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>>HELLO, EVERYONE.  I WANT TO 

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THANK EVERYONE FOR COMING.  IT 

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IS GREAT TO SEE EVERYONE IN 

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PERSON FOR A CHANGE.  I WANT TO 

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GIVE A FEW COMMENTS ABOUT THE 

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CENTER THAT THE CENTER WAS 

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ORIGINALLY ORGANIZED TO GET 

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COLLABORATIONS GOING AND GET 

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PEOPLE TALKING ABOUT HIV AND 

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CANCER VIROLOGY.  THIS YEAR 

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VINAY AND I WERE ASKED TO BE 

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PART OF IT WE ARE WELCOMING 

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SUGGESTIONS AND COMMENTS AND 

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IDEAS AND WOULD LIKE TO GROW THE

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CENTER GETTING PEOPLE MORE 

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INVOLVED AND COMMUNITY ORIENTED.

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GIVING A FEW LOGISTICS.  MAIN 

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SEMINARS ARE IN THIS ROOM.  

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THERE IS AN OVERFLOW ROOM G1 AND

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G2 AND THERE ARE REFRESHMENTS 

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THERE.  FEEL FREE TO COME AND GO

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IN THE ROOMS AND POSTER SESSIONS

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THIS AFTERNOON WILL START AT 1 

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O'CLOCK IN THE LEFT ROOMS C1/C2 

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AND AB AND PRESENTERS AND JUDGES

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WILL COME AROUND AND LOOK AT 

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YOUR POSTERS.  PLEASE BE THERE 

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AT 1 O'CLOCK.  SCHEDULE IS 

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TIGHT.  LET KEEP THINGS MOVING. 

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WITH THAT I WILL HAND IT TO VEFA

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WHO WILL INTRODUCE DREW TO HIS 

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TALK UP. 

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>>RESILIENCE AND
CONTINUOUS 

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RIGOROUS EFFORT.  THESE PAPERS 

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ARE RIGOROUS AND SCIENCE IS 

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BASIC SCIENCE BUT SHOULD BE AN 

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INCREDIBLE EXAMPLE FOR YOU YOUNG

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PEOPLE IF YOU HAVE A PASSION AND

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IDEA YOU WANT TO PURSUE, YOU 

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SHOULD REALLY DO IT.  YOU NEVER 

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KNOW WHETHER IT WILL WORK WELL 

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OR NOT AND DREW SAID THIS 

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MORNING, IT COULD ALSO NOT HAVE 

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WORKED AND I WOULD HAVE SPENT 

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ALL THESE YEARS TO WORK. 

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ONE MORE THING TO TELL YOU.  

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DREW TRAINED AT NIH WITH TONY 

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FAUCI AND CAREER TOOK OFF 

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TREMENDOUSLY IN THE LAST SEVERAL

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YEARS AND OBTAINED AN IMPORTANT 

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PRIZE LIKE JAPAN PRIZE AND 

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ALASKA PRIZE AND THOSE THAT GET 

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ALASKA PRIZE MIGHT GET A NOBLE 

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PRIZE AND HAPPY HE AGREED TO 

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TALK WITH YOU YOUNG PEOPLE.  HE 

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TOLD ME THIS MORNING HE LIKES TO

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TALK TO YOUNG PEOPLE.  REALLY, 

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YOU ARE THE FUTURE FOR SCIENCE 

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AND THANK YOU DREW FOR COMING. 

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THANK YOU VERY MUCH FOR INVITING

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ME.  I TOLD BETHEL THIS MORNING 

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THAT ONE THING I PUT HIGH ON MY 

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LIST IS TALKING TO YOUNG 

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SCIENTISTS. 

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YOU -- YOU KNOW, IT IS GREAT, US

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OLD FOLKS, TO BE DOING RESEARCH.

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WE ARE HAPPY TO BE RECOGNIZE THE

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FOR THAT.  OUR MAIN JOB REALLY 

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IS THAT OUR CRITICAL JOB IS 

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TRAINING YOUNG SCIENTISTS NOT 

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ONLY TO TAKE OVER FOR US BUT TO 

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ADVANCE SCIENCE AND BE THE 

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FUTURE OF SCIENCE.  SO, THANK 

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YOU FOR INVITING ME HERE.  

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I WANTED TO TALK TO YOU FIRST 

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ABOUT THE VACCINES.  I WANTED TO

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CONCENTRATE ON HOW THE VACCINES 

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WORK. 

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PEOPLE DON'T REALIZE THE 

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MECHANISMS THAT ARE BEHIND THE 

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POTENCY OF THE RNALNP VACC-LNP .

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I WILL TALK ABOUT THE 

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BACKGROUND.  I TALK TO LAY 

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AUDIENCES AND ONE THING THEY ARE

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GUARANTEED TO TELL ME IS I DON'T

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WANT TO TAKE THE RNA VACCINE 

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BECAUSE IT WAS INVENTED IN 10 

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MONTHS AND I DON'T TRUST IT.  

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THAT IS, OF COURSE, RIDICULOUS. 

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MRNA WAS DISCOVERED IN 1961. 

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FIRST TIME IT WAS INJECTED INTO 

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ANIMALS WITH IDEA OF USING IT TO

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DELIVER THERAPEUTIC PROTEINS WAS

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IN 1990.  AFTER THAT, IT WAS 

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MAINLY STUDIED IN AN UNUSUAL 

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VACCINE PLATFORM TAKING 

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DENDRITIC CELLS OUT OF ANIMALS 

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AND OUT OF HUMANS AND PULSE THEM

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WITH MRNA AND GIVE THEM BACK.  

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THAT MRNA COULD BE IN VITRO 

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TRANSCRIBED OR PURIFIED FROM 

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TUMOR CELLS OR A VARIETY OF 

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DIFFERENT SOURCES. 

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THE REASON THAT WAS DONE WAS 

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BECAUSE OF THIS.  THERE ARE 

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CURRENTLY 7 TAENDIFFERENT INNATE

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IMMUNE CENSORS THAT RECOGNIZE 

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RNA AND THEY PRODUCE A VARIETY 

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OF MEDIATORS INCLUDING 

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INFLAMMATORY CYTOKINES AND TYPE 

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1 INTERFERONS AND DIRECTLY 

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INHIBIT TRANSLATION BY ENACTING 

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ON RIBOSOMES AND INDUCE 

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APOPTOSIS AND CELL DEATH.  LATER

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WHEN KATIE AND I STUDIED MRNA, 

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WE WOULD INJECT IT INTO AN 

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ANIMAL WHICH WOULD GET SICK.  

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THIS GREATLY, OF COURSE, UPSET 

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KATIE.  

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YOU CAN'T MAKE SOMEBODY SICK 

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WHEN YOU GIVE THEM A DRUG.  I 

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WAS LESS CONCERNED BECAUSE 

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STUDIES OF IT SHOWED REASONS 

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THAT THEY GOT SICK WAS BECAUSE 

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OF INNATE IMMUNE CENSORS AND 

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THEY RECOGNIZE THE IN VITRO 

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TRANSCRIBED RNA INDUCING ADJUNCT

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ACTIVI

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ACTIVITIES. 

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WE WANTED TO DEVELOP AN RNA THAT

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DIDN'T MAKE ANIMALS SICK.  WE 

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HAD TO STUDY WHY RNA WAS SO 

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INFLAMMATORY AND TELLING 

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EXPERIMENT AFTER 7 YEARS OF 

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WORK, WHAT WE DID WAS MAKE A 

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VARIETY OF DIFFERENT TYPES OF 

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RNA FROM BACTERIA MAMMALIAN 

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CELLS THAT AT THE TIME WERE THE 

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WAYS THAT YOU COULD SUBDIVIDE 

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RNA FROM A CELL.  WHEN WE TESTED

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THEM ON DENDRITIC CELLS THAT 

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HAVE MOST INNATE IMMUNE CENSORS,

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THE TWO POSSIBILITIES WERE THAT 

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ALL OF THE RNAS WOULD BE 

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INFLAMMATORY AND THAT IS BECAUSE

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RNA IS INFLAMMATORY.  THIS IS 

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THE ALTERNATIVE.  IT SURPRISED 

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US.  CERTAIN TYPES OF RNA, 

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PARTICULARLY TRANSFER RNAS WERE 

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NOT INFLAM. 

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THAT LED US TO A HYPOTHESIS.  

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TRANSFER RNAS HAVE 25% OF THIR 

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NUCLEOSIDES ARE MODIFIED.  THERE

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IS OVER 100 DIFFERENT TYPES AND 

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THEY ARE PUT IN AFTER RNA IS 

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MADE BY THE CELL BY VARIETY OF 

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RNA-DRIVEN ENZYME SYSTEMS THAT 

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ARE DONE IN A SEQUENCE-SPECIFIC 

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MANNER OF THESE ARE ICE 

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OMERIZATIONS LIKE URIDINE AND 

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METHYLATIONS OF THE BASE OR OF 

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THE SUGARS AND DIFFERENT 

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ADDITIONS OF AMINO ACIDS AND 

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COMPLEX MODIFICATIONS THAT OCCUR

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IN CONSERVED POSITIONS. 

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THAT MEANS IF YOU LOOK AT A 

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BACTERIAL RIBOSOMAL RNA, ITS 

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MODIFICATION IS AT THE SAME TIME

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OF A MAMMALIAN RIBOSOMAL RNA AND

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THEY HAVE OBVIOUS BIOLOGICAL 

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FUNCTIONS, MANY OF WHICH WE 

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DON'T KNOW.  M6A WAS RECENTLY 

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SHOWN TO BE REVERSIBLE.  OUR 

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PROBLEM WAS WE HAD TO MAKE 

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MODIFIED M RCHLT NRNA. 

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MOST OF THE ENZYMES FOR 

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MODIFICATION WEREN'T UNDERSTOOD.

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EACH IF THEY WERE LIKE PSEUDI 

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YOU'RE IDDINE MODIFICATION 

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SYSTEMS THEY WERE RNA DEPENDENT.

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OUR IDEA WAS LET'S TRICK 

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THEPHAGE HOPPIM RACE.  YOU TAKE 

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A DNA TEMPLATE THAT HAS A 

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PROMOTER RECOGNIZED BY A PHAGE 

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RNA POLYMERASE.  AFTER IT BINDS 

186
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MAKING AN RNA COPY OF THE DNA 

187
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TEMPLATE.  IT FALLS OFF AND 

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KEEPS DOING IT OVER AND OVER AND

189
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OUR THOUGHT WAS COULD WE 

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EXCHANGE COGNATE NUCLEOTIDE 

191
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TRIPHOSPHATES FOR MONOSIDE 

192
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NUCLEOTIDE TRIPHOSPHATES?  

193
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WE TRIED ABOUT 10 DIFFERENT 

194
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MODIFIED NUCLEOSIDE 

195
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TRIPHOSPHATES THAT WERE 

196
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AVAILABLE AT THE TIME.  FIVE OF 

197
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THEM WORKS THAT WE TESTED ON 

198
00:10:12,280 --> 00:10:14,760
DENDRITIC CELLS.  SOME HAD 

199
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REDUCED INFLAMMATORY ACTIVITY 

200
00:10:15,920 --> 00:10:18,040
THAT WAS DONE AT THE TIME ON 

201
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PRIMARY DC.  SO, PURIVEFIED FROM

202
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LEUKO FORESIS SAMPLES FROM 

203
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HUMANS. 

204
00:10:26,840 --> 00:10:31,680
WHAT IS INTERESTING IS ONLY 

205
00:10:31,680 --> 00:10:32,920
URIDINE MODIFICATIONS WORKED AND

206
00:10:32,920 --> 00:10:35,880
WE AND OTHERS LATER FOUND OUT 

207
00:10:35,880 --> 00:10:41,520
THAT URIDINE IS CRITICAL FOR 

208
00:10:41,520 --> 00:10:43,640
INFLAMMATORY INFLAMMATION 

209
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RECOGNITION BY THE CENSORS. 

210
00:10:45,320 --> 00:10:48,640
WE HAD A SURPRISE.  DO MODIFIED 

211
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RNAS, HERE, 100% OF THE YEWS OF 

212
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YOU'RI SEER ADEAN AND 

213
00:10:58,880 --> 00:11:01,840
[INDISCERNIBLE] COULD THEY WE 

214
00:11:01,840 --> 00:11:03,920
TRANSLATED?  NO.  WE WERE WRONG.

215
00:11:03,920 --> 00:11:05,720
WASN'T ONLY TIME THAT OUR 

216
00:11:05,720 --> 00:11:07,200
HYPOTHESIS WAS WRONG, BUT NOT 

217
00:11:07,200 --> 00:11:09,440
ONLY WAS IT TRANSLATED BUT IT 

218
00:11:09,440 --> 00:11:18,800
WAS TRANSLATED MUCH BETTER BY 

219
00:11:18,800 --> 00:11:20,960
CELLS, ESPECIALLY PRIMARY CELLS 

220
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THAT GAVE AN RNA THAT WASN'T 

221
00:11:24,200 --> 00:11:25,640
INFLAMMATORY THAT DIDN'T MAKE 

222
00:11:25,640 --> 00:11:29,640
ANIMALS SICK AND MADE MUCH MORE 

223
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PROT

224
00:11:33,680 --> 00:11:33,960
PROTEIN. 

225
00:11:33,960 --> 00:11:36,400
I WOULD GO TO MEETINGS AND TALK 

226
00:11:36,400 --> 00:11:38,080
TO TONY AND SENIOR PEOPLE IN THE

227
00:11:38,080 --> 00:11:40,480
FIELD.  THEY WOULD LISTEN TO MY 

228
00:11:40,480 --> 00:11:42,360
RESEARCH SAYING THAT IS VERY 

229
00:11:42,360 --> 00:11:45,160
NICE.  NOBODY WILL EVER USE RNA.

230
00:11:45,160 --> 00:11:47,360
IT FAILED CLINICAL TRIALS 

231
00:11:47,360 --> 00:11:49,160
EARLIER ON.  WHY DON'T YOU DO 

232
00:11:49,160 --> 00:11:50,960
SOMETHING USEFUL WITH YOUR LIFE?

233
00:11:50,960 --> 00:11:56,080
WHY DON'T YOU TRY DOING RESEARCH

234
00:11:56,080 --> 00:11:59,600
THAT MIGHT ACTUALLY HELP THE 

235
00:11:59,600 --> 00:12:01,480
FIE

236
00:12:01,480 --> 00:12:02,120
FIELD. 

237
00:12:02,120 --> 00:12:04,360
I'M A VERY CAN QUIET GUY AND 

238
00:12:04,360 --> 00:12:10,320
WOULD SAY THANK YOU AND TRY TO 

239
00:12:10,320 --> 00:12:13,680
ARGUE WITH HIM POINTING OUT IN 

240
00:12:13,680 --> 00:12:15,320
PHARMACEUTICAL DEVELOPMENT 

241
00:12:15,320 --> 00:12:17,280
PROTEIN THERAPEUTICS ARE MOST 

242
00:12:17,280 --> 00:12:23,320
RAPIDLY GROWN FIELD MONOCLONAL 

243
00:12:23,320 --> 00:12:27,720
AUTO BODY THERAPIES AND THEY 

244
00:12:27,720 --> 00:12:31,600
KEEP DEVELOPING MORES. 

245
00:12:31,600 --> 00:12:33,240
TO MAKE THESE DRUGS, YOU START 

246
00:12:33,240 --> 00:12:39,280
WITH A 50,000 LITER DRUM FULL OF

247
00:12:39,280 --> 00:12:40,840
KHO CELLS OR OTHER CELLS AND 

248
00:12:40,840 --> 00:12:42,680
HAVE TO FIGURE OUT HOW TO PURIFY

249
00:12:42,680 --> 00:12:45,440
THAT PROTEIN AWAY FROM THE CELL 

250
00:12:45,440 --> 00:12:47,800
CULTURE CONTAMINANTS. 

251
00:12:47,800 --> 00:12:49,640
EVERY NEW DRUG OR PROTEIN YOU 

252
00:12:49,640 --> 00:12:52,240
START OVER AND MAKE A NEW CELL 

253
00:12:52,240 --> 00:12:54,160
AND FIGURE OUT HOW TO GROW IT 

254
00:12:54,160 --> 00:12:56,360
AND HOW TO PURIFY IT.  THE COST 

255
00:12:56,360 --> 00:13:01,040
OF A PROTEIN THERAPEUTIC FOR 

256
00:13:01,040 --> 00:13:03,840
THESE MONOCLONALS ARE IN 

257
00:13:03,840 --> 00:13:10,040
TYPICALLY 50 TO $100,000 A YEAR 

258
00:13:10,040 --> 00:13:10,440
RAN

259
00:13:10,440 --> 00:13:10,680
RANGE. 

260
00:13:10,680 --> 00:13:12,040
THEY ARE COSTS MANY IN THE 

261
00:13:12,040 --> 00:13:14,280
UNITED STATES AND ACROSS THE 

262
00:13:14,280 --> 00:13:16,000
WORLD CAN'T AFFORD.  MY ARGUMENT

263
00:13:16,000 --> 00:13:21,000
IS RNA IS A SIMPLE REACTION THAT

264
00:13:21,000 --> 00:13:24,720
DOESN'T USE MAMMALIAN CELLS BUT 

265
00:13:24,720 --> 00:13:28,680
ENZYME AND MODERNA AND BIOTECH 

266
00:13:28,680 --> 00:13:32,280
WHEN USING THEIR VACCINE USE 100

267
00:13:32,280 --> 00:13:34,440
LITER REACTORS THAT THEY MAKE AS

268
00:13:34,440 --> 00:13:37,920
MUCH VACCINE OF 50,000 LEADERS 

269
00:13:37,920 --> 00:13:41,640
OF CHO CELLS MAKING ADENO 

270
00:13:41,640 --> 00:13:44,080
VIRUSES OR PROTEINS.  IT IS 

271
00:13:44,080 --> 00:13:45,680
SIMPLE.  ONLY THING YOU HAVE TO 

272
00:13:45,680 --> 00:13:47,000
CHANGE IS THE CODING SEQUENCE 

273
00:13:47,000 --> 00:13:49,800
WHEN YOU WANT TO MAKE A NEW 

274
00:13:49,800 --> 00:13:51,680
PROTEIN OR VACCINE.  YOU DON'T 

275
00:13:51,680 --> 00:13:54,320
HAVE TO REINVENT ANYTHING.  YOU 

276
00:13:54,320 --> 00:13:57,320
PLUG IN THE NEW DNA TEMPLATE AND

277
00:13:57,320 --> 00:13:59,360
EVERYTHING IS THE SAME IDT 

278
00:13:59,360 --> 00:14:01,360
REACTION, PURIFICATION, LIPID 

279
00:14:01,360 --> 00:14:05,120
COMPLEXING IS IDENTICAL.  IT IS 

280
00:14:05,120 --> 00:14:05,600
SIMP

281
00:14:05,600 --> 00:14:07,240
SIMPLER.  IT IS QUICK.  YOU CAN 

282
00:14:07,240 --> 00:14:09,440
RAPIDLY EXPAND THESE, AS WE HAVE

283
00:14:09,440 --> 00:14:10,000
SEEN. 

284
00:14:10,000 --> 00:14:12,600
IT IS SAFER.  INSTEAD OF HAVING 

285
00:14:12,600 --> 00:14:16,400
A CHO CELL MAKE YOUR PROTEIN, 

286
00:14:16,400 --> 00:14:17,640
SOMETIMES IT DOESN'T QUITE 

287
00:14:17,640 --> 00:14:21,640
MODIFY THE PROTEIN OR DOESN'T 

288
00:14:21,640 --> 00:14:23,080
GLYCOSCILLATE CORRECTLY AND BAD 

289
00:14:23,080 --> 00:14:25,200
EVENTS HAVE HAPPENED FROM THAT. 

290
00:14:25,200 --> 00:14:27,440
HOST CELLS MAKE THE PROTEIN.  

291
00:14:27,440 --> 00:14:30,080
HOST CELLS KNOW HOW TO MAKE 

292
00:14:30,080 --> 00:14:32,960
PROTEINS OFF OF RNA.  IT SHOULD 

293
00:14:32,960 --> 00:14:35,360
BE GREATLY REDUCED COST AND EASE

294
00:14:35,360 --> 00:14:38,520
OF PRODUCTION.  THE PROBLEM WAS:

295
00:14:38,520 --> 00:14:41,400
HOW DO YOU DELIVER THE RNA?  

296
00:14:41,400 --> 00:14:43,000
JUST ABOUT EVERY FLUID AND CELL 

297
00:14:43,000 --> 00:14:47,400
IN OUR BODY HAS RNASES IN IT.  

298
00:14:47,400 --> 00:14:50,600
IF YOU INJECT UNCOMPLEX NAKED 

299
00:14:50,600 --> 00:14:53,680
RNA INTO AN ANIMAL OR HUMAN, 30 

300
00:14:53,680 --> 00:14:56,480
SECONDS LATER, IT IS GONE.  IT 

301
00:14:56,480 --> 00:14:59,360
IS DEGRADED. 

302
00:14:59,360 --> 00:15:01,320
WE LOOKED AT PROBABLY 50 

303
00:15:01,320 --> 00:15:03,720
DIFFERENT FORMULATIONS DESCRIBED

304
00:15:03,720 --> 00:15:07,080
FOR DELIVERY NUCLEIC ACIDS 

305
00:15:07,080 --> 00:15:08,800
IDENTIFYING LIPID NANOPARTICLES 

306
00:15:08,800 --> 00:15:12,480
AS BEING THE BEST.  LNPS WERE 

307
00:15:12,480 --> 00:15:15,760
DEVELOPED FOR SRNA DELIVERY THAT

308
00:15:15,760 --> 00:15:19,600
WAS DRIVEN BY A COMPANY AD-NILUM

309
00:15:19,600 --> 00:15:23,840
WITH 3FDA APPROVED DRUGS AND 

310
00:15:23,840 --> 00:15:28,520
FOUR LIPIDS SELF-ASSEMBLING WITH

311
00:15:28,520 --> 00:15:31,320
RNA FORMING 60 TO 100 

312
00:15:31,320 --> 00:15:32,560
NANOPARTICLES AND THEY HAVE NO 

313
00:15:32,560 --> 00:15:35,880
CHARGE.  THEY ARE NOT TOXIC AND 

314
00:15:35,880 --> 00:15:41,000
BIND APOE AND GO TO THE LIVER 

315
00:15:41,000 --> 00:15:42,400
AND FOUND THAT FOR MRNA THEY 

316
00:15:42,400 --> 00:15:47,400
WORK BEST AND WE P MAKE THIS 

317
00:15:47,400 --> 00:15:53,440
LUCIFERASE CODEINE AND 

318
00:15:53,440 --> 00:15:55,880
LUCIFERASE ACTS ON SUBSTRATE AND

319
00:15:55,880 --> 00:15:59,080
YOU CAN GIVE MICE THAT AND THEY 

320
00:15:59,080 --> 00:16:00,680
WILL GLOW.  YOU STICK THEM UNDER

321
00:16:00,680 --> 00:16:03,480
A CAMERA AND MEASURE LIGHT 

322
00:16:03,480 --> 00:16:08,320
PRODUCTION.  WE GAVE LUCIFERASE 

323
00:16:08,320 --> 00:16:12,160
RNALMPS BY VARIETY OF INJECTION 

324
00:16:12,160 --> 00:16:13,960
ROOTS.  EVERYTHING WAS SYSTEMIC 

325
00:16:13,960 --> 00:16:15,760
CIRCULATION THAT WENT TO THE 

326
00:16:15,760 --> 00:16:18,360
LIVER AS EXPECTED AND WAS 

327
00:16:18,360 --> 00:16:19,440
TRANSLATED FOR A DAY AND 

328
00:16:19,440 --> 00:16:21,800
DISAPPEARED.  WHAT WAS 

329
00:16:21,800 --> 00:16:23,160
INTERESTING FROM AN 

330
00:16:23,160 --> 00:16:24,480
VACCINOLOGIST POINT OF VIEW WHEN

331
00:16:24,480 --> 00:16:30,040
WE INJECTED PERIPHERALLY IDIM 

332
00:16:30,040 --> 00:16:31,640
SUB Q WE HAD PROTEIN INJECTION 

333
00:16:31,640 --> 00:16:35,120
AT SITE OF THE INJECTION AND 

334
00:16:35,120 --> 00:16:37,040
DRAINING LYMPH NODES FOR ABOUT 

335
00:16:37,040 --> 00:16:38,400
10 DAYS. 

336
00:16:38,400 --> 00:16:43,120
KNOWING VACCINES, BEST VACCINES 

337
00:16:43,120 --> 00:16:45,680
ARE TYPICALLY LIVE VIRUS THAT 

338
00:16:45,680 --> 00:16:48,160
INFECT CELLS AND PRODUCE PROTEIN

339
00:16:48,160 --> 00:16:51,440
FOR A FEW DAYS LOADING GERMINAL 

340
00:16:51,440 --> 00:16:51,880
CELLS. 

341
00:16:51,880 --> 00:16:56,200
PROTEIN THERAPEUTICS LIKE TET 

342
00:16:56,200 --> 00:16:59,840
ANNIS TOX YOID, YOU PUT THEM IN 

343
00:16:59,840 --> 00:17:03,720
A FEW HOURS LATER AND THEY ARE 

344
00:17:03,720 --> 00:17:13,840
GONE. 

345
00:17:19,520 --> 00:17:24,400
WE LOOKED AT RNA-LNP MODIFIED 

346
00:17:24,400 --> 00:17:26,400
VACCINES.  SHOWING YOU HOW EASY 

347
00:17:26,400 --> 00:17:28,640
IT IS, FOR COLLABORATORS, EASY 

348
00:17:28,640 --> 00:17:31,600
IS A SIMPLE THING TO PUT ON THE 

349
00:17:31,600 --> 00:17:33,560
SLIDE.  THERE IS LOTS OF SCIENCE

350
00:17:33,560 --> 00:17:36,440
THAT GOES BEHIND IT.  WHEN YOU 

351
00:17:36,440 --> 00:17:39,240
HAVE SEQUENCE OF IMMUNOGENERAL, 

352
00:17:39,240 --> 00:17:42,680
IN EARLY JANUARY OF 2020 WHEN 

353
00:17:42,680 --> 00:17:44,760
CHINESE RELEASED COVID-19 

354
00:17:44,760 --> 00:17:46,280
SEQUENCE, WE TOOK THE SPIKE AND 

355
00:17:46,280 --> 00:17:48,520
STARTED TO MAKE RNA VACCINES 

356
00:17:48,520 --> 00:17:50,680
WITH IT.  YOU DON'T NEED THE 

357
00:17:50,680 --> 00:17:52,680
VIRUS OR PROTEINS JUST THE 

358
00:17:52,680 --> 00:18:03,200
SEQUENCE TO MAKE AN RNA VACCINE.

359
00:18:06,280 --> 00:18:06,840
YOU CODON OPTIMIZE SEQUENCE TO 

360
00:18:06,840 --> 00:18:08,520
INCREASE PROTEIN PRODUCTION 

361
00:18:08,520 --> 00:18:12,000
MAKING A D-DNA TEMPLATE AND 

362
00:18:12,000 --> 00:18:17,360
STICK IN REACTION WITH PHAGE RNA

363
00:18:17,360 --> 00:18:20,160
POLYMERASES AND YOU HAVE RNA TWO

364
00:18:20,160 --> 00:18:23,120
HOURS LATER.  -- MIX IT WITH 

365
00:18:23,120 --> 00:18:26,560
LIPIDS AND ETHANOL 

366
00:18:26,560 --> 00:18:27,760
SELF-ASSEMBLING INTO 

367
00:18:27,760 --> 00:18:29,760
NANOPARTICLES AND FILTER AWAY 

368
00:18:29,760 --> 00:18:32,400
ETHANOL IN SALTS AND STICK IN A 

369
00:18:32,400 --> 00:18:34,440
VILE AND YOU MADE A VACCINE.  IT

370
00:18:34,440 --> 00:18:36,360
IS VERY QUICK AND EASY.  WE HAVE

371
00:18:36,360 --> 00:18:39,680
A ROBOT THAT CAN MAKE 96RNAS AT 

372
00:18:39,680 --> 00:18:42,840
A TIME.  WE CAN MAKE 1,000 RNAS 

373
00:18:42,840 --> 00:18:49,440
IN A COUPLE DAYS VERY EASILY. 

374
00:18:49,440 --> 00:18:53,680
THAT IS HOW MODERNA AND BIOTECH 

375
00:18:53,680 --> 00:18:56,240
MAKE VACCINES ON A BIGGER SCALE 

376
00:18:56,240 --> 00:18:59,440
OF 100 LITER BIOREACTORS 

377
00:18:59,440 --> 00:19:02,560
STARTING FIRST WITH HIV AND 

378
00:19:02,560 --> 00:19:04,360
INFLUENZA.  I WILL SHOW YOU 

379
00:19:04,360 --> 00:19:05,880
INFLUENZA BECAUSE THEY WERE 

380
00:19:05,880 --> 00:19:08,200
SUCCESSFUL.  INFLUENZA IS A 

381
00:19:08,200 --> 00:19:09,360
SEASONAL RESPIRATORY DISEASE 

382
00:19:09,360 --> 00:19:13,200
MAINLY IN THE WINTER TIME THAT 

383
00:19:13,200 --> 00:19:15,840
KILLS ABOUT 30 TO 60,000 PEOPLE 

384
00:19:15,840 --> 00:19:18,080
A YEAR IN THE UNITED STATES.  

385
00:19:18,080 --> 00:19:22,120
THERE IS PANDEMIC YEARS THAT ARE

386
00:19:22,120 --> 00:19:26,280
MUCH MORE SEVERE THAT MAINLY 

387
00:19:26,280 --> 00:19:28,320
KILLS PEOPLE OVER AGE OF 65 AND 

388
00:19:28,320 --> 00:19:31,680
PEOPLE WITH IMMUNE DEFICIENCIES.

389
00:19:31,680 --> 00:19:34,200
THIS IS A REVIEW OF VACCINES IN 

390
00:19:34,200 --> 00:19:37,960
DEVELOPMENT WHEN WE WORKED ON 

391
00:19:37,960 --> 00:19:44,640
RNA VACCINES I WANTED TO SHOW 

392
00:19:44,640 --> 00:19:50,760
YOU IN INBRED MOUSE DRAINS WITH 

393
00:19:50,760 --> 00:19:53,440
H1N1 VIRUS TWO IMMUNIZATIONS OF 

394
00:19:53,440 --> 00:19:57,960
A MOUSE GIVE TIGHTERS PSEUDONEWT

395
00:19:57,960 --> 00:19:59,320
TRILLIZATION TIGHTER OF AROUND 

396
00:19:59,320 --> 00:20:01,360
100.  IT THAT IS PRETTY GOOD.  1

397
00:20:01,360 --> 00:20:04,040
TO 40 IS PROTECTED.  WHEN WE DID

398
00:20:04,040 --> 00:20:08,880
OUR ARE.  NA VACCINE THAT IS AN 

399
00:20:08,880 --> 00:20:14,080
MRNA THAT ENCODES HRMN MOLECULE 

400
00:20:14,080 --> 00:20:17,640
IN LIPID PROTOCOLS IN A MOUSE 

401
00:20:17,640 --> 00:20:24,440
GAVE A TIGHTER OF  -- 5 TIMES 

402
00:20:24,440 --> 00:20:27,080
BETTER THAN A LIVE VIRUS 

403
00:20:27,080 --> 00:20:31,720
INFECTION.  I GAVE SERUM TO 

404
00:20:31,720 --> 00:20:35,160
SCOTT HENSLY WHO IS AT PENN AND 

405
00:20:35,160 --> 00:20:36,920
TOOK HIM A MONTH TO GIVE ME THE 

406
00:20:36,920 --> 00:20:39,720
RESULTS WHEN HE FINISHED HE WAS 

407
00:20:39,720 --> 00:20:41,280
UPSET AND STORMED IN MY OFFICE 

408
00:20:41,280 --> 00:20:43,960
AND SAID WHAT DID YOU DO?  DID 

409
00:20:43,960 --> 00:20:47,080
YOU PUT MONOCLONAL ANTIBODIES 

410
00:20:47,080 --> 00:20:49,720
INTO THE SAMPLES I HAVEN'T SEEN 

411
00:20:49,720 --> 00:20:51,680
TIGHTERS THIS HIGH.  TOOK A 

412
00:20:51,680 --> 00:20:53,640
MONTH HE HAD TO DO DILUTION 

413
00:20:53,640 --> 00:20:56,640
AFTER DILUTION TO MEASURE 

414
00:20:56,640 --> 00:20:57,680
TIGHTERS. 

415
00:20:57,680 --> 00:21:01,520
THIS DATA IS REAL AND EXCITED 

416
00:21:01,520 --> 00:21:04,160
COMPANIES LIKE MODERNA AND 

417
00:21:04,160 --> 00:21:05,600
BIOTECH AND PFIZER AND OTHERS 

418
00:21:05,600 --> 00:21:08,480
BECAUSE IT WAS A SIMPLE AND 

419
00:21:08,480 --> 00:21:10,840
INCREDIBLY POTENT VACCINE.  AS A

420
00:21:10,840 --> 00:21:12,960
BASIC SCIENTIST, I WANTED TO 

421
00:21:12,960 --> 00:21:15,520
KNOW HOW IT WORKED.  THIS IS HOW

422
00:21:15,520 --> 00:21:20,120
B CELLS RECOGNIZE ANTI-GENERALS,

423
00:21:20,120 --> 00:21:30,640
VIRUSES, PARTICLES, ET CETERA.  

424
00:21:33,360 --> 00:21:36,080
B CELLS PROLIFERATE RAPIDLY 

425
00:21:36,080 --> 00:21:38,080
SHIFTING BETWEEN LIGHT AND DARK 

426
00:21:38,080 --> 00:21:40,440
CELLS OF GERM CENTER AND 

427
00:21:40,440 --> 00:21:42,320
AFFINITY MATURE AND CLASS SWITCH

428
00:21:42,320 --> 00:21:45,080
AND FORM PLASMA CELLS AND MEMORY

429
00:21:45,080 --> 00:21:45,760
B CELLS. 

430
00:21:45,760 --> 00:21:50,160
SO, WE MEASURED THESE 

431
00:21:50,160 --> 00:21:50,520
POPULATIONS. 

432
00:21:50,520 --> 00:21:54,120
THIS IS AN ANTI-GENERAL SPECIFIC

433
00:21:54,120 --> 00:21:57,080
MANAGER AND ADDED THIS TO FLOW 

434
00:21:57,080 --> 00:22:01,360
COCKTAIL AND STAINED FOR THE B 

435
00:22:01,360 --> 00:22:06,560
CELL POPULATIONSGEN SPECIFIC 

436
00:22:06,560 --> 00:22:07,200
MANAGER AND ADDED THIS TO FLOW 

437
00:22:07,200 --> 00:22:07,840
COCKTAIL AND STAINED FOR THE B 

438
00:22:07,840 --> 00:22:11,040
CELL POPULATIONS. 

439
00:22:11,040 --> 00:22:14,760
WE SAW A 50-FOLD INCREASE IN 

440
00:22:14,760 --> 00:22:18,640
ANTIBODY TIGHTERS. 

441
00:22:18,640 --> 00:22:20,840
WE FORGOT ABOUT MICE FOR A YEAR 

442
00:22:20,840 --> 00:22:23,760
AND WENT BACK AND LOOKED AT BONE

443
00:22:23,760 --> 00:22:26,960
MARROW WHERE LONG-LIVED PLASMA 

444
00:22:26,960 --> 00:22:29,880
CELLS RESIDE AND MEASURED 

445
00:22:29,880 --> 00:22:32,000
HA-SPECIFIC PLASMA CELLS AND 

446
00:22:32,000 --> 00:22:35,040
TIGHTERS AND NUMBERS WERE 

447
00:22:35,040 --> 00:22:38,080
ENORMOUS, .05% OF NUCLEATED 

448
00:22:38,080 --> 00:22:41,480
CELLS IN BONE MARROW WERE MAKING

449
00:22:41,480 --> 00:22:44,000
HAA ANTIBODY THAT IS MORE THAN 

450
00:22:44,000 --> 00:22:47,400
ANY PROGENITOR CELL IN THE BONE 

451
00:22:47,400 --> 00:22:49,160
MARROW. 

452
00:22:49,160 --> 00:22:51,600
IT DIDN'T EXPLAIN HOW THE 

453
00:22:51,600 --> 00:22:53,840
VACCINE WAS WORKING AND WE HAD A

454
00:22:53,840 --> 00:22:57,160
PROBLEM.  RNA HAD NO ADJUNCT 

455
00:22:57,160 --> 00:23:01,200
ACTIVITY MAKING NO INFLAMMATORY 

456
00:23:01,200 --> 00:23:03,720
CYTOKINES OR STIMULATED 

457
00:23:03,720 --> 00:23:06,040
RECEPTORS OR INNATE IMMUNE 

458
00:23:06,040 --> 00:23:09,200
CENSORS AND LNPS AT THE TIME 

459
00:23:09,200 --> 00:23:11,840
DIDN'T BIND INNATE IMMUNE 

460
00:23:11,840 --> 00:23:14,920
CENSORS AND WEREN'T THOUGHT TO 

461
00:23:14,920 --> 00:23:16,840
HAVE AJEFFANT ACTIVITY.  WHERE 

462
00:23:16,840 --> 00:23:20,840
WAS IT COMING FROM VACCINES 

463
00:23:20,840 --> 00:23:23,080
REQUIRE AJIFIENTS YOU HAVE TO 

464
00:23:23,080 --> 00:23:26,560
STIMULATE IMMUNE SYSTEM TO MAKE 

465
00:23:26,560 --> 00:23:28,800
AN IMMUNE RESPONSE FROM 

466
00:23:28,800 --> 00:23:32,360
ANTIBODIES WE WERE SEEING WE 

467
00:23:32,360 --> 00:23:34,880
THOUGHT T FOLLICULAR CELLS WERE 

468
00:23:34,880 --> 00:23:38,520
INVOLVED IT IS A CD4 HELPER THAT

469
00:23:38,520 --> 00:23:40,720
MAKES GERMINAL CENTERS IF YOU 

470
00:23:40,720 --> 00:23:42,560
DON'T HAVE THEM A FEW DISEASES 

471
00:23:42,560 --> 00:23:45,200
WHERE THEY ARE DEAFISHIENT YOU 

472
00:23:45,200 --> 00:23:48,000
DON'T MAKE GERMINAL CENTERS 

473
00:23:48,000 --> 00:23:50,800
MAKING LOUSY ANTIBODY RESPONSES 

474
00:23:50,800 --> 00:23:52,520
THEY SUPPLY HELP TO GERMINAL 

475
00:23:52,520 --> 00:23:54,840
CENTER B CELLS ALLOWING HIGH 

476
00:23:54,840 --> 00:23:57,520
AFFINITY B CELLS TO PROLIFERATE 

477
00:23:57,520 --> 00:23:59,600
AND EXPAND AND LOW AFFINITIES 

478
00:23:59,600 --> 00:24:02,760
DIE OUT.  THAT IS THEIR JOB.  

479
00:24:02,760 --> 00:24:05,200
THEY DRIVE AFFINITY INCREASES 

480
00:24:05,200 --> 00:24:08,480
AND CLASS SWITCH AND FORMATION 

481
00:24:08,480 --> 00:24:18,920
OF N STAGE MEMORY CELLS. 

482
00:24:24,040 --> 00:24:29,680
WE DID A COMPARISON.  WE DID AN 

483
00:24:29,680 --> 00:24:32,720
MRNA-LNP ENCODING HIV ENVELOPE 

484
00:24:32,720 --> 00:24:36,800
IMMUNOGEN AND COMPARED TO 

485
00:24:36,800 --> 00:24:39,760
IDENTICAL ENVELOPE PROTEIN 

486
00:24:39,760 --> 00:24:41,000
ADGENTLEMAN VENTEDED WITH DOUBLE

487
00:24:41,000 --> 00:24:47,640
STRANDED RNA A POTENT T INDUCING

488
00:24:47,640 --> 00:24:50,560
ADGENTLEMAN VENTS YOU CAN SEE NO

489
00:24:50,560 --> 00:24:53,680
COMPARISON.  THEY PRODUCED 

490
00:24:53,680 --> 00:24:57,480
ENORMOUS LEVELS OF THHS IN 

491
00:24:57,480 --> 00:24:59,440
SINGLE VACCINATION IN MONKEYS 

492
00:24:59,440 --> 00:25:03,320
AND RABBITS AND FERRETS AND 

493
00:25:03,320 --> 00:25:07,400
CHICKENS AND PIGS AND FISH.  

494
00:25:07,400 --> 00:25:10,240
EVERY IMAGINABLE ANIMAL SPECIES 

495
00:25:10,240 --> 00:25:15,360
WE HAVE VACCINATED SO FAR AND 

496
00:25:15,360 --> 00:25:15,640
HUMANS. 

497
00:25:15,640 --> 00:25:20,040
WE DID A CALCULATION IN A 

498
00:25:20,040 --> 00:25:21,720
TYPICAL ADGENTLEMAN VEPTED 

499
00:25:21,720 --> 00:25:25,600
VACCINE WITH ANY A SERIES 

500
00:25:25,600 --> 00:25:28,480
ADGENTLEMAN VENTS 5% OF CD4 

501
00:25:28,480 --> 00:25:33,240
HELPERS ARE TFHS AND RNA-LNPS IS

502
00:25:33,240 --> 00:25:37,520
OVER 50%.  THIS IS AN AGENTLEMAN

503
00:25:37,520 --> 00:25:40,720
VENT THAT DRIVES THF RESPONSES 

504
00:25:40,720 --> 00:25:43,120
THAT DRIVE ANTIBODY RESPONSES 

505
00:25:43,120 --> 00:25:46,200
AND WHY VACCINE TIGHTERS ARE 5 

506
00:25:46,200 --> 00:25:50,000
TIMES HIGHER THAN CONVALESCIENT 

507
00:25:50,000 --> 00:25:51,920
PATIENT ANTIBODY LEVELS. 

508
00:25:51,920 --> 00:25:55,000
WE MADE THIS INFLUENZA VACCINE 

509
00:25:55,000 --> 00:25:55,880
WITH TIGHTERS THAT WERE THROUGH 

510
00:25:55,880 --> 00:25:57,520
THE ROOF.  WE WANTED TO 

511
00:25:57,520 --> 00:26:02,280
UNDERSTAND HOW GOOD WAS IT?  

512
00:26:02,280 --> 00:26:04,520
INFLUENZA, WE MAKE A NEW VACCINE

513
00:26:04,520 --> 00:26:08,320
EVERY YEAR.  HEAD OF THE HA 

514
00:26:08,320 --> 00:26:12,320
MUTATES.  IT AVOIDS LAST YEAR'S 

515
00:26:12,320 --> 00:26:13,640
VACCINES AND IMMUNE RESPONSES 

516
00:26:13,640 --> 00:26:17,440
AND THERE ARE PANDEMIC STRAINS 

517
00:26:17,440 --> 00:26:23,040
THAT ARE H5 AND H7 AND A FEW 

518
00:26:23,040 --> 00:26:24,600
OTHERS AND OCCASIONALLY SHOW UP 

519
00:26:24,600 --> 00:26:26,720
IN THE WORLD WITH NO IMMUNITY IN

520
00:26:26,720 --> 00:26:29,560
THOSE AND CAUSES A WORLDWIDE 

521
00:26:29,560 --> 00:26:38,120
INFECTION AND WE IMMUNE IIZE WI 

522
00:26:38,120 --> 00:26:48,760
H1 AND HAD 100% PROTECTION.  

523
00:26:48,760 --> 00:26:53,800
HEADS AND STRAINS. 

524
00:26:53,800 --> 00:26:57,560
ANIMALS LOST NO WEIGHT AND 

525
00:26:57,560 --> 00:27:00,800
SURVIVED THE CHALLENGE. 

526
00:27:00,800 --> 00:27:05,080
REASONING WAS RNA-LNP VACCINES 

527
00:27:05,080 --> 00:27:06,920
MAKE RESPONSES AGAINST 

528
00:27:06,920 --> 00:27:10,200
SUBDOMINANT EPITOEPS WITH IMMUNE

529
00:27:10,200 --> 00:27:13,240
SYSTEM THAT DOESN'T RESPOND TO 

530
00:27:13,240 --> 00:27:15,000
IT C

531
00:27:15,000 --> 00:27:18,240
IT.  GERM NAL CENTERS ARE BIG 

532
00:27:18,240 --> 00:27:22,000
THAT SUBDOMINANT RESPONSES CAN 

533
00:27:22,000 --> 00:27:32,160
SURV

534
00:27:33,720 --> 00:27:35,120
SURVIVE. 

535
00:27:35,120 --> 00:27:38,600
MECHANISMS OF IT WERE TWO MAIN 

536
00:27:38,600 --> 00:27:38,800
ONES. 

