER LEVELS OF
INFLAMMATION BY ACCELERATING
ACTIVE REPLICATION, SO WE LOOKED
AT DIFFERENTIAL EXPRESSED GENES
IN THE HUMAN TRANSCRIPTS OF THE
DIFFERENT TISSUES OF THE MICE.
I'M SHOWING A PLOT OF JUST THE
LUNG.
WE SAW DIFFERENT EXPRESSED
GENES, BUT WHEN WE LOOK FURTHER
INTO THE INFLAMMATION-RELATED
PATHWAYS WE SAW A VERY NICE
DOWNREGULATION OF MANY OF THESE
GENES IN THE DIFFERENT TISSUES
OF THE MICE.
SO WHETHER THIS IS RELATED TO
REDUCTION OF INFECTION OR JUST
ANOTHER DIRECT EFFECT OF SP
REMAINS TO BE DETERMINED, BUT IN
A GENERAL MANNER, IT SHOWS THAT
THERE IS VERY -- THERE'S ADDED
BENEFIT OF ADDING THIS DRUG TO
FRONT LINE THERAPY.
SO NOW WE ARE GEARING UP TO
STUDY THE EFFECTS OF
SPIRONOLACTONE IN THE NON-HUMAN
PRIMATE MODEL, AND WE WORKED
WITH DAVID EVANS AT THE
WISCONSIN PRIMATE CENTER FOR
THESE, AND WE DID A
PHARMACOKINETIC STUDY WHERE WE
JUST GAVE ORAL DOSES OF
SPIRONOLACTONE TO ANIMALS AT
INCREASING CONCENTRATIONS FROM S
PER KILOGRAM PER DAY WITH A ONE
WEEK WASHOUT BETWEEN DOSES, AND
WE COLLECTED PBMCs AT THE END
OF EACH TWO WEEKS OF DOSING AND
WE LOOKED AT XPB DEGRADATION,
AND IN THE BOTTOM RIGHT, YOU SEE
THE GRAPH SHOWING THE DIFFERENT
ANIMALS RECEIVE THIS NICE DOSE
DEPENDENT DEGRADATION OF XPB IN
INCREASING CONCENTRATIONS OF
SPIRONOLACTONE.
DOSES OVER 24 MILLIGRAMS PER
KILOGRAM, WE CAN -- MORE THAN
50% REDUCTION IN XPB.
ON THE RIGHT SIDE WE HAVE PLASMA
CONCENTRATION SO WE MANAGED TO
REACH -- LEVELS DESIRED -- THEY
DIDN'T CHANGE ANY -- WE DIDN'T
SEE ANY ADVERSE EVENTS.
SO FINALLY WE ARE INTERESTED IN
LOOKING AT THE EFFICACY IN THE
HUMAN COHORTS.
SO WE HAVE STARTED TO PUT UP A
NETWORK WITH DIFFERENT
COLLABORATORS.
WITH DAVID SMITH AND -- FOR THE
LAST -- THE NATURAL HISTORY
COHORT AND WITH MHRP THE
AFRICOS, THE RV419 COHORT, THE
CLINIC LOCATED IN BRAZIL AS WELL
AS HERE IN WASHINGTON.
SO JUST OF NOTE THE TRANSGENDER
POPULATION USES HIGH DOSES OF
SPIRONOLACTONE DURING THEIR
FEMINIZING HORMONE THERAPY SO
WE'RE VERY INTERESTED IN THIS
POPULATION THAT USES HIGHER
DOSES OF SPIRONOLACTONE.
SO FOR INSTANCE, I'M JUST GOING
TO GIVE YOU AN EXAMPLE OF A
STUDY THAT WE STARTED LOOKING
AT.
SO WE HAVE RECEIVED ALREADY A
SERIES OF SAMPLES FROM THE
NATURAL HISTORY STUDY.
WE HAVE INDIVIDUALS THAT HAD
RECEIVED SPIRONOLACTONE FOR A
SERIES OF REASONS, AND WE HAVE
DIFFERENT TIME POINTS, DIFFERENT
INDIVIDUALS WITH DIFFERENT
DURATIONS ON SP AND WE HAVE
TIMES BEFORE AND AFTER SP
INITIATION AND WE ARE CURRENTLY
STUDYING THESE SAMPLES.
FINALLY I WANT TO TELL YOU OF A
STUDY IN VITRO LOOKING AT THE
ABILITY OF USING TWO SPs IN
EXI NATION.
COMBINATION.
WE'RE USING A TAT INHIBITOR THAT
WILL BLOCK THE RECRUITMENT AND
WHAT DOES THAT LOOK TOGETHER.
SO FOR THIS STUDY WE DECIDE TO
CHOOSE A CELL LINE THAT WAS
VERY, VERY HARD TO INHIBIT WITH
A SINGLE INHIBITOR.
WE USED 10.6 CELLS WHICH HAVE
GFP IN PLACE OF ENVELOPE.
AS YOU CAN SEE A SINGLE DRUG SP
IN BLUE, DCA IN RED, LIMITED IN
TERMS OF WHAT YOU CAN INHIBIT
HOWEVER IF YOU USE THEM IN
COMBINATION YOU SEE THIS NICE
SUPPRESSION TO BELOW DETECTION
LEVELS.
WE ARE VERY INTERESTED IN
DETERMINING WHETHER THIS IS A
LONG TERM SUPPRESSION SO WE
FOREMANNPERFORMED A TREATMENT
INTERRUPTION STUDY.
IN LIGHT GREEN YOU SEE THERE WAS
NO VIRAL REBOUND WHEN TREATED
WITH THESE TWO DRUGS.
FURTHERMORE, WE WANTED TO KNOW
WHETHER THIS WAS SUFFICIENT TO
REDUCE A STRONG REACTIVATION
EVENT WITH AN LRA SO FOR THAT WE
USED PMA.
ON THE LEFT SIDE YOU HAVE
WITHOUT STIMULATION, ON THE
RIGHT SIDE WITH PMA, SO THE
CONTROL CELLS REACTIVATED BY
80.1%, AND IN THE PRESENCE --
NOT PRESENCE, ABSENCE, I MEAN,
THEY HAD BEEN PRIOR TREATED
WITHOUT DRUGS FOR 90 DAYS, THERE
WAS ABSOLUTELY NO REACTIVATION.
SO THIS IS VERY PROMISING, TWO
DRUGS TOGETHER PROBABLY VERY
POTENT AT BLOCKING REACTIVATION
FROM LATENCY.
SO THE TAKE HOME MESSAGE -- THIS
LONG SP FORMULATIONS RESULTS IN
LOW PLASMA CONCENTRATIONS BUT
NEVERTHELESS WE SAW VERY NICE,
EFFICIENT SUPPRESSION AND
ACCELERATION OF VIRAL
TRANSCRIPTION.
SO ADDITION OF SP, WE SAW DOWN
REGULATES INFLAMMATORY GENES IN
THE BLT MOUSE.
ORAL DOSES OF SP OF MORE THAN
24 MILLIGRAMS PER KILOGRAM IN
RHESUS MACAQUES SEEMS SUFFICIENT
TO REDUCE XPB PROTEIN, FORGING
THE WAY FOR FUTURE STUDIES IN
THIS MODEL.
AND WE HAVE NOW ASSEMBLED A
GLOBAL INFRASTRUCTURE AND
TECHNIQUES TO INTERROGATE S P
AND OTHER SPAs IN PEOPLE
LIVING WITH HIV.
FINALLY, W USING TWO LATENCY
PROMOTING AGENTS IN COMBINATION
HAS SHOWN REALLY GOOD PROMISE IN
IRREVERSIBLY SILENCING HIV.
AND I WOULD LIKE TO THANK ALL
THE FOLKS -- THERE'S NO
ACKNOWLEDGMENT SLIDE.
SORRY, IT'S MISSING.
I ENCOURAGE YOU TO GO SEE THE --
THEY HAVE POSTERS ON SP, I'D
LIKE TO THANK VICTOR GARCIA AND
DAVID EVANS AS WELL AS ALL OF
THE HOPE FAMILY FOR THIS WORK.
THANK YOU.
[APPLAUSE]
>> I WOULD LIKE TO START BY
ACKNOWLEDGING COMEMBERS OF
RF3 AS WELL AS YOUNG
INVESTIGATORS FROM OUR
LABORATORIES WHO HAVE PERFORMED
THE WORK THAT I'M GOING TO BE
SHOWING TODAY.
IN PARTICULAR, I WOULD LIKE TO
THANK COLLABORATORS -- FROM
UNIVERSITY OF WISCONSIN WHO
PERFORMED A LARGE PART OF THE
WORK.
SO THE HYPOTHESIS OF RF3 IS THAT
WE ARE TRYING TO DEVELOP GENOME
INJURING MOLECULES THAT ARE
SAFER AND INTRODUCE POINT
MUTATIONS IN THE PRO VIRUS AND
HOST DEPENDENCY FACTORS AND THIS
CAN LEAD TO THE PERMANENT
INACTIVATION OF HIV.
THE GOAL IS TO USE PROGRAMMABLE
DPEGENE EDITING MODULES -- IN TE
GENOME.
SO THE IDEA IS TO INTRODUCE
THESE POINT MUTATIONS IN BOTH
THE PROVIDERS AND HOST GENE
PROTEINS THAT CAN CRITICALLY
BLOCK VIRAL GENE TRANSCRIPTION
WITHOUT AFFECTING -- ONLY THE
HOST FUNCTION.
IMPORTANTLY WE'RE TRYING TO
DELIVER BY DIRECT DELIVERY TO
THE CELLS AND TISSUES OF
INTEREST -- THERAPEUTICS.
HERE IS THE PLAIN LANGUAGE
SLIDE, TO DEVELOP SAFER GENE
THERAPY METHODS FOR THE CURE OF
HIV PRACTICAL FOR WIDESPREAD
USE.
IMPORTANTLY WE ARE TRYING TO
ADMINISTRATE THESE THERAPEUTIC
TREATMENTS DIRECTLY WITHOUT
REQUIRING TRANSPLANT REGIMENS.
SO ALONG THE LINES OF
PROGRAMMABLE GENOME EDITING,
WE'RE USING CAS9 BASE AND PRIME
EDITING APPROACHES WHICH CAN
INTRODUCE POINT MUTATIONS AND
DIRECTLY CONVERT SINGLE
NUCLEOTIDE BASE CHANGES IN THE
GENOME WITHOUT INTRODUCING
DOUBLE STRANDED DNA BREAKS OR --
THE PLATE.
SO THESE USE CAS9 -- THE ONE I'M
GOING TO BE TALKING TODAY USES
REVERSE TRANSCRIPTASE AND
INTRODUCES POINT MUTATIONS.
THE IDEA IS TO AGAIN SEE THAT WE
CAN DIRE DIRECTLY INACTIVATE THE
VIRUS OR HOST GENES,
PARTICULARLY HOST GENES OTHER
THAN -- EVEN CURTAILING THE
APPLICATION OF BOTH X4 AND
R5 HIV ISOLATES.
SO ALONG THESE LINES, WE'VE BEEN
LOOKING AT EDITING CYCLIN --
THESE STUDIES HAVE BEEN DONE IN
COLLABORATION WITH NATURE LIKE I
MENTIONED.
THIS SLIDE SHOWS THE SUPER
ELONGATION COMPLEX OF HIV AND
THE SUPER ELONGATION COMPLEX IS
REQUIRED CRITICALLY FOR
TRANSCRIPTIONAL ELONGATION OF
DNA TRANSCRIPTS FROM DNA
PROVIDERS.
IN THE GENOME OF THE HOST CELLS.
SO THE SUPERELONGATION
COMPLEX -- THE RECRUITMENT IS
INITIATED WITH THE RECRUITMENT
OF P-TEFB, AND THIS IS RECRUITED
BY THE VIRAL TAT PROTEIN --
STRUCTURE.
SO VERY EARLY STUDIES HAD SHOWN
THAT HUMAN -- ALONE IS
CAPABLE -- THE MURINE IT DOES
NOT, AS SHOWN ON THE RIGHT PART
OF THE SLIDE.
THIS IS BECAUSE INTERACTION WITH
TAT AND TAR REQUIRES A ZINC ION
WHICH IS CRITICALLY SUPPORTED
WITH THE PRESENCE OF A
CYSTINE -- POSITION 261 OF HUMAN
CYCLINE T1.
THE CYSTINE IS MISSING IN THE
MURINE HOMOLOGUE AND REPRESSING
THE TYROSINE -- WITH THE CYSTINE
DISSTODISTORTS INTERACTION WITHT
AND TAR.
SO THEY INTRODUCED THE TYROSINE
OF THE MURINE -- THE MURINE
TYROSINE RESIDUE IN HUMAN CYCLIN
T1 WITH TRADITIONAL CASPER CRISP
9 STRATEGY AND I'M SHOWING YOU
DATA HERE WITH TWO CLONES THAT
ARE PRODUCED IN JURKATS, NOW
INTRODUCING THE TYROSINE
MUTATION DID NOT CHANGE THE
EXPRESSION LEVELS OF CCNT1, NOR
DID IT CHANGE THE PHYSIOLOGY OF
THESE CELLS, THEY PRO LIVE PROLD
LIKE WILD TYPE CELLS.
HOWEVER, WHEN WE CHALLENGED
THESE CELLS WITH MULTIPLE
STRAINS OF HIV, BOTH OF THE --
WE FOUND THAT THE VIRUSES WERE
UNABLE TO REPLICATE IN THESE
CELLS AS SHOWN BY FLOW CYTOMETRY
PLOTS WHERE WE COULD NOT PICK UP
GAG EXPRESSION INSIDE THE CELLS.
THESE ARE ALSO NEGATIVE IN --
WITH CULTURES -- THESE CELLS.
EXTENDED CULTURE OF THESE CELLS
WITH HIGH DOSE -- DID NOT LEAD
TO ANY VIRUS ESCAPE.
CHALLENGE OF THESE CELLS WITH
CLINICALLY -- VARIANCE OF HIV
AFTER THESE CELLS WERE MATRIX --
SHOWED WERE INCAPABLE OF
SUPPORTING REPLICATION.
SINCE -- INVOLVED IN
TRANSCRIPTION OF MANY VIRAL
GENES, WE LOOKED AT HOW IT
AFFECTED THE PHYSIOLOGY OF
CELLS.
WE FOUND THAT INTRODUCTION OF
THE TYROSINE MUTATION IN HUMAN
CYCLIN T1 DID NOT DISRUPT -- CD
K-9 AS NORMAL AND WHEN WE LOOKED
AT THE TRANSCRIPTIONAL PROFILE
OF MUTATOR CELLS TO THE PARENTAL
WILD TYPE SHOWN ON THE X AXIS,
THE MAGNITUDE OF DIFFERENCES IN
TRANSCRIPTOMIC CHANGES WERE
RATHER MINOR, ABOUT TWOFOLD,
COMPARED TO WHAT WE SAW --
COMPARED TO WHAT WE OBSERVED
WITH THE VIRAL TAT TRANSCRIPTION
WHICH IS ABOUT 100 FOLD.
ANALOGOUS TO THE TAT PROTEIN,
THE P50 IS ALSO RECRUITED BY
BLD4, A HUMAN PROTEIN FOR --
PROMOTERS AND WE LOOKED AT
THE -- WHICH HAD THE MUTANT
CYCLIN D1 WE FOUND NO MAJOR
CHANGES TO.
WE THEN MOVED ON TO SEE IF WE
COULD EDIT THE SINGLE NUCLEOTIDE
GENE USING THE PRIME EDITING
APPROACH.
THE PRIME EDITOR WAS DESIGNED TO
BRING ABOUT A SINGLE -- WHICH
CREATE THIS HAD RESIDUE.
WE WERE ABLE TO GET THESE
MUTATIONS DONE AGAIN IN JURKAT
CELLS AND WE FIND THAT THESE
CELLS THAT HAVE BEEN EDITED BY
PRIME EDITING -- BOTH BY
REPORTER ASSAYS AND IN ASSAYS
USING -- WITH CULTURE SUPER
NATENTS.
THE NEXT STEPS IS TO ACTUALLY
DELIVER THESE GENOME EDITING
MOLECULES TO BRING ABOUT THIS
CHANGE IN VIVO IN HUMANIZED
MICE.
WE PLAN TO DO THIS BY TARGETING
BOTH HUMAN T-CELLS AS WELL AS
HEMATOPOIETIC STEM CELLS.
SO TARGET T-CELLS WE HAVE A
VIRUS LIKE PLATFORM WHICH
TARGETS T-CELLS BECAUSE OF --
BY -- BECAUSE IT'S DECORATED
WITH ANTIBODIES TOO -- THIS VLP
PLATFORM PACKAGES RIBO -- THUS
LEADS TO SCARLESS GENOME EDITING
AND IN MIXED CULTURES WITH
T-CELLS AND B CELLS, YOU CAN
FIND THAT THE REPORTER GFP
EXPRESSION IS ONLY SEEN IN
T-CELLS AND NOT IN B CELLS WHICH
DON'T EXPRESS CD #.
CD9.
VLPs THAT ENCASED --
ADMINISTERED BY SIMPLE IV
INJECTIONS TO HUMANIZED MICE
THAT WERE INFECTED AND
SUPPRESSED ON ART.
WHEN THESE MICE WERE RELEASED
FROM ANTIRETROVIRAL THERAPY WE
SAW TREATMENT -- WE SAW
TREATMENT FOR THESE -- THAT
TARGETED -- LED TO STIMULATION
OF THESE CELL LEVELS AND
EXPANSION OF T-CELL LEVELS,
WHEREAS VIRAL LOADS THAT
INITIALLY REBOUNDED WERE QUICKLY
CONTROLLED AND THESE MICE WERE
ACTUALLY LOOKED AT, WE FOUND
THAT WE COULD GET -- GREATER
THAN 60% IN THESE MICE.
SO WE PLANNED THIS APPROACH
REALLY TO TARGET CCNT12 1 AS WE.
-- HAS BEEN DEVELOPING LIPID
NANOPARTICLES THAT CAN ENCASE N
MRNA MOLECULES, WITH SOME
SPECIAL FEATURES.
THEY HAVE A LINKAGE THAT
UNDERGOES HYDROLYSIS AT --
ENABLES SUFFICIENT
CYTOPLASMIC -- AT THE ENDOSOMES.
GREATER POE PENS IT TO TRANSDUCE
HEMATOPOIETIC STEM CELLS.
THESE WERE FIRST -- WHICH HAVE A
PREFLOCKSED -- IN GREEN AND
CELLS THAT TAKE A LIPID
NANOPARTICLE WITH THE CRE RNA IN
T WHEN THESE MICE WERE TREATED
AND ANALYZED FOUR WEEKS POST
TREATMENT FOUND THAT UP TO 40%
OF THE HEMATOPOIETIC STEM CELLS
IN THE BONE MARROW TURNED GREEN.
-- THAT DIFFERENTIATED FROM
THESE CELLS.
THE HEMATOPOIETIC STEM CELLS
WERE ALSO TRANSPLANTABLE TO
RECIPIENT MICE AND THUS THEY ARE
TRUE HEMATOPOIETIC STEM CELLS.
SO CONCLUDE WE ARE DEVELOPING
THESE -- TESTING THESE MICE FOR
TARGETING BOTH THE PRO VIRAL DNA
AS WELL AS CCN NT1.
THIS IS MY ACKNOWLEDGMENT SLIDE.
THANK YOU.
[APPLAUSE]
>> GOOD MORNING, EVERYONE.
MY NAME IS PATRICIA DEFECHEREUX.
I USE MY PRONOUNS SHE AND HER.
EVEN THOUGH I'M PETRIFIED
TALKING TO A FULL AUDIENCE AND
FLYING, I'M HERE TO TALK TO YOU
ABOUT COMMUNITY ENGAGEMENT
ACTIVITY FOR THE HOPE
COLLABORATORY.
I'M HERE BECAUSE I'M SO BLESSED
TO BE WORKING WITH THESE FOLKS.
OUR COMMUNITY VISION WAS BASED
ON AND IS BASED ON THE BELIEF
THAT EVERY PARTNER, EVERY WHEEL
IN THE HOPE MACHINERY HAS AN
IMPORTANT PART, AN IMPORTANT
ACTIVITY TO PLAY IN THAT
BASICALLY EVEN THOUGH WE HAVE
THIS BELIEF THERE EXISTS A HUGE
BALANCE OF POWER THAT COMES INTO
ACTION WHEN WE GET PEOPLE
TOGETHER.
AND THAT IS WHY WE HAVE ANCHORED
AT THE HEART OF OUR HOPE
COMMUNITY ENGAGEMENT ACTIVITIES
A COMMUNITY ARTS INTEGRATED
RESEARCH PROGRAM, WHICH WE HOPE
HELP ALLEVIATE SOME OF THESE
CHALLENGES.
REALLY, HOPE IS ABOUT THE
PEOPLE.
AND I REALLY WOULD LIKE AT THIS
TIME, MY COMMUNITY PARTNER,
RAEF, IF YOU'RE IN THE AUDIENCE,
NO PRESSURE, AND ALISHA, THOMAS,
RICHARD, PLEASE STAND UP.
I AM SO LUCKY TO BE WORKING WITH
YOU ALL.
AND OUR FOLKS -- YEAH.
[APPLAUSE]
OUR FOLKS WHO CAN'T BE HERE IN
BRAZIL, SAO PAULO, UGANDA, WE
HAVE OUR COMMUNITY ARTS
INTEGRATED RESEARCH TEAM IN
CANADA, AND IN OUR OPERATION IN
SYDNEY, I HAVE UNWAVERING
COMMITMENT AND SUPPORT FROM OUR
PIs, SO I WANT TO THANK YOU
ALL.
WE BELIEVE THAT EVERYBODY HAS A
TALENT AND A SKILL THAT CAN BE
PUT IN LIGHT, IN THE COMMUNITY
ENGAGEMENT, AND ONE OF THESE
PERSONS IS RAEF, A VERY
RESPECTFUL AND TALENTED SOCIAL
MEDIA, AND HAS REALLY TAKEN UPON
ITSELF TO CREATE THIS
HOPE-RELATED HIV CURE-RELATED
CONTENT ON SEER MHOS.
SOCIAL MEDIA WHICH
INVOLVED NOT ONLY PEOPLE AND
MEMBERS OF THE HOPE TEAM, BUT
ALSO FROM OTHER MDCs AND EVEN
FROM OUR SCIENTIFIC ADVISORY
BOARD.
AND THIS IS A WAY FOR US TO
REACH AUDIENCES WHICH ARE NOT IN
THE USUAL CIRCLES OF HAVING
ACCESS TO CURE-RELATED RESEARCH.
WE HAVE A HUGE CHALLENGE, WHICH
IS HOW DO WE TRANSLATE THIS VERY
COMPLEX SCIENCE THAT WE'RE ALL
LISTENING IN TODAY AND WE'RE
VERY FAMILIAR WITH THE LANGUAGE
FOR FOLKS THAT DO NOT HAVE THIS
BASIC LANGUAGE UNDERSTANDING.
AND SO ONE OF THE THINGS THAT
THE TEAM HAS DONE IS REALLY
BRING TOGETHER CLINICIANS,
ARTISTS, COMMUNITY MEMBERS AND
OTHER MEMBERS OF OUR COMMUNITY
ENGAGEMENT TEAM TO CREATE A
LITTLE ANIMATION WHICH WE NOW
HAVE TO CHANGE BECAUSE IT'S NOT
BLOCK, LOCK -- ANYMORE, IT'S
BLOCK, LOCK, STOP.
SO THAT'S SOMETHING WE SHARED
YESTERDAY AT OUR COMMUNITY
REUNION, THE RAVE WITH JESSICA,
AND IF YOU GO BEYOND THEIR VERY
LIMITED GOOGLE METRIC PERCEPTION
OF WHAT GENDER IDENTITY IS, WE
WERE TRYING TO LOOK AT WHERE THE
AUDIENCES OF ALL OF THE MEDIA,
THE SOCIAL MEDIA COVERAGE THAT
RAIF HAS DONE.
A MAJORITY OF THE PEOPLE ARE IN
THE U.S. AND INDIA, BUT YOU CAN
SEE IT'S ALSO IN OTHER PARTS OF
THE WORLD.
MAJORITY OF FOLKS BETWEEN THE
AGE OF 25 AND 44, THAT IS MORE
FOR THE PEOPLE IN INTERESTED IN
KIND OF DATA ANALYSIS.
BUT REALLY, A PICTURE IS WORTH A
LOT OF WORDS, SO WE'VE CREATED A
LITTLE VIDEO FOR YOU TODAY THAT
I'M GOING TO TRY TO PLAY BECAUSE
I'M KIND OF A TECHNOLOGY CLUT
HERE. KLUTZ
HERE.
CAN WE HAVE THE MUSIC?
WE TESTED IT AT THE BREAK AND
THEY TOLD ME IT WAS WORKING SO
HOPEFULLY WE'LL MAKE IT WORK.
SORRY ABOUT THAT.
I CAN IMPROVISE, I CAN DO A
LITTLE SONG AND DANCE.
WE DID DANCE AT OUR ANNUAL
MEETING.
IN VIDEO IS REALLY, REALLY THE
PRO DUCT OF ALL OF US WORKING
TOGETHER, BUT SYDNEY HERE PUT IT
TOGETHER FOR US.
AND WHAT YOU CAN SEE ACTUALLY,
THE COMMUNITY ARTS INTEGRATED
RESEARCH PROGRAM IS ACTUALLY NOT
JUST PEOPLE DOING ART, IT'S
REALLY A BEHAVIORAL SOCIAL
SCIENCE PROGRAM WHERE PEOPLE NOT
ONLY RESPOND TO SURVEYS AND HAVE
FOCUS GROUP KIND OF MODALITIES
WHERE WE CAN ASK THEM QUESTION
ABOUT PERCEPTION AROUND HIV CURE
BUT ALSO BRINGING THE SCIENTISTS
TO KIND OF MAYBE THINK ABOUT THE
WAY THEY'RE DOING HIV CURE
RESEARCH IN DIFFERENT WAYS,
BECAUSE WE'RE IN A ROOM TOGETHER
MAKING ART RATHER THAN HAVING
SOMEBODY TALKING DOWN TO YOU
FROM A PODIUM OR BEING AN
INVESTIGATOR COMING WITH
QUESTIONS, WHEN YOU'RE
ART-MAKING, YOU'RE ACTUALLY
SHIFTING YOUR PERSPECTIVES.
AND SOME OF THESE ART PRODUCTS
THAT YOU MAY HAVE SEEN ON THE
VIDEO IS ACTUALLY ALLOWING
PEOPLE TO TALK ABOUT WHAT IT
MEANS FOR THEM FOR IDENTITIES,
COMMUNITY MEMBERS AS WELL AS
RESEARCHER, WHAT IT MEANS FOR
THEM TO WORK TOWARDS AN HIV CURE
TOGETHER.
THIS IS A LITTLE EXCERPT OF THE
BLOCK, LOCK, STOP VIDEO I WAS
TELLING YOU ABOUT.
WHICH HAS A NARRATIVE DONE BY
RAIF, WHO'S AN AMAZING SPEAKER.
I THANK YOU ALL.
SORRY ABOUT THE MUSIC.
I DON'T KNOW WHERE IT
DISAPPEARED.
[APPLAUSE]
THANK YOU VERY MUCHMENT SORRY
VEVERY MUCH.SORRY ABOUT THE VID.
IS IT AVAILABLE ON RAIF'S
YOUTUBE CHANNEL?
MAYBE WE'LL FIGURE OUT A WAY TO
SHOW IT AT SOME POINT.
I KNOW THAT WE ARE SCHEDULED FOR
LUNCH RIGHT NOW, BUT I WOULD
LIKE TO OPEN IT UP JUST FOR A
FEW MINUTES FOR A FEW QUESTIONS
IF ANYONE HAS QUESTIONS, COME ON
UP TO THE MIC AND IF ANYONE
ONLINE HAS QUESTIONS, WE'LL FIND
OUT FROM OUR PEOPLE IN THE BACK.
>> -- MARTINS. SUSANA, I'M
GLAD TO SEE THE STUDIES WITH
SPIRONOLACTONE ARE GOING SO
WELL.
WERE ANY OF YOUR MONKEYS MALES,
AND IF THEY WERE, DID YOU SEE
SUPPRESSION IN TESTOSTERONE IN
THEM?
>> LOOKED AT THE TESS TESTOSTEE
LEVELS.
THEY WERE VERY LOW AT THE
BEGINNING SO WE DIDN'T SEE ANY
CHANGES.
TYPICALLY THE TESS TESTOSTERONE
LEVELS STAY THE SAME WITH
SPIRONOLACTONE.
WHAT HAPPENS IS THERE'S A
COMPETITION FOR THE RECEPTOR.
SO THE LEVELS ARE THE SAME, IT'S
JUST THE FUNCTION THAT IS
REDUCED.
>> INTERESTING.
>> SO WE WOULDN'T EXPECT ANY
CHANGES ANYWAY.
>> OKAY, GOOD.
>> CHRIS PETERSON, FRED HUTCH
FOR PRITI.
A COUPLE QUESTIONS.
ONE FOR CYCLIN T1, HAVE YOU
THOUGHT ABOUT WHAT -- WHAT IS
THAT MUTATION, WHAT EFFECT IS IT
GOING TO HAVE ON HUMAN PROTEIN,
AND NUMBER TWO, IF YOU HAVE
INDELS THAT YOU GENERATE AT THAT
SITE WITHOUT INSERTING YOUR
CHANGE OR INACTIVATING THE
PROTEIN AND WHAT WILL THAT DO?
>> SO FOR THE FIRST QUESTION,
DID YOU ASK ME WHAT IT DOES TO
THE PROTEIN LEVEL?
>> HOW DOES IT IMPACT THE HUMAN
PROTEIN FUNCTION VERSUS YOU'RE
INTRODUCING A MOUSE MUTATION.
>> IT SEEMS TO BE PERFECTLY
NORMAL.
THAT WAS THE WHOLE IDEA OF THE
TRANSCRIPTIONAL PROFILING WE
DID.
SO WHEN WE LOOK WITH TYROSINE
MUTATION, IT SEEMS TO WORK
PERFECTLY NORMALLY.
IT DOESN'T SEEM TO CHANGE
ANYTHING WITH RESPECT TO -- IN
HOST CELLS.
AND WE ARE USING BASE EDITING
THAT ONLY CHANGES ONE
NUCLEOTIDE, IT'S ONE SINGLE
NUCLEOTIDE IN THE WHOLE PROTEIN
THAT CHANGES TO MURINE
HOMOLOGUE.
SO WE HAVEN'T LOOKED AT INDELS.
I KNOW FROM THE LITTLE BIT THAT
WE'VE DONE AT LEAST WITH THE
PRIMARY EDITING A PROACH, WE'RE
ONLY ABLE TO SEE THAT PARTICULAR
CHANGE IN THAT SINGLE NUCLEOTIDE
CHANGE.
WE DON'T SEE SOMETHING BEYOND
THAT.
>> THE OTHER QUESTION IS, HOW
ARE YOU TARGETING YOUR LMPs
FOR STEM CELLS?
>> SO THIS WORK IS DONE WITH --
GROUP I IN RF3, SO THEY'RE
ACTUALLY SCREENING NOVEL LIPIDS
THAT HAVE GOT A HIGHER
PROPENSITY TO REALLY TARGET THE
HEMATOPOIETIC STEM CELLS.
THESE ARE BEING DONE IN VITRO,
SO WHILE THEY MAY TARGET OTHER
CELLS AS WELL, THE PROPENSITY TO
GET TO STEM CELLS IS VERY HIGH
PAUSE OF THESE NOVEL LIPID
FORMULATION.
>> SHARON?
>> THANKS.
I HAD TWO QUESTIONS.
FIRST OF ALL CONGRATULATIONS ON
THE VIDEO.
I'M FEELING VERY LOW TECH,
INDEED YOU'VE RAISED THE BAR ON
HOW TO PROMOTE WHAT WE DO.
FABULOUS WORK.
I HAD A QUESTION FOR SUSANA,
FIRST TELL US WHY YOU THINK
SPIRONOLACTONE CAN CREATE
IRREVERSIBLE SILENCING, WHAT
LEADS TO THE PERSISTENCE.
AND THEN ONE QUICKLY FOR PRITI,
IF YOU CAN TELL US A LITTLE BIT
ABOUT WHY YOU'RE TARGETING
CD7 SPECIFICALLY WITH YOUR VLP.
SO MAYBE SUSANA FIRST, WHAT'S
MAKING IT IRREVERSIBLE?
>> SO I DON'T KNOW YET.
THAT'S WHAT WE'RE TRYING TO
INVESTIGATE.
JUST SO YOU KNOW, BY ITSELF,
SPIRONOLACTONE BY ITSELF, IT'S
NOT IRREVERSIBLE BECAUSE AS SOON
AS YOU REMOVE SPIRONOLACTONE,
YOU HAVE XPB PRODUCTION AGAIN
AND THERE'S A JUMP START IN
TRANSCRIPTION.
SO BY ITSELF, IT'S NOT DOING THE
BLOCK.
HOWEVER, IN COMBINATION, IT
SEEMS THAT IT ACCELERATES THE
REDUCTION, THERE IS -- AND
SOMEHOW THERE MIGHT BE SOME
EPIGENETIC DIFFERENCES.
THAT'S EXACTLY WHAT WE'RE
LOOKING INTO RIGHT NOW.
SO ACTUALLY I DIDN'T SHOW BUT
THERE'S VERY INTERESTING DATA,
IT'S LIKE WHEN WE STOP THE
SINGLE DRUGS ALONE, SO IF WE
STOP THE SINGLE DRUG AFTER --
THIS EXPERIMENT IS A LITTLE BIT
INSANE.
MORE THAN 400 SOME DAYS, THERE'S
A LOT OF CRITICISM THAT CAN GO
INTO THAT, BUT IT'S JUST THE
ONLY WAY WE HAVE TO GO THIS
LONG-RANGE AND LOOK AT THE
EPIGENETIC CHANGES.
SO WHEN WE STOP SP ALONE, WE SEE
REBOUND, AND EVENTUALLY IT COMES
BACK TO KIND OF THE CONTROL OF
THE ART ALONE LEVELS.
IF YOU DO THE DCA STOP, WHAT WE
SAW IN THIS PARTICULAR MODEL, SO
IF YOU HAVE COMPLETE
SUPPRESSION -- YOU TYPICALLY
DON'T HAVE REBOUND BUT IN THIS
CASE IF IT'S NOT COMPLETELY
SUPPRESSED, THERE WAS SOME
REBOUND.
WHAT YOU'RE SEEING OVER TIME NOW
IS THAT NOW WE'RE COMING BACK TO
ALMOST BELOW THE TREATED CELLS
SO WE'RE BACK TO VERY, VERY
INDETECTABLE LEVELS.
SO WHETHER THERE'S PHENOMENON OF
REACTIVATION AND WE ELIMINATED
ALL THE TRANSCRIPTIONALLY --
CELLS AND NOW INCREASING THE
POPULATION WITH VERY
TRANSCRIPTIONALLY SILENCED
POPULATION SO WE NEED TO LOOK AT
THIS VERY PRECISELY.
>> PRITI, CD7 TO ARE YOUR
TARGETING --
>> CD7 IS A MOLECULE THAT'S
PRESENT ON ALMOST ALL T-CELLS
AND A LARGE PROPORTION OF
MONOCYTES AS WELL, MONOCYTES AND
MACROPHAGES.
SO TARGETING CD7 DOESN'T APPEAR
TO HAVE ANY DETRIMENTAL EFFECTS
ON THE T-CELL.
WE'VE TRIED TARGETING MANY OTHER
MOOL KEULS BUT WHAT'S
INTERESTING IS WHEN WE USED OUR
HUMAN ANTIBODIES AGAINST CD7, IT
LEADS TO VERY, VERY QUICK
ENDOCYTOSIS OF THE MOLECULE,
GETS WITHIN A FEW SECONDS AND
THEN YOU CAN SEE IT RECYCLE BACK
TO THE SURFACE IN ABOUT 15
MINUTES.
SO IT GIVES YOU A MANNER IN
WHICH YOU CAN ACTUALLY TARGET
THE CELL AND WITH -- YOU NEED
FUSION FROM THE ENDOSOME FOR
RELEASE OF THE CARGO, SO
TARGETING SOMETHING TO THE
ENDOSOME MECHANISM THROUGH RAPID
ENDOCYTOSIS SEEMS TO BE THE WAY
TO REALLY GET GOOD EFFICIENCIES
AND WE FIND EXCELLENT
EFFICIENCIES BY TARGETING CD7 BY
USING THE -- APPROACH.
THAT'S THE REASON WHY WE USE IT.
>> WE'LL TAKE ONE MORE QUESTION.
SORRY, RICH, I DON'T WANT TO
HOLD UP LUNCH TOO MUCH LONGER.
>> ANDY FROM NIAID.
ONE QUICK QUESTION IS, WHAT ARE
THE SIDE EFFECTS OF SP, AND SORT
OF A PHILOSOPHICAL QUESTION TOO
IS, IF YOU GUYS ARE TALKING
ABOUT USING A COUPLE DIFFERENT
DRUGS THAT MAY HAVE TO BE TAKEN
ON A REGULAR BASIS ON A SEMI
REGULAR BASIS, ISN'T THIS REALLY
JUST ANOTHER CLASS OF ARVs AND
NOT NECESSARILY LIKE A CURE
MODALITY?
OBVIOUSLY THAT'S NOT THE CASE
FOR THINGS WHERE YOU WANT TO CUT
OUT AND PERMANENTLY SILENCE, BUT
IN SOME OF THE GENES, SP, IF YOU
TAKE IT AWAY, IT COMES RIGHT
BACK.
SO HOW ARE YOU GUYS THINKING OF
THAT?
>> SO TO ADDRESS YOUR FIRST
QUESTION IN TERMS OF THE
TOXICITY, SP HAS BEEN USED IN
DOSES THAT RANGE FROM
25 MILLIGRAMS PER DAY, 100 -- IN
SOME CASES 100 MILLIGRAMS PER
DAY AND THE MAXIMUM TYPICALLY
DONE DURING TRANSITION,
FEMINIZING HORMONE THERAPIES,
400 MILLIGRAMS PER KILOGRAM.
THERE'S NOT A LOT OF TOXICITY
ASSOCIATED -- WELL, WITH THE
400 MILLIGRAMS PER KILOGRAM,
THERE'S THIS IDEA WHICH IS NOT
CLEARLY DEFINED IN THE
LITERATURE EITHER THAT YOU CAN
BLOCK THE ACTIVITY OF
TESTOSTERONE AND IT HELPS DURING
TRANSITION.
BUT ACTUALLY MANY INDIVIDUALS
HAVE MOVED AWAY FROM USING
SPIRONOLACTONE.
I DON'T KNOW IF IT'S THAT
EFFICIENT IN THAT RESPECT.
VERY HIGH DOSES DO AFFECT THE
TESTIS DEVELOPMENT AND SO FORTH,
IT'S BEEN SEEN IN DOGS AND RATS
AND SO FORTH.
VERY, VERY HIGH DOSES.
SO IN HUMANS WE NEED TO FIND
THAT SWEET SPOT WHERE WE SEE
INHIBITION OF HIV TRANSCRIPTION
WITHOUT THE EFFECTS OR THESE
OTHER SIDE EFFECTS, BUT THESE
TYPICALLY COME WITH THE VERY,
VERY HAO DOSE.
HIGH DOSE.
LOOKING AT USING DRUGS IN
COMBINATION OR ARE WE JUST
REPLACING ART FOR ANOTHER ARKTS
I TART, ITHINK THERE'S DEFINITET
OF ADDING TRANSCRIPTIONAL
INHIBITOR BECAUSE WE ARE
ACCELERATING VIRAL SUPPRESSION,
THEREFORE WE'RE PROBABLY
REDUCING THE SIZE OF THE
RESERVOIR.
AND THEN I THINK THE IDEA OF
USING THIS AS A BLOCK AND
LOCKAGE IS THAT WE CAN GET TO A
POINT WHERE WE CAN ACTUALLY
LEAVE ART FREE.
SO WE NEED TO UNDERSTAND HOW
LONG DO WE TREAT WITH ALL THESE
DIFFERENT DRUGS TOGETHER AND
BEFORE WE CAN LIFT ART AND HAVE
THIS ART-FREE PERIOD.
SO THESE ARE STILL OUTSTANDING
QUESTIONS THAT WE NEED TO
ADDRESS IN DIFFERENT MODELS.
GOOD AFTERNOON.
I'M A PROGRAM OFFICER IN THE
DIVISION OF AIDS AT NIAID.
NEXT WE WILL HEAR TWO
PRESENTATIONS FROM THE CONSORTIA
FOR INNOVATIVE HIV/AIDS VACCINE
AND CURE RESEARCH, ABBREVIATED
CIAVCRs.
THE TWO CIAVCRs ARE BASED AT
EMORY AND DUKE UNIVERSITY.
THE FIRST PRESENTATION WILL BE
GIVEN BY DR. ERIC HUNTER FROM
THE EMORY CONSORTIUM, FOLLOWED
BY DR. GUIDO FERRARI FROM THE
DUKE CONSORTIUM AND THEY WILL
TAKE QUESTIONS AFTERWARDS.
WITH THAT, I'LL HAND IT OVER TO
YOU, ERIC.
>> THANK YOU, BRI GIT.
BRIGITTE.
SO THE EMORY CONSORTIUM FOR
INNOVATIVE HIV/AIDS VACCINE AND
CURE RESEARCH, A MOUTHFUL THAT
WE DON'T RELISH, I MUST ADMIT,
IS HEADED UP BY MYSELF AND RAMA
AMARA.
IT'S REALLY DIVIDED INTO TWO
SECTIONS.
FOCUS ONE IS ON PREVENTION AND
INNOVATIVE VACCINE APPROACHES.
WE'VE BEEN REALLY PARTICULARLY
INTERESTED IN COMBINING A
DURABLE NEUTRALIZING ANTIBODY
RESPONSE WITH A TISSUE TARGETED
CDA RESPONSE AS A PREVENTIVE
VACCINE FOR HIV.
THERE ARE 10 INVESTIGATORS THAT
ARE BASED AT EMORY INVOLVED IN
THE CONSORTIUM WITH
COLLABORATORS THAT ARE PART OF
THE CONSORTIUM AT THE LA JOLLA
INSTITUTE FOR IMMUNOLOGY, THE
UNIVERSITY OF MINNESOTA,
STANFORD, UNIVERSITY OF
WASHINGTON AND LSU.
FOCUS TWO HAS REALLY BEEN HEADED
UP BY GEA DOUGH SILVESTRI SO
I'LL BE SPEAKING ON HIS BEHALF
THIS AFTERNOON, AND
COINVESTIGATORS CONTRIBUTING TO
THE STUDY I'LL BE TALKING ABOUT
AND WE HAVE A COLLABORATIVE UNIT
AT UNC CHAPEL HIP WITH NANCY
ARCHINAND DR. MARGOLIS.
IT'S BEEN A VERY PRODUCTIVE
INTERACTION.
THE FOCUS FROM THE BEGINNING, WE
HAD A MUCH EASIER ACRONYM,
CONSORTIUM FOR INNOVATIVE AIDS
RESEARCH, CIAR, AND THAT FOCUS
HAS BEEN -- FOCUS TWO, THE CURE
COMPONENT, HAS PURSUED SHOCK AND
KILL STRATEGY FOR HIV AND I
DON'T HAVE TO GO INTO DETAILS ON
THAT, ALTHOUGH WE HAVE BEEN
WORKING WITH DAVE AND THE TEAM
AT UNC ON IDENTIFICATION OF
NOVEL LATENCY REACTIVATION
INHIBITORS, LRAs, LET ME JUST
PUT IT THAT WAY, NOVEL LRAs
THAT COULD THEN BE TESTED IN
VIVO IN MACAQUES.
I GUESS NEITHER BRIGITTE NOR I
POINTED OUT THAT THE CONSORTIA
THAT WE'LL BE TALKING ABOUT
TODAY ARE FOCUSED ON STUDIES IN
NHPs.
SO IN THE FIRST ITERATION OF
THIS IN THE CIAR, WE IDENTIFIED
SMACK MIMETICS AS A POTENTIAL
NOVEL LRA.
IT WAS THE FIRST IN NHP STUDIES,
A COMBINATION IN NHPs AND
HUMANIZED MICE, IN THE NIXON ET
AL. NATURE PAPER, AND THAT
SHOWED THAT NON-CANONICAL NF CAB
SIGNALING INDUCED BY
AZD5822 COULD GENERATE SYSTEMIC
HIV AND SIV LATENCY REVERSAL.
ONE OF THE POINTS THAT WAS
REALLY IMPORTANT, THOUGH, WAS TO
SHOW THAT THERE COULD BE AN
ENHANCEMENT OF LATENCY REVERSAL
BY DEPLETING AT THE SAME TIME
CD8 T-CELLS.
AND THAT CAME FROM THE FACT FROM
DEANNA'S WORK THAT SUGGESTED
THAT CD8 CELLS, IN ADDITION TO
THEIR CYTOTOXIC FUNCTION, COULD
HAVE A SUPPRESSIVE FUNCTION THAT
ACTUALLY FACILITATED LATENCY
RATHER THAN KILLING THE CELLS.
WE WERE ABLE TO SHOW IN THIS
MCBRIEN, ET AL. PAPER THAT YOU
COULD GET A VERY ROBUST AND
PERSISTENT SIV AND REACTIVATION,
AND HIV REACTIVATION UNDER ART
BY THE IL15 SUPERAGONIST
NA03 COMBINED WITH
CD8 DEPLETION.
THIS JUST SHOWS THE REACTIVATION
OF VIRUS UNDER THAT CONDITION,
REALLY DEMONSTRATING FOR THE
FIRST TIME, VIRAL LOADS IN
EXCESS OF 10,000, SOME OF THE
MOST ROBUST REACTIVATION OF
VIRUS SEEN AT THAT POINT, BY
THIS COMBINATION OF
CD8 DEPLETION AND THE N-803.
IN THESE STUDIES, N-803 ALONE
DID NOT RESULT IN ANY BLIPS OF
VIRUS REACTIVATION, AND SO EVEN
THOUGH IT HAD BEEN SHOWN IN
VITRO TO BE A POTENTIAL LRA,
THAT WAS NOT THE CASE IN THE
MACAQUES THAT WERE STUDIED IN
THIS STUDY.
THAT WAS FOLLOWED UP BY TWO
ADDITIONAL STUDIES.
ONE LOOKING AT SHIV REACTIVATION
AND A SECOND LOOKING INSTEAD AT
A SECOND LRA, THE SMACK MIMETIC
AZD5582.
SO ALL THREE OF THESE REALLY
SHOWED HOW CD8 DEPLETION COULD
ENHANCE LATENCY REACTIVATION IN
VIVO IN MACAQUES.
BRAD TALKED ABOUT THIS EARLIER
TODAY.
THIS IS FROM DEANNA'S LAB, BUT
IT EXPLAINS TO A CERTAIN EXTENT
WHY WE'RE SEEING THIS EFFECT IN
VIVO, AND THAT'S BECAUSE
CD8 CELLS ARE PROMOTING CHANGES
IN THE CD4 T-CELL TRANSCRIPTOME
THAT RESULTS IN INCREASED
SURVIVAL, QUIESCENCE AND STEM
CELLNESS.
ALL OF THOSE THINGS PUSH VIRAL
TRANSCRIPTION DOWN, ALLOWING
CELLS TO MORE EASILY GO INTO A
LATENT STATE.
THOSE STUDIES SHOWED VERY ROBUST
LATENCY REACTIVATION, BUT WHAT
WAS FOUND IN EACH OF THOSE
STUDIES WAS THAT THERE WAS NO
IMPACT ON THE SIZE OF THE VIRAL
RESERVOIR.
AND SO ONE OF THE QUESTIONS THEN
ASKED WAS, WE'VE BEEN ABLE TO
GET THE KICK, WHAT ABOUT THE
KILL?
CAN WE ADD ADDITIONAL REAGENTS
TO THE MIX THAT MIGHT THEN
REDUCE THE VIRAL RESERVOIR, AND
THAT WAS FACILITATED BY THE
AVAILABILITY OF MONOCLONAL
ANTISIV ANTIBODIES, A VIRUS
THAT'S ACTUALLY VERY DIFFICULT
TO RAISE NEUTRALIZING ANTIBODIES
AGAINST, THAT CAME FROM MARIO
ROEDERE'S LAB AND IT WAS ALSO
FACILITATED BY PRODUCTION FOR
THE NAP STUDIES BY THE CVI.
SO IN THIS CASE, AS YOU CAN SEE
THERE ARE FOUR ARMS.
THE FIRST WAS ART-TREATED, THE
SECOND WAS ART-TREATED WITH TWO
DOSES OF ANTIBODY.
THE THIRD, TWO DOSES OF ANTIBODY
INCLUDING -- I CAN'T REALLY READ
THE SLIDES HERE -- INCLUDING THE
AZD5582, AND THEN THE LAST WAS
ONE THAT INCLUDED ALSO N-803,
THE IL15 SUPER AGONIST.
WE WERE ABLE TO SEE AGAIN A
ROBUST REACTIVATION IN THESE
EXPERIMENTS, AND IN THE ANIMALS
TREATED WITH AZD582 AND
CD8 DEPLETION ALONG WITH
ANTIBODIES, WE SAW THE -- WE SAW
A REDUCTION IN THE VIRAL
RESERVOIR IN LYMPH NODE CELLS,
AND THAT WAS CONFIRMED BY A
REDUCTION -- A SIGNIFICANT
REDUCTION, ALTHOUGH MODEST
REDUCTION IN THE QVOA ASSAY.
THE ANALYSIS OF VI VIREMIA FULLY
RECAPITULATED THE RESULTS OF
NIXON AND ALL SHOWIN.
THIS INFUSION OF THE BROAD
ANTIBODIES WAS WELL TOLERATED.
ART INTERRUPTION WAS NOT
PERFORMED BECAUSE WE WANTED TO
LOOK AT ALL THE TISSUES, THIS
LONGITUDINAL ASSESSMENT OF
RESERVOIR SIZE REVEALED A
REDUCTION SIGNAL IN LYMPH NODES
FOR BOTH CELL ASSOCIATED SIV DNA
AND QVOA.
AND I THINK OPTIMIZATION OF THIS
APPROACH MAY LEAD TO ENHANCED
RESERVOIR CLEARANCE.
CD8 CELLS THEN CLEARLY PLAY A
ROLE IN REDUCTION OF -- IN HEL
HELPING ESTABLISH -- SORRY,
HELPING MAINTAIN LATENCY.
BUT WHAT IS THE ROLE OF THESE
CELLS IN THE ESTABLISHMENT OF
THE PERSISTENT RESERVOIR OF
LATENTLY INFECTED CELLS?
SO WHAT WE'VE RECENTLY DONE IS
TO ASK, WELL, WHAT HAPPENS IF
YOU DEEPLY -- IF YOU DEPLETE CD,
AND THEN PUT THE ANIMALS ON ART,
PRIOR TO THE ART ITSELF BUT TWO
WEEKS AFTER INFECTION, COMPARED
TO ANIMALS THAT WERE SIMPLY
INFECTED AND PUT ON ART, LEFT
FOR ALMOST A YEAR ON ART
SUPPRESSION AND THEN UNDERGOING
A TREATMENT INTERRUPTION.
WHAT WE NOTICED WAS THAT IN EACH
OF THE THREE GROUPS, THE PEAK
VIRAL LOAD WAS QUITE SIMILAR.
BUT THERE WAS A VERY DISTINCT
DIFFERENCE IN THE SLOPE OF VIRAL
DECAY, AND THAT'S SHOWN HERE
WHERE THE READ IS -- THE ANIMALS
THAT WERE TREATED WITH ART --
SORRY -- WERE DEPLETED OF
CD8 CELLS PREINFECTION WERE --
VERSUS THOSE THAT WERE DEPLETED
IMMEDIATELY BEFORE ART COMPARED
TO THE CONTROLS.
BUT DESPITE THAT SLOWER DECAY,
THERE WAS NO DIFFERENCE IN THE
SIZE OF THE VIRAL RESERVOIR
UNDER ART, AND THAT WAS TRUE
BOTH IN PERIPHERAL CELLS SHOWN
ON THE LEFT, TOTAL DNA OR INTACT
VIRUSES, OR IN LYMPH NODES SHOWN
ON THE RIGHT.
WITH AGAIN, A TOTAL VIRAL DNA,
AND INTACT VIRUSES.
AND IN FACT, THAT WAS BORNE OUT
BY THE FACT THAT THERE WAS NO
DIFFERENCE IN THE KINETICS OF
VIRAL REBOUND AFTER ATI.
SO CD8 DEPLETION DOES RESULT IN
A SLOWER DECLINE OF VIRAL
REBOUND AFTER DAY 15, INDICATING
THAT CD8 LYMPHOCYTES REDUCE THE
LIFESPAN OF PRODUCTIVELY
INFECTED CELLS, PRESUMABLY
THROUGH SIV-SPECIFIC CTL
ACTIVITY.
HOWEVER, IT DIDN'T CHANGE THE
SIZE OF THE PERSISTENT VIRAL
RESERVOIR, MEASURED DIRECTLY OR
BY IPDA OR FUNCTIONALLY BY
KINETICS OF REBOUND.
SO IT INDICATES THAT DURING
EARLY SIV INFECTION, THE
PERSISTENT RESERVOIR IS
ESTABLISHED PRIMARILY IN CELLS
PRIOR TO THE INDUCTION OF CTL
CONTROL OR INDEPENDENTLY OF CTL
CONTROL.
THAT LEADS US TO OUR MOST
CURRENT STUDIES, WHICH IS CAN
VACCINE INDUCED T-CELLS IMPACT
THE ESTABLISHMENT AND STABILITY
OF THE VIRAL RESERVOIR.
WE RECENTLY PUBLISHED ON THE
FACT THAT T-CELL INDUCING
VACCINE CAN PREVENT MUCOSAL SHIV
INFECTION EVEN WITH LOW AND
NEUTRALIZING ANTIBODY TITERS.
THIS WAS COMBINING THREE
HETEROLOGOUS VECTOR EXPRESSING
GAG ALONG WITH TRIMER
VACCINATION TO GENERATE NEWT
LASING -- AUTOLOGOUS --
TR2 AUTOLOGOUS NEUTRALIZING
ANTIBODY.
THIS APPROACH RESULTS IN A VERY
HIGH LEVEL OF CD8 CELLS IN THE
PERIPHERY AS WELL AS IN TISSUES.
AND IN FACT WHAT WE SAW WAS THAT
WHILE ANIMALS WITH A
NEUTRALIZING TIGHTER GREATER
THAN 300 WERE PROTECTED FROM
CHALLENGE.
THE BULK OF THE ANIMALS THAT
WERE PROTECTED IN THE CASE OF
THE HETEROLOGOUS VECTOR PLUS
SUBSET GROUP HAD TITERS LESS
THAN 300 AND YET WERE PROTECTED.
AND THAT'S VERY DISTINCT FROM
ANIMALS THAT WERE SIMPLY
VACCINATED, SUGGESTING A REAL
SYNERGY BETWEEN ANTIBODY AND
T-CELL.
SO THE REAL QUESTION IS, CAN WE
GENERATE TISSUE TARGETED
CD8 T-CELL MEDIATED
ANTIRESERVOIR EFFECT BY
VACCINATING THE ANIMALS IN THIS
SAME WAY FOR CD8 CELLS PRIOR TO
SIEVE INFECTION, CAN WE GENERATE
A TISSUE TARGETED CD8 T-CELL
MEDIATED ANTIRESERVOIR EFFECT
VACCINATING UNDER ART AND IF WE
COMBINE THESE TOGETHER, CAN WE
REDUCE THE SIZE OF THE RESERVOIR
AND GENERATE A CD8 T-CELL
MEDIATED LONG TERM VIRAL
SUPPRESSION?
THIS JUST SHOWS THE DESIGN.
ONE GROUP, GROUP TWO, WILL BE
VACCINATED USING AGAIN THE
HETEROLOGOUS VECTORS PRIOR TO
PUTTING THE -- PRIOR TO
INFECTION AND PUTTING THE
ANIMALS ON ART.
ANOTHER GROUP, GROUP ONE, WILL
BE PUT ON ART AND THEN
VACCINATED AGAIN TO SEE WHETHER
WE CAN GET THE SAME LEVEL OF
TISSUE LOCALIZED CD8 CELLS.
GROUP THREE IS A STANDARD ART,
AND GROUP FOUR WILL BE
VACCINATED AS IN GROUP 2 BUT
WILL BE BOOSTED DURING ART TO
SEE WHETHER DURING -- WITH THAT
BOOST, WE CAN REDUCE THE VIRAL
RESERVOIR.
WE DON'T HAVE A COMMUNITY PART
OF OUR PROGRAM, BUT JUST FOR
THOSE IN THE COMMUNITY, WHAT THE
NHP EXPERIMENTS ALLOW US TO DO
IS USE INTERVENTIONS THAT ARE
IMPOSSIBLE AT THIS POINT TO DO
IN HUMANS, BUT ALLOW US TO TEST
HYPOTHESES THAT MAY BE VERY
USEFUL IN FUTURE STUDIES IN
HUMANS.
AND THAT INCLUDES THE USE OF NEW
LRAs, IT INCLUDES THE USE OF
CD8 DEPLETION, AS WELL AS
VACCINATION, AND WE ARE HOPEFUL
THAT IT WILL CONTRIBUTE TO THE
CURE EFFORT IN A SIGNIFICANT
WAY.
I WOULD LIKE TO JUST POINT OUT,
THIS TYPE OF WORK TAKES A
VILLAGE, AND WE'D LIKE TO THANK
ALL OF OUR COLLABORATORS.
THANK YOU.
[APPLAUSE]
AND I GUESS GUIDO IS GOING TO
FOLLOW ME.
>> THANK YOU, ERIC, AND THANK
YOU FOR EXHIBIT DU FOR INTRODUCT
OF THE CIAVCR WHICH SEEMS LIKE A
GOOD SERIES FOR A TV SHOW,
COMBINING SCIENCE AND SPY
FICTION.
WE ARE -- I'M THE CO-PI WITH DRR
CONSORTIA.
AND WE ARE VERY FORTUNATE TO
HAVE SO MANY COLLABORATORS THAT
ARE WELL ESTABLISHED IN THE
FIELD, DESIGNING VACCINE,
IDENTIFYING MONOCLONAL
ANTIBODIES, IDENTIFYING LATENCY
REVERSING AGENTS, AND DEFINING
WHAT IS THE PROFILE OF THE
TRANSCRIPTOMIC OF THE CELLS THAT
ARE INFECTED AND RESPONSIBLE FOR
THE RESERVOIR, BUT I WANT TO
POINT OUT THAT WE'RE ALL HONORED
TO HAVE DREW WISEMAN AMONG OUR
COLLABORATORS AND WHAT THEY'VE
DONE FOR US.
SO I WANTED TO TAKE THIS
OPPORTUNITY.
AND ALONG WITH THE
COLLABORATORS, WE HAVE A VERY
INSPIRING AND DEVOTED MEMBER OF
THE SCIENTIFIC ADVISORY BOARD,
AS WELL AS OUR PROJECT OFFICERS.
AS ERIC MENTIONED, WE HAVE TO --
IN THE PROGRAM.
ONE IS MEANT TO BE PREVENTION,
ONE IS MEANT TO BE ERADICATION
OF INFECTION.
THE FIRST IS LED BY
DR. WILLIAMS, AND THE SECOND BY
DR. BETTS AND MYSELF.
WE ALSO HAVE A CENTRALIZED
RESOURCE DIRECTED BY.
TODAY I WILL REALLY FOCUS ON
THESE TWO PARTS OF OUR FOCI.
EVERYTHING IS BASED ON NHP.
SO ERADICATION STRATEGY IN
CD8 T-CELL RESPONSES WOULD BE
THE OPTIMAL REGIMEN TO ERADICATE
HIV INFECTION.
THE GOAL IS TO EXPLORE MRNA
CONSTRUCT THAT CAN DELIVER
THERAPEUTIC B AND T-CELL
RESPONSES.
OUR WORK REALLY STEMS FROM THE
VACCINE STRATEGY THAT WAS
REPORTED BY DR. SANDERS WHO
OBSERVED THE TRANSMITTED FOUNDER
SOSIP TRIMER ELICITED PROTECTIVE
AUTOLOGOUS TIER 2 NEUTRALIZING
ANTIBODIES IN RHESUS MACAQUES.
AS INDICATED IN THE CURVE BY THE
BLUE LINE REPRESENTING THE
ANIMALS WITH HIGHEST
NEUTRALIZING ANTIBODY TITERS.
THIS VACCINE STRATEGY WILL BE
TESTED ALSO IN THE ACT
ACTG5422 CLINICAL TRIALS, AND WE
THINK THAT OUR PROGRAM WILL HAVE
A RELEVANT IMPACT IN DEFINING
SOME OF THE MECHANISTIC ASPECT
OF THE IMPACT OF THIS VACCINE IN
THE CLINIC AND BE TRANSLATIONAL
TO THAT POINT.
JUST AS A REMINDER, THE FACT
THAT THE SOSIP, ESTABLISHED
SOSIP TRIMER IS BASED ON THE
CONCEPT THAT A BOND BETWEEN THE
GP130 AND GP41 WITH PROLINE
ADDITION IN 558 STABILIZED THE
TRIMER AND MAINTAIN THE
CONFORMATION OF THE ENVELOPE AS
INDICATED IN THE
ELECTROMICROSCOPY ON THE RIGHT
COMPARED TO THE NON-STABILIZED
ON THE LEFT.
THE NEW VACCINE IMMUNOGENS ARE
WHAT WE'RE AIMING AT IN FOCUS
ONE AND THEY WILL FEED FOCUS TWO
AS WE MOVE ALONG.
SO THIS IS A HIGHLY ITERATIVE
PROCESS BETWEEN PREVENTING AND
ERADICATING THE INFECTION.
THE PARADIGM THAT WE WILL TEST
IS BASED ESSENTIALLY ON THE
ABILITY OF REACTIVATING THE
LATENT RESERVOIR TO MAKE THE
CELLS RECOGNIZABLE BY THE
IMMUNOTHERAPY INTERVENTION THAT
ARE BASED ON VACCINE AND
MONOCLONAL ANTIBODY MOLECULES.
LET'S TALK FOR A SECOND ABOUT
THE MONOCLONAL ANTIBODY BASED
MOLECULES TO FOLLOW UP WITH SOME
OF THE DISCUSSION THAT I BROUGHT
IN TO THIS AUDIENCE THIS MORNING
ABOUT HLA-E RECOGNITION OF THE
INFECTED CELLS.
IN THIS PROGRAM WE WILL TEST
ANTIBODIES TO THE
MAMU-E/VL9 COMPLEXES THAT CAN
BLOCK THE INHIBITORY SIGNAL OF
THE LIVER TO THE NK CELLS AND
PREVENT THE NK CELLS FROM
RECOGNIZING THE INFECTED CELLS,
AS WELL AS FOR THE CD8.
BUT WE'RE ALSO TRYING TO DEVELOP
ANTIBODIES TO THE MAMU-E/GAG RLE
INFECTED CELLS.
SO WHERE DOES THE RESEARCH
RESOURCE COMING IN WITH THE BAR
IN THE CENTER?
THEY ARE COMING IN BECAUSE IT
WILL PROVIDE US WITH THE
BARCODED SHIV, WHICH ESSENTIALLY
MOST OF YOU KNOW BUT THANKS TO
THE INSERTION OF A 34 BASED
CASSETTE WITH A 10 RANDOM BASES
BETWEEN THE VPX AND VPR
CONSTRUCT, WE CAN HAVE MORE THAN
10,000 VARIANTS IN OUR STOCK,
AND UP WI 1,000 UNIQUE INFECTION
EVENTS FOR EACH IV CHALLENGE.
AND WE KNOW THAT THIS INSERTION
DOESN'T AFFECT THE INFECTIVITY
OF THE VIRUS.
WHAT THIS ALLOWS US TO DO IS
THAT WE CAN FOLLOW THE PROGENY
OF THESE VIRUSES DURING THE
ACUTE PHASE OF THE TIME THAT WE
START ART AND FOLLOW UP IN THE
LEVEL OF THE TISSUE WHERE THESE
CLONOESTABLISHED LATE CEASE AND
IDLATENCY ANDIDENTIFY WHAT IS T.
IN ORDER TO ACHIEVE THE
ERADICATION WE'VE BEEN THINKING
ABOUT TWO POSSIBLE STRATEGY.
ONE IS THE STRATEGY WHERE THE
IMMUNOTHERAPY WILL START AT TIME
OF UNDETECTABLE VIREMIA AFTER
ART INITIATION.
AND IN ORDER TO DO THIS, THE
GOAL IS TO DEFINE THE MECHANISM
EFFECTS OF VACCINE INDUCED
RESPONSES ON RESERVOIR AFTER
VIREMIA IS UNDETECTABLE.
HERE IS THE DESIGN OF OUR STUDY.
AS WE SAID, WE ARE THE YOUNG KID
ON THE BLOCK, WE JUST STARTED
LAST YEAR, THIS IS ALL IN THE
PROCESS.
WE WILL USE THE BARCODE SHIV TO
INFECT THE AN MALTS ANIMALS ANDL
START ANTIRETROVIRAL THERAPY.
AS SOON AS DETECTABLE, WE WILL
DETERMINE WHAT IS THE SIZE OF
THE RESERVOIR AND WE WILL
IMMUNIZE THE ANIMALS WITH THE
MRNA EXPRESSING THE ASSOCIATE
TRIMER.
DURING THE ROUNDS OF
IMMUNIZATION, WE WILL ALSO
ADMINISTER A COCKTAIL OF LATENCY
REVERSING AGENT SO THAT WE'RE
TRYING TO DEFINE AT THE MOMENT,
AND IN ORDER TO MAKE SURE THAT
WE CAN REACTIVATE THE RESERVOIR
AT THE TIME THAT WE'RE INDUCING
THE IMMUNE RESPONSES.
AT THIS POINT, WE WILL EVALUATE
THE IMMUNE RESPONSES AND THE
SIZE OF THE RESERVOIR AT THE END
OF THE IMMUNIZATION AND COMPARE
THAT TO THE TWO CONTROL GROUPS,
ONE OF WHICH WILL RECEIVE
POLYCLONAL AGG AND MONOCLONAL
ANTIBODIES THAT WERE DERIVED
FROM THE PROTECTED ANIMALS.
WHAT IS THE SIZE OF THE
RESERVOIR ACROSS THESE THREE
GROUPS WILL TELL US HOW
SUCCESSFUL THIS STRATEGY WAS, AS
WELL AS WHAT IS THE TIME OF
REBOUND AND THE COMPOSITION OF
THE RESERVOIR IN THESE ANIMALS.
THERE IS ALSO ANOTHER STRATEGY,
ANOTHER GOAL THAT WE WANT TO
ACHIEVE, AND THIS IS TO TEST THE
POSSIBILITY THAT AFTER
DELIVERING THE VACCINE, CAN WE
ALSO DELIVER A COCKTAIL OF
MONOCLONAL ANTIBODIES AND
IDENTIFY WHAT CAN BE THE --
EFFECT OF MONOCLONAL ANTIBODY
AND VACCINE IN SEQUENCE.
AND I'M NOT GOING TO SHOW THE
DESIGN OF THIS AT THIS POINT,
BUT IN TERMS OF
IMMUNOMONITORRING, WE WILL
CHECK -- RESPONSES, THESE ARE
ALL INVOLVED IN THE SIZE OF THE
RESERVOIR AS WELL AS WHERE THE
VIRUS IS INSERTED IN
TRANSCRIPTOMIC PROFILE.
THE EXPECTED OUTCOME IS THAT
THIS STRATEGY WILL ALLOW US TO
DETERMINE THE INDIVIDUAL AND
SEQUENTIAL IMPACT OF A
THERAPEUTIC VACCINE, INFUSION,
IN TIME TO REBOUND.
BUT WE KNOW WE CAN HEARD A LOT
TODAY ABOUT WHAT CAN WE DO AT
TIME OF ART INITIATION.
THIS THE STRATEGY WE WANT TO
PURSUE IN THIS PROGRAM, TO START
OUR IMMUNOTHERAPY AT THE TIME WE
START ART.
SO THIS IS OUR SECOND STRATEGY.
AND TO FIND WHAT THE MECHANISM
THAT CAN BE ABLE TO ERADICATE
THE RESERVOIR.