537
00:27:38,800 --> 00:27:49,320
FIRST, THEY INDUCED POTENT TFH 

538
00:27:52,360 --> 00:27:52,880
RESPONSES.  SECOND IS THEY 

539
00:27:52,880 --> 00:27:53,520
PRODUCED IMMUNOGEN FOR UP TO 10 

540
00:27:53,520 --> 00:27:54,160
DAYS LOADING GERM NAL CENTERS TO

541
00:27:54,160 --> 00:28:01,640
MAKE A GOOD B CELL RESPONSE. INO

542
00:28:01,640 --> 00:28:05,480
MAKE A GOOD B CELL RESPONSE.  

543
00:28:05,480 --> 00:28:07,480
WE HAVE WORKED ON 30 + PATHOGENS

544
00:28:07,480 --> 00:28:09,560
WITH COLLABORATORS AROUND THE 

545
00:28:09,560 --> 00:28:11,880
WORLD WE WANT TO IMPROVE 

546
00:28:11,880 --> 00:28:13,360
IMMUNOGENS WE ARE DELIVERING AND

547
00:28:13,360 --> 00:28:16,720
KNOW THAT OTHERS HAVE SHOWN THAT

548
00:28:16,720 --> 00:28:19,480
VRPS VIRAL PARTICLES ARE BETTER 

549
00:28:19,480 --> 00:28:21,520
IMMUNOGENS THAT ARE SECRETED OR 

550
00:28:21,520 --> 00:28:23,440
CELL SURFACED PROTEINS AND 

551
00:28:23,440 --> 00:28:27,160
PROBLEM IS HOW DO YOU MAKE A VLP

552
00:28:27,160 --> 00:28:30,160
WITH MRNAS?  WE HAVE DONE IT A 

553
00:28:30,160 --> 00:28:34,320
FEW DIFFERENT WAYS AND NEWEST IS

554
00:28:34,320 --> 00:28:37,320
FOR HCV AND NUMBER OF TRIALS 

555
00:28:37,320 --> 00:28:39,320
WITH IT THAT HAVE FAIL AND 

556
00:28:39,320 --> 00:28:42,240
DIDN'T MAKE STRONG ENOUGH AND 

557
00:28:42,240 --> 00:28:46,120
CROSS-REACTIVE RESPONSES. 

558
00:28:46,120 --> 00:28:49,680
HCV IS AN RNA VIRUS WITH A 

559
00:28:49,680 --> 00:28:53,520
SINGLE RNA PRODUCT CLEAVED BY 

560
00:28:53,520 --> 00:29:00,720
CELLULAR AND ENVIRONAL PROETASS 

561
00:29:00,720 --> 00:29:02,400
AND ARE NORN STRUCTURAL AND CORE

562
00:29:02,400 --> 00:29:04,280
STRUCTURAL PROTEINS AND THERE IS

563
00:29:04,280 --> 00:29:06,800
ONE PROTEIN OF INTEREST CALLED 

564
00:29:06,800 --> 00:29:10,760
P7.  IT LOOKS LIKE AN ION 

565
00:29:10,760 --> 00:29:11,200
CHANNEL.  

566
00:29:11,200 --> 00:29:17,640
IT WAS ASSOCIATED WITH VIRAL 

567
00:29:17,640 --> 00:29:20,480
VIRION FORMATION AND IF YOU TOOK

568
00:29:20,480 --> 00:29:23,680
IT OUT, VIRUS INFECTED JUST AS 

569
00:29:23,680 --> 00:29:26,080
WELL.  OUR IDEAS AND IDEA OF A 

570
00:29:26,080 --> 00:29:28,520
GRAD STUDENT IN MY LAB IS 

571
00:29:28,520 --> 00:29:34,560
INCLUDING P7 IN MRNA WOULD MAKE 

572
00:29:34,560 --> 00:29:37,800
BETTER VIRAL PARTICLES IN A 

573
00:29:37,800 --> 00:29:40,760
BETTER VACCINE.  SHE MADE TWO 

574
00:29:40,760 --> 00:29:43,840
RNAS ONE WITH CORE E12 ONE 

575
00:29:43,840 --> 00:29:47,080
WITHOUT P7 AND PUT THEM INTO A 

576
00:29:47,080 --> 00:29:49,800
VARIETY OF CELL TYPES THAT ARE 

577
00:29:49,800 --> 00:29:52,960
HELPA TOMORROWA CELLS WE HAVE 

578
00:29:52,960 --> 00:29:56,080
DONE SAME IN DENDRITIC CELLS AND

579
00:29:56,080 --> 00:30:00,040
WHEN P7 WAS PRESENT, AMOUNT OF 

580
00:30:00,040 --> 00:30:02,280
SECRETED C PROTEIN OR CORE 

581
00:30:02,280 --> 00:30:04,960
PROTEIN WAS MUCH HIGHER.  THIS 

582
00:30:04,960 --> 00:30:07,240
SUGGESTED THAT WE WERE GETTING 

583
00:30:07,240 --> 00:30:10,160
BETTER VLP RELEASE FROM VIRUSES.

584
00:30:10,160 --> 00:30:15,560
WE LOOKED AT IT WITH CRYO-EM.  

585
00:30:15,560 --> 00:30:19,360
YOU CAN'T QUANTITY TATE WITH 

586
00:30:19,360 --> 00:30:21,720
CRYO-EM.  THEY ARE SAMPLE IMAGES

587
00:30:21,720 --> 00:30:25,960
AND RED ARROW ARE VHPS FOR HCLV 

588
00:30:25,960 --> 00:30:28,440
AND LOOKING AT NUMBERS THERE IS 

589
00:30:28,440 --> 00:30:35,120
ABOUT 5 TIMES MORE VLPS WHEN P7 

590
00:30:35,120 --> 00:30:37,040
WAS PRESENT AND PUT INTO MOUSE 

591
00:30:37,040 --> 00:30:40,400
SYSTEMS LOOKING AT IMMUNOGENISTY

592
00:30:40,400 --> 00:30:43,480
AND SAW HIGHER TIGHTERS AND 

593
00:30:43,480 --> 00:30:45,640
CROSS-REACTIVITY WITH P7 

594
00:30:45,640 --> 00:30:48,600
CONTAINING IMMUNOGEN.  THEY ARE 

595
00:30:48,600 --> 00:30:50,560
GOING FORWARD TOWARDS HUMAN 

596
00:30:50,560 --> 00:30:52,320
CLINICAL TRIALS THAT WE HAVE 

597
00:30:52,320 --> 00:30:53,880
ALSO DONE THIS FOR HIV.  

598
00:30:53,880 --> 00:30:55,920
EVERYBODY KNOWS WE HAVE BEEN 

599
00:30:55,920 --> 00:31:00,240
WORKING ON HIV VACCINES FOR 30 

600
00:31:00,240 --> 00:31:06,880
YEARS TI TRIAL HAD A SIGNAL THAT

601
00:31:06,880 --> 00:31:09,200
MAYBE COULDN'T BE REPLICATED IN 

602
00:31:09,200 --> 00:31:12,840
THE AFRICAN TRIAL IN MY VIEW WE 

603
00:31:12,840 --> 00:31:15,040
HAVEN'T MADE A VACCINE THAT MADE

604
00:31:15,040 --> 00:31:19,000
A STRONG PROTECTIVE RESPONSE. 

605
00:31:19,000 --> 00:31:22,080
THAT IS A GOAL RETIRING HEAD OF 

606
00:31:22,080 --> 00:31:24,760
NAID HAS MADE IT A GOAL HIS 

607
00:31:24,760 --> 00:31:28,360
ENTIRE CAREER.  OUR IDEA WAS 

608
00:31:28,360 --> 00:31:31,840
LET'S MAKE VLPS WITH HIV VACCINE

609
00:31:31,840 --> 00:31:33,080
AND THAT WAY YOU HAVE ENVELOPE 

610
00:31:33,080 --> 00:31:35,080
ON VIRAL PARTICLE THAT WILL BE 

611
00:31:35,080 --> 00:31:37,960
MORE IMMUNOGENIC AND YOU HAVE 

612
00:31:37,960 --> 00:31:41,520
GAG CD4 AND CD8 RESPONSES IT 

613
00:31:41,520 --> 00:31:44,000
THAT WILL AID IN PROTECTION AND 

614
00:31:44,000 --> 00:31:48,520
WE COMBINE TWO RNAS, ONE FOR HIV

615
00:31:48,520 --> 00:31:53,160
OR SIV GAG AND ONE FOR HIV 

616
00:31:53,160 --> 00:31:55,880
ENVELOPE AND PUT THEM INTO CELLS

617
00:31:55,880 --> 00:31:57,800
COLLECTING SUPER-NATANT AND 

618
00:31:57,800 --> 00:32:01,040
STAINED FOR GAG AND ENVELOPE.  

619
00:32:01,040 --> 00:32:04,640
HERE, THIS IS HUMAN PLASMAS 

620
00:32:04,640 --> 00:32:09,080
MEASURING HIV GAG AND SEE GAG IN

621
00:32:09,080 --> 00:32:12,080
ENVELOPE PRESENT.  THIS IS SIV 

622
00:32:12,080 --> 00:32:15,760
GAG SIRA AND SEE SIV GAG AND 

623
00:32:15,760 --> 00:32:17,680
ENVELOPE PRESENT AT HIGH LEVELS.

624
00:32:17,680 --> 00:32:22,920
WE WERE ABLE TO MAKE A SECRETED 

625
00:32:22,920 --> 00:32:25,400
VIRAL PARTICLE THAT EXPRESSED 

626
00:32:25,400 --> 00:32:28,720
GAG AND ENVELOPE AND SHOWING 

627
00:32:28,720 --> 00:32:30,560
THAT WE HAVE VIRAL PARTICLES BUT

628
00:32:30,560 --> 00:32:32,840
THIS IS PRETTY CONVINCING. 

629
00:32:32,840 --> 00:32:36,800
BUT, HIV IS NOT SO 

630
00:32:36,800 --> 00:32:38,600
STRAIGHTFORWARD.  THE PROBLEM 

631
00:32:38,600 --> 00:32:40,880
IS, IS THAT THE ENVELOPE IS 

632
00:32:40,880 --> 00:32:42,520
ESSENTIALLY LOOKING AT IT AS A 

633
00:32:42,520 --> 00:32:45,680
BAG OF JELL-O THAT IS A 

634
00:32:45,680 --> 00:32:47,280
CONSTANTLY MOVING STRUCTURE THAT

635
00:32:47,280 --> 00:32:51,000
IS OFTEN IN CONFIRMATIONS THAT 

636
00:32:51,000 --> 00:32:56,960
HAVE NON-NEUTRALIZING EPITOEPS 

637
00:32:56,960 --> 00:32:58,960
AND WE AND OTHERS HAVE LOOKED AT

638
00:32:58,960 --> 00:33:01,200
WAYS OF STABILIZING THE ENVELOPE

639
00:33:01,200 --> 00:33:03,680
SO IT RETAINS BROADLY 

640
00:33:03,680 --> 00:33:05,680
NEUTRALIZING EPITOEPS AND 

641
00:33:05,680 --> 00:33:07,600
DOESN'T EXPRESS DISTRACTING 

642
00:33:07,600 --> 00:33:07,840
EPITOEPS. 

643
00:33:07,840 --> 00:33:11,240
THIS IS A SERIES OF 5 

644
00:33:11,240 --> 00:33:11,600
MODIFICATIONS. 

645
00:33:11,600 --> 00:33:15,320
WE STARTED WITH AN ENVELOPE.  

646
00:33:15,320 --> 00:33:18,600
CH848 AND IT IS A CHILD D 

647
00:33:18,600 --> 00:33:23,240
PATIENT FROM AFRICA WHO MADE 

648
00:33:23,240 --> 00:33:24,640
STRONG GLYCAN BNAB RESPONSE.  

649
00:33:24,640 --> 00:33:27,320
THEY FOLLOWED THE PASH YENTD FOR

650
00:33:27,320 --> 00:33:32,840
YEARS IDENTIFYING VIRUSES AND 

651
00:33:32,840 --> 00:33:35,200
ANTI-VIRUSES OVER TIME MAKING A 

652
00:33:35,200 --> 00:33:38,400
BNAB RESPONSE AND DT ARE V1 

653
00:33:38,400 --> 00:33:40,520
GLYCANS THAT HAVE BEEN REMOVED 

654
00:33:40,520 --> 00:33:43,120
FROM THE IMMUNOGEN ALLOWING IT 

655
00:33:43,120 --> 00:33:47,560
TO BIND TO UCA, UNMUTATED COMMON

656
00:33:47,560 --> 00:33:50,280
ANCESTOR OF THE ANTIBODY WHICH 

657
00:33:50,280 --> 00:33:52,720
IS HOW YOU START AN ANTIBODY 

658
00:33:52,720 --> 00:33:56,760
RESPONSE AND WE ADDED A SERIES 

659
00:33:56,760 --> 00:33:58,200
OF MUTATIONS FILLING GLYCAN 

660
00:33:58,200 --> 00:34:01,160
HOLES AND PUT MUTATIONS LOCKING 

661
00:34:01,160 --> 00:34:04,240
DOWN CD4 AND LOCKING DOWN V3 AND

662
00:34:04,240 --> 00:34:09,640
V1 AND V2.  THIS IS THE SERIES. 

663
00:34:09,640 --> 00:34:15,640
WE TOOK OUT THE CLEAVAGE SITE.  

664
00:34:15,640 --> 00:34:19,320
WE STUDIED THEM FOR 

665
00:34:19,320 --> 00:34:21,600
ANTIGENICITIY.  TOP 3 ARE COMMON

666
00:34:21,600 --> 00:34:25,480
BROADLY NEUTRALIZING ANTIBODIES 

667
00:34:25,480 --> 00:34:28,520
RECOGNIZING EPITOEPS AT BINDING 

668
00:34:28,520 --> 00:34:34,560
SITE AND 7 TAEN-B IS A CDI SITE.

669
00:34:34,560 --> 00:34:38,560
374 IS A LINEAR V3 EPITOEP.  

670
00:34:38,560 --> 00:34:41,520
BOTH OF THESE ARE BAD.  THESE 

671
00:34:41,520 --> 00:34:43,080
ARE DISTRACTING EPITOEPS. 

672
00:34:43,080 --> 00:34:47,680
WE HAVE DONE A VARIETY OF CODON 

673
00:34:47,680 --> 00:34:49,680
OPTIMIZATIONS TO THE RNA.  

674
00:34:49,680 --> 00:34:53,080
WE DID THIS TO TEST FOR MAKING 

675
00:34:53,080 --> 00:34:55,360
THE MOST ENVELOPE.  YOU CAN 

676
00:34:55,360 --> 00:34:56,280
CLEARLY SEE THAT CODON 

677
00:34:56,280 --> 00:34:58,680
OPTIMIZATION IS IMPORTANT.  RED 

678
00:34:58,680 --> 00:35:01,640
IS ENVELOPE-BINDING WITH THESE 

679
00:35:01,640 --> 00:35:04,880
DIFFERENT ANTIBODIES. 

680
00:35:04,880 --> 00:35:07,400
GOING THROUGH THE SERIES OF 

681
00:35:07,400 --> 00:35:08,040
MODIFICATIONS, WE WERE ABLE TO 

682
00:35:08,040 --> 00:35:10,560
GREATLY INCREASE AMOUNT OF BNAB 

683
00:35:10,560 --> 00:35:12,200
BINDING TO THEM.  WE WERE ABLE 

684
00:35:12,200 --> 00:35:17,640
TO GET RID OF THE CD4I SITE.  WE

685
00:35:17,640 --> 00:35:21,280
HAVEN'T BEEN ABLE TO GET RID OF 

686
00:35:21,280 --> 00:35:24,240
THE V3 SITE.  V3 IS STILL 

687
00:35:24,240 --> 00:35:26,600
STICKING OUT IN THIS IMMUNOGEN 

688
00:35:26,600 --> 00:35:28,920
AND WE ARE CONTINUING WITH MORE 

689
00:35:28,920 --> 00:35:30,680
MODIFICATIONS TO GET RID OF V3. 

690
00:35:30,680 --> 00:35:35,040
WE HAVE REDUCED IT BUT HAVEN'T 

691
00:35:35,040 --> 00:35:40,160
GOTTEN RID OF IT YET.  THIS 

692
00:35:40,160 --> 00:35:41,200
IMMUNOGEN [INDISCERNIBLE] TO 

693
00:35:41,200 --> 00:35:44,320
INDUCE BNAB RESPONSES HOPEFULLY 

694
00:35:44,320 --> 00:35:47,200
AND WE DO IT WITH MANY HIV 

695
00:35:47,200 --> 00:35:49,120
ENVELOPES WE MAKE.  PLAN IS TO 

696
00:35:49,120 --> 00:35:52,960
MAKE ENVELOPES THAT STIMULATE AT

697
00:35:52,960 --> 00:35:56,160
LEAST THREE DIFFERENT BNAB 

698
00:35:56,160 --> 00:35:59,680
EPITOEP.  CD4 INTERFACE V3 

699
00:35:59,680 --> 00:36:05,600
GLYCAN V1 AND V2NPER TO PUT THEM

700
00:36:05,600 --> 00:36:07,840
TOGETHER INTO A FINAL VACCINE 

701
00:36:07,840 --> 00:36:09,400
THAT WILL HOPEFULLY PROTECT 

702
00:36:09,400 --> 00:36:10,840
PEOPLE.  I WILL STOP THERE AND 

703
00:36:10,840 --> 00:36:12,920
TAKE A FEW QUESTIONS BEFORE I 

704
00:36:12,920 --> 00:36:17,320
MOVE ON TO THE SECOND PART OF MY

705
00:36:17,320 --> 00:36:27,440
TALK.  

706
00:36:27,840 --> 00:36:30,520
>>HI.  THANK YOU SO MUCH.
THIS

707
00:36:30,520 --> 00:36:33,040
IS SO INTERESTING.  I REMEMBER 

708
00:36:33,040 --> 00:36:36,680
IT THAT I VISITED PENN A FEW 

709
00:36:36,680 --> 00:36:38,640
YEARS AGO TO GIVE A TALK AND YOU

710
00:36:38,640 --> 00:36:40,720
MET WITH ME AND SHOWED ME YOUR 

711
00:36:40,720 --> 00:36:42,440
DATA AND I WAS BLOWN AWAY.  I 

712
00:36:42,440 --> 00:36:44,720
HAD A QUESTION.  YOU KNOW, YOU 

713
00:36:44,720 --> 00:36:47,200
SHOWED US HOW IN THE ANIMAL 

714
00:36:47,200 --> 00:36:49,680
MODELS THAT THE DURATION WAS 

715
00:36:49,680 --> 00:36:51,920
LONGER THAN ANTIBODIES COMPARED 

716
00:36:51,920 --> 00:36:54,040
TO OTHER VACCINE PLATFORMS AND 

717
00:36:54,040 --> 00:36:56,680
MY QUESTION IS BASICALLY WHY DO 

718
00:36:56,680 --> 00:36:59,000
YOU THINK IT IS SO SHORT IN 

719
00:36:59,000 --> 00:37:01,480
HUMANS WITH COVID-19 VACCINES?  

720
00:37:01,480 --> 00:37:04,440
>>I DON'T THINK IT IS SO
SHORT 

721
00:37:04,440 --> 00:37:07,040
BUT WHAT HAS HAPPENED IS THAT 

722
00:37:07,040 --> 00:37:09,560
VARIANTS HAVE APPEARED AND 

723
00:37:09,560 --> 00:37:11,400
PROBLEMS IS THAT EVERY VARRANT 

724
00:37:11,400 --> 00:37:13,200
IS LESS SENSITIVE TO THE 

725
00:37:13,200 --> 00:37:13,760
VACCINE. 

726
00:37:13,760 --> 00:37:16,760
YOU KNOW, DELTA VARIANTS WERE 

727
00:37:16,760 --> 00:37:20,160
ABOUT 30 OR 35% LESS SENSITIVE 

728
00:37:20,160 --> 00:37:25,000
AND OMICRONS ARE 80% LESS 

729
00:37:25,000 --> 00:37:27,360
SENSITIVE AND ONLY WAY WE HAD TO

730
00:37:27,360 --> 00:37:29,120
ADDRESS THAT WAS TO BOOST THE 

731
00:37:29,120 --> 00:37:30,680
OVERALL TIGHTER. 

732
00:37:30,680 --> 00:37:33,680
IDEA WAS IF AT BASELINE THEY ARE

733
00:37:33,680 --> 00:37:36,000
20% SENSITIVE, IF YOU GIVE A 

734
00:37:36,000 --> 00:37:37,640
BOOSTER YOU CAN INCREASE IT TO 

735
00:37:37,640 --> 00:37:38,920
50 OR 60%. 

736
00:37:38,920 --> 00:37:42,080
WE WERE BOOSTING THE OLD 

737
00:37:42,080 --> 00:37:44,600
ANTIBODIES THAT BARELY 

738
00:37:44,600 --> 00:37:47,320
NEUTRALIZED. 

739
00:37:47,320 --> 00:37:49,520
BOOSTERS ARE NOT BECAUSE 

740
00:37:49,520 --> 00:37:51,720
DURABILITY IS POOR BUT VARIANTS 

741
00:37:51,720 --> 00:37:53,120
KEPT APPEARING.  WE NEEDED A LOT

742
00:37:53,120 --> 00:37:56,080
OF ANTIBODY TO PROTECT AGAINST 

743
00:37:56,080 --> 00:37:56,320
THEM. 

744
00:37:56,320 --> 00:37:58,520
>>I PRESUME WE ARE NOT
LOOKING 

745
00:37:58,520 --> 00:38:01,600
AT RIGHT REDIAL.  IT IS NOT 

746
00:38:01,600 --> 00:38:05,080
NECESSARILY SERUM TIGHTERS BUT 

747
00:38:05,080 --> 00:38:07,120
PLASMA BLASTS OR B CELLS THAT 

748
00:38:07,120 --> 00:38:08,280
PROBABLY WOULD STAY LONGER BUT 

749
00:38:08,280 --> 00:38:11,200
ARE NOT NECESSARILY ACTIVELY 

750
00:38:11,200 --> 00:38:11,520
PRODUCED?  

751
00:38:11,520 --> 00:38:13,760
>>HUMAN VACCINES, WAY
THAT YOU 

752
00:38:13,760 --> 00:38:15,680
DETERMINE WHEN YOU NEED A 

753
00:38:15,680 --> 00:38:17,560
BOOSTER IS FOLLOW PEOPLE WHEN 

754
00:38:17,560 --> 00:38:18,880
THEY GIVE A DISEASE AGAIN YOU 

755
00:38:18,880 --> 00:38:21,640
GIVE A BOOSTER AND FOR TET AN US

756
00:38:21,640 --> 00:38:24,120
IT IS 10 YEARS AND SMALL POX IT 

757
00:38:24,120 --> 00:38:26,000
IS A LIFETIME.  WE WON'T KNOW 

758
00:38:26,000 --> 00:38:28,200
WITH COVID BECAUSE OF ALL 

759
00:38:28,200 --> 00:38:29,360
BOOSTERS WE HAVE GIVEN. 

760
00:38:29,360 --> 00:38:32,200
>>COULD YOU COMMENT ON
YOUR 

761
00:38:32,200 --> 00:38:33,640
EXPERIENCE ON THE ABILITY OF 

762
00:38:33,640 --> 00:38:36,000
DIFFERENT IMMUNOGEN TO ACTUALLY 

763
00:38:36,000 --> 00:38:39,680
GIVE YOU THIS LONG-LIVED PLASMA 

764
00:38:39,680 --> 00:38:42,560
CELLS OR -- SO, DO YOU KNOW WHAT

765
00:38:42,560 --> 00:38:45,640
-- YOU MUST HAVE DONE 

766
00:38:45,640 --> 00:38:46,120
COMPARATIVE STUDIES. 

767
00:38:46,120 --> 00:38:48,720
>>YEAH.  IT IS REALLY TWO

768
00:38:48,720 --> 00:38:49,000
PROBLEMS. 

769
00:38:49,000 --> 00:38:52,040
IF YOU LOOK AT GERMINAL CENTERS 

770
00:38:52,040 --> 00:38:56,960
AFTER RNA-LNPS WE HAVE DONE IN 

771
00:38:56,960 --> 00:39:06,640
MICE AND MCKAKS.  GERMINAL 

772
00:39:06,640 --> 00:39:09,320
CENTERS LAST 3 OR 4 + MONTHS 

773
00:39:09,320 --> 00:39:10,960
GERMINAL CELL ACTIVITY CONTINUES

774
00:39:10,960 --> 00:39:12,640
FOR A LONG TIME.  WHAT WE HAVE 

775
00:39:12,640 --> 00:39:17,000
SEEN WITH HIV IS WE GET A BIG 

776
00:39:17,000 --> 00:39:19,840
INCREASE IN ENVELOPE-BINDING 

777
00:39:19,840 --> 00:39:23,120
ANTIBODIES AND LOOKING AT BNABS 

778
00:39:23,120 --> 00:39:25,560
WE SEE AN INCREASE AND THEY 

779
00:39:25,560 --> 00:39:27,360
START TO DROP FAIR WILL I 

780
00:39:27,360 --> 00:39:29,720
QUICKLY AND LIKELY IS GERMINAL 

781
00:39:29,720 --> 00:39:31,640
CENTERS CONTINUING TO MUTATE 

782
00:39:31,640 --> 00:39:35,240
THOSE CELLS AND ARE LOSING BNAB 

783
00:39:35,240 --> 00:39:36,840
SPECIFICITY OVER TIME.  LOOKING 

784
00:39:36,840 --> 00:39:39,680
AT ZIKA IN MCCABBINGS WE 

785
00:39:39,680 --> 00:39:42,360
IMMUNIZED ONCE AND FOR A YEAR 

786
00:39:42,360 --> 00:39:44,320
TIGHTERS NEVER DROPPED.  THERE 

787
00:39:44,320 --> 00:39:46,400
IS LOTS OF IMMUNOGEN INFLUENCE 

788
00:39:46,400 --> 00:39:48,040
ON DURABILITY OF THE RESPONSE 

789
00:39:48,040 --> 00:39:49,040
FOR MANY REASONS. 

790
00:39:49,040 --> 00:39:53,440
PART OF IT IS SOME IMMUNOGENS 

791
00:39:53,440 --> 00:39:55,480
INDUCE NOT VERY DURABLE 

792
00:39:55,480 --> 00:39:57,480
RESPONSES AND FLU IS 

793
00:39:57,480 --> 00:40:00,000
CHARACTERISTIC FOR THAT SOME 

794
00:40:00,000 --> 00:40:01,760
IMMUNOGENS GERMINAL CENTER 

795
00:40:01,760 --> 00:40:05,440
REACTION YOU LOSE BNAB BROADLY 

796
00:40:05,440 --> 00:40:06,760
NEUTRALIZING RESPONSES YOU WANT 

797
00:40:06,760 --> 00:40:13,640
BECAUSE OF BNAB AND GC ACTIVITY.

798
00:40:13,640 --> 00:40:15,760
>>WE DON'T KNOW WHY?  

799
00:40:15,760 --> 00:40:18,920
>>WE DON'T KNOW WHY YET. 

800
00:40:18,920 --> 00:40:20,640
ALL RIGHT.  I WILL MOVE ON.  SO,

801
00:40:20,640 --> 00:40:22,760
WHAT I WANTED TO TALK TO YOU 

802
00:40:22,760 --> 00:40:26,760
ABOUT NEXT WAS THE FUTURE OF RNA

803
00:40:26,760 --> 00:40:27,080
THERAPEUTICS. 

804
00:40:27,080 --> 00:40:29,280
WE HAVE GOT A LOT OF VACCINES. 

805
00:40:29,280 --> 00:40:31,440
WE HAVE 7 PHASE 1 CLINICAL 

806
00:40:31,440 --> 00:40:36,480
TRIALS GOING ON RIGHT NOW FOR 

807
00:40:36,480 --> 00:40:42,000
HIV, INFLUENZA, GENITAL HERPES, 

808
00:40:42,000 --> 00:40:45,440
MALARIA, CDIF, NEUROVIRUS AND 

809
00:40:45,440 --> 00:40:45,960
MORE ON THE WAY. 

810
00:40:45,960 --> 00:40:48,080
WE HAVE BEEN LOOKING AT NEW WAYS

811
00:40:48,080 --> 00:40:50,400
OF USING RNA. 

812
00:40:50,400 --> 00:40:53,640
RNA CAN BE USED TO DELIVER 

813
00:40:53,640 --> 00:40:55,640
PROTEIN THERAPEUTICS. 

814
00:40:55,640 --> 00:40:58,560
IT CAN TREAT ACUTE AND CHRONIC 

815
00:40:58,560 --> 00:40:58,840
DISEASES. 

816
00:40:58,840 --> 00:41:03,880
TO ME, MOST IMPORTANTLY IT CAN 

817
00:41:03,880 --> 00:41:05,840
MEDIATE GENE THERAPY SAFELY. 

818
00:41:05,840 --> 00:41:09,680
BIGGEST PROBLEM WITH RNA AND ANY

819
00:41:09,680 --> 00:41:13,600
NUCLEIC ACID THERAPEUTIC IS 

820
00:41:13,600 --> 00:41:15,200
DELIVERY GETTING THEM TO CELLS 

821
00:41:15,200 --> 00:41:17,640
OF INTEREST AND LNPS GO TO THE 

822
00:41:17,640 --> 00:41:20,040
LIVER AND THERE HAS ALREADY BEEN

823
00:41:20,040 --> 00:41:23,720
A PHASE 1 TRIAL DELIVERING CAS9 

824
00:41:23,720 --> 00:41:29,640
IN A MODIFIED RNA-LNP FOR 

825
00:41:29,640 --> 00:41:32,120
TRANSPI REITANT AM ILLOID DOSIS 

826
00:41:32,120 --> 00:41:36,640
THAT WAS SUCCESSFUL.  LNPS GO TO

827
00:41:36,640 --> 00:41:38,800
THE LIVER AND TRANSFAT 98% OF 

828
00:41:38,800 --> 00:41:40,920
THE CELLS AND GAVE GOOD 

829
00:41:40,920 --> 00:41:43,160
KNOCKOUT.  WHAT IF YOU WANT TO 

830
00:41:43,160 --> 00:41:45,280
DELIVER TO BONE MARROW STEM 

831
00:41:45,280 --> 00:41:48,080
CELLS OR T CELLS OR LUNGS OR 

832
00:41:48,080 --> 00:41:49,280
HEART OR BRAIN WE DON'T HAVE A 

833
00:41:49,280 --> 00:41:51,400
WAY OF DOING THAT.  THERE IS NOT

834
00:41:51,400 --> 00:41:54,080
A LIPID SYSTEM THAT DOES THAT 

835
00:41:54,080 --> 00:41:54,560
WELL. 

836
00:41:54,560 --> 00:41:57,640
SO, MY LAB YEARS AGO STARTED TO 

837
00:41:57,640 --> 00:42:02,320
STUDY WAYS OF TARGETING LNPS TO 

838
00:42:02,320 --> 00:42:03,840
OTHER TISSUES, ORGANS AND CELLS 

839
00:42:03,840 --> 00:42:07,320
AND WE CONCENTRATED ON THREE 

840
00:42:07,320 --> 00:42:09,720
TYPES OF TARGETING FOR 

841
00:42:09,720 --> 00:42:12,960
ENDOTHELIAL AND T CELLS AND BONE

842
00:42:12,960 --> 00:42:14,520
MARROW STEM CELLS. 

843
00:42:14,520 --> 00:42:17,040
APPROACH THAT WE TOOK WAS TO 

844
00:42:17,040 --> 00:42:21,640
MODIFY THE SURFACE OF THE LIPID 

845
00:42:21,640 --> 00:42:25,280
NANOPARTICLE.  LNPS HAVE A DSPC 

846
00:42:25,280 --> 00:42:29,760
OR OTHER CARRIER LIPID PLASMA 

847
00:42:29,760 --> 00:42:31,880
MEMBRANE-LIKE STRUCTURE. 

848
00:42:31,880 --> 00:42:34,480
IMBEDDED IN THAT ARE PEGGOLATED 

849
00:42:34,480 --> 00:42:37,640
LIPIDS AND INSIDE OF IT ARE CATI

850
00:42:37,640 --> 00:42:45,000
ONIC LIPIDS BINDING RNA AND 

851
00:42:45,000 --> 00:42:48,320
CHOLESTEROL THAT STABILIZES WE 

852
00:42:48,320 --> 00:42:51,720
ADDED ANTIBODIES AND LIGANDS TO 

853
00:42:51,720 --> 00:42:54,440
PEG MOLECULES ON SURFACE LNP.  

854
00:42:54,440 --> 00:42:57,640
WHEN WE DID THAT WE MAINTAINED 

855
00:42:57,640 --> 00:42:59,960
MORPHOLOGY OF LNP AND THEY GOT A

856
00:42:59,960 --> 00:43:02,720
LITTLE BIGGER THAT IS ABOUT SIZE

857
00:43:02,720 --> 00:43:05,160
OF THE N BODY CODEINE.  

858
00:43:05,160 --> 00:43:06,800
IMPORTANTLY, THEY MAINTAIN 

859
00:43:06,800 --> 00:43:08,720
SURFACE CHARGE.  YOU CAN'T GIVE 

860
00:43:08,720 --> 00:43:11,040
A CHARGED PARTICLE TO A PERSON. 

861
00:43:11,040 --> 00:43:14,160
IT ACTIVATES COAGULATION AND 

862
00:43:14,160 --> 00:43:17,600
ACTIVATES A VARIETY OF TOXICITY 

863
00:43:17,600 --> 00:43:17,920
PATHWAYS. 

864
00:43:17,920 --> 00:43:21,600
WHEN WE ADDED ANTIBODIES, THEY 

865
00:43:21,600 --> 00:43:23,280
REMAIN NON-CHARGED. 

866
00:43:23,280 --> 00:43:26,520
WE INJECTED THEM INTO ANIMALS.  

867
00:43:26,520 --> 00:43:29,160
FIRST, WE TRIED THEM ON PRIMARY 

868
00:43:29,160 --> 00:43:33,640
HUMAN CELLS THAT ARE UVACS, 

869
00:43:33,640 --> 00:43:36,480
ENDOTHELIAL CELLS AND ABSENCE OF

870
00:43:36,480 --> 00:43:38,800
TARGETING, YOU GET NO RNA 

871
00:43:38,800 --> 00:43:41,720
UPTAKE.  LNPS ARE NOT TAKEN UP 

872
00:43:41,720 --> 00:43:46,440
BY UVACS.  PCAN IS HIGHLY 

873
00:43:46,440 --> 00:43:48,880
EXPRESSED ON ENDOTHELIAL CELLS 

874
00:43:48,880 --> 00:43:53,480
TARGETING LNPS WITH ANTIBODY AND

875
00:43:53,480 --> 00:43:56,960
DID GFP ENCODING RNA AND YOU SEE

876
00:43:56,960 --> 00:43:59,040
EVERY CELL IN THE CULTURE IS 

877
00:43:59,040 --> 00:44:02,720
MAKING GNP.  TOOK UP LNPS AND 

878
00:44:02,720 --> 00:44:04,760
TRANSLATED RNA.  WHEN WE 

879
00:44:04,760 --> 00:44:09,720
INJECTED PARTICLES INTO THE 

880
00:44:09,720 --> 00:44:12,320
ANIMALS, WE SAW TWO THINGS. 

881
00:44:12,320 --> 00:44:15,000
FIRST, WHEN WE ADDED ANTIBODY TO

882
00:44:15,000 --> 00:44:18,880
THE SURFACE THAT IS CONTROL IGG 

883
00:44:18,880 --> 00:44:21,480
OR ANTI-PCAM, WE REDUCED LIVER 

884
00:44:21,480 --> 00:44:22,960
UPTAKE THAT IS LIKELY BECAUSE WE

885
00:44:22,960 --> 00:44:25,640
ARE BLOCKING AND BINDING AND 

886
00:44:25,640 --> 00:44:27,920
REDUCING LIVER TARGETING AND 

887
00:44:27,920 --> 00:44:30,320
ADDING PCAM, LUNGS NOW LIT UP 

888
00:44:30,320 --> 00:44:32,840
AND ABOUT HALF OF THE ACTIVITY 

889
00:44:32,840 --> 00:44:34,360
IS NOW IN THE LUNGS. 

890
00:44:34,360 --> 00:44:37,840
PCAM IS HIGHLY EXPRESSED ON 

891
00:44:37,840 --> 00:44:40,320
ENDOTHELIAL CELLS WITH LUNGS 

892
00:44:40,320 --> 00:44:42,680
WITH HIGHEST DENSITY OF 

893
00:44:42,680 --> 00:44:44,600
ENDOTHELIAL CELLS AND TARGET 

894
00:44:44,600 --> 00:44:47,920
LUNGS WITH ANTI-PCAM ANTIBODY 

895
00:44:47,920 --> 00:44:51,040
AND I'M ALWAYS ASKED ABOUT 

896
00:44:51,040 --> 00:44:51,840
NEUROLOGIC TARGETING.  I DON'T 

897
00:44:51,840 --> 00:44:54,480
-- THERE IS A VARIETY OF REASONS

898
00:44:54,480 --> 00:44:56,280
PROBABLY BUT WE DON'T HAVE TO 

899
00:44:56,280 --> 00:44:57,440
GET INTO THAT. 

900
00:44:57,440 --> 00:45:01,360
AS A PHYSICIAN, WHEN I WAS A 

901
00:45:01,360 --> 00:45:04,920
RESIDENT, MY BIGGEST NIGHTMARE 

902
00:45:04,920 --> 00:45:06,320
CAME WHEN A STROKE PATIENT CAME 

903
00:45:06,320 --> 00:45:10,560
IN.  THIS IS WHAT A CT SCAN OR 

904
00:45:10,560 --> 00:45:12,280
MRI OF A STROKE PATIENT LOOKS 

905
00:45:12,280 --> 00:45:15,760
LIKE.  THIS IS MIDDLE CEREBRAL 

906
00:45:15,760 --> 00:45:17,080
ARTERY DISTRIBUTION HERE.  WHEN 

907
00:45:17,080 --> 00:45:19,800
THEY FIRST COME IN THE DOOR WITH

908
00:45:19,800 --> 00:45:22,840
TYPICALLY HEMIPORESIS IT IS 

909
00:45:22,840 --> 00:45:25,520
BECAUSE MIDDLE CEREBRAL ARTERY 

910
00:45:25,520 --> 00:45:28,400
GOT PLUGGED UP.  YOU FOLLOW THEM

911
00:45:28,400 --> 00:45:29,800
FOR A FEW DAYS. 

912
00:45:29,800 --> 00:45:31,680
ALSO, WHAT OFTEN HAPPENS IS 

913
00:45:31,680 --> 00:45:35,160
THIS.  THE STROKE EXPANDS. 

914
00:45:35,160 --> 00:45:37,760
YOU WIPE OUT ONE ENTIRE SIDE OF 

915
00:45:37,760 --> 00:45:39,720
THE BRAIN.  THIS IS BECAUSE ALL 

916
00:45:39,720 --> 00:45:45,640
OF THE DEAD CELLS ARE RELEASING 

917
00:45:45,640 --> 00:45:49,840
INFLAMMATORY MEDIATORS AND A 

918
00:45:49,840 --> 00:45:52,480
VARIETY OF DAMAGE-INDUCING 

919
00:45:52,480 --> 00:45:54,640
EFFECTS CAUSING VASCULAR LEAKAGE

920
00:45:54,640 --> 00:45:55,920
AND EXPANSION OF THE STROKE.  

921
00:45:55,920 --> 00:45:59,680
SO, THERE ARE WAYS OF 

922
00:45:59,680 --> 00:46:02,480
APPROACHING THIS.  THERE IS 

923
00:46:02,480 --> 00:46:03,880
ENZYMES THAT CAN DESTROY CLOTS 

924
00:46:03,880 --> 00:46:06,280
AND THERE ARE SURGERIES THAT CAN

925
00:46:06,280 --> 00:46:06,800
REPAIR.  

926
00:46:06,800 --> 00:46:09,040
BUT, THERE IS NO WAY TO TREAT 

927
00:46:09,040 --> 00:46:11,120
THIS.  STEROIDS DON'T WORK AND 

928
00:46:11,120 --> 00:46:12,680
OTHER THINGS DON'T WORK. 

929
00:46:12,680 --> 00:46:16,840
WE HAD THE IDEA.  WE HAD A MODEL

930
00:46:16,840 --> 00:46:20,560
SYSTEM WHERE WE COULD INJECT TNF

931
00:46:20,560 --> 00:46:23,560
INTO ONE HEMISPHERE OF A MOUSE 

932
00:46:23,560 --> 00:46:26,800
BRAIN.  IT THAT CAUSED LOCAL 

933
00:46:26,800 --> 00:46:28,000
INFLAMMATION AND IT WAS IN HALF 

934
00:46:28,000 --> 00:46:30,600
OF THE BRAIN OF THE MOUSE. 

935
00:46:30,600 --> 00:46:36,160
WE DEVELOPED A THERAPEUTIC.  WE 

936
00:46:36,160 --> 00:46:39,720
ENCODED TLOEM BOW MODULIN THAT 

937
00:46:39,720 --> 00:46:41,560
INHIBITS COAGULATION AS 

938
00:46:41,560 --> 00:46:43,720
ANTIINFLAMMATORY MOLECULE AND 

939
00:46:43,720 --> 00:46:46,720
PUT ON LNP WE TARGET TO THE 

940
00:46:46,720 --> 00:46:49,040
BLOOD BRAIN BARRIER USING ANTI-V

941
00:46:49,040 --> 00:46:51,480
CAM ANTIBODIES THAT WE ANALYZE 

942
00:46:51,480 --> 00:46:54,760
BOTH SIDES THIS IS A SIDE THAT 

943
00:46:54,760 --> 00:46:57,040
TNF WAS INJECTED AND THIS IS THE

944
00:46:57,040 --> 00:47:01,000
OTHER SIDE.  ON OTHER SIDE, YOU 

945
00:47:01,000 --> 00:47:02,840
SEE THAT TREATMENT HAD SOME BUT 

946
00:47:02,840 --> 00:47:05,640
NOT MUCH EFFECT.  THERE WASN'T 

947
00:47:05,640 --> 00:47:07,840
MUCH VASCULAR LEAKAGE.  WHERE 

948
00:47:07,840 --> 00:47:10,680
TNF WAS INJECTED WE HAD HUGE 

949
00:47:10,680 --> 00:47:12,640
AMOUNTS OF VASCULAR LEAKAGE.  

950
00:47:12,640 --> 00:47:15,520
WHEN WE DELIVERED TLOEMO MODULIN

951
00:47:15,520 --> 00:47:19,360
WITH TARGETED LNP, WE COULD GET 

952
00:47:19,360 --> 00:47:22,040
RID OF IT AND ALL VASCULAR 

953
00:47:22,040 --> 00:47:24,160
LEAKAGE FROM THAT INFLAMMATORY 

954
00:47:24,160 --> 00:47:26,680
INSULT.  WE ARE TAKING THIS 

955
00:47:26,680 --> 00:47:29,400
FORWARD INTO LARGER ANIMAL 

956
00:47:29,400 --> 00:47:32,600
MODELS AS A WAY OF TREATING 

957
00:47:32,600 --> 00:47:35,160
BRAIN INFLAMMATION AND NEUR 

958
00:47:35,160 --> 00:47:37,960
LOGIC INFLAMMATION DUE TO 

959
00:47:37,960 --> 00:47:41,320
INFLAMMATORY INSULTS.  MY LAB 

960
00:47:41,320 --> 00:47:43,440
HAD LONG INTEREST IN HIV SINCE I

961
00:47:43,440 --> 00:47:46,880
WAS AT NIH IN TONY'S LAB WANTING

962
00:47:46,880 --> 00:47:50,840
TO KNOW IF WE COULD TARGET CD4 

963
00:47:50,840 --> 00:47:54,000
CELL AS WAY OF ADDRESSING HIV 

964
00:47:54,000 --> 00:47:56,000
LATENCY.  WE DID THE SAME THING 

965
00:47:56,000 --> 00:47:58,840
AND ADDED ANTI-CD4 ANTIBODIES TO

966
00:47:58,840 --> 00:48:01,080
THE LNPS. 

967
00:48:01,080 --> 00:48:04,120
WHAT YOU HAVE TO KNOW ABOUT T 

968
00:48:04,120 --> 00:48:06,360
CELLS IS THEY HAVE NO ENDO 

969
00:48:06,360 --> 00:48:10,160
CRITIC ACTIVITY AND IF YOU GIVE 

970
00:48:10,160 --> 00:48:13,320
THEM A PARTICLE OR ANY LIPID 

971
00:48:13,320 --> 00:48:16,480
CARRIER, THEY DO NOT -- THEY 

972
00:48:16,480 --> 00:48:20,880
HAVE NO ENDOCYTIC ACTIVITY AND 

973
00:48:20,880 --> 00:48:25,120
CAN'T PRELY SITE OES NUCLEIC 

974
00:48:25,120 --> 00:48:27,760
ACIDS.  YOU CAN'T ELECTROPORATE 

975
00:48:27,760 --> 00:48:30,240
ALL T CELLS IN A BODY. 