AND HERE IS ESSENTIALLY ALL THE
ARROWS, THE ART STARTS BUT THE
VACCINE IS DELIVERED AT THE SAME
TIME, WE WILL CHECK THE
RESERVOIR AND THEN WE WILL GO IN
WITH THE SECOND ROUND OF THE
VACCINE BOOST, AND MONOCLONAL
ANTIBODY INFUSION.
THIS IS THE DESIGN, IS AFTER
INFECTION WITH THE VIRUS, WE
WILL DELIVER ART AND VACCINE
WITH ONE CAVEAT.
THE VACCINE WILL NOT JUST BE
DESIGNED ON ONE SEQUENCE.
THE VACCINE WILL BE DESIGNED
BASED ON WHAT WE LEARN ABOUT THE
BREAKTHROUGH INFECTION IN FOCUS
ONE FOR -- RESERVOIR IN FOCUS
TWO, WHAT ARE THE VARIANCE OF
THE ENVELOPE, CAN WE USE THEM.
MOREOVER, WE WILL ALSO INCLUDE
MRNA THAT CAN DELIVER TARGET FOR
CD8 RESPONSES.
AT THIS POINT, WE WILL LET THE
SYSTEM REST, AND WE WILL GO IN
WITH AN ADDITIONAL BOOST THAT
WILL BE FOLLOWED WITH THE
INFUSION OF LRAs, AND
SUBSEQUENTLY, MONOCLONAL
ANTIBODIES.
WE HAVE -- THE SIZE OF THE
RESERVOIR WILL BE EVALUATED AT
THE END AND COMPARED TO OUR
CONTROL.
AT THE END, WE WILL STILL GO
INTO OUR INTERRUPTION, TIME TO
REA BOUND,REBOUND, AND COMPOSITE
RESERVOIR.
SO THE EXPECTED OUTCOMES ARE TO
EXPAND THE BREADTH OF THE
RESPONSES AND PUT THE IMMUNE
SYSTEM AHEAD OF THE INSUR JENS H
THE ADDITION OF NEUTRALIZING
ANTIBODY IN HLA-E ANTIBODY
COMPLEXES COMBINATION.
WHAT ARE THE KEY QUESTIONS THAT
WE'RE GOING TO TRY TO ADDRESS IN
THE UPCOMING YEARS.
CAN WE USE MRNA BASED VACCINE TO
INDUCE HIGHLY EFFECTIVE
ANTIBODIES CAPABLE OF PREVENTING
THE INFECTION OF OUR CELLS ALONG
WITH CELLULAR RESPONSES TO
ELIMINATE THE CELLS WHERE THE
VIRUS IS HIDING?
AND CAN WE COMBINE THE
VACCINATION WITH THE INFUSION OF
ANTIBODY BASED MOLECULES SUCH
THAT THE KILLER CELLS OF OUR
IMMUNE SYSTEM CAN RECOGNIZE THE
INFECTED CELLS IN A WAY THAT IS
UNIVERSAL AND NOT RESTRICTED BY
THE GENETIC-BASED DIFFERENCES IN
EACH INDIVIDUAL'S IMMUNE CELLS?
THE OUTCOME IS THAT WE WANT THE
STUDIES CONDUCTED IN ANIMAL
MODELS TO BE HIGHLY APPLICABLE
TO THE CLINICAL SETTINGS.
AND WHAT ARE THE NEXT STEPS?
WELL, WE JUST STARTED.
AND AGAIN, THANKS TO ALL THE
COLLABORATORS, AND HAPPY TO
ANSWER QUESTIONS.
[APPLAUSE]
>> SO WE HAVE TIME FOR
QUESTIONS.
GO AHEAD.
-- ARE YOU THINKING ABOUT DOING
IM OR IV INJECTION, WHAT'S THE
PLAN?
>> RIGHT NOW THE MRNA WILL BE
DELIVERED IN THE SAME WAY THAT
WE ARE DELIVERING THE COVID
VACCINE MRNA.
THIS IS OUR FORMULATION.
THE LATEST ONE HAS A NUMBER 315,
AND THIS IS WHAT IS GOING TO BE
IN THE CLINIC, AND THIS IS WHAT
WE'RE WORKING ON WITH THE TEST
TO ENCAPSULATE THE MRNA.
>> AND IM, I'M ASSUMING?
>> YES.
>> SO SINCE NO ONE ELSE WILL ASK
THIS, I WILL ASK THOSE WERE
CADI-CODED VIRUSES?
>> YES.
>> KT BARCODED.
>> I KNOW, I KNOW.
>> BUT YOU DON'T WANT TO POINT
IT OUT BECAUSE YOU'RE ONLY GOING
TO FEED HIM AND HE'S GOING TO
GET WORSE.
>> THAT'S A HARD QUESTION TO
FOLLOW, BUT I'LL TRY.
QEE DOUGUIDO, CAN YOU TALK ABOUE
RATIONALE FOR HOW YOU CHOSE THE
TIMING OF VACCINATION, WE'RE
WAITING FOR ART SUPPRESSION,
PRESUMABLY BECAUSE OF IMMUNE
ACTIVATION BUT WERE THERE OTHER
FACTORS IN THINKING ABOUT THE
TIMING?
>> SO THE FACT IS THAT I CAN
MAKE A CLINICAL REMARK THAT WE
HAVE 39 MILLION PEOPLE LIVING
WITH HIV WHO HAVE BEEN ON ART
FOREVER AND THEY'RE WAITING FOR
A STRATEGY THAT CAN REALLY BE
IMPLEMENTED.
SO YES, WE CAN DO FOR EARLIER
IMMUNIZATION, AND THIS IS WHAT
WE'RE TRYING DO IN STRATEGY TWO.
WE'RE LOOKING FORWARD FOR
UNFORTUNATELY THE NEXT ROUND OF
INFECTIONS WE HAVE TO DEAL WITH,
BUT WE STILL HAVE TO THINK ABOUT
HOW WE IMPACTED THE RESERVOIR IN
THOSE PEOPLE LIVING WITH HIV.
AND THAT'S WHY WE TRIED TO LET
THE IMMUNE SYSTEM REST AS MUCH
AS POSSIBLE, AND THIS, WE THINK,
IS ALSO GOING TO BE A
TRANSLATIONAL ASPECT AS I SAID
WITH THE ACTG TRIAL THAT IS
COMING UP.
DOES THAT MAKE SENSE?
>> IT DOES, THANKS.
[APPLAUSE]
>> WE HAVE ONE MORE QUESTION.
>> I JUST WANTED TO ASK, WHAT'S
THE RATIONALE FOR USING THE
MONOCLONAL ANTIBODIES DURING
ART, TREATMENT WITH --
>> SO THE MONOCLONAL ANTIBODY,
MAYBE I WASN'T CLEAR, I'M SORRY,
BUT WE WILL ADMINISTER THEM
WHILE WE ARE ALSO ADMINISTERING
LATENCY REVERSING AGENTS.
IF YOU -- SORRY, DIDN'T POINT
OUT SPECIFIC DETAILS BUT IF YOU
LOOK THE MONOCLONAL ANTIBODIES
ARE ALWAYS DELIVERED IN
COMBINATION BECAUSE WE THINK
THAT THERE IS A BETTER WAY TO --
FOR THEM TO WORK IF THE ANTIGENS
ARE EXPRESSED RATHER THAN TO
WAIT FOR NATURAL REACTIVATION
THAT COULD OCCUR DURING THE
PLIPS THABLIPS THAT WE KNOW.
>> I ACTUALLY ALSO HAVE A
QUESTION BOTH FOR ERIC AND
GUIDO.
YOU KNOW WHEN YOU LOOK AT YOUR
PROPHYLACTIC VACCI VACCINE PARTD
THERAPEUTIC PART, DO YOU USE THE
SAME VACCINE OR DO YOU
REFORMULATE OR CHANGE THE DOSING
SCHEDULE OR HOW DO YOU APPROACH
THESE TWO PARTS OF THE
CONSORTIUM?
>> SO FOR THE EMORY CONSULTING,
WE ARE USING THE SAME VACCINE
APPROACH BECAUSE IT'S A
HETEROLOGOUS VIRAL VECTOR
APPROACH.
SO THE VECTORS ARE NOT
INTERFERING WITH ONE ANOTHER.
BY ANTIVECTOR RESPONSES.
AND WE'RE PLANNING TO USE
EXACTLY THE SAME SCHEDULE OF
VACCINATION AS WE DID IN OUR
PROPHYLACTIC VACCINE APPROACH
THAT WAS PROTECTIVE.
WHERE WE ARE GOING TO BE
VACCINATING BEFORE ART AND THEN
BOOSTING DURING ART, WE WILL USE
A DIFFERENT VECTOR SET, AND
WE'RE STILL DETERMINING WHAT THE
OPTIMAL VECTORS WILL BE FOR
THAT, BUT THEN TO AVOID
ANTIVECTOR RESPONSES BEING --
INTERFERING WITH THE BOOST.
>> GUIDO?
>> DID YOU WANT TO SAY SOMETHING
AS WELL?
>> GUIDO, IF YOU'RE WATCHING, WE
HAVEN'T TALKED TO YOU ABOUT THIS
YET.
GUIDO SYLVESTRI.
>> WE WILL DO IT THE SAME WAY,
THE SAME VACCINE, THERE WILL BE
A LITTLE DISCONNECT, WE'RE GOING
TO USE THE SAME VACCINE IN FOCUS
TWO AS IN FOCUS ONE.
AND WE WILL DEVELOP A FOCUS TWO
BASED ON THE RESULTS.
ANY INDUCTION OF ANTIBODY
RESPONSES IN FOCUS ONE, SO FOCUS
TWO FOLLOWS IN THEIR -- WILL
FEED FROM FOCUS ONE.
>> WILTON, DO YOU HAVE ANYTHING
TO ADD?
>> VERY EXCITED TO BE PART OF
THE CONSORTIUM AND JOIN THE CURE
BECAUSE I'VE ALWAYS BEEN ON THE
VACCINE SIDE OF THINGS.
>> THANK YOU VERY MUCH FOR TWO
EXCELLENT PRESENTATIONS.
AND WE MOVE ON TO THE NEXT
COLLABORATORY.
[APPLAUSE]
>> HELLO AGAIN.
I AMELIEI AM LEIA NOVACK.
IT IS MY PLEASURE TO INTRODUCE
THE BEAT-HIV COLLABORATORY.
BASED AT THE WISTART INSTITUTE,
LED BY THREE PRINCIPAL
INVESTIGATORS, LUIS MONTANER,
JIM RILEY FROM THE UNIVERSITY OF
PENNSYLVANIA AND ALSO BOB
SILICANO.
WITH THAT, I WILL HAND IT OVER
TO LUIS TO GET STARTED.
>> THANK YOU FOR THE OPPORTUNITY
TO REPRESENT THE TEAM.
I'M BASICALLY THE WARMUP TO FOUR
STORIES THAT YOU'RE GOING TO
HEAR ABOUT, MOSTLY UNPUBLISHED.
LASTLY FEATURING A COMMUNITY
FOCUSED SOCIAL SCIENCE AGENDA
WHICH HAS BEEN REALLY PRODUCTIVE
AS WELL.
I WOULD LIKE TO GIVE YOU AN
OVERVIEW OF OUR TEAM AND SOME
HIGHLIGHTS OF WHERE WE'RE HEADED
REGARDING STRATEGIES AND ONGOING
WORK THAT'S DEFINING THIS YEAR
AND THE NEXT COMPLETION OF THE
AWARD.
I THINK WE'VE BEEN REALLY
FORTUNATE TO RECRUIT AND RETAIN
A LARGE NUMBER OF INVESTIGATORS
THROUGHOUT OUR TENURE AND THIS
CONTINUES.
AND OUR WEBINAR SERIES ARE OPEN
TO ANYONE, SO IF YOU WANT TO BE
PART OF IT, PLEASE REACH OUT.
MANY OF THE COLLABORATORIES
PARTICIPATE ON THE -- THAT WE
SPONSOR.
PART OF THE OBJECTIVE IS TO
HIGHLIGHT THE INITIATIVES THAT
WE CAN COLLABORATE WITH, AND WE
HAVE BEEN VERY ACTIVE IN THAT
REGARD IN CONNECTING PEOPLE AND
WE CAN REFLECT THAT IN THE
RECORDS OR PUBLICATIONS THAT
INCLUDE TWO, THREE OR MORE OF
OUR INVESTIGATORS IN THE SAME
PUBLICATION.
I JUST HIGHLIGHTED FOUR EXAMPLES
IN RED ARE THE COLLABORATORY
MEMBERS, JUST TO HIGHLIGHT THAT
ONE OF THE MISSIONS THAT WE WANT
TO PROMOTE IS COLLABORATION AND
THAT RELATES TO PUBLICATIONS.
ONE OF THE SUCCESSES THIS YEAR
IS REALLY THE MOVEMENT OF SOME
OF OUR INITIATIVES, PARTICULARLY
BEING LED BY JEANNE RILEY AND
UPON BLOW TAVAS ON THE GENE
THERAPY APPROACHES THAT COULD
ACTUALLY BE IMPLEMENTED IN THE
CLINIC.
WE WERE VERY FORTUNATE TO HAVE
THE OPPORTUNITY TO TAKE
ADVANTAGE OF THE NEW ACTG SMALL
CLINICAL TRIALS INITIATIVE TO
MOVE A NEW SORT OF STRATEGY
UNDER JIM AND PABLO, AND
BASICALLY THE STRATEGY IS TRYING
TO ENHANCE THE FREQUENCY OF
CAR-T CELLS BY GIVING
VACCINATIONS DURING THE PERIOD
OF ART WHEN THE CARs ARE
PRESENT, DOING SO WITH THE
CONSTRUCTS WITHIN THE CAR
ITSELF, THAT HAVE ALREADY BEEN
NOTED TO PROTECT AND ALSO TARGET
HIV INFECTED CELLS THROUGH CD4.
AND THE DNA ENCODED VACCINE IS
ALSO ANOTHER CONNECTION TO THE
BEAT THROUGH DAVID WEINER.
WE ALSO INITIATED A MORE FORMAL
WORKING GROUP AND THIS INCLUDES
THE HLA-E, THE GENE MODIFIED IN
CASE, THE BITES INITIATIVE AND
ALSO CLINICAL DEVELOPMENT IDEAS,
SO THIS HAS BEEN TSH AND YOU'RE
GOING TO HEAR A DISCUSSION ABOUT
ECD 4-IG AND THERE'S A COUPLE
POSTERS THAT ALSO RELATE TO THIS
AGENDA.
I THINK ON GOING, WE CONTINUE TO
BE FOCUSED ON TRANSLATIONAL
INITIATIVES.
YOU'RE GOING TO HEAR WITHDREW
WIESSMAN THAT TED IS GOING TO
PRESENT.
ALSO THERE'S A POSTER ON
NOVEL -- USED BY NATURAL HEALERS
WE'RE TRYING TO MOVE INTO
CLINICAL DEVELOPMENT.
AS FAR AS EFFECTOR STRATEGIES, I
LIST HERE SIX OF WHICH POSTERS
AND TALKS WOULD AGRES THE STORY
AND THE SOCIAL SCIENCE WHICH IS
PART OF OUR COMMUNITY
ENGAGEMENT, THERE'S THREE
POSTERS OUT ON THAT INITIATIVE
OUTSIDE, AND IN ADDITION TO
THAT, WE HAVE NOW BASICALLY
COMPLETED A VERY LARGE EFFORT ON
AT HOME VIRAL LOAD COLLECTION OF
DEVICES, OVER 5500 OF THESE,
WHICH WE HOPE TO REPORT AT QUOA
NEXT YEAR IF THE POSTERS
OBVIOUSLY GET ACCEPTED.
AND THEN WE ALSO ARE STARTING AN
INITIATIVE ON THE CURE IN SOUTH
AFRICA.
SO REGARDING THE BIOLOGY, I
THINK WE STILL CONTINUE TO MOVE
UNDER THE PARADIGM OF
UNDERSTANDING THE RESERVOIR WITH
MORE RESOLUTION, AND WE'VE GONE
FROM OBVIOUSLY INTACT TO
DEEIVETTIVE TO GENOMIC,
NON-GENOMIC, REPRESSED, AND
WE'RE NOW IN THE EPIGENETICS
TISSUE MICROENVIRONMENT AND THE
DYNAMIC BETWEEN REPLICATION
COMPETENT AND IMMUNE RESPONSES,
AND THERE'S A POSTER OUTSIDE ON
THE KINETICS ON SIV THAT
BASICALLY SUGGEST WE NEED TO
WAIT A PERIOD OF UP TO TWO YEARS
TO SEE ADEQUATE DECAY, SO I
WOULD ACTUALLY ENCOURAGE YOU TO
LOOK OUT FOR THAT.
THERE'S A DISCUSSION FROM YACHI
HO ON WHERE THE RESERVOIR SITS
AND WE HAVE SEVERAL
INVESTIGATORS LOOKING INTO THAT.
IN ADDITION TO THE WORK WITH TOM
AND YACHI ON RETENTION OF
RESERVOIR BETWEEN BLOOD AND
TISSUE, THAT'S ALSO A VERY
ACTIVE AREA WITHIN OUR GROUP.
AND THE SILICANO INITIATIVE ON
HOST FACTORS AND ANTIBODY, I
THINK WE'LL TALK ABOUT THAT BUT
WE'VE ALSO CONTRIBUTED TO THAT.
SO WITH THAT, I NEED TO THANK
ALL OUR RESEARCH PARTICIPANTS
FOR THE CONTRIBUTION OF ALL OF
THESE STUDIES, AND I WANT TO
HIGHLIGHT THAT WE ALSO JUST
REDID OUR WEBSITE, SO PLEASE
VISIT IT, IT HAS A LOT MORE
COMMUNITY FEATURES AND VIDEOS,
AND PART OF OUR MISSION OF
EDUCATING THE COMMUNITY ALSO
INCLUDES EDUCATING OUR PROVIDERS
WHICH ARE REALLY THE GATEKEEPERS
FOR RECRUITMENT TO SOME OF OUR
TRIALS.
AND WE'RE FORTUNATE ENOUGH TO
FEATURE A VIDEO THAT HIGHLIGHTS
THE BEAT-HIV PROGRAM 7 MINUTES
AND IF YOU -- TODAY IS WHEN ID
WEEK, THE LARGEST INFECTIOUS
DISEASE MEETING STARTS IN
BOSTON.
IF YOU GO TO THEIR WEBSITE AND
GO UNDER ID TV, YOU'LL SEE THAT
THE BEAT-HIV HAS A VIDEO THERE
INSTRUCTING THE PROGRAM ABOUT
WHAT THE MARCHING DELANEY
PROGRAM IS AND WHY IT'S
IMPORTANT TO MOVE FORWARD.
SO WITH THAT, I WANT TO THANK
OBVIOUSLY THE TEAM, THIS IS THE
GROUP THAT FINALLY MET AFTER
COVID, AND ALL OF THE SUPPORT
AND DIVISION OF NIH, AND WITH
THAT, I WILL HAND IT OVER TO
YA-CHI, WHO WILL START THE
DISCUSSIONS ON THE RESEARCH.
THANK YOU.
[APPLAUSE]
>> THANK YOU, LEWIS.
THANKS TO THE ORGANIZERS FOR THE
OPPORTUNITY TO PRESENT OUR WORK.
TODAY I'M GOING TO SHARE SOME
WORK FROM OUR LAB INCLUDING
THREE VERY TALENTED YOUNG
STUDENTS AND POSTDOCS.
DESPITE YEARS OF RESEARCH,
WHAT'S STILL PUZZLING IS THAT
HOW MUCH HAVE WE LEARNED ABOUT
LATENT RESERVOIR?
SUPPOSE AFTER REVERSAL ALL THESE
ARE EXPRESSING PROTEINS --
SOMETIMES THEY DON'T.
THE SECOND, SOMETIMES THEY
DON'T, WHY?
THIRD, NOT ONLY JUST SIT THERE
OVER TIME, THEY PROLIFERATE FROM
ONE INTO MANY, MANY.
AND FOURTH, THESE HIV INFECTED
CELLS ARE HIGHLY HETEROGENEOUS.
IMAGINE THAT IF WE STUDY THESE
CANCER MUTATIONS THROUGH
DESIGNED SPECIFIC TREATMENT,
HAVE WE KNOWN ENOUGH ABOUT THE
HETEROGENEITY OF HIV-INFECTED
CELLS?
SO BASICALLY WE HAVE THIS ONE
IMMEDIATE PROBLEM THAT ONLY
ONE -- CONTINUES INFECTIOUS HIV
SO IT LIKE A NEEDLE IN THE
HAYSTACK OR NEEDLE IN THE
NEEDLESTACK PROBLEM BECAUSE WE
DON'T UNDERSTAND WHERE TO FIND
THEM AND WHAT THEY LOOK LIKE.
T-CELLS -- FOR US TO TRY TO
UNDERSTAND HIV RESERVOIR IS HARD
AS TRYING TO FIND THESE BLACK
HOLES IN THE MIDDLE OF THE
GALAXY.
AND THIS IS WHY WE LIKE TO TAKE
A SINGLE CELL APPROACH BASICALLY
TO TALLY DOWN THE -- FOR T-CELLS
AND FIND THOSE RARE HIV INFECTED
CELLS INSTEAD WHICH BASICALLY
PROFILES 99.9% OF UNINFECTED
CELLS.
USING GENOME WIDE PROFILING, WE
HOPE TO HAVE A MORE -- OF THESE
CELLS INSTEAD OF TARGETED
PROFILINGLY WILL NEED TO BE
BASED ON EXISTING KNOWLEDGE.
THIS HAS BEEN A VERY EXCITING
YEAR.
FIND A GROUP OF HIV-POSITIVE
CELLS FOR PROFILING.
THEY USED -- TO RECONSTRUCT THE
PROVIDER GENOME WITH COUPLED AND
SINGLE CELL PROTEIN EXPRESSION
PROFILES.
VINCENT U AND MICHAEL BETTS
USED -- TO USE A TRANS POE ACE
TO DETECT HIV DNA COUPLED WITH
SINK EL CELL PROTEIN PROFILES.
EXCISE SEQ AND DOGMA SEQ TRYING
TO UNDERSTAND HIV INFECTED CELLS
THROUGH -- BASICALLY FROM DNA,
RNA, AND PROTEIN EXPRESSION.
SO WE FIRST STARTED WITH TRYING
TO UNDERSTAND THESE HIV RNA
POSITIVE CELLS THAT ARE
TRANSCRIPTIONALLY ACTIVE.
WE COLLABORATED WITH FRED HUTCH,
BASICALLY WE TOOK BLOOD SAMPLES
FROM PEOPLE HAVING HIV HAVING
VIREMIA AFTER VIRAL SUPPRESSION
TO SEE WHAT HAPPENED THROUGHOUTT
TIME.
IT'S LIKE -- USING THESE
COUPLING OF BARCODES, YOUR CELL
AND REAGENTS, NOW WE CAN SEE ALL
THESE DIFFERENT MODALITIES
WITHIN THE SAME SINGLE CELL.
FOR EXAMPLE, USING
TRANSCRIPTIONAL ANALYSIS, WE CAN
LOOK AT THESE T-CELL PROFILES.
USING SURFACE PROTEIN STAINING,
YOU CAN SEE WHICH ARE NAIVE
VERSUS CENTRAL MEMORY.
WE CAN SEE WHICH CELLS ARE
HIV-POSITIVE, AND T-CELL
RECEPTOR SEQUENCE, WE CAN SEE
WHICH ARE THE CELLS THAT
PROLIFERATED MOST IN THE BODY.
DARK BLUE REGION, THESE ARE THE
MANY CELLS HAVING THE SAME
T-CELL RECEPTOR SEQUENCE, THESE
ARE THE CELLS THAT REALLY
PROLIFERATED INTO MANY, MANY.
BY TRACKING THESE CELLS THAT
PRIF LATE TO MANY, BACK TO THE
TRANSCRIPTOME, WITH YOU KNOW IT
IS A SITE OF TOXO -- MOST IN THE
BODY.
TRYING TO CARE HIV RNA POSITIVE
CELLS VERSUS UNINFECTED CELLS,
THEN WE CAN SEE IN ADDITION TO
ACTIVATION MARKERS AND --
MARKERS THAT PEOPLE HAVE
IDENTIFIED IN THE FIELD AS
MARKERS FOR HIV INFECTED CELLS,
WE FOUND THAT HIV INFECTED CELLS
ARE ENRICHED IN CYTOTOXIC CD4 --
THIS STUDY HAS BEEN
RECAPITULATED -- B S THESE ARE S
THAT PROLIFERATED SO WELL, AND
SECOND, THEIR NATURAL JOB -- TO
KILL THE TARGET CELLS, BUT TO
PREVENT SELF INFLICTED INJURY,
THESE CELLS WOULD ALSO MAKE THIS
SPER PIN B9.
THE PROBLEM IS WHEN HIV INFECTS
IT, THE CD8 T-CELLS WANT TO KILL
THTHE INFECT -- T-CELL KILLING
WHEN CHRONIC INTERSTIMULATION
CONTINUES THESE CELLS MAY
CONTINUE TO PROLIFERATE.
USING HIV RNA MAPPING WE
IDENTIFY TRANSCRIPTIONAL --
HOWEVER -- WHICH DO NOT EXPRESS
VIRAL RNA CANNOT BE CAPTURED
THIS WAY, SO USING THE SAME
COALITION, WE USE A DIFFERENT
APPROACH, DONE BY A VERY TALENT
THED POSTDOC AT ULONG.
YOU CAN USE ATAC SEQ, RNA SEQ
AND PRO FILING ALL TOGETHER
WITHIN THE SAME SINGLE CELL.
BY MAPPING IN THE TRANSCRIPTOME,
NOW WE CAN SEE THESE INFECTED
CELLS WITH THEIR ATAC
TRANSCRIPTOME AND PROTEIN
EXPRESSION PROFILE, IN EVERY
SINGLE DOT THAT YOU SEE ON THIS
FILE.
WE CAN ALSO SEE HIV DNA AND HIV
RNA INSIDE THESE CELLS.
SO TAKING THEM ALL TOGETHER, NOW
WE CAN IDENTIFY THOSE HIV
LATENTLY AFFECTED CELLS WHICH
ARE POSITIVE HIV DL DNA BUT MAYE
STILL EXPRESSED BUT BELOW THE
DE -- THIS IS THE FIRST TIME
WE'RE ABLE TO IDENTIFY THE
SINGLE CELL PROFILE OF LATENTLY
AFFECTED CELLS.
WE CAPTURE THEM BOTH DURING
VIREMIA AND AFTER VIRAL
SUPPRESSION.
SO NOW WE CAN LOOK AT THE
SELLING ENVIRONMENT IN DIFFERENT
WAYS.
FIRST USING ATACSEQ --
DIFFERENTIATION WHILE THE
ACTIVELY INFECTED CELLS --
ACTIVITY.
WHEN I LOOK -- I THOUGHT IT WAS
EXACTLY THE SAME BECAUSE THEY
WERE LATENT.
NOW WE FOUND THERE'S STILL SOME
DIFFERENCE, THAT THERE ARE
DIFFERENCES IN GENE EXPRESSION
THAT WE COULD TELL THESE APART,
ESPECIALLY FOR THE -- ACCURATELY
DESCRIBED CELLS.
-- T-CELL RESPONSES,
L2 PRODUCTION, ALPHA 4 WHICH HAS
BEEN PREVIOUSLY REPORTED AS A
MARKER FOR IMMUNE INFECTED CEL
CELLS.
KNOWN TO TEACH INDUCING B CELL
TWO EXPRESSION, INTO THIS GENE,
HAS BEEN PREVIOUSLY REPORTED IN
DIFFERENT STUDIES.
IN GENE IS AMAZING BECAUSE WHEN
WE TRIED TO FIGURE OUT WHY --
DON'T DIE OF CYTOPATHIC EFFECTS.
THEY SHOULD DIE, THEY DIDN'T.
SO WE IDENTIFIED THIS
PROLIFERATION SURVIVAL PROGRAM
THAT THERE ARE GENES COEXPRESSED
WITH PROLIFERATIVE MARKER.
THESE -- AND IKC OF 3,
SUGGESTING THAT ICZ OF THREE
WHWHEN WE INFECT T-CELLS WITH
DIFFERENT VIRUSES, THESE WERE
INCREASE -- EXPRESSION AND THESE
HIGHER LEVELS, IKZF3 -- MAY
INDUCE -- AND HELP
PROLIFERATION.
FINALLY, THE PROTEIN MARKERS ORE
SIMILAR TO -- WE SEE SOME T
MARKERS FOR THESE LATENTLY
AFFECTED CELLS.
BY THE END, ALL OF THESE
TRANSCRIPTOME DATA PUTTING THE
TOGETHER, WE NOW SEE THE PICTURE
OF THESE HIV INFECTED CELLS, BUT
ALL OF THEM TOGETHER WE FOUND
THEY ARE RETROGENUS, YES, BUT
THEY ARE SELF -- DICTATING THE
FATE OF THESE CELLS.
-- WILL ACTIVATE SELF
PROLIFERATION AND ACTIVATION
MARKERS.
SOME CELL WILL DIE OF VIRAL
CYTOTOXIC -- SOME CELLS UNDER
AP1 DRIVEN TRANSCRIPT ACTIVATION
OF TNF ALPHA -- THIS HELPS A
LOT -- BUT WHAT DO WE DO WITH
THE DISH EU?
WE CA CAN DO A SINGLE CELL ANASS
THE PROBLEM IS WE MISSED THE
INTERACTION PART BETWEEN CELLS.
TRY TO PROFILE THESE INFECTED
CELLS AND THEY'RE AT RESOLUTION
WHICH IS THE MIXTURE OF CELLS,
10-MICRON RESOLUTION USING
SPATIAL -- WITH THAT TAKING CLAB
RAYTIVE SAMPLES FROM TOM
HAUPT -- DURING THE EARLY
REBOUND PHASE FOUR DAYS AFTER
TREATMENT INTERRUPTION SO WE CAN
EXTEND OUR SCOPE FROM BLOOD INTO
TISSUE AT THE SPATIAL LEVEL.
SO SUMMARY FOR THE EXEUNT.
THE KEY QUESTION IS HOW DO WE
ADVANCE THE HIV CURE FIELD?
IT TOOK US 13 YEARS TO FIND THE
RESERVOIR, 22 YEARS TO DEFINE
THE QUANTITY OF THEM.
NOW THAT WE'RE NOT SATISFIED
WITH HOW MANY AND WHAT ARE THEY,
WE WANT TO UNDERSTAND WHY AND
HOW HIV PERSISTS.
SO BEYOND HIV OR RNA SEQUENCING,
DNA SEQUENCING, WE CAN NOW LOOK
AT THE CIVIL LANDSCAPE CH THESE
HIV INFECTED CELLS.
IDENTIFIED MARKERS IN TARGETS
THAT CAN BE -- HELPING PROVISION
OF HIV INFECTED CELLS -- TO BE
KILLED BY THE IMMUNE SYSTEM,
BOTH CAN BE TARGETED BY DRUGS
USED IN THE CANCER FIELD.
FINALLY, WE ARE BUILDING A MAP,
A HIGH RESOLUTION GENOME-WIDE
SINGLE CELL MAP FOR US TO
UNDERSTAND BETTER ABOUT THE
HETEROGENEOUS HIV RESERVOIR, AND
WE'RE HOPING TO USE THIS TO
GUIDE.
WITH THAT I'D LIKE TO THANK THE
STUDY PARTICIPANT IN OUR LAB AND
THE FUNDING SOURCES.
THANK YOU.
[APPLAUSE]
>> GOOD AFTERNOON, EVERYONE.
I'M VERY HAPPY TO BE HERE TO
INTRODUCE OUR WORK FOR DNA ECD
4IG TO DECREASE THE HIV-1
RESERVOIR AND ALSO TO DELAY THE
VIRAL REBOUND THROUGH IL15
TRANSGENIC BLT MICE.
THE KEY QUESTION WE WANT TO ASK
IS, CAN DNA DELIVERED THERAPY
ACT TO DETECT OR PLAN TO KILL
HIV INFECTED RESERVOIR CELLS
DURING ART SUPPRESSION, AND ALSO
DELAY VIRAL REBOUND IF
ADMINISTERED?
AND WE FIND USING HUMANIZED
MICE, DNA DELIVERY TOGETHER WITH
ENZYMES THAT OPTIMIZE ITS
EXPRESSION REDUCE RESERVOIR ART
AND DELAY THE VIRAL REBOUND BY
PROVIDING KILLER CELLS BY USING
A SPECIFIC PART OF ECD 4IG.
DATA SUPPORTS A NOVEL TREATMENT
STRATEGY THAT COULD BE EXTENDED
TO HUMAN TESTING ALONE, OR AS
PART OF AN ERADICATION STRATEGY.
ECD 4-I GWAS INVENTED BY --
GROUP AND INCLUDES ONE PART OF
THE CD4 D1-D2 DOMAIN FOR BINDING
SITE AND THE CCR5 MIMETIC
PEPTIDE TO BIND WITH THE CD
CDR5 BINDING POINT.
UNAVOIDABLE ON THE ENVELOPE AND
WITH A HIGH POTENCY.
IT IS HARD TO BE ESCAPED.
AND WITH THIS, SEVERAL
PUBLICATIONS USE AAV EXPRESS THE
ECD IG TO SHOW THE DURABLE
PROTECTION THROUGH THE MULTIPLE
SIV OR SHIV CHALLENGE IN THE
RHESUS MACAQUE MODEL.
ALSO THERE IS WORK SHOWING THE
ECD-IG PROMOTES ACTIVITY THROUGH
BINDING TO THE RECEPTOR OF --
CELLS AND OUR PREVIOUS WORK SHOW
THE -- TO MEDIATE SULFATION IN
FURTHERING ENHANCE THE POTENCY
BY THREE FOLD.
WITH ALL OF THIS INFORMATION,
WE'VE HI HYPOTHESIZED IF WE
CODELIVER AND THE D2, WE MAY
REDUCE THE REGULAR SIZE AND
DELAY THE REBOUND IN VIVO.
WITH THIS HYPOTHESIS, WE START
OUR IN-HOUSE NSG HUMANIZED MICE
AND THE CHALLENGE ANIMALS WITH
HIV FOLLOWED BY THE VIREMIA AND
THE ART SUPPRESSION.
AND THEN WE GAVE THREE TIMES OF
THE INTRAMUSCULAR DELIVERY OF
THE EC5G AND -- DNA AND WE USE A
P VAX ANTIVECTOR AS A CONTROL.
AFTER THREE TIMES OF THE
TREATMENT, WE CANNOT FIND ANY
OBVIOUS DECLINE OF THE BODY
WEIGHT AND ALL OF THE MICE ARE
HEALTHY, BUT IN THE -- DERIVE
THE -- MICE, THE NK FREQUENCY IS
RELATIVELY LOW.
AND WE ONLY FIND A LONG ONE-WEEK
DELAY AND NOT TOO MUCH DELAY
COMPARED TO THE EMPTY CONTROL.
THEN WE FURTHER WANT TO IMPROVE
OUR SYSTEM AND WE USE
INTERLEUKIN 15 TRANSGENIC NSG
BLT DERIVED MICE SO SEE IF WE
CAN HAVE MORE -- THIS IS FROM
THE SPLENOCYTES OF BOTH MODELS.
THE NK CELL IS COLOR-CODED IN
PINK AND WE CAN SEE THE
INTERLEUKIN 15 TRANSGENIC BLT
MICE HAVE MORE ROBUST
ENVIRONMENT THAN NSG BLT MICE.
WITH THIS TRANSGENIC BLT MICE
WITH HIGHER NK FREQUENCY, WE
REPEATED WHAT WE THOUGHT IN
THOSE WILD TYPE NSG MICE.
AND EXCITINGLY WE FIND THAT THIS
MODEL WHICH HAVE THE MORE NK
FREQUENCY, THE ECD 4-IG TREATED
ANIMAL CAN DELAY THE REBOUND UP
TO SIX WEEKS COMPARED TO THE
EMPTY CONTROL.
THEN WE START TO THINK ABOUT
WHAT'S THE MECHANISM BEHIND THIS
BECAUSE AFTER WE START TO
INCREASE NK CELLS WE FIND THE
REBOUND IS FURTHER DELAYED.
THE HYPOTHESIS IS THIS WILL BE
AN FC MEDIATED REGION PROCESS.
WE USE A MUTATION VERSION OF
THE -- OTHER ARM AND REPEAT WHAT
WE HAVE DONE, AND THIS MUTATION
CAN PREVENT THE FC BINDING WITH
THE EFFECTOR CELLS.
FROM THE SURVIVAL CURVE, AND WE
CAN'T SEE THE -- CAN DELAY THE
REA BOUND UP TO SIX WEEKS, BUT
TO THE -- MUTATION DIMINISHED TO
THIS EFFECT, AND THE OUTCOME
COMPARABLE TO THE EMPTY VECTOR.
THEN FROM THE FLOW DATA, WE FIND
INTERESTINGLY THE CD4 -- THE
UPPER PANEL IS THE
CD4 DEPLETION, AND WE CAN FIND
THE COLOR-CODED OF THE ECD 4IG
ANIMAL TREATED IN RED AND THE
ECD 4 TREATED ANIMALS HAVE
PRETTY GOOD CD -- BECAUSE OF THE
REBOUND DELAY.
AND THE FURTHER WE FIND THAT ALL
OF THE ECD4IG TREATED ANIMALS,
THEY HAVE THE INCREASED NK
FREQUENCY, AND COMPARED TO THE
LA LA LA OR THE VECTOR CONTROL.
THEN WE WANT TO CONFIRM OUR
TREATMENT IN VIVO CAN PROMOTE
THE ADCC ACTIVITY THROUGH THE
BINDING TO FC RECEPTOR -- K
CELLS.
THE PANEL F, IT IS -- INSIDE OF
HUMANIZED MICE SERUM AND WE CAN
FIND CONCENTRATION -- ROUND YO
YOUR -- WHICH IS CONSISTENT TO
THE PANEL G IN THE ELI IS A DATA
AFTER EACH OF THE DNA TREATMENT,
THE PEAK OF THE EXPRESSION ALSO
AROUND THE 4 TO 6.
WE CAN FIND ONLY THE INTACT --
CAN GIVE OUT TO THE STRONG ADCC,
BUT THERE IS VERY MINIMUM ADCC
FROM THE CD8 T-CELLS OR FROM THE
LALEMIEUX TAITION OF THE ECD FOR
G.
FURTHER WE WANT TO INVESTIGATE
WHETHER OUR TREATMENT CAN REDUCE
THE INTACT VIRAL DNA AND THIS
INTERLEUKIN 15 TRANSGENIC MODEL,
AND WE DESIGNED EXPERIMENT TO
THE -- AND TO PREVENT GENERATE
MORE CLONES AND WE USE IPD ASSAY
IN THE MU HANNIZED MICE
SPLENOCYTES AND EXCITINGLY WE
FIND THE TREATED ANIMALS, THEY
HAVE THE SIGNIFICANTLY LOWER PRO
VIRAL DNA SIZE COMPARED TO THE
LALA AND THE VECTOR TREATED
MODEL.
ESPECIALLY THE INTACT PRO VIRUS.
AND THIS DNA ASSAY DOWN BY THE
NASCENT BOARD FROM BOB'S GROUP.
THEN WE WANT TO RECONFIRM WHAT
WE FOUND IN OTHER ASSAYS IN THE
TISSUE MEASURES FROM THE HUMAN
ICED MICEHUMANIZED MICE LYMPH N.
IN THE HUMANIZED MICE WE USED IN
THE STUDY, AND FROM THE
COLOR-CODED RESULT OF THE
CD4 IN -- AND THE HIV DNA
COLORED IN RED, AND WE MANUALLY
COUNT MORE THAN 1,500 CELLS PER
SLIDE, AND NORMALIZE THE RESULT
OF THE HIV-POSITIVE HARBORING
CELLS PER MILLION CD4 T-CELLS.
AND EXCITINGLY, CONSISTENTLY, WE
FIND THE ECD 4-IG TREATED
ANIMALS HAVE SIGNIFICANTLY LOWER
HIV HARBORING CELLS PER MILLION
CD4 T-CELLS.
CONCLUSION, THE -- THE DELAY OF
THE VIRAL REBOUND IN THE HIV
INFECTED INTERLEUKIN 15
TRANSGENIC BLT MICE AND OUR
TREATMENT ALSO DECREASED THE
TISSUE HIV PRO VIRAL DNA,
ESPECIALLY THE -- AND THE
MECHANISMS OF THIS ACTION, IT
IS -- TO THE PROCESS BECAUSE A
LOT OF MUCATIONS DIMINISH THIS
PROCESS AND ALSO OUR TREATMENT
PRO PLOATS ADCC ACTIVITIES
THROUGH -- FC RECEPTOR OF NK
CELLS RATHER THAN CD8 T-CELLS.
FURTHER INVESTIGATION REQUIRED
TO DETERMINE THE POTENTIAL OF
OUR TREATMENT TO CONTROL AND
CONTRIBUTE TO ERADICATION WHEN
USED ON AND AFTER ART
INTERRUPTION.
THANKS TO OUR CO-AUTHORS,
COLLABORATORS.
THANKS FOR YOUR ATTENTION.
[APPLAUSE]
>> HI.
MY NAME IS TIM KREIDER.
I'LL BE TELLING YOU TODAY ABOUT
CD4 TARGETED DELIVERY OF TAT
MRNA FOR REVERSING HIV LATENCY.
FOR OUR PLAIN IN ENGLISH SUMMAR,
THE KE QUESTION, CAN WE UNCOVER
THE HIDDEN VIRUSES WITHOUT
HARMING A PERSON OR THEIR CELLS.
WHAT WE ACCOMPLISHED IS, WE
COULD UNCOVER SOME HIDDEN
VIRUSES USING A TARGETED MRNA
GENE THERAPY.
AND THIS RELATES TO THE CARE
AGENDA BECAUSE LATENT VIRUSES
ARE HIDDEN FROM THE IMMUNE
SYSTEM AND OUR THERAPIES, SO WE
NEED NEW METHODS FOR UNCOVERING
THEM THAT ARE NOT TOXIC, AND
THIS IS IMPORTANT BECAUSE THIS
TYPE OF INTERVENTION COULD BE
PART OF A CURE STRATEGY AND MAY
TEACH US IMPORTANT LESSONS OF
HOW VIRUSES HIDE AND FLY UNDER
THE RADAR.
AS AN EXAMPLE, I'M SHOWING A
PICTURE OF TWO HOUSES WHERE A
VIRUS IS HIDING.
WE DON'T WANT TO DISORGANIZE THE
WHOLE HOUSE, TRYING TO FIND THE
VIRUS.
INSTEAD, WE WANT TO GO RIGHT
WHERE THE VIRUS IS, AND UNCOVER
IT.
SO AS SOME BACKGROUND, THIS
CROWD KNOWS THAT HIV CAN PERSIST
WITHIN PEOPLE LIVING WITH HIV AS
A LATENT PRO VIRUS DESPITE
COMBINATION ANTIRETROVIRALS.
LATENCY REVERSALS MAY BE A
NECESSARY ASPECT OF A DRUG-FREE
HIV CURE.
IN PREVIOUSLY USED LATENCY
REVERSING AGENTS EMPLOY MULTIPLE
MECHANISMS THAT LARGELY TARGET
THE HOST.
THIS INCLUDES OPENING UP
CHROMATIN, SIGNALING THROUGH
HOST PATHWAYS THAT DRIVE
TRANSCRIPTION, CHECKPOINT
INHIBITION, CD8 DEPLETION AND
MORE.
THE QUESTION WE TRIED TO ANSWER
ARE THERE VIRUS-SPECIFIC WAYS OF
REVERSING LATENCY?
TO ADDRESS THIS QUESTION, WE
RETURNED TO THE REGULATION OF
VIRAL TRANSCRIPTION.
DEPICTED HERE IS A GENOMIC MAP
OF AN INTERGREATE INTEGRATED VID
BY TWO -- THE 5 PRIME LTR, THE
TATA BOX IS INDICATED IN GREEN
AND IN FALL COLORS I HAVE A
COUPLE TRANSCRIPTION FACTOR
BINDING SITES KNOWN TO DRIVE
TRANSCRIPTION.
IT'S LARGELY REGULATED BY THE
PLENS OR ABSENCE OF A VIRAL
PROTEIN CALLED TAT.
IN THE ABSENCE OF TAT, THERE
ACTUALLY IS TRANSCRIPTION
INITIATION WITH THE
TRANSCRIPTION OF THE FIRST
APPROXIMATELY 16 NUCLEOTIDES OF
THE HIV GENOME.
THIS IS CALLED THE TAR STEM LOOP
AND IT FORMS A VERY TIGHT
HAIRPIN.
HOWEVER, TRANSCRIPTION
ELONGATION IS ARRESTED, AND THIS
LEADS TO THE ACCUMULATION OF
ABORTIVE TRANSCRIPTS WITHIN A
SELL.
CELL.
THIS LEADS TO MASSIVE CHANGES TO
TRANSCRIPTION WITHIN THE CELL,
WITH RELEASE OF THE
TRANSCRIPTIONAL COMPLEX FROM
NEGATIVE REGULATORS,
HYPERPHOSPHORYLATION OF RNA POL.
THE ULTIMATE RESULT IS A MASSIVE
ELONGATION OF TAR STEM LOOPS.
THIS RESULTS IN RNA
TRANSCRIPTION AND PROTEIN
EXPRESSION.
THIS HAS ACTUALLY BEEN SHOWN IN
SAMPLES FROM PEOPLE LIVING WITH
HIV TO BE AN IMPORTANT BLOCK IN
THE REVERSAL OF LATENCY AND I'LL
SHOW DATA FROM THE 2018 PAPER IN
WHICH THEY LOOKED AT A WIDE
VARIETY OF PEOPLE LIVING WITH
HIV AND QUANTIFIED THE DIFFERENT
RNA SPECIES WITHIN THEIR CELL.
EACH DIFFERENT COLOR IS A
DIFFERENT PERSON.
ON THE Y AXIS IS THE AMOUNT OF
RNA FOUND IN THAT CELL.
THE X AXIS IS DIFFERENT TYPES OF
RNA SPECIES.
YOU CAN SEE BY FAR THE MOST
ABUNDANT RNA SPECIES ARE TAR
STEM LOOPS, THOSE LITTLE
HAIRPINS I SHOWED YOU ON THE
LAST SLIDE.
WHEN THEY QUANTIFIED THIS,
NORMALIZING TO THE AMOUNT OF DNA
INTEGRATED IN THESE CELLS, THEY
ESTIMATED BETWEEN 89 AND 100% OF
CELLS MAKE THESE ABORTIVE
TRANSCRIPTS.
SO CAN WE SUPPLY EXOGENOUS TAT,
WE'VE GOT A COUPLE OF PROBLEMS
WITH THIS STRATEGY.
ONE, TAT IS POLYFUNCTIONAL, AND
TWO, IT KILLS CELLS.
SO SHOWN HERE IS A STRUCTURE OF
TAT.
IT'S ENCODED BY TWO EXONS WITH A
NUMBER OF FUNCTIONAL DOMAINS
THAT HAVE BEEN STUDIED OVER
DECADES OF RESEARCH.
I'M GOING TO SHOW YOU DATA
SHOWING ONE WILD TYPE TAT AND A
SECOND VARIANT THAT'S 86 AMINO
ACIDS IN LENGTH CALLED THE R5M4.
THE REASON R5 M4 WAS CHOSEN IS
BASED ON THIS 2016 PAPER IN
WHICH THIS VARIANT WAS FIRST
DESCRIBED.
THEY INCORPORATED A SERIES OF
ALANINE MUTATIONS IN THE
SEQUENCE OF TAT AND FOUND THAT
IT COMPLETELY ATTENUATED THE
CYTOTOXIC ASPECT OF THIS PROT
PROTEIN.
SHOWN HERE ARE PRIMARY CD4s
THAT THEY TREATED WITH EITHER
THE WILD VERSION OF TAT OR R5
M4.
AS YOU SEE THEY INCREASED THE
TYPE OF WILD TYPE TAT THEY PUT
ON THESE CELLS, THESE CELLS ARE
LESS VIABLE.
HOWEVER THE R5M4 SHOWED NO
IMPACT ON CELL VIABILITY.
SO WE TESTED THESE AT MRNAs IN
A CELL LINE THAT EXPRESSES --
UNDER THE CONTROL OF THE HIV
PROMOTER.
RNA EXPRESSING EITHER JR CSF,
R -- I INCLUDED A RNA ENCODING
OF FLUORESCENT PRO TEEFNLT ON
THE Y AXIS, I HAVE LUCIFERASE
SIGNAL AND ON THE X AXIS THE
DOSE.
CAN YOU SEE BOTH THE JRC --
POTENTLY TRANS ACTIVATE
EXPRESSION FROM THE HIV
PROMOTER.
AND THUS THESE CHANGES THAT ARE
SUPPOSED TO ATTENUATE
CYTOTOXICITY DO NOT IMPACT TRANS
ACTIVATION FUNCTION.
WE ALSO TESTED THIS IN THE JLA
T10 .6 MODEL OF LATENCY AND I
WON'T GO THROUGH ALL THE DATA
BUT SHOW YOU A SUMMARY OF A
DOSE-RESPONSE CURVE IN WHICH WE
PUT INCREASING AMOUNTS OF TAT
MRNA LRPs ON JLATS.
AS COMPARED TO THE NEGATIVE
CONTROL LUCIFERASE YOU SEE THAT
THERE IS A SIGMOID D AS L CURVE
WITH INCREASING DOSES OF TAT
LEADING TO MORE REACTIVATION OF
LAY TEBT HIV IN STLATENT HIV IN.
WE TOOK THE DOSE IN WHICH WE HAD
ABOUT 60% GFP POSITIVE CELLS AND
PERFORMED MULTIPLE PARAMETER
PROFILING ON THIS USING ATAC SEQ
AND SINGLE CELL RNA SEQ.
SHOWN HERE IS A PRINCIPAL
COMPONENT ANALYSIS RNA SEEK
COMPARING FOUR CONDITIONS.
IN PURPLE WE HAVE CELLS TREATED
WITH INCREDIBLY ACTIVATED -- AND
IN THE THREE OTHER COLORS WE HAD
EITHER CELLS TREATED WITH TAT
MRNA TWO DAYS PRIOR, LMPs
THREE DAYS PRIOR OR LUCIFERASE
MRNA LMPs THREE DAYS PRIOR.
WHAT I HOPE YOU TAKE FROM THIS
SLIDE IS THAT SHOWN IN PURPLE IS
COMPLETELY DIFFERENT
TRANSCRIPTIONALLY THAN ALL THREE
OTHER CONDITIONS.
AND THUS THE INCLUSION OF TAT
DOES NOT SEEM TO HAVE GLOBAL
IMPACT ON THE TRANSCRIPTIONAL
PROFILE OF JLAT 10.6 CELLS.
WHAT ARE THE DIFFERENT
TRANSCRIPTS THAT SHOW
SIGNIFICANT CHANGES COMPARING
LUCIFERASE TO TAT?
WE FOUND ONLY FOUR.
THOSE FOUR ARE SHOWN HERE.
THE FIRST ONE IS A MITOCHONDRIAL
PROTEIN.
THE SECOND A RIBOSOMAL
COMPONENT, AND THE LAST ONE, A
LONG NON-CODING RNA WITH NO
DESCRIBED FUNCTION.
AND IMPORTANTLY, HIV GENOME
TRANSCRIPTION CAME OUT OF THIS,
WHICH WAS GOOD.
THESE DATA SUGGESTED TO US THAT
THIS IS A RELATIVELY SPECIFIC
WAY OF MODIFYING RNA EXPRESSION
OF SPECIFICALLY THE HIV GENOME.
AND IN FACT, IN DATA THAT I
DON'T HAVE TIME TO SHOW TODAY,
WE'VE LOOKED AT TAT MRNA LNP
T-CELLS AND FOUND NO EVIDENCE OF
APOPTOSIS OR ACTIVATION OF THOSE
CELLS, SUGGESTING THAT WE ARE
NOT GLOBALLY AFFECTING THE CELLS
WITH OUR TREATMENT.
HOWEVER, CD4 T-CELLS ARE
DIFFICULT TO TRANSVECT AND
ACTUALLY DO NOT TAKE UP MRNA
LIPID NANOPARTICLES USUALLY.
AND SO WE'VE DEVELOPED A METHOD
IN THE LAB TO CHEMICALLY CON JEW
GATE LIPID PARTICLES SUCH THAT
THEY EXPRESS AN ANTIBODY ON
THEIR EXTERIOR SURFACE.
THIS TAKES A LNP THAT WHEN
INJECTED INTRAVENOUSLY REDIRECTS
THE MRNA TO ANOTHER CELL TYPE.
I USE THE FDA APPROVED
MONOCLONAL ANTIBODY THAT IS
RAPIDLY INTERNALIZED IN CELLS.
IN PREVIOUS WORK IN THE LAB HAS
SHOWN THAT CD4 TARGETING CAN
REDIRECT LNPs TO CD4 POSITIVE
T-CELLS INCLUDING RESTING CELLS
AND SHOWS EVIDENCE OF DELIVERY
OF MRNA TO LYMPHOID RESOIDING
CELLS.
ON THIS NEXT SLIDE I'M SHOWING
YOU DATA DEMONSTRATING THAT
IEBLIZUMAB TARGETING
EFFICIENTLY -- THE T-CELLS.
THESE WERE TREATED WITH
TARGETED -- I'M PLOTTING GFP
INTENSITY VERSUS FREAK Z THE
CONTROLS SHOWN HERE, NO
TREATMENT IS SHOWN IN BLACK WITH
A GREY FILL.
THE NON-TARGETED LNPs SHOWN IN
PINK ONLY IN THE RHESUS
CONDITION SHOW COMPLETE OVERLAP
DEMONSTRATING THAT CONJUGATION
OF THIS ANTIBODY IS NECESSARY
FOR MRNA -- DID NOT RESULT IN
FLUORESCENT SIGNAL.
HOWEVER, WHEN WE DELIVERED GFP
USING THIS METHOD, WE SEE
EFFICIENT DELIVERY TO
CD4 T-CELLS IN THIS MIXED
POPULATION TAKEN FROM SOMEONE
WITHOUT ACTIVATION.
FINALLY WE TOOK THIS INTO CELLS
FROM PEOPLE LIVING WITH HIV IN
WHICH WE TESTED THE ABILITY OF
THIS INTERVENTION TO REACTIVATE
BIOPROTEIN EXPRESSION.
IN THREE SUBJECTS, WE WERE ABLE
TO IDENTIFY P24 EXPRESSION IN
BOTH CELLULAR PELLET AND
SUPERNATENT AS SHOWN HERE,
COMPARED TO NO TREATMENT,
ANTICD -- TREATMENT, ANTICD4 TAT
MRNA LNP AND THEN A SHAM.
IN EACH CASE YOU WITH SEE
DETECTION OF P24 IN BOTH
COMPARTMENTS.
SO IN CONCLUSION, WE THINK THESE
DATA DEMONSTRATE THAT
TRANSCRIPTIONAL PROGRAMS
INCLUDING HIV-1 LATENCY CAN BE
PRECISELY MODIFIED USING MRNA
GENE THERAPY.
AND I THINK THIS PRINCIPLE CAN
BE APPLIED TO OTHER SYSTEMS,
INFECTIOUS OR OTHERWISE, BUT WE
SPECIFICALLY HAVE BEEN STUDYING
HIV, AND I THINK THAT
CD4 TARGETED TAT MRNA LNPs
OFFER SOME BENEFITS OVER OTHER
LATENCY APPROACHINGS.
FIRST THIS IS TRANSIENT, MRNA
WILL DEGRADE OVER TIME AND A YOU
WYOUWILL HAVE LOSS OF ECK PRETIF
THE GENE.
THIS IS A SELF-DIRECTED TYPE
METHOD IN WHICH WE CAN GET THE
CARGO TO THE TISSUES AND THE
CELLS WHERE IT NEEDS TO BE.
IN ADDITION, WE THINK WE'VE
DEVELOPED SOMETHING THAT'S
VIRUS-SPECIFIC.
AND THERE'S OPTIONS TO EXTEND
THIS APPROACH TO INCLUDE
HOST-SPECIFIC INTERVENTIONS.
HOWEVER, THIS WILL HOPEFULLY
ALLOW US TO DECREASE TOXICITY.
IN ADDITION, I DIDN'T HAVE TIME
TO SHOW YOU, WE WERE ABLE TO
DEMONSTRATE THAT MEMBRANE
PERMEATION OF THIS TAT VARIANT
WAS RETAINED.
AND THIS WAS INCREDIBLY POTENT.
I JUST REALIZED THIS, IS ONE
BEHIND EVERYTHING.
I APOLOGIZE IF MY ANIMATIONS
WERE OFF.
SO THIS IS A LARGE GROUP ERTMENT
EFFORT.I APOLOGIZE IF IT WAS DIT
TO TELL WHAT I WAS TALKING
ABOUT.
[APPLAUSE]
>> HI, EVERYONE.
GOOD AFTERNOON.
I'D LIKE TO THANK THE LEADERSHIP
FOR THIS INVITATION TO DISCUSS
THE COMMUNITY ENGAGEMENT GROUP
OR CEG MODEL.
WE'LL DISCUSS THE CAB, EXAMPLES
OF COMMUNITY ENGAGED PROJECTS
AND THE SOCIAL BEHAVIORAL ETHICS
WORKING GROUP.
THIS INTEGRATES BASIC AND
CLINICAL BIOMEDICAL SCIENTISTS,
THE CAB AND AN ESTABLISHED
COMMUNITY-BASED ORGANIZATION,
PHILADELPHIA FIGHT.
THE CEG ALSO INCLUDES A WORKING
GROUP WHICH HELPS INTEGRATE THE
VARIOUS ELEMENTS.
THE CAB FOCUSES ON PROVIDING
INPUT INTO THE RESEARCH PROCESS,
ACTS AS A SOUNDING BOARD AND
ALSO ENGAGES IN COMMUNITY
EDUCATION, AND MEMBERS CAN
PARTICIPATE IN DESIGNING SOCIAL
BEHAVIORAL RESEARCH PROJECTS.
PHILADELPHIA FIGHT PROVIDES THE
HISTORICAL PARTNERSHIP AND
KNOWLEDGE OF THE PATIENT
PARTICIPANT POPULATION, AND ALSO
PROVIDES EXPERTISE IN COMMUNITY
OUTREACH AND HELPS BRIDGE HIV
PREVENTION, TREATMENT AND CARE.
IT'S ALSO A CLINICAL RESEARCH
SITE.
SOME OF OUR OPERATING PRINCIPLES
ARE LISTED ON THIS SLIDE.
SINCE THE INCEPTION OF BEAT-HIV
COLLABORATORY IN 2016, THE CEG
HAS DOCUMENTED ITS LESSONS
LEARNED.
POTENTIAL STRENGTHS INCLUDE
SYNERGIES BETWEEN THE DIFFERENT
COMPONENTS, GREATER AWARENESS OF
HOW WE CAN WORK TOGETHER AND
HELPING OVERCOME THE
SHORTCOMINGS OF A TRADITIONAL
CAB SCIENTIST-ONLY MODEL.
CHALLENGES HAVE INCLUDED
DIFFERENTIAL TIME COMMITMENTS,
DETERMINING LEAD ARE SHIP FOR
PROJECTS, AND ENSURING COMMUNITY
RECOMMENDATIONS GET INTEGRATED
INTO ALL STAGES OF RESEARCH
DESIGNS.
AND THERE ARE WAYS TO EVALUATE
COMMUNITY ENGAGEMENT USING
REALIST FRAME WORKS.
THE BEAT-HIV CAB MEETS EVERY
MONTH AND THERE ARE ALSO
DIFFERENT COMMITTEES.
THE VISION AND MISSION STATEMENT
ARE LISTED HERE AND THEY'RE READ
AT THE START OF EVERY MEETING.
THIS SLIDE SHOWS CURRENT
BEAT-HIV CAB MEMBERS.
WILL CARTER IS THE CHAIR, OUR
COURAGEOUS AND HIGHLY EFFECTIVE
COORDINATOR, AND DAVE METZGER
ALSO PROVIDES LEADERSHIP FROM
U-PENN.
HOME BASED VIRAL LOAD
ACCEPTABILITY STUDY, A SURVEY OF
PEOPLE WITH HIV IN PHILADELPHIA
AND A PROVIDER SURVEY AND THAT
IS POSTER 50.
THERE'S ALSO AN ACTIVE SOCIAL
BEHAVIOR SCIENCES AND ETHICS
WORKING GROUP, GOALS TO
ASSESS -- GENERATE ETHICAL
CONSIDERATIONS, SET REALISTIC
EX-PIEXPECTATIONS, PROVIDE
INFORMATION TO COMMUNITIES OF
INTEREST AND ALSO SUPPORT THE
INCLUSIVE ENGAGEMENT OF
COMMUNITIES.
ONE OF THE RECENTLY COMPLETED
HIV SOCIAL BEHAVIORAL RESEARCH
PROJECT HAS BEEN A CAB-DRIVEN
PARTICIPANT EXPERIENCES STUDY AS
PART OF THE BEAT-HIV TRIAL IN
CONNECTION WITH THE U-PENN --
ONE IS CURRENTLY IN PRESS IN HIV
RESEARCH AND CLINICAL PRACTICE
AS SEPAR PART OF A SPECIAL ISSU.
ANOTHER PROJECT HAS BEEN THE CEG
DRIVEN ACCEPTABILITY STUDY OF A
HOME BASED DEVICE FOR TESTING
AND HIV CURE TRIALS WITH ATI.
THIS WAS ALSO IN COLLABORATION
WITH MEMBERS OF THE AIDS
TREATMENT ACTIVIST COALITION.
THERE'S A LOT OF INTEREST IN
THIS ACTIVITY TO HELP REDUCE
PARTICIPANT BURDEN DURING
ATIs.
IN THE LAST YEAR WE'VE CONTINUED
ADVOCACY ON THE TOPIC OF PARTNER
PROTECTIONS TO HELP REDUCE THE
RISK OF UNINVENTED HIV RISK
DURING TREATMENT INTERRUPTIONS.
THERE'S ALSO A POSTER AT THIS
MEETING, NUMBER 77.
TOGETHER WITH THE CAB, WE'VE
BEEN ADVOCATING FOR INCREASING
DIVERSITY BY SEX AND GENDER,
RACE/ETHNICITY.
DEVELOPMENTOF A CHAPTER ON WOMEN
AND CURE RESEARCH, AND WE'VE
ALSO RECENTLY PUBLISHED A
MANUSCRIPT ON INCREASING THE
MEANINGFUL INVOLVEMENT OF WOMEN
IN HIV CURE RESEARCH IN
COLLABORATION WITH OTHER CABs.
THESE HAVE INCLUDED DARE, RID
HIV, HOPE, AND ERASE HIV.
A NEW AREA OF RESEARCH HAS BEEN
UTILIZING -- TO HELP INFORM HOW
TO MOVE HIV CURE RELATED TRIALS
TO RESOURCE LIMITED PARTS OF THE
WORLD OR THE MAJORITY WORLD.
WE NOW HAVE COLLABORATION
WITH -- IN DURBIN, SOUTH AFRICA.
AND THE UNIVERSITY, AND WE ARE
INTEGRATING RESEARCH CONCEPTS
INTO TRIAL DESIGN.
AND WE NEED TO KEEP DEVELOPING
THE PSYCHOSOCIAL SUPPORT AND
RESEARCH INFRASTRUCTURE.
SO HERE IS OUR COMMUNITY SLIDE.
OUR KEY QUESTION IS, HOW CAN WE
MAKE HIV CURE SCIENCE MORE SIBL
AND ETHICAL TO COMMUNITIES OF
INTEREST TO FACILITATE EVENTUAL
UPTAKE?
IT HELPS BRIDGE BASIC AND
BIOMEDICAL RESEARCH WITH
COMMUNITY PRIORITIES.
WHAT'S BEING ACCOMPLISHED?
AND WHY IS THIS IMPORTANT?
AT THE END OF THE DAY WE NEED TO
MAKE SURE THAT ANY HIV CURE
STRATEGY THAT'S DEVELOPED IS
GOING TO BE MEANINGFUL TO PEOPLE
WITH HIV.
AND ONCE AGAIN, IT TAKES A
VILLAGE.
THANK YOU SO MUCH.
[APPLAUSE]
>> WONDERFUL, THANK YOU.
WE'D LIKE TO GO AHEAD AND TAKE
SOME QUESTIONS NOW, SO FEEL FREE
TO COME UP TO THE MICROPHONE.
WHILE WE'RE WAITING, I SAW SOME
OF THE DATA IN YOUR TRANSGENIC
MICE, YOUR TREATMENT ALSO SEEMED
TO REDUCE SOME OF THE DEFECTIVE
RESERVOIRS.
WAS THAT TRUE?
>> SORRY, CAN YOU REPEAT THAT?
THE ECD 4-IG IN THE MICE, I
THINK I SAW ON SOME OF YOUR DATA
SLIDES THAT INTACT PRO VIRUS WAS
REDUCED BUT ALSO IT LOOKED LIKE
SOME OF THE --
>> YES, THE DEFECTIVE ONES, WE
ALSO FIND THE REDUCTION AND THIS
ONE WE ALSO DISCUSSED WITH
UPON'S GROUP AND CURRENTLY WE
THINK THAT THE DEFECT ONES, THEY
ALSO MAY HAVE THE ENVELOPE
EXPRESSION ON CELL SURFACE.
>> THAT'S WHAT I WAS CURIOUS
ABOUT.
OKAY.
INTERESTING.
GO AHEAD.
>> HI.
I HAVE A QUESTION FOR TED.
THE TAT LMP STUFF, THAT'S
TANTALIZING, FOR SPECIFICITY.
I COULDN'T SEE, DID YOU HAVE ANY
SORT OF POSITIVE CONTROL?
I MEAN, HOW MUCH OF THE LATENT
RESERVOIR WERE YOU REACTIVATING?
DO YOU HAVE A SORT OF CLUE, WERE
YOU GETTING 1%, 10%, 50%?
>> FIRST OFF I APOLOGIZE, I DID
NOT REALIZE I USED THE WORD
SUBJECT AND I DID NOT MEAN TO.
I APOLOGIZE TO ALL MEMBERS OF
THE AUDIENCE.
I MEANT TO SAY PARTICIPANT.
AND I -- I APOLOGIZE.
TO GET AT YOUR QUESTION, SO WE
HAVE LOOKED AT VARIOUS IN VITRO
MODELS.
SO WE DO SEE POTENT REACTIVATION
IN TZMBM CELLS, JLAT CELLS, WE
CAN HIT ABOUT 90 TO 95% OF JLA
T-CELLS, WE NEVER HIT 100% USING
LNP TRANS FEX.
JLATS ARE NOT PARTICULARLY
COMPETENT.
BUT WERE YOU TALKING ABOUT A
DIFFERENT TYPE OF --
>> I THOUGHT YOU SHOWED SOME
DATA MAYBE IN CELLS FROM PEOPLE
LIVING WITH HIV --
>> OH, I APOLOGIZE.
I MISUNDERSTOOD.
SO THOSE SUBJECTS DO HAVE
PARTICULARLY LARGE RESERVOIRS,
SO WE'RE IN THE PROCESS OF
QUANTIFYING ALL OF THE
RESERVOIRS IN ORDER TO DO A MORE
SYSTEMATIC ANALYSIS, BUT THEY
HAVE IPDA VALUES GREATER THAN
100 PER MILLION.
AND WE DO NOT HAVE THE EXACT
QUANTITATION OF WHAT PERCENT OF
CELLS REACTIVATED AMONG THOSE,
BECAUSE THESE ARE BULK
MEASUREMENTS.
SORRY ABOUT THAT.
SORRY I MISUNDERSTOOD THE
QUESTION.
>> HI.
I HAVE A QUESTION FOR THE
GENTLEMAN WHO PRESENTED THE ECD
4IG DATA.
THINK YOU SHOWED A PANEL WHERE
LEVELS WERE DECAYING AFTER EACH.
WHAT'S MEDIATING THAT DECAY?
ARE THE CELLS DYING, IS IT
SILENCING OF THE PLASMID?
>> SO THE ECD 4IG, THE
EXPRESSION LEVEL THEY DECAY,
RIGHT?
>> THAT'S WHAT I MEAN.
I THINK I SAW A PRESENTATION
WHERE THE LEVELS FROZE AND THEN
DECAYED OVER TIME.