976
00:48:30,240 --> 00:48:32,720
OUR HYPOTHESIS WAS THAT IF WE 

977
00:48:32,720 --> 00:48:37,000
BOUND AN ANTIGEN THAT 

978
00:48:37,000 --> 00:48:38,560
ENDOCYTOSIS AFTER BINDING WOULD 

979
00:48:38,560 --> 00:48:44,040
BRING LNP INTO THE CELL RNA 

980
00:48:44,040 --> 00:48:45,720
COULD BE RELEASED AND TRANSLATED

981
00:48:45,720 --> 00:48:49,000
AND WE LOOKED AT CD4 FIRST.  

982
00:48:49,000 --> 00:48:52,240
THESE ARE PURIFIED HUMAN CD4T 

983
00:48:52,240 --> 00:48:54,600
CELLS AND ONLY TIME YOU GET 

984
00:48:54,600 --> 00:48:57,520
ACTIVITY FROM RNA UPTAKE OF LNPS

985
00:48:57,520 --> 00:48:59,600
IS WHEN THEY ARE TARGETED WITH 

986
00:48:59,600 --> 00:49:02,560
-- AGAINST THEIR CD4 MOLECULE. 

987
00:49:02,560 --> 00:49:07,000
WE HAD EFFECTIVE DELIVERY WITH 

988
00:49:07,000 --> 00:49:08,600
ANTI-CD4 ANTIBODIES. 

989
00:49:08,600 --> 00:49:11,040
WE INJECTED THESE INTO A MOUSE. 

990
00:49:11,040 --> 00:49:14,080
WE SEE NOW UPTAKE IN THE SPLEEN 

991
00:49:14,080 --> 00:49:17,960
THAT HAS DECENT NUMBERS OF CD4 

992
00:49:17,960 --> 00:49:19,520
HELPERS IN IT.  

993
00:49:19,520 --> 00:49:21,720
WHAT WE DID WAS SOMETHING 

994
00:49:21,720 --> 00:49:22,240
INTERESTING. 

995
00:49:22,240 --> 00:49:24,680
WE IMAGED MICE AGAIN AFTER WE 

996
00:49:24,680 --> 00:49:27,920
REMOVED ALL OF THE ORGANS ON THE

997
00:49:27,920 --> 00:49:29,800
PREVIOUS SLIDE. 

998
00:49:29,800 --> 00:49:34,360
WHAT WE SAW IS THAT LYMPH NODES 

999
00:49:34,360 --> 00:49:39,560
WERE NOW LIGHTING UP PARAAORTIC 

1000
00:49:39,560 --> 00:49:41,800
[INDISCERNIBLE] LYMPH NODES WHEN

1001
00:49:41,800 --> 00:49:44,000
THIS LNP ESCAPED FROM 

1002
00:49:44,000 --> 00:49:45,800
CIRCULATION AND WENT INTO 

1003
00:49:45,800 --> 00:49:47,800
TISSUES AND INTO DRAINING 

1004
00:49:47,800 --> 00:49:49,400
LYMPHATICS BACK TO DRAINING 

1005
00:49:49,400 --> 00:49:51,440
LYMPH NODES WHERE THEY WERE 

1006
00:49:51,440 --> 00:49:54,400
TAKEN UP BY CD4 POSITIVE T CELLS

1007
00:49:54,400 --> 00:49:58,640
WHERE RNA COULD BE EXPRESSED.  

1008
00:49:58,640 --> 00:50:01,240
HERE, WE PURIFY T CELLS SHOWING 

1009
00:50:01,240 --> 00:50:04,320
THEY HAD ACTIVITY AND THAT MEANS

1010
00:50:04,320 --> 00:50:07,400
LNPS COULD BE GIVEN IV FOR 

1011
00:50:07,400 --> 00:50:10,160
SYSTEMIC TISSUE THERAPEUTICS. 

1012
00:50:10,160 --> 00:50:12,360
WE SWITCHED TO A PRELOCKED 

1013
00:50:12,360 --> 00:50:16,240
SYSTEM THAT ALLOWS US HIGHER 

1014
00:50:16,240 --> 00:50:17,200
SENSITIVITY. 

1015
00:50:17,200 --> 00:50:19,480
PRELOCKS, YOU HAVE USUALLY A 

1016
00:50:19,480 --> 00:50:21,920
STOP CODON IN FRONT OF A 

1017
00:50:21,920 --> 00:50:24,720
FLUORESCENT PROTEIN SURROUNDED 

1018
00:50:24,720 --> 00:50:29,320
BY LOCKS P SITES AND IT CUTS OUT

1019
00:50:29,320 --> 00:50:33,040
STOP CODON TURNING ON PROTEIN. 

1020
00:50:33,040 --> 00:50:38,120
WE INJECTED MICE AND LOOKED AT 

1021
00:50:38,120 --> 00:50:40,920
SPLENOCYTES AND LYMPH NODES AND 

1022
00:50:40,920 --> 00:50:45,080
Y AXIS IS THE COLOR OF THE GREEN

1023
00:50:45,080 --> 00:50:47,080
FLUORESCENT PROTEIN AND X AXIS 

1024
00:50:47,080 --> 00:50:51,320
IS AN ACTIVATION MARKER.  

1025
00:50:51,320 --> 00:50:55,000
HIV, WE KNOW PROVIRAL HIV 

1026
00:50:55,000 --> 00:50:58,960
LATENCY IS IN UNACTIVATED T 

1027
00:50:58,960 --> 00:50:59,280
CELLS. 

1028
00:50:59,280 --> 00:51:03,160
WE SAW WE HAD EQUAL LEVELS OF G 

1029
00:51:03,160 --> 00:51:05,480
RECOMBINATION IN RESTING T CELLS

1030
00:51:05,480 --> 00:51:09,680
THAT IS CRITICAL FOR ANY HIV 

1031
00:51:09,680 --> 00:51:11,200
LATENCY THERAPEUTICS THAT SHOWS 

1032
00:51:11,200 --> 00:51:16,080
THAT LNPS CAN TARGET RESTING T 

1033
00:51:16,080 --> 00:51:21,560
CELLS AND MEDIATE ACTIVITY. 

1034
00:51:21,560 --> 00:51:23,640
OUR CONCLUSIONS WERE WE FIGURED 

1035
00:51:23,640 --> 00:51:28,680
OUT HOW TO TARGET OTHER CELLS 

1036
00:51:28,680 --> 00:51:31,560
PART OF TARGETING REDUCED LIVER 

1037
00:51:31,560 --> 00:51:33,640
UPTAKE AND INCREASED SPECIFIC 

1038
00:51:33,640 --> 00:51:37,480
UPTAKE IN CELLS AND TISSUES OF 

1039
00:51:37,480 --> 00:51:40,800
INTEREST.  YOU CAN USE TO 

1040
00:51:40,800 --> 00:51:44,000
DELIVER THERAPEUTIC PROTEINS TO 

1041
00:51:44,000 --> 00:51:47,280
GENE EDITING TECHNOLOGIES AND 

1042
00:51:47,280 --> 00:51:51,040
WHATEVER YOU WANT. 

1043
00:51:51,040 --> 00:51:53,440
COMING FROM PEN, PEN HAS A LOT 

1044
00:51:53,440 --> 00:51:56,520
OF NOTABLE THINGS AND TWO OF 

1045
00:51:56,520 --> 00:51:59,120
THEM ARE RECLINICALLY DEVELOPED 

1046
00:51:59,120 --> 00:52:04,200
FIRST CAR T CELLS AND FIRST 2FDA

1047
00:52:04,200 --> 00:52:06,600
APPROVED T CELL CAR T THERAPIES 

1048
00:52:06,600 --> 00:52:11,000
THAT CAME OUT OF PEN WORK.  WE 

1049
00:52:11,000 --> 00:52:19,040
ALSO DEVELOPED THE FIRST FDA 

1050
00:52:19,040 --> 00:52:20,240
APPROVED GENE THERAPY FOR 

1051
00:52:20,240 --> 00:52:22,800
BLINDNESS. 

1052
00:52:22,800 --> 00:52:25,720
SO, OUR IDEA WAS COULD WE 

1053
00:52:25,720 --> 00:52:29,560
DELIVER RNA'S THAT MODULATE T 

1054
00:52:29,560 --> 00:52:30,400
CELL FUNCTION?  

1055
00:52:30,400 --> 00:52:33,200
IN THIS CASE, IT WAS CAR T 

1056
00:52:33,200 --> 00:52:33,600
CELLS. 

1057
00:52:33,600 --> 00:52:35,920
SO, I'M SURE THAT YOU GUYS KNOW 

1058
00:52:35,920 --> 00:52:38,120
WHAT CAR T CELLS ARE.  I WILL 

1059
00:52:38,120 --> 00:52:41,160
QUICKLY GO OVER IT.  WAYS THAT A

1060
00:52:41,160 --> 00:52:44,240
T CELL RECOGNIZES A TUMOR OR 

1061
00:52:44,240 --> 00:52:48,200
INFECTED CELL IS IT SEES A 

1062
00:52:48,200 --> 00:52:50,360
PEPTIDE IN ASSOCIATION WITH MHC 

1063
00:52:50,360 --> 00:52:54,480
ON A T CELL RECEPTOR WITH 

1064
00:52:54,480 --> 00:52:55,360
SIGNALING [INDISCERNIBLE] THAT 

1065
00:52:55,360 --> 00:52:57,720
ACTIVATE THE T CELL.  WHAT A CAR

1066
00:52:57,720 --> 00:53:00,080
DOES IS IT REPLACES THE EXTERNAL

1067
00:53:00,080 --> 00:53:03,720
REGION WITH A SINGLE-CHAIN ANTI 

1068
00:53:03,720 --> 00:53:05,680
BODY OR OTHER ANTI BODIES THAT 

1069
00:53:05,680 --> 00:53:09,360
BIND A TUMOR-ASSOCIATED OR 

1070
00:53:09,360 --> 00:53:11,400
TUMOR-SPECIFIC ANTIGEN AND FIRST

1071
00:53:11,400 --> 00:53:13,640
DEVELOPED BOUND CD19 THAT WERE 

1072
00:53:13,640 --> 00:53:17,480
USE THE FOR B CELL LYMPHOMAS AND

1073
00:53:17,480 --> 00:53:20,200
LEUKEMIAS THAT ARE INCREDIBLY 

1074
00:53:20,200 --> 00:53:23,400
SUCCESSFUL WITH CURE RATES IN 70

1075
00:53:23,400 --> 00:53:27,600
TO 80% RANGE WITH CAR T 

1076
00:53:27,600 --> 00:53:28,480
THERAPIES. 

1077
00:53:28,480 --> 00:53:30,960
PROBLEM IS MAKING CAR TS. 

1078
00:53:30,960 --> 00:53:35,160
TO MAKE A CAR T, YOU HAVE TO 

1079
00:53:35,160 --> 00:53:37,680
FIRST LUCHO FORRESE THE PATIENT 

1080
00:53:37,680 --> 00:53:39,400
MEANING PUTTING THEM ON A 

1081
00:53:39,400 --> 00:53:41,040
MACHINE FOR A COUPLE HOURS 

1082
00:53:41,040 --> 00:53:43,800
TAKING OUT A FEW BILLION T CELLS

1083
00:53:43,800 --> 00:53:46,520
AND YOU INFECT T CELLS WITH A 

1084
00:53:46,520 --> 00:53:48,880
LENGTHY VIRUS THAT DELIVERS THE 

1085
00:53:48,880 --> 00:53:51,200
CAR GENE AND YOU EXPAND THOSE T 

1086
00:53:51,200 --> 00:53:54,720
CELLS FOR 10 + DAYS TO MAKE 

1087
00:53:54,720 --> 00:53:56,960
TRILLIONS OF CELLS THAT YOU GIVE

1088
00:53:56,960 --> 00:53:59,440
BACK TO THE PATIENT. 

1089
00:53:59,440 --> 00:54:03,760
THE TWO FDA APPROVED CD19 DRUGS 

1090
00:54:03,760 --> 00:54:07,640
COST I THINK AROUND $450,000 A 

1091
00:54:07,640 --> 00:54:08,800
DOSE. 

1092
00:54:08,800 --> 00:54:12,480
THIS IS TWO WEEKS OF GMP CELL 

1093
00:54:12,480 --> 00:54:13,800
CULTURE FACILITY WORK. 

1094
00:54:13,800 --> 00:54:19,280
THERE THEY ARE LIMITED WHERE IT 

1095
00:54:19,280 --> 00:54:23,920
IS GIVEN MAINLY US AND WESTERN 

1096
00:54:23,920 --> 00:54:26,880
EUROPE AND THERE IS ONE SITE IN 

1097
00:54:26,880 --> 00:54:29,160
CHINA BUT REST OF THE WORLD HAS 

1098
00:54:29,160 --> 00:54:31,440
NO ACCESS TO CAR T CELLS. 

1099
00:54:31,440 --> 00:54:36,400
OUR IDEA WAS COULD WE TARGET CAR

1100
00:54:36,400 --> 00:54:41,160
T CELLS WITH LNPS DELIVERING AN 

1101
00:54:41,160 --> 00:54:44,360
MRNA THAT CODED CAR MOLECULE AND

1102
00:54:44,360 --> 00:54:47,840
PRODUCE CAR PROTEINS T CELL 

1103
00:54:47,840 --> 00:54:49,320
WOULD EXPRESS AND TARGET 

1104
00:54:49,320 --> 00:54:51,200
WHATEVER CAR BOUND.  WE STARTED 

1105
00:54:51,200 --> 00:54:53,120
WITH CAR CALLED AGAINST -- A 

1106
00:54:53,120 --> 00:54:55,680
PROTEIN CALLED FAP THAT IS 

1107
00:54:55,680 --> 00:54:58,480
EXPRESSED BY ACTIVATED 

1108
00:54:58,480 --> 00:55:01,560
FIBERGLASS USED IN VARIETY OF 

1109
00:55:01,560 --> 00:55:04,280
CANCER THERAPIES AND FOR 

1110
00:55:04,280 --> 00:55:04,520
FIBROSIS. 

1111
00:55:04,520 --> 00:55:09,040
WE ALSO CHOSE CD5 FOR TARGETING 

1112
00:55:09,040 --> 00:55:11,360
WHICH IS A SCAVENGER RECEPTOR ON

1113
00:55:11,360 --> 00:55:15,640
T CELLS MEANING IT IS ENDOCITE 

1114
00:55:15,640 --> 00:55:17,400
OESED AFTER BINDING. 

1115
00:55:17,400 --> 00:55:21,520
SO, WE TESTED THIS AND MADE CD5 

1116
00:55:21,520 --> 00:55:25,640
TARGETED LNPS DELIVERING P

1117
00:55:25,640 --> 00:55:28,240
PREECOMBINATES TO LOXENE MICE 

1118
00:55:28,240 --> 00:55:32,680
AND SAW 80% OF CD4S AND CD8S 

1119
00:55:32,680 --> 00:55:34,040
WERE GENE MODIFIED AFTER A 

1120
00:55:34,040 --> 00:55:36,360
SINGLE TREATMENT AND WE COULD 

1121
00:55:36,360 --> 00:55:38,520
EFFECTIVELY DELIVER TO T CELLS 

1122
00:55:38,520 --> 00:55:41,560
IN TISSUES AND SPLEEN AND LYMPH 

1123
00:55:41,560 --> 00:55:44,360
NODES AND WE COLLABORATED WITH A

1124
00:55:44,360 --> 00:55:46,480
CARDIOLOGIST WHO HAD A FIBROSIS 

1125
00:55:46,480 --> 00:55:49,520
MODEL AND WHAT THEY DID WAS TOOK

1126
00:55:49,520 --> 00:55:51,680
PUMPS AND PUT HYPERTENSIVE 

1127
00:55:51,680 --> 00:55:54,520
AGENTS IN THE PUMPS.  THEY MADE 

1128
00:55:54,520 --> 00:55:57,240
THE MICE HYPERTENSIVE.  WHEN YOU

1129
00:55:57,240 --> 00:55:59,960
DO THAT, HEART IS FIBR ROWS. 

1130
00:55:59,960 --> 00:56:02,320
THE WAY THAT YOU MEASURE 

1131
00:56:02,320 --> 00:56:05,440
FIBROSIS IS AN ECHO CARDIOGRAM 

1132
00:56:05,440 --> 00:56:07,800
THAT TAKES PICTURES OF THE HEART

1133
00:56:07,800 --> 00:56:09,520
AND HEART WALL FIBROSIS DOESN'T 

1134
00:56:09,520 --> 00:56:12,480
MOVE AS WELL.  IT IS STIFF.  

1135
00:56:12,480 --> 00:56:13,800
VOLUMES OF THE HEART INCREASE 

1136
00:56:13,800 --> 00:56:15,440
AND WHAT WE ARE MEASURING HERE 

1137
00:56:15,440 --> 00:56:18,160
AND THIS IS AFTER BEATING AND 

1138
00:56:18,160 --> 00:56:20,040
BEFORE BEATING THE SIZE OR 

1139
00:56:20,040 --> 00:56:21,680
VOLUME OF THE HEART.  THEY ARE 

1140
00:56:21,680 --> 00:56:23,320
MUCH HIGHER AND HEART IS STIFF 

1141
00:56:23,320 --> 00:56:26,800
AND IT CAN'T MOVE.  THIS IS THE 

1142
00:56:26,800 --> 00:56:28,000
INJECTION FRACTION THAT IS HOW 

1143
00:56:28,000 --> 00:56:29,880
MUCH BLOOD DOES THE HEART FORCE 

1144
00:56:29,880 --> 00:56:31,520
OUT WITH EACH BEEP.  WHEN THE 

1145
00:56:31,520 --> 00:56:35,800
HEART IS STIFF, IT CAN'T PUMP 

1146
00:56:35,800 --> 00:56:38,160
BLOOD OUT AND INJECTION FRACTION

1147
00:56:38,160 --> 00:56:39,040
DROPS. 

1148
00:56:39,040 --> 00:56:43,120
GRAY, IT IS UNTREATED ANIMALS.  

1149
00:56:43,120 --> 00:56:47,400
THIS IS NORMAL.  YELLOW IS 

1150
00:56:47,400 --> 00:56:48,920
HYPERTENSIVE MICE AND RED 

1151
00:56:48,920 --> 00:56:51,320
TREATED HYPERTENSIVE MICE WITH 

1152
00:56:51,320 --> 00:56:52,920
SINGLE TREATMENT OF T CELL 

1153
00:56:52,920 --> 00:56:59,040
TARGETED RNA-LNPS ENCODING FAT 

1154
00:56:59,040 --> 00:57:01,400
CAR.  ECHOCARDIO GRAPHIC 

1155
00:57:01,400 --> 00:57:04,920
MEASURES HEART FUNCTION RETURNS 

1156
00:57:04,920 --> 00:57:08,400
TO NORMAL WE TOOK HEARTS OUT 

1157
00:57:08,400 --> 00:57:10,160
STAINING THEM FIBROSIS IN RED 

1158
00:57:10,160 --> 00:57:13,520
AND CONTROL ANIMALS HAVE MINIMAL

1159
00:57:13,520 --> 00:57:17,480
AND HYPERTENSIVE HUGE AMOUNTS OF

1160
00:57:17,480 --> 00:57:22,600
FIBROSIS IN MIOCARD YUM.  SINGLE

1161
00:57:22,600 --> 00:57:24,440
TREATMENT FIBROSIS IS RETURNING 

1162
00:57:24,440 --> 00:57:27,000
TO NORMAL.  OFF THE SHELF LNP WE

1163
00:57:27,000 --> 00:57:29,200
CAN DELIVER A CAR T TO AN ANIMAL

1164
00:57:29,200 --> 00:57:35,080
AND HAVE A THERAPEUTIC OUTCOME 

1165
00:57:35,080 --> 00:57:37,080
IN THEORY THIS MAKES CAR TS 

1166
00:57:37,080 --> 00:57:38,840
AVAILABLE TO THE ENTIRE WORLD 

1167
00:57:38,840 --> 00:57:42,800
AND TREATING CD19 LEUKEMIA 

1168
00:57:42,800 --> 00:57:44,680
HEALTH SYSTEM SAYS A HALF A 

1169
00:57:44,680 --> 00:57:47,320
MILLION IS NOT A HIGH PRICE 

1170
00:57:47,320 --> 00:57:48,960
COMPARED TO COST OF TREATING 

1171
00:57:48,960 --> 00:57:53,080
THAT PATIENT.  IF TREATING H 

1172
00:57:53,080 --> 00:57:54,840
ICHHIV 

1173
00:57:54,840 --> 00:57:57,920
YOU CAN'T DO EX-VIVO THERAPY IN 

1174
00:57:57,920 --> 00:58:00,440
AFRICA TO CURE HIV OR IN ANY 

1175
00:58:00,440 --> 00:58:03,200
OTHER PARTS OF THE WORLD AND 

1176
00:58:03,200 --> 00:58:06,040
WITH OFF THE SHELF FROZEN LNP 

1177
00:58:06,040 --> 00:58:07,920
YOU INJECT INTO THE PERSON, YOU 

1178
00:58:07,920 --> 00:58:09,960
CAN DO THAT MOVING THIS FORWARD 

1179
00:58:09,960 --> 00:58:18,520
PART OF HIV CURE STRATEGY AS AN 

1180
00:58:18,520 --> 00:58:21,400
IMMUNOLOGIST I WAS INTERESTED IN

1181
00:58:21,400 --> 00:58:24,280
BONE BARROW STEM CELLS AND 

1182
00:58:24,280 --> 00:58:26,200
THOUSANDS OF GENETIC DISORDERS 

1183
00:58:26,200 --> 00:58:28,480
OF BONE MARROW STEM CELLS.  NO. 

1184
00:58:28,480 --> 00:58:32,760
1 ON THE LIST IS SICKLE CELL 

1185
00:58:32,760 --> 00:58:34,560
ANEMIA.  IN SICKLE CELL 300,000 

1186
00:58:34,560 --> 00:58:36,080
PEOPLE A YEAR ARE BORN WITH THE 

1187
00:58:36,080 --> 00:58:39,720
DISEASE THAT ARE MAINLY IN SUBIS

1188
00:58:39,720 --> 00:58:42,080
A HARRANT AFRICA BUT ARE 

1189
00:58:42,080 --> 00:58:44,160
SCATTERED THROUGHOUT THE WORLD 

1190
00:58:44,160 --> 00:58:47,280
AND THERE ARE GENE THERAPIES 

1191
00:58:47,280 --> 00:58:47,960
BEING DEVELOPED FOR SICKLE CELL 

1192
00:58:47,960 --> 00:58:50,080
THAT INVOLVE TAKING LOTS OF BONE

1193
00:58:50,080 --> 00:58:53,880
MARROW OUT OF A PATIENT 

1194
00:58:53,880 --> 00:58:55,400
INFECTING THEM WITH LENGTHY 

1195
00:58:55,400 --> 00:58:58,920
VIRUS TO FIX THE GENE AND GIVING

1196
00:58:58,920 --> 00:59:00,960
BACKBONE MARROW IS PROBABLY A 

1197
00:59:00,960 --> 00:59:05,400
MILLION A SHOT.  YOU CAN'T TREAT

1198
00:59:05,400 --> 00:59:07,960
300,000 PEOPLE IN AFRICA WITH 

1199
00:59:07,960 --> 00:59:09,640
THAT KIND OF TECHNOLOGY THAT IS 

1200
00:59:09,640 --> 00:59:15,800
NOT AVAILABLE AT A MILLION A 

1201
00:59:15,800 --> 00:59:22,480
SHOT OUR IDEA WAS TARGETING BONE

1202
00:59:22,480 --> 00:59:25,680
STEM CELLS IN VIVO -- WE COULD 

1203
00:59:25,680 --> 00:59:27,120
CURE SICKLE CELL WITH SIMPLE 

1204
00:59:27,120 --> 00:59:31,320
INJECTION OF RNA-LNPS AT A COST 

1205
00:59:31,320 --> 00:59:34,240
OF I DON'T KNOW A COUPLE HUNDRED

1206
00:59:34,240 --> 00:59:36,200
DOLLARS PER AND EASY TO DELIVER 

1207
00:59:36,200 --> 00:59:39,560
IT.  FIRST THING, WE HAD TO 

1208
00:59:39,560 --> 00:59:41,160
TARGET BONE MARROW STEM CELLS 

1209
00:59:41,160 --> 00:59:44,360
AND THERE ARE VERY FEW OF ANY 

1210
00:59:44,360 --> 00:59:46,400
MARKERS THAT IDENTIFY 

1211
00:59:46,400 --> 00:59:49,680
EPOPULATING BONE MARROW STEM 

1212
00:59:49,680 --> 00:59:56,240
CELLS WE STARTED WITH CD117 OR 

1213
00:59:56,240 --> 00:59:58,120
EXPRESS KIT AND THEY HAVE STEM 

1214
00:59:58,120 --> 01:00:00,720
CELLS AND MANY PROGENITORS AND 

1215
01:00:00,720 --> 01:00:06,080
VARIETY OF TISSUES AND GAVE MICE

1216
01:00:06,080 --> 01:00:12,760
A SINGLE TREATMENT 85% OF 

1217
01:00:12,760 --> 01:00:14,560
LINEAGE NEGATIVE BONE MARROW 

1218
01:00:14,560 --> 01:00:17,440
CELLS WERE GENE MODIFIED.  WE 

1219
01:00:17,440 --> 01:00:18,880
FOLLOWED MICE FOR SIX MONTHS AND

1220
01:00:18,880 --> 01:00:24,040
THEIR NUMBERS DIDN'T DROP.  WE 

1221
01:00:24,040 --> 01:00:28,080
THEN DID A SECONDARY TRANSPLANT.

1222
01:00:28,080 --> 01:00:30,480
THAT INVOLVES TAKING BONE MARROW

1223
01:00:30,480 --> 01:00:32,160
FROM TREATED MICE AND PUTTING 

1224
01:00:32,160 --> 01:00:35,360
THEM INTO A RADIATED RECIPIENT 

1225
01:00:35,360 --> 01:00:37,680
MICE AND YOU ASK WHAT DO THE 

1226
01:00:37,680 --> 01:00:39,160
BONE MARROW STEM CELLS OR 

1227
01:00:39,160 --> 01:00:44,120
PRODUCT CELLS LOOK LIKE?  

1228
01:00:44,120 --> 01:00:47,120
100% OF RED CELLS AND WHITE 

1229
01:00:47,120 --> 01:00:50,440
CELLS AND GRANULOCYTES WERE GENE

1230
01:00:50,440 --> 01:00:53,920
MODIFIED IN SECONDARY 

1231
01:00:53,920 --> 01:00:55,840
TRANSPLANTS AND WHAT IT MEANS IS

1232
01:00:55,840 --> 01:00:59,560
WE GENE MODIFIED 100% OF 

1233
01:00:59,560 --> 01:01:02,720
REPOPULATING BONE MARROW STEM 

1234
01:01:02,720 --> 01:01:11,640
CELLS WITH .1 MICROGRAMS THAT IS

1235
01:01:11,640 --> 01:01:15,000
.005MGS PER GIG.  VERY LOW DOSE 

1236
01:01:15,000 --> 01:01:15,920
TAKING TECHNOLOGY FORWARD 

1237
01:01:15,920 --> 01:01:19,320
DEVELOPING VARIETY OF GENE 

1238
01:01:19,320 --> 01:01:20,840
EDITING APPROACHES TO ADDRESS 

1239
01:01:20,840 --> 01:01:24,640
SICKLE CELL AND IS A BC11A 

1240
01:01:24,640 --> 01:01:27,440
LOCUST THAT TURNS ON FETAL 

1241
01:01:27,440 --> 01:01:29,600
HEMOGLOBIN THAT YOU CAN ALSO USE

1242
01:01:29,600 --> 01:01:34,600
PRIME EDITORS TO FIX BETA 

1243
01:01:34,600 --> 01:01:36,520
HEMOGLOBIN GENETIC MUTATIONS AND

1244
01:01:36,520 --> 01:01:38,160
ALL THAT IS TAKEN FORWARD WITH 

1245
01:01:38,160 --> 01:01:40,800
THE PLAN OF DOING CLINICAL 

1246
01:01:40,800 --> 01:01:42,480
TRIALS TO TREAT SICKLE CELL.  

1247
01:01:42,480 --> 01:01:45,400
THAT HAS EASY EXPANSION TO 

1248
01:01:45,400 --> 01:01:47,880
THOUSANDS OF OTHER BONE MARROW 

1249
01:01:47,880 --> 01:01:49,080
GENETIC DISEASES THAT I 

1250
01:01:49,080 --> 01:01:52,600
MENTIONED EARLIER THAT THEY HAVE

1251
01:01:52,600 --> 01:02:01,000
ALREADY USE RNA-LNPS.  WITH 

1252
01:02:01,000 --> 01:02:05,600
INCREASED TARGETING WE CAN TREAT

1253
01:02:05,600 --> 01:02:07,680
MORE DISEASES WITH GENE 

1254
01:02:07,680 --> 01:02:10,000
TECHNOLOGY.  POTENTIAL FOR LNP 

1255
01:02:10,000 --> 01:02:13,960
TECHNOLOGY IS ENORMOUS AND SPANS

1256
01:02:13,960 --> 01:02:17,680
JUST ABOUT EVERY DISEASE AND 

1257
01:02:17,680 --> 01:02:19,320
EVERY THERAPEUTIC POTENTIAL. 

1258
01:02:19,320 --> 01:02:21,240
SO, WHAT WE HAVE DEVELOPED IS A 

1259
01:02:21,240 --> 01:02:24,360
WAY TO HIGHLY EFFICIENTLY GENE 

1260
01:02:24,360 --> 01:02:27,160
EDIT CELLS IN VIVO WITH THE HOPE

1261
01:02:27,160 --> 01:02:31,840
OF MOVING THAT FORWARD BOTH FOR 

1262
01:02:31,840 --> 01:02:33,320
THERAPEUTIC APPLICATIONS 

1263
01:02:33,320 --> 01:02:34,200
DELIVERING THERAPEUTIC PROTEINS 

1264
01:02:34,200 --> 01:02:39,080
AND CELLS OF INTEREST OR GENE 

1265
01:02:39,080 --> 01:02:39,840
EDITING TECHNOLOGY.  

1266
01:02:39,840 --> 01:02:43,920
WE STARTED THE PROCESS OF 

1267
01:02:43,920 --> 01:02:45,800
DELIVERING THE BRAIN.  WE NEED A

1268
01:02:45,800 --> 01:02:48,040
LOT MORE WORK TO DO THAT 

1269
01:02:48,040 --> 01:02:49,760
EFFECTIVELY.  WHEN YOU CROSS THE

1270
01:02:49,760 --> 01:02:51,520
BLOOD BRAIN BARRIER, NOW YOU 

1271
01:02:51,520 --> 01:02:55,360
HAVE TO TARGET PLAQUES OR TARGET

1272
01:02:55,360 --> 01:02:58,200
DOPAMINERGIC CELLS OR OTHER 

1273
01:02:58,200 --> 01:03:00,360
REGIONS OF THE BRAIN AND WE ARE 

1274
01:03:00,360 --> 01:03:01,680
WORKING ON THAT AND THINK IN THE

1275
01:03:01,680 --> 01:03:04,840
NEAR FUTURE THAT WE CAN TREAT A 

1276
01:03:04,840 --> 01:03:07,800
VARIETY OF NEURODEGENERATIVE 

1277
01:03:07,800 --> 01:03:09,320
DISORDERS IN THE BRAIN. 

1278
01:03:09,320 --> 01:03:10,560
AND LET'S SEE.  

1279
01:03:10,560 --> 01:03:15,840
I THINK I WILL STOP THERE.  I 

1280
01:03:15,840 --> 01:03:17,160
USUALLY LIKE TO GIVE A QUICK 

1281
01:03:17,160 --> 01:03:19,880
TALK ON EQUITY.  WE DON'T HAVE 

1282
01:03:19,880 --> 01:03:21,440
TIME.  I NEED TO THANK ALL OF 

1283
01:03:21,440 --> 01:03:23,600
THE PEOPLE IN MY LAB AND ALL 

1284
01:03:23,600 --> 01:03:25,560
LABS THAT WE COLLABORATE THAT 

1285
01:03:25,560 --> 01:03:32,680
HAVE DONE THIS WORK.  THANK YOU.

1286
01:03:32,680 --> 01:03:35,120
>>[APPLAUSE]. 

1287
01:03:35,120 --> 01:03:45,240
>>IF THERE ARE ANY
QUESTIONS, 

1288
01:03:45,240 --> 01:03:46,600
PLEASE COME UP TO THE MIC. 

1289
01:03:46,600 --> 01:03:49,600
>>YOU THOUGHT ABOUT
OBVIOUSLY 

1290
01:03:49,600 --> 01:03:52,400
SHOWED YOU CAN TARGET CELLS.  

1291
01:03:52,400 --> 01:03:55,320
CAN YOU THINK ABOUT POSSIBLY 

1292
01:03:55,320 --> 01:03:57,520
TARGETING VIRUSES OR VIRUS 

1293
01:03:57,520 --> 01:03:59,920
SEQUENCE INSIDE OF CELLS.  CAN 

1294
01:03:59,920 --> 01:04:02,400
YOU ERADICATE VIRUSES FROM THE 

1295
01:04:02,400 --> 01:04:02,840
GENOME?  

1296
01:04:02,840 --> 01:04:05,640
>>WE ARE TRYING WITH HIV.
WHAT

1297
01:04:05,640 --> 01:04:08,400
WE ARE ABLE TO TARGET RESTING 

1298
01:04:08,400 --> 01:04:11,240
CD4 CELLS AND WE ARE DELIVERING 

1299
01:04:11,240 --> 01:04:16,040
-- THERE IS AN ENZYME KNOWN AS 

1300
01:04:16,040 --> 01:04:21,400
BREK1 THAT IS A PRERECOMBINACE 

1301
01:04:21,400 --> 01:04:24,320
PROGRAM FOR RLT SEQUENCES AND 

1302
01:04:24,320 --> 01:04:27,840
DELIVERED CAS9 THAT PEOPLE FROM 

1303
01:04:27,840 --> 01:04:30,440
PHILADELPHIA HAD DEVELOPED AS A 

1304
01:04:30,440 --> 01:04:33,440
WAY OF INACTIVATING HIV AND WE 

1305
01:04:33,440 --> 01:04:35,520
ARE LOOKING AT IT AS PART OF A 

1306
01:04:35,520 --> 01:04:37,760
CURE STRATEGY AND THE PROBLEM IS

1307
01:04:37,760 --> 01:04:40,640
THAT AROUND 1 IN A MILLION 

1308
01:04:40,640 --> 01:04:45,200
RESTING T CELLS HAVE LIVE 

1309
01:04:45,200 --> 01:04:45,920
REPLICATION COMPETENT VIRUS IN 

1310
01:04:45,920 --> 01:04:48,880
IT MEANING YOU HAVE TO HAVE AN 

1311
01:04:48,880 --> 01:04:52,560
EFFICIENCY IN THE 99.99999 

1312
01:04:52,560 --> 01:04:52,840
RANGE. 

1313
01:04:52,840 --> 01:04:54,880
I DON'T THINK WE WILL EVER GET 

1314
01:04:54,880 --> 01:04:58,720
THAT HIGH WITH LNP DELIVERY. 

1315
01:04:58,720 --> 01:05:01,080
IF IF WE COMBINE IT WITH HIV 

1316
01:05:01,080 --> 01:05:04,480
CARS AND DELIVERY OF BNABS AND 

1317
01:05:04,480 --> 01:05:08,800
OTHER HIV THERAPIES, WE MIGHT BE

1318
01:05:08,800 --> 01:05:11,960
ABLE TO CURE OR TO MAKE PATIENTS

1319
01:05:11,960 --> 01:05:22,400
NOT REQUIRE ART THERAPY.  

1320
01:05:24,840 --> 01:05:29,680
>>FOR STEM CELL THERAPY
RNASE 

1321
01:05:29,680 --> 01:05:33,160
COULD MAINTAIN FOR A LONG TIME. 

1322
01:05:33,160 --> 01:05:36,160
AT EVERY SINGLE PROGENITOR CELLS

1323
01:05:36,160 --> 01:05:38,240
AND HOW THAT CAN BE ACHIEVED.  

1324
01:05:38,240 --> 01:05:41,000
IF THAT MEANS IT HAS BEEN 

1325
01:05:41,000 --> 01:05:42,080
INTEGRATED INTO DNA?  

1326
01:05:42,080 --> 01:05:44,880
>>NO.  SO, WE ARE -- RNA 

1327
01:05:44,880 --> 01:05:47,560
DOESN'T LAST VERY LONG IN A 

1328
01:05:47,560 --> 01:05:47,960
CELL. 

1329
01:05:47,960 --> 01:05:51,200
MAYBE 24 TO 36 HOURS BUT WE 

1330
01:05:51,200 --> 01:05:54,680
ENCODE GENE EDITING AND CAS9 AND

1331
01:05:54,680 --> 01:05:57,640
OTHER GENE EDITING TECHNOLOGIES 

1332
01:05:57,640 --> 01:06:02,560
IN THE RNA THAT CHANGE DNA AND 

1333
01:06:02,560 --> 01:06:03,840
AFFIX GENETIC DEFECTS. 

1334
01:06:03,840 --> 01:06:05,680
>>OKAY.  THAT PHENOTYPE? 

1335
01:06:05,680 --> 01:06:08,600
>>YEAH.  THE RNA ENCODES 

1336
01:06:08,600 --> 01:06:11,760
ENZYMES THAT FIX DNA SCOMBL 

1337
01:06:11,760 --> 01:06:11,960
OKAY. 

1338
01:06:11,960 --> 01:06:15,120
>>RNA DOES NOT EFFECT.  I
SAY 

1339
01:06:15,120 --> 01:06:17,040
THIS BECAUSE I -- YOU KNOW, 

1340
01:06:17,040 --> 01:06:18,800
CRAZY PEOPLE ON THE INTERNET SAY

1341
01:06:18,800 --> 01:06:21,680
THAT RNA CHANGES THEIR GENOME 

1342
01:06:21,680 --> 01:06:23,880
AND MAKES YOU INFERTILE AND 

1343
01:06:23,880 --> 01:06:26,320
GIVES YOU CANCER AND MAKES YOU 

1344
01:06:26,320 --> 01:06:27,720
MAGNETIC.  I HAVE HEARD THEM 

1345
01:06:27,720 --> 01:06:31,040
ALL.  RNA DOES NOT CHANGE DNA 

1346
01:06:31,040 --> 01:06:33,520
AND DOESN'T GO INTO THE NUCLEUS.

1347
01:06:33,520 --> 01:06:36,240
IT CANNOT CHANGE OR CANNOT 

1348
01:06:36,240 --> 01:06:36,680
INTEGRATE. 

1349
01:06:36,680 --> 01:06:39,840
>>JUST A FOLLOW-UP
QUESTION 

1350
01:06:39,840 --> 01:06:41,440
FROM SOME OF THE DISCUSSION. 

1351
01:06:41,440 --> 01:06:45,680
YOU MENTIONED TARGETING OF CD4 

1352
01:06:45,680 --> 01:06:47,800
POSITIVE T CELLS. 

1353
01:06:47,800 --> 01:06:50,280
AND THAT YOU WOULD GET TO 

1354
01:06:50,280 --> 01:06:53,720
EFFICIENCY OF 99.999%.  WHAT IS 

1355
01:06:53,720 --> 01:06:57,640
CURRENT EFFICIENCY OF DELIVERY 

1356
01:06:57,640 --> 01:07:02,400
TO C4 CELLS IN VIVO IN YOUR 

1357
01:07:02,400 --> 01:07:04,120
EXPERIMENTS?  WE HAVE SEEN SO 

1358
01:07:04,120 --> 01:07:06,440
FAR IN MICE THAT THERE IS ABOUT 

1359
01:07:06,440 --> 01:07:10,600
80% GENE EDITING WITH A SINGLE 

1360
01:07:10,600 --> 01:07:13,200
TREATMENTWE HAVE SEEN SO FAR INT

1361
01:07:13,200 --> 01:07:13,840
THERE IS ABOUT 80% GENE EDITING 

1362
01:07:13,840 --> 01:07:14,840
WITH A SINGLE TREATMENT>WE
HAVE 

1363
01:07:14,840 --> 01:07:15,440
THAT THERE IS ABOUT 80% GENE 

1364
01:07:15,440 --> 01:07:16,560
EDITING WITH A SINGLE TREATMENT 

1365
01:07:16,560 --> 01:07:17,160
THAT THERE IS ABOUT 80% GENE 

1366
01:07:17,160 --> 01:07:18,320
EDITING WITH A SINGLE TREATMENT 

1367
01:07:18,320 --> 01:07:18,920
THAT THERE IS ABOUT 80% GENE 

1368
01:07:18,920 --> 01:07:19,560
EDITING WITH A SINGLE TREATMENT.

1369
01:07:19,560 --> 01:07:20,160
THE ADVANTAGE WITH 4 OR 5 

1370
01:07:20,160 --> 01:07:20,840
VACCINE TREATMENTS IS YOU CAN 

1371
01:07:20,840 --> 01:07:23,120
REPEAT TREATMENTS.  IN THEORY, 

1372
01:07:23,120 --> 01:07:25,480
WE CAN TREAT PEOPLE WEEKLY FOR 

1373
01:07:25,480 --> 01:07:27,040
HOWEVER LONG WE NEED TO, TO GET 

1374
01:07:27,040 --> 01:07:29,560
THAT EFFICIENCY UP AND DON'T 

1375
01:07:29,560 --> 01:07:31,600
THINK WE WILL EVER GET TO THAT 

1376
01:07:31,600 --> 01:07:34,320
NEEDED TO GET TO 1 OVER A 

1377
01:07:34,320 --> 01:07:36,400
MILLION EFFECTORATE CELLS BUT WE

1378
01:07:36,400 --> 01:07:37,200
CAN GET VERY HIGH. 

1379
01:07:37,200 --> 01:07:40,640
>>RIGHT.  IN TERMS OF
GENE 

1380
01:07:40,640 --> 01:07:43,320
EDITING, IT MIGHT BE POSSIBLE TO

1381
01:07:43,320 --> 01:07:46,880
TARGET THE VAST MAJORITY OF CD4 

1382
01:07:46,880 --> 01:07:49,640
POSITIVE T CELLS AND EDIT THEM 

1383
01:07:49,640 --> 01:07:51,800
FOR SOME OTHER GENE MAYBE NOT 

1384
01:07:51,800 --> 01:07:53,400
PROFILE SEQUENCES BUT FOR OTHER 

1385
01:07:53,400 --> 01:07:53,640
GENES. 

1386
01:07:53,640 --> 01:07:55,520
>>WE ARE ACTUALLY LOOKING
AT 

1387
01:07:55,520 --> 01:07:57,240
BONE MARROW STEM CELLS TO DO 

1388
01:07:57,240 --> 01:07:59,840
THAT FOR KNOCKING OUT CCR5. 

1389
01:07:59,840 --> 01:08:02,120
>>YEAH. 

1390
01:08:02,120 --> 01:08:06,560
>>OR INSERT IING AN HIV
GENE 

1391
01:08:06,560 --> 01:08:08,400
INTO.  PROBLEM WITH THAT AND T 

1392
01:08:08,400 --> 01:08:11,040
CELLS IS THEY ARE MOSTLY TERMIN 

1393
01:08:11,040 --> 01:08:13,960
ALLEY OR CLOSE TO TERMIN ALLEY 

1394
01:08:13,960 --> 01:08:14,320
DIFFERENTIATED. 

1395
01:08:14,320 --> 01:08:19,480
THEY ARE CONSTANTLY REPLACED.  

1396
01:08:19,480 --> 01:08:21,480
STEM CELLS WILL BE BETTER FOR 

1397
01:08:21,480 --> 01:08:21,680
THAT. 

1398
01:08:21,680 --> 01:08:23,560
>>I AGREE.  THANK YOU. 
THANK 

1399
01:08:23,560 --> 01:08:27,520
YOU FOR AN INSPIRING TALK. 

1400
01:08:27,520 --> 01:08:30,000
>>THANK YOU.  

1401
01:08:30,000 --> 01:08:35,000
>>THANK YOU VERY MUCH.  

1402
01:08:35,000 --> 01:08:37,600
>>[APPLAUSE]. 

1403
01:08:37,600 --> 01:09:08,760
>>I WILL INTRODUCE
CO-CHAIR FOR

1404
01:09:08,760 --> 01:09:10,760
>>GOOD MORNING AND
WELCOME TO 

1405
01:09:10,760 --> 01:09:13,960
THE SESSION AND I'M A SCIENTIST 

1406
01:09:13,960 --> 01:09:17,600
IN THE HIV [INDISCERNIBLE] AND 

1407
01:09:17,600 --> 01:09:20,200
FIRST SPEAKER IS [INDISCERNIBLE]

1408
01:09:20,200 --> 01:09:25,880
A PHD CANDIDATE IN 

1409
01:09:25,880 --> 01:09:26,280
[INDISCERNIBLE]. 

1410
01:09:26,280 --> 01:09:31,880
>>THANK YOU.  GOOD
MORNING, 

1411
01:09:31,880 --> 01:09:33,440
EVEN.  THANK YOU FOR BEING HERE 

1412
01:09:33,440 --> 01:09:38,600
TO ATTEND I'M IN THE HIV AND 

1413
01:09:38,600 --> 01:09:44,480
AIDS MALIGNANCY BRANCH AND 

1414
01:09:44,480 --> 01:09:54,920
PLEASED TO SHARE MY WORK. 

1415
01:09:55,160 --> 01:10:00,480
IN THE LAB WE STUDY 

1416
01:10:00,480 --> 01:10:03,000
GAMMAHERPESVIRUSES A SUBFAMILY 

1417
01:10:03,000 --> 01:10:09,040
OF CANCER CAUSING VIRUSES. 

1418
01:10:09,040 --> 01:10:13,760
 -- EBV IS UBIQUITOUS WORLDWIDE 

1419
01:10:13,760 --> 01:10:15,400
INFECTING OVER 95% OF THE 

1420
01:10:15,400 --> 01:10:19,600
POPULATION THAT CAN LEAD TO 

1421
01:10:19,600 --> 01:10:21,560
VARIOUS LYMPHOMAS AS WELL AS 

1422
01:10:21,560 --> 01:10:27,560
GASTRIC AND NASAL CARCINOMAS AND

1423
01:10:27,560 --> 01:10:35,280
TRANSZ PLANT PROLIFERATION -- IT

1424
01:10:35,280 --> 01:10:41,320
CAN LEAD TO PRIMARY EH FUSION 

1425
01:10:41,320 --> 01:10:42,360
LYMPHOMA AND [INDISCERNIBLE] 

1426
01:10:42,360 --> 01:10:42,720
DISEASE. 

1427
01:10:42,720 --> 01:10:45,680
HERPES VIRUSES ARE LARGE DOUBLE 

1428
01:10:45,680 --> 01:10:48,640
STRAND ND DNA VIRUSES ENCODING 

1429
01:10:48,640 --> 01:10:51,160
OVER 80 FUNCTIONAL PROTEINS AND 

1430
01:10:51,160 --> 01:10:53,120
BECAUSE OF THIS BRING WITH THEM 

1431
01:10:53,120 --> 01:10:55,520
THEIR OWN CORE REPLICATION 

1432
01:10:55,520 --> 01:10:59,640
MACHINERY CONSISTING OF VIRAL 

1433
01:10:59,640 --> 01:11:01,640
DNA POLYMERASE AND SINGLE STRAND

1434
01:11:01,640 --> 01:11:05,680
DNA BINDING PROTEINS AND 

1435
01:11:05,680 --> 01:11:09,080
HELICASE PRIMARY COMPLEX.  CORE 

1436
01:11:09,080 --> 01:11:11,360
REPLICATION MACHINERY IS 

1437
01:11:11,360 --> 01:11:12,440
ESSENTIAL FOR REP MRIKS AND 

1438
01:11:12,440 --> 01:11:15,000
KNOCKING OUT IN CELLS AND 

1439
01:11:15,000 --> 01:11:18,360
PATHOGEN ESIS IN VIVO LEADING TO

1440
01:11:18,360 --> 01:11:22,960
NONREPRODUCTIVE VERSION OF THE 

1441
01:11:22,960 --> 01:11:25,400
VIRUS AND HERPES CODE WORD 

1442
01:11:25,400 --> 01:11:28,320
TERMED AS ACCESSORY PROTEINS 

1443
01:11:28,320 --> 01:11:30,600
INVOLVED IN NUCLEOTIDE 

1444
01:11:30,600 --> 01:11:33,640
METABOLISM IN DNA REPAIR AND 

1445
01:11:33,640 --> 01:11:35,960
HOMOLOGS OF HIGHLY CONSERVED 

1446
01:11:35,960 --> 01:11:39,640
ENZYMES AND ACCESSORY PROTEINS 

1447
01:11:39,640 --> 01:11:41,560
ARE THOUGHT TO BE DISPENSABLE 

1448
01:11:41,560 --> 01:11:44,600
FOR CELL CULTURE NOT UNTIL WE 

1449
01:11:44,600 --> 01:11:47,880
INFECT IN VIVO MOUSE MODELS FOR 

1450
01:11:47,880 --> 01:11:48,400
EXAMPLE IN OUR CASE THAT 

1451
01:11:48,400 --> 01:11:50,320
REPLICATION PHENOTYPES ARE 

1452
01:11:50,320 --> 01:11:51,880
OBSERVED AND AT THIS POINT I 

1453
01:11:51,880 --> 01:11:53,400
WANT TO PAUSE BRIEFLY TO EXPLAIN

1454
01:11:53,400 --> 01:11:57,160
WE USE THE MOUSE GAMMA HERPES 

1455
01:11:57,160 --> 01:12:01,000
MHV68 THAT IS A MODEL SYSTEM 

1456
01:12:01,000 --> 01:12:02,920
STUDYING HUMAN GAMMA HERPES 

1457
01:12:02,920 --> 01:12:04,600
VIRUSES AND NICE SYSTEM THAT 

1458
01:12:04,600 --> 01:12:07,920
SHARES GENETIC AND BIOLOGICAL 

1459
01:12:07,920 --> 01:12:11,880
PARALLELS WITH GAMMA HERPES 

1460
01:12:11,880 --> 01:12:13,920
VIRUSES ALLOWING US TO UNVAIL 

1461
01:12:13,920 --> 01:12:15,680
PHENOTYPES OF ACCESSORY PROTEINS

1462
01:12:15,680 --> 01:12:17,960
THAT INCLUDE THOSE ENZYMES 

1463
01:12:17,960 --> 01:12:21,240
INVOLVED IN NUCLEOTIDE 

1464
01:12:21,240 --> 01:12:25,000
METABOLISM AND RIBONUCLEOTIDE 

1465
01:12:25,000 --> 01:12:26,640
REDUCTASE SMALL AND LARGE 

1466
01:12:26,640 --> 01:12:29,200
SUBUNITS AND OUR LAB IS FOCUSED 

1467
01:12:29,200 --> 01:12:36,000
ON DNA REPAIR ENZYME URACIL DNA 

1468
01:12:36,000 --> 01:12:39,720
GLYCOL ASIS AND IT IS ACTIVE AND

1469
01:12:39,720 --> 01:12:41,440
CAN COMPLEMENT FOR INTERESTING 

1470
01:12:41,440 --> 01:12:44,640
FUNCTIONS OF HOST UNG AND MOST 

1471
01:12:44,640 --> 01:12:47,640
IMPORTANT FOR THIS TALK PREVIOUS

1472
01:12:47,640 --> 01:12:49,960
WORK IN LAB HAS SHOWN THAT A 

1473
01:12:49,960 --> 01:12:53,200
KNOCKOUT VIRUS WITH SEVERELY 

1474
01:12:53,200 --> 01:12:56,880
ATTENUATED FORPATHOGEN ESIS IN 

1475
01:12:56,880 --> 01:12:57,720
VIVO.  

1476
01:12:57,720 --> 01:13:03,840
WHAT IS URACIL DNA GLYCOLYSIS 

1477
01:13:03,840 --> 01:13:07,520
AND WHAT DOES IT DO?  

1478
01:13:07,520 --> 01:13:13,000
URACIL CAN ARISE IN DNA THROUGH 

1479
01:13:13,000 --> 01:13:14,920
MISIN-CORPORATION AND -- IN CASE

1480
01:13:14,920 --> 01:13:19,880
OF MISIN-CORPORATION DNA 

1481
01:13:19,880 --> 01:13:22,480
POLYMERASE MAY NOT DISCRIMINATE 

1482
01:13:22,480 --> 01:13:27,120
AND IN CELLS WITH SCREENED -- 

1483
01:13:27,120 --> 01:13:30,120
THERE IS A HIGHER CHANCE OF 

1484
01:13:30,120 --> 01:13:37,640
MISINCORPORATION OF URACIL 

1485
01:13:37,640 --> 01:13:39,720
RESIDUES AND CYTOSINE -- SO, UNG

1486
01:13:39,720 --> 01:13:42,760
THROUGH ITS HIGHLY CONSERVED 

1487
01:13:42,760 --> 01:13:45,360
ENZYMATIC DOMAINS SCANS DNA 

1488
01:13:45,360 --> 01:13:47,760
EXCISES URACIL FROM DNA LEADING 

1489
01:13:47,760 --> 01:13:49,880
TO A BASIC SITE IT THAT IS 

1490
01:13:49,880 --> 01:13:52,080
FILLED IN BY HOST BAITS EXCISION

1491
01:13:52,080 --> 01:13:55,480
REPAIR PATHWAY.  SO, IT IS HYPE 

1492
01:13:55,480 --> 01:13:58,720
OJ CRIED IN HERPES FIELD THAT 

1493
01:13:58,720 --> 01:14:02,920
HERPES VIRUSES CO-OPTED URACIL 

1494
01:14:02,920 --> 01:14:06,960
DNA GLYCOS ILLACE TO KEEP THEM 

1495
01:14:06,960 --> 01:14:09,120
FREE OF GLYCOLIZATION.  WE ARE 

1496
01:14:09,120 --> 01:14:14,600
INTERESTED IN ENZYMATIC 

1497
01:14:14,600 --> 01:14:20,720
FUNCTIONS FOR VIRAL UNG.  

1498
01:14:20,720 --> 01:14:22,680
SO, JUST SOME BACKGROUND AND 

1499
01:14:22,680 --> 01:14:27,080
PREVIOUS DATA IN THE LAB, WE 

1500
01:14:27,080 --> 01:14:30,160
HYPOTHESIZED VIRAL UNG ENZYMATIC

1501
01:14:30,160 --> 01:14:31,440
ACTIVITY WAS IMPORTANT IN 

1502
01:14:31,440 --> 01:14:33,320
REPLICATION IN OUR MOUSE SYSTEM 

1503
01:14:33,320 --> 01:14:37,560
AND WE CONSTRUCTED A VIRAL UNG 

1504
01:14:37,560 --> 01:14:41,480
CATALYTIC MUTANT OR VIRAL UNG.CM

1505
01:14:41,480 --> 01:14:45,640
MAKING KEY CHANGES IN UNG 

1506
01:14:45,640 --> 01:14:48,600
ENZYMATIC DOMAINS AND SHOWED 

1507
01:14:48,600 --> 01:14:51,840
THIS VIRUS WAS ABERGATED FOR ITS

1508
01:14:51,840 --> 01:14:54,400
ABILITY TO EXCISE URACIL 

1509
01:14:54,400 --> 01:14:58,880
RESIDUES IN VITRO.  WHAT IS 

1510
01:14:58,880 --> 01:15:01,680
PHENOTYPE OF CATALYTIC MUTANT 

1511
01:15:01,680 --> 01:15:05,320
VIRUS?  INFECTING MICE WITH THIS

1512
01:15:05,320 --> 01:15:09,040
MHV68 VIRUS AND CASE OF STOP OR 

1513
01:15:09,040 --> 01:15:11,960
KNOCKOUT VIRUS IT WAS SEVERELY 

1514
01:15:11,960 --> 01:15:13,720
ATTENUATED IN ACCUSE PHASE OF 

1515
01:15:13,720 --> 01:15:16,160
REPLICATION IN LUNGS AND LATENCY

1516
01:15:16,160 --> 01:15:18,680
ESTABLISHMENT IN THE SPLEEN 

1517
01:15:18,680 --> 01:15:21,240
COMPARED TO WILD TYPE VIRUS 

1518
01:15:21,240 --> 01:15:25,240
INFECTING MICE WITH UNG VIRAL 

1519
01:15:25,240 --> 01:15:27,520
CATALYTIC -- OR IN LATENCY 

1520
01:15:27,520 --> 01:15:29,080
ESTABLISHMENT IN THE SPLEEN. 

1521
01:15:29,080 --> 01:15:30,400
THESE RESULTS WERE SURPRISING TO

1522
01:15:30,400 --> 01:15:33,520
US AND INDICATED THAT VIRAL UNG 

1523
01:15:33,520 --> 01:15:37,640
MUST HAVE IMPORTANT NONENZYMATIC

1524
01:15:37,640 --> 01:15:41,160
FUNCTIONS TOWARDS PATHOGEN ESIS 

1525
01:15:41,160 --> 01:15:42,760
IN VIVO.  BEGINNING TO 

1526
01:15:42,760 --> 01:15:44,400
UNDERSTAND WHAT VIRAL UNG MIGHT 

1527
01:15:44,400 --> 01:15:47,000
DO OUTSIDE OF ENZYMATIC ACTIVITY

1528
01:15:47,000 --> 01:15:50,000
WE WERE INTERESTED IN STUDYING 

1529
01:15:50,000 --> 01:15:52,200
POTENTIAL PROTEIN PROTEIN 

1530
01:15:52,200 --> 01:15:53,520
INTERACTIONS WITH OTHER VIRAL 

1531
01:15:53,520 --> 01:15:55,840
FACTORS COLLABORATING WITH 

1532
01:15:55,840 --> 01:15:57,800
KEVIN'S GROUP AT THE CANCER 

1533
01:15:57,800 --> 01:16:03,440
CENTER TO PERFORM 

1534
01:16:03,440 --> 01:16:05,880
CO-IMMUNOPRECIPITATION MAS SPECK

1535
01:16:05,880 --> 01:16:11,080
TROMTRY AGAINST ANTIVIRAL UNG I 

1536
01:16:11,080 --> 01:16:12,440
INFECTED PERMISSIVE YOU'RE EVEN 

1537
01:16:12,440 --> 01:16:14,720
FIBERGLASS CELLS WITH VIRUS THAT

1538
01:16:14,720 --> 01:16:18,320
EXPRESSES YFP SENDING CELL 

1539
01:16:18,320 --> 01:16:21,480
PALETTES TO KEVIN'S GROUP FOR 

1540
01:16:21,480 --> 01:16:23,960
ANALYSIS USING FLOW CITOMETRY 36

1541
01:16:23,960 --> 01:16:25,800
HOURS POST INFECTION WAS HIGHEST

1542
01:16:25,800 --> 01:16:28,120
LEVEL OF INFECTED AND UNG 

1543
01:16:28,120 --> 01:16:31,880
POSITIVE CELLS USING THIS TIME 

1544
01:16:31,880 --> 01:16:37,880
FOR CO-IP/MS.  THESE ARE RESULTS

1545
01:16:37,880 --> 01:16:44,400
OF CO-IP/MS ANALYSIS AND KEVI'S

1546
01:16:44,400 --> 01:16:46,120
GROUP HAD A RANGE OF HOST 

1547
01:16:46,120 --> 01:16:48,360
FACTORS AND IMPORTANTLY TWO 

1548
01:16:48,360 --> 01:16:49,960
VIRAL PROTEINS WERE MUCH HIGHER 

1549
01:16:49,960 --> 01:16:52,560
IN HITS THAN A FEW OTHER VIRAL 

1550
01:16:52,560 --> 01:16:54,600
PROTEINS THAT I WILL FOCUS ON IN

1551
01:16:54,600 --> 01:16:58,120
THIS TALK THOSE WERE VIRAL DNA 

1552
01:16:58,120 --> 01:17:00,480
POLYMERASE AND PROCESSIVETY 

1553
01:17:00,480 --> 01:17:02,840
FACTOR SEEMING LIKE VIRAL UNG 

1554
01:17:02,840 --> 01:17:05,680
MIGHT INTERACT PHYSICALLY WITH 

1555
01:17:05,680 --> 01:17:07,360
VIRAL REPLICATION COMPONENTS AND

1556
01:17:07,360 --> 01:17:09,120
BASED ON THIS AND DATA THAT I 

1557
01:17:09,120 --> 01:17:13,880
DON'T HAVE TIME TO GO OVER, WE 

1558
01:17:13,880 --> 01:17:18,600
HYPOTHESIZED THAT MHV68 -- VIRAL

1559
01:17:18,600 --> 01:17:21,520
DNA POLYMERASE PROCESS OF YOUTH 

1560
01:17:21,520 --> 01:17:23,280
FACTOR THINKING THIS INTERACTION

1561
01:17:23,280 --> 01:17:26,160
IS INDEPENDENT OF ENZYMATIC 

1562
01:17:26,160 --> 01:17:28,320
ACTIVITY I WILL REFER TO VIRAL 

1563
01:17:28,320 --> 01:17:30,800
DNA POLYMERASE AS B POLL AND 

1564
01:17:30,800 --> 01:17:33,640
PROCESS FACTOR IS BPS AND HOPE 

1565
01:17:33,640 --> 01:17:35,600
THAT MAKES SENSE MOVING FORWARD 

1566
01:17:35,600 --> 01:17:41,640
AND HAPPY TO PRESENT TWO 

1567
01:17:41,640 --> 01:17:52,160
APPROACHES -- SO, THIS IS THE 

1568
01:18:03,360 --> 01:18:07,880
CO-IPMS DATA FOR 

1569
01:18:07,880 --> 01:18:11,000
IMMUNOPRECIPITATION FOLLOWING 

1570
01:18:11,000 --> 01:18:13,720
VPF LOOKING AT THIS YOU GET TO 

1571
01:18:13,720 --> 01:18:16,360
FIGURE A IN HIGHLIGHTED REGION 

1572
01:18:16,360 --> 01:18:19,240
ABLE TO SHOW THAT IT PULLED DOWN

1573
01:18:19,240 --> 01:18:21,640
BOTH VIRAL POLYMERASE AND VIRAL 

1574
01:18:21,640 --> 01:18:23,760
UNG AND IN FIGURE B, THIS IS A 

1575
01:18:23,760 --> 01:18:27,400
REPEAT OF THE EXPERIMENT THAT I 

1576
01:18:27,400 --> 01:18:31,720
TRANSFEKTED IN VIRAL UNG 

1577
01:18:31,720 --> 01:18:34,680
CATALYTIC PLAS MANT AND IT LEADS

1578
01:18:34,680 --> 01:18:37,920
TO PULLDOWN OF PULL AND UNG AND 

1579
01:18:37,920 --> 01:18:42,880
AGAIN ECHOING WHAT WE SAW WITH 

1580
01:18:42,880 --> 01:18:45,320
CO-IP/MS DATA AND I PERFORMED 

1581
01:18:45,320 --> 01:18:49,000
THIS EXPERIMENT IN THE CONTEXT 

1582
01:18:49,000 --> 01:18:49,680
OF IMMUNOPRECIPITATION AGAINST 

1583
01:18:49,680 --> 01:18:53,240
VIRAL UNG AND LOOKING AT 

1584
01:18:53,240 --> 01:18:55,880
HIGHLIGHTING REGION THIS IS 

1585
01:18:55,880 --> 01:18:59,880
TRIPLE TRANSVEKS REGION AND 

1586
01:18:59,880 --> 01:19:01,040
POLYMERASE AND [INDISCERNIBLE] 

1587
01:19:01,040 --> 01:19:04,680
IN PULLDOWN AND THIS HOLDS TRUE 

1588
01:19:04,680 --> 01:19:07,320
IN [INDISCERNIBLE] AND THESE 

1589
01:19:07,320 --> 01:19:12,680
DATA SEEM TO CONFIRM CO IPMS 

1590
01:19:12,680 --> 01:19:15,760
DATA AND IT MIGHT NOT BE 

1591
01:19:15,760 --> 01:19:17,160
REQUIRED FOR INTERACTIONS. 

1592
01:19:17,160 --> 01:19:20,680
SO, THE NEXT APPROACH THAT WE 

1593
01:19:20,680 --> 01:19:22,840
PERFORMED WAS IMMUNOFLUORESCENCE

1594
01:19:22,840 --> 01:19:25,880
TO EXAMINE POTENTIAL 

1595
01:19:25,880 --> 01:19:28,320
COLOCALIZATION BETWEEN VIRAL UNG

1596
01:19:28,320 --> 01:19:31,440
WITH V POLL AND UPPF AND 

1597
01:19:31,440 --> 01:19:35,120
INFECTED CELLS WITH VIRUSES THAT

1598
01:19:35,120 --> 01:19:39,040
EXPRESS GFP TAG POLL TO LOOK AT 

1599
01:19:39,040 --> 01:19:41,200
COLOCALIZATION WITH UNG AND 

1600
01:19:41,200 --> 01:19:45,640
INFECTED CELLS WITH VIRAL UNG 

1601
01:19:45,640 --> 01:19:49,400
CATALYTIC MUTANT VIRUS. 

1602
01:19:49,400 --> 01:19:51,200
HERE IS RESULTS OF THE 

1603
01:19:51,200 --> 01:19:54,960
EXPERIMENT THAT I INFECTED 

1604
01:19:54,960 --> 01:19:57,560
NIH3G12 FIBERGLASS WITH HIGH MOI

1605
01:19:57,560 --> 01:20:00,480
AND IF WE LOOK AT RED THIS IS 

1606
01:20:00,480 --> 01:20:02,280
VIRAL UNG STAIN AND IN THE GREEN

1607
01:20:02,280 --> 01:20:06,040
IS THE POLL OR PPF AND AS TIME 

1608
01:20:06,040 --> 01:20:09,080
INCREASES SIZE OF THE VIRAL 

1609
01:20:09,080 --> 01:20:09,960
REPLICATION COMPARTMENTS 

1610
01:20:09,960 --> 01:20:12,320
INCREASES AND TOP ROW SHOWS OR 

1611
01:20:12,320 --> 01:20:19,800
EMERGE OF VIRAL UNGPOL AND PPF 

1612
01:20:19,800 --> 01:20:21,960
AND THERE IS LARGE 

1613
01:20:21,960 --> 01:20:24,000
COLOCALIZATION BETWEEN VIRAL 

1614
01:20:24,000 --> 01:20:27,040
FACTORS AT EACH TIME POINT IN 

1615
01:20:27,040 --> 01:20:28,080
THE STUDY. 

1616
01:20:28,080 --> 01:20:29,560
NEXT, I WANT TO DETERMINE 

1617
01:20:29,560 --> 01:20:31,600
WHETHER CATALYTIC ACTIVITY OF 

1618
01:20:31,600 --> 01:20:34,280
VIRAL UNG IS REQUIRED FOR 

1619
01:20:34,280 --> 01:20:35,880
COLOCALIZATION AND INFECTED 

1620
01:20:35,880 --> 01:20:38,760
CELLS WITH CATALYTIC MUTANT 

1621
01:20:38,760 --> 01:20:40,560
VIRUS AND WILD TYPE VIRUS AND IF

1622
01:20:40,560 --> 01:20:44,920
WE LOOK AT TOP ROWS THIS IS THE 

1623
01:20:44,920 --> 01:20:48,320
MERGE SHOWING VIRAL UNG AND 

1624
01:20:48,320 --> 01:20:49,960
PROCESSIVETY FACTOR THAT 

1625
01:20:49,960 --> 01:20:50,960
OVERLAPPED AND AT EACH TIME 

1626
01:20:50,960 --> 01:20:53,800
POINT WE ANALYZE THERE IS LARGE 

1627
01:20:53,800 --> 01:20:56,200
OVERLAP BETWEEN VIRAL UNG AND 

1628
01:20:56,200 --> 01:20:58,360
PROCESSIVETY FACTOR THAT IS 

1629
01:20:58,360 --> 01:20:59,560
INDEPENDENT WHETHER I INFECTED 

1630
01:20:59,560 --> 01:21:03,800
WITH CATALYTIC MUTANT WITH WILD 

1631
01:21:03,800 --> 01:21:07,880
TYPE VIRUS. 

1632
01:21:07,880 --> 01:21:09,640
HERPES VIRUS LITERATURE 

1633
01:21:09,640 --> 01:21:12,520
INDICATES VIRAL UNG CAN INTERACT

1634
01:21:12,520 --> 01:21:15,760
WITH VIRAL POLYMERASE AND 

1635
01:21:15,760 --> 01:21:21,560
PROCESSIVETY FACTOR FOR HSV AND 

1636
01:21:21,560 --> 01:21:25,440
EBV AND SUGGESTS THAT ENZYMATIC 

1637
01:21:25,440 --> 01:21:27,080
ACTIVITY OF IT IS NOT REQUIRED 

1638
01:21:27,080 --> 01:21:29,600
FOR INTERACTIONS MOVING FORWARD 

1639
01:21:29,600 --> 01:21:31,800
WE ARE REALLY EXCITED TO TRY 

1640
01:21:31,800 --> 01:21:35,760
SOME OF THIS IN KSHV WHERE LESS 

1641
01:21:35,760 --> 01:21:37,880
IS KNOWN BETWEEN INTERACTION OF 

1642
01:21:37,880 --> 01:21:39,840
VIRAL UNG AND REPLICATION 

1643
01:21:39,840 --> 01:21:41,680
MACHINERY AND BASED ON THIS AND 

1644
01:21:41,680 --> 01:21:43,560
OTHER DATA I HAVEN'T HAD TIME TO

1645
01:21:43,560 --> 01:21:45,720
SHOW WE PROPOSE A MODEL WHERE 

1646
01:21:45,720 --> 01:21:48,480
VIRAL UNG IS PRESENT IF ACTIVE 

1647
01:21:48,480 --> 01:21:50,240
SITES OF VIRAL REPLICATION 

1648
01:21:50,240 --> 01:21:52,440
POTENTIALLY INVOLVED IN A 

1649
01:21:52,440 --> 01:21:54,280
SCAFFOLDING FUNCTION WITH VIRAL 

1650
01:21:54,280 --> 01:21:58,040
DNA POLYMERASE AND VIRAL DNA 

1651
01:21:58,040 --> 01:22:00,160
POLYMERASE PROCESS FACTOR 

1652
01:22:00,160 --> 01:22:02,960
EXCISING VIRAL GENOMIC URACILS 

1653
01:22:02,960 --> 01:22:07,440
TO MAINTAIN FIDELITY OF VIRAL 

1654
01:22:07,440 --> 01:22:09,240
REPLICATION. 

1655
01:22:09,240 --> 01:22:13,680
SO, IN SUMMARY, I HAVE SHOWN CO 

1656
01:22:13,680 --> 01:22:15,680
IPMS DATA DEMONSTRATING VIRAL 

1657
01:22:15,680 --> 01:22:17,880
POLYMERASE AND PROCESSIVETY 

1658
01:22:17,880 --> 01:22:21,040
FACTOR INTERACT WITH THIS AND IN

1659
01:22:21,040 --> 01:22:23,800
COLLABORATION WITH KEVIN MCBRIDE

1660
01:22:23,800 --> 01:22:26,560
AT MD ANDERSON AND PRECIPITATION

1661
01:22:26,560 --> 01:22:29,640
THAT SUPPORTS THIS SUGGESTING 

1662
01:22:29,640 --> 01:22:31,920
ENZYMATIC ACTIVITY MIGHT BE 

1663
01:22:31,920 --> 01:22:34,160
DISPENSABLE FOR THE INTERACTION 

1664
01:22:34,160 --> 01:22:36,640
SHOWING VIRAL UNG COLOCALIZES 

1665
01:22:36,640 --> 01:22:39,000
WITH CORE REPLICATION FACTORS IN

1666
01:22:39,000 --> 01:22:42,440
CASE OF PPF COLOCALIZATION 

1667
01:22:42,440 --> 01:22:45,240
APPEARED INDEPENDENTLY WITH THE 

1668
01:22:45,240 --> 01:22:48,760
ENZOMATIC DOMAIN AND IN FUTURE 

1669
01:22:48,760 --> 01:22:49,840
DETERMINING THIS IS IMPORTANT 

1670
01:22:49,840 --> 01:22:52,200
FOR INTERACTION AND 

1671
01:22:52,200 --> 01:22:54,440
COLOCALIZATION AND MUTATE THOSE 

1672
01:22:54,440 --> 01:22:55,520
DOMAINS TO DETERMINE THE EFFECT 

1673
01:22:55,520 --> 01:23:00,960
ON THESE PHENOTYPES AND 

1674
01:23:00,960 --> 01:23:02,800
ULTIMATELY PATHOGEN ESIS. 

1675
01:23:02,800 --> 01:23:05,920
WE THINK ELUCIDATING THESE 

1676
01:23:05,920 --> 01:23:07,400
INTERACTIONS WITH VIRAL 

1677
01:23:07,400 --> 01:23:08,760
REPLICATION MACHINERY MIGHT BE 

1678
01:23:08,760 --> 01:23:11,160
IMPORTANT TO PRODUCE 

1679
01:23:11,160 --> 01:23:15,840
THERAPEUTICS TO TAFRG ET KSHV IN

1680
01:23:15,840 --> 01:23:20,480
COMBINATION WITH RASE SUCCESSFUL

1681
01:23:20,480 --> 01:23:20,840
NUCLEOANALOGS. 

1682
01:23:20,840 --> 01:23:23,080
SO, WITH THAT, I WOULD LIKE TO 

1683
01:23:23,080 --> 01:23:26,600
THANK MY LAB AND MENTOR LORI 

1684
01:23:26,600 --> 01:23:29,920
CREW.  I'M A GPP STUDENT FROM 

1685
01:23:29,920 --> 01:23:31,920
STONEY BROOK UNIVERSITY AND 

1686
01:23:31,920 --> 01:23:33,440
WOULD LIKE TO THANK MY COMMITTEE

1687
01:23:33,440 --> 01:23:39,400
AND FUNDING SOURCES AND KEVIN 

1688
01:23:39,400 --> 01:23:41,240
MCBRIDE'S GROUP AT MD ANDERSON 

1689
01:23:41,240 --> 01:23:44,480
WHO IS HECHFUL IN THE ENTIRE 

1690
01:23:44,480 --> 01:23:47,960
PROJECT AND WITH THAT I'M HAPPY 

1691
01:23:47,960 --> 01:23:56,240
TO TAKE ANY QUESTIONS.  

1692
01:23:56,240 --> 01:23:58,040
>>ANY QUESTIONS?  

1693
01:23:58,040 --> 01:24:02,520
>>I HAVE ONE.  SO, THE
VIRAL --

1694
01:24:02,520 --> 01:24:05,000
IT IS ONE OF THE HOST.  THE HOST

1695
01:24:05,000 --> 01:24:07,960
PROBABLY CAN'T DO THIS AND WHAT 

1696
01:24:07,960 --> 01:24:09,600
IS DIFFERENCE BETWEEN TWO?  

1697
01:24:09,600 --> 01:24:11,920
>>HOST AND VIRUS AND UNGS

1698
01:24:11,920 --> 01:24:13,480
ACROSS THESE ARE HIGHLY 

1699
01:24:13,480 --> 01:24:15,760
CONSERVED AT ENZYMATIC DOMAINS 

1700
01:24:15,760 --> 01:24:17,920
AND ARE DIFFERENCES FOR EXAMPLE 

1701
01:24:17,920 --> 01:24:21,120
HOST HAS A LONGER END TERMINUS 

1702
01:24:21,120 --> 01:24:23,440
AND WHAT COLLABORATOR KEVIN 

1703
01:24:23,440 --> 01:24:27,200
MCBRIDE IS INTERESTED IN AND 

1704
01:24:27,200 --> 01:24:28,880
HOST REPLICATION FACTORS AND 

1705
01:24:28,880 --> 01:24:31,880
HOST UNG ACTUALLY LEADS TO ERROR

1706
01:24:31,880 --> 01:24:34,760
PRONE REPAIR OF MUTATIONS IN 

1707
01:24:34,760 --> 01:24:37,040
VEET TROE AND WE THINK IT IS 

1708
01:24:37,040 --> 01:24:39,760
POSSIBLE THAT VIRAL UNG MIGHT BE

1709
01:24:39,760 --> 01:24:42,680
SHIELDING BASIC SITES FROM 

1710
01:24:42,680 --> 01:24:43,880
POTENTIALLY DELETERIOUS HOST 

1711
01:24:43,880 --> 01:24:45,640
FACTORS THAT ARE THINGS THAT WE 

1712
01:24:45,640 --> 01:24:48,080
ARE INTERESTED IN LOOKING AT 

1713
01:24:48,080 --> 01:24:48,480
MOVING FORWARD. 

1714
01:24:48,480 --> 01:24:51,640
>>ALL RIGHT.  THANK YOU. 

1715
01:24:51,640 --> 01:25:02,200
>>I CAN INTRODUCE YOU. 
SHE IS 

1716
01:25:27,000 --> 01:25:29,640
A RESEARCH FELLOW IN THE 

1717
01:25:29,640 --> 01:25:31,880
LABORATORY TUMOR VIRUS VIROLOGY 

1718
01:25:31,880 --> 01:25:33,960
SECTION IN CCR.  SHE WILL 

1719
01:25:33,960 --> 01:25:36,840
PRESENT DATA ABOUT SELECTIVE 

1720
01:25:36,840 --> 01:25:41,640
EXPRESSION ABOUT ONCOGENES 

1721
01:25:41,640 --> 01:25:44,800
[INDISCERNIBLE] IN LINE WITH 

1722
01:25:44,800 --> 01:25:45,800
MULTIPLE INTEGRATION SITES.  SHE

1723
01:25:45,800 --> 01:25:47,160
IS CONNECTING THROUGH ZOOM.  YOU

1724
01:25:47,160 --> 01:25:50,640
CAN GO.  EVERYTHING IS FINE. 

1725
01:25:50,640 --> 01:25:55,360
>>OKAY.  THANK YOU FOR
THE 

1726
01:25:55,360 --> 01:25:57,160
INTRODUCTION.  GOOD MORNING, 

1727
01:25:57,160 --> 01:26:00,440
EVERYONE.  THANK YOU TO MEETING 

1728
01:26:00,440 --> 01:26:01,680
ORGANIZERS TO GIVE ME THE 

1729
01:26:01,680 --> 01:26:04,600
OPPORTUNITY TO INTRODUCE WORK 

1730
01:26:04,600 --> 01:26:12,280
HERE.  HUMAN PAPILLOMA VIRUS 

1731
01:26:12,280 --> 01:26:13,640
[INDISCERNIBLE] DISEASE IS NOT 

1732
01:26:13,640 --> 01:26:15,840
PART OF THE VIRUS LIFE CYCLE.  

1733
01:26:15,840 --> 01:26:18,400
IN FACT, INTEGRATION IS THAT END

1734
01:26:18,400 --> 01:26:21,000
FOR THE VIRUS.  IT IS NO LONGER 

1735
01:26:21,000 --> 01:26:25,040
ABLE TO REPLICATE AND MAKE A NEW

1736
01:26:25,040 --> 01:26:27,520
VIRUS.  HPV INTEGRATION BY 

1737
01:26:27,520 --> 01:26:30,400
DISRUPTION OF E1 AND E2 GENES 

1738
01:26:30,400 --> 01:26:32,960
RESULTS IN INCREASED EXPRESSION 

1739
01:26:32,960 --> 01:26:40,240
OF E6 AND E7 ONCOGENES AND HAS 

1740
01:26:40,240 --> 01:26:43,160
DEGRADATION OF [INDISCERNIBLE]. 

1741
01:26:43,160 --> 01:26:45,480
CONSEQUENTLY PROMOTING CELL 

1742
01:26:45,480 --> 01:26:48,360
[INDISCERNIBLE] THIS GAVE CELLS 

1743
01:26:48,360 --> 01:26:51,840
A SELECTIVE ADVANTAGE AND 

1744
01:26:51,840 --> 01:26:52,960
PROMOTES ONCHOGENIC PROGRESSION 

1745
01:26:52,960 --> 01:26:56,520
AND HPV ASSOCIATED CANCERS ARE 

1746
01:26:56,520 --> 01:26:59,240
DEPENDENT ON EXPRESSION OF 

1747
01:26:59,240 --> 01:27:00,560
VIRUSES ONCOGENES FOR CANCER 

1748
01:27:00,560 --> 01:27:04,720
CELL PROLIFERATION AND SURVIVAL.

1749
01:27:04,720 --> 01:27:08,960
IT IS THAT THERE IS INTEGRATED 

1750
01:27:08,960 --> 01:27:11,240
VIRAL GENOME IS OFTEN DISRUPTED 

1751
01:27:11,240 --> 01:27:13,800
NEXT 1 AND E2 GENES IN CANCER 

1752
01:27:13,800 --> 01:27:16,160
TISSUES THAT MIGHT BE A 

1753
01:27:16,160 --> 01:27:18,440
SELECTIVE FEATURE OF CANCER 

1754
01:27:18,440 --> 01:27:20,720
PROGRESSION AND DISRUPTION OF E1

1755
01:27:20,720 --> 01:27:31,440
AND E2 DESTROY SIGNAL FOR E6 AND

1756
01:27:31,440 --> 01:27:37,800
E7 EXPRESSION. 

1757
01:27:37,800 --> 01:27:41,400
E6 AND E7 USES THEM AND THEY ARE

1758
01:27:41,400 --> 01:27:46,000
EARLY PROMOTER P97 AND 

1759
01:27:46,000 --> 01:27:47,280
TRANSCRIBES WITH [INDISCERNIBLE]

1760
01:27:47,280 --> 01:27:52,480
CALLED E6 PROTEIN AND OTHER TWO 

1761
01:27:52,480 --> 01:27:54,240
TRANSCRIPTS WITH SPLICED OPEN 

1762
01:27:54,240 --> 01:27:56,320
READING FRAME.  ALL THESE 

1763
01:27:56,320 --> 01:28:01,040
TRANSCRIBE TO USE THIS EARLY AT 

1764
01:28:01,040 --> 01:28:02,760
DIVISION SITE VIRUS INFECTION.  

1765
01:28:02,760 --> 01:28:05,920
FROM THIS FIGURE, WE CAN SEE IF 

1766
01:28:05,920 --> 01:28:09,960
E1 AND E2 IS DISRUPTED THAT ALL 

1767
01:28:09,960 --> 01:28:13,880
THESE WILL LOSE EARLY POLY A 

1768
01:28:13,880 --> 01:28:18,960
SITE THAT WON'T MAKE E6 AND E7 

1769
01:28:18,960 --> 01:28:19,280
ONCHOPROTEIN. 

1770
01:28:19,280 --> 01:28:23,200
QUESTION IS HOW DOES HPV 

1771
01:28:23,200 --> 01:28:25,560
INTEGRATE TO EXPRESS THESE GENES

1772
01:28:25,560 --> 01:28:29,720
IN CANCER CELLS?  

1773
01:28:29,720 --> 01:28:32,680
FIRST, WE ANALYZE THIS DATA FOR 

1774
01:28:32,680 --> 01:28:37,080
HPV INTEGRATION FROM TCG DATA 

1775
01:28:37,080 --> 01:28:41,720
BASE AND THESE DATA BASES. 

1776
01:28:41,720 --> 01:28:45,000
HERE IS PRINCIPLE FOR DATA 

1777
01:28:45,000 --> 01:28:49,640
ANALYSIS IN JUNE SEQUENCING 1D 

1778
01:28:49,640 --> 01:28:52,440
FRAGMENTED IS SEQUENCED TO FIRM 

1779
01:28:52,440 --> 01:28:55,000
BOTH DIRECTIONS AND INTEGRATION 

1780
01:28:55,000 --> 01:28:58,960
ANALYSIS FOCUS DOWN THIS VIRUS 

1781
01:28:58,960 --> 01:29:02,320
HOST JUNCTION RATES CALLED CGRS 

1782
01:29:02,320 --> 01:29:03,920
THAT REFLECT THIS INTEGRATION 

1783
01:29:03,920 --> 01:29:05,720
SITE IT THAT IS VIRAL. 

1784
01:29:05,720 --> 01:29:11,080
7 TAENCASES OF 55HPV16 AND 18 

1785
01:29:11,080 --> 01:29:14,320
POSITIVE CANCER TISSUES SHOWS 

1786
01:29:14,320 --> 01:29:16,320
MULTIPLE DENATURE INTEGRATION 

1787
01:29:16,320 --> 01:29:18,800
SITE AND ONE SITE EXPRESSES 

1788
01:29:18,800 --> 01:29:21,280
[INDISCERNIBLE] AND EXEMPLIFIED 

1789
01:29:21,280 --> 01:29:26,720
IN THIS TISSUE.  HERE IS HP16 

1790
01:29:26,720 --> 01:29:30,280
RISK COVERAGE SHOWING GENOME IS 

1791
01:29:30,280 --> 01:29:33,520
COVERED BY THIS FROM ALL 

1792
01:29:33,520 --> 01:29:40,760
INTEGRATED SIZE SHOWING RATES 

1793
01:29:40,760 --> 01:29:44,760
WITH NO RATES FROM VERY EARLY 

1794
01:29:44,760 --> 01:29:46,480
POLYINSIGHT AND DAZE AH 

1795
01:29:46,480 --> 01:29:50,600
INTEGGATED INTEGRATION AT TISSUE

1796
01:29:50,600 --> 01:29:53,160
LED TO THIS. 

1797
01:29:53,160 --> 01:29:57,600
DNA SEQUENCE CGR MAPPING 

1798
01:29:57,600 --> 01:29:59,760
IDENTIFIED INTEGRATION SITES IN 

1799
01:29:59,760 --> 01:30:02,520
THE TISSUE. 

1800
01:30:02,520 --> 01:30:11,840
IT SHOWS THIS WAS EXPRESSED.  

1801
01:30:11,840 --> 01:30:15,320
BASED ON CGR DETECTED WE CAN MAP

1802
01:30:15,320 --> 01:30:22,200
HOW IT WAS INTEGRATED AND 

1803
01:30:22,200 --> 01:30:22,520
EXPRESSED. 

1804
01:30:22,520 --> 01:30:28,560
THIS IS HOST GENOME MAP FIELD 

1805
01:30:28,560 --> 01:30:32,600
AND SHOWN IN THE FIGURE 

1806
01:30:32,600 --> 01:30:34,080
[INDISCERNIBLE] INSERTED INTO 

1807
01:30:34,080 --> 01:30:36,680
[INDISCERNIBLE] REGION ON 

1808
01:30:36,680 --> 01:30:43,160
CHROMOSOME 4.  POLY A SIGNAL 

1809
01:30:43,160 --> 01:30:46,960
DOWNSTREAM WAS LOST TOO.  E6 AND

1810
01:30:46,960 --> 01:30:53,640
E7 TRANSCRIPTS WOULDN'T BE 

1811
01:30:53,640 --> 01:30:55,360
[INDISCERNIBLE] SUBSEQUENTLY WE 

1812
01:30:55,360 --> 01:30:58,800
CONSTRUCT HOST GENOME THAT IS 

1813
01:30:58,800 --> 01:31:05,640
BASED ON 2 CHEMMER JUNCTION 

1814
01:31:05,640 --> 01:31:09,960
SITES.  SPLICING OF THIS E6 AND 

1815
01:31:09,960 --> 01:31:13,240
E7 AND A TO DOWNSTREAM HOST POLY

1816
01:31:13,240 --> 01:31:18,320
A SITE LOCATED IN CHROMOSOME 4. 

1817
01:31:18,320 --> 01:31:24,200
THIS SPLICING PRODUCED TO THESE 

1818
01:31:24,200 --> 01:31:27,280
TRANSCRIPTS AND TRANSCRIPT 2 

1819
01:31:27,280 --> 01:31:31,200
PRODUCING E7 PROTEIN.  

1820
01:31:31,200 --> 01:31:33,760
EXAMPLE, ALL OF THESE TISSUE 

1821
01:31:33,760 --> 01:31:36,040
SAMPLES DISPLAYED IN THIS TABLE 

1822
01:31:36,040 --> 01:31:37,880
AT MULTIPLE INTEGRATION SITES 

1823
01:31:37,880 --> 01:31:40,680
AND BY ANALYSIS AND SURPRISINGLY

1824
01:31:40,680 --> 01:31:42,560
IN EACH CASE THIS SHOWS THAT 

1825
01:31:42,560 --> 01:31:46,800
ONLY ONE OF THE INTEGRATED 

1826
01:31:46,800 --> 01:31:49,240
CHROMOSOMES THAT WERE EXPRESSING

1827
01:31:49,240 --> 01:31:51,760
CHEM ERIC -- AFTER THIS ANALYSIS

1828
01:31:51,760 --> 01:31:54,680
WE FOUND ONLY ONE INTEGRATED 

1829
01:31:54,680 --> 01:31:58,400
SITES ON THE CHROMOSOME THAT IS 

1830
01:31:58,400 --> 01:32:02,000
EXPRESSING CHEM ERIC HOST 

1831
01:32:02,000 --> 01:32:02,480
PROGRAM. 

1832
01:32:02,480 --> 01:32:06,480
IN ORDER TO VERIFY OBSERVED HPV 

1833
01:32:06,480 --> 01:32:07,800
INTEGRATION EXPRESSION, WE 

1834
01:32:07,800 --> 01:32:09,520
PERFORM THIS ANALYSIS AND ANSWER

1835
01:32:09,520 --> 01:32:11,720
IS CANCER CELL LINES WITH THIS 

1836
01:32:11,720 --> 01:32:14,600
DATA YOU THAT IS AVAILABLE FROM 

1837
01:32:14,600 --> 01:32:16,600
PUBLIC DATA BASE AND VERIFIED IS

1838
01:32:16,600 --> 01:32:19,920
RESULTS BY TRADITIONAL TECHNICS 

1839
01:32:19,920 --> 01:32:24,400
INCLUDING THIS 3 PRIME RATES AND

1840
01:32:24,400 --> 01:32:25,520
NONBLOT. 