>> THAT DECAY, BECAUSE THE
KINETICS I SHOW THE ELI IS A IR
THE EXPRESSION, WE DID ANOTHER
BATCH OF THE ANIMAL AND THE --
TIME IS LONGER THAN WE HAVE IN
THE EXPERIMENT.
AND IN THE EXPERIMENT, WE GAVE
THE EC4IG TREATMENT EVERY TWO
WEEKS BUT IN THAT ELI IS A DATA,
WE HAVE THE ELONGATED AND WE
WANTED TO SEE HOW LONG IT CAN
LAST AND HOW BAD THE DECAY.
SO WE ELONGATED IN TURBO TIME.
>> RIGHT.
DO YOU HAVE ANY IDEA WHY IT'S
DECAYING?
ARE THE TRANSFECTED CELLS DYING
OR IS IT SOMETHING TO DO WITH
THE PLASMA BEING SILENCED?
>> BECAUSE WE DELIVER THE ECD 4
IG NOT THROUGH THE AV, WE USE A
DNA DELIVERY, WE ONLY CAN HAVE
SEVERAL WEEKS OF THE EXPRESSION.
AND AFTER THAT, THAT EXPRESSION
IS LOWER AND LOWER.
>> THANK YOU.
>> MICHAEL?
>> HI.
MY NAME IS MICHAEL.
I'M WITH THE DARE CAB.
I HAVE A QUESTION, WE HAVE THIS
BASIC SCIENCE GOING ON AND WE
HAVE ALL THIS COMMUNITY-LED
SOCIAL SCIENCE WORK GOING ON.
WHAT'S THE ADVANTAGE OF HAVING
THESE TWO THINGS TOGETHER?
COULD YOU EACH THINK OF TELLING
ME LIKE HOW DOES THE SOCIAL
SCIENCE WORK HELP YOUR
INDIVIDUAL RFs DO WHAT THEY
WANT TO DO AND HOW -- I KNOW HOW
YOU GUYS ARE PROBABLY HELPING
COMMUNITY SCIENCE.
I'M JUST WONDERING HOW IT WORKS
TOGETHER AND WHAT VALUE YOU FEEL
YOU'RE GETTING FROM HAVING
COMMUNITY-LED SCIENCE ALONG WITH
YOUR BASIC SCIENCE THAT YOU'RE
GOING THROUGH.
>> THANK YOU.
SO I THINK IT'S REALLY
COMPLEMENTARY BECAUSE LIKE FOR
EXAMPLE, WHEN WE WERE DEFINING
OUR CLINICAL TRIAL DESIGNS, WE
NEVER REALLY TOOK INTO ACCOUNT
THE STRESS ASSOCIATED WITH THE
REBOUND IN TRYING TO ACTUALLY
INTENTIONALLY TARGET THAT PERIOD
FOR SUPPORT OF PARTICIPANTS.
DURING THE SOCIAL SCIENCE
EVALUATION OF WHAT WAS THE
EXPERIENCE OF INDIVIDUALS IN THE
TRIAL, WE LEARNED THAT PERIOD
WAS ACTUALLY QUITE A STRESSFUL
PERIOD.
BUT YET WE DIDN'T KNOW THAT WHEN
WE WERE DESIGNING AT THE
BEGINNING.
THE SAME THING FOR THE
PARTICIPANT STUDIES ABOUT HOME
DEVICES.
WE DID NOT KNOW EXACTLY TO WHAT
EXTENT THAT WOULD BE ACCEPTED IN
THE COMMUNITY, SHOULD WE
ACTUALLY DEVELOP THIS WITH A
COMMERCIAL PARTNER LIKE MERCK
THAT HAS BEEN REALLY SUPPORTIVE,
AND WE DID THREE DIFFERENT
STUDIES ON A NATIONAL SURVEY, ON
A LOCAL SURVEY, AND IN A WORKING
GROUP TO DETERMINE IS THIS
SOMETHING THAT WE SHOULD INVEST
IN FOR DEVELOPMENT.
AND ALL OF THOSE STUDIES SHOWED
THAT THERE WAS AN INCREDIBLE
AMOUNT OF INTEREST AND HOW TO
COMMUNICATE FOR PEOPLE TO
ACTUALLY ENGAGE IN THESE TYPES
OF STRATEGIES.
SO I THINK THAT WE CAN TALK
ABOUT THE SCIENCE BUT IF THERE'S
NOT ACCEPTABILITY, IF THERE'S
NOT UNDERSTANDING AND WE DON'T
KNOW THE DYNAMICS OF HOW THIS IS
GOING TO IMPACT THE LIFE OF
SOMEBODY LIVING WITH HIV, I
THINK THAT WE WOULD BE
UNINFORMED.
SO I THINK THE SOCIAL SCIENCE
STUDIES REALLY COMPLEMENT THE
BASIC RESEARCH AGENDA.
[APPLAUSE]
>> HELLO.
I HAVE A QUESTION FOR TED ABOUT
THE TARGETING OF THE LMPs.
IN VITRO, YOU CAN GET THEM TO GO
TO A CD4 T-CELL RATHER THAN A
HEMATOPOIETIC STEM CELL, BUT IN
VIVO, IN AN ACTUAL BODY, IF
YOU'RE GOING TO DEPLOY THESE
THINGS INTO THE BLOODSTREAM, HOW
ARE YOU GOING TO MAKE SURE IT
ALSO GETS TO THE TISSUE RESIDENT
T-CELLS?
LIKE WHAT WOULD YOUR SUCCESS
RATE BE TO GETTING COVERAGE OF
INFECTED CELLS?
>> IT'S A FANTASTIC QUESTION.
SO THIS HAS BEEN BEST WORKED OUT
IN MURINE MODELS, SO
CD4 DELIVERY IN MURINE MODELS
ACTUALLY DOES DELIVER TO
RESIDENT CD4s IN TISSUES, BUT
IT IS NOT 100%.
SO THAT IS AN ISSUE THAT WE ARE
GOING TO HAVE TO OVERCOME FOR
INTERVENTIONS THAT REQUIRE 100%
DELIVERY TO EVERY SINGLE CELL.
ONE OF THE THINGS THAT I DIDN'T
HAVE TIME TO GO INTO IS I THINK
THAT THIS INTERVENTION, BECAUSE
TAT IS ABLE TO SECRETE AND GO
INTO NEIGHBORING CELLS, YOU
DON'T HAVE TO HIT 100%, SO AS
LONG AS YOU'RE GETTING TO ALL OF
THE ANATOMIC LOCATIONS THAT YOU
NEED TO, YOU MAY BE ABLE TO HAVE
TAT 50 ELSEWHERE.
AND OTHERS HAVE ASKED ME ABOUT
IS IT ONLY CD4 T-CELLS?
NO, IT WILL NOT BE ONLY
CD4 T-CELLS BUT I AGAIN VIEW
THAT AS A POSSIBLE BENEFIT
BECAUSE THEY COULD BE PRODUCER
CELLS WITHIN WHATEVER TISSUES
THEY RESIDE AND GIVE OUT.
SO IT IS A HURDLE FOR THE
DELIVERY SYSTEM.
BUT THANKFULLY FOR THIS
APPLICATION, I DON'T THINK IT
WILL BE AS LARGE OF A HURDLE,
BUT AN IMPORTANT ONE.
>> THAT'S REALLY EXCITING.
THANK YOU.
>> WE'LL TAKE THE LAST QUESTION
FROM CHRIS AND THEN THE BREAK.
>> FOLLOWING UP ON THAT
QUESTION, HAVE YOU LOOKED AT
OTHER DELIVERY METHODS FOR
TISSUE, LIKE INTRAMURAL,
INTRANODAL OR OTHER WAYS TO GET
YOUR LNPs INTO --
>> OTHER SITES OF INJECTION?
>> YEAH.
>> I HAVE NOT PERSONALLY.
I CAN SAY MANY PEOPLE HAVE.
PEOPLE HAVE INJECTED LNPs INTO
THE BONE MARROW, PEOPLE HAVE
DONE A LOT OF THINGS.
SO I'M NOT AWARE OF EVERYTHING
OUT THERE.
I THINK GETTING INTO LYMPHOID
TISH SUE IS PARTICULARLY HARD
BECAUSE LYMPHOID TISSUE IS
THROUGHOUT THE BODY, SO THERE
WON'T BE AN ANATOMIC LOCATION
THAT I CAN THINK OF ON THE SPOT
THAT WOULD BE GOOD FOR THAT.
BUT YES, FOR OTHER APPROACHES,
PEOPLE HAVE DONE DIRECT
ANATOMIC, DELIVER THE LNPs
RIGHT TO THE SITE.
THANK YOU.
I'M DIANE LAWRENCE, WELCOME
AGAIN, AND I'M HERE TO INTRODUCE
THE DARE COLLABORATORY.
THIS IS THE THIRD ITERATION OF
THE DARE GROUP, AND ONE JUST
REALLY QUICK ANNOUNCEMENT FOR
THOSE WATCHING ONLINE, THERE IS
A SEND LIVE FEEDBACK BUTTON AT
THE BOTTOM, SO IF YOU HAVE ANY
QUESTIONS, THAT WILL GET TO US
AND WE CAN SHARE YOUR QUESTIONS
LIVE HERE IN THE ROOM.
SO FEEL FREE TO DO THAT.
GREAT.
SO I'M HAPPY TO INTRODUCE THE
DARE COLLABORATORY.
FIRST STARTING US OFF IS ONE OF
THE PRINCIPAL INVESTIGATORS, DR.
STEVE?
>> THANK YOU, DIANE.
SO ON BEHALF OF THE DARE
COLLABORATORY, I WAS GOING TO DO
JUST A VERY BRIEF INTRODUCTION
AS TO WHO WE ARE, AND THEN WE
CAN JUMP INTO THE SCIENTIFIC
PRESENTATIONS.
AS DIANE SAID, THIS IS OUR THIRD
TIME AROUND.
SINCE DAY ONE, THE GROUP, WHICH
HAS SORT OF EVOLVED IN TERMS OF
ITS MEMBERSHIP, HAS ALWAYS
REALLY BEEN FOCUSED ON
DEVELOPING IMMUNOTHERAPIES
ESSENTIALLY LARGELY TO CONTROL
SIV AND HIV IN THE ABSENCE OF
THERAPY, AND THIS TIME AROUND
WE'RE ALSO MAKING AN INVESTMENT
IN HOW WE CAN MODIFY THE IMMUNE
RESPONSE TO CLEAR THE RESERVOIR.
SO WE'RE PRIMARILY CLINICIANS
AND IMMUNOLOGISTS BUT KE
CERTAINLY HAVE OUR FOCUS ON THE
VIROLOGY AS WELL.
THERE ARE THREE RFs, BUT THE
FIRST, THE BASIC SCIENCE ONE, WE
HAVE BASICALLY TWO GROUPS.
WE HAVE FOCUSING ON THE ACTIVE
RESERVOIR, THOSE CELLS THAT ARE
ACTUALLY PRODUCING RNA AND
PROTEINS, AND WHILE WE'RE DOING
THIS, HOW BIG IS IT, WHAT'S THE
MECHANISM OF IT, WHAT'S THE
CONSEQUENCES OF IT, THE
IMPLICATIONS FOR CLONAL PRO LIVE
PROLIFERATION, THAT KIND OF
THING, AND WE HAVE A SECOND DI
VIEWS AND VERY LARGE GROUP
LOOKING AT MECHANISMS OF IN
PEOPLE OF POST TREATMENT
CONTROL, POST INTERVENTION
CONTROL LARGELY USING SAMPLES
FROM CLINICAL TRIALS AND
CLINICAL COHORTS.
AND WE'LL HEAR FROM MAURO GARCIA
ON SOME OF THE EARLY DATA COMING
OUT FROM THAT PARTICULAR WORKING
GROUP.
RF 2 IS LEVERAGING THE NON-HUMAN
PRIMATE MODEL TO DEVELOP NEW
IMMUNOTHERAPIES TO CONTROL SIV
IN THE ABSENCE OF ART.
AND RF THREE, SORT OF A NEW
INITIATIVE FOR US, LED BY SHARON
AND FOCUSING ON AGAIN SORT OF
MODIFYING INTERCELLULAR PATHWAYS
TO ELIMINATE THE RESERVOIR
PARTICULARLY THOSE THAT ARE
FOCUSED ON CELL SURVIVAL.
SO RATHER THAN GOING INTO OUR
GREATEST HITS, I'D RATHER TAKE
THE NEXT COUPLE MINUTES AND
DESCRIBE HOW WE COLLABORATE.
I THINK WE REALLY ARE A SOLID
GROUP OF INVESTIGATORS BEEN
WORKING TOGETHER FOR A WHILE WHO
COLLABORATE NATURALLY ON VARIOUS
DIFFERENT PROGRAMS.
THERE ARE JUST THREE SORT OF
STORY LINES THAT I WANT TO
MENTION.
THAT GO ACROSS THE RFs
THAT INVOLVE MULTIPLE
INSTITUTIONS, MULTIPLE
INVESTIGATORS.
FOR EXAMPLE, AS I SAID, WE HAVE
THIS VERY INTENSE GROUP OF
VIROLOGISTS, IMMUNOLOGISTS
LOOKING AT THE ACTIVE RESERVOIR.
AND WE'RE DOING THIS IN PART
BECAUSE THE IMMUNOTHERAPIES THAT
ARE BEING DEVELOPED BY THE OTHER
RFs ACTUALLY TARGET BASICALLY
THE RESERVOIR, CELLS THAT MAKE
PROTEIN, SOME OF THE WORK THAT
LOUIS WILL DISCUSS AND THIS
LARGE GROUP OF INVESTIGATORS,
PATHWAYS ASSOCIATED WITH CELL
DEATH GENERALLY REQUIRE THAT THE
RESERVOIR BE ACTIVE.
SO THERE'S A LOT OF CROSSTALK
BETWEEN THESE GROUPS IN TERMS OF
THESE DIFFERENT PATHWAYS, AND WE
MOVE FROM SORT OF THE BASIC
BIOLOGY TO THE MORE
TRANSLATIONAL WORK INTO ANIMALS
AND OF COURSE OUR ULTIMATE GOAL
AND WE'VE BEEN QUITE SUCCESSFUL
IN DOING THIS IS MOVING THIS
INTO THE CLINICAL ARENA, AND WE
ACTUALLY HAVE AN ONGOING STUDY
ON THE BCL2 INHIBITOR BASED ON
THIS WORK.
WE'RE ALSO INTERESTED IN POST
TREATMENT CONTROL AND
INCREASINGLY POST INTERVENTIONAL
CONTROL IN THE AREA OF CLINICAL
MEDICINE, KIND OF GLOBALLY THERE
ARE POPPING UP ALL OVER THE
PLACE THESE INDIVIDUALS
CONTROLLING HIV AS A CONSEQUENCE
OF AN INTERVENTION, USUALLY
BROADLY NEWT LICED ANTIBO DEAS,
VACCINES, SO WE'RE ASSEMBLING
THESE CASES, THE STUDY POST
INTERVENTIONAL CONTROL IN
PEOPLE, WE'RE DOING A VARIETY OF
DIFFERENT INTERVENTIONS IN THE
MONKEY MODEL.
AS I SAID, WE'RE LOOKING AT
THESE POST INTERVENTIONAL
CONTROLS FROM THE CLINICAL
TRIALS, FROM THE COHORTS,
COLLECTING THESE SAMPLES, AND
USING THIS COMBINED KNOWLEDGE TO
DO THE NEXT GENERATION OF
IMMUNOTHERAPIES.
THIS TIME AROUND, WE'RE VERY
INTERESTED IN THE CONCEPT OF THE
INTERCEPT.
THIS IS WHAT'S HAPPENING IN THE
RESERVOIR POST ART, PREREBOUND.
BASED ON WORK FROM LYDDIE
TRAWTMAN, MAJOR INVESTIGATOR IN
THE GROUP, SHE HAD A PUBLICATION
THAT WILL FORM THE BASE I OF A
LOT OF WHAT WE'RE DOING IN DARE.
WHEN WE'RE PUTTING THE GRANT
TOGETHER WHERE SHE OBSERVED THAT
THE ANTIGEN CELL, DENDRITIC
RESPONSE TO THE VIRUS DURING
THIS VERY VULNERABLE PERIOD
ACTUALLY COULD HAVE A BIG IMPACT
ON WHAT HAPPENS SUBSEQUENTLY, SO
WE HAVE BUILT A CLINICAL COHORT
AND NON-HUMAN PRIMATE MODELS
AROUND DOING DEEP INVESTIGATION
OF WHAT MIGHT BE HAPPENING.
AS SOON AS THAT VIRUS BEGINS TO
REBOUND AROUND DAY 10.
LOUIS HAS REFERRED TO THIS AS
LOCAL REBOUND, ALSO THE
INTERCEPT, WHEN THE VIRUS AND
THE HOST FIRST INTERACT.
SO WE HAVE WORK GOING ON IN
VITRO.
LOUIS'S TEAM IS LOOKING AT
WHAT'S HAPPENING IN THE IN VIVO
MODEL WITH PD-1 BLOCKADE AS JUST
ONE EXAMPLE.
THERE'S BEEN A NUMBER OF
DIFFERENT INTERVENTIONS, AND
THERE'S A POSTER HERE BY DEMI
SINDELL I'D ENCOURAGE YOU TO
SEE.
A HANDFUL OF THE DARE POSTERS
ARE KIND OF IN THE BACK
UPSTAIRS, YOU HAVE TO LOOK FOR
IT, WE'VE BEEN LEVERAGING A
STUDY THAT REALLY DEEPLY, DEEPLY
INVESTIGATES THIS INTERCEPT, AND
SHE'S GOT SOME FASCINATING DATA,
I'D ENCOURAGE YOU GO TO HER
POSTER.
BUT EACH OF THESE THREE STORY
LINES BASICALLY INVOLVES
MULTIPLE INS TUESDAY TEUTIONS,
INSTITUTIONS, WE THINKTHE TEAM E
WELL.
NOW LET'S GET INTO SOME OF THE
SCIENCE.
I'M GOING TO TURN IT OVER TO
MAURO.
[APPLAUSE]
>> THANK YOU FOR THE OPPORTUNITY
TO PRESENT OUR LAB'S WORK HERE
TODAY.
MY NAME IS MAURO GARCIA, I'M A
GRADUATE STUDENT IN BOB AND
JANET SILICANO'S LAB.
THE FRACTION OF HIV VARIANTS
READILY NEUTRALIZE BY YOU AUTOLS
IGG ANTIBODIES PRIOR TO AN ATI,
CORRELATES WITH THE TIME TO
VIRAL REBOUND.
ANTIRETROVIRAL THERAPY
SUPPRESSES VIREMIA TO BELOW THE
LIMIT OF DETECTION.
HOWEVER, ART IS NOT CURATIVE.
FOLLOWING TREATMENT
INTERRUPTION, THERE'S RAPID AND
EXPONENTIAL VIRAL REBOUND THAT
OCCURS, AND THIS IS DUE TO A
POPULATION OF LATENTLY INFECTED
CELLS WITH A VERY LONG HALF-LIFE
THAT HARBOR INDUCIBLE
REPLICATIINDUCIBLE REPLY --PRINE
RESEARCH.
AND WE CAN ASSESS THE INDUCIBLE
REPLICATION COMPETENT RESERVOIR
IN PEOPLE WITH HIV USING THE
QUANTITATIVE ASSAY IN WHICH WE
PURIFY RESTING CD4 POSITIVE
T-CELLS WHICH ARE NOT PRODUCING
VIRUS, ACTIVATE THE CELLS WITH
THE MITOGEN AND FROM AN
INDIVIDUAL LATENTLY INFECTED
CELL WE CAN PRODUCE ENOUGH VIRUS
WITH A RELATIVELY SENSITIVE ELI
IS A TWO WEEKS LATER.
THIS REQUIRES EXPONENTIAL
REPLICATION.
AND THE QVOA PROVIDES AN
ESTIMATE OF THE -- THEY USED THE
QVOR TO INDICATE THE RESERVOIR
DECAYS VERY SLOWLY IN THE FIRST
SEVEN YEARS ON ART WITH THE
HALF-LIFE OF 44 MONTHS.
THIS RATE IS SLOW ENOUGH TO
GUARANTEE LIFE-LONG PERSISTENCE
OF HIV EVEN WITHOUT IN INFECTION
EVENTS.
NANCY ARCHIN REPEATED THIS STUDY
WITH INDIVIDUALS ON NEWER
REGIMENS AND GOT THE SAME
HALF-LIFE.
SO THESE ARE DATA FROM JANET'S
2003 QVOA STUDY AND WE CAN ASK
WHETHER THE RESERVOIR CONTINUES
TO DECAY AT THE SAME RATE ON
LONG-TERM ART, AND WHAT EFFECT
THE CHANGES IN THE INTEGRATION
SITE LANDSCAPE HAVE HAD AS
DESCRIBED IN THE ELEGANT WORK.
JANET PREVIOUSLY SHOWED THAT
PERSISTENT HIV PRO VIRUSES ARE
PRIMARILY INTEGRATED INTO
ACTIVELY TRANSCRIBED HOST GENES.
HOWEVER, OVER TIME, THERE SEEMS
TO BE A SELECTION PROCESS IN
WHICH INTACT HIV GENOMES ARE
PRIMARILY FOUND IN NON-GENIC AND
CENTROMERIC REGIONS FOR PRO
VIRAL INDUCTION.
SO WE ASKED WOULD INDUCIBLE
REPLICATION COMPETENT PRO VIRUS
BECOME EVEN LESS FREQUENT WITH
TIME ON ART?
WITH THE HELP OF R REBECCA HO AD
STEVE DEEKS, WE RECRUITED
42 PEOPLE WITH HIV ON LONG TERM
SUPPRESSIVE ART FOR AN AVERAGE
OF 22 YEARS, AND SOME
PARTICIPANTS FROM JANET'S 2003
STUDY WERE STILL ON SUPPRESSIVE
ART REGIMENTS, AND THEY HAD NO
LONG-TERM DECAY IN THE INDUCIBLE
REPLICATION-COMPETENT RESERVOIR.
AND HERE ARE THE OTHER
PARTICIPANTS IN THE STUDY.
AND IN THE BEST FIT MODEL, THERE
IS INITIAL DECAY AND THEN
INFLECTION AT SEVEN YEARS AND
THE RESERVOIR SEEMS TO INCREASE
SLIGHTLY OVER TIME.
WHICH WE CAN DESCRIBE WITH A
DOUBLING TIME OF 23 YEARS.
SO OVERALL, THERE'S NO NET DECAY
IN THE FREQUENCY OF RESTING
CD4 POSITIVE T-CELLS WITH
INDUCIBLE REPLICATION-COMPETENT
PRO VIRUSES OVER TIME.
AND MOST PRO VIRUSES DETECTED
APPEAR TO BE DERIVED FROM THE
CLONAL EXPANSION OF PREVIOUSLY
INFECTED CELLS BECAUSE THE
ISOLATES ARE OFTEN IDENTICAL.
AND THESE EXPANDED CLONES HAVE
THE POTENTIAL TO CAUSE REBOUND
BUT INTERESTINGLY, IN SOME
PEOPLE, RAPID AND EXPONENTIAL
VIRAL REBOUND FOLLOWING
TREATMENT INTERRUPTION COMES
FROM PHYLOGENETICALLY DISTINCT
MINOR VARIANTS THAT WERE NOT
PREVIOUSLY DETECTED IN THE ASSAY
PRIOR TO AN ANALYTICAL TREATMENT
INTERRUPTION.
AND THIS WAS FIRST SHOWN BY
MICHELLE -- AND KATIE BARR.
SEVERAL EXPLANATIONS WERE
OFFERED FOR THESE FINDINGS BUT
WE HIGH POTASSIUM SEISE THE
VIRUS RELEASED FROM LEASE LARGE
CLONES ARE READILY NEUTRALIZED
BY AUTOLOGOUS NEUTRALIZING
ANTIBODIES.
SO CLASSIC STUDIES DEMONSTRATED
THAT DURING UNTREATED INFECTION,
NEUTRALIZING ANTIBODIES ARISE,
BUT VIRAL EVOLUTION ALLOWS FOR
CONTINUAL ESCAPE FROM THE
ANTIBODY RESPONSE, ALLOWING FOR
LITTLE CONTEMPORANEOUS
NEUTRALIZATION.
AND FOR THIS REASON, THE
AUTOLOGOUS NEUTRALIZING ANTIBODY
RESPONSE HAS BEEN PAID LITTLE
ATTENTION TO.
AND SO IF VIRUSES ARE DEPOSITED
IN THE RESERVOIR THROUGHOUT
UNTREATED INFECTION, AND AT THE
TIME OF ART INITIATION, THEN
SOME RESERVOIR ISOLATES SHOULD
BE SENSITIVE WHEREAS OTHERS
MIGHT BE RESISTANT TO AUTOLOGOUS
NEUTRALIZING ANTIBODIES.
THEREFORE, ISOLATES THAT ARE
RESISTANT TO THE CO CONTEMPORANS
ANAB RESPONSE MAY REBOUND IF ART
IS STOPPED.
TO SEE IF THIS WAS THE CAUSE IN
INDIVIDUALS WITH HIV, A STUDY
LED BY LYNN BERTAGNOLLI INCLU
INCLUDED -- AND ASKED IF
AUTOLOGOUS NEUTRALIZING
ANTIBODIES COULD BLOCK SOME BUT
NOT ALL RESERVOIR VIRUSES AND
PLATED THESE CELLS IN THE
MODIFIED QVOA IN WHICH THERE
WERE THREE ARMS, WITHOUT AND
ANTIBODY, NEGATIVE DONOR AND
AUTOLOGOUS IGG ANTIBODIES AND
LACKED FOR A REDUCTION MEDIATED
BY AUTOLOGOUS NEUTRALIZATION.
HERE'S A REPRESENTATIVE
PARTICIPANT FROM THE STUDY
SHOWING THE AUTOLOGOUS IGG
ANTIBODIES INDEED WERE ABLE TO
BLOCK SOME BUT NOT ALL ISOLATES.
AND PHYLOGENETIC ANALYSES
REVEALED THAT ONLY A SMALL
SUBSET OF RESERVOIR ISOLATES
SHOWN IN RED WERE ABLE TO GROW
OUT IN THE QVOA IN THE PRESENCE
OF LOW CONCENTRATIONS OF
AUTOLOGOUS IGG ANTIBODIES, AND
THESE ISOLATES HAD MUTATIONS IN
THE VARIABLE LOOPS OF ENVELOPE
CONSISTENT WITH ANTIBODY ESCAPE.
THESE ISOLATES WERE HIGHLY
RESISTANT TO AUTOLOGOUS IGG
ANTIBODIES WHEREAS THESE TWO
LARGE CLONES WERE HIGHLY
SENSITIVE.
THESE RESULTS EXPLAIN WHY SOME
LARGE CLONES DETECTED IN QVOAs
DON'T CAUSE REBOUNDS.
AND OUR LAB HAS GONE ON TO
ESTABLISH THE PHYLOGENETIC
RELATIONSHIP OF VIRUSES GROWING
OUT IN THE PRESENCE OF
AUTOLOGOUS IGG IN VIRUSES
CAUSING REPOUND IN VIVO.
SO BASED ON THIS DATA I'VE
PRESENTED, REBOUND IS A
SELECTION PROCESS.
ANTIGENS CONTINUOUSLY ACTIVATE
CELLS COMPRISING THE LATENT
RESERVOIR, LEADING TO RESIDUAL
VIREMIA.
SOME VIRUSES RELEASED FROM THE
RESERVOIR ARE READILY
NEUTRALIZED BY YOU AUTOLOGOUS
ANALYZING ANTIBODIES.
HOWEVER, SOME VIRUSES MAY BE
RESISTANT AND IF ART IS STOPPED
MAY CONTRIBUTE TO VIRAL REBOUND.
AND IN PREVIOUS ATI STUDIES, WE
KNOW THAT THERE'S HETEROGENEITY
IN THE TIME TO VIRAL REBOUND
THAT'S DIFFICULT TO DESCRIBE AND
PINPOINT.
AND IN STUDIES WHERE VERY EARLY
ART WAS INITIATED AND RESTRICTED
RESERVOIR SIZE, WE ALSO SEE
DELAYED TIMES TO VIRAL REBOUND.
AND THIS WAS A STUDY SHOWN BY
DEBORAH PERSAUD.
SO THERE'S VARIOUS FACTORS THAT
MAY INFLUENCE VIRAL REBOUND
DYNAMICS FOLLOWING TREATMENT
INTERRUPTION.
AND SO WE ASKED, DO AUTOLOGOUS
NEUTRALIZING ANTIBODIES
INFLUENCE THE TIME TO VIRAL
REBOUND?
SO FOR THIS STUDY, WE COLLECTED
CELLS, RESTING CD4 POSITIVE
T-CELLS AND CONTEMPORANEOUS
AUTOLOGOUS IGG FROM PARTICIPANTS
PRIOR TO AN ATI, AND CONDUCTED
THESE MODIFIED QVOAs.
AND WE USED THE SCOPE ATI COHORT
WHICH RECEIVED NO INTERVENTION
TO DIRECTLY ASSESS TIME TO
REBOUND IN THE CONTEXT OF
AUTOLOGOUS NEUTRALIZING
ANTIBODIES.
HERE WE SHOW A STATISTICALLY
SIGNIFICANT CORRELATION BETWEEN
THE TIME TO REBOUND AND THE
PERCENTAGE OF INDUCIBLE
REPLICATION COMPETENT RESERVOIR
ISOLATES THAT ARE NEUTRALIZED BY
AUTOLOGOUS NEUTRALIZING
ANTIBODIES PRIOR TO THE ATI.
IN SOME OF THESE ATI
PARTICIPANTS, WE'VE IDENTIFIED
LARGE ANAB RESISTANT CLONES
PRIOR TO THE ATI, USING THE
MODIFIED QVOA, AND WE
HYPOTHESIZE THAT THESE ISOLATES
MAY BE IDENTICAL OR GENETICALLY
SIMILAR TO THE VIRUS THAT CAUSES
REBOUND IN VIVO ONCE ART IS
STOPPED.
AND WE'RE CURRENTLY WORKING WITH
LILLIAN COHEN AND ANNA SHURMAN
TO INVESTIGATE THIS FURTHER.
SO IN CONCLUSION, THE INDUCIBLE
REPLICATION COMPETENT RESERVOIR
DOES NOT CONTINUE TO DECAY IN
PEOPLE ON LONG TERM ART.
AUTOLOGOUS NAUGHT KNUTEIZEING
ANTIBODIES PREVENT OUTGROWTH OF
SOME BUT NOT ALL INDUCIBLE
REPLICATION COMPETENT ISOLATES
AND THE DEGREE OF NEUTRALIZATION
VARIES AMONG PARTICIPANTS.
THE FRACTION OF ANAB -- SORRY
THE FRACTION OF ANAB SENSITIVE
VIRUSES IN THE RESERVOIR
STRONGLY CORRELATES WITH THE
TIME TO VIRAL REBOUND, AND
LASTLY, ATI STUDIES USING TIME
TO REBOUND AS AN OUTCOME
MEASUREMENT SHOULD CONSIDER THE
AUTOLOGOUS NEUTRALIZING ANTIBODY
RESPONSE.
AND WE'D LIKE TO THANK OUR
COLLABORATORS, LILLIAN COHEN,
ANNA SHURMAN, L LUIS MONTANER, Y
FELLOW LAB MATES, AND MY PIs,
AS WELL AS OUR FUNDING SOURCES
AND THE STUDY PARTICIPANT.
AND NOW I'LL HAND IT OVER TO
LOUIS PICKER.
[APPLAUSE]
>> THOSE WERE REALLY BEAUTIFUL
SLIDES AND A BEAUTIFUL STORY IF
I SAY SO MYSELF.
WELL, BEFORE I START, I JUST
WANTED TO ADDRESS
>> I HAVE BEEN QUOTED SAYING
ANTIBODIES ARE SOMETHING YOU BUY
TO STUDY T-CELLS.
HERE YOU SEE THAT I'M ON AN
ABSTRACT OR A TALK WHERE
ANTIBODY IS IN THE TITLE.
BUT I JUST WANT TO TELL YOU
THIS, IS REALLY ABOUT IT. CELLS
THIS TALK, EVEN THOUGH
NEUTRALIZING ANTIBODIES ARE IN
THE TITLE.
I ALSO WANT TO MAKE SURE I GIVE
APPROPRIATE CREDIT TO THE PEOPLE
THAT ACTUALLY DID THE WORK WHICH
IS THE GROUP AT OHSU.
I AM ONE OF THE OLDER STATEMEN
THAT KEEPS AN EYE ON THINGS, BUT
THE ACTUAL PERSON OUT IN THE
FIELD DOING THE WORK IS HE AND
HIS GROUP.
AND ALL THE REST OF THE NHP
PEOPLE IN OUR GROUP ARE LISTED
ON HERE.
SO PREVIOUS WORK OVER MANY YEARS
BY OUR GROUP AND MANY OTHERS HAS
SHOWN THAT PERHAPS THE MOST
FUNDAMENTAL REASON THAT THE
IMMUNE SYSTEM OR THE CELLULAR
IMMUNE SYSTEM CAN CONTROL HIV OR
SIV IS THE DYNAMIC MISMATCH
BETWEEN EXPONENTIAL VIRAL
REPLICATION AND THE LAGGING
EITHER PRIMARY OR AMNESTIC
CD8 T-CELL RESPONSE THAT OCCURS
DURING -- IN THIS PARTICULAR
CASE, AFTER YOU DISCONTINUE ART.
THE COIN TOO LITTLE, TOO LATE
WAS FIRST COINED FOR PRIMARY
INFECTION BUT IT'S EENGLY
APPLICABLE TO POST ART, ALTHOUGH
IT'S A LITTLE BIT FASTER BECAUSE
YOU HAVE A PREVIOUSLY
ESTABLISHED IMMUNE RESPONSE IN
ANIMALS THAT WERE TREATED WITH
ART.
BUT WHEN THE IMMUNE EVASIVE
VIRUS SUCH AS HIV, IT'S REALLY
HARD IF NOT IMPOSSIBLE UNLESS
YOU HAVE VERY SPECIAL
CIRCUMSTANCES LIKE HIGHLY
PROTECTIVE ALLELES FOR THE
C8 T-CELL SYSTEM TO CONTROL AN
INFECTION THAT IT FOLLOWS RATHER
THAN PRECEDES.
SO ONE OF OUR HYPOTHESES IN
RF2 AND INDEED IN THE DARE
COLLABORATORY IS REALLY TO FOCUS
ON IMMUNE INTERVENTIONS THAT
INVOLVE IMMUNE STIMULATION IN
THE PERIARTERY LEASE PERIOD.
THE IDEA IS TO GET -- IS TO
CHANGE THE TIMING AND CHANGE THE
DYNAMICS OF WHAT WE HAVE COINED
AS THE INTERCEPT.
TO ACTUALLY HAVE THE T-CELL
RESPONSE PEAK RIGHT AS THE VIRUS
IS COMING OUT OF AND BEGINNING
TO SPREAD IN LOCAL REBOUND
RATHER THAN FOLLOWING THAT LOCAL
REBOUND.
AND SO THE HYPOTHESIS IS THE
SOONER AND BIGGER MIGHT EQUAL
BETTER.
HOWEVER, THERE ARE CAVEATS TO
THIS, AND THIS IS JUST AN
EXAMPLE TO SHOW A CAVEAT OF A
STUDY THAT WE DID A WHILE BACK,
STILL HAVEN'T PUBLISHED IT YET,
BUT BASICALLY WHERE WE'RE USING
N820, WHICH IS A COMBINATION
ANTICD20 AND IL15 SUPERAGONIST,
AND BASICALLY WHAT WE SHOWED IS
THAT MORE ISN'T ALWAYS BETTER,
IF YOU GIVE A REALLY POTENT
IMMUNE STIMULATION AT THE TIME
OF ART RELEASE AS SHOWN IN THE
RED, YOU CAN GET HUGE
PROLIFERATIVE INCREASES IN
C4 T-CELLS WHICH RESPONDS AS AIN
CREASE IN VIRAL REPLICATION POST
ART RATHER THAN A DECREASE.
SO THESE DATA SUGGEST TO US THAT
PERHAPS A MORE SUBTLE T-CELL
STIMULATION MIGHT BE INFECTIVE,
PARTICULARLY ONE THAT MIGHT ALSO
INDEPENDENTLY SUPPRESS VIRAL
SPREAD.
AND THAT COMES -- IS WHERE WE
CAME INTO ANTIBODIES, BECAUSE IT
HAS BEEN PROPOSED THROUGH A
NUMBER OF STUDIES, INITIALLY IN
RHESUS MACAQUE, BUT MORE
RECENTLY IN HUMANS, OF THE
SO-CALLED VACCINEAL EFFECT, THE
POTENTIAL FOR NEUTRALIZING, THAT
IS ABLE TO BIND THE ACTUAL VIRUS
NEUTRALIZING ANTIBODIES TO FORM
IMMUNE COMPLEXES THAT POTENTIATE
CD8 T-CELL RESPONSES.
THERE ARE PAPERS IN THE
LITERATURE SHOWN ON TOP SHOWING
THAT THIS CAN INCREASE RESPONSES
AND THERE ARE STUDIES IN HUMAN
IN THE SHORT AND LOWER PANEL IN
WHICH PEOPLE MAINTAIN VIRAL
CONTROL AFTER THE INITIALIZING
ANTIBODY BASICALLY DECAYED THAT
SUGGESTED THAT THIS MIGHT BE THE
MECHANISM OF THAT PROLONGED
SUPPRESSION IN THE ABSENCE OF
ANY MORE ACTIVE ANTIBODY.
SO WE SET OUT TO ASK THE
QUESTION, CAN WE USE VISUALIZING
ANTIBODIES IN THE -- 9 SYSTEM TO
CHANGE THE DYNAMICS POST ARTERY
LEASE.
AND THAT IS, TO SIMULTANEOUSLY
SUPPRESS VIRUS WITH THE
ANTIBODY, MAYBE ALLOWING A
LITTLE BIT TO COME UP TO BE ABLE
TO INHIBIT -- TO STIMULATE THE
IMMUNE SYSTEM, HAVE A SOONER,
QUICKER, BIGGER IMMUNE RESPONSE
THAT COMES BEFORE THAT GROWTH
AND SYSTEMIZATION OF THE VIRUS,
AND THEREFORE HAS A BETTER
CHANCE OF SUPPRESSING IT.
AND THAT'S THE BASIC CONCEPT.
NOW, IN RECENT YEARS, AT LEAST
TWO POTENT INITIALIZING
ANTIBODIES HAVE BEEN DEVELOPED
FOR THIS VIRUS.
THERE'S THE ITS SUN 03.01 BY
MARIO ROEDERER AND THE K11 BY
DENNIS BURTON, BOTH HAVE
DOCUMENTED ADCC ACTIVITY AND
THEREFORE I THINK ALLOW US TO
TEST THIS HYPOTHESIS.
AND I WOULD ALSO ADD THAT IN
PILOT STUDIES THAT I DON'T HAVE
TIME TO SHOW YOU THE COMBINATION
OF THESE ANTIBODIES, WE'RE ABLE
TO POTENTLY SUPPRESS ACTIVE
VIREMIA IN INFECTED ANIMALS WHEN
THE NEUTRALIZATION TIGHT TITER S
ABOVE 1 TO 500.
STUDY 1, THESE ANIMALS WERE PUT
ON ART AT DAY 9, THE DAY THEY
HAVE WHAT WE DESCRIBE AS A FULL
RESERVOIR, AND THEY WERE
SUPPRESSED BY A POTENT
ANTIRETROVIRAL THERAPY FOR
72 WEEKS.
AS SHOWN IN THE TOP MIDDLE.
THREE DAYS AFTER THE LAST DOSE
OF ART, THEY WERE EITHER GIVEN A
CONTROL ANTI ANTIBODY OR THEY WE
GIVEN A COMBINATION OF THE TWO
NEUTRALIZING ANTIBODIES I
MENTIONED AT 20 MGS PER KG AND
THEN THEY WERE FOLLOWED
CAREFULLY.
AS WE HAVE EXPECTED, THERE WAS A
HUGE DELAY IN VIRAL REBOUND,
THAT IN THIS PARTICULAR CASE WAS
LIKE 10 WEEKS OR 12 WEEKS.
I CAN'T SEE WELL ENOUGH TO SEE
WHAT IT IS.
THAT'S A LONG TIMEMENT VERY
SIGNIFICANT.
BASICALLY ALL THE ANIMALS
REBOUNDED WHEN THE NEUTRALIZING
ANTIBODY TITERS REACHED BELOW
1 TO 500, IN THIS CASE 1 TO 330.
HOWEVER, WHEN WE LOOKED AT --
WHEN WE NORMALIZED ALL THESE
ANIMALS TO REBOUND AND ASKED THE
QUESTION WHAT HAPPENED WITH POST
ART CONTROL, WE SAW NOTHING.
SO LOOKING AT THE VIRAL LOAD
PROFILES IN THE LOWER LEFT OR
THE SUMMATION OF THE VIRAL SET
POINT ON THE RIGHT GRAPH, THERE
WAS NO DIFFERENCE IN POST ART
VIRAL SET POINTS.
SO WE DID NOT SEE ANYTHING IN
THIS RESEMBLING A VACCINAL
EFFECTIVE EXPERIMENT SO WE SAID
LET'S PUT OUR FINGER ON THE
SCALE HERE AND SEE IF WE CAN
HELP THE IMMUNE RESPONSE.
INSTEAD OF PUTTING ANIMALS ON
ART AT DAY NINE, LET'S PUT THEM
ON AT DAY 35, LET'S ASK THE
QUESTION WHETHER THIS GIVES THEM
A MORE POE AT THE PRESENT TIME
RESPONSE BY MAKING SURE THAT ALL
THE ANIMALS IS BOTH GROUPS HAD
PROTECTIVE MHC1 ALLELES AND
ASKED THE SAME QUESTION.
AND AGAIN WE REPEATED THE
EXPERIMENT, AS SHOWN IN THE
LOWER LEFT, THE NEUTRALIZING
ANTIBODIES HAD THE SAME PROFOUND
DELAY IN VIRAL REBOUND.
BUT AGAIN THERE WAS NO CHANGE IN
THE SET POINT VIREMIA AFTER
REBOUND, AND IN FACT IN THE
LOWER RIGHT, YOU CAN SEE THAT
THE CD8 T-CELL RESPONSES TO
REBOUND WERE OVERLAPPING.
SO THERE WAS NO APPARENT
VACCINAL EFFECT IN THIS
EXPERIMENT EITHER.
ONE LAST EXPERIMENT WE ALSO
ASKED THE QUESTION, WOULD
NEUTRALIZING ANTIBODIES
POTENTIATE ANOTHER
IMMUNOTHERAPY, IN THIS CASE,
ANTIPD-1 BLOCKADE.
STEVE SHOWED YOU AND IT'S SHOWN
IN THE TOP PANEL HERE, WE HAVE
PREVIOUSLY SHOWN THAT JUST
GIVING ANTIPD-1 IN THE
PERIARTERY LEASE PERIODPERIARTRT
DEPRESSION OF THE VIRAL SET
POINT AT LEAST WHILE THE
ANTIBODY IS THERE.
WE REPEATED THE EXPERIMENT IN
ANIMALS THAT WERE GIVEN THE
NEUTRALIZING ANTIBODIES, AND AS
SHOWN IN THE FAR RIGHT, EVEN
THOUGH THE REBOUND WAS DELAYED
BY WEEKS IN THESE ANIMALS, THE
END RESULT, THE EFFECT OF THE
PD-1 WAS EXACTLY THE SAME, SO
THERE'S NO POTENTIATION OF THAT
EFFECT.
SO IN TERMS OF SUMMARY, AND THIS
IS A VERY LAY LANGUAGE SUMMARY
OR CLEAR ENGLISH SUMMARY.
NEUTRALIZING ANTIBODIES AT THE
TIME OF ARTERY LEAF
SIGNIFICANTLY DELAYS TIME TO SIV
REBOUND.
THIS WAS NICE TO SEE -- HOWEVER,
THE APPLICATION OF THESE
NEUTRALIZING ANTIBODIES DID NOT
PROVIDE FOR ANY ENHANCED POST
ART CONTROL.
THERE'S NO EVIDENCE OF A
FUNCTIONAL VACCINAL EFFECT OR
ANY BENEFICIAL MODIFICATION OF
THE T-CELL VIRAL INTERCEPT.
SIV REBOUND DYNAMICS WERE
ASSOCIATED WITH DECAY IN
NEUTRALIZING ANTIBODY TITERS
INDICATING AT FULLY SUPPRESSIVE
LEVELS, NEUTRALIZING ANTIBODIES
EFFECTIVELY LIMIT VIRAL SPREAD.
TO US THEY LOOKED LIKE
NEUTRALIZING ANTIBODY ART.
THE COMBINATION OF NABS WITH
ANTIPD-1 DID NOT SHOW ENHANCED
POST ART ANTIVIRAL CONTROL.
IT'S POSSIBLE THAT NO LONGER NAB
SUPPRESSION OR DIFFERENT NABS
WOULD REVEAL PAIR PEW TICK
BENEFIT OR NOT.
TOTAL OF THREE EXPERIMENTS WHICH
I SHOWED YOU.
OKAY, AND THAT'S IT.
[APPLAUSE]
>> THANK YOU.
I'M GOING TO SPEAK WITH RESEARCH
FOCUS THREE ON BEHALF OF MYSELF
AND JAKE ESTES.
THIS IS THE TEAM INVOLVED IN
RF3.
WE COLLABORATE WITH A NUMBER OF
PHARMACEUTICAL COMPANIES, AND
THE MAIN GOAL OF RF3 IN DARE IS
TO IDENTIFY NOVEL STRATEGIES TO
ENHANCE CELL DEATH OF INFECTED
CELLS THAT PERSIST ON ART USING
IAP ANTAGONISTS, OR
BCL2 ANTAGONISTS TO
SIGNIFICANTLY REDUCE THE
RESERVOIR.
I'M GOING TO SPEAK TO YOU MAINLY
ON OUR WORK THAT WAS RECENTLY
PUBLISHED ON VENETOCLAX IN
COMBINATION WITH ANOVA
ANTISURVIVAL PROTEIN IN EX VIVO
SAMPLES OF HUMANIZED MICE.
MIMETIC WORK MAINLY FOCUSING ON
MONOVALENT SMACK MIMETICS SO I
ENCOURAGE YOU TO GO SEE THE
POSTER.
SO AS WE HEARD EARLIER TODAY,
GREAT OVERVIEW FROM ANDREW
BADLEY, BCL2 IS IMPORTANT FOR
THE SURVIVAL OF LATENTLY
INFECTED CELLS.
MANY GROUPS IS SHOWN THAT
LATENTLY INFECTED CELLS
OVEREXPRESS THE PROTEIN BCL2,
TIPPING THE PRO AND
ANTI-APOPTOTIC MACHINERY OF
EVERY CELL IN FAVOR OF SURVIVAL.
AND THEREFORE INHIBITING THAT
PROTEIN WITH A DRUG SUCH AS
VENETOCLAX COULD POTENTIALLY TIP
THE CELL INTO APOPTOSIS.
AS YOU HEARD EARLIER, VENETOCLAX
IS A BCL2 ANTAGONIST LICENSED
FOR THE TREATMENT OF CHRONIC
LYMPHOCYTIC LEUKEMIA -- CLINICAL
EXPERIENCE WITH USING THIS DRUG.
EX VIVO, A NUMBER OF GROUPS HAVE
SHOWN THAT VENETOCLAX LEADS TO
THE SELECTIVE DEATH OF LATENTLY
INFECTED CELLS, PRESUMABLY
BECAUSE OF THIS OVEREXPRESSION
AND DEPENDENCE ON BCL2 FOR
SURVIVAL.
AND OTHERS HAVE SHOWN THAT THE
EFFECTS ARE ENHANCED IN THE
PRESENCE OF CD8 T-CELLS, MAKING
THEM MORE AMENABLE TO TOXICITY
AND ALSO WE'VE SHOWN THAT IN THE
PRESENCE OF HRV PROTEINS OR
LATENCY APPROACHING AGENTS THIS
EFFECT IS ENHANCED.
SO TOGETHER WITH MARK PILLIGRINI
WHERE VENETOCLAX WAS DISCOVERED,
MARK TESTED VENETOCLAX IN A
HUMANIZED MOUSE MODEL.
HE TOOK HUMANIZED MOUSE MODEL
INFECTED WITH HIV, PLACED THOSE
ANIMALS ON ART AND GAVE
DIFFERENT DURATION OF
VENETOCLAX.
INITIALLY FIVE DAYS, WHICH
SHOWED LIMITED IMPACT ON TIME TO
VIRAL REBOUND, AND THEN GAVE
REPEATED DOSING, SIX COURSES OF
VENETOCLAX, EACH OF FIVE DAYS
WITH A TWO-DAYBREAK IN BETWEEN
EACH COURSE.
AND WHAT MARK SHOWED WAS INDEED
THAT THIS TREATMENT OF
VENETOCLAX COMPARED TO A VEHICLE
CONTROL LED TO A SIGNIFICANT
DELAY IN VIRAL REBOUND.
HE THEN ASKED WHETHER THIS
EFFECT COULD BE ENHAN ENHANCED Y
BROCKBLOCKING OVER BCL2 PROTEIN.
IT SHOWS A RANGE OF PROTEINS
THAT SIT IN THE BCL2 FAMILY.
YOU CAN SEE BCL2, BCLXL, BCLW,
MCL1 AND.
1.
THERE ARE OTHER COMPOUNDS THAT
BLOCK THESE OTHER PRO SURVIVAL
PROTEINS.
ONE OF THOSE BEING SX3845 AND
MCL1 INHIBITOR NOT YET LICENSED.
SO MARK GAVE THIS COMBINATION TO
HUMANIZED MICE, THIS TIME WITH A
REDUCED DOSE OF VENETOCLAX, JUST
THREE CYCLES TOGETHER WITH THE
MCL-1 INHIBITOR, AND AGAIN
SHOWED DELAYED TIME TO VIRAL
REBOUND.
WE THEN WORKED WITH MARK TO
DECIDE WHAT VENETOCLAX WAS DOING
TO CELLS THAT CAME FROM
PARTICIPANTS LIVING WITH HIV ON
ANTIRETROVIRAL THERAPY.
THEY UNDERWENT LEUKOPHORESIS AND
TREATMENT EX VIVO WITH
VENETOCLAX, AND WE COULD SHOW
THAT ON THE LEFT, THERE WAS A
DOSE DEPENDENT REDUCTION IN
INTEGRATED DNA AND ON THE RIGHT,
A DOSE DEPENDENT REDUCTION IN
INTACT DNA MEASURED BY THE IPDA
ASSAY.
AND THERE WAS NO EFFECT ON
DEFECTIVE VIRUS.
WE USED DIFFERENT CONCENTRATIONS
OF VENETOCLAX EX VIVO, 5, 10 AND
100 NANOMOLAR.
JUST TO NOTE THAT 1,000
NANOMOLAR HAS NOT BEEN USED, IT
HAS BEEN USED IN OTHER
PUBLICATIONS, IT LED TO
SIGNIFICANT GENERALIZED CELLULAR
TOXICITY.
SO THE NEXT QUESTION WAS WHY AND
WHAT WAS VENETOCLAX DOING TO
THESE CELLS.
AND WE ADDRESSED THIS BY TAKING
CD4 T-CELLS IN PEOPLE WITH HIV
ON ANTIRETROVIRAL THERAPY,
TREATED EX VIVO WITH VENETOCLAX
AND LOOKED AT THE SELECTIVE
IMPACT OF DEATH OF T-CELL
SUBSETS AND ALSO PERFORMED RNA
SEQ.
SO THIS JUST SHOWS YOU THE
PERCENTAGE OF CELLS THAT WERE
DYING AMONGST CENTRAL MEMORY,
TRANSITIONAL MEMORY, EFFECTIVE
MEMORY AND DIFFERENTIATED
T-CELLS AT FIVE DIFFERENT DOSES
OF VENETOCLAX, 5, 10 AND 100
NANOMOLAR, THE INTENSITY OF THE
BLUE SHOWS YOU MORE DEATH WITH A
DEEPER BLUE.
SO YOU CAN SEE HERE THAT REALLY
AT THE LOWER DOSES, THERE'S
SIMILAR DEATH AMONGST THE T-CELL
SUBSETS BUT MORE DEATH IN
EFFECTOR MEMORY AND NAIVE
T-CELLS AND THAT'S CLEARLY
ENHANCED AT THE HIGHER DOSE.
WE THEN DID RNA SEQ AND LOOKED
AT THE EXPRESSION OF RNA OF PRO
DEATH PROTEINS, AND PRO SURVIVAL
PROTEINS.
SO IF VENETOCLAX IS TIPPING, IF
YOU'VE REDUCED THE PROTEIN BCL2,
THE DIES THAT ARE DYING EXPRESS
THE PRO DEATH MARKER.
SO YOU CAN SEE THIS IS EXACTLY
WHAT WE SAW, THAT THE CELLS THAT
WERE PICKED OFF BY VENETOCLAX
WERE ONES THAT WERE
OVEREXPRESSING PRO DEATH
TRANSCRIPTS.
AND YOU CAN SEE THAT THIS
SIGNIFICANTLY DECLINED WITH
VENETOCLAX, WHILE THE
PRO-SURVIVAL TRANSCRIPTS WERE
UNCHANGED, MEANING THAT THOSE
CELLS WERE NOT TIPPED TOWARDS
DYING.
SO THE OVERALL MODEL WE HAVE IS
THAT AMONGST LATENTLY INFECTED
CELLS, THERE'S INCREASED
EXPRESSION OF WHAT'S CALLED
BH3 ONLY PROTEINS THAT FAVOR
CELL DEATH IN THE PRESENCE OF
VENETOCLAX OR OTHER DRUGS THAT
BLOCK PRO-SURVIVAL PROTEINS.
THE INFECTED CELLS ARE MORE
LIKELY TO DIE, AND THAT'S WHY WE
GET SELECTIVE DEATH OF INFECTED
CELLS.
SO WHAT ARE THE NEXT STEPS?
WE'RE NOW GOING TO MOVE THIS
INTO MONKEYS.
WE'RE LOOKING AT STARTING
VENETOCLAX INTRAMUSCULARLY IN
NON-HUMAN PRIMATES.
DOSING HAS BEEN VERY KINDLY
INFORMED BY THE ARRAYS TEAM,
MA.IT SEEMS TO BE BEST DONE IM,
10 MILLIGRAMS PER KILOGRAM.
WE'RE FIRST GOING TO DO THIS IN
THE SETTING OF OTHERWISE
HEALTHY -- IN MONKEYS THAT ARE
VIE REMIBG AND THEN IN MONKEYS
THAT ARE ON ART AND UNDERGOING A
TREATMENT INTERRUPTION, AND THEN
THE GOAL WILL BE TO COMBINE
VENETOCLAX WITH OTHER AGENTS
THAT WE SHOW SYNERGY WITH EX
VIVO.
AT THE SAME TIME, WE'RE
SEPARATELY ABOUT TO START A
CLINICAL TRIAL OF VENETOCLAX
CALLED THE AMBA STUDY.
THIS IS LED BY THOMAS RASMUSSEN
IN DENMARK.
AND THIS STUDY HAS TWO PHASES.
THERE'S A DOSE ESCALATION PHASE,
200, 400 AND 800 MILLIGRAMS OF
VENETOCLAX WHICH IS BEING DOSED
AT OVER TWO WEEKS, AND THEN A
TWO-WEEK BREAK AND TWO WEEKS
AGAIN.
WE EXPECT THAT THIS IS GOING TO
BE SAFE, GIVEN WHAT WE KNOW FROM
OTHER CLINICAL TRIALS.
AND THEN AT THE FOURTH COHORT,
COHORT D WILL BE A PLACEBO
CONTROL STUDY OF VENETOCLAX, NO
TREATMENT INTERRUPTION, BUT TO
SEE THE EFFECT ON THE RESERVOIR.
THE MAIN GOAL BEING SAFETY AND
THEN, OF COURSE, UNDERSTAND THE
EFFECT OF THE RESERVOIR.
SO IN MY PLAIN ENGLISH SUMMARY,
WHAT ARE WE DOING?
WE ASKED WHETHER THE LICENSED
ANTICANCER DRUG VENETOCLAX COULD
INDUCE SELECTIVE DEATH OF THE
VIRAL RESERVOIR THROUGH
INHIBITING THE PROS OF OUR
PROTEIN BCL2.
WHAT DID WE FIND?
WE FOUND IN A HUMANIZED MOUSE
MODEL THIS DID INDEED LED TO
SIGNIFICANT DELAY OF REBOUND.
COULD BE REDUCED WHEN GIVEN WITH
ANOTHER PRO APOPTOTIC DRUG AND
ANTE MCL-1 INHIBITOR AND DOSE --
SEEN IN CELLS WITH PEOPLE HIV
TREATED WITH VENETOCLAX EX-VEE
RE VO.
IT'S LICENSED, IT'S SAFE, IN THE
ABSENCE OF CANCER, AND IT COULD
INDUCE SELECTIVE DEATH OF THE
RESERVOIR.
SO IN OUR TESTING ALONE AND IN
COMBINATION IN MACAQUES AND A
DOSE ESCALATION CLINICAL TRIAL
OF VENETOCLAX IS SOON TO START
WHICH I THINK WILL TELL US A LOT
NOT JUST ONLY IN THE
QUANTITATIVE CHANGE IN THE
RESERVOIR BUT WE PLAN TO LOOK
VERY DEEPLY AT THE QUALITATIVE
CHANGES IN THE RESERVOIR.
AND JUST WHAT WANT TO ABLG KNOE
ACKNOWLEDGE ALLTHE PEOPLE WHO D.
PARTICULARLY MARK AND PHIL, WHO
LED THE MOUSE STUDIES, AND I'LL
STOP THERE.
THANKS VERY MUCH.
[APPLAUSE]
>> HI, EVERYBODY.
THANKS FOR HANGING IN TO ALMOST
THE BITTER END.
SO I AM THE DARE COMMUNITY
ENGAGEMENT COORDINATOR, AND I'M
GOING TO TELL YOU ABOUT WHAT WE
DID IN THE FIRST YEAR AND WHAT
WE LEARNED, WHAT WE'RE DOING
THIS YEAR, AND WHAT WE PLAN TO
DO.
LAST YEAR WE HAD A CELL AND GENE
THERAPY WEBINAR SERIES.
I'M A BIG BELIEVER IN STRUCTURE
AND REPETITION.
AND SO WHAT WE DID WAS, MONTHLY,
WE HAD THESE MEETINGS WITH
REALLY GREAT SCIENTISTS AND
COMMUNITY PEOPLE FROM AROUND THE
COUNTRY.
WE'RE A U.S.-BASED CAB SO OUR
COMMUNITY PEOPLE ARE PRETTY MUCH
FROM THE UNITED STATES.
ANYWAY, WE LEARNED A LOT HERE, I
MEAN, WE HAD THE RESEARCHERS
INTERACT WITH COMMUNITY PEOPLE,
AND WHAT WE LEARNED WAS THAT WE
WANTED TO TRY AND DO IT
DIFFERENTLY.
SO THIS YEAR WE'VE BEEN DEALING
WITH IF-50-PLUS PEOPLE, LONG TEM
SURVIVORS, PEOPLE WITH HIV, AND
WE PILOTED THIS TO SEE HOW IT
WOULD GO OVER WITH PEOPLE OF
COLOR AND WITH OLDER PEOPLE,
ACTUALLY WENT VERY WELL AND WAS
COVERED BY POSITIVELY AWARE, A
GREAT HIV-POSITIVE NEWSLETTER.
ANYWAY, SO WHAT WE DID WITH THIS
NEW SERIES, WHICH IS AGAIN SEVEN
WEEKS FOR SEVEN MONTHS -- EXCUSE
ME, SEVEN MONTHS OF SERIES.
ANYWAY, WITH LONG TERM
SURVIVORS, COLLABORATORS, WHICH
WE BELIEVE IN ALSO, DARE, RID
HIV, CRISPR FOR CURE, WE BELIEVE
THERE'S A LOT OF SYNERGY IN
WORKING TOGETHER ON THESE
THINGS.
IF YOU'LL SEE ON THE BOTTOM,
THERE ARE 18 DIFFERENT
ORGANIZATIONS THAT WERE
SPONSORED.
AND SO THIS TIME INSTEAD OF
PUTTING ONE PERSON ON A PANEL
WITH AN INVESTIGATOR, WE PUT TWO
OR THREE AND 16 OF THESE 18
ORGANIZATIONS WERE INCLUDED IN
THOSE PANELS.
HERE'S THE FIRST, WE GET AN
INTRO TO AGING, INTRO TO CURE
RESEARCH, A SESSION ON ATIs,
WOMEN WITH HIV, AND LIFETIME
SURVIVORS.
THOSE TWO SESSIONS WERE REALLY
WONDERFUL.
WE LEARNED SO MUCH AND SO MUCH
NEW INFORMATION FROM PEOPLE THAT
ARE USUALLY NOT INCLUDED.
I'LL JUST PUT IT THAT WAY.
THE LAST TWO SESSIONS ARE GOING
TO BE JUST COMMUNITY PEOPLE.
TRIAL PARTICIPANTS, GIVEN THEIR
EXPERIENCES.
AND WHERE DO WE GO FROM HERE.
AND WE WERE PLEASANTLY
SURPRISED, BECAUSE WHAT HAPPENS
WITH THIS?
WHAT HAPPENED WITH THIS IS WITH
THAT STRUCTURE AND REPETITION
AND WITH INCLUDING ALL OF THESE
OTHER ORGANIZATIONS, IT HAS LIKE
A RIPPLE EFFECT.
SO THE KNOWLEDGE WE LEARN FROM
THE INVESTIGATORS COMES DOWN TO
THE COMMUNITY AND COMMUNITY
LEADERS AND THEN THEY TAKE TO
THEIR COMMUNITIES AND IT REALLY
ENDS UP -- WE HAVE OUR OWN
LITTLE COHORT, YOU KNOW, OUR
U.S. COHORT OF PEOPLE THAT
ATTEND OUR MEETINGS PRETTY
REGULARLY.
AND WE HAD ALMOST THREE TIMES
THE NUMBER OF PEOPLE AT THESE
SESSIONS THAN WE DID LAST YEAR,
SO YOU CAN SEE THE TOTAL CALL,
THIS IS FOR FIVE MONTHS.
WE'VE GOT TWO MORE SESSIONS TO
GO.
OVER 700 PEOPLE, 2618 FOR
YOUTUBE AND 600 ON FACEBOOK.
THANK YOU, MICHAEL LUELLA, FOR
EXAP TOURING ALL THAT.
AND YOU KNOW, WE ACTUALLY
EXTENDED THE SESSIONS TO AN HOUR
AND A HALF TO GIVE THE COMMUNITY
PEOPLE TIME TO EXPRESS WHAT THEY
WERE GOING TO SAY OR WANTED TO
SAY AND OUR EVALUATION SCORES
WERE LIKE 80%.
SO WE ARE DOING A OVER 60
BEHAVIORAL RESEARCH STUDY, YOU
CAN SEE WHAT THE FIGURES --
EXCUSE ME -- WHAT THE QUESTIONS
WILL BE, THAT'S A STUDY KARINA
IS DOING WITH CRISPR GRID AND
DARE.
WE'VE DONE TWO PAPERS WITH
KARINE THIS YEAR, WOMEN IN HIV,
WOMEN IN CURE RESEARCH AND
PARTNER PROTECTIONS DURING
ATIs, WE'VE DONE A LOT OF
ADVOCACY.
YOU CAN SEE ALL THE DIFFERENT
PLACES, BUT THE MOST IMPORTANT I
THINK ARE WITH THE FDA.
WE'VE INVITED -- WE INVITED ALL
THE COLLABORATORIES TO THAT.
WE'VE HAD A MEETING WITH CBER IN
FEBRUARY AND A REALLY LARGE
MEETING WITH CDR THAT INCLUDED
MORE THAN THE DARE CAB.
AND WE'RE HAVING ANOTHER MEETING
IN DECEMBER.
SO FOR FUTURE, WE'RE GOING TO DO
SOMETHING WITH THE LAST -- IN
JANUARY AND OUR LAST SERIES IS
GOING TO BE ON VIRAL RESERVOIRS.
WE'RE GOING TO CONTINUE TO WORK
WITH COMMUNITY PARTNERS,
SAN FRANCISCO AIDS FOUNDATION,
LGBT CENTER AND WE'RE GOING TO
TRY TO WORK WITH OAKLAND AGAIN.
WE THANK THE INVESTIGATORS FOR
BEING SO COLLEGIAL AND
SUPPORTIVE, AND TO THE DARE CAB,
WE'VE GOT EBONY, KARINE, I KNOW
DERRICK IS HERE AND MICHAEL,
WOULD YOU STAND UP, PLEASE?
THEY'RE ON THE CAB, AND BRIGITTE
IS ONE OF OUR COLLABORATORS.
SO GIVE THEM A HAND TOO.
[APPLAUSE]
>> THANK YOU FOR LISTENING.
>> WE HAVE SEVERAL MINUTES BE
FOR QUESTIONS.
>> WE ENDED ON TIME.
ANY QUESTIONS?
>> STEVE, YOU MENTIONED
SOMETHING ABOUT BACK ROOMS IN
THE POSTER SESSION.
WHERE IS THIS PLACE?
>> I DIDN'T SEE IT AT THE END
BUT ABOVE US, ON THE SIDE IN THE
BALCONY, THERE'S SORT OF A
DARKROOM.
>> I SAID I DIDN'T GO THERE
TODAY SO I JUST WANTED TO KNOW.
THANKS.
>> OKAY.
>> QUESTION FOR LOUIS.
SO FIRST I WAS REALLY HAPPY TO
SEE YOUR DATA, BECAUSE WE HAD
TALKED ABOUT THESE THINGS BEF
BEFORE.
SO IF I SAW YOUR SLIDES
CORRECTLY, YOU SHOW THAT WITH OR
WITHOUT THE BNABs IN THE EARLY
PART AND THE MAGNITUDE AND THE
PROFILE VIREMIA ONCE YOU GET
REBOUND THE SAME SO YOU
CONCLUDED IN YOUR EXPERIMENT AT
LEAST THERE WAS NO VAXAL EFFECT.
DID YOU ACTUALLY MEASURE THE
T-CELL RESPONSES EXPLICITLY IN
THE PERIPHERY AND THE LYMPH
NODES?
>> YEAH, I MEAN, I SHOWED ONE
SLIDE OF THAT.
THE BIGGEST RESPONSE WE GET IS
ACTUALLY LOOKING IN THE BOWEL
BECAUSE THAT'S AN EFFECTOR SITE
THAT REALLY CHANGES A LOT WITH
REBOUND AND ALL THREE
EXPERIMENTS, WE DIDN'T SEE ANY
DIFFERENCE IN THE RESPONSE TO
REBOUND.
SO IN PERIPHERAL BLOOD, IT'S
SIMILAR, THE CHANGES WEREN'T AS
DRAMATIC.
>> SO HOW DO YOU INTERPRET YOUR
DATA ALONGSIDE THE PREVIOUS
STUDIES THAT AT LEAST HAD
CONCLUDED THAT THERE WAS A
VACCINAL EFFECT?
>> WELL, YOU KNOW, DIFFERENT
ANTIBODIES, DIFFERENT
SITUATIONS.
IT MAY BE THAT THESE ANTIBODIES
WERE TOO GOOD.
THAT THEY ACTUALLY ACTED JUST
LIKE ART.
THEY DIDN'T ALLOW ENOUGH ANTIGEN
OR IMMUNE COMPLEX GENERATION TO
BE ABLE TO STIMULATE THE T-CELL
RESPONSE IN A PARTICULARLY
POTENT WAY.
MAYBE THE ONES THAT HAVE SHOWN
THE EFFECT ARE ANTIBODIES OR
VIRUS COMBINATIONS WHERE IT'S
NOT AS GOOD.
THERE'S LOTS OF POTENTIAL
DIFFERENCES.
I NEVER REALLY FELT -- I MEAN,
WE'RE ACTUALLY WORKING WITH
T-CELL VACCINES AT THE PAI PERIT
PERIOD WHICH HAVE A HUGE EFFECT
ON T-CELL RESPONSES AND DATA ARE
GOING TO SHOW BY THE NEXT
MEETING DO SEEM TO DELAY REBOUND
AND MEDIATE SOME POST ART
CONTROL.