1841
01:32:25,520 --> 01:32:27,720
WE FIRST MAPPED CASCADE 

1842
01:32:27,720 --> 01:32:30,760
[INDISCERNIBLE] TO HPV16 GENOME 

1843
01:32:30,760 --> 01:32:32,480
AND LOWER PART HAS FRAMES IT 

1844
01:32:32,480 --> 01:32:37,360
THAT WE CAN SEE E6 AND E7 AND E1

1845
01:32:37,360 --> 01:32:38,960
READING FRAME IN TACT THAT 

1846
01:32:38,960 --> 01:32:41,040
TRANSCRIPTION IS TERMINATED AT 

1847
01:32:41,040 --> 01:32:43,600
STUDY 7 AND 29 AT E2 RATING THAT

1848
01:32:43,600 --> 01:32:47,280
IS INDICATING THAT INTEGRATION 

1849
01:32:47,280 --> 01:32:49,640
REMOVES THIS POLY A SIGNAL AND 

1850
01:32:49,640 --> 01:32:51,920
HOST POLY A SIGNAL DOWNSTREAM 

1851
01:32:51,920 --> 01:32:55,320
MUST BE AVAILABLE FOR E6 AND E7 

1852
01:32:55,320 --> 01:33:01,640
EXPRESSION AND THESE CELLS HAVE 

1853
01:33:01,640 --> 01:33:03,640
-- MAPPING THE [INDISCERNIBLE] 

1854
01:33:03,640 --> 01:33:06,880
TO HUMAN AND HPV16 GENOME WITH 

1855
01:33:06,880 --> 01:33:11,120
MOST OF THE CGR JUVENGSS CAME 

1856
01:33:11,120 --> 01:33:13,640
FROM HOST CHROMOSOME 6 AT 

1857
01:33:13,640 --> 01:33:16,640
SPECIFICATION AND THIS 

1858
01:33:16,640 --> 01:33:18,640
TRANSCRIBES AND THIS IS E2 GENE 

1859
01:33:18,640 --> 01:33:21,040
INDICATING IT THIS IS ONLY 

1860
01:33:21,040 --> 01:33:23,280
CHROMOSOME REGION EXPRESSING 

1861
01:33:23,280 --> 01:33:25,080
THIS.  

1862
01:33:25,080 --> 01:33:27,080
NEXT, WE MAP TWO CHEM ERIC 

1863
01:33:27,080 --> 01:33:30,400
JUNCTION SITES FROM THIS TO 

1864
01:33:30,400 --> 01:33:31,080
CHROMOSOME 6 IN THESE CELLS IT 

1865
01:33:31,080 --> 01:33:33,640
THAT IS SHOWING IN THE FIGURE 

1866
01:33:33,640 --> 01:33:36,760
THE LINEAR [INDISCERNIBLE] HPV16

1867
01:33:36,760 --> 01:33:39,960
WAS INSERTED INTO INTERGENIC 

1868
01:33:39,960 --> 01:33:43,600
REGION IN CHROMOSOME 6 AND 

1869
01:33:43,600 --> 01:33:45,720
INTEGRATION JUNCTION SITES 

1870
01:33:45,720 --> 01:33:49,200
VERIFIED IN PCR SEQUENCING 

1871
01:33:49,200 --> 01:33:51,800
ACCORDING TO THESE SUBSEQUENTLY 

1872
01:33:51,800 --> 01:33:55,280
CUBED VARIOUS HOST OF CHEM ERIC 

1873
01:33:55,280 --> 01:33:58,320
GENOME AND RATES TO 

1874
01:33:58,320 --> 01:34:00,800
[INDISCERNIBLE] AS SHOWN HERE, 

1875
01:34:00,800 --> 01:34:03,800
WAS TRANSCRIBED FROM EARLY 

1876
01:34:03,800 --> 01:34:06,520
PROMOTER P97 AND SPLICED TWICE 

1877
01:34:06,520 --> 01:34:10,440
BEFORE REACHING TO HOST POLY A 

1878
01:34:10,440 --> 01:34:15,240
SITE.  THIS IS VERIFIED BY 3 

1879
01:34:15,240 --> 01:34:18,440
PRIMASE.  THESE ALTERNATIVE 

1880
01:34:18,440 --> 01:34:20,520
SPLICING PRODUCED THIS 

1881
01:34:20,520 --> 01:34:22,000
TRANSCRIBES AND WE CONFIRM 

1882
01:34:22,000 --> 01:34:25,600
DISEASE PRODUCTS BY THIS USING A

1883
01:34:25,600 --> 01:34:31,000
VERY SPECIFIC PROBE, C2 FROM E7 

1884
01:34:31,000 --> 01:34:34,600
REGION. 

1885
01:34:34,600 --> 01:34:37,640
TO CONFIRM THIS EXPRESSION FROM 

1886
01:34:37,640 --> 01:34:40,160
IDENTIFIED INTEGRATION SITE ON 

1887
01:34:40,160 --> 01:34:41,960
CHROMOSOME 6, WE DESIGNED A HOST

1888
01:34:41,960 --> 01:34:43,760
THAT IS AS BIG AS 

1889
01:34:43,760 --> 01:34:47,400
[INDISCERNIBLE].  AS I SEE, IT 

1890
01:34:47,400 --> 01:34:50,440
THIS IS HOST GENE NEXT TO CGR 

1891
01:34:50,440 --> 01:34:52,880
JUNCTION ON CHROMOSOME 6 AND 

1892
01:34:52,880 --> 01:34:55,040
THIS BLOT ANALYSIS CONFIRMED 

1893
01:34:55,040 --> 01:34:57,600
THIS PROTEIN EXPRESSION WAS 

1894
01:34:57,600 --> 01:34:59,160
ABOLISHED UPON THIS SPECIFIC AS 

1895
01:34:59,160 --> 01:35:04,480
KNOCKED DOWN WHEN COMPARED TO 

1896
01:35:04,480 --> 01:35:06,320
TARGETING CONTROL AND SHOWN IN 

1897
01:35:06,320 --> 01:35:09,320
CELL PROLIFERATIONS HERE THIS 

1898
01:35:09,320 --> 01:35:11,680
GROWS AND NOT TO HPV NEGATIVE 

1899
01:35:11,680 --> 01:35:14,680
THIS CELL WAS INHIBITED BY 

1900
01:35:14,680 --> 01:35:17,880
SPECIFIC KNOCKING DOWN WHEN 

1901
01:35:17,880 --> 01:35:20,360
COMPARED TO THIS.  

1902
01:35:20,360 --> 01:35:23,200
LIKE WE DID IN THESE CELLS WE 

1903
01:35:23,200 --> 01:35:24,760
DESIGNED HOST SPECIFIC 

1904
01:35:24,760 --> 01:35:26,800
[INDISCERNIBLE] TARGETING HOST 

1905
01:35:26,800 --> 01:35:29,640
[INDISCERNIBLE] NEXT TO CGR 

1906
01:35:29,640 --> 01:35:33,040
JUVENGSS CHROMOSOME 18 CELLS AND

1907
01:35:33,040 --> 01:35:35,880
WESTERN BLOT ANALYSIS CONFIRM 

1908
01:35:35,880 --> 01:35:38,440
THESE PROTEIN EXPRESSION WAS 

1909
01:35:38,440 --> 01:35:39,480
ABOLISHED SPECIFIC AS IT WAS 

1910
01:35:39,480 --> 01:35:43,560
KNOCKED DOWN WHEN COMPARED TO 

1911
01:35:43,560 --> 01:35:44,320
THESE. 

1912
01:35:44,320 --> 01:35:49,560
AND HEELO CELL GROWS BUT NOT 

1913
01:35:49,560 --> 01:35:52,960
THIS A CELLS INHIBITED BY 

1914
01:35:52,960 --> 01:35:56,240
SPECIFIC WHEN KNOCKED DOWN WHEN 

1915
01:35:56,240 --> 01:35:57,760
COMPARED TO THIS.  

1916
01:35:57,760 --> 01:35:59,720
SO, FROM THE CLINICAL STANDPOINT

1917
01:35:59,720 --> 01:36:02,560
AND CELL INTEGRATION ANALYSIS, 

1918
01:36:02,560 --> 01:36:04,840
WE CAN SEE HPV INTEGRATION 

1919
01:36:04,840 --> 01:36:09,840
HAPPENS RANDOMLY AND HOST GENOME

1920
01:36:09,840 --> 01:36:12,600
REGION WITH INTEGRATION HAS 

1921
01:36:12,600 --> 01:36:14,680
DELETION ARRANGEMENTS AND 

1922
01:36:14,680 --> 01:36:17,200
INTEGRATES INTO THE GENOME AND 

1923
01:36:17,200 --> 01:36:19,920
IF THIS POLY A SITE WAS LOST 

1924
01:36:19,920 --> 01:36:22,000
THIS IMPORTANT THING FOR THE 

1925
01:36:22,000 --> 01:36:26,720
VIRUS IS FINDING HOST POLICY A 

1926
01:36:26,720 --> 01:36:29,640
SITE NEARBY FOR THIS GENE 

1927
01:36:29,640 --> 01:36:31,360
EXPRESSION AND HIGH STABLE E6 

1928
01:36:31,360 --> 01:36:35,120
AND E7 EXPRESSION FROM 

1929
01:36:35,120 --> 01:36:37,360
INTEGRATION SITE IS ESSENTIAL 

1930
01:36:37,360 --> 01:36:38,040
FOR FURTHER [INDISCERNIBLE] 

1931
01:36:38,040 --> 01:36:39,280
EXPANSION AND [INDISCERNIBLE]. 

1932
01:36:39,280 --> 01:36:44,880
IN THIS REPORT, WE SHOWED THAT 

1933
01:36:44,880 --> 01:36:46,720
ONCOGENES ARE EXPRESSED IN 

1934
01:36:46,720 --> 01:36:48,080
SINGLE INTEGRATION SITES IN 

1935
01:36:48,080 --> 01:36:50,320
CANCER TISSUES AND CELL LINES 

1936
01:36:50,320 --> 01:36:52,320
WITH MULTIPLE [INDISCERNIBLE] 

1937
01:36:52,320 --> 01:36:54,640
INTEGRATION SITES AND INTEGRATED

1938
01:36:54,640 --> 01:36:56,160
[INDISCERNIBLE] ARE FRAGMENTED 

1939
01:36:56,160 --> 01:37:01,200
AND EXPRESSED GENOMIC DNASE 

1940
01:37:01,200 --> 01:37:04,320
LACKING PROMOTERS SPLICING SITES

1941
01:37:04,320 --> 01:37:07,640
OR [INDISCERNIBLE].  E1 AND E2 

1942
01:37:07,640 --> 01:37:09,720
REGION FOR INTEGRATION AND 

1943
01:37:09,720 --> 01:37:12,920
EXPRESSION OF ONCHOGENIC E6 AND 

1944
01:37:12,920 --> 01:37:15,880
7 MUST UTILIZE HOST POLY A 

1945
01:37:15,880 --> 01:37:18,280
SIGNAL DOWNSTREAM OF INTEGRATION

1946
01:37:18,280 --> 01:37:21,120
SITE AND CELL PROLIFERATION AND 

1947
01:37:21,120 --> 01:37:22,480
CLONAL CELL EXPANSION.  I WANT 

1948
01:37:22,480 --> 01:37:26,560
TO THANK ALL MEMBERS IN OUR LAB.

1949
01:37:26,560 --> 01:37:29,160
OUR [INDISCERNIBLE] TEAM, ALEX 

1950
01:37:29,160 --> 01:37:32,760
AND MAGGIE AND [INDISCERNIBLE] 

1951
01:37:32,760 --> 01:37:39,400
FOR HIS  ADVICE ON OUR ANALYSIS 

1952
01:37:39,400 --> 01:37:43,240
AND [INDISCERNIBLE] FOR 

1953
01:37:43,240 --> 01:37:45,200
PROVIDING E6 ANTIBODIES AND 

1954
01:37:45,200 --> 01:37:47,960
THANKS ALL FOR LISTENING.  I'M 

1955
01:37:47,960 --> 01:37:51,240
HAPPY TO TAKE ANY QUESTIONS. 

1956
01:37:51,240 --> 01:37:53,640
>>[APPLAUSE]. 

1957
01:37:53,640 --> 01:38:04,160
>>>>THAT WAS A
NICE TALK.  

1958
01:38:10,520 --> 01:38:13,720
WHAT DO YOU THINK EFFECTS COULD 

1959
01:38:13,720 --> 01:38:15,960
BE ON CELL BEHAVIOR, FOR 

1960
01:38:15,960 --> 01:38:16,760
EXAMPLE?  

1961
01:38:16,760 --> 01:38:21,200
>>WE DID LOTS OF E6 AND
E7 

1962
01:38:21,200 --> 01:38:22,680
KNOCKDOWN EXPERIMENTS BEFORE.  

1963
01:38:22,680 --> 01:38:27,040
IF WE DO THAT, CELL GROWS 

1964
01:38:27,040 --> 01:38:28,240
INHIBITED AND CELL WILL DIE. 

1965
01:38:28,240 --> 01:38:30,120
>>THANK YOU.  

1966
01:38:30,120 --> 01:38:30,800
>>THANK YOU.  

1967
01:38:30,800 --> 01:38:33,120
>>I ACTUALLY HAVE AN
ADDITIONAL

1968
01:38:33,120 --> 01:38:35,560
QUESTION.  DO YOU KNOW IF THERE 

1969
01:38:35,560 --> 01:38:36,640
IS A DIFFERENCE BETWEEN 

1970
01:38:36,640 --> 01:38:38,480
INTEGRATION SITES IN PEOPLE THAT

1971
01:38:38,480 --> 01:38:40,880
PROCEED OR NOT TOWARDS 

1972
01:38:40,880 --> 01:38:43,200
DEVELOPMENT OF THE CONCERT OF 

1973
01:38:43,200 --> 01:38:45,080
THE KREFB CAL LEVEL?  

1974
01:38:45,080 --> 01:38:46,240
>>VERY GOOD QUESTION.  WE
DON'T

1975
01:38:46,240 --> 01:38:48,720
HAVE THE DATA, UNFORTUNATELY.  

1976
01:38:48,720 --> 01:38:52,840
WE ONLY HAVE DATA FROM CANCER 

1977
01:38:52,840 --> 01:38:53,040
STAGE. 

1978
01:38:53,040 --> 01:39:02,520
>>THANK YOU. 

1979
01:39:02,520 --> 01:39:07,400
>>NEXT SPEAKER IS SARAH
DREMEL.

1980
01:39:07,400 --> 01:39:15,600
SHE WILL TALK ABOUT ALTERNATIVE 

1981
01:39:15,600 --> 01:39:19,640
SPLICING AND CIRCRNA BIOGENESIS 

1982
01:39:19,640 --> 01:39:25,640
DRIVEN BY ALPHA AND GAMMA HERPES

1983
01:39:25,640 --> 01:39:25,880
VIRUSES. 

1984
01:39:25,880 --> 01:39:36,440
>>>>GOOD MORNING. 
SORRY FOR 

1985
01:40:40,280 --> 01:40:43,720
THAT.  I'M SARAH IN THE LAB IN 

1986
01:40:43,720 --> 01:40:46,400
HIV AND AIDS MALIGNANCY BRANCH 

1987
01:40:46,400 --> 01:40:48,760
AND KYLE GAVE AN INTRODUCTION 

1988
01:40:48,760 --> 01:40:51,560
EARLIER ON HERPES VIRUSES THAT I

1989
01:40:51,560 --> 01:40:53,240
STUDY THEM ALSO AND WON'T TALK 

1990
01:40:53,240 --> 01:40:56,960
MUCH ABOUT THEM THEMSELVES MY 

1991
01:40:56,960 --> 01:40:58,720
PROJECT FOCUSES ON CIRCULAR RNAS

1992
01:40:58,720 --> 01:41:01,240
THAT ARE A NOVEL CLASS OF 

1993
01:41:01,240 --> 01:41:02,800
TRANSCRIPTS FORMING CONTINUOUS 

1994
01:41:02,800 --> 01:41:07,080
LOOP DUE TO 5 PRIME TO 3 PRIEF 

1995
01:41:07,080 --> 01:41:10,280
CO-VAILANT LINKAGE TO BACKMRASH 

1996
01:41:10,280 --> 01:41:11,480
JUNCTION.  

1997
01:41:11,480 --> 01:41:15,240
THROUGHOUT THE TALK YOU WILL SEE

1998
01:41:15,240 --> 01:41:16,920
BACKSPLASH JUNCTION THEY HAVE 

1999
01:41:16,920 --> 01:41:21,160
EXTENDED HALF LIVES AND ARE NOT 

2000
01:41:21,160 --> 01:41:22,400
GENERALLY MUTAGENIC.  THEY 

2001
01:41:22,400 --> 01:41:26,560
FUNCTION TO MODULATE GENE 

2002
01:41:26,560 --> 01:41:31,320
EXPRESSION AND -- IN SOME 

2003
01:41:31,320 --> 01:41:32,520
INSTANCES THEY ACTUALLY 

2004
01:41:32,520 --> 01:41:35,840
THEMSELVES CONSERVE AS 

2005
01:41:35,840 --> 01:41:38,400
TRANSLATIONAL TEMPLATES. 

2006
01:41:38,400 --> 01:41:40,360
IN LAST 5 YEARS THESE WERE 

2007
01:41:40,360 --> 01:41:42,160
DISCOVERED STARTING WITH HERPES 

2008
01:41:42,160 --> 01:41:44,480
VIRUSES THEMSELVES AND LIST 

2009
01:41:44,480 --> 01:41:47,520
EXTENDEDS TO DOZENS OF VIRUSES 

2010
01:41:47,520 --> 01:41:50,800
BOTH RNA AND DNA GENOME.  MY 

2011
01:41:50,800 --> 01:41:53,760
PROJECT IN PARTICULAR FOCUSES ON

2012
01:41:53,760 --> 01:41:55,920
CIRCULAR RNAS EXPRESSED BY 

2013
01:41:55,920 --> 01:41:59,200
DIFFERENT HERPES VIRUSES AND 

2014
01:41:59,200 --> 01:41:59,840
DEFINING CHARACTERISTIC OF 

2015
01:41:59,840 --> 01:42:02,040
HERPES VIRUSES IS ABILITY TO 

2016
01:42:02,040 --> 01:42:04,280
UNDERGO LYTIC AND LATIENT MODES 

2017
01:42:04,280 --> 01:42:07,360
OF INFECTION REACTIVATES TO 

2018
01:42:07,360 --> 01:42:09,800
VARIOUS RESPONSES OF STIMULI.  

2019
01:42:09,800 --> 01:42:11,840
LOOKING AT TRANSCRIPTS GENERATED

2020
01:42:11,840 --> 01:42:19,760
IN SPECIFIC PHASES OF LIFECYCLE.

2021
01:42:19,760 --> 01:42:22,680
HERPES VIRUS AND THIS VIRUS 68 

2022
01:42:22,680 --> 01:42:25,520
AND ALPHA VIRUS SIMPLEX VIRUS 

2023
01:42:25,520 --> 01:42:28,160
TYPE 1 AND LOOKED AT CELL 

2024
01:42:28,160 --> 01:42:30,760
CULTURE AND ANIMAL MODELS OF THE

2025
01:42:30,760 --> 01:42:37,600
VIRUSES TAKING TOTAL RNA -- SO, 

2026
01:42:37,600 --> 01:42:40,680
THESE ARE ANALYZED WITH SPECIFIC

2027
01:42:40,680 --> 01:42:42,280
BIOINFORMATIC PIPELINE ALLOWING 

2028
01:42:42,280 --> 01:42:45,640
US TO DIFFERENTIATE LINEAR 

2029
01:42:45,640 --> 01:42:47,240
VERSUS CIRCULAR REEDS BASED ON 

2030
01:42:47,240 --> 01:42:49,880
PRESENCE OF SOMETHING CALLED A 

2031
01:42:49,880 --> 01:42:51,680
BACKSPLICE JUNCTION THAT IS ONLY

2032
01:42:51,680 --> 01:42:53,560
UNIQUE SEQUENCE COMPONENT TO A 

2033
01:42:53,560 --> 01:42:56,120
CIRCULAR RNA FROM LINEAR 

2034
01:42:56,120 --> 01:42:57,200
COUNTERPART MADE FROM THE SAME 

2035
01:42:57,200 --> 01:42:59,240
GENE.  USING THAT WE CAN 

2036
01:42:59,240 --> 01:43:01,520
QUANTIFY LINEAR AND CIRCULAR 

2037
01:43:01,520 --> 01:43:02,840
TRANSCRIPTS. 

2038
01:43:02,840 --> 01:43:05,560
OKAY.  HERE, I'M SHOWING YOU 

2039
01:43:05,560 --> 01:43:08,480
RAW COUNTS FROM PART OF MY DATA 

2040
01:43:08,480 --> 01:43:13,200
SITE LOOKING AT REEDS CONTAINING

2041
01:43:13,200 --> 01:43:16,640
BACKSPLICING JUNCTION.  CIRCULAR

2042
01:43:16,640 --> 01:43:19,360
NRA READS -- HERE ARE THOSE 

2043
01:43:19,360 --> 01:43:21,640
DERIVED FROM THE HOST GENOME.  I

2044
01:43:21,640 --> 01:43:24,480
WAS SURPRISED TO SEE THOUSANDS 

2045
01:43:24,480 --> 01:43:26,920
OF VIRAL BACKSPLICE JUCHGSS 

2046
01:43:26,920 --> 01:43:30,680
PRESENT IN DATA SIS CIRCRNAS ARE

2047
01:43:30,680 --> 01:43:34,480
THOUGHT OF AS LOW INCIDENCE 

2048
01:43:34,480 --> 01:43:36,280
EVENTS PRESENT DURING LYTIC 

2049
01:43:36,280 --> 01:43:38,840
PHASE OF THE LIFECYCLE.  

2050
01:43:38,840 --> 01:43:42,440
UNSURPRISING THAT IS WHEN 

2051
01:43:42,440 --> 01:43:44,160
MAJORITY OF TRANSCRIPTIONAL 

2052
01:43:44,160 --> 01:43:46,360
ACTIVITY OCCURS THINK OF THIS AS

2053
01:43:46,360 --> 01:43:49,440
FUNCTION OF GENOME SIZE AND 

2054
01:43:49,440 --> 01:43:51,880
INCIDENCE OF BACKSPLICING GENOME

2055
01:43:51,880 --> 01:43:54,280
INCIDENCE FOR HERPES VIRUSES IS 

2056
01:43:54,280 --> 01:43:58,200
ANYWHERE FROM 800 TO 30,000 FOLD

2057
01:43:58,200 --> 01:44:00,800
GREATER FROM INCIDENCE OF 

2058
01:44:00,800 --> 01:44:02,200
BACKSPLICING FROM THE HOST 

2059
01:44:02,200 --> 01:44:03,400
GENOME.  IN DATA I DON'T HAVE 

2060
01:44:03,400 --> 01:44:05,480
TIME TO TALK ABOUT TODAY.  

2061
01:44:05,480 --> 01:44:07,920
SEQUENCING RESULTS CONFIRMED FOR

2062
01:44:07,920 --> 01:44:12,120
MODELS USING RIBONUKE LEEACE 

2063
01:44:12,120 --> 01:44:15,200
RESISTENT DNAS TO CONFIRM 

2064
01:44:15,200 --> 01:44:16,880
CIRCULAR NATURE OF THESE 

2065
01:44:16,880 --> 01:44:19,960
TRANSCRIPTS AND APPLYING 

2066
01:44:19,960 --> 01:44:22,480
ORTHOGONAL APPROACH TO VALIDATE 

2067
01:44:22,480 --> 01:44:23,560
FINDINGS. 

2068
01:44:23,560 --> 01:44:25,960
SO, WHAT DO THESE CIRCULAR NRA 

2069
01:44:25,960 --> 01:44:27,080
READS LOOK LIKE?  

2070
01:44:27,080 --> 01:44:30,600
I WILL FOCUS ON TWO MODELS OF 

2071
01:44:30,600 --> 01:44:33,920
LATENT INFECTION AND VIRUS AND 

2072
01:44:33,920 --> 01:44:36,880
HSV1.  HERPES VIRUSES ENCODE A 

2073
01:44:36,880 --> 01:44:39,720
SMALL HANDFUL OF TRANSCRIPTS 

2074
01:44:39,720 --> 01:44:41,800
DURING LATENT PHASE OF THE LIFE 

2075
01:44:41,800 --> 01:44:44,280
CYCLE AND TRANSCRIPTS 

2076
01:44:44,280 --> 01:44:46,280
SURROUNDING THIS AND HSV1 THIS 

2077
01:44:46,280 --> 01:44:49,200
INCLUDES LATENCY ASSOCIATED 

2078
01:44:49,200 --> 01:44:52,000
TRANSCRIPT LONG NONCODING RNA IN

2079
01:44:52,000 --> 01:44:54,160
ITSELF CONTAINS STABLE INNERIM 

2080
01:44:54,160 --> 01:44:55,720
THAT WE WERE PARTICULARLY 

2081
01:44:55,720 --> 01:44:57,640
INTERESTED IN CIRCULAR RNAS 

2082
01:44:57,640 --> 01:45:02,720
BEING DERIVED FROM THE LOCUST. 

2083
01:45:02,720 --> 01:45:05,240
SO, HERE I'M SHOWING YOU 

2084
01:45:05,240 --> 01:45:06,920
SOMETHING CALLED A PLOT THAT HAS

2085
01:45:06,920 --> 01:45:09,720
A DEPTH OF THE ARC THAT 

2086
01:45:09,720 --> 01:45:12,080
INDICATES NUMBER OF READS FOR 

2087
01:45:12,080 --> 01:45:13,800
THE BACKSPLICE JUVENGS AND 

2088
01:45:13,800 --> 01:45:16,160
ACTUAL POSITIONS IS SLICE DONOR 

2089
01:45:16,160 --> 01:45:19,360
AND ACCEPTOR FOR CIRCULAR RNA 

2090
01:45:19,360 --> 01:45:22,240
I'M SHOWING MODELS FOR LATENT 

2091
01:45:22,240 --> 01:45:24,240
INFECTION AND HERE WE IDENTIFIED

2092
01:45:24,240 --> 01:45:25,840
A NUMBER OF DIFFERENT CIRCULAR 

2093
01:45:25,840 --> 01:45:29,320
ARE.  NAS DERIVED FROM K12 AND 

2094
01:45:29,320 --> 01:45:31,560
THIS 72 LOCUST AND WE WERE 

2095
01:45:31,560 --> 01:45:34,320
EXCITED TO SEE CIRCULAR RNAS 

2096
01:45:34,320 --> 01:45:37,120
DERIVED FROM THIS STABLE INTRON 

2097
01:45:37,120 --> 01:45:41,280
DURING HSV1 MODEL LATENCIES. 

2098
01:45:41,280 --> 01:45:44,080
WE CAN ACTUALLY FIND THAT SAME 

2099
01:45:44,080 --> 01:45:46,640
CIRCULAR RNA IDENTIFIED IN LATE 

2100
01:45:46,640 --> 01:45:48,760
MODELS OF LYTIC INFECTION. 

2101
01:45:48,760 --> 01:45:51,160
SO, TO NOTE, THIS ADDS 

2102
01:45:51,160 --> 01:45:53,320
ADDITIONAL TRANSCRIPTS THAT ARE 

2103
01:45:53,320 --> 01:45:56,400
PRESENT HAVING A FUNCTIONAL ROLE

2104
01:45:56,400 --> 01:45:59,080
DURING HERPES VIRUS LATENCY TO 

2105
01:45:59,080 --> 01:46:01,320
DATE IT IS FIRST REPORT OF THIS.

2106
01:46:01,320 --> 01:46:03,040
SO, NOW, MOVING ON I WILL SHOW 

2107
01:46:03,040 --> 01:46:06,040
YOU DATA SPECIFICALLY FOR LYTIC 

2108
01:46:06,040 --> 01:46:08,000
MODELS OF INFECTION AND I'M 

2109
01:46:08,000 --> 01:46:10,520
SHOWING YOU REED TRACES FOR 

2110
01:46:10,520 --> 01:46:13,080
LINEAR AND BACKSPLICE READS 

2111
01:46:13,080 --> 01:46:19,120
MAPPED TO KSHV GENOME WITH 

2112
01:46:19,120 --> 01:46:21,840
SELECT GENES ANNOTATED BELOW AND

2113
01:46:21,840 --> 01:46:24,680
PATTERNS OF REEDS IN BLACK AND 

2114
01:46:24,680 --> 01:46:28,000
RED YOU WILL SEE THEY LOOK 

2115
01:46:28,000 --> 01:46:29,600
IDENTICAL.  PATTERNS LOOK 

2116
01:46:29,600 --> 01:46:31,800
SIMILAR AND IS SURPRISING AND 

2117
01:46:31,800 --> 01:46:33,880
INSTANCES OF FORWARD SPLICING 

2118
01:46:33,880 --> 01:46:36,640
SEE IF THEY CORRELATE WITH 

2119
01:46:36,640 --> 01:46:38,160
BACKSPLICING AND IN GRAY I 

2120
01:46:38,160 --> 01:46:39,640
PLOTTED REEDS THAT ARE FORWARD 

2121
01:46:39,640 --> 01:46:42,000
SPLICE AND DON'T CORRELATE WITH 

2122
01:46:42,000 --> 01:46:44,360
REGIONS OF BACKSPLICING AND 

2123
01:46:44,360 --> 01:46:46,480
PLOTTING HOST REEDS MAPS THE 

2124
01:46:46,480 --> 01:46:48,840
SAME WAY YOU DON'T SEE THIS 

2125
01:46:48,840 --> 01:46:51,000
PHENOTYPE.  I WENT AHEAD AND 

2126
01:46:51,000 --> 01:46:53,680
QUANTIFIED THIS OBSERVATION.  I 

2127
01:46:53,680 --> 01:46:54,960
PERFORMED LINEAR REGRESSION 

2128
01:46:54,960 --> 01:46:57,680
ANALYSIS LOOKING AT LINEAR AND 

2129
01:46:57,680 --> 01:46:59,200
BACKSPLICE REEDS MAPPING TO 

2130
01:46:59,200 --> 01:47:02,640
VIRAL GENOME IN PURPLE OR HOST 

2131
01:47:02,640 --> 01:47:05,640
GENOME IN YELLOW IT IS A BUBBLE 

2132
01:47:05,640 --> 01:47:11,840
BLO THE AND R2 VALUE BACKSPLICE 

2133
01:47:11,840 --> 01:47:13,040
TRANSCRIPT ABUNDANCE AND CIRCLE 

2134
01:47:13,040 --> 01:47:15,720
SIZE ITSELF INDICATES GIVEN LOCI

2135
01:47:15,720 --> 01:47:20,280
WILL GIVE RISE TO CIRCULAR RNA. 

2136
01:47:20,280 --> 01:47:21,800
SMALLER BUBBLE MORE LIKELY THAT 

2137
01:47:21,800 --> 01:47:25,000
GENE IS -- IN PURPLE LINEAR 

2138
01:47:25,000 --> 01:47:27,080
REGRESSION ANALYSIS HIGH 

2139
01:47:27,080 --> 01:47:29,000
STRENGTH OF CORRELATION FOR 

2140
01:47:29,000 --> 01:47:31,600
VIRAL REEDS INDICATING CIRCULAR 

2141
01:47:31,600 --> 01:47:34,240
ABUNDANCE IS CORRELATED WITH 

2142
01:47:34,240 --> 01:47:37,000
LINEAR TRANSCRIPT ABUNDANCE SAME

2143
01:47:37,000 --> 01:47:39,120
OBSERVATION IS NOT TRUE FOR HOST

2144
01:47:39,120 --> 01:47:41,480
GENOME.  THIS ANALYSIS CAN TELL 

2145
01:47:41,480 --> 01:47:43,760
US LIKELIHOOD GIVEN REGION GIVES

2146
01:47:43,760 --> 01:47:46,920
RISE TO CIRCULAR RNA IN THIS 

2147
01:47:46,920 --> 01:47:52,960
MODEL KHV LYTIC INFECTION 4 -- 

2148
01:47:52,960 --> 01:47:59,240
THIS MEANS IN THE DATA SET .2% 

2149
01:47:59,240 --> 01:48:02,200
OF VOOIRL READS WERE CIRCULAR 

2150
01:48:02,200 --> 01:48:03,600
RNASE.  THIS INDICATES IT MIGHT 

2151
01:48:03,600 --> 01:48:08,360
BE A SEQUENCE INDEPENDENT 

2152
01:48:08,360 --> 01:48:12,000
MECHANISM MAKING THESE.  I WENT 

2153
01:48:12,000 --> 01:48:17,800
AHEAD AND DID THIS.  I'M SHOWING

2154
01:48:17,800 --> 01:48:20,200
VENN DIAGRAMS AND CENSUS MOTIFS 

2155
01:48:20,200 --> 01:48:23,800
FOR THESE.  WE SEE CANON CAL 

2156
01:48:23,800 --> 01:48:26,040
SPLICE -- PRESENCE IN MOST HOST 

2157
01:48:26,040 --> 01:48:28,000
CIRCULAR RNAS MAKING SENSE THAT 

2158
01:48:28,000 --> 01:48:30,600
THEY HAVE BEEN SHOWN TO BE MADE 

2159
01:48:30,600 --> 01:48:34,560
BY HOST LYSOSOME WE DON'T SEE 

2160
01:48:34,560 --> 01:48:37,880
FOR VIRAL -- THIS IS SEQUENCE 

2161
01:48:37,880 --> 01:48:42,400
INDEPENDENT SYNTHESIS AND QUICK 

2162
01:48:42,400 --> 01:48:44,920
SUMMARY, THEY DON'T CORRESPOND 

2163
01:48:44,920 --> 01:48:46,600
BEFORE SPLICING INJUNCTIONS AND 

2164
01:48:46,600 --> 01:48:48,680
DON'T USE CANON CAL SPLICE DONOR

2165
01:48:48,680 --> 01:48:50,880
AND ACCEPTOR AND DON'T HAVE TIME

2166
01:48:50,880 --> 01:48:53,400
TO SHOW TODAY.  EXPRESSION IS 

2167
01:48:53,400 --> 01:48:56,440
RESISTANT TO MAJOR SPLICEOSOME 

2168
01:48:56,440 --> 01:48:59,280
INHIBITION.  IS SOMETHING 

2169
01:48:59,280 --> 01:49:00,000
SPECIFIC TO LYTIC PHASE OF THE 

2170
01:49:00,000 --> 01:49:03,560
LIFE CYCLE PROMOTING THIS UNIQUE

2171
01:49:03,560 --> 01:49:05,400
RNA SYNTHESIS MECHANISM?  

2172
01:49:05,400 --> 01:49:06,560
TESTING IT THAT TOOK ADVANTAGE 

2173
01:49:06,560 --> 01:49:08,680
OF THIS ACTIVE REPORTER PRESENT 

2174
01:49:08,680 --> 01:49:12,240
IN THE KSHV GENOME.  IT IS UNDER

2175
01:49:12,240 --> 01:49:14,880
THE EF1 ALPHA PROMOTER AND IN 

2176
01:49:14,880 --> 01:49:19,120
THIS WAY I CAN LOOK AT CIRCULAR 

2177
01:49:19,120 --> 01:49:28,880
RNASE DURING LYTIC AND NATIVE 

2178
01:49:28,880 --> 01:49:33,600
PHASE OF THIS.  HERE, I'M 

2179
01:49:33,600 --> 01:49:34,800
PLOTTING CIRCULAR A TRANSCRIPT 

2180
01:49:34,800 --> 01:49:38,480
RATIO OF CIRCULAR TO LINEAR 

2181
01:49:38,480 --> 01:49:40,640
REEDS FROM THE LOCUST AND GRAY 

2182
01:49:40,640 --> 01:49:43,960
IS LYTIC REACTIVATION AND BLUE 

2183
01:49:43,960 --> 01:49:48,160
IS LATENT REINFECTION. 

2184
01:49:48,160 --> 01:49:53,560
IN NASCENT RNA YOU SEE TEN FOLD 

2185
01:49:53,560 --> 01:49:55,440
INCREASE AND SEEMS LYTIC PHASE 

2186
01:49:55,440 --> 01:49:59,200
OF THIS LIFE CYCLE IS DRIVING 

2187
01:49:59,200 --> 01:50:02,240
THIS.  SO, THAT BROUGHT ME TO 

2188
01:50:02,240 --> 01:50:04,400
QUESTION WHAT UNIQUE EFFECTERS 

2189
01:50:04,400 --> 01:50:07,600
ARE PRESENT DURING THE LYTIC 

2190
01:50:07,600 --> 01:50:08,880
PHASE PROMOTING CIRCULAR PHASE? 

2191
01:50:08,880 --> 01:50:13,760
VIRAL RNA BINDING PRO E- TEEN OR

2192
01:50:13,760 --> 01:50:16,520
RNA57 AND HOMOLOG IN ALL HERPES 

2193
01:50:16,520 --> 01:50:17,960
VIRUSES FANTASTIC WORK IN THE 

2194
01:50:17,960 --> 01:50:21,480
FIELD WE KNOW INTERACTS WITH 

2195
01:50:21,480 --> 01:50:22,840
HOST SPLICING MACHINERY AND HAS 

2196
01:50:22,840 --> 01:50:26,880
ROLE TO PREVENT RNA DECAY IN 

2197
01:50:26,880 --> 01:50:28,960
CONTEXT OF PROJECT I WANT TO SEE

2198
01:50:28,960 --> 01:50:33,080
IF IT BINDS TO THIS.  SECOND OF 

2199
01:50:33,080 --> 01:50:36,280
ALL, HOW MIGHT IT EFFECT 

2200
01:50:36,280 --> 01:50:39,160
ACCUMULATION IS IT THIS 

2201
01:50:39,160 --> 01:50:41,720
IMPACTING SPLICING OR IS IT POST

2202
01:50:41,720 --> 01:50:44,160
TRANSCRIPTIONAL IN THAT IT MIGHT

2203
01:50:44,160 --> 01:50:46,120
PREVENT DEGRADATION IN 

2204
01:50:46,120 --> 01:50:47,320
COLLABORATION WITH NICK CONRAD 

2205
01:50:47,320 --> 01:50:52,040
AT SOUNL WESTERN WE ANALYZED 

2206
01:50:52,040 --> 01:50:56,000
457E CLIP DATA IN THE PIPELINE 

2207
01:50:56,000 --> 01:50:59,480
WE CAN SEE IF THEY BIND THESE I 

2208
01:50:59,480 --> 01:51:00,960
AM SHOWING FORWARD AND 

2209
01:51:00,960 --> 01:51:02,640
BACKSPLICE JUNCTION REEDS IN 

2210
01:51:02,640 --> 01:51:06,640
SIZE MATCH INPUT OR 457IP AND 

2211
01:51:06,640 --> 01:51:10,400
YOU SEE 11-FOLD ENRICHMENT IN IP

2212
01:51:10,400 --> 01:51:13,480
INDICATING 57 BINDS FOR CIRCULAR

2213
01:51:13,480 --> 01:51:16,160
RNASE AND WHEN WE LOOK AT HUMAN 

2214
01:51:16,160 --> 01:51:20,960
REEDS WE SEE THAT 57 SEEMS TO 

2215
01:51:20,960 --> 01:51:22,960
PREFERENTIALLY BIND ADJACENT TO 

2216
01:51:22,960 --> 01:51:24,240
FORWARD AND BACKSPLICE JUVENGSS 

2217
01:51:24,240 --> 01:51:27,880
AND INVESTIGATING WHAT IMPACT OF

2218
01:51:27,880 --> 01:51:30,400
THESE MIGHT BE AND I EMPLOYED 

2219
01:51:30,400 --> 01:51:32,680
TOTAL AND NASCENT RNA SEQUENCING

2220
01:51:32,680 --> 01:51:35,880
AND IN THIS TIME DID IN CONTEXT 

2221
01:51:35,880 --> 01:51:39,240
COMPARING WILD TYPE OR R57 NULL 

2222
01:51:39,240 --> 01:51:41,360
MUN.  I CAN LOOK AT CHANGESES IN

2223
01:51:41,360 --> 01:51:44,360
NASCENT AND TOTAL POPULATION TO 

2224
01:51:44,360 --> 01:51:46,160
SEE WHICH STAGE N57 MIGHT HAVE A

2225
01:51:46,160 --> 01:51:48,320
ROLE.  I CLUSTERED TRANSCRIPTS 

2226
01:51:48,320 --> 01:51:51,160
AND AGAIN YOU ARE SEEING HERE A 

2227
01:51:51,160 --> 01:51:54,840
PLOT LOG TWO FOLD CHANGE OF NULL

2228
01:51:54,840 --> 01:51:58,000
OVER WILD TYPE X AXIS LOOKS AT 

2229
01:51:58,000 --> 01:52:04,640
TOTE AT RNA ABUNDANCE AND Y AXIS

2230
01:52:04,640 --> 01:52:06,880
LOOKING AT CO-TRANSCRIPTIONAL 

2231
01:52:06,880 --> 01:52:08,880
ABUNKED ANSZ.  IF SOMETHING 

2232
01:52:08,880 --> 01:52:11,560
FALLS IN TOP RIGHT QUADRANT IT 

2233
01:52:11,560 --> 01:52:13,640
IS R57 REPRESSED BEYOND THAT 

2234
01:52:13,640 --> 01:52:16,120
LOOKING AT LEVELS ARE MORE 

2235
01:52:16,120 --> 01:52:18,360
IMPACTED IN NASCENT ARE TOTAL 

2236
01:52:18,360 --> 01:52:20,960
RNA IF SOMETHING FALLS IN 

2237
01:52:20,960 --> 01:52:25,640
QUADRANT ABOVE DIAGONAL OR 57 

2238
01:52:25,640 --> 01:52:27,160
ENHANCES ACCUMULATION POST 

2239
01:52:27,160 --> 01:52:28,520
TRANSCRIPTION ALLEY I APPLIED 

2240
01:52:28,520 --> 01:52:31,200
DATA AND CLUSTERING TECHNIQUE TO

2241
01:52:31,200 --> 01:52:33,240
LINEAR TRANSCRIPTS YOU CAN SEE 

2242
01:52:33,240 --> 01:52:36,600
EVERY TRANSCRIPT FALLS IN BOTTOM

2243
01:52:36,600 --> 01:52:38,080
LEFT QUADRANT AND BEYOND THAT 

2244
01:52:38,080 --> 01:52:41,640
THEY FALL ABOVE THE DIAGONAL 

2245
01:52:41,640 --> 01:52:42,440
INDICATING ENHANCED POST 

2246
01:52:42,440 --> 01:52:43,840
TRANSCRIPTION ALLEY THAT IS IN 

2247
01:52:43,840 --> 01:52:46,000
LINE WITH WHAT IS PUBLISHED 

2248
01:52:46,000 --> 01:52:50,600
ABOUT R57'S ROLE IN MODULATING 

2249
01:52:50,600 --> 01:52:53,640
RNA DECAY THERE WERE NOTABLE 

2250
01:52:53,640 --> 01:52:55,080
EXCEPTIONS THAT WOULD BE 

2251
01:52:55,080 --> 01:52:57,200
CLASSIFIED AT OR 57 REPRESSED 

2252
01:52:57,200 --> 01:52:59,680
THAT IS IN LINE WITH RECENT PUB 

2253
01:52:59,680 --> 01:53:02,000
KAITION IN CONRAD LAB THAT 

2254
01:53:02,000 --> 01:53:05,040
DEMONSTRATES THAT IT WILL 

2255
01:53:05,040 --> 01:53:06,240
PROMOTE DEGRADATION FOR LATE 

2256
01:53:06,240 --> 01:53:09,200
TRANSCRIPT MADE PRIOR TO DNA 

2257
01:53:09,200 --> 01:53:11,640
REPLICATION PROVIDING CONFIDENCE

2258
01:53:11,640 --> 01:53:14,560
IN CLUSTERING METHOD AND 

2259
01:53:14,560 --> 01:53:17,640
TECHNIQUES USED APPLYING TO 

2260
01:53:17,640 --> 01:53:20,400
CIRCULAR REEDS THIS IS HOW DATA 

2261
01:53:20,400 --> 01:53:23,120
LOOKS MAJORITY OF THESE FALLS IN

2262
01:53:23,120 --> 01:53:25,280
BOTTOM LEFT QUADRANT OR 57 

2263
01:53:25,280 --> 01:53:35,800
ENHANCED ABOVE THE DIAGONAL. 

2264
01:53:39,360 --> 01:53:42,920
THESE SEEM TO BE REPRESSIONED IN

2265
01:53:42,920 --> 01:53:44,640
LOW SIZE SPECIFIC FASHION.  WITH

2266
01:53:44,640 --> 01:53:46,720
THAT I WOULD LIKE TO THANK 

2267
01:53:46,720 --> 01:53:49,200
EVERYONE IN THE LAB WHO MADE IT 

2268
01:53:49,200 --> 01:53:51,080
POSSIBLE AND COLLABORATORS NICK 

2269
01:53:51,080 --> 01:53:54,600
AND CISTY AND BIOINFORMACIST WHO

2270
01:53:54,600 --> 01:53:56,240
HAS BEEN PHENOMENAL WITH THIS 

2271
01:53:56,240 --> 01:53:57,680
PROJECT AND WITH THAT I WOULD 

2272
01:53:57,680 --> 01:54:08,160
LOVE TO TAKE ANY QUESTIONS. 

2273
01:54:09,400 --> 01:54:10,280
>>ANY QUESTIONS?  

2274
01:54:10,280 --> 01:54:14,000
>>I MAY ASK.  

2275
01:54:14,000 --> 01:54:16,920
>>UH-HUH.  

2276
01:54:16,920 --> 01:54:19,000
>>DATA NEEDED SPLICING
YOU HAVE

2277
01:54:19,000 --> 01:54:21,160
THOUGHT ABOUT WHAT MECHANISMS TO

2278
01:54:21,160 --> 01:54:21,640
USE?  

2279
01:54:21,640 --> 01:54:23,520
>>MY DIAGRAM IS SHOWING
IT 

2280
01:54:23,520 --> 01:54:25,320
SLICES INDEPENDENT THAT IS 

2281
01:54:25,320 --> 01:54:27,920
OPPOSITE WHAT IS SHOWN FOR HUMAN

2282
01:54:27,920 --> 01:54:30,480
CIRCULATED RNAS AND 

2283
01:54:30,480 --> 01:54:31,080
INVESTIGATING A NUMBER OF 

2284
01:54:31,080 --> 01:54:33,080
DIFFERENT METHODS FOR THIS THERE

2285
01:54:33,080 --> 01:54:35,520
ARE RNA LYINGASES THOUGHT OF IN 

2286
01:54:35,520 --> 01:54:39,680
TERMS OF TRNA BIOLOGY AND NOVEL 

2287
01:54:39,680 --> 01:54:42,360
ONE FOUND FOR HOST BONA FIDE 

2288
01:54:42,360 --> 01:54:47,480
LYINGACE THAT IS POSSIBLE IT IS 

2289
01:54:47,480 --> 01:54:49,560
RESPONSIBLE FOR CO-VAILIENT 

2290
01:54:49,560 --> 01:54:49,800
LINKAGES. 

2291
01:54:49,800 --> 01:54:53,880
>>ANY OTHER QUESTIONS?  

2292
01:54:53,880 --> 01:55:04,040
OKAY.  

2293
01:55:41,640 --> 01:55:44,680
>>I WILL INTRODUCE YOU TO
JAMES

2294
01:55:44,680 --> 01:55:51,120
STAMOS WHO WORKS IN THE LAB. 

2295
01:55:51,120 --> 01:55:56,000
HE RECENTLY GRADUATED.  WHEN I 

2296
01:55:56,000 --> 01:55:58,400
SAY RECENT, IT WAS MONDAY.  VERY

2297
01:55:58,400 --> 01:56:00,960
RECENT AND WILL PRESENT TO YOU 

2298
01:56:00,960 --> 01:56:04,080
DATA ABOUT OPPOSING EFFECT ON 

2299
01:56:04,080 --> 01:56:08,040
SIVMAC 251 ACQUISITION OF 

2300
01:56:08,040 --> 01:56:10,520
MONOCLONAL ANTIBODIES 

2301
01:56:10,520 --> 01:56:14,120
RECOGNIZING SIV V2 IN AN A HELIX

2302
01:56:14,120 --> 01:56:17,720
AND B SHEET CONFORMATION. 

2303
01:56:17,720 --> 01:56:21,040
>>AS DR. WOISMAN NOTED
THIS 

2304
01:56:21,040 --> 01:56:23,560
MORNING THIS PHASE 3 CLINICAL 

2305
01:56:23,560 --> 01:56:26,640
TRIAL WAS ONLY EFFICACIOUS 

2306
01:56:26,640 --> 01:56:29,720
VACCINE CLINICAL TRIAL TO DATE 

2307
01:56:29,720 --> 01:56:31,880
THEY ANALYZED IMMUNE CORRELATES 

2308
01:56:31,880 --> 01:56:34,840
IN THE STUDY AND FOUND 

2309
01:56:34,840 --> 01:56:37,720
NONNEUTRALIZING IGG BINDING 

2310
01:56:37,720 --> 01:56:41,400
BOOPS OF THIS REDUCED RISK OF 

2311
01:56:41,400 --> 01:56:43,280
ACQUISITION AND RIGHT SIDE AND 

2312
01:56:43,280 --> 01:56:45,880
YOUR LEFT SIDE YOU SEE HIV 

2313
01:56:45,880 --> 01:56:50,720
VARRANT AND SURFACE OF GP120 

2314
01:56:50,720 --> 01:56:53,120
TRIMERS AND BOTTOM 3-DIMENSIONAL

2315
01:56:53,120 --> 01:56:54,720
STRUCTURE OF IT AS IF LOOKING 

2316
01:56:54,720 --> 01:56:56,800
FROM TOP DOWN AND RED IN GREEN 

2317
01:56:56,800 --> 01:56:59,760
ARE V2 LOOPS POSITIONED AT APEX 

2318
01:56:59,760 --> 01:57:02,840
OF TRIEMER AND V1 DIRECTLY 

2319
01:57:02,840 --> 01:57:05,280
ADJACENT TO IT SORT OF COVERING 

2320
01:57:05,280 --> 01:57:05,680
IT. 

2321
01:57:05,680 --> 01:57:09,360
IN THE TRIAL ALSO AS A SECONDARY

2322
01:57:09,360 --> 01:57:17,040
CORRELATE IN A VAXINESE WITH LOW

2323
01:57:17,040 --> 01:57:19,840
THESE ANTIBODIES ARE 

2324
01:57:19,840 --> 01:57:21,680
NONNEUTRALIZING AND BINDING TO 

2325
01:57:21,680 --> 01:57:25,800
INITIAL INFECTED CELLS IN MUCOSA

2326
01:57:25,800 --> 01:57:27,280
CLEARING HELLS FROM HOST BEFORE 

2327
01:57:27,280 --> 01:57:30,840
IT GOES ON TO SEE SYSTEMIC 

2328
01:57:30,840 --> 01:57:31,160
INFECTION. 

2329
01:57:31,160 --> 01:57:33,680
SUBSEQUENT ANALYSIS V2 POSITION 

2330
01:57:33,680 --> 01:57:37,640
166 TO 178 FOUND TO CONFORM TO 

2331
01:57:37,640 --> 01:57:41,240
ALPHA HELICAL STRUCTURE ANTIBODY

2332
01:57:41,240 --> 01:57:45,120
HOTSPOT FOR ADCC.  V2 LOOP IS 

2333
01:57:45,120 --> 01:57:46,560
PARTICULARLY ATTRACTIVE HIV 

2334
01:57:46,560 --> 01:57:50,760
VACCINE TARGET.  THE LOOP BINDS 

2335
01:57:50,760 --> 01:57:53,680
TO MUCOSA -- ACTIVATES CD4 

2336
01:57:53,680 --> 01:57:56,040
POSITIVE T CELLS AND 

2337
01:57:56,040 --> 01:57:57,240
PREFERENTIALLY EFFECTS THIS 

2338
01:57:57,240 --> 01:58:00,560
EARLY ON AND POSITIVE MUCOSAL T 

2339
01:58:00,560 --> 01:58:02,760
CELLS V2 LOOP MIGHT BE ABLE TO 

2340
01:58:02,760 --> 01:58:05,160
TARGET VIRUS CELLS ACTIVATING 

2341
01:58:05,160 --> 01:58:08,040
THEM CREATING MORE TARGET TO 

2342
01:58:08,040 --> 01:58:09,640
CELLS CREATING FUEL INFECTION 

2343
01:58:09,640 --> 01:58:11,800
AND THROUGH MANY VACCINE STUDIES

2344
01:58:11,800 --> 01:58:14,000
WHERE WE TOOK THIS VACCINE AND 

2345
01:58:14,000 --> 01:58:16,840
TRANSLATED BACK TO PRECLINICAL 

2346
01:58:16,840 --> 01:58:21,560
MODEL AND THIS IS A REPRODUCIBLE

2347
01:58:21,560 --> 01:58:24,200
CORRELATE RISK OF INFECTION THAT

2348
01:58:24,200 --> 01:58:27,400
SHOWS MCCOCK MODEL IS PREDICTIVE

2349
01:58:27,400 --> 01:58:31,320
MODEL FIGURING OUT HIV VACCINES 

2350
01:58:31,320 --> 01:58:33,680
WE GET SAME CORRELATES AS WE DO 

2351
01:58:33,680 --> 01:58:37,560
IN HUMANS AND HYPOTHESIS THAT 

2352
01:58:37,560 --> 01:58:39,880
V1V2IDG CORRELATE NEEDS TO BE 

2353
01:58:39,880 --> 01:58:41,320
REFINED AND WE BELIEVE ADJACENCY

2354
01:58:41,320 --> 01:58:45,080
OF V1 TO V2 INTERFERE WITH V2 

2355
01:58:45,080 --> 01:58:46,960
ANTIBODIES AND SO DOWN HERE YOU 

2356
01:58:46,960 --> 01:58:49,920
ARE SEEING THAT V1 NEXT TO V2 

2357
01:58:49,920 --> 01:58:51,760
STRUCTURE AND 3-DIMENSIONAL 

2358
01:58:51,760 --> 01:58:54,560
STRUCTURE YOU SEE V1 IN GRAY IS 

2359
01:58:54,560 --> 01:58:57,280
PARTLY MASKING VERY 2 THAT IS 

2360
01:58:57,280 --> 01:58:58,480
DOWN HERE IN RED.  

2361
01:58:58,480 --> 01:59:00,600
AND IN FACT WHEN WE LOOKED AT A 

2362
01:59:00,600 --> 01:59:03,680
LARGE NUMBERS OF VACCINATED 

2363
01:59:03,680 --> 01:59:05,360
ANIMALS, WE FOUND THAT ANIMALS 

2364
01:59:05,360 --> 01:59:07,960
WITH LOW AND WITH HIGH LEVELS OF

2365
01:59:07,960 --> 01:59:11,000
ANTI-V1 ANTIBODIES SHOWN IN 

2366
01:59:11,000 --> 01:59:13,280
DASHED CAPITAL MEYER CURVE 

2367
01:59:13,280 --> 01:59:17,080
COMPARED TO ANIMALS OF LOW V1 

2368
01:59:17,080 --> 01:59:18,440
ANTIBODIES ACQUIRE INFECTION 

2369
01:59:18,440 --> 01:59:21,080
MUCH EARLIER AND V1 IS 

2370
01:59:21,080 --> 01:59:22,080
INTERFERING WITH VACCINE 

2371
01:59:22,080 --> 01:59:25,240
PROTECTION INCREASING RISK OF 

2372
01:59:25,240 --> 01:59:27,120
ACQUISITION IN MCKOCHL.  WHAT WE

2373
01:59:27,120 --> 01:59:29,320
DECIDED TO DO WAS DELETE OUT THE

2374
01:59:29,320 --> 01:59:33,280
V1 FROM THE RV144 LIKE VACCINE 

2375
01:59:33,280 --> 01:59:36,480
WE DEVELOPED AND IN 

2376
01:59:36,480 --> 01:59:37,520
COLLABORATION WITH STRUCTURAL 

2377
01:59:37,520 --> 01:59:40,760
[INDISCERNIBLE] KOR DOZO WE 

2378
01:59:40,760 --> 01:59:44,880
GENERATED DELTA V1GP120 

2379
01:59:44,880 --> 01:59:46,960
IMMUNOGEN EXCISING OUT V1 LOOP 

2380
01:59:46,960 --> 01:59:50,320
AND PREDICTED V2 LOOP WOULD BE 

2381
01:59:50,320 --> 01:59:53,400
IN ALPHA HELICAL STRUCTURE 

2382
01:59:53,400 --> 01:59:55,080
TARGETED BY VACCINE AND LOOKING 

2383
01:59:55,080 --> 01:59:58,400
AT THIS YOU SEE THAT THEY 

2384
01:59:58,400 --> 02:00:01,040
ACQUIRE THE INFECTION LATER OR 

2385
02:00:01,040 --> 02:00:02,320
ARE PROTECTED FROM INFECTION 

2386
02:00:02,320 --> 02:00:04,360
COMPLETELY ALL TOGETHER AND 

2387
02:00:04,360 --> 02:00:08,040
MIRACULOUSLY IN SAME STUDY HE 

2388
02:00:08,040 --> 02:00:11,760
INSERTED GPG GLYCINE MUTATION AT

2389
02:00:11,760 --> 02:00:14,680
EXCISION SITE OF V1 PREDIKTSING 

2390
02:00:14,680 --> 02:00:17,640
IT WOULD FORM A BETA STRAND 

2391
02:00:17,640 --> 02:00:23,480
INSTEAD OF A-HELIX TARGETING 

2392
02:00:23,480 --> 02:00:28,080
ACC.  JUST THREE AMINO ACID SITE

2393
02:00:28,080 --> 02:00:29,280
COMPLETELY DESTROYING THIS. 

2394
02:00:29,280 --> 02:00:31,320
IN THE PLATFORM WE FOUND THROUGH

2395
02:00:31,320 --> 02:00:33,440
MANY DIFFERENT STUDIES WITH SAME

2396
02:00:33,440 --> 02:00:37,320
VACCINE V2 SPECIFIC ADCC IS A 

2397
02:00:37,320 --> 02:00:39,880
STRONG CORRELATE OF REDUCED RISK

2398
02:00:39,880 --> 02:00:41,880
THIS APPEARS TO BE AUGMENTING 

2399
02:00:41,880 --> 02:00:43,960
THESE CAPABILITIES OF A VACCINE 

2400
02:00:43,960 --> 02:00:46,280
AND THIS COLLECTIVELY SHOWS 

2401
02:00:46,280 --> 02:00:47,960
CONFIRMATION OF V2 IS CRITICAL 

2402
02:00:47,960 --> 02:00:51,120
TO VACCINE EFFICACY SHIFTING 

2403
02:00:51,120 --> 02:00:54,040
FROM ALPHA HELICAL TO ß-SHEET 

2404
02:00:54,040 --> 02:00:55,400
CONFIRMATION TO COMPLETELY 

2405
02:00:55,400 --> 02:00:57,520
DESTROY THE VACCINE. 

2406
02:00:57,520 --> 02:00:59,720
OVERALL, THIS MODEL REVEALED 

2407
02:00:59,720 --> 02:01:02,040
SYSTEMIC IMMUNE RESPONSES 

2408
02:01:02,040 --> 02:01:03,560
REPRODUCIBLE ACROSS MANY STUDIES

2409
02:01:03,560 --> 02:01:07,240
NO. 1 ANTI-V2 ANTIBODIES THAT 

2410
02:01:07,240 --> 02:01:09,160
ARE FOUND IN THE PLASMA AND AS 

2411
02:01:09,160 --> 02:01:13,680
WELL AS CHARACTERIZING BY EPI 

2412
02:01:13,680 --> 02:01:15,960
GENETIC TECHNIQUES INCREASING 

2413
02:01:15,960 --> 02:01:18,280
CHROMATIN ACCESSIBILITY IN KREB 

2414
02:01:18,280 --> 02:01:20,120
1 GENE ACCESSIBILITY THERE 

2415
02:01:20,120 --> 02:01:23,840
ASSOCIATED WITH PROCESS CALLED 

2416
02:01:23,840 --> 02:01:27,520
EF ROWCYTOSIS AND THESE ARE 

2417
02:01:27,520 --> 02:01:32,000
PRODUCED IN PLASMA AS WELL 

2418
02:01:32,000 --> 02:01:33,600
ANTIINFLAMMATORY MOLECULES AND 

2419
02:01:33,600 --> 02:01:34,640
WE HYPOTHESIZED THAT THESE 

2420
02:01:34,640 --> 02:01:36,320
EFFECTORS GET THERE AND THERE IS

2421
02:01:36,320 --> 02:01:39,320
EARLY INFECTION OF TARGET CELLS 

2422
02:01:39,320 --> 02:01:42,280
FOCUS OF INFECTION AND V2 

2423
02:01:42,280 --> 02:01:45,880
ANTIBODIES RECOGNIZE A-HELIX OF 

2424
02:01:45,880 --> 02:01:49,040
GP120 AND MEDIATE THESE THROUGH 

2425
02:01:49,040 --> 02:01:52,000
N CASE CELLS AND EVERIO CITES 

2426
02:01:52,000 --> 02:01:55,840
COMING FROM KREB ONE INCREASED 

2427
02:01:55,840 --> 02:01:58,160
ACCESSIBILITY GET TO MUCOSA 

2428
02:01:58,160 --> 02:02:00,360
CLEARING UP DEAD APOP TO THEIC 

2429
02:02:00,360 --> 02:02:05,680
CELLS FROM MUCOSA MAINTAINING 

2430
02:02:05,680 --> 02:02:08,040
ANTIINFLAMMATORY ENVIRONMENT IN 

2431
02:02:08,040 --> 02:02:10,960
MUCOSA WITH THE INFECTION 

2432
02:02:10,960 --> 02:02:14,280
WITHOUT CREATING MORE TARGET 

2433
02:02:14,280 --> 02:02:15,360
CELLS. 

2434
02:02:15,360 --> 02:02:19,280
 -- PRODUCING IL-7 TAENSTRONG 

2435
02:02:19,280 --> 02:02:21,680
CORRELATE REDUCED INFECTION 

2436
02:02:21,680 --> 02:02:23,720
ACROSS SEVERAL STUDIES AND FIND 

2437
02:02:23,720 --> 02:02:27,840
IN MANY STUDIES THESE TH1 AND 

2438
02:02:27,840 --> 02:02:30,080
TH2 CELLS CORRELATE WITH REDUCED

2439
02:02:30,080 --> 02:02:31,760
RISK IN THE BLOOD AND FIND CELLS

2440
02:02:31,760 --> 02:02:34,640
ARE GETTING TO MUCOSA CREATING 

2441
02:02:34,640 --> 02:02:37,000
LESS TARGET CELLS FOR THE VIRUS 

2442
02:02:37,000 --> 02:02:38,840
AND MORE PROTECTION THAT LED ME 

2443
02:02:38,840 --> 02:02:41,600
TO ASK THE QUESTION THAT 

2444
02:02:41,600 --> 02:02:44,040
RESEARCH HYPOTHESIS WAS 

2445
02:02:44,040 --> 02:02:47,640
MONOCLONAL ANTIBODIES TO PROTECT

2446
02:02:47,640 --> 02:02:49,720
THESE AGAINST SIV ACQUISITION 

2447
02:02:49,720 --> 02:02:55,120
AND DOING THIS USE PAST 

2448
02:02:55,120 --> 02:02:57,480
IMMUNIZATION AND THESE CHALLENGE

2449
02:02:57,480 --> 02:03:01,200
WITH SIV251 AND DOING THIS I 

2450
02:03:01,200 --> 02:03:03,440
USED TWO ANTIBODIES THAT WERE 

2451
02:03:03,440 --> 02:03:04,960
CLONED IN COLLABORATION BETWEEN 

2452
02:03:04,960 --> 02:03:06,880
OUR LAB AND VRC. 

2453
02:03:06,880 --> 02:03:09,200
THEY CLONED OUT B CELLS AND 

2454
02:03:09,200 --> 02:03:11,160
VACCINATED AND PROTECTED MCCOCK 

2455
02:03:11,160 --> 02:03:14,200
THAT IS CHALLENGED 22 TIMES AND 

2456
02:03:14,200 --> 02:03:16,320
NEVER BECAME INFECTED CHOSE 

2457
02:03:16,320 --> 02:03:19,840
ANIMAL TO PROFILE V2 SPECIFIC 

2458
02:03:19,840 --> 02:03:21,160
RESPONSES FOUND THAT THESE B 

2459
02:03:21,160 --> 02:03:23,840
CELLS BY USING PROBES WITH B1 

2460
02:03:23,840 --> 02:03:26,160
WITH B2 PROBES WITH DIFFERENT 

2461
02:03:26,160 --> 02:03:28,120
STRAINS OF SIV AND THEY FOUND 

2462
02:03:28,120 --> 02:03:38,680
TWO ANTIBODIES NCI05 AND NCI09. 

2463
02:03:38,680 --> 02:03:43,400
 -- OVERLAPPING EPITOEP IN V2C 

2464
02:03:43,400 --> 02:03:46,120
REGION DOWN HERE OVERLAPS WITH 

2465
02:03:46,120 --> 02:03:48,520
THIS BINDING SITE DOWN HERE. 

2466
02:03:48,520 --> 02:03:49,920
VERY IMPORTANTLY FOR THIS STUDY 

2467
02:03:49,920 --> 02:03:52,960
IS THAT THESE TWO ANTIBODIES 

2468
02:03:52,960 --> 02:03:54,600
HAVE COMPLETELY DIFFERENT FABS 

2469
02:03:54,600 --> 02:03:57,080
BUT IGG1 EFFECTIVE FUNCTION 

2470
02:03:57,080 --> 02:03:58,400
SHOULD BE THE SAME THAT IS 

2471
02:03:58,400 --> 02:04:00,600
IMPORTANT AS I PROGRESS IN THE 

2472
02:04:00,600 --> 02:04:01,720
TALK. 

2473
02:04:01,720 --> 02:04:04,720
SO, THEY CHARACTERIZED -- WE 

2474
02:04:04,720 --> 02:04:07,120
CHARACTERIZED THE THREE 

2475
02:04:07,120 --> 02:04:08,320
DIMENSIONAL EPITOEP STRUCTURE 

2476
02:04:08,320 --> 02:04:10,280
RECOGNIZED BY TWO DIFFERENT 

2477
02:04:10,280 --> 02:04:12,640
ANTIBODIES THIS RECOGNIZES V2 IN

2478
02:04:12,640 --> 02:04:15,600
ROUGHLY LINEAR EPITOEP 

2479
02:04:15,600 --> 02:04:16,200
STRUCTURE.  

2480
02:04:16,200 --> 02:04:21,000
THIS IS IN CONTRAST TO THE NCI05

2481
02:04:21,000 --> 02:04:22,880
RECOGNIZING A HELICAL COIL 

2482
02:04:22,880 --> 02:04:24,520
STRUCTURE IN V2.  YOU CAN SEE 

2483
02:04:24,520 --> 02:04:27,840
THESE TWO ANTIBODIES RECOGNIZE 

2484
02:04:27,840 --> 02:04:31,080
VERY DIFFERENT EPITOEP 

2485
02:04:31,080 --> 02:04:33,080
CONFIRMATIONS FROM ONE ANOTHER. 

2486
02:04:33,080 --> 02:04:34,480
NEXT, WE COMPARE DIFFERENT 

2487
02:04:34,480 --> 02:04:37,320
EFFECTOR FUNCTIONS OF ANTIBODIES

2488
02:04:37,320 --> 02:04:43,360
BETWEEN NCI05 IN RED AND NCI09 

2489
02:04:43,360 --> 02:04:45,840
IN BLUE. 

2490
02:04:45,840 --> 02:04:51,320
WE TAKE STEM CELLS CODING WITH 

2491
02:04:51,320 --> 02:04:53,600
GP120 AND THEY KILL CODED CELLS 

2492
02:04:53,600 --> 02:04:55,440
AND WERE ABLE TO MEASURE THAT 

2493
02:04:55,440 --> 02:04:59,960
AND NCI05 AND NCI09 MEDIATE 

2494
02:04:59,960 --> 02:05:03,080
EQUIVALENT LEVELS OF ADCC.  

2495
02:05:03,080 --> 02:05:05,680
DIFFERENT ASSAY PERFORMED BY 

2496
02:05:05,680 --> 02:05:09,520
DAVID AT UNIVERSITY WISCONSIN 

2497
02:05:09,520 --> 02:05:12,160
MADISON WITH INFECTED CELLS IN 

2498
02:05:12,160 --> 02:05:14,520
PRESENCE OF SOLUBLE CD4 THAT 

2499
02:05:14,520 --> 02:05:17,800
BINDS TO TRIMERIC GDP120 ON 

2500
02:05:17,800 --> 02:05:19,880
VIRUS INFECTED CELLS OPENING THE

2501
02:05:19,880 --> 02:05:22,320
STRUCTURE AND WHAT WE FIND IS 

2502
02:05:22,320 --> 02:05:25,800
THAT NCI05 IS ABLE TO MEDIATE 

2503
02:05:25,800 --> 02:05:30,000
THESE INFECTED CELLED WITH -- 

2504
02:05:30,000 --> 02:05:32,360
NCI09 DOES NOT AND NUANCED 

2505
02:05:32,360 --> 02:05:34,680
DIFFERENCE IN WAY THAT THIS 

2506
02:05:34,680 --> 02:05:36,640
PERFORMS BASED ON WHETHER 

2507
02:05:36,640 --> 02:05:38,240
CONFIRMATION EPITOEP 

2508
02:05:38,240 --> 02:05:39,800
CONFIRMATION IS EXPOSE THE IN 

2509
02:05:39,800 --> 02:05:44,520
PRESENCE OF CD4 OR NOT AND NCI09

2510
02:05:44,520 --> 02:05:49,360
DOES NOT DO THAT AND HOWEVER 

2511
02:05:49,360 --> 02:05:51,080
NCI09 ENGAGES PROCESS CALLED 

2512
02:05:51,080 --> 02:05:52,960
[INDISCERNIBLE] AND 

2513
02:05:52,960 --> 02:05:55,160
IMMUNOEVASION MECHANISM USED BY 

2514
02:05:55,160 --> 02:05:57,720
PATHOGENS AND THIS MEASURES STEM

2515
02:05:57,720 --> 02:06:01,000
CELLS CODED WITH GDP120. 

2516
02:06:01,000 --> 02:06:03,960
THE THP1 CELLS ARE ABLE TO 

2517
02:06:03,960 --> 02:06:06,640
EXTRACT OFF BOTH ANTIGEN AND 

2518
02:06:06,640 --> 02:06:12,480
ANTIBODY FOR SURFACE OF THE CELL

2519
02:06:12,480 --> 02:06:14,360
REDUCING IMMUNE RECOGNITION. 

2520
02:06:14,360 --> 02:06:16,640
FURTHER, THERE WAS ANOTHER 

2521
02:06:16,640 --> 02:06:21,240
DIFFERENCE THAT THE NCI09 

2522
02:06:21,240 --> 02:06:25,680
PROMOTES ANTIBODY CELLULAR 

2523
02:06:25,680 --> 02:06:28,960
PHAGOCYTOSIS STRONGER THAN NCI05

2524
02:06:28,960 --> 02:06:30,440
-- INFECTION OF MORE TARGET 

2525
02:06:30,440 --> 02:06:32,000
CELLS YOU CAN SEE HERE I 

2526
02:06:32,000 --> 02:06:35,160
MENTIONED BOTH ANTIBODIES HAVE 

2527
02:06:35,160 --> 02:06:38,680
SAME IGG1 FC REGION HOWEVER 

2528
02:06:38,680 --> 02:06:41,360
DIFFERENT FAB AND WAY THAT 

2529
02:06:41,360 --> 02:06:43,400
ANTIBODY BINDS TO SURFACE OF 

2530
02:06:43,400 --> 02:06:46,480
GP120 CODED CELLS ARE INFECTED 

2531
02:06:46,480 --> 02:06:47,680
CELLS COMPLETELY CHANGES PROFILE

2532
02:06:47,680 --> 02:06:50,040
OF THE ANTIBODIES WE BELIEVE 

2533
02:06:50,040 --> 02:06:52,120
THEY ARE BALANCED IN DIFFERENT 

2534
02:06:52,120 --> 02:06:55,320
DIRECTIONS AND NCI09 APPEARS TO 

2535
02:06:55,320 --> 02:06:56,360
HAVE COMPETING EFFECTOR 

2536
02:06:56,360 --> 02:07:01,200
FUNCTIONS TAKING AWAY FROM ADCC.

2537
02:07:01,200 --> 02:07:04,000
FURTHER, WE LOOKED AT ABILITY OF

2538
02:07:04,000 --> 02:07:06,720
ANTIBODIES TO BLOCK V2 BIENTDING

2539
02:07:06,720 --> 02:07:12,440
TO ALPHA 4 BETA 7 AND THEY 

2540
02:07:12,440 --> 02:07:15,640
EQUIVALENTLY BLOCK -- NCI09 

2541
02:07:15,640 --> 02:07:17,680
APPEARS TO BLOCK T CELL 

2542
02:07:17,680 --> 02:07:20,200
ACTIVATION MARKED BY CC5 UP 

2543
02:07:20,200 --> 02:07:22,760
REGULATION MORE TARGET CELLS FOR

2544
02:07:22,760 --> 02:07:26,120
VIRUS AND NCI09 DOESN'T BLOCK T 

2545
02:07:26,120 --> 02:07:29,640
CELL ACTIVATION BY B2.  SO, I 

2546
02:07:29,640 --> 02:07:32,320
DESIGNED A MASSIVE IMMUNOIZATION

2547
02:07:32,320 --> 02:07:36,520
STUDY AT MCKOCHL AND TOP IN RED 

2548
02:07:36,520 --> 02:07:42,280
ARE NCI05 ANIMALS AND DOWN HERE 

2549
02:07:42,280 --> 02:07:42,680
NCI09. 

2550
02:07:42,680 --> 02:07:45,640
WHAT WE DID IN THE GROUPS IS 

2551
02:07:45,640 --> 02:07:48,520
PASSIVE IMMUNIZED ANIMALS 4 DAYS

2552
02:07:48,520 --> 02:07:51,480
PRIOR TO CHALLENGE TO HAVE 

2553
02:07:51,480 --> 02:07:53,240
ANTIBODIES REACH HIGH LEVELS OF 

2554
02:07:53,240 --> 02:07:56,040
MUCOSA AND 3 TIMES AND 

2555
02:07:56,040 --> 02:07:57,600
REINOCULATED ANIMALS AGAIN WITH 

2556
02:07:57,600 --> 02:07:59,080
ANTIBODY TO MAINTAIN HIGH LEVELS

2557
02:07:59,080 --> 02:08:02,600
OF ANTIBODIES CHALLENGING 

2558
02:08:02,600 --> 02:08:04,960
ANIMALS UNTIL THEY WERE INFECTED

2559
02:08:04,960 --> 02:08:08,400
AND NEITHER OF THEM PROTECTED 

2560
02:08:08,400 --> 02:08:10,560
MCKOCHL AGAINST ACQUISITION OF 

2561
02:08:10,560 --> 02:08:13,320
THESE COMPARED TO CONTROLS AND 

2562
02:08:13,320 --> 02:08:17,840
V2 MONOCLONAL ANTIBODIES 

2563
02:08:17,840 --> 02:08:20,840
THEMSELVES AND THE V2 REQUIRES 

2564
02:08:20,840 --> 02:08:23,840
PRESENCE OF OTHER VACCINE 

2565
02:08:23,840 --> 02:08:25,280
INDUCED INNATE IMMUNE RESPONSES 

2566
02:08:25,280 --> 02:08:27,280
TO HARNESS PROTECTIVE 

2567
02:08:27,280 --> 02:08:28,040
CAPABILITIES AND HOWEVER THAT IS

2568
02:08:28,040 --> 02:08:30,960
NOT THE FULL STORY WHEN I LOOKED

2569
02:08:30,960 --> 02:08:34,120
CAREFULLY IN RECTAL MUCOSA 

2570
02:08:34,120 --> 02:08:36,840
MEASURING LEVEL OF MONOCLONAL 

2571
02:08:36,840 --> 02:08:38,800
ANTIBODY IN THIS WHEN LOOKING AT

2572
02:08:38,800 --> 02:08:40,200
THIS GROUP THERE WAS A STRONG 

2573
02:08:40,200 --> 02:08:43,400
CORRELATION WITH DELAYED 

2574
02:08:43,400 --> 02:08:45,640
ACQUISITION WITH THIS SPECIFIC 

2575
02:08:45,640 --> 02:08:49,640
ANTIBODY AND MIGHT BE PART OF 

2576
02:08:49,640 --> 02:08:52,040
VULNERABILITY SITE EXPOSED UPON 

2577
02:08:52,040 --> 02:08:54,480
CD4 BINDING INDUCING ADCC AND WE

2578
02:08:54,480 --> 02:08:58,240
SEE THIS AND NO CORRELATION WITH

2579
02:08:58,240 --> 02:09:00,040
NCI09 GROUP AND HOWEVER WHEN WE 

2580
02:09:00,040 --> 02:09:01,960
LOOK AT PLASMA THIS IS 

2581
02:09:01,960 --> 02:09:03,960
CORRELATED WITH INCREASED RISK 

2582
02:09:03,960 --> 02:09:06,520
OF ACQUISITION.  FURTHER IN THE 

2583
02:09:06,520 --> 02:09:10,360
ADCC MEASURED IN PLASMA IS ALSO 

2584
02:09:10,360 --> 02:09:11,720
TRENDING TOWARDS REDUCED RISK IN

2585
02:09:11,720 --> 02:09:17,160
THE NCI05 GROUP AND NOT NCI09 

2586
02:09:17,160 --> 02:09:20,640
GROUP AND THISCYTOSIS MEASURED 

2587
02:09:20,640 --> 02:09:22,120
IN BASELINE POSITIVE SITES 

2588
02:09:22,120 --> 02:09:24,840
STRONGLY CORRELATED REDUCED 

2589
02:09:24,840 --> 02:09:25,200
RISK. 

2590
02:09:25,200 --> 02:09:30,120
SO, WHAT IS MISSING FROM THE 

2591
02:09:30,120 --> 02:09:32,880
PASSIVE IMMUNIZATION STUDIES WE 

2592
02:09:32,880 --> 02:09:35,800
HAVE CRYTOCITAL RESPONSES THAT 

2593
02:09:35,800 --> 02:09:38,200
ARE REDUCED BY LBAC VACCINATION 

2594
02:09:38,200 --> 02:09:41,320
AND CELLS ARE ABLE TO GET INTO 

2595
02:09:41,320 --> 02:09:42,560
MUCOSA AND WHEN THERE IN 

2596
02:09:42,560 --> 02:09:45,080
PRESENCE OF V2 ANTIBODIES CAN 

2597
02:09:45,080 --> 02:09:49,360
THEY MEDIATE AUGMENTED ADCC IS 

2598
02:09:49,360 --> 02:09:51,080
WHAT WE BELIEVE AND THESE 

2599
02:09:51,080 --> 02:09:53,000
CLEANING UP APOP TO THEIC CELLS 

2600
02:09:53,000 --> 02:09:56,120
ARE NOT THERE PASSIVE 

2601
02:09:56,120 --> 02:09:57,200
IMMUNOIZATION EXPERIENCE YOU 

2602
02:09:57,200 --> 02:09:59,440
NEED THESE LOCALIZED THERE TO 

2603
02:09:59,440 --> 02:10:03,400
HARNESS CAPABILITIES OF V2 

2604
02:10:03,400 --> 02:10:06,480
ANTIBODIES AND HELICAL 

2605
02:10:06,480 --> 02:10:09,280
COILS/ALPHA HELICAL G2 APPEAR TO

2606
02:10:09,280 --> 02:10:11,800
BE VERY IMPORTANT IN OUR 

2607
02:10:11,800 --> 02:10:12,080
VACCINE. 

2608
02:10:12,080 --> 02:10:16,000
THERE IS ALSO WE ARE MISSING 

2609
02:10:16,000 --> 02:10:18,720
NKP44 POSITIVE ILC17 POSITIVE 

2610
02:10:18,720 --> 02:10:20,040
CELLS AAND REDEUCED NUMBER OF 

2611
02:10:20,040 --> 02:10:22,960
TARGETED CELLS YOU NEED SYMPHONY

2612
02:10:22,960 --> 02:10:26,040
OF IMMUNE RESPONSES IN MUCOSA TO

2613
02:10:26,040 --> 02:10:28,480
PRODUCE RISK OF SIB ACQUISITION 

2614
02:10:28,480 --> 02:10:30,440
AND WITH THAT THAFKING LAB AND 

2615
02:10:30,440 --> 02:10:32,240
EVERYONE ELSE IN MY LAB I DON'T 

2616
02:10:32,240 --> 02:10:34,800
HAVE TIME TO NECESSARILY GO 

2617
02:10:34,800 --> 02:10:35,280
OVER. 

2618
02:10:35,280 --> 02:10:37,600
VACCINE RESEARCH CENTER 

2619
02:10:37,600 --> 02:10:39,000
PARTICULARLY [INDISCERNIBLE] 

2620
02:10:39,000 --> 02:10:41,480
HELPED RESOLVE THE STRUCTURE OF 

2621
02:10:41,480 --> 02:10:46,720
NCI05 AND MHRP AND UNIVERSITY OF

2622
02:10:46,720 --> 02:10:51,760
WISCONSIN MADISON NIAD AND NYU 

2623
02:10:51,760 --> 02:10:53,760
AND EMORY HELPED TO DO THE 

2624
02:10:53,760 --> 02:10:55,560
STUDIES AND WITH THAT I WILL 

2625
02:10:55,560 --> 02:10:58,720
TAKE ANY QUESTIONS YOU HAVE. 

2626
02:10:58,720 --> 02:10:59,600
>>[APPLAUSE]. 

2627
02:10:59,600 --> 02:11:09,760
>>OKAY.  

2628
02:11:14,080 --> 02:11:14,640
>>THANK YOU. 

2629
02:11:14,640 --> 02:11:17,440
>>I WOULD LIKE TO THANK 

2630
02:11:17,440 --> 02:11:19,880
SPEAKERS AGAIN.  

2631
02:11:19,880 --> 02:11:20,720
>>[APPLAUSE]. 

2632
02:11:20,720 --> 02:11:24,920
>>WE HAVE A 15 MINUTE
BREAK SO 

2633
02:11:24,920 --> 02:11:28,720
SEE YOU AT 11:15.  THANK YOU.  

2634
02:11:28,720 --> 02:11:29,760
>>WELCOME EVERYONE TO THE

2635
02:11:29,760 --> 02:11:31,040
SECOND SESSION.  KEEPING THINGS 

2636
02:11:31,040 --> 02:11:40,120
ON TIME, WE HAVE THE FIRST 

2637
02:11:40,120 --> 02:11:42,640
SPEAKER, RAMONA MOLS WHO WILL 

2638
02:11:42,640 --> 02:11:47,200
TALK ABOUT ROLE OF MONOCYTES, 

2639
02:11:47,200 --> 02:11:51,040
CTL, AND NK CELLS IN PRIMARY 

2640
02:11:51,040 --> 02:11:51,840
HTLV-1 INFECTION. 

2641
02:11:51,840 --> 02:11:54,040
>>THANK YOU.  I WANT TO
THAFK 

2642
02:11:54,040 --> 02:11:56,120
THE COMMITTEE GIVING ME 

2643
02:11:56,120 --> 02:11:59,560
OPPORTUNITY TO PRESENT MY WORK 

2644
02:11:59,560 --> 02:12:06,920
ON ROLE OF MONOCYTES IN HTLV-1 

2645
02:12:06,920 --> 02:12:08,160
INFECTION.  BRIEF INTRODUCTION 

2646
02:12:08,160 --> 02:12:14,600
OF THE VIRUSES HTLV-1 IS RETRO 

2647
02:12:14,600 --> 02:12:18,600
VIRUS AND ONCOVIRUS THAT EFFECTS

2648
02:12:18,600 --> 02:12:20,280
10 TO 20 MILLION PEOPLE 

2649
02:12:20,280 --> 02:12:21,760
WORLDWIDE EVEN IF REAL NUMBER IS

2650
02:12:21,760 --> 02:12:23,560
HIGHER DUE TO LACK OF TESTING IN

2651
02:12:23,560 --> 02:12:27,520
MANY COUNTRIES. 

2652
02:12:27,520 --> 02:12:33,880
HTLV-1 IS AGENT OF HUMAN T CELL 

2653
02:12:33,880 --> 02:12:43,400
LEUKEMIA VIRUS TYPE 1. 

2654
02:12:43,400 --> 02:12:47,120
IT IS COMMONLY OBSERVED IN 

2655
02:12:47,120 --> 02:12:50,000
NATURED D1 INFECTED INDIVIDUALS 

2656
02:12:50,000 --> 02:12:51,800
AND THIS IS REPRESENTATION OR 

2657
02:12:51,800 --> 02:12:56,480
PICTURE OF HTLV-1 PATIENT 

2658
02:12:56,480 --> 02:12:59,040
DISPLAYING INVEKTED DERMATITIS 

2659
02:12:59,040 --> 02:13:02,920
THAT IS INDUCED BY THE VIRUS. 

2660
02:13:02,920 --> 02:13:07,520
HTLV-1 TARGET PRIMARILY CD4T 

2661
02:13:07,520 --> 02:13:10,080
CELL TO LESS EXTENT 

2662
02:13:10,080 --> 02:13:12,120
[INDISCERNIBLE] CELL AND VIRAL 

2663
02:13:12,120 --> 02:13:15,960
DNA FOUND TO BE DYE SECTABLE IN 

2664
02:13:15,960 --> 02:13:18,440
PATIENT AND MONOCYTE AND DEN 

2665
02:13:18,440 --> 02:13:21,600
DRIDIC CELLS AND OPTION OF THESE

2666
02:13:21,600 --> 02:13:23,960
CD4 CELLS AND CELLULAR 

2667
02:13:23,960 --> 02:13:25,240
TRANSFORMATION THAT WILL 

2668
02:13:25,240 --> 02:13:28,360
ULTIMATELY LEAD TO THE 

2669
02:13:28,360 --> 02:13:34,320
DEVELOPMENT OF THIS LYMPHOMA AND

2670
02:13:34,320 --> 02:13:36,720
H1 INFECTED INDIVIDUAL IS 

2671
02:13:36,720 --> 02:13:38,440
DEREGULATION OF IMMUNE RESPONSE 

2672
02:13:38,440 --> 02:13:41,560
WITH ALTERATION AND PERTUBATION 

2673
02:13:41,560 --> 02:13:44,840
OF [INDISCERNIBLE] AND HTLV-1 

2674
02:13:44,840 --> 02:13:46,720
INFECTION IS LIFELONG DISEASE 

2675
02:13:46,720 --> 02:13:50,240
AND VIRUS PERSISTS IN HOST OF 

2676
02:13:50,240 --> 02:13:52,360
FACE OF STRONG ADAPTIVE 

2677
02:13:52,360 --> 02:13:54,880
RESPONSES AND IN VIRUS OF 

2678
02:13:54,880 --> 02:13:56,600
[INDISCERNIBLE] AND VIRAL 

2679
02:13:56,600 --> 02:13:59,720
PROTEIN P12 AND MP8 PLAY AN 

2680
02:13:59,720 --> 02:14:02,880
IMPORTANT ROLE THAT IS A 

2681
02:14:02,880 --> 02:14:04,400
SCHEMATIC REPRESENTATION OF THIS

2682
02:14:04,400 --> 02:14:11,800
GENOME THAT ENCODES FOR VIRAL 

2683
02:14:11,800 --> 02:14:13,600
PROTEIN. 

2684
02:14:13,600 --> 02:14:18,760
P12 LOCALIZE ON ENDOPLASMATIC 

2685
02:14:18,760 --> 02:14:23,480
RETICULUM AND IN GOLGI 

2686
02:14:23,480 --> 02:14:26,480
UNDERGOING CLEAVAGE AND THEY 

2687
02:14:26,480 --> 02:14:28,960
LOCALIZE ON CELLULAR MEMBRANE. 

2688
02:14:28,960 --> 02:14:32,560
THE VIRAL PROTEIN P12 IS PLAYING

2689
02:14:32,560 --> 02:14:35,240
AN IMPORTANT ROLE IN PROTECTING 

2690
02:14:35,240 --> 02:14:37,440
INFECTED CELL FROM IMMUNE 

2691
02:14:37,440 --> 02:14:39,480
RECOGNITION BY DOWNREGULATING 

2692
02:14:39,480 --> 02:14:42,920
THEM ON C + 1 ON SURFACE OF 

2693
02:14:42,920 --> 02:14:46,480
INFECTED CELL THAT PROVIDES 

2694
02:14:46,480 --> 02:14:52,800
PROTECTION AGAINST CD8 + -- 

2695
02:14:52,800 --> 02:14:54,080
INFECTED CELL MORE SUSCEPTIBLE 

2696
02:14:54,080 --> 02:14:57,600
TO THE KILLING AND P12 IS 

2697
02:14:57,600 --> 02:14:59,160
DOWNREGULATING INCOME 1 AND 2 

2698
02:14:59,160 --> 02:15:03,280
THAT ARE MOLECULES THAT PROTECT 

2699
02:15:03,280 --> 02:15:05,480
INFECTED CELL FROM THIS KILLING.