BUT THIS IS A RELATIVELY WEAK
EFFECT, BUT IF IT WAS USEFUL, WE
WOULD HAVE LIKED TO HAVE USED IT
OOAND BUILT UPON IT WITH OTHER
IMMUNOTHERAPIES BUT SO FAR WE
HAVEN'T SEEN MUCH REASON TO
CONTINUE AT LEAST WITH THESE TWO
ANTIBODIES IN THE MACK 239
SYSTEM.
>> THANKS.
>> CAN I JUMP IN HERE, LOUIS?
>> YEAH.
>> BECAUSE IF YOU LOOK, DAN, I
MEAN, I KNOW YOU GUYS WERE
TALKING ABOUT THE MONKEY DATA,
BUT IF YOU LOOK IN THE HUMAN
DATA, THERE'S TWO PHENOMENA.
SOMETIMES WITH SOME OF THESE
ANTIBODIES, WHEN 101074 WAS USED
BY ITSELF, THE VIRUS IS SIMPLY
SHOT STRAIGHT UP LIKE IN LEWIS'
MONKEYS.
BUT WHEN YOU USE OTHER
ANTIBODIES, CD4 BINDING SITE
ANTIBODY, YOU'VE GOT THAT
INITIAL DELAY IN THE UPSLOPE.
THOSE ARE THE INDIVIDUALS, AT
LEAST IN THE CLINICAL TRIALS,
FOR WHOM YOU ENDED UP HAVING A
CHANCE OF POST TREATMENT
CONTROL.
THAT'S MY GESTALT TO THE DATA.
I WONDER IF SIV -- TOO FAST.
>> IS JUST TOO FAST, RIGHT?
BECAUSE THE VACCINAL EFFECT WAS
INITIALLY WITH SHIV, WHERE IT
WAS SEEN PRETTY EASILY, THEN
WITH HIV, WHERE IT'S SEEN
SOMETIMES, CERTAIN ANTIBODIES,
BUT THEN YOU'RE NOT SEEING WITH
SIV, WHICH IS A REALLY ROBUST
VIRUS THAT I THINK IS JUST TOO
POWERFUL FOR THESE ANTIBODIES.
>> IN OUR STUDIES WITH SHIV, WE
ALSO DID NOT SEE EVIDENCE OF THE
VACCINAL EFFECT WITH A VARIETY
OF ANTIBODIES ALSO.
THAT'S A SLOWER VIRUS ALSO.
>> MAURO, THAT WAS BEAUTIFUL
DATA.
I WAS CURIOUS, WHEN YOU SEE THE
INCREASE IN TOTAL NUMBERS OF I
IUPM OVER TIME, IF YOU EXPRESS
THAT AS A TOTAL AMOUNT OF HIV
DNA IN THE SAMPLES, IS THE TOTAL
AMOUNT OF HIV DNA GOING UP AS
WELL?
>> I HAVEN'T LOOKED AT THAT YET,
BUT I KNOW PREVIOUS DATA HAVE
CORRELATED TOTAL DNA AND RNA
WITH TIME TO REBOUND.
BUT WE HAVEN'T ASSESSED THAT.
MAINLY BECAUSE IT INCLUDES
TRANSCRIPTS FROM DEFECTIVE PRO
VIRUSES THAT WOULDN'T CONTRIBUTE
TO REBOUND.
BUT THAT'S SOMETHING WE COULD
LOOK AT.
>> RIGHT.
PRESUMABLY IT MAY BE DUE TO
CLONAL EXPANSION OF REPLICATION
COMPETENT PRO VIRUSES.
IT WOULD BE INTERESTING TO KNOW,
THAT SOME OF THOSE PRO VIRUSES
OVER TIME MAY DELETE, BECOME
SOLO LTR, SO USING A DEA DENOMIR
THAT ACTUALLY CAPTURES LTRs,
WHICH I GUESS SOME OF THE ASSAYS
DO AND SOME DON'T, MIGHT BE VERY
USEFUL.
>> THANK YOU FOR THE SUGGESTION.
THANK YOU.
>> HI.
THIS IS FOR SHARON.
BEAUTIFUL DATA.
SO IT SEEMS THAT AT LEAST FOR
THE DATA THAT YOU SHOWED WITH
VENETOCLAX, -- ON EFFECTOR
MEMORY ARE REALLY SENSITIVE BUT
CENTRAL MEMORY AND TRANSITIONAL
MEMORY DON'T SEEM TO BE AS
EFFECTIVE TO THE ANTI-APOPTOSIS
INDUCING.
SO DO YOU THINK THAT -- DO YOU
THINK THAT THAT WOULD BE A
PROBLEM YOU TRY TO REDUCE THE
RESERVOIR BECAUSE CENTRAL MEMORY
ARE GOING TO HAVE A BIG PORTION
OF THE LATENT RESERVOIR?
>> VENETOCLAX WILL DEPLETE ALL
T-CELLS, IT'S A MATTER OF ITS
DEPENDENCY ON BCL2 AND WHAT WE
SAW, THERE WAS GREATER
DEPENDENCY OF NAIVE AND EFFECTOR
MEMORY T-CELLS.
IF YOU LOOK AT THE INTACT DNA,
IT WAS ABOUT A 50% REDUCTION.
SO THERE ARE CELLS THAT SURVIVE
VENETOCLAX, EITHER BECAUSE IT'S
IN T-CELL SUBSETS THAT ARE
RELATIVELY RESISTANT, OR THERE
ARE OTHER FACTORS AS WE HEARD
EARLIER THIS MORNING, YOU KNOW,
HOST FACTORS THAT LEAD TO
SURVIVAL OF SOME CELLS.
BUT WE THOUGHT IT MIGHT BE --
BECAUSE YOU'RE SELECTIVELY
REMOVING MORE NAIVE AND EFFECTOR
MEMORY CELLS AND, THEREFORE,
MORE LIKELY TO GET MORE OF THE
RESERVOIR, BUT WE DIDN'T SORT
INTO DIFFERENT T-CELL SUBSETS TO
ANSWER THAT SPECIFIC QUESTION.
>> THANKS.
>> JEFF BARRY, CRISPR FOR CURE
AND THE REUNION PROJECT.
I WANT TO THANK ALL THE
PRESENTERS FOR A VERY CLEAR
PRESENTATION BUT PARTICULARLY
MAURO, I THINK AS SOMEONE FROM
THE COMMUNITY WHO DOESN'T
NECESSARILY HAVE A SCIENTIFIC
BACKGROUND, IT WAS REALLY
CONCISE AND CLEAR AND
UNDERSTANDABLE, SO THANK YOU.
I KNOW YOUR STUDY DIDN'T INVOLVE
ANALYTICAL TREATMENT
INTERRUPTION BUT I WONDERED IF
YOU OR STEVE WANTED TO COMMENT
ON ANALYTICAL TREATMENT --
ATIs IN LONG TERM SURVIVORS.
YOU ALLUDED TO SOME OF THAT
YESTERDAY IN YOUR TALK, STEVE.
>> HEY, JEFF.
MAURO, DO YOU WANT TO TAKE THAT?
>> SURE.
SO IN PARTICIPANTS ON LONG TERM
ART, IT WAS DATA THAT I DIDN'T
SHARE TODAY BUT THESE
PARTICIPANTS, I SHOWED THAT THE
RESERVOIR MIGHT BE INCREASING
AND THESE CLONES ARE RESISTANT
TO YO AUTOLOGOUS NEUTRALIZING
ANTIBEES MOANTIBODIES SO IF ARTE
STOPPED THEN, THESE LARGE CLONES
THAT MIGHT BE ANAB RESISTANT
MIGHT CONTRIBUTE TO REBOUND.
IN THREE OF THE PARTICIPANTS
THAT I SHOWED ON THE CORRELATION
GRAPH, TWO OF THEM ACTUALLY
REBOUNDED THE FASTEST, WHEREAS
ONE REBOUNDED -- THEY HAD THE
LONGEST TIME TO VIRAL REBOUND,
SO I'LL LET STEVE TAKE OVER.
>> SO THOSE ARE GOOD POINTS.
I THINK JEFF WAS ALSO CURIOUS, I
BELIEVE FOLLOW-UP ON DISCUSSION
FROM YESTERDAY WHERE WE WERE
DISCUSSING ABOUT THE CHALLENGE
AND THE ETHICS OF DOING THESE
TREATMENT INTERRUPTIONS AND LONG
TERM SURVIVORS.
THERE'S ACTUALLY A REALLY A REAY
INTERESTING QUESTIONS THAT CAN
BE ASKED TO PEOPLE ON
ANTIRETROVIRAL THERAPY FOR 20,
30 YEARS, BY DEFINITION THOSE
PEOPLE ARE 25, 30 YEARS OLDER
THAN MOST PEOPLE, SO THEY'RE NOW
IN THEIR 60s AND 70s AND
THERE TRADITIONALLY HAS BEEN
PUSHBACK ABOUT DOING THESE TYPES
OF STUDIES ON PEOPLE OF THAT
AGE, BUT THERE'S A BIG
POPULATION OF PEOPLE WHO REALLY
WANT TO ENGAGE IN THIS WORK.
WE'RE VERY ALTRUISTIC.
WE WANT TO GIVE BACK TO THE
COMMUNITY, WHO HAVE THE TIME,
AND NOW THEY' THERE ARE REALLY
INTERESTING QUESTIONS.
SO THERE HAS BEEN A DISCUSSION
AND DEBATE, NOT DEBATE ACTUALLY,
A REALLY HEALTHY QUESTION WITH
SCIENTISTS AND COMMUNITY ABOUT
WHETHER OR NOT THE QUESTION
BEING ASKED IS APPROPRIATE.
I THINK IT IS, I THINK JEFF
THINKS IT, AND WHETHER WE CAN DO
IT CAREFULLY AND SAFELY, AND I
DO THINK HE WITH CAN.
SO THERE'S A PROCESS WHERE I
THINK WE'LL BEGIN TO DO SOME OF
THESE STUDIES IN LONG TERM
SURVIVORS WHO HAVE GENERALLY
BEEN EXCLUDED FROM THESE CURE
STUDIES, AND I THINK THAT'S A
GOOD THING.
BUT IT'S AN ONGOING DISCUSSION.
>> THANK YOU.
>> HI.
OLIVIA COUNCIL FROM UNC.
>> ONE OF ARE OUR AGENDA ITEMS
IS ACTUALLY -- THE KARINE WE'RE
DOING THAT STUDY WITH KARINE
ABOUT PEOPLE OVER 65 WITH HIV IS
SO WE CAN INCLUDE THEM AS SOON
AS POSSIBLE.
WE'VE NEVER REALLY REALLY
SURVEYED THEM ABOUT WHAT WORKS
FOR THEM, WHAT DOESN'T,
THEIR DEGREE OF WILLINGNESS TO
DO ATIs, DIFFERENT STRATEGIES
AND THAT SORT OF THING.
SO WE'VE ACTUALLY TALKED TO THE
FDA ABOUT PEOPLE OVER 65 AND
THEY ABSOLUTELY MENTIONED THE
RISKINESS OF TRIALS AT THIS
POINT, BUT THEY HAVE NO
OBJECTION TO IT ESSENTIALLY IF
PEOPLE FIT WITHIN THE
INCLUSION/EXCLUSION CRITERIA.
AND INTERESTINGLY, LAST THING,
WE HAD SOMEBODY ON ONE OF OUR
CALLS, ACTUALLY THE FDA CALL,
AND HE DID A REVIEW OF ALL
PROTOCOLS FOR -- I DON'T KNOW
FOR HOW MANY YEARS, IT WAS AT
THE CRO IN NEW YORK.
THE BOTTOM LINE IS THE PEOPLE
JUST CUT AND PASTE IN 65 YEARS,
AND SO MANY OTHER THINGS.
SO IT'S JUST REALLY TIME TO LOOK
AT THAT DIFFERENTLY.
THANKS.
SORRY.
>> JEFF, THAT WAS A GREAT
QUESTION, BUT IT TOOK UP WAY TOO
MUCH TIME SO WE HAVE TO STOP.
I'M SORRY.
>> THAT'S FINE.
NOT A PROBLEM.
>> OKAY.
>> THANKS VERY MUCH TO THE DARE
TEAM.
[APPLAUSE]
WE'LL MOVE ON.
OUR FINAL SESSION OF THE DAY.
>> SO NOW WE'RE GOING TO HAVE
SOME FUN.
WE'RE GOING TO HAVE AN OPEN
DISCUSSION.
SO MOST OF THE WORK, AND I'LL
ASK THE PANELISTS TO COME ON UP.
MOST EVERYTHING THAT'S BEING
PRESENTED TODAY AND TOMORROW
INVOLVE KIND OF BLUNT INSTRUMENT
INTERVENTIONS THAT WE'RE HOPING
ARE GOING TO HAVE EFFECTIVENESS
AGAINST THE BROADER POPULATION
OF INDIVIDUALS.
AND WE WANTED TO ASK THE
QUESTION, YOU KNOW, SOMETIMES IN
THESE SMALL TRIALS OR SMALL
MONKEY STUDIES, YOU'LL SEE AN
EFFECT IN SOME INDIVIDUALS AND
NOT IN OTHERS.
WE WANT TO ASK THE QUESTION, ARE
WE GETTING TO THE POINT WHERE WE
COULD POTENTIALLY TAILOR
INTERVENTIONS SPECIFICALLY TO
THE VIROLOGIC AND IMMUNOLOGIC
BACKGROUND OF THE PARTICIPANTS.
AND SO THAT'S WHAT WE'VE ASKED
THE PANEL TO COMMENT ON TODAY,
AND DR. RICHARD D'AQUILA IS OUR
MODERATOR.
>> THANK YOU, KARL.
IT'S A PRIVILEGE TO BE HERE WITH
THIS GROUP, AND YOU KNOW, THE
BACKGROUND IS UP ON THE SLIDE,
AND LEIA AND HER COLLEAGUES AT
DAIDS DEVELOPED THIS CONCEPT.
THE GOAL IS NOT, AND I WANT TO
EMPHASIZE, NOT TO TRY TO
PERSONALIZE A CURE APPROACH FOR
EVERY INDIVIDUAL, BUT THE GOAL
IS TO SEE IF WE CAN TEST THE
HYPOTHESIS THAT IF YOU HAVE AN
OPTIMAL SITUATION, A CURATIVE
INTERVENTION CAN ACTUALLY WORK.
SO THE IDEA IS TO TAILOR TO WHAT
WE THINK IS A BEST CASE
SCENARIO.
AND THEN PROVE THE CONCEPT THAT
CURE CAN BE DONE IN THAT BEST
CASE SCENARIO AND LEARN LESSONS
FROM THAT.
THIS CONCEPT HAS BEEN APPROVED,
AS YOU SEE ON THE BOTTOM OF THE
SLIDE, SO IT'S POSSIBLE THERE
WILL BE A NOTICE OF FUNDING
OPPORTUNITY IN THE FUTURE, AND
DAIDS IS VERY INTERESTED TODAY
IN HEARING A DISCUSSION ABOUT
HOW FEASIBLE SUCH APPROACHES
MIGHT BE.
SO WE HAVE A GREAT PANEL WHO ARE
EACH GOING TO GET ABOUT FIVE
MINUTES TO TELL US IF THEY THINK
THIS IS FEASIBLE, AND HOW SUCH
AN APPROACH MIGHT BE DONE.
I'LL ASK EACH PANELIST TO GIVE A
BRIEF INTRODUCTION OF YOURSELF,
YOUR NAME AND YOUR INSTITUTION,
AND WE'LL HAVE TIME FOR
DISCUSSION AFTER THE PANELISTS
ARE DONE.
>> MY NAME IS GAURUV GAIHA.
I'M A PHYSICIAN SCIENTIST IN MY
LAB AT THE REAGAN INSTITUTE.
>> I'M MARC WAGNER WITH THE I4C
COMMUNITY ADVISORY BOARD.
>> I'M MATHIAS LICHTERFELD.
I'M AN INFECTIOUS DISEASE
PHYSICIAN AT BRIGHAM AND MGH IN
BOSTON.
>> I'M MORGANE ROLLAND, U.S.
MILITARY HIV RESEARCH PROGRAM.
>> HI, MY NAME IS NILU
GOONETILEKE, I'M AT UNC.
>> I GUESS I'LL GET STARTED.
SO I'M PLANNING TO SPEAK ABOUT A
BIT ABOUT OUR FOCUS ON
PARTICULARLY T-CELL RESPONSES
AND OPTIMIZING T-CELL VACCINES.
SO TO THE SPECIFIC QUESTION OF
WHETHER WE THINK THIS IS A PROOF
OF CONCEPT APPROACH THAT IS
FEASIBLE, I THINK MY KIND OF
ANSWER FROM THE OUTSIDE IS
ABSOLUTELY YES.
I THINK THAT IN THE DESIGN OF
T-CELL VACCINES, THERE REALLY
HAVE BEEN KIND OF A FEW
APPROACHES THAT HAVE BEEN TAKTA,
INCORPORATED INTO KIND OF FULL
LENGTH PROTEINS AS PART OF A
T-CELL VACCINE CONCEPT OR TRYING
TO INCLUDE CERTAIN REGIONS
ACROSS THE HIV PROTEOME THAT MAY
BE CONSERVED OR RESISTANT TO
MUTATION.
I THINK IN DESIGNING THOSE
PARTICULAR VACCINES, THERE'S
EFFORT TO REALLY TRY TO HAVE
BROAD COVERAGE TO BASICALLY
COVER AS MANY PEOPLE AS POSSIBLE
BUT I THINK THERE ARE
LIMITATIONS WHEN TRYING TO DO
THAT IN TERMS OF OPTIMIZING
CONSENTS FOR INDIVIDUAL
PARTICIPANTS.
I THINK THAT DOES IN SOME WAYS
LIMIT SOME OF THESE PROOF OF
CONCEPT STUDIES.
SO I THINK A TAILORING APPROACH
TO INDIVIDUALS, I THINK THE
FIRST MAJOR ADVANTAGE WE HAVE
FROM THE T-CELL PERSPECTIVE IS
TO HAVE AN HLA GENOTYPING
SPECIFICALLY OF THE INDIVIDUAL
WHICH IS QUITE FEASIBLE TO DO,
AND THEN REALLY OP OPTIMIZING
T-CELL VACCINES WHERE WE SELECT
SPECIFIC EPITOPE THAT REALLY
MATCH THE ALEALS OF
PARTICIPANTS.
KNOWING THE HLA GE GENOTYPES --
HIGHLY MUTATION-CONSTRAINED, WE
CAN THEN ALSO OPTIMIZE CASSETTES
IN TERMS OF IMMUNODOMINANCE
HIERARCHIES TO REALLY TRY TO GET
AS BROAD T-CELL RESPONSES TO
THIS INDIVIDUAL TARGET, SO
RATHER THAN TRYING TO USE THIS
OFF THE SHELF VACCINE, AND
REALLY TRYING TO HAVE THAT BE
USED FOR INDIVIDUALS FOR A
PERSONAL APPROACH -- EPITOPE
SELECTION TO MATCH THEIR
GENOTYPE.
I THINK SECONDLY, WE'LL TALK
BHOR SEQUENCING THE COMPETENT
RESERVOIR, THE UNDERLYING
RESERVOIR WE'RE TRYING TO
SUPPRESS AND KNOWING THE
SEQUENCES OF THOSE PARTICULAR
EPITOPE TARGET THAT'S GOING TO
FURTHER FACILITATE THE SELECTION
OF EPITOPES IN THE DESIGN OF
VACCINES, WE CLEARLY CAN
INCORPORATE THOSE EPITOPES IN
POLYMORPHISMS IN ORDER TO HAVE
STRONG SUPPRESSION OF THE VIRUS.
SO I THINK THAT GIVES US A
FURTHER OPTIMIZATION AND ABILITY
TO REALLY SELECT WHAT EPITOPES
AND THE SEQUENCES TO INCLUDE
THAT WILL MATCH THE RESERVOIR
AND HELP US UNDERSTAND FROM A
PROOF OF CONCEPT PERSPECTIVE IF
WE HAVE THE RIGHT T-CELL
RESPONSE DIRECTED TO THE RIGHT
TARGETS AND EPITOPES THAT MATCH
SEQUENCE OR THAT ACTUALLY HAVE
SOME IMPACT ON POST ART
SUPPRESSION.
I THINK THIS WILL ALSO JUST
GENERALLY FACILITATE VACCINE
DESIGN, MAKING THESE LARGE
CONSTRUCTS CAN BE QUITE
CUMBERSOME, HAVING MORE FOCUSED
CASSETTES FOR INDIVIDUALS I
THINK WILL JUST BE MUCH EASIER.
THE LAST THING I'D LIKE TO SAY,
WITH THE ADVENT OF THESE NUCLEIC
ACID VACCINE APPROACHES, CLEARLY
FROM OUR EXPERIENCE WITH
COVID-19, PARTICULARLY NUCLEIC
ACID, THE RNA VACCINES, THERE'S
A CLEAR PRECEDENT FOR USING
THESE NUCLEIC ACID BASED
APPROACHES IN PERSONALIZED
CANCER THERAPY.
I THINK ACTUALLY MAKING GMP
PRODUCT IN A REASONABLE TIME
FRAME THAT CAN BE UTILIZED FOR
SPECIFIC INDIVIDUALS CAN REALLY
BE DONE IN A MUCH MORE
FACILITATED MANNER NOW.
SO I THINK IN TERMS OF EPITOPE
SELECTION FROM AN HLA
STANDPOINT, IN TERMS OF MATCHING
THE VACCINE TO THE UNDERLYING
RESERVOIR IN INDIVIDUALS AND
ACTUALLY GENERATING THE VACCINE
MATERIAL ITSELF IN THE
APPROPRIATE DESIGN, I THINK ALL
OF THESE COMPONENTS ARE QUITE
FEASIBLE AND REALLY MAKE A -- DO
A PROOF OF CONCEPT STUDY WHEN WE
LOOK AT THE ROLE PERHAPS OF
T-CELL IMMUNITY THAT'S OPTIMIZED
FOR INDIVIDUALS ON POTENTIAL
SUPPRESSION.
SO I THINK THE ANSWER IS A
DECIDED YES.
>> I'M MARC WAGNER, A COMMUNITY
MEMBER BUT I ALSO DO SCIENCE.
BUT YOU KNOW, WE'RE MORE THAN 40
YEARS INTO THE PANDEMIC, AND
39-PLUS YEARS OF THAT, I'VE BEEN
LIVING WITH HIV.
I THINK THAT REALLY SHOWS US THE
CHALLENGE THIS VIRUS POSES TO
ALL CURE STRATEGIES.
EVEN WITH THAT IN PLACE, I HAVE
HOPE AND I DARE TO BELIEVE THAT
WE CAN BEAT THIS CONDITION AND
RID THE BODY OF THIS VIRUS.
IT'S MORE THAN IMMUNOTHERAPY FOR
CURE WHICH IS THE CAB I SIT ON
BUT THE I4C IS A VISION AND I
THINK IT'S A VISION ALL OF US
SHARE ACROSS ALL THE
COLLABORATORIES, THE VISION OF
REACHING A CURE.
DURING YESTERDAY'S RAVE,
DR. DEEKS BROUGHT UP ABOUT SOME
OF THE LEGACY EFFECTS OF SOME OF
THE OLDER MEDICATIONS, D4T BEING
ONE OF THEM WI BUT MANY MORE AS.
I THINK THESE THINGS NEED TO BE
CONSIDERED FOR THEIR IMPACT ON
CURE RESEARCH.
BUT I THINK WE ALSO NEED TO
THINK ABOUT WHAT THERAPIES
PEOPLE ARE ON CURRENTLY FOR HIV.
JUST FOR EXAMPLE, ABACAVIR, TO
MOP VEER, TUSCOVI ALL HAVE
COMPOUNDS IN THEM THAT HAVE
PURINES IN THEIR CHEMICAL
STRUCTURES.
AND THESE PURINES ARE SIMILAR TO
ADENOSINE.
SO IF THEY WERE ABLE TO BIND TO
THE ADENOSINE RECEPTORS ON
IMMUNE CELLS, ONE WOULD IMAGINE
THAT THEY WOULD NOT ONLY
DECREASE INFLAMMATION BUT THEY
WOULD ALSO HAVE A SUPPRESSIVE
EFFECT.
SO I THINK WE NEED TO UNDERSTAND
WHAT THE MEDICATIONS MAY BE
PLAYING IN ON THE OVERALL
STRATEGIES.
I THINK THIS IS A GOOD CONCEPT.
IT SHOULD MOVE FORWARD.
I THINK WE DON'T KNOW WHAT IS
THE OPTIMAL, BUT WE NEED TO
START SOMEWHERE AND I APPRECIATE
THE FACT THAT NIH AND EVERYBODY
IN THIS ROOM IS PUTTING FORTH
THE EFFORT TO CHANGE THE FUTURE
FOR ALL OF US, EVEN IF IT TAKES
10, 20 OR 30 MORE YEARS.
THANK YOU.
[APPLAUSE]
>> FROM MY PERSPECTIVE, I
BELIEVE FIRST OF ALL IT'S GREAT
WE'RE HAVING THIS DISCUSSION.
I BELIEVE IT'S IN A WAY
REFLECTING IMPORTANT ADVANCES
THAT WE HAVE MADE IN OUR
COMMUNITY IN THE LAST COUPLE OF
YEARS THAT WE CAN NOW SORT OF
RAISE QUESTIONS OF HOW TO
POTENTIALLY TAILOR CURE
STRATEGIES.
IT'S REFLECTING FROM MY
PERSPECTIVE THAT THERE HAVE A
LOT MORE DATA AVAILABLE NOW ON
THE RESERVOIR.
LARGELY DRIVEN BY TECHNOLOGY
DEVELOPMENT THAT BECAME
AVAILABLE IN THE LAST COUPLE OF
YEARS.
AND WE CAN IN A WAY COLLECT A
LOT OF PIECES OF INFORMATION
ABOUT THE RESERVOIR CELLS FROM
THESE TYPES OF TECHNOLOGIES.
WE KNOW A LOT ABOUT THE VIRUS,
THAT'S WHAT GAURUV TALKED ABOUT
BUT WE CAN ALSO TALK ABOUT THE
INFECTED CELL, THEIR
SUSCEPTIBILITIES, POTENTIAL
VULNERABILITIES AND ALL THIS
INFORMATION IS USEFUL.
AT THE SAME TIME, I ALSO BELIEVE
WE ARE FAR AWAY FROM KNOWING ALL
THAT WE NEED TO KNOW IN A WAY.
THERE'S A LOT OF UNCERTAINTIES
AND A LOT OF THINGS THAT WE
JUST -- THAT THE TECHNOLOGIES
ARE NOT GOOD ENOUGH AT THE
CURRENT STAGE TO KNOW ABOUT.
THE SEQUENCING TECHNOLOGIES THAT
OUR GROUP HAS USED, AND WE ARE
FULLY RECOGNIZING WE'RE GETTING
A VERY SMALL PROPORTION OF THE
RESERVOIR, AND IT'S HARD TO
CONCLUDE BASED ON THAT TYPE OF
ANALYSIS WHAT THE OVERALL POOL
OF RESERVOIR CELLS ARE DOING, SO
THERE'S LOTS OF OPPORTUNITIES
FOR IMPROVEMENT, I BELIEVE, AND
THESE LIMITATIONS, WE NEED TO
SORT OF KEEP IN MIND AS WE MOVE
FORWARD WITH THIS PARTICULAR
AGENDA.
ALSO, WHAT'S SORT OF A BLACK BOX
TO A LARGE EXTENT IS THE TISSUE,
IT'S VERY HARD TO CHARACTERIZE
AND TO ANALYZE, SO WHAT'S GOING
ON IN THE TISSUES, WE DON'T KNOW
TO A LARGE EXTENT AND THAT
COMPLICATES THIS FURTHER.
SO FROM MY PERSPECTIVE, AGAIN AS
I SAID I BELIEVE IT'S A GREAT
QUESTION TO TALK ABOUT AND TO A
LARGE EXTENT, NEW TECHNOLOGIES
WILL BE HELPFUL IN DRIVING THIS
FURTHER AND GETTING US TO A
POINT THAT WE CAN ASK THESE
TYPES OF QUESTIONS EVEN MORE
PRECISELY.
THANKS.
>> THANKS.
SO I THINK IT'S TO ADDRESS THE
QUESTION, I THINK IT'S CURRENTLY
FEASIBLE, BUT THE EXTENT
PROBABLY DEPENDS SO ON THE STUDY
CONDITIONS.
AND MAYBE I'LL TALK ABOUT OUR
STUDY, A STUDY THAT WAS
CONDUCTED AT MHRP.
THE FIRST STUDY ON BNAB INFUS
INFUSIONS ON ATI -- IN THE END
IT'S A SMALL GROUP OF
PARTICIPANTS, AND WHEN PEOPLE
REBOUNDED, WE FOUND THAT THE
PEOPLE THAT REBOUNDED THE
FASTEST HAD VIRUSES THAT WERE
RESISTANT TO VRCON.
OF COURSE THAT WAS A -- AND I
THINK SINCE WE'RE ENROLLING
PARTICIPANTS IN STUDIES WHO HAVE
BEEN ON ART FOR A LONG TIME, WE
HAVE AN OPPORTUNITY TO
CHARACTERIZE THEIR VIRUS IN
ADVANCE BEFORE THEY'RE ACTUALLY
ENROLLED, AND SO FOR FUTURE
STUDIES, THAT'S WHAT WE'RE
DOING.
WE'RE GOING TO ENROLL
PARTICIPANTS, ONE OF THE
ELIGIBILITY CRITERIA WILL BE
THAT THEY HAVE VIRUSES THAT WE
THINK ARE SENSITIVE TO THE BNABS
THAT WILL BE USED IN THE ATI.
AND HERE, I GUESS IT ALSO REALLY
VERY MUCH DEPENDS ON THE STUDY
CONSIDERATIONS, BECAUSE WE'RE
WORKING WITH A COHORT IN
BANGKOK, IN THAILAND, 254
COHORT.
IT'S A COHORT OF PEOPLE WHO
STARTED TREATMENT IN ACUTE
INFECTION.
SO IT'S MUCH EASIER TO KNOW WHAT
VIRUSES THEY HAVE, BECAUSE
THERE'S VERY LITTLE DIVERSITY IN
THEIR VIRUSES, SO TYPICALLY WE
HAVE A CLONAL VIRAL POPULATION
SO WE'RE NOT WORRIED AS MUCH
ABOUT HAVING THE RESISTANT
VARIETY OF VIRUSES THAT CAN BE
RESISTANT AT DIFFERENT LEVELS
DUE TO VIRAL EVOLUTION.
SO IN TERMS OF THINKING THAT IT
IS FEASIBLE, THERE ARE LOTS OF
LIMITATIONS THAT ARE DUE TO --
AND OF COURSE WE CAN ALSO TRY TO
IDENTIFY CONDITIONS THAT WOULD
BE BETTER AND MAKE US HAVE SORT
OF OPTIMAL -- AN OPTIMAL -- WE
NEED TO FIND OPTIMAL CONDITIONS
THAT ARE BETTER FOR THE
PARTICIPANTS, AND CONSIDERING
THE LIMITATIONS THAT WE HAVE
ALSO TECHNOLOGICALLY.
>> YES, MY SHORT ANSWER IS YES
TO DEVELOP A RESEARCH PLATFORM.
JUST TO FRAME THE DISCUSSION
FROM MY MIND, AT LEAST, IN THE
ABSENCE OF TRANSPLANTATION IN
CURATIVE STUDIES, POST TREATMENT
CONTROL IS STILL PHENOMENONICAL.
WE SEE TO TAKE IT A PART.
SO TO ME THIS IS COMING AT IT
FROM THE OTHER END AND
RECOGNIZING THAT EVERYBODY'S HIV
INFECTION AND SUBSEQUENT DISEASE
COURSE IS UNIQUE.
EVERY INDIVIDUAL IS INFECTED
WITH A DIFFERENT VIRUS BECAUSE
OF HLA DIVERSITY, THE SUBSEQUENT
EVOLUTION WITHIN THAT PERSON IS
DISTINCT AND, THEREFORE, THE
T-CELL RESPONSE TO THAT PATHOGEN
IS DISTINCT.
THAT THEN IMPACTS THE ANTIBODY
RESPONSE WITHIN THAT PERSON
BECAUSE YOU HAVE DIFFERENT
LEVELS OF EVOLUTION,
RECOMBINATION THAT ARE
OCCURRING.
THAT LEVEL OF EVOLUTION IS
DEPENDENT ON HOW LONG THAT
INDIVIDUAL IS UNTREATED.
SO TREATMENT IN ADE ACUTE VERSUS
CHRONIC, WHICH WE'RE ALREADY
DOING.
WE'RE ALREADY DOING TALENT
STUDIES BECAUSE WE'RE PICKING OR
IDENTIFYING STUDY PARTICIPANTS
DEPENDENT ON WHEN THEY'RE
TREATED.
SUBSEQUENTLY ONCE WE INITIATE
ART THERAPY, THE TIME OF ART
TREATMENT IS VERY RELEVANT
BECAUSE WE HAVE TO ALLOW IMMUNE
RESTORATION FOR THOSE
INDIVIDUALS WHO REMAIN UNTREATED
FOR MANY, MANY YEARS.
SO IN TERMS OF CAN WE STUDY IT,
I THINK WE HAVE A LOT OF THE
TOOLS.
OF COURSE A LOT MORE NEEDS TO BE
DONE.
WE CAN RECOVER REPLICATION
COMPETENT VIRUS LIMITING
DELUSION, WE CAN SEQUENCE IT, WE
CAN THEN LOOK TO SEE IF IT IS
SUSCEPTIBLE TO THE CIRCULATING
T-CELL RESPONSES, THE
CIRCULATING ANAB RESPONSES,
YOU'VE HEARD ABOUT ALL OF THAT
THIS WEEK.
WE CAN THEN IDENTIFY PERHAPS IF
WE HAVE A SUITE, LET'S SAY, OF
10 BNABs THAT ARE AVAILABLE,
WHICH THREE OF THAT PARTICULAR
INDIVIDUAL'S RESERVOIR VIRUS TO
THE EXTENT THAT WE SEE IT CAN BE
SUSCEPTIBLE TO.