2700
02:15:05,480 --> 02:15:09,600
VIRAL PROTEIN P12 IS PROMOTING 

2701
02:15:09,600 --> 02:15:11,520
[INDISCERNIBLE] OF VIRUS 

2702
02:15:11,520 --> 02:15:13,440
INDUCING TRANSCRIPTION FACTOR 

2703
02:15:13,440 --> 02:15:15,040
INVOLVING T CELL GROWTH THAT 

2704
02:15:15,040 --> 02:15:18,840
INCLUDE STAT 5 AND NFAT.  

2705
02:15:18,840 --> 02:15:22,040
VIRAL PROTEIN P8 IS RELEASE BY 

2706
02:15:22,040 --> 02:15:24,520
-- FROM CLEAVAGE FROM THE VIRAL 

2707
02:15:24,520 --> 02:15:29,040
PROTEIN P12 THAT LOCALIZED ON 

2708
02:15:29,040 --> 02:15:32,360
CELLULAR MEMBRANE AND PROMOTING 

2709
02:15:32,360 --> 02:15:34,520
TRANSMISSION OF THE VIRUS.  YOU 

2710
02:15:34,520 --> 02:15:38,200
CAN SEE HERE IN MICROSCOPY 

2711
02:15:38,200 --> 02:15:38,520
PICTURE. 

2712
02:15:38,520 --> 02:15:41,600
VIRAL PROTEIN PH IS POSITION OF 

2713
02:15:41,600 --> 02:15:46,000
THE VIRUS FROM INFECTED CELL TO 

2714
02:15:46,000 --> 02:15:47,680
UNINFECTED CELLS AND ALSO VIRAL 

2715
02:15:47,680 --> 02:15:51,440
PROTEIN P12 IS UPREGULATING LFA1

2716
02:15:51,440 --> 02:15:53,760
ON SURFACE OF INFECTED CELL THIS

2717
02:15:53,760 --> 02:15:57,360
IS CLASSROOM MARKET PROMOTING 

2718
02:15:57,360 --> 02:16:00,800
RECRUITMENT OF UNINFECTED CD4 TO

2719
02:16:00,800 --> 02:16:02,840
SITE OF INFECTION WHERE THEY 

2720
02:16:02,840 --> 02:16:06,240
WILL GET INFECTED THAT IS 

2721
02:16:06,240 --> 02:16:08,520
MECHANISM THAT INVOLVES USE TO 

2722
02:16:08,520 --> 02:16:11,200
PROMOTE SPREADING ON VIRUS AND 

2723
02:16:11,200 --> 02:16:13,640
VIRAL PROTEIN P8 PROTECT 

2724
02:16:13,640 --> 02:16:19,120
INFECTED CELL FROM CDA MEDIATED 

2725
02:16:19,120 --> 02:16:22,040
KILLING DOWNBINDING ON CD4 ON 

2726
02:16:22,040 --> 02:16:23,480
CELL SURFACE AND [INDISCERNIBLE]

2727
02:16:23,480 --> 02:16:25,200
RESPOND TO BE PARTICULARLY 

2728
02:16:25,200 --> 02:16:28,160
IMPORTANT FOR CONSISTENCE OF THE

2729
02:16:28,160 --> 02:16:30,280
VIRUS.  IN ANIMAL STUDY 

2730
02:16:30,280 --> 02:16:34,160
PERFORMED IN OUR LAB, WE SHOWED 

2731
02:16:34,160 --> 02:16:37,760
THAT HLB1P KNOCKOUT VIRUS THAT 

2732
02:16:37,760 --> 02:16:40,200
IS LACKING EXPRESSION OF VIRAL 

2733
02:16:40,200 --> 02:16:44,000
PROTEIN P12 AND P8 GIVE 

2734
02:16:44,000 --> 02:16:45,440
UNININSTRUCTION IN THE INFECTION

2735
02:16:45,440 --> 02:16:47,640
IN [INDISCERNIBLE] IN THIS STUDY

2736
02:16:47,640 --> 02:16:50,840
WE INOCULATED [INDISCERNIBLE] 

2737
02:16:50,840 --> 02:16:54,280
WITH WILD TYPE VIRUS AND P12KO 

2738
02:16:54,280 --> 02:16:57,200
VIRUS AND FOLLOWED 20 WEEK POST 

2739
02:16:57,200 --> 02:17:01,880
INOCULATION OF THE VIRUS AND 

2740
02:17:01,880 --> 02:17:04,120
USED WESTERN BLOT TO DETECT 

2741
02:17:04,120 --> 02:17:06,800
PRESENCE OF THE ANTIBODY AND 

2742
02:17:06,800 --> 02:17:10,320
POSITIVE AND NEGATIVE WESTERN 

2743
02:17:10,320 --> 02:17:11,400
BLOCK TO LOOK LIKE AND PRESENCE 

2744
02:17:11,400 --> 02:17:13,160
OF ANTIBODY WE HAVE ACTIVITY 

2745
02:17:13,160 --> 02:17:17,440
AGAINST HTLV-1 ANTIGEN AND 

2746
02:17:17,440 --> 02:17:21,040
ABSENCE OF ANTIBODY THERE IS NO 

2747
02:17:21,040 --> 02:17:22,880
ACTIVITY AGAINST THESE ANTIGEN 

2748
02:17:22,880 --> 02:17:25,240
AND THESE REMAINED COMPLETELY 

2749
02:17:25,240 --> 02:17:27,360
BLANK.  BASED ON THIS STUDY AND 

2750
02:17:27,360 --> 02:17:30,320
OUR STUDY PERFORMED IN THE LAB 

2751
02:17:30,320 --> 02:17:32,640
WE ASSESS INFECTIVITY OF WILD 

2752
02:17:32,640 --> 02:17:37,320
TYPE VIRUS TO BE 50 TO 75%.  ON 

2753
02:17:37,320 --> 02:17:39,560
OTHER END KNOCKLATING INDIVIDUAL

2754
02:17:39,560 --> 02:17:43,760
WITH THIS VIRUS NONE OF THE 

2755
02:17:43,760 --> 02:17:44,440
ANIMALS CONVERTED AND WE 

2756
02:17:44,440 --> 02:17:46,720
COULDN'T DETECT PRESENCE OF 

2757
02:17:46,720 --> 02:17:50,040
VIRAL DNA IN THIS OF ALL ANIMAL 

2758
02:17:50,040 --> 02:17:51,760
AT ANY TIME POINT DURING THE 

2759
02:17:51,760 --> 02:17:55,840
STUDY THAT ASSESS INFECTIVITY OF

2760
02:17:55,840 --> 02:18:00,880
P12 KNOCKOUT VIRUS TO BE 0%.  

2761
02:18:00,880 --> 02:18:05,080
OUR LAB SHOWS IMPORTANCE IN THE 

2762
02:18:05,080 --> 02:18:09,400
PERSISTENCE AND ORF1 IS 

2763
02:18:09,400 --> 02:18:11,960
PROTECTING DEVELOP FROM MEDIATED

2764
02:18:11,960 --> 02:18:14,360
KILLING IN VITRO AND THE 

2765
02:18:14,360 --> 02:18:16,960
EXPRESSION IS REQUIRED FOR 

2766
02:18:16,960 --> 02:18:19,960
PERSISTENCE OF THIS AND VIRAL 

2767
02:18:19,960 --> 02:18:23,320
DNA WAS FOUND TO BE DETECTIBLE 

2768
02:18:23,320 --> 02:18:27,240
IN A MONOCITE ISOLATED FROM HV1 

2769
02:18:27,240 --> 02:18:31,840
INFECTED PATIENT AND LAB SHOWS 

2770
02:18:31,840 --> 02:18:34,280
P12 KNOCKOUT VIRUS LACKING 

2771
02:18:34,280 --> 02:18:38,680
EXPRESSION OF ORF-1 UNABLE TO 

2772
02:18:38,680 --> 02:18:40,320
GIVE -- ALL THIS EVIDENCE LEADS 

2773
02:18:40,320 --> 02:18:42,720
US TO OUR HYPOTHESIS THAT IS 

2774
02:18:42,720 --> 02:18:48,960
THAT NKCTL OR MONOCITE INFECTION

2775
02:18:48,960 --> 02:18:50,760
IN VIVO AND THIS KNOWLEDGE IS 

2776
02:18:50,760 --> 02:18:52,200
PARTICULARLY IMPORTANT FOR OUR 

2777
02:18:52,200 --> 02:18:53,960
LAB.  FINAL GOAL OF THE LAB IS 

2778
02:18:53,960 --> 02:19:00,240
TO DEVELOP A PROTECTIVE HLV1 

2779
02:19:00,240 --> 02:19:03,040
[INDISCERNIBLE] SO, TO STUDY 

2780
02:19:03,040 --> 02:19:07,720
IMPORTANCE OF THE CD8 AND NK 

2781
02:19:07,720 --> 02:19:10,680
MONOCYTE IN EARLY HTLV-1 

2782
02:19:10,680 --> 02:19:12,680
INFECTION WE INOCULATED 

2783
02:19:12,680 --> 02:19:14,440
[INDISCERNIBLE] WITH THE VIRUS 

2784
02:19:14,440 --> 02:19:18,480
FOLLOWING THE DEPLETION OF THOSE

2785
02:19:18,480 --> 02:19:20,360
SPECIFIC SUBSET.  THIS 

2786
02:19:20,360 --> 02:19:23,040
SLIDESHOW, OUR STUDY DESIGN AND 

2787
02:19:23,040 --> 02:19:24,400
DIVIDED ANIMAL IN THREE GROUP 

2788
02:19:24,400 --> 02:19:27,160
AND FIRST GROUP WE DEPLETED 

2789
02:19:27,160 --> 02:19:30,600
ANIMAL CD8 AND NK AND SECOND 

2790
02:19:30,600 --> 02:19:34,280
GROUP DEPLETE IT ALONE AND THIRD

2791
02:19:34,280 --> 02:19:36,600
GROUP DEPLETE MONOCYTE AND 

2792
02:19:36,600 --> 02:19:40,680
MACROPHAGES AND INOCULATE ANIMAL

2793
02:19:40,680 --> 02:19:44,080
WITH WILD TIEF OR P12 KNOCKOUT 

2794
02:19:44,080 --> 02:19:47,800
VIRUS AND FOLLOW INFECTION FOR 

2795
02:19:47,800 --> 02:19:52,240
20 WEEKS GROUP OF DATA SHOWS -- 

2796
02:19:52,240 --> 02:19:54,240
INOCULATED WITH WILD TYPE VIRUS 

2797
02:19:54,240 --> 02:19:56,920
SHOWS ALL ANIMALS FULLY 

2798
02:19:56,920 --> 02:19:59,400
CONVERTED WITH CONVERSION START 

2799
02:19:59,400 --> 02:20:02,480
AS EARLY AS WEEK 4 POST 

2800
02:20:02,480 --> 02:20:04,280
INOBJECTION OF THE VIRUS AND 

2801
02:20:04,280 --> 02:20:09,600
DEPLETED WITH CD8 ALONE WE SHOW 

2802
02:20:09,600 --> 02:20:11,040
ANIMALS CONVERTED WITH 

2803
02:20:11,040 --> 02:20:13,760
[INDISCERNIBLE] AS EARLY AS WEEK

2804
02:20:13,760 --> 02:20:15,800
8 POST INOCULATION VIRUS AND 

2805
02:20:15,800 --> 02:20:20,120
GROUP OF ANIMAL DEPLETED WITH 

2806
02:20:20,120 --> 02:20:22,160
MONOCYTE AND MACROPHAGES ALL 

2807
02:20:22,160 --> 02:20:24,760
ANIMALS CONVERTED AND END OF 

2808
02:20:24,760 --> 02:20:26,960
STUDY AND WEEK 21 WE START TO 

2809
02:20:26,960 --> 02:20:29,520
SEE DECREASED LEVEL OF ANTIBODY 

2810
02:20:29,520 --> 02:20:31,280
IN PLASMA OF ANIMAL SUGGESTING 

2811
02:20:31,280 --> 02:20:32,560
IN THIS CONDITION THAT INFECTION

2812
02:20:32,560 --> 02:20:36,720
IS NOT SUSTAINED AND WE THEN 

2813
02:20:36,720 --> 02:20:40,720
CONFIRM OUR DATA BY TESTING 

2814
02:20:40,720 --> 02:20:46,000
ANTIBODY TIGHTER AGAINST HW1 

2815
02:20:46,000 --> 02:20:51,720
ANTIGEN.  THIS DILUTES PLASMA IN

2816
02:20:51,720 --> 02:20:55,800
INDIVIDUAL AND WE PLOTTED 

2817
02:20:55,800 --> 02:20:59,280
HIGHEST DILUTION AND ACT AGAINST

2818
02:20:59,280 --> 02:21:02,880
HTLV-1 ANTIGEN IN THIS CONTEXT 

2819
02:21:02,880 --> 02:21:05,000
HIGHER DILUTION IS ASSOCIATE THE

2820
02:21:05,000 --> 02:21:06,680
WITH HIGHER ANTIBODY IN THE 

2821
02:21:06,680 --> 02:21:08,440
PLASMA OF THE INDIVIDUAL AND 

2822
02:21:08,440 --> 02:21:10,320
STUDIES SHOW GROUP OF ANIMAL 

2823
02:21:10,320 --> 02:21:12,760
THAT IS DOUBLE DEPLETED FOR CD8 

2824
02:21:12,760 --> 02:21:15,280
AND NK IS A GROUP OF ANIMAL WITH

2825
02:21:15,280 --> 02:21:17,760
HIGHER LEVEL OF ANTIBODY 

2826
02:21:17,760 --> 02:21:19,560
SUGGESTING THAT THIS DEPLETION 

2827
02:21:19,560 --> 02:21:22,200
IS DEPLETION THAT EXACERBATES 

2828
02:21:22,200 --> 02:21:23,800
THE INFECTION THE MOST AND SHOW 

2829
02:21:23,800 --> 02:21:26,960
THAT IN GROUP OF ANIMAL DEPLETED

2830
02:21:26,960 --> 02:21:30,160
WITH MONOCYTE AND MACROPHAGES 

2831
02:21:30,160 --> 02:21:32,880
END OF THE STUDY IN WEEK 21 WE 

2832
02:21:32,880 --> 02:21:35,760
START TO SEE DECREASE IN 

2833
02:21:35,760 --> 02:21:37,440
ANTIBODY TIGHTER SHOWING 

2834
02:21:37,440 --> 02:21:40,600
INFECTION IS NOT SUSTAINED AND 

2835
02:21:40,600 --> 02:21:42,560
PRESENCE OF INFECTION AND DETECT

2836
02:21:42,560 --> 02:21:45,240
VIRAL DNA IN THIS ANIMAL AND 

2837
02:21:45,240 --> 02:21:47,800
DATA SHOW ALL ANIMALS FULLY 

2838
02:21:47,800 --> 02:21:49,200
CONVERTED ARE FOUND TO BE 

2839
02:21:49,200 --> 02:21:53,560
POSITIVE FOR VIRAL DNA IN PBNC 

2840
02:21:53,560 --> 02:21:55,960
AND IN GROUP OF ANIMAL THAT IS 

2841
02:21:55,960 --> 02:21:59,240
DOUBLE DEPLETED FOR THIS 

2842
02:21:59,240 --> 02:22:00,920
INOCULATED WITH P12 KNOCKOUT 

2843
02:22:00,920 --> 02:22:03,480
VIRUS ALL ANIMALS ARE FULLY 

2844
02:22:03,480 --> 02:22:05,840
CONVERTED SHOWING FIRST TIME 

2845
02:22:05,840 --> 02:22:08,720
DOUBLE DEPLETION NK FULLY RESCUE

2846
02:22:08,720 --> 02:22:12,960
LACK OF [INDISCERNIBLE] OF P12 

2847
02:22:12,960 --> 02:22:16,840
KNOCKOUT VIRUS AND CONVERSION 

2848
02:22:16,840 --> 02:22:19,760
STARTING AS EARLY AS WEEK 8 POST

2849
02:22:19,760 --> 02:22:21,840
INOCULATION OF THE VIRUS AND WE 

2850
02:22:21,840 --> 02:22:24,640
SHOW ONE ANIMAL FULLY CONVERTED 

2851
02:22:24,640 --> 02:22:30,360
OUT OF 4 AND GROUP OF ANIMAL 

2852
02:22:30,360 --> 02:22:32,320
DEPLETED WITH MONOCYTE 

2853
02:22:32,320 --> 02:22:34,240
MACROPHAGES ONE ANIMAL CONVERTED

2854
02:22:34,240 --> 02:22:36,280
OUT OF 5 AND ONCE AGAIN BY END 

2855
02:22:36,280 --> 02:22:38,720
OF THE STUDY WEEK 21 WE HAVE 

2856
02:22:38,720 --> 02:22:40,640
DECREASED LEVEL OF ANTIBODY THAT

2857
02:22:40,640 --> 02:22:42,520
IS AGAINST IN THE PLASMA OF THE 

2858
02:22:42,520 --> 02:22:44,240
ANIMAL THAT IS SUGGESTING IN 

2859
02:22:44,240 --> 02:22:45,960
THIS CONTEXT THAT INFECTION IS 

2860
02:22:45,960 --> 02:22:47,320
NOT SUSTAINED. 

2861
02:22:47,320 --> 02:22:51,560
WE CONFIRMLE OUR DATA BY USING 

2862
02:22:51,560 --> 02:22:55,840
THIS P24 ANTIBODY TIGHTER AND 

2863
02:22:55,840 --> 02:22:59,840
SHOW THAT GROUP OF ANIMAL DOUBLE

2864
02:22:59,840 --> 02:23:02,720
DEPLETED FOR CDNK HAS HIGHER 

2865
02:23:02,720 --> 02:23:05,280
LEVEL OF ANTIBODY AND CONFIRMING

2866
02:23:05,280 --> 02:23:08,600
PRESENCE OF VIRAL DNA IN THIS 

2867
02:23:08,600 --> 02:23:11,520
PVC OF THE ANIMAL AND SHOW ALL 

2868
02:23:11,520 --> 02:23:13,960
ANIMAL CONVERTED TO BE FOUND 

2869
02:23:13,960 --> 02:23:17,840
POSITIVE FOR VIRAL DNA IN PBNC 

2870
02:23:17,840 --> 02:23:21,080
AND INSIST P12 KNOCKOUT VIRUS AS

2871
02:23:21,080 --> 02:23:24,560
POINT MUTATION DESTROYING ATG OF

2872
02:23:24,560 --> 02:23:26,840
ORF1 AND DECIDE TO SEQUENCE 

2873
02:23:26,840 --> 02:23:29,840
VIRUS TO MAKE SURE NO REVERSION 

2874
02:23:29,840 --> 02:23:32,640
OF P12 KNOCKOUT MUTATION INTO 

2875
02:23:32,640 --> 02:23:37,080
THE WILD TYPE AND DATA SHOWS NO 

2876
02:23:37,080 --> 02:23:38,080
REVERSION DEMONSTRATING THIS IS 

2877
02:23:38,080 --> 02:23:40,280
A TRUE INFECTION OF THE P12 

2878
02:23:40,280 --> 02:23:41,680
KNOCKOUT VIRUS. 

2879
02:23:41,680 --> 02:23:44,920
SO, IN SUMMARY, OUR DATA SHOWS 

2880
02:23:44,920 --> 02:23:48,040
THAT IN CONTEXT OF THE WILD TYPE

2881
02:23:48,040 --> 02:23:51,760
VIRUS ALL DEPLETION RESULTS IS 

2882
02:23:51,760 --> 02:23:53,800
EXACERBATING INFECTION SHOWING 

2883
02:23:53,800 --> 02:23:56,880
100% INFECTIVITY AND DOUBLE 

2884
02:23:56,880 --> 02:23:59,800
DEPLETION OF CDNK IS DEPLETION 

2885
02:23:59,800 --> 02:24:03,400
THAT EXACERBATES INFECTION MOST 

2886
02:24:03,400 --> 02:24:06,440
WITH AS EARLY AS WEEK 4 POST 

2887
02:24:06,440 --> 02:24:09,600
INOCULATION OF THE VIRUS AND 

2888
02:24:09,600 --> 02:24:11,000
[INDISCERNIBLE] BY END OF THE 

2889
02:24:11,000 --> 02:24:13,080
STUDY DECREASED LEVEL OF 

2890
02:24:13,080 --> 02:24:14,840
ANTIBODY SUGGESTING THAT IN THIS

2891
02:24:14,840 --> 02:24:16,920
CONDITION THAT INFECTION IS NOT 

2892
02:24:16,920 --> 02:24:17,240
SUSTAINED. 

2893
02:24:17,240 --> 02:24:22,160
IN THE CONTEXT OF THE P12 

2894
02:24:22,160 --> 02:24:26,680
KNOCKOUT VIRUS SHOWING FIRST 

2895
02:24:26,680 --> 02:24:30,400
TIME DEPLETION OF CD8/NK -- WE 

2896
02:24:30,400 --> 02:24:32,160
SHOW THAT DEPLETION OF THIS 

2897
02:24:32,160 --> 02:24:34,640
ALONE RESULTS IN 25% OF 

2898
02:24:34,640 --> 02:24:37,440
INFECTION AND DEPLETION OF 

2899
02:24:37,440 --> 02:24:40,440
MONOCYTE 20% INFECTION AND AGAIN

2900
02:24:40,440 --> 02:24:44,120
IN CONTEXT OF P12 KNOCKOUT WE 

2901
02:24:44,120 --> 02:24:47,440
SHOW MONOCYTE DEPLETION RESULT 

2902
02:24:47,440 --> 02:24:49,200
IN SUSTAINING INFECTION AND IN 

2903
02:24:49,200 --> 02:24:51,760
SUMMARY, DATA SHOWS THAT 

2904
02:24:51,760 --> 02:24:56,960
DEPLETION OF CD8NK MONOCYTE 

2905
02:24:56,960 --> 02:24:58,960
MACROPHAGES -- INFECTION AND 

2906
02:24:58,960 --> 02:25:00,840
DATA POINTS OUT CRUCIAL ROLE OF 

2907
02:25:00,840 --> 02:25:06,560
K CELL RESTRICTING EARLY HIV-1 

2908
02:25:06,560 --> 02:25:08,600
INFECTION SUGGESTING THAT 

2909
02:25:08,600 --> 02:25:11,800
VACCINE SHOULD PRODUCE AN 

2910
02:25:11,800 --> 02:25:14,280
ADAPTIVE RESPONSE AND STRONG 

2911
02:25:14,280 --> 02:25:16,200
INNATE RESPONSE TO PROMPTLY 

2912
02:25:16,200 --> 02:25:18,520
ELIMINATE THE CELLS AND DATA 

2913
02:25:18,520 --> 02:25:20,920
HIGHLIGHTS DOUBLE ROLE OF 

2914
02:25:20,920 --> 02:25:23,720
MONOCYTE ON ONE SIDE.  MONOCYTE 

2915
02:25:23,720 --> 02:25:25,720
AND MACROPHAGE RESTRICT EARLY IN

2916
02:25:25,720 --> 02:25:27,600
ONE INFECTION AND OTHER SIDE 

2917
02:25:27,600 --> 02:25:30,480
CELL TYPES ARE NEEDED FOR VIRUS 

2918
02:25:30,480 --> 02:25:32,960
TO PERSIST IN THE HOST AND DATA 

2919
02:25:32,960 --> 02:25:34,840
THAT I'M PRESENTING TODAY ARE 

2920
02:25:34,840 --> 02:25:37,760
RECENTLY ACCEPTED FOR 

2921
02:25:37,760 --> 02:25:38,960
PUBLICATION ON [INDISCERNIBLE] 

2922
02:25:38,960 --> 02:25:43,800
AND I'M A CO-AUTHOR IN THIS 

2923
02:25:43,800 --> 02:25:44,600
PUBLICATION TOGETHER WITH 

2924
02:25:44,600 --> 02:25:45,400
[INDISCERNIBLE] AND WOULD LIKE 

2925
02:25:45,400 --> 02:25:49,880
TO THANK MENTORS FOR SUPPORTING 

2926
02:25:49,880 --> 02:25:53,400
THIS PROJECT.  AND MY LAB AND 

2927
02:25:53,400 --> 02:25:54,600
COLLABORATORS TO MAKE THE 

2928
02:25:54,600 --> 02:25:57,880
PROJECT POSSIBLE AND I'M HAPPY 

2929
02:25:57,880 --> 02:26:05,120
TO TAKE ANY QUESTIONS. 

2930
02:26:05,120 --> 02:26:07,320
>>SO, GIVEN IMPORTANCE OF
THE 

2931
02:26:07,320 --> 02:26:11,240
P12 AND P8 PROTEINS AND THAT 

2932
02:26:11,240 --> 02:26:13,320
CLEAVAGE SITE I'M ASSUMING IT IS

2933
02:26:13,320 --> 02:26:15,280
PRETTY CONSERVED PEOPLE TRYING 

2934
02:26:15,280 --> 02:26:18,200
TO DEVELOP SMALL MOLECULE 

2935
02:26:18,200 --> 02:26:19,520
INHIBITORS TO THAT SITE ARE THEY

2936
02:26:19,520 --> 02:26:20,680
SAME AS KNOCKOUT?  

2937
02:26:20,680 --> 02:26:24,960
>>THERE ARE MUTATIONS AND
SOME 

2938
02:26:24,960 --> 02:26:27,200
HAVE PRIMARY EXPRESSION DEPENDS 

2939
02:26:27,200 --> 02:26:29,720
ON LIMITATION AND EXPRESS P12 

2940
02:26:29,720 --> 02:26:32,200
AND P8 OR BOTH.  BOTH OF THEM. 

2941
02:26:32,200 --> 02:26:32,680
>>RIGHT. 

2942
02:26:32,680 --> 02:26:35,040
>>IN PATIENT WE KNOW THIS
LOAD 

2943
02:26:35,040 --> 02:26:38,680
IS HIGHER WHEN THEY EXPRESS BOTH

2944
02:26:38,680 --> 02:26:41,320
AND WE THINK THIS IS BIOLOGICAL 

2945
02:26:41,320 --> 02:26:42,400
ADVANTAGE AT THE SAME TIME. 

2946
02:26:42,400 --> 02:26:43,200
>>OKAY. 

2947
02:26:43,200 --> 02:26:45,520
>>I HAVE A COUPLE
QUESTIONS. 

2948
02:26:45,520 --> 02:26:48,000
>>WHEN YOU GET OR DO THE 

2949
02:26:48,000 --> 02:26:50,360
INFECTION, YOU GET ZERO 

2950
02:26:50,360 --> 02:26:51,800
CONVERSION.  IS THAT LONG AFTER 

2951
02:26:51,800 --> 02:26:54,160
THAT, EVEN IN HUMANS THAT THEY 

2952
02:26:54,160 --> 02:26:55,960
WOULD SHOW THESE ANTIBODIES?  

2953
02:26:55,960 --> 02:26:58,120
>>YEAH.  NORMALLY WHEN
THEY 

2954
02:26:58,120 --> 02:26:59,600
START OR HAVE SYMPTOMS THEY 

2955
02:26:59,600 --> 02:27:02,880
START TO HAVE HIGH LEVEL OF 

2956
02:27:02,880 --> 02:27:04,920
ANTIBODIES AND THEY STAY HIGH 

2957
02:27:04,920 --> 02:27:08,480
AND IN MCCOCK NORMALLY WHAT WE 

2958
02:27:08,480 --> 02:27:11,760
SEE WHEN WE HAVE CONDITION OF 

2959
02:27:11,760 --> 02:27:13,280
DEPLETION IN CONDITION OF WILD 

2960
02:27:13,280 --> 02:27:16,200
TYPE VIRUS WITH HIGH LEVEL OF 

2961
02:27:16,200 --> 02:27:19,800
ANTIBODY THEY STAY HIGH SO THEY 

2962
02:27:19,800 --> 02:27:22,840
DON'T LOSE IT USUALLY AROUND 20 

2963
02:27:22,840 --> 02:27:23,080
WEEKS. 

2964
02:27:23,080 --> 02:27:25,480
>>CONVERSION OF WESTERN
BLOTS 

2965
02:27:25,480 --> 02:27:28,240
YOU SEE ONE COME OUT AT THE 

2966
02:27:28,240 --> 02:27:30,400
BOTTOM YOU ARE NOT CALLING IT 

2967
02:27:30,400 --> 02:27:31,160
[INDISCERNIBLE] CONVERSION IS 

2968
02:27:31,160 --> 02:27:34,200
THAT BECAUSE IT IS INDUCED 

2969
02:27:34,200 --> 02:27:36,560
ITSELF VIRUS COMING IN NOT NEW 

2970
02:27:36,560 --> 02:27:37,560
VIRUS?  

2971
02:27:37,560 --> 02:27:39,000
>>THEY ARE WESTERN BLOT 

2972
02:27:39,000 --> 02:27:40,960
[INDISCERNIBLE] FOR PATIENTS AND

2973
02:27:40,960 --> 02:27:43,320
BASED ON KIT YOU CAN TALK ABOUT 

2974
02:27:43,320 --> 02:27:45,080
PATIENT BEING POSITIVE WHEN YOU 

2975
02:27:45,080 --> 02:27:46,960
HAVE THESE THREE BANDS.  

2976
02:27:46,960 --> 02:27:48,640
OTHERWISE IT MIGHT BE YOU COME 

2977
02:27:48,640 --> 02:27:50,880
ACROSS THIS.  YOU CAN DO 

2978
02:27:50,880 --> 02:27:53,320
SOMETHING.  WE ARE NOT 

2979
02:27:53,320 --> 02:27:53,600
CONFIDENT. 

2980
02:27:53,600 --> 02:27:55,840
>>OKAY.  

2981
02:27:55,840 --> 02:28:06,200
>>OKAY.  THANK YOU. 

2982
02:28:10,200 --> 02:28:14,880
>>OKAY.  NEXT SPEAKER IS
HANA 

2983
02:28:14,880 --> 02:28:19,760
WHO WILL TALK ABOUT GUANO LATE 

2984
02:28:19,760 --> 02:28:23,200
BINDING PROTEIN 5 IMPAIRING 

2985
02:28:23,200 --> 02:28:27,480
VIERI ON INFECTIVITY BY 

2986
02:28:27,480 --> 02:28:39,040
TARGETING ENVELOPE GLYENVELOPE  

2987
02:28:53,560 --> 02:28:55,840
>>SOME OF THEM IN
PARTICULAR 

2988
02:28:55,840 --> 02:28:58,320
CAN TARGET ENVELOPE 

2989
02:28:58,320 --> 02:29:00,840
GLYCOPROTEINS.  AMONG THOSE FOR 

2990
02:29:00,840 --> 02:29:04,600
EXAMPLE ARE IF DOMS DOWNREGULATE

2991
02:29:04,600 --> 02:29:06,640
AND BLOCK ENVELOPE FOLDING AND 

2992
02:29:06,640 --> 02:29:14,480
WE HAVE LARGE PROTEINS AND WE 

2993
02:29:14,480 --> 02:29:15,640
HAVE GUANYLATE BINDING PROTEINS 

2994
02:29:15,640 --> 02:29:17,880
THAT I WOULD LIKE TO DEDICATE 

2995
02:29:17,880 --> 02:29:21,720
THESE TO THE TALK.  BROADLY 

2996
02:29:21,720 --> 02:29:26,120
SPEAKING GUANYLATE -- THERE IS 7

2997
02:29:26,120 --> 02:29:31,800
MEMBERS OF THE FAMILY GBP1 TO 

2998
02:29:31,800 --> 02:29:33,400
GBP7.  THEY HAVE A COMMON 

2999
02:29:33,400 --> 02:29:35,920
FEATURE THAT IS POST IN HOST 

3000
02:29:35,920 --> 02:29:38,600
DEFENSE AGAINST IMPORTANCE 

3001
02:29:38,600 --> 02:29:41,400
PATHOGENS FOR EXAMPLE 

3002
02:29:41,400 --> 02:29:44,160
MICROBACTERIA CLIM IDDIA AND 

3003
02:29:44,160 --> 02:29:47,160
HYSTERIA AND GBP5 GETS ATTENTION

3004
02:29:47,160 --> 02:29:49,520
IN FIELD OF VIROLOGY IT IS SHOWN

3005
02:29:49,520 --> 02:29:51,800
TO SHOW BROAD ANTIVIRAL 

3006
02:29:51,800 --> 02:29:53,440
ACTIVITY.  NAMELY BLOCKING 

3007
02:29:53,440 --> 02:29:55,440
REPLICATION OF DIFFERENT VIRUSES

3008
02:29:55,440 --> 02:29:58,800
INCLUDING HIV AND HIGHLY 

3009
02:29:58,800 --> 02:30:01,880
PATHOGENIC VIRUSES LIKE MEASLES 

3010
02:30:01,880 --> 02:30:09,240
AND HIV AND IN PARTICULAR GBP5 

3011
02:30:09,240 --> 02:30:11,640
REPORTABLY SHOWN TO -- SO WHAT 

3012
02:30:11,640 --> 02:30:14,160
RESEARCHERS HAVE PROPOSED IS IN 

3013
02:30:14,160 --> 02:30:16,520
PRESENCE OF GDP5 THIS ACTIVITY 

3014
02:30:16,520 --> 02:30:18,880
IS SIGNIFICANTLY REDUCED AND 

3015
02:30:18,880 --> 02:30:20,320
RIGHT-HAND SIDE YOU SEE A 

3016
02:30:20,320 --> 02:30:22,760
SCHEMATIC WHAT MIGHT BE GOING ON

3017
02:30:22,760 --> 02:30:25,720
IN CELL IN PRESENCE OF GBP5 AND 

3018
02:30:25,720 --> 02:30:27,560
THIS PROTEIN REQUIRES THIS 

3019
02:30:27,560 --> 02:30:32,960
CLEAVANCE TO GET PROCESS INTO 

3020
02:30:32,960 --> 02:30:36,200
GP100 -- NOW IN PRESENCE OF GBP5

3021
02:30:36,200 --> 02:30:39,680
SINCE ACTIVITIES IS INHIBITED OR

3022
02:30:39,680 --> 02:30:43,160
SIGNIFICANTLY REDUCED WE GET 

3023
02:30:43,160 --> 02:30:45,840
THIS AND CONSEQUENTLY LEVEL OF 

3024
02:30:45,840 --> 02:30:48,360
THIS IS REDUCED.  NOW, THAT 

3025
02:30:48,360 --> 02:30:53,840
MEANS NEWLY ASSEMBLED VIRIONS 

3026
02:30:53,840 --> 02:30:55,880
AND AS A CONSEQUENCE THEIR 

3027
02:30:55,880 --> 02:30:59,360
INFECTIVITY IS REDUCED.  

3028
02:30:59,360 --> 02:31:02,400
HOWEVER, AS SEEMS -- YEAH.  

3029
02:31:02,400 --> 02:31:04,520
HOWEVER.  IT MIGHT NOT BE AS 

3030
02:31:04,520 --> 02:31:07,040
STRAIGHTFORWARD AS IT SEEMS AND 

3031
02:31:07,040 --> 02:31:10,040
PREVIOUS POST DOCK RESEARCH 

3032
02:31:10,040 --> 02:31:11,520
FELLOW IN OUR LAB OBSERVED 

3033
02:31:11,520 --> 02:31:13,960
RUNNING SAMPLES ON THIS TRIAL 

3034
02:31:13,960 --> 02:31:19,440
AND INCREASE CONCENTRATION OF 

3035
02:31:19,440 --> 02:31:23,040
GDP5 MOEKT SHIFTS AND YOU CAN 

3036
02:31:23,040 --> 02:31:25,280
HOPEFULLY APPRECIATE ON LAB HAND

3037
02:31:25,280 --> 02:31:28,200
SIDE OF THE CELL SAMPLES ON THE 

3038
02:31:28,200 --> 02:31:32,040
PLOT AND IN FACT GBP5 MIGHT HAVE

3039
02:31:32,040 --> 02:31:35,040
EFFECT ON GLYCOLIZIZATION OF 

3040
02:31:35,040 --> 02:31:40,280
PROTEINS AND ASK OURSELF HOW GBF

3041
02:31:40,280 --> 02:31:51,040
INHIBIT GLYCOSCILLATYLATION. 

3042
02:31:55,480 --> 02:31:56,520
WE COULD PSEUDOTYPE WITH 

3043
02:31:56,520 --> 02:32:00,280
ENVELOPES FROM HIV OR SPIKE 

3044
02:32:00,280 --> 02:32:05,920
PROTEIN FROM SARZ COV OR SARZ 

3045
02:32:05,920 --> 02:32:07,800
COV2 VIRUS. 

3046
02:32:07,800 --> 02:32:11,600
WE NORMALIZE INFECTIOUS VARIOUS 

3047
02:32:11,600 --> 02:32:14,160
SEALED TO REVERSE TRANSCRIPTASE 

3048
02:32:14,160 --> 02:32:18,120
VALUE AND USE THIS TO -- TWO 

3049
02:32:18,120 --> 02:32:22,080
DAYS AFTER INFECTION, WE WERE 

3050
02:32:22,080 --> 02:32:24,840
THEN ABLE TO MEASURE LUCIFEROUS 

3051
02:32:24,840 --> 02:32:27,440
ACTIVITY USE TOTD DETERMINATE 

3052
02:32:27,440 --> 02:32:30,280
INFECTIOUS YIELD OF PSEUDOTYPE 

3053
02:32:30,280 --> 02:32:31,960
VIRUSES USED TO DETERMINE 

3054
02:32:31,960 --> 02:32:34,840
INFECTIVITY IN PRESENCE OR 

3055
02:32:34,840 --> 02:32:37,640
ABSENCE OF GBP5 AND BEFORE 

3056
02:32:37,640 --> 02:32:38,720
PERFORMING THESE EXPERIMENTS I 

3057
02:32:38,720 --> 02:32:41,080
WANT TO UNDERSTAND WHAT IS 

3058
02:32:41,080 --> 02:32:43,360
PHYSIOLOGICAL RELEVANT AMOUNT OF

3059
02:32:43,360 --> 02:32:46,360
GBP5 AND ANSWERING THIS QUESTION

3060
02:32:46,360 --> 02:32:50,800
I TREATED THESE CELLS WITH -- 

3061
02:32:50,800 --> 02:32:55,840
INDUCIBLE GENE AND I WAS 

3062
02:32:55,840 --> 02:33:00,480
SUCCESSFULLY ABLE TO DETECT GDP5

3063
02:33:00,480 --> 02:33:03,000
-- MOST IMPORTANTLY I WAS ABLE 

3064
02:33:03,000 --> 02:33:04,280
TO SHOW THIS TRANCE INSPECTION 

3065
02:33:04,280 --> 02:33:07,560
OF THESE CELLS CAN MIMIC 

3066
02:33:07,560 --> 02:33:10,880
ENDOGENOUS EXPRESSION OF GBP5 

3067
02:33:10,880 --> 02:33:13,800
UPON TREATMENT WITH INTERFERON 

3068
02:33:13,800 --> 02:33:15,360
GAMMA.  GOING BACK TO DATA WHERE

3069
02:33:15,360 --> 02:33:19,040
I HAVE MENTIONED THAT SHE 

3070
02:33:19,040 --> 02:33:22,800
OBSERVED SHIFT IN GB20 AND 41 

3071
02:33:22,800 --> 02:33:26,080
AND OBSERVING CONCENTRATION 

3072
02:33:26,080 --> 02:33:27,080
INCREASES CONCENTRATION 

3073
02:33:27,080 --> 02:33:28,920
INDEPENDENT INCREASE IN 

3074
02:33:28,920 --> 02:33:30,920
INFECTIVITY OF VIRUS THAT IS 

3075
02:33:30,920 --> 02:33:32,760
CONSISTENT WITH ALREADY 

3076
02:33:32,760 --> 02:33:35,160
PUBLISHED DATA REPRODUCING DATA 

3077
02:33:35,160 --> 02:33:37,840
THIS TIME USING PHYSIOLOGICAL 

3078
02:33:37,840 --> 02:33:39,880
RELEVANT AMOUNT OF GDP5 AND 

3079
02:33:39,880 --> 02:33:43,920
SIMILAR TO DATA SAW SHIFT IN 

3080
02:33:43,920 --> 02:33:49,400
GB120 -- CONCENTRATION OF GBP5 

3081
02:33:49,400 --> 02:33:50,000
INCREASED NOW UNDERSTANDING 

3082
02:33:50,000 --> 02:33:53,360
WHETHER THIS IS REALLY AS A 

3083
02:33:53,360 --> 02:33:55,800
CONSEQUENCE BECAUSE OF GDP5 

3084
02:33:55,800 --> 02:33:57,600
MIGHT HAVE ROLE IN GLYCOLIZATION

3085
02:33:57,600 --> 02:34:01,440
OF PROTEINS TREATED SAMPLES 

3086
02:34:01,440 --> 02:34:03,840
WHICH IS A [INDISCERNIBLE] THAT 

3087
02:34:03,840 --> 02:34:08,200
CLEAVES OFF ALL N LINK GLYCO -- 

3088
02:34:08,200 --> 02:34:11,680
N LINK SACCHARIDES FROM PROTEINS

3089
02:34:11,680 --> 02:34:13,600
AND IN SAMPLE YOU TREAT THE 

3090
02:34:13,600 --> 02:34:15,600
SAMPLE YOU GET A VERY HIGH 

3091
02:34:15,600 --> 02:34:19,360
MOBILITY SHIFT FOR ALL BANDS 

3092
02:34:19,360 --> 02:34:22,640
REPRESENTING GP60 AND THEY HAVE 

3093
02:34:22,640 --> 02:34:25,760
BEEN SHOPPED OFF FROM ENVELOPE 

3094
02:34:25,760 --> 02:34:26,640
GLYCOPROTEIN AND WITHOUT 

3095
02:34:26,640 --> 02:34:29,800
TREATMENT AND IN PRESENCE OF 

3096
02:34:29,800 --> 02:34:34,360
GBP5 WE SEE MOBILITY SHIFT IN 20

3097
02:34:34,360 --> 02:34:38,720
AND 41 BANDS ASSUMING THAT 

3098
02:34:38,720 --> 02:34:40,200
[INDISCERNIBLE] THAT IS INDEED 

3099
02:34:40,200 --> 02:34:43,000
THE CASE WE WOULD EXPECT TO SEE 

3100
02:34:43,000 --> 02:34:47,440
UPON TREATMENT WITH PNJF SAME 

3101
02:34:47,440 --> 02:34:49,120
MOBILITY SHIFT IN TREATED 

3102
02:34:49,120 --> 02:34:53,440
CONTROL SAMPLE.  YOU SEE BOTH 

3103
02:34:53,440 --> 02:34:57,160
BANDS REPRESENTING GBP120 AND 41

3104
02:34:57,160 --> 02:35:00,920
AND 160 ARE SAME MOLECULAR WAIT 

3105
02:35:00,920 --> 02:35:05,800
AND GBF PIEF REDUCES 

3106
02:35:05,800 --> 02:35:09,560
[INDISCERNIBLE] ENVELOPE 

3107
02:35:09,560 --> 02:35:10,840
GLYCOSYLATION.  

3108
02:35:10,840 --> 02:35:12,960
SO, I PSEUDOTYPE WITH SPIKE 

3109
02:35:12,960 --> 02:35:18,200
PROTEIN WITH COV AND COV2 

3110
02:35:18,200 --> 02:35:21,760
VIRUSES SPIKE FROM COV2 GETS 

3111
02:35:21,760 --> 02:35:26,600
CLEAVED AND SARZ COV SPIKE 

3112
02:35:26,600 --> 02:35:28,200
PROTEIN REQUIRES A DIFFERENT 

3113
02:35:28,200 --> 02:35:33,760
HOUSE PROTEASE.  I ALSO OBSERVED

3114
02:35:33,760 --> 02:35:35,880
A MOBILITY SHIFT AS 

3115
02:35:35,880 --> 02:35:39,200
CONCENTRATION OF GBP5 INCREASED 

3116
02:35:39,200 --> 02:35:40,840
AND INTERESTINGLY ENOUGH, 

3117
02:35:40,840 --> 02:35:43,000
ACTIVITY OF VIRUS WAS INCREASED 

3118
02:35:43,000 --> 02:35:45,720
IN CONCENTRATION DEPENDENT 

3119
02:35:45,720 --> 02:35:50,880
MANAGER OF GBP5 INCREASED AND 

3120
02:35:50,880 --> 02:35:52,880
SIMILAR RESULT OBSERVED IN THIS 

3121
02:35:52,880 --> 02:35:56,800
SPIKE AND YOU SEE HERE NICE 

3122
02:35:56,800 --> 02:35:58,880
MOBILITY SHIFT AS THIS BAND 

3123
02:35:58,880 --> 02:36:01,760
CLEAVED IN HIGH PRESENCE OF GBF5

3124
02:36:01,760 --> 02:36:05,040
AND LIKEWISE INFECTIVITY OF 

3125
02:36:05,040 --> 02:36:08,640
VIRUS REDUCED IN CONCENTRATION 

3126
02:36:08,640 --> 02:36:12,680
DEPENDENT MANNER AND THIS IS THE

3127
02:36:12,680 --> 02:36:14,840
CASE BECAUSE I TREATED SAMPLES 

3128
02:36:14,840 --> 02:36:17,720
WITH THIS ENZYME AGAIN AND THIS 

3129
02:36:17,720 --> 02:36:22,160
IS IN CASE OF SARZ COV SPIKE AND

3130
02:36:22,160 --> 02:36:25,880
CONTROL SAMPLE WE SEE MOBILITY 

3131
02:36:25,880 --> 02:36:28,920
SHAPE SPIKE WITH TREATMENT OF 

3132
02:36:28,920 --> 02:36:32,440
THIS BECAUSE SACKARICHARIDES HA 

3133
02:36:32,440 --> 02:36:34,960
BEEN CHOPPED OFF AND WITHOUT 

3134
02:36:34,960 --> 02:36:38,960
TREATMENT WE SEE MOBILITY SHIFT 

3135
02:36:38,960 --> 02:36:39,760
BECAUSE OF REDUCTION OF 

3136
02:36:39,760 --> 02:36:42,280
GLYCOSYLATION AND WE SEE WEIGHT 

3137
02:36:42,280 --> 02:36:44,200
BANDS AS IN CONTROL TREATED 

3138
02:36:44,200 --> 02:36:45,800
SAMPLE AND SAME DATA WAS 

3139
02:36:45,800 --> 02:36:48,920
OBSERVED WHEN I DID THAT WITH 

3140
02:36:48,920 --> 02:36:52,440
SARZ COV2 SPIKE YOU CAN 

3141
02:36:52,440 --> 02:36:54,600
APPRECIATE MOBILITY SHIFT IN 

3142
02:36:54,600 --> 02:36:57,760
PREFERENCE OF GBP5 WITHOUT 

3143
02:36:57,760 --> 02:36:59,760
TREATMENT AND WE GET SAME 

3144
02:36:59,760 --> 02:37:02,720
RESPONSES IN CONTROL SAMPLE AND 

3145
02:37:02,720 --> 02:37:05,280
REDUCES GLYCOSYLATION OF 

3146
02:37:05,280 --> 02:37:11,360
GLYCOPROTEINS AND USING COV AND 

3147
02:37:11,360 --> 02:37:13,520
COV2 SPIKE PROTEINS WHETHER FOR 

3148
02:37:13,520 --> 02:37:15,520
INTOOE PENDIENT PROCESSING AND 

3149
02:37:15,520 --> 02:37:20,120
SUMMARIZING OUR WORK, WE SHOW 

3150
02:37:20,120 --> 02:37:24,640
THAT GBP5 -- WE SHOW THAT IT 

3151
02:37:24,640 --> 02:37:27,440
REDUCES HIV-1 ACTIVITY BY 

3152
02:37:27,440 --> 02:37:28,960
INTERFERING WITH ENVELOPE 

3153
02:37:28,960 --> 02:37:31,120
PROCESSING AND KRORNGS AND SHOW 

3154
02:37:31,120 --> 02:37:33,200
IT REDUCES CORPORATION AND 

3155
02:37:33,200 --> 02:37:36,400
VARIOUS INFECTIVITY FOR SARZ COV

3156
02:37:36,400 --> 02:37:39,680
AND COV2 VIRUSES AND IMPORTANTLY

3157
02:37:39,680 --> 02:37:43,760
AND NOT LASTLY SHOWING THAT IT 

3158
02:37:43,760 --> 02:37:47,480
INHIBITS GLYCOPROTEINS 

3159
02:37:47,480 --> 02:37:48,920
INCREASING MOBILITY OF SHIFT 

3160
02:37:48,920 --> 02:37:52,800
THAT ANALYZES IT EFFECTS 

3161
02:37:52,800 --> 02:37:54,880
GLYCOLIZATION AND LASTLY 

3162
02:37:54,880 --> 02:37:57,160
PSEUDOTYPING COV AND SPIKE 

3163
02:37:57,160 --> 02:37:59,800
PROTEINS WE SHOW THIS EFFECT 

3164
02:37:59,800 --> 02:38:01,800
HAPPENS REGARDLESS WHETHER 

3165
02:38:01,800 --> 02:38:03,320
GLYCOPROTEINS REQUIRE FOR 

3166
02:38:03,320 --> 02:38:05,720
DEPENDENT OR INDEPENDENT 

3167
02:38:05,720 --> 02:38:07,360
CLEAVAGE AND WITH THAT I WOULD 

3168
02:38:07,360 --> 02:38:10,080
LIKE TO THANK LAB IN PARTICULAR 

3169
02:38:10,080 --> 02:38:13,840
DR. ERIC AND BONNIE AND GERALD 

3170
02:38:13,840 --> 02:38:15,360
EVEN THAT WERE HEAVILY INVOLVED 

3171
02:38:15,360 --> 02:38:17,320
IN THE PROJECT AND ALL IN THE 

3172
02:38:17,320 --> 02:38:18,560
AUDIENCE FOR YOUR ATTENTION.  IF

3173
02:38:18,560 --> 02:38:22,680
YOU HAVE QUESTIONS, I WILL BE 

3174
02:38:22,680 --> 02:38:27,160
HAPPY TO TAKE THAT.  

3175
02:38:27,160 --> 02:38:29,200
>>HAVE YOU LOOKED AT
OTHER 

3176
02:38:29,200 --> 02:38:32,400
RETRO VIRUSES LIKE MLBS?  ARE 

3177
02:38:32,400 --> 02:38:35,040
THEY INFECTED?  

3178
02:38:35,040 --> 02:38:37,920
>>WE HAVE LOOKED AT 

3179
02:38:37,920 --> 02:38:39,560
[INDISCERNIBLE] GLYCOPROTEIN AND

3180
02:38:39,560 --> 02:38:41,320
WORKING ON FINALIZING DATA 

3181
02:38:41,320 --> 02:38:44,320
DOESN'T SEEM TO BE EFFECT ON 

3182
02:38:44,320 --> 02:38:46,040
ACTIVITY BUT NOT SURE BECAUSE OF

3183
02:38:46,040 --> 02:38:48,160
AMOUNT OF GLYCOPROTEIN THAT HAS 

3184
02:38:48,160 --> 02:38:49,360
TO BE [INDISCERNIBLE] AND 

3185
02:38:49,360 --> 02:38:52,480
INCORPORATION SEEMS TO BE 

3186
02:38:52,480 --> 02:38:52,760
EFFECTED. 

3187
02:38:52,760 --> 02:38:58,200
WE LOOK IN TUMORS IN TERMS OF 

3188
02:38:58,200 --> 02:39:01,920
[INDISCERNIBLE] WITH SARZ CV AND

3189
02:39:01,920 --> 02:39:11,080
SARZ CO-V2 VIRUSES. 

3190
02:39:11,080 --> 02:39:12,800
>>YOU HAVE LOOKED AT
OTHER 

3191
02:39:12,800 --> 02:39:13,160
PROTEINS?  

3192
02:39:13,160 --> 02:39:18,520
>>TREATED CD4 -- THERE IS
A 

3193
02:39:18,520 --> 02:39:21,560
FACT.  WE DON'T THINK IT 

3194
02:39:21,560 --> 02:39:24,440
PARTICULARLY ONLY TARGETS VIRI 

3195
02:39:24,440 --> 02:39:27,960
ON GLYCOPROTEINS. 

3196
02:39:27,960 --> 02:39:31,200
>>HAVE YOU LOOKED AT
VIRUSES 

3197
02:39:31,200 --> 02:39:33,120
THAT USE CELL TO CELL 

3198
02:39:33,120 --> 02:39:35,280
TRANSMISSION AND LOOKING AT 

3199
02:39:35,280 --> 02:39:37,280
RECEPTORS THAT BIND AND HOW 

3200
02:39:37,280 --> 02:39:38,280
ABOUT CELL TO CELL?  

3201
02:39:38,280 --> 02:39:40,720
>>WE HAVE NOT LOOKED AT
OTHER 

3202
02:39:40,720 --> 02:39:42,680
VIRUSES ONLY OTHER ONES WE 

3203
02:39:42,680 --> 02:39:47,960
LOOKED AT WERE GLYCOPROTEINS COV

3204
02:39:47,960 --> 02:39:49,320
AND [INDISCERNIBLE] MORE WE 

3205
02:39:49,320 --> 02:39:51,320
COULD EXPAND INTO TESTING MORE 

3206
02:39:51,320 --> 02:39:55,320
WITH THE SYSTEM IT THAT WE HAVE.

3207
02:39:55,320 --> 02:40:04,800
THANK YOU. 

3208
02:40:04,800 --> 02:40:05,400
>>HELLO.  EVERYONE IS DOG
A 

3209
02:40:05,400 --> 02:40:08,760
GREAT JOB STAYING ON TIME.  I'M 

3210
02:40:08,760 --> 02:40:12,840
AMAZED BY THAT.  NEXT TALK IS BY

3211
02:40:12,840 --> 02:40:15,760
CONSTANCE RINK.  HIS TITLE IS 

3212
02:40:15,760 --> 02:40:17,880
EVALUATING HIV-1 GAG KINETICS 

3213
02:40:17,880 --> 02:40:22,920
WITH RNAS USING SWITCHSENSE 

3214
02:40:22,920 --> 02:40:24,520
TECHNOLOGY.  

3215
02:40:24,520 --> 02:40:26,080
>>THANK YOU.  

3216
02:40:26,080 --> 02:40:36,520
>>>>THANK YOU FOR
THAT 

3217
02:40:47,320 --> 02:40:48,840
INTRODUCTION.  I'M CONNIE AND A 

3218
02:40:48,840 --> 02:40:51,400
POST DOC IN ALLAN RYAN'S LAB AND

3219
02:40:51,400 --> 02:40:54,080
WILL TALK ABOUT KINETICS OF GAG 

3220
02:40:54,080 --> 02:40:56,800
BINDING TO DIFFERENT RNAS AND 

3221
02:40:56,800 --> 02:40:59,600
PROJECT FOCUSES ON VIRAL 

3222
02:40:59,600 --> 02:41:01,240
ASSEMBLY THAT IS QUITE SIMPLY 

3223
02:41:01,240 --> 02:41:04,600
THE FORMATION OF NEW VIRAL 

3224
02:41:04,600 --> 02:41:04,920
PARTICLES. 

3225
02:41:04,920 --> 02:41:07,680
AND THERE ARE TWO COMPONENTS IN 

3226
02:41:07,680 --> 02:41:09,800
VIRUS ASSEMBLY, STRUCTURAL 

3227
02:41:09,800 --> 02:41:12,160
PROTEIN GAG AND VIRAL RNA. 

3228
02:41:12,160 --> 02:41:15,000
GAG SELECTS DIMERS OF VIRAL 

3229
02:41:15,000 --> 02:41:18,360
GENOME TO PACKAGING TO VIRAL 

3230
02:41:18,360 --> 02:41:21,320
PARTICLES AND PROCESS OCCURS AT 

3231
02:41:21,320 --> 02:41:22,680
PLASMA MEMBRANE AND LONGSTANDING

3232
02:41:22,680 --> 02:41:24,680
QUESTION IN THE FIELD IS HOW 

3233
02:41:24,680 --> 02:41:27,960
GENOMIC RNA IS SELECTED FOR 

3234
02:41:27,960 --> 02:41:29,320
INCLUSION INTO ASSEMBLING 

3235
02:41:29,320 --> 02:41:31,640
PARTICLES AND PROBLEM IS VIRAL 

3236
02:41:31,640 --> 02:41:34,080
GENOME IS IN VAST PRESENCE OF A 

3237
02:41:34,080 --> 02:41:39,680
BUNCH OF CELLULAR MRNAS AND TO 

3238
02:41:39,680 --> 02:41:42,400
QUITE EASILY DEPICT THIS, 

3239
02:41:42,400 --> 02:41:45,400
IMAGINE IT IS LIKE WHERE'S 

3240
02:41:45,400 --> 02:41:47,720
WALDO.  THE GENOME IS LIMITING 

3241
02:41:47,720 --> 02:41:52,200
IN A VAST POOL OF CELLULAR MRNA.

3242
02:41:52,200 --> 02:41:54,040
IT HAS BEEN ESTABLISHED IN THE 

3243
02:41:54,040 --> 02:41:56,440
FOO ELD THAT VIRAL GENOME IS 

3244
02:41:56,440 --> 02:41:57,960
EXCLUSIVELY PACKAGED IN PRESENCE

3245
02:41:57,960 --> 02:42:00,520
OF CELLULAR MRNA AND VIRAL 

3246
02:42:00,520 --> 02:42:02,240
GENOME WHEN IT IS NOT IN THE 

3247
02:42:02,240 --> 02:42:05,920
CELL THAT GAG LEAVISHIENTLY AND 

3248
02:42:05,920 --> 02:42:07,240
INDISCRIMINANTLY PACKAGE 

3249
02:42:07,240 --> 02:42:10,440
CELLULAR MRNA. 

3250
02:42:10,440 --> 02:42:15,280
SO, HOW DOES GAG ABLE TO 

3251
02:42:15,280 --> 02:42:16,640
RECOGNIZE AND PACKAGE VIRAL 

3252
02:42:16,640 --> 02:42:17,600
GENOME?  

3253
02:42:17,600 --> 02:42:21,640
SIMPLY IT IS ABLE TO SELECTIVELY

3254
02:42:21,640 --> 02:42:25,480
PACKAGE 9KGB GENOME IT CONTAINS 

3255
02:42:25,480 --> 02:42:27,040
PACKAGING SIGNAL OR 

3256
02:42:27,040 --> 02:42:28,520
[INDISCERNIBLE] IT IS LOCATED IN

3257
02:42:28,520 --> 02:42:31,600
THAT PACKAGING SIGNAL IS CONTAIN

3258
02:42:31,600 --> 02:42:35,400
THE IN 5 PRIME UTR SHOWN IN THE 

3259
02:42:35,400 --> 02:42:37,000
SECONDARY STRUCTURE THAT IS A 

3260
02:42:37,000 --> 02:42:39,120
SECONDARY REGION WITH STEM LOOPS

3261
02:42:39,120 --> 02:42:41,360
AND IS ONLY A VERY SMALL REGION 

3262
02:42:41,360 --> 02:42:45,320
WITHIN THE LARGE 9KB GENOME ONLY

3263
02:42:45,320 --> 02:42:48,200
356 NUCLEOTIDES AND SPECIFICALLY

3264
02:42:48,200 --> 02:42:51,200
THE PACK ABLGING SIGNAL IS A 

3265
02:42:51,200 --> 02:42:53,520
SMALLER SUBSET IN THE 5 PRIME 

3266
02:42:53,520 --> 02:42:56,000
UTR THAT IS COMPRISED OF LOOPS 

3267
02:42:56,000 --> 02:43:00,040
1, 2, AND 3 AND POINTING OUT 

3268
02:43:00,040 --> 02:43:02,040
ANOTHER IMPORTANT FEATURE WITHIN

3269
02:43:02,040 --> 02:43:05,320
PSI IS IN STEM LOOP 1 AND THIS 

3270
02:43:05,320 --> 02:43:07,400
REGION SUPPORTS GENOME 

3271
02:43:07,400 --> 02:43:11,360
DIMERIZATION THROUGH DIS THAT IS

3272
02:43:11,360 --> 02:43:12,680
DIMERIZATION INITIATION SITE AND

3273
02:43:12,680 --> 02:43:15,880
THIS IS A SMALL REGIONALLY 6 

3274
02:43:15,880 --> 02:43:19,000
NUCLEOTIDES THAT IS A PALINDROME

3275
02:43:19,000 --> 02:43:21,200
SEQUENCE AND THIS IS WHERE 

3276
02:43:21,200 --> 02:43:23,800
GENOME DIMERIZATION OCCURS AND 

3277
02:43:23,800 --> 02:43:28,280
WE KNOW PSI CONFERS SELECTIVE 

3278
02:43:28,280 --> 02:43:31,520
PACKAGING AND NATURE WHICH 

3279
02:43:31,520 --> 02:43:34,480
OUTCOMPETE CELLULAR PACKAGING IS

3280
02:43:34,480 --> 02:43:36,440
UNKNOWN AND MANY THEORIES COULD 

3281
02:43:36,440 --> 02:43:38,320
THEY HAVE A HIGH BINDING 

3282
02:43:38,320 --> 02:43:43,120
AFFINITY FOR PSI AND IT LEAD TO 

3283
02:43:43,120 --> 02:43:46,920
ASSEMBLY EFFICIENTLY BINDING TO 

3284
02:43:46,920 --> 02:43:50,280
NON-PSIRNA OR DOES IT HAVE A 

3285
02:43:50,280 --> 02:43:51,240
KINETIC ADVANTAGE OF IT COULD 

3286
02:43:51,240 --> 02:43:52,760
ONE OF THESE OR COMBINATION OF 

3287
02:43:52,760 --> 02:43:56,920
ANY ONE OF THESE THEORIES?  

3288
02:43:56,920 --> 02:43:58,560
FIRST STARTING OFF PREVIOUSLY 

3289
02:43:58,560 --> 02:44:00,360
OUR LAB AND OTHERS HAVE LOOKED 

3290
02:44:00,360 --> 02:44:02,240
AT WHETHER OR NOT GAG COULD HAVE

3291
02:44:02,240 --> 02:44:07,160
HIGH AFFINITY FOR PSIRNA DONE 

3292
02:44:07,160 --> 02:44:09,960
WITH IN VITRO BINDING STUDIES 

3293
02:44:09,960 --> 02:44:12,080
DONE WITH RECOMBINANT GAG AND 

3294
02:44:12,080 --> 02:44:16,360
DIFFERENT FEATURES OF RNA 

3295
02:44:16,360 --> 02:44:23,400
TRANSCR

3296
02:44:23,400 --> 02:44:23,960
TRANSCRIPTS. 

3297
02:44:23,960 --> 02:44:27,120
ITERATING THAT POINT THIS IS 

3298
02:44:27,120 --> 02:44:29,880
DATA FROM OUR LAB AND QUENCHING 

3299
02:44:29,880 --> 02:44:32,200
ASSAYS AND COMPARING MONOMERIC 

3300
02:44:32,200 --> 02:44:39,680
AND DIPSI AND CONTROL GRAP THAT 

3301
02:44:39,680 --> 02:44:42,280
IS REGION FURTHER UPSTREAM IN 

3302
02:44:42,280 --> 02:44:44,360
THE GENOME AND SEQUENCE FROM 

3303
02:44:44,360 --> 02:44:46,680
ANOTHER RETRO VIRUS AND YOU SEE 

3304
02:44:46,680 --> 02:44:49,600
TAKE HOME POINT IS BINDING 

3305
02:44:49,600 --> 02:44:51,000
CURVES OVERLAP OR ARE QUITE 

3306
02:44:51,000 --> 02:44:53,000
CLOSE TO ONE ANOTHER AND WHEN 

3307
02:44:53,000 --> 02:44:55,240
KDS ARE DERIVED FROM THERE, 

3308
02:44:55,240 --> 02:44:57,560
THERE IS NO DIFFERENCE FROM 

3309
02:44:57,560 --> 02:45:00,560
AFFINITY FROM THESE DIFFERENT 

3310
02:45:00,560 --> 02:45:01,080
RNAS. 

3311
02:45:01,080 --> 02:45:03,520
SO, SELECTIVE PACKAGING CANNOT 

3312
02:45:03,520 --> 02:45:06,200
BE EXPLAINED SIMPLY BY JUST 

3313
02:45:06,200 --> 02:45:08,720
HIGHER BINDING AFFINITIES. 

3314
02:45:08,720 --> 02:45:11,080
SO, OUR LABORATORY HAS COME UP 

3315
02:45:11,080 --> 02:45:14,720
WITH A HYPOTHESIS TO EXPLAIN 

3316
02:45:14,720 --> 02:45:17,720
SELECTIVE PACKAGING THAT PSIRNA 

3317
02:45:17,720 --> 02:45:21,400
IS SELECTIVELY PACKAGED DUE TO 

3318
02:45:21,400 --> 02:45:23,160
EFFICIENCY OF THIS PROCESS.  

3319
02:45:23,160 --> 02:45:27,520
THAT MEANS WHEN GAG BINDS TO 

3320
02:45:27,520 --> 02:45:30,280
PSIRNA NUKE LEEATION KINETICS OR

3321
02:45:30,280 --> 02:45:32,720
FEW GAGS THAT BIND OR CREATE A 

3322
02:45:32,720 --> 02:45:36,880
SEED KINETICS OCCUR FASTER THAN 

3323
02:45:36,880 --> 02:45:38,560
PSIRNA AND OTHER RNAS IN THE 

3324
02:45:38,560 --> 02:45:42,160
CELL THAT LEADS TO MORE 

3325
02:45:42,160 --> 02:45:45,640
EFFICIENT LATTICE FORMATION ON 

3326
02:45:45,640 --> 02:45:48,480
PSIRNA THAN ON OTHER CELLULAR 

3327
02:45:48,480 --> 02:45:50,880
RNAS AND UNANSWERED QUESTION IS 

3328
02:45:50,880 --> 02:45:54,680
WHETHER OR NOT GAG BINDS WITH 

3329
02:45:54,680 --> 02:45:58,760
DIFFERENT KINETICS TO PSI AND 

3330
02:45:58,760 --> 02:46:00,640
NONPSIRNA AND ADDRESSING 

3331
02:46:00,640 --> 02:46:04,080
QUESTION WE UTILIZE SWITCHSENSE 

3332
02:46:04,080 --> 02:46:06,440
TECHNOLOGY.  SWITCHSENSE USES A 

3333
02:46:06,440 --> 02:46:10,320
BIOCHIP THAT ON THE BIOCHIP ARE 

3334
02:46:10,320 --> 02:46:11,960
FOUR FLUIDIC WELLS AND WITHIN 

3335
02:46:11,960 --> 02:46:17,040
EACH OF THE WELLS IS 6 DETECTION

3336
02:46:17,040 --> 02:46:18,480
SPOTS.  ON THOSE DETECTION SPOTS

3337
02:46:18,480 --> 02:46:22,880
IS MONOLAYER OF DNA NANOLEVERS 

3338
02:46:22,880 --> 02:46:24,720
THAT ARE UNIQUE SEQUENCE THAT 

3339
02:46:24,720 --> 02:46:27,240
EACH OF THEM IS LABELED RED OR 

3340
02:46:27,240 --> 02:46:29,440
GREEN AND FROM THERE YOU ARE 

3341
02:46:29,440 --> 02:46:33,640
ABLE TO HYBRIDIZE YOUR RNA OF 

3342
02:46:33,640 --> 02:46:34,600
INTEREST.  

3343
02:46:34,600 --> 02:46:37,160
AND AN IMPORTANT FEATURE OF THIS

3344
02:46:37,160 --> 02:46:39,160
TECHNOLOGY IS WE ARE ABLE TO 

3345
02:46:39,160 --> 02:46:40,720
DIRECTLY COMPARE AT THE SAME 

3346
02:46:40,720 --> 02:46:43,520
TIME TWO DIFFERENT RNAS TO IN 

3347
02:46:43,520 --> 02:46:47,760
THIS CASE BINDING OF GAG 

3348
02:46:47,760 --> 02:46:48,240
PROTEINS. 

3349
02:46:48,240 --> 02:46:52,240
SO, WHAT THE -- AN EXAMPLE OF 

3350
02:46:52,240 --> 02:46:54,960
KINETIC REED OUT OF THE KINETIC 

3351
02:46:54,960 --> 02:46:56,360
MEASUREMENTS IS FOR SWITCHSENSE 

3352
02:46:56,360 --> 02:46:59,400
WE ARE OBSERVING CHANGE IN 

3353
02:46:59,400 --> 02:47:00,720
FLUORESCENCE OVER TIME AND 

3354
02:47:00,720 --> 02:47:03,480
INITIALLY YOU WILL HAVE A 

3355
02:47:03,480 --> 02:47:06,000
BASELINE FLUORESCENCE VALUE FOR 

3356
02:47:06,000 --> 02:47:08,560
RNAS HYBRIDIZED TO THE SURFACE 

3357
02:47:08,560 --> 02:47:10,560
AND INTRODUCE PROTEIN OF 

3358
02:47:10,560 --> 02:47:13,960
INTEREST THAT BINDS TO RNA AND 

3359
02:47:13,960 --> 02:47:16,000
YOU WILL OBSERVE QUENCHING OF 

3360
02:47:16,000 --> 02:47:17,160
SIGNAL OVER TIME AND THIS CURVE 

3361
02:47:17,160 --> 02:47:21,200
YOU WILL BE ABLE TO DRIVE A KON 

3362
02:47:21,200 --> 02:47:23,760
OR ASSOCIATION RATE AND LOOKING 

3363
02:47:23,760 --> 02:47:25,640
AT DISASSOCIATION WE WILL 

3364
02:47:25,640 --> 02:47:27,440
INTRODUCE BUFFER ALONE.  WE WILL

3365
02:47:27,440 --> 02:47:30,080
LOOK AT UNQUENCHING OR 

3366
02:47:30,080 --> 02:47:32,400
RESTORATION OF FLUORESCENCE AS 

3367
02:47:32,400 --> 02:47:34,720
YOUR PROTEIN UNBINDS FROM THE 

3368
02:47:34,720 --> 02:47:37,920
RNA.  FROM THERE, THESE CURVES 

3369
02:47:37,920 --> 02:47:43,120
DERIVE A DISSOCIATION KOFF RATE.

3370
02:47:43,120 --> 02:47:46,560
SO, TO SHOW SOME RAW DATA, THIS 

3371
02:47:46,560 --> 02:47:49,760
IS SHOWING GAG BINDING KINETICS 

3372
02:47:49,760 --> 02:47:52,640
TO PSIRNA.  YOU CAN SEE WE ARE 

3373
02:47:52,640 --> 02:47:56,520
ABLE TO SUCCESSFULLY MONITOR GAG

3374
02:47:56,520 --> 02:47:59,240
RNA BINDING GAGS USING 

3375
02:47:59,240 --> 02:48:01,960
SWITCHSENSE AND HERE WE MEASURE 

3376
02:48:01,960 --> 02:48:03,640
WITH INCREASING GAG 

3377
02:48:03,640 --> 02:48:05,720
CONCENTRATION TO 5 TO 0 

3378
02:48:05,720 --> 02:48:08,920
NANOMOLAR OF GAG AND SEE 

3379
02:48:08,920 --> 02:48:10,000
QUANTIFIABLE CHANGE IN 

3380
02:48:10,000 --> 02:48:12,320
ASSOCIATION OF CURVES AND FASTER

3381
02:48:12,320 --> 02:48:14,720
RATES AS GAG IS TIGHT TREATED IN

3382
02:48:14,720 --> 02:48:18,360
AND POINTING OUT IN 

3383
02:48:18,360 --> 02:48:19,560
PHYSIOLOGICAL CELLS BUFFER, 

3384
02:48:19,560 --> 02:48:21,560
INTERACTION BETWEEN GAG AND RNA 

3385
02:48:21,560 --> 02:48:25,800
IS A STABLE INTERACTION.  WE CAN

3386
02:48:25,800 --> 02:48:27,280
CONCLUDE THAT BECAUSE FOR 

3387
02:48:27,280 --> 02:48:31,400
DISSOCIATION CURVES THERE IS NO 

3388
02:48:31,400 --> 02:48:32,640
QUANTIFIABLE DISSOCIATION BEING 

3389
02:48:32,640 --> 02:48:34,040
ABLE TO BE MEASURED BECAUSE 

3390
02:48:34,040 --> 02:48:36,560
THERE IS NO RESTORATION IN 

3391
02:48:36,560 --> 02:48:37,720
FLUORESCENCE AND REST OF THE 

3392
02:48:37,720 --> 02:48:39,600
DATA WE ARE SHOWING IT IS ONLY 

3393
02:48:39,600 --> 02:48:41,080
ASSOCIATION RATES THAT WE WILL 

3394
02:48:41,080 --> 02:48:42,960
TALK ABOUT. 

3395
02:48:42,960 --> 02:48:46,200
SO, FIRST OFF, WE WANTED TO 

3396
02:48:46,200 --> 02:48:47,920
COMPARE DIFFERENT FULL LENGTH 

3397
02:48:47,920 --> 02:48:51,520
PSI.  IT IS 145 NUCLEOTIDES IN 

3398
02:48:51,520 --> 02:48:53,520
LENGTH CONTAINING STEM LOOPS 1, 

3399
02:48:53,520 --> 02:48:58,800
2, AND 3 AND MAKING IT EASIER 

3400
02:48:58,800 --> 02:49:02,000
MUTATED DIS SIGNAL CONTAINING 

3401
02:49:02,000 --> 02:49:04,800
6CS INHIBITING DIMERIZATION WITH

3402
02:49:04,800 --> 02:49:07,440
ANOTHER PSI MOLECULE THAT WE 

3403
02:49:07,440 --> 02:49:10,200
COMPARED TO A MULTIPLE BINDING 

3404
02:49:10,200 --> 02:49:12,280
SITE MUTANT.  WHAT EXACTLY THAT 

3405
02:49:12,280 --> 02:49:15,280
MEANS IS IT HAS BEEN SHOWN 

3406
02:49:15,280 --> 02:49:16,560
PREVIOUSLY THAT THERE ARE 

3407
02:49:16,560 --> 02:49:18,520
NUMEROUS UNPAIRED GS THAT ARE 

3408
02:49:18,520 --> 02:49:21,520
PROBABLY 16 OF THEM THAT ARE 

3409
02:49:21,520 --> 02:49:23,560
LOCATED WITHIN PSI.  

3410
02:49:23,560 --> 02:49:25,360
THEY HAVE BEEN LINKED TO BE 

3411
02:49:25,360 --> 02:49:28,280
IMPORTANT IN PACKAGING AND WE 

3412
02:49:28,280 --> 02:49:30,320
MUTATED GS TO AS AND ANOTHER 

3413
02:49:30,320 --> 02:49:32,680
CONTROL IS WE HAVE A SCRAMBLED 

3414
02:49:32,680 --> 02:49:36,120
UP PSI THAT WE LOOKED AT BINDING

3415
02:49:36,120 --> 02:49:38,040
KINETICS AND SHOWING COMPARISON 

3416
02:49:38,040 --> 02:49:43,080
OF GAG ASSOCIATION RATES BETWEEN

3417
02:49:43,080 --> 02:49:46,800
PSI MULTIBINDING SITE MUTANT 

3418
02:49:46,800 --> 02:49:49,640
UNSCRAMBLED AND WE SEE K ON RATE

3419
02:49:49,640 --> 02:49:52,200
FOR PSI IS SIGNIFICANTLY FASTER 

3420
02:49:52,200 --> 02:49:54,720
THAN SCRAMBLED AND MULTIPLE 

3421
02:49:54,720 --> 02:49:55,760
BINDING SITE MUTANT. 

3422
02:49:55,760 --> 02:49:58,400
SO, LOOKING AT OVERALL TREND OF 

3423
02:49:58,400 --> 02:50:01,680
THE DATA WE INTERESTINGLY FOUND 

3424
02:50:01,680 --> 02:50:04,280
THAT A CONCENTRATION DEPENDENT 

3425
02:50:04,280 --> 02:50:06,200
INCREASE IN GAG ASSOCIATION 

3426
02:50:06,200 --> 02:50:08,240
RATES MEANING WE FOUND A FASTER 

3427
02:50:08,240 --> 02:50:10,680
RATE PER GAG MOLECULE AND TREND 

3428
02:50:10,680 --> 02:50:12,640
IN DATA MAY SUGGEST 

3429
02:50:12,640 --> 02:50:14,560
COOPERATIVITY OF GAG FINDING AND

3430
02:50:14,560 --> 02:50:15,920
IMPORTANT TAKE-HOME MESSAGE IS 

3431
02:50:15,920 --> 02:50:19,480
THAT YOU CAN SEE PSIRNA IS FAR 

3432
02:50:19,480 --> 02:50:22,040
MORE SENSITIVE TO INCREASING GAG

3433
02:50:22,040 --> 02:50:24,320
CONCENTRATIONS THAN SCRAMBLED IN

3434
02:50:24,320 --> 02:50:26,080
MULTIPLE BINDING SITE MUTANT. 

3435
02:50:26,080 --> 02:50:28,120
SO, NOW THAT WE HAVE FOUND THAT 

3436
02:50:28,120 --> 02:50:30,280
THERE IS A DIFFERENCE IN 

3437
02:50:30,280 --> 02:50:32,040
KINETICS BETWEEN PSI AND OTHER 

3438
02:50:32,040 --> 02:50:34,160
RNAS WE WANTED TO SEE WHETHER OR

3439
02:50:34,160 --> 02:50:36,040
NOT FAST KINETICS COULD BE 

3440
02:50:36,040 --> 02:50:38,800
MAPPED TO A SPECIFIC REGION OF 

3441
02:50:38,800 --> 02:50:40,800
PSI.  DOING THAT WE TOOK IT AND 

3442
02:50:40,800 --> 02:50:42,440
BROKE IT DOWN INTO STEM LOOP 

3443
02:50:42,440 --> 02:50:45,080
PAIRS CONTAINING SL1 AND 2 OR 

3444
02:50:45,080 --> 02:50:47,960
COMPARING IT TO SL2 AND 3 AND WE

3445
02:50:47,960 --> 02:50:50,320
LOOKED AT ALSO IF YOU TOOK PSI 

3446
02:50:50,320 --> 02:50:52,400
AND BROKE IT DOWN FURTHER INTO 

3447
02:50:52,400 --> 02:50:53,880
INDIVIDUAL STEM LOOP COMPONENTS 

3448
02:50:53,880 --> 02:50:56,480
LOOKING AT GAG BINDING KINETICS 

3449
02:50:56,480 --> 02:50:59,720
AND SHOWING FIRST OFF LOOKING AT

3450
02:50:59,720 --> 02:51:02,560
THE DISCRETE REGIONS OF PSI 

3451
02:51:02,560 --> 02:51:05,160
COMPARING STEM LOOPS 1 AND 2 AND

3452
02:51:05,160 --> 02:51:07,400
PSI2 AND 3 SCRAMBLED WITH 

3453
02:51:07,400 --> 02:51:08,560
INCREASING GAG CONCENTRATION 

3454
02:51:08,560 --> 02:51:11,440
THAT IS SHOWN IN THE GREEN THAT 

3455
02:51:11,440 --> 02:51:14,520
IN FACT PSI2 AND 3 HAS 

3456
02:51:14,520 --> 02:51:17,480
SIGNIFICANTLY FASTER GAG 

3457
02:51:17,480 --> 02:51:19,800
ASSOCIATION RATES THAN SCRAMBLED

3458
02:51:19,800 --> 02:51:22,560
RNA IN PURPLE AND INTERESTINGLY 

3459
02:51:22,560 --> 02:51:25,480
LOW RATE OF CONCENTRATION OF GAG

3460
02:51:25,480 --> 02:51:28,160
WE FOUND LOWEST DIFFERENCE IN 

3461
02:51:28,160 --> 02:51:30,520
ASSOCIATION RATES SCRAMBLED IN 

3462
02:51:30,520 --> 02:51:34,240
125 NANOMOLAR OF GAG.  WE THEN 

3463
02:51:34,240 --> 02:51:35,720
LOOKED AT THE INDIVIDUAL STEM 

3464
02:51:35,720 --> 02:51:36,200
LOOPS. 

3465
02:51:36,200 --> 02:51:39,040
YOU CAN SEE HERE THAT ACROSS THE

3466
02:51:39,040 --> 02:51:41,000
INDIVIDUAL STEM LOOPS WITH 

3467
02:51:41,000 --> 02:51:44,240
INCREASING GAG CONCENTRATION 

3468
02:51:44,240 --> 02:51:47,760
THAT THESE RNAS HAVE SIMILAR GAG

3469
02:51:47,760 --> 02:51:49,200
ASSOCIATION RATES TO ONE 

3470
02:51:49,200 --> 02:51:51,760
ANOTHER.  AND TO SCRAMBLE. 

3471
02:51:51,760 --> 02:51:53,640
SO, THE INDIVIDUAL STEM LOOPS, 

3472
02:51:53,640 --> 02:51:56,640
THEY ARE NOT REALLY CONTRIBUTING

3473
02:51:56,640 --> 02:51:59,280
TO THE FAST FINDING KINETICS WE 

3474
02:51:59,280 --> 02:52:01,080
ARE OBSERVING WITH COMBINATION 

3475
02:52:01,080 --> 02:52:03,720
OR WITH THE LENGTH PSI. 

3476
02:52:03,720 --> 02:52:07,320
SO, IN CONCLUSION I HAVE SHOWN 

3477
02:52:07,320 --> 02:52:09,480
YOU WE SEE A MODEST AND 

3478
02:52:09,480 --> 02:52:11,960
REPRODUCIBLE GAG ASSOCIATION IN 

3479
02:52:11,960 --> 02:52:13,920
KINETICS BETWEEN PSI AND 

3480
02:52:13,920 --> 02:52:17,560
SCRAMBLED ARE.  NA AND RESULTS 

3481
02:52:17,560 --> 02:52:18,840
CONSISTENT WITH HYPOTHESIS 

3482
02:52:18,840 --> 02:52:20,200
KINETIC EXPLANATION WITH 

3483
02:52:20,200 --> 02:52:23,000
SPECIFIC PACKAGING OF VIRAL 

3484
02:52:23,000 --> 02:52:25,040
GENOME AND INCREASE IN GAG 

3485
02:52:25,040 --> 02:52:27,040
ASSOCIATION RATES FASTER RATE 

3486
02:52:27,040 --> 02:52:28,760
PER GAG MOLECULE AND 

3487
02:52:28,760 --> 02:52:31,480
INTERESTINGLY, WE SEE THAT THE 

3488
02:52:31,480 --> 02:52:33,080
SPECIFIC UNPAIRED GS WITHIN PSI 

3489
02:52:33,080 --> 02:52:35,960
ARE CONTRIBUTING TO RAPID 

3490
02:52:35,960 --> 02:52:38,240
BINDING KINETICS WHEN MUTATED 

3491
02:52:38,240 --> 02:52:42,080
THEY HAVE SIMILAR KINETICS TO 

3492
02:52:42,080 --> 02:52:44,200
UNSCRAMBLED RNA AND GAG 

3493
02:52:44,200 --> 02:52:46,160
ASSOCIATION RATES ARE ACTUALLY 

3494
02:52:46,160 --> 02:52:48,200
LOST WHEN BROKEN DOWN INTO 

3495
02:52:48,200 --> 02:52:50,800
INDIVIDUAL STEM LOOPS THAT THESE

3496
02:52:50,800 --> 02:52:52,920
SEQUENCES ARE NOT IMPACTING 

3497
02:52:52,920 --> 02:52:55,240
BINDING KINETICS INTERESTINGLY 

3498
02:52:55,240 --> 02:52:56,720
TWO STEM LOOPS TOGETHER 

3499
02:52:56,720 --> 02:52:59,080
PARTICULARLY 2 AND 3 HAS FASTER 

3500
02:52:59,080 --> 02:53:00,840
ASSOCIATION RATES THAN ANOTHER 

3501
02:53:00,840 --> 02:53:03,320
REGION WITHIN PSI IMPLYING THAT 

3502
02:53:03,320 --> 02:53:06,640
GAG BINDING KINETICS IS 

3503
02:53:06,640 --> 02:53:08,240
DETERMINED BY 3D STRUCTURAL 

3504
02:53:08,240 --> 02:53:10,400
ORGANIZATION OF PSI EXPLAINING 

3505
02:53:10,400 --> 02:53:14,200
WHY PSI HAS FASTER K ON RATES 

3506
02:53:14,200 --> 02:53:18,400
THAN A SCRAMBLED RNA AND LASTLY 

3507
02:53:18,400 --> 02:53:20,120
ONGOING EXPERIMENTS WE WANT TO 

3508
02:53:20,120 --> 02:53:22,800
DETERMINE BINDING AFFINITIES OF 

3509
02:53:22,800 --> 02:53:24,960
KDS THAT COULDN'T BE DERIVED 

3510
02:53:24,960 --> 02:53:27,120
FROM SWITCHSENSE STATUS WE 

3511
02:53:27,120 --> 02:53:28,760
WEREN'T ABLE TO OBSERVE 

3512
02:53:28,760 --> 02:53:30,760
DISSOCIATION AND LOOKING AT 

3513
02:53:30,760 --> 02:53:33,200
MICROSKWAL THERMOFORESIS FOR 

3514
02:53:33,200 --> 02:53:35,040
THAT AND WANT TO DETERMINE GAG 

3515
02:53:35,040 --> 02:53:37,680
MOLECULES FOR RNAS WE HAVE BEEN 

3516
02:53:37,680 --> 02:53:39,640
TESTING USING A NEW TECHNOLOGY 

3517
02:53:39,640 --> 02:53:42,880
COMING TO NCI WHICH IS MASS 

3518
02:53:42,880 --> 02:53:44,840
SPECK TROMTRY AND WE WILL LOOK 

3519
02:53:44,840 --> 02:53:48,720
AT IN VIVO EFFECTS LOOKING AT 

3520
02:53:48,720 --> 02:53:52,160
STEM LOOP FOR IN VIVO PACKAGING 

3521
02:53:52,160 --> 02:53:55,640
EFFICIENCY AND WITH THAT 

3522
02:53:55,640 --> 02:53:56,480
THANKING MENTOR FOR ALL THEIR 

3523
02:53:56,480 --> 02:53:59,760
HELP ON THE PROJECT AND 

3524
02:53:59,760 --> 02:54:02,840
BIOPHYSICS RESEARCH SURVEY IN 

3525
02:54:02,840 --> 02:54:04,360
MARZENA FOR HELP WITH 

3526
02:54:04,360 --> 02:54:05,840
TECHNOLOGIES USED IN THE STUDY 

3527
02:54:05,840 --> 02:54:09,400
AND WITH THAT I WILL TAKE ANY 

3528
02:54:09,400 --> 02:54:13,200
QUESTI

3529
02:54:13,200 --> 02:54:13,480
QUESTIONS. 

3530
02:54:13,480 --> 02:54:16,840
>>DO YOU KNOW IF THERE
ARE 

3531
02:54:16,840 --> 02:54:18,920
CHANGES IN DIFFERENT 

3532
02:54:18,920 --> 02:54:21,040
[INDISCERNIBLE] OF HIV IN STEM 2

3533
02:54:21,040 --> 02:54:21,880
AND 3?  

3534
02:54:21,880 --> 02:54:25,360
>>SO, THAT REGION IS
HIGHLY 

3535
02:54:25,360 --> 02:54:26,120
CONSERVED.  SO -- 

3536
02:54:26,120 --> 02:54:26,960
>>[INDISCERNIBLE]. 

3537
02:54:26,960 --> 02:54:29,840
>>WELL, NOT EXACTLY
COMPLETELY.

3538
02:54:29,840 --> 02:54:31,440
THERE IS A FEW MUTATIONS THAT 

3539
02:54:31,440 --> 02:54:33,680
ARE HERE AND THERE AND GENERALLY

3540
02:54:33,680 --> 02:54:37,920
IN THAT SPECIFIC REGION IT IS 

3541
02:54:37,920 --> 02:54:41,320
QUITE CONSERVED. 

3542
02:54:41,320 --> 02:54:43,400
>>GOING BACK TO THE FIRST
TALK 

3543
02:54:43,400 --> 02:54:45,480
THIS MORNING, WHAT ARE YOUR 

3544
02:54:45,480 --> 02:54:48,640
THOUGHTS ABOUT USING CD4 

3545
02:54:48,640 --> 02:54:52,440
TARGETING LIPID NANOPARTICLES 

3546
02:54:52,440 --> 02:54:54,120
DELIVERING THESE THAT WOULD 

3547
02:54:54,120 --> 02:54:55,200
EITHER DISRUPT STEM LOOP 

3548
02:54:55,200 --> 02:54:58,360
STRUCTURE OF PSI OR PREVENT GAG 

3549
02:54:58,360 --> 02:55:04,160
INTERACTION WITH PSI?  

3550
02:55:04,160 --> 02:55:07,960
>>IT IS A POSSIBILITY.  I
KNOW 

3551
02:55:07,960 --> 02:55:10,160
THAT SMALL MOLECULE INHIBITORS 

3552
02:55:10,160 --> 02:55:14,080
HAVE BEEN DEVELOPED TO TARGET 

3553
02:55:14,080 --> 02:55:17,000
INTERACTIONS OF NC AND STEM LOOP

3554
02:55:17,000 --> 02:55:18,280
3. 

3555
02:55:18,280 --> 02:55:19,960
SO, GS SORT OF THE ONLY ISSUE 

3556
02:55:19,960 --> 02:55:22,440
WITH THAT IS THAT THERE IS HIGH 

3557
02:55:22,440 --> 02:55:24,320
TOXICITY AND OTHER THINGS. 

3558
02:55:24,320 --> 02:55