SO IN SOME WAYS I THINK WE'RE
ALREADY MOVING TOWARDS IT, BUT
PERHAPS ONE OF THE THINGS WE CAN
AIM FOR IS RECOGNIZING JUST LIKE
CANCER, WE MAY NOT BE ABLE TO
CURE OR FUNCTIONAL LIQUEUR 100%
OF PEOPLE, BUT MAYBE IN THE
FIRST INSTANCE, 10% IS GOOD.
BUT VERY IMPORTANTLY, KNOWING
WHY WE ACHIEVED POST TREATMENT
CONTROL IN THAT 10% TO ME IS A
STEP FORWARD, TO MOVE AWAY FROM
IF HE PHENOMENA.
>> THANK YOU ALL.
I WANTED TO MAKE AN OBSERVATION,
BUT WE HAVE A VERY PATIENT
GENTLEMAN HERE.
>> I JUST WAS -- SO I DON'T
UNDERSTAND WHAT IT MEANS THAT
WE'RE TALKING ABOUT, WHAT YOU'RE
TALKING ABOUT IS THIS CON ACCEPT
THAT'S BEEN APPROVED, IS THIS
NOW RESEARCH, IS THIS A WAY LIKE
HOW SCHOOLHOUSE ROCK DIDN'T
TEACH ME WHAT COMES WITH THE
CONCEPT THAT'S APPROVED, WHAT'S
IT BECOMING AND I DON'T KNOW
WHAT WE'RE TALKING ABOUT.
SO IT'S LIKE HOW AM I SUPPOSED
TO FEEL ABOUT IT?
SO I WOULD LOVE TO KNOW WHAT
THIS IS GOING ON, I DON'T
UNDERSTAND WHAT YOU GUYS ARE
DISCUSSING.
>> I'M SORRY, I DIDN'T DO A GOOD
JOB WITH MY PLAIN ENGLISH
SUMMARY.
SO A CONCEPT MEANS THAT IN THE
NEXT YEAR OR SO, IT MAY TURN
INTO A REQUEST FOR PROPOSAL,
SOME SORT OF --
>> OH, COOL.
>> -- NOTICE OF FUNDING
OPPORTUNITY.
AND YOU KNOW, THIS WAS APPROVED
BY THE NIAID COUNCIL IN JUNE,
AND I THINK DAIDS TODAY IS
LOOKING FOR THIS KIND OF
SCIENTIFIC CONVERSATION WITH A
BROADER AUDIENCE, INCLUDING
COMMUNITY, TO SEE DOES THIS
REALLY MAKE SENSE.
I WAS ON THE AIDS RESEARCH
ADVISORY COMMITTEE THAT
DISCUSSED THIS AT THE COUNCIL
MEETING, AND THAT COMMITTEE, AS
YOU'VE HEARD FROM THIS PANEL,
WAS STRONGLY SUPPORTIVE.
>> RIGHT.
IT HELPS A LOT KNOWING WHAT WE
WERE TALKING ABOUT BECAUSE NOW
I'M LIKE, AH, NOW I GET IT.
BUT I UNDERSTAND THE VISION, I
LOVE THE DEFINITION AND THE
CONCERNS, BUT NOT KNOWING WHAT I
WAS TALKING ABOUT OR WHAT YOU
WERE TALKING ABOUT, THAT'S WHY I
STOOD UP HERE ALL THIS TIME
BECAUSE I WAS LIKE WAIT, WHAT
ARE YOU TALKING ABOUT, YOU
DIDN'T TELL US.
THANK YOU SO MUCH.
>> YOU'RE WELCOME.
>> I JUST WANT TO MAKE ONE
OBSERVATION, THAT I AGREE WITH
EVERYTHING THAT EACH OF THE
PANELISTS SAID, AND EACH OF
THE -- AND I THINK WE NEED THIS
KIND OF OPPORTUNITY IN ORDER TO
DO WHAT YOU'RE ALL THINKING
ABOUT AND POTENTIALLY PROPOSING,
BECAUSE IT ALL TAKES A LONG TIME
TO CHARACTERIZE HLA ALLELES, THE
VIRAL EPITOPES, THE INTEGRATION
SITE, THE PRO VIRUS, WHETHER
THERE'S AUTOLOGOUS NEUTRALIZING
ANTIBODIES MAYBE IS ANOTHER
FACTOR.
BUT I DO THINK THERE ARE MAYBE
QUICKER THINGS THAT WE COULD
CHARACTERIZE THAT MAYBE COULD BE
DONE EVEN WITHOUT A SPECIFIC
NOFO ON THIS, LIKE
CHARACTERIZING INFLAMMATION
PRIOR TO AN ATI.
ESPECIALLY IF WE'RE USING LRAs
THAT ARE ACTIVATING CELLULAR
PROMOTERS, WHAT'S THAT DOING TO
INFLAMMATION?
I THINK IT'S VERY PERTINENT IF
WE'RE TALKING ABOUT MAKING MORE
OPPORTUNITIES TO INCLUDE OLDER
LONG TERM SURVIVORS IN CURE
RESEARCH.
OBVIOUSLY IT DOESN'T APPLY TO
EVERY INTERVENTION FOR CURE, BUT
IT MIGHT TO SOME, AND THE
HISTORY OF ART IS VERY IMPORTANT
BECAUSE IT ALSO INDICATES HOW
WELL SUPPRESSED SOMEONE HAS
BEEN, I THINK, AND WHEN IT COMES
TO TISSUE RESERVOIRS, IMAGING IS
ANOTHER THING WE SHOULD CONTINUE
TO BE PUSHING THE FRONTIER AND
DEVELOP.
SO I THINK SOME OF THOSE THINGS,
WE COULD KIND OF COLLECT THE
DATA PROSPECTIVELY, AND THEN
RETROSPECTIVELY ANALYZE WHICH
FACTORS ARE ASSOCIATED WITH A
BETTER RESPONSE.
OKAY, I'LL GET OFF MY SOAP BOX
AND OPEN UP THE --
>> HI.
THANK YOU ALL SO MUCH FOR
SHARING.
I HAD A QUESTION, WHEN THINKING
ABOUT THESE APPROACHES, WE ARE
TENDING TO ASSUME THAT THESE
APPLICATIONS CAN BE APPLIED SO
HAVING SEQUENCING DONE REQUIRES
AN INSTITUTION THAT HAS ACCESS
TO SEQUENCERS, AND HAVING AN
INDIVIDUAL HLA TYPED REQUIRES,
YOU KNOW, A RESEARCH INSTITUTION
OR SOME SORT OF MORE ADVANCED,
YOU KNOW, MEDICAL SITE THAT
AREN'T NECESSARILY AVAILABLE IN
EVERY COMMUNITY, AND SO I THINK
THAT HOW WOULD THIS APPLY TO THE
BROADER FIELD AND NOT JUST
HAVING THESE OPPORTUNITIES
AVAILABLE TO INDIVIDUALS WHO
LIVE IN VERY ADVANCED BIOMEDICAL
RESEARCH, I GUESS FOCUSED CITIES
AND REGIONS?
>> THAT'S A VERY GOOD POINT, AND
I ACTUALLY BROUGHT THAT UP WITH
NIH BEFORE, THAT THERE SHOULD BE
CENTRALIZED TESTING FOR
ESPECIALLY HLA AND KERR TYPING
BECAUSE TH THESE ARE MORE
CHALLENGING THINGS TO BE DONE,
AND I THINK IF NIH WOULD INVEST
IN THAT, THEN RESEARCHERS THAT
ARE FUNDED THROUGH NIH COULD
THEN MAKE USE OF THAT.
IT WOULD BE STANDARDIZED, IT
WOULD BE DONE WELL, TAKE THE
BURDEN OFF OF THE INDIVIDUAL
SITES TO BE ABLE TO DO SOME OF
THOSE THINGS.
MY UNDERSTANDING, YOU CAN TELL
ME IF I'M WRONG, I BELIEVE
IPDAs ARE ALSO AVAILABLE
THROUGH NIH.
IS THAT CORRECT, KARL?
SO THAT'S ONE THING, BUT I THINK
OTHERS DEFINITELY NEED TO BE
ADDRESSED.
AND I'LL LET ANYONE ELSE ANSWER.
>> WELL, I'LL JUST MAKE ONE
QUICK OBSERVATION THAT I THINK
THE DELANEY COLLABORATORIES ARE
A GOOD EXAMPLE OF HOW GROUPS OF
RESEARCHERS CAN WORK TOGETHER
AND KIND OF SPREAD ACCESS TO
RESOURCES, INCLUDING TO PLACES
THAT, YOU KNOW, PARTICIPANTS MAY
HAVE THEIR SPECIMENS SHIPPED
ELSEWHERE FOR ANALYSIS.
>> I WOULD JUST ADD THAT I THINK
THAT THE UTILITY OF THIS IS
REALLY TO TRY TO UNDERSTAND
SCIENTIFIC CONCEPTS, SO I THINK
THAT PERHAPS IF WE SEE THIS AS
AN OPPORTUNITY TO -- OPTIMAL
CONDITIONS, UNDERSTAND WHAT CAN
WORK, MAYBE THAT CAN HELP INFORM
BROADER STRATEGIES.
SO RATHER THAN THIS NECESSARILY
BE THE APPROACH WE TRY TO APPLY
BUT REALLY FOCUS ON A FEW
PARTICIPANTS FROM A STUDY
PERSPECTIVE TO REALLY KNOWING
WITH OPTIMAL CONDITION WHAT CAN
AND CANNOT WORK IS WHERE THE
UTILITY REALLY IS.
>> THANK YOU.
AND I WOULD AGREE THAT I THINK
IT'S BABY STEPS.
IF WE CAN ACTUALLY CONFIDENTLY
PREDICT WHY 10% MAY ACTUALLY
RESPOND TO TREATMENT, AT THAT
JUNCTURE, YOU'RE LOOKING FOR
BIOMARKERS TO SCREEN THE
POPULATION FOR THAT 10%.
>> LET'S GO OVER TO THIS SIDE.
>> ANDY FROM NIAID.
SO ONE THING AS A COMMENT AND
THEN A QUESTION IS, ONE OF THE
THINGS ABOUT TAILORING A CURE
FOR INDIVIDUALS IS WE NEED TO
KNOW MORE ABOUT DIFFERENT
INDIVIDUALS.
WE'RE STARTING TO SEE IT A
LITTLE MORE WHERE SO MUCH OF
CURE WORK WAS ONLY DONE IN THE
UNITED STATES, USUALLY DONE IN
MOSTLY MALE POPULATIONS, AND I
THINK IF WE STUDY MORE DIVERSE
POPULATIONS IN AFRICA AS WELL AS
MALE AND FEMALE, AGAIN, OLDER
INDIVIDUALS, ACUTE, CHRONIC, ET
CETERA, I THINK WE'RE GOING TO
LEARN MORE, WHICH WILL HELP MAKE
THIS A REALITY, RIGHT?
IF WE ONLY STUDY PEOPLE WHO ARE
TREATED DURING ACUTE INFECTION
AND ONLY MALES, WE'RE MISSING A
HUGE AMOUNT OF INFORMATION.
BUT IT NICE TO SEE MORE OF THAT
BEING INCLUDED IN -- THE
DELANEYS ARE JUST RESEARCH IN
GENERAL.
BUT THE SECOND COMMENT IS -- ON
THIS IS SOME WORK BY MELISSA
SMITH THAT JUST CAME OUT IN
NATURE COMMUNICATIONS THAT
SHOWED THAT THERE'S A LOT MORE
DIVERSITY IN THINGS LIKE THE VDJ
RECOMBINANT REGIONS OF OUR
ANTIBODIES.
AND SO HOW DO YOU GUYS THINK, AS
WE DRILL DEEPER INTO EACH
INDIVIDUAL, THE COMPLEXITY GETS
THAT MUCH MORE COMPLEEX?
AND LIKE WE REALLY CAN'T CURE
ANYBODY WITH PERFECT SITUATIONS
NOW, LIKE AS IT GETS MORE AND
MORE COMPLEX, HOW DO YOU GUYS
THINK WE'LL DEAL WITH THAT LEVEL
OF COMPLEXITY?
>> JUST A BRIEF COMMENT ON THAT.
SO I BELIEVE WHAT IS REALLY
HELPFUL AT THE CURRENT STAGE OF
DEVELOPMENT ARE THESE SORT OF N
EQUALS 1 STUDY, SO GOING DEEP ON
ONE PARTICULAR PERSON WHO HAS A
VERY ATYPICAL RESERVOIR OR A
VERY ATYPICAL DISEASE COURSE
AFTER TREATMENT INTERRUPTION.
THAT BY ITSELF CAN BE INCREDIBLY
INFORMATIVE, AND USING THAT FULL
PIPELINE OF TECHNOLOGIES THAT IS
AVAILABLE AT THE CURRENT TIME
CAN BE A SORT OF REVEALING
PATTERNS AND MECHANISMS AND
BIOLOGY THAT WAS JUST NOT
OBVIOUS BEFORE.
SO I BELIEVE ZOOMING IN ON
INDIVIDUAL PERSONS IS AN
IMPORTANT ASPECT OF IT, AS YOU
SAID, AND ALSO DIVERSITY IS
INCREDIBLY IMPORTANT.
JUST THAT DIFFERENCE THAT YOU
MENTIONED BETWEEN MALE AND
FEMALE, I BELIEVE HAS A
FUNDAMENTAL IMPACT ON WHAT THE
IMMUNE SYSTEM CAN DO AGAINST THE
RESERVOIR, AND IT'S GREAT THAT
THERE'S NOW MORE RECOGNITION FOR
THAT.
>> IN I CO IF I COULD MAKE AN EL
COMMENT, MATHIAS.
I'VE HAD CONVERSATIONS WITH
STATISTICIANS WHO RAISE CONCERNS
ABOUT N EQUALS 1 STUDIES BECAUSE
YOU CAN'T COMPARE, RIGHT?
SO YOU'RE NEVER REALLY SURE.
SO I THINK THAT'S AN AREA WHERE
WE WANT STUDY DESIGNS WHERE
THERE CAN BE LIKE A CROSSOVER,
YOU KNOW, SO YOU EVALUATE
SOMETHING BEFORE AND AFTER AN
INTERVENTION, OR YOU KNOW, SOME
WAY WITHIN THE INDIVIDUAL TO
HAVE A COMPARISON.
>> YOU ALL HAVE DONE A REALLY
GREAT JOB EXPLAINING HOW WE
COULD TAILOR HIV CURE STRATEGIES
TO THE INDIVIDUAL PARTICIPANT
FROM A VIROLOGICAL AND
IMMUNOLOGICAL STAND POINTS.
HAVE YOU ALSO CONSIDERED
INTEGRATING PSYCHOSOCIAL MARKERS
AND ACCEPTABILITY MARKERS TO
MAKE SURE THAT THESE STRATEGIES
REMAIN ACCEPTABLE TO
PARTICIPANT?
WE KNOW ATIs ARE ASSOCIATED
WITH VIREMIA RELATED WORRY AND
PEOPLE HAVE DIFFERENT TOLERANCE
FOR RISK SO IT SEEMS LIKE WE
COULD LEARN A LOT ABOUT THE
ACCEPTABILITY OF THESE DIFFERENT
MODALITIES.
AND ALSO ARE YOU INTEGRATING
ETHICAL CONSIDERATIONS FOR
PERSONALIZED CURE?
IT SEEMS LIKE WE WANT TO PREVENT
INCREASING DISPARITIES WITH
THESE STRATEGIES.
>> DOES ANYBODY WANT TO COMMENT
ON THAT?
>> I I BELIEVE YOU SHOULD BE
SITTING UP HERE TO TALK ABOUT
THIS.
THESE ARE VERY IMPORTANT PARTS
OF IT, RIGHT, AND IT NEEDS TO BE
TAKEN INTO CONSIDERATION AS MUCH
AS ALL THE OTHER THINGS AS THE
BROADLY NEUTRALIZING ANTIBODIES,
THE T-CELLS, SO IT SHOULD BE
HAVING -- IT SHOULD BE
INCORPORATED INTO ALL THESE
DISCUSSIONS.
SO I'M HAPPY TO LEARN FROM YOU,
IT SOUNDS LIKE YOU HAVE A LOT OF
THINGS TO CONTRIBUTE WHEN IT
COMES TO THESE QUESTIONS.
>> KARINE, I GUESS MY
UNDERSTANDING OF THE QUESTION
IS, I DON'T THINK WE'RE TRYING
TO PUSH ATI, I THINK WE'RE
ACTUALLY TRYING TO LEARN A LOT
MORE BEFORE AND THEN SELECTIVELY
IDENTIFY THE BEST CHANCES FOR AN
ATI.
SO I THINK WE'RE MOVING THE
OTHER WAY, PERSONALLY, FROM MY
PERSPECTIVE.
>> I THINK IT'S ACTUALLY -- I
MEAN, A LOT OF THIS IS TRYING TO
MAKE -- TO OPTIMIZE CONDITIONS
SO FOR THE PARTICIPANTS IT'S
BETTER.
>> LYNDA?
>> YEAH, SO YOU SAID THAT MAYBE
IN A YEAR OR SO, THERE MIGHT BE
SOME SORT OF REQUEST FOR
PROPOSAL ON THIS, AND I JUST
WONDER, I MEAN, IT SOUNDS
FABULOUS, BUT THERE ARE
CONTROVERSIES ABOUT PRO VIRUS,
AND WHAT IMMUNOLOGIC PROFILE ARE
WE LOOKING AT?
LOU I I LOVE THIS, ALWAYS LIKES
TO SAY, IT'S ALL ONE SYSTEM AND
ONE PIECE, YOU KNOW, AFFECTS THE
OTHER PIECES.
YOU KNOW, IT'S A WHOLE MOVING
THING INSTEAD OF JUST ONE LITTLE
CD4 OR CD8, THAT SORT OF THING.
SO WHAT WOULD THE IMMUNOLOGIC
PROFILE BE?
I THINK WE'RE KIND OF -- MAYBE
THREE YEARS?
I DON'T KNOW ABOUT NEXT YEAR.
I BELIEVE IN FORWARD PLANNING,
BUT --
>> I WOULD JUST ADD THAT, AND
LYNDA, I THINK FROM THE LESSONS
WE'VE LEARNED FROM ALL THESE
COHORT STUDY, ACROSS ALL THESE
COLLABORATORIES, I THINK THERE'S
SOME GENERAL THOUGHT THAT A
POTENT CD -- RESPONSE COULD
POTENTIALLY HAVE AN IMPACT.
I THINK CLEARLY THE BNABS, IF
THEY'RE HITTING SENSITIVE RE --
TAKE PATIENTS OFF TREATMENT,
CLEARLY AUTOLOGOUS TO
ANTIBODIES, EMERGING SOME OF
THESE INNATE IMMUNE FACTORS.
I THINK THE IDEA IS WE KIND OF
TAKE THAT COLLECTIVE KNOWLEDGE
AND IF WE ARE GOING TO TRY TO
TAILOR A STRATEGY, HOW CAN WE
OPTIMIZE ALL THOSE COLLECTIVE
COMPONENTS FOR A GIVEN
INDIVIDUAL BEFORE WE CONSIDER?
AND IF WE DO OPTIMIZE CERTAIN
COMPONENTS VERSUS OTHERS, OR
SOME KIND OF COMBINATION
THEREOF, WHAT EFFECT DOES THAT
HAVE?
I THINK THAT'S WHERE THE REAL
POSSIBILITY FOR LEARNINGS CAN
TAKE PLACE.
SO WHAT HAPPENS WHEN THINGS ARE
OPTIMIZED, WHAT'S THE OUTCOME
SUBSEQUENTLY.
>> ISN'T THAT BETTER IN A BIG
GROUP THAN TRYING TO DO THAT
PATIENT BY PATIENT, THOUGH?
IS IT IN EACH PARTICIPANT?
>> THAT'S THE IDEA.
>> GOOD LUCK.
[LAUGHTER]
>> HI.
I WOULD LIKE TO BRING YOUR
ATTENTION BACK TO THE TISSUE
LEVEL.
SO I KIND OF AGREE THAT A TISSUE
LEVEL IS KIND OF LIKE A BLACK
BOX RIGHT NOW.
SO I JUST WISH TO THINK ABOUT
WHEN WE STARTED THE TISSUE --
THE STILL LIKE IT'S A BABY AND
THE -- GET FROM THE T-CELL.
SO I THINK PROBABLY IT'S A
LITTLE MORE -- IT'S SO DIFFICULT
TO STUDY, AND SHOULD IT BE MORE
ENCOURAGED FOR THIS.
THANK YOU.
SO FOR THE -- WE JUST MENTIONED
ABOUT THE -- -- THE TISSUES.
SO I -- WE JUST WANT TO GET MORE
ENCOURAGING IN THIS FIELD AND
MORE PROGRESS IN THIS FIELD.
>> I BELIEVE IT'S GREAT THAT
YOU'RE BRINGING IT UP, AND IN MY
EXPERIENCE, I CAN ONLY SAY WE
DID A RECENT STUDY WHERE WE
LOOKED AT THE PHENOTYPE OF
RESERVOIR CELLS IN TISSUES
VERSUS BLOOD AND IT LOOKS VERY
DIFFERENT.
>> THAT'S EXACTLY WHAT I WANT TO
SAY.
SO WHAT WE SEE IS SO DIFFERENT
BETWEEN THE -- THE T-CELL, SO
WHAT -- OR I DON'T -- IT'S SO
DIFFERENT.
>> IT'S A CHALLENGE FOR ALL OF
US, I BELIEVE, IN THIS
COMMUNITY, AND THE ANIMAL STUDY
KS HELP TO SOME EXTENT, AND THE
TISSUES USING AUTOPSY MATERIAL
THAT YOU ARE DOING, BUT IT'S
GOOD TO HAVE A BIGGER DISCUSSION
ABOUT HOW WE ARE ADDRESSING
THAT.
>> THANK YOU.
>> HI.
I THINK IT'S A REALLY VERY
WELL -- THIS APPROACH, I THINK
THE ADVENT OF SYSTEM BIOLOGY IS
WHEN WE CAN REALLY RE-TAILOR
PERSONALIZED MEDICINE.
-- AND MYSELF, WE WORK FOR 15
YEARS ON PERSONALIZED APPROACHES
TO VACCINATION, AND WE SHOWED
CLEARLY THERE ARE PROFILES THAT
CAN PREDICT -- RESPOND TO
VACCINES.
I THINK WE HAVE NOW THE SAME
DATA, -- HAS IDENTIFIED WHERE WE
SEE ABOUT FIVE -- AVAILABLE, IS
ALMOST WHAT YOU EAT.
IT'S THE -- AND MICROBES THAT
SHAPE THE -- AND SHAPE THE AREAS
THAT CONTROL THE VIRUS.
SO THIS APPROACH, THIS STRATEGY,
I THINK NOT ONLY CAN BE FOCUSED
ON -- FACTORS WHICH I'M SURE ARE
THERE, HOST IMMUNE FACTORS, WE
CHOSE -- AND -- THE GROUP TO
THINK OUTSIDE OF THE BOX, AND
THINK WHAT IN FACT IS REALLY
WHAT DICTATES THE SHAPE OF
IMMUNE RESPONSE EVERY DAY.
THAT HAS CLEARLY BEEN SHOWN IN
CANCER.
THERE WAS A MEETING OF --
MICROBE AND METABALOME FOR TWO
DAYS AND ALL I HEARD IS YOU MAY
EAT HIGH FIBER, LOW FIBER DIET,
THERAPIES TO CANCER, PANCREATIC
CANCER, SO THAT REALLY HAS TO GO
INTO OUR MIND.
MAYBE WHAT YOU EAT CAN BE
EXTREMELY GENERIC, BUT YOU
WHATEVER INTAKE WE TAKE, THAT
NOW WE CAN HAVE VERY IMPORTANT
EFFECTS ON THE RESPONSE AND
POTENTIAL VIRAL -- BECAUSE -- OF
COURSE -- CAN CONTROL VIRAL
LATENCY SO I REALLY URGE THE
GROUP --
>> THANK YOU.
>> HI.
JULIE, HRP.
REALLY GREAT TO HEAR ALL OF THE
COMMENTS SO FAR IN THIS SESSION.
AND TO REALLY ACKNOWLEDGE THAT I
THINK, YOU KNOW, TOOLS AND
COHORTS ARE RAPIDLY DEVELOPING,
ARE HERE.
RESEARCH PLATFORMS ARE VERY
FEASIBLE.
YOU KNOW, THE CH CHALLENGE, OFT,
IS THE MANUFACTURING.
I THINK IT'S VERY EASY TO THINK
ABOUT HOW THIS SHOULD BE SO MUCH
BETTER WITH MRNA, BUT THE FACT
OF THE MATTER IS FOR MOST
GROUPS, THERE'S NO EASY BUTTON
FOR MRNA.
THERE'S ONLY A VERY, VERY HARD
BUTTON FOR MRNA, RIGHT NEXT TO A
SPEND A LOT OF TIME WITH YOUR
LAWYER BUTTON BECAUSE OF ALL OF
THE VERY INTENSE THINGS LIKE
LIPID ENCAPSULATION.
THAT I THINK IS THE BIGGEST
CHALLENGE, HAVING -- THAT WE CAN
ACTUALLY FULFILL THE PROMISE.
I KNOW THAT WE HAVE COLLEAGUES
AT THE DIVISION OF AIDS THAT
REALLY THINKING ABOUT THIS, NOT
JUST IN THIS SETTING, BUT ACROSS
THE HIV PROARL.
PORTFOLIO.
I'D BE REALLY INTERESTED TO HEAR
WHAT PEOPLE'S THOUGHTS ARE ON
THAT.
>> THAT'S A REALLY GOOD POINT.
IN TERMS OF THE MANUFACTURING TO
MAKE THIS A REALITY, THAT'S A
BIPG.
ONE QUESTION THAT MAYBE SHOULD
BE CONSIDERED IS SHOULD THERE BE
SOME KIND OF PUBLIC PRIVATE
PARTNERSHIP, WHO DOES THIS IN
THE PERSONALIZED CANCER VACCINE
SPACE, AND THAT WOULD JUST
FURTHER FACILITATE ADVANCES IN
MORE RAPID FASHION OR IS THERE
WAY TO GET ACCESS OF SOME KIND
OF STANDARDIZED MRNA PRODUCTION
FACILITY TO PROVIDE THIS
SPECIFICALLY FOR THIS PROGRAM.
BUT I THINK THE PUBLI
PUBLIC/PRIVATE --
>> CAN I SUGGEST A HAPPY MEDIUM,
SOMETHING MORE LIKE THE CANCER,
THERAPY FOR EVERY INDIVIDUAL BUT
OPTIMIZED COMBINATION FOR
INDIVIDUALS.
SO IF YOU HAVE THE SUITE OF --
IF YOU HAVE A CHOICE OF GMP-MADE
VACCINES FOR T-CELLS DEPENDING
ON THE SEQUENCE PRE-EXISTING
ESCAPE, PRE-EXISTING RESPONSE
WHICH INDIVIDUAL WILL RESPOND TO
WHICH VACCINE AND CHOOSE THOSE.
AGAIN, RFIQ TALKED ABOUT PD-1
SUSCEPTIBILITY.
CANCER THERAPY CHOOSES PATIENTS
NOW, RESPONSIVENESS.
SO I WOULD GO WITH THAT TO SORT
OF THE INTERMEDIATE, AND THEN
THAT MAKES IT MORE EQUITABLE,
RIGHT?
OTHERWISE PERSONALIZED, ONLY IT
WILL HAPPEN IN AMERICA AND
EUROPE.
>> REALLY EXCELLENT POINTS.
THANKS.
>> IF I COULD JUST ADD, WE'VE
HEARD ALREADY TODAY, AND I'M
SURE WE'RE GOING TO HEAR MORE
TOMORROW ABOUT A VERY BROAD
RANGE OF DIFFERENT THINGS IN THE
TOOLBOXES OF ALL THE
COLLABORATORIES AND THEIR
PARTNERS INCLUDING PRIVATE
ENTERPRISE PARTNERS.
SO YOU KNOW, I'M HOPEFUL THAT
LARGE CONSORTIA CAN BE PUT
TOGETHER THAT CAN ADDRESS THESE
CHALLENGING IDEAS.
>> I JUST WANTED TO ASK THE
PANEL MAYBE TO COMMENT ON
MODELS.
MY UNDERSTANDING IS THAT THIS
CONCEPT WILL NOT INCLUDE
CLINICLINICAL TRIALS IN HUMANS,T
WILL BE EITHER PRIMARILY METHOD
DEVELOPMENT OR ANIMAL MODEL
WORK.
AND WHEN WE GET TO THE ANIMAL
MODEL WORK, THERE'S A DISCUSSION
FOR EXAMPLE IN NON-HUMAN PRIMATE
ABOUT HOW LONG WE NEED TO KEEP
ANIMALS ON ART BEFORE THEY TRULY
GET TO A LOW RESERVOIR, WHICH
THE DISCUSSION IS ANYWHERE
BETWEEN SIX MONTHS TO TWO YEARS.
SO BY THE TIME YOU GET THE
ANIMALS, YOU PUT THEM ON ARKTS
YOU WAIT, YOU'RE BASICALLY IN
THE LAST BASICALLY YEAR AND A
HALF TO TWO OF THE FIVE-YEAR
CYCLE.
IF WE GO TO HUMANIZED MICE, THEN
THERE ARE SHORT TERM ANSWERS TO
SPECIFIC QUESTIONS BUT LONGEVITY
AND IMPACT OF STRATEGY LONG TERM
IS REALLY HARD TO EVALUATE
BECAUSE OF THE LYMPHOID
TRAFFICKING LIMITATIONS AND B
CELL RESPONSE LIMITATIONS.
SO CAN MAYBE YOU COMMENT ON WHAT
TYPES OF -- HOW DO WE DEAL WITH
THAT, HOW DO WE DEAL TO
PERSONALIZED APPROACH WITHOUT
HUMAN TRIAL DEPENDENT ON MODELS
OR METHOD DEVELOPMENT?
>> I'M GOING TO GO OUT ON A LIMB
FIRST AND JUST SAY THERE COULD
BE HUMAN RESEARCH WITHOUT A
CLINICAL TRIAL, AND YOU CAN
COLLECT A LOT OF DATA AND MAKE
ASSOCIATIONS.
>> I BELIEVE THAT'S A VERY
IMPORTANT POINT THAT YOU'RE
BRINGING UP.
WHAT I WOULD EMPHASIZE FROM MY
PERSPECTIVE IS THAT IT DOESN'T
NECESSARILY HAVE TO BE MODEL
SYSTEMS.
YOU COULD ALSO DO A TISSUE
CULTURE SYSTEM AND MAYBE GET A
LOT OF INFORMATION IN THAT
SETTING.
SO FOR EXAMPLE, WHAT TYPE OF PRO
VIRUSES RESPOND TO WHAT TYPE OF
LATENCY REVERSING AGENT.
THAT'S SORT OF BROADLY FITTING
INTO THIS IDEA, AND THAT CAN BE
ADDRESSED IN A TISSUE CULTURE
SYSTEM, FOR EXAMPLE, OR WHAT'S
THE PHENOTYPE OF THE RESERVOIR
CELLS AND HOW IT DOES TARGETING
OF ONE PARTICULAR MARKER THAT'S
EXPRESSED ON A RESERVOIR CELL,
HOW DOES THAT INFLUENCE THE
FREQUENCY OF THE RESERVOIR IN AN
IN VITRO SYSTEM.
I MEAN, AS A FIRST STEP, I
BELIEVE THOSE ARE RELATIVELY
SIMPLE TYPES OF ASSAYS AND
EXPERIMENTS COULD ALSO BE
INFORMATIVE.
>> YOU WOULD ADD THE CONCEPT OF
HLA DIVERSITY CLEARLY AN ISSUE
FOR THE T-CELL-BASED APPROACHES.
YOU CAN LOOK AT DIFFERENT KIND
OF OPTIMIZED CASSETTE DESIGN
WITHIN HLA TRANS GEGENIC AND
KNOCK-IN MICE, WHAT ARE
POTENTIALLY -- TO SOME DEGREE AS
WELL WHERE YOU HAVE THE EXTENT
OF MHC DIVERSITY IN HUMANS AS
NON-HUMAN PRIMATE BUT IT STILL
EXISTS AND THERE'S WAYS OF
ACTUALLY TESTING OPTIMIZED
T-CELL APPROACHES IN THAT
SETTING AS WELL.
I THINK YOU PROBABLY IN SOME
WAYS GET BNAB SENSITIVITY THAT
WOULD VARY ACROSS AFFECTED
ANIMALS.
SO I THINK THERE ARE WAYS WHERE
THE MODEL SYSTEMS CAN PROVE TO
BE VERY INFORMATIVE FROM A KIND
OF TAILORED APPROACH.
ANY OTHER COMMENTS?
THANK YOU ALL FOR GREAT
QUESTIONS.
THANKS TO ALL OUR PANELISTS
FOR A GREAT DISCUSSION.
WE DO HAVE ANOTHER PANEL JUST
LIKE THR AT THE END OF
TOMORROW'S SESSION THAT'S
SPECIFICALLY FOCUSED ON
EXPANDING HIF CURE RESEARCH
GLOBALLY AND IN DIFFERENT
POPULATIONS, SO PLEASE STICK
AROUND TOMORROW FOR THAT.
I HAVE A COUPLE OTHER
ANNOUNCEMENTS, THE MDC CAB, ALL
THE 10 NPC CABS ARE SPONSORING
COMMUNITY EVENT TONIGHT FROM
6:30 TO 8:00 P.M. AT BUS BOYS
AND POETS IN ANACOSTIA IN
SOUTHEAST D.C. ENTITLED
INTRODUCTION TO HIV CURE
RESEARCH, AND THERE ARE FREE
FOOD AND DRINKS PROVIDED.
SO EVERYONE IS WELCOME TO ATTEND
THAT.
ALSO FOR THE REACH SPEAKERS,
YOU'RE UP FIRST TOMORROW SO GET
A GOOD NIGHT'S SLEEP, TRY TO GET
THROUGH SECURITY EARLY SO THAT
OUR SPEAKERS ARE HERE.
WE WILL START SHARPLY ON TIME AT
8:30 A.M., AND AGAIN, THANKS TO
ALL OUR SPEAKERS, EVERYONE THAT
ASKED QUESTIONS.
IT WAS A GREAT DAY.
THANK YOU.
[APPLAUSE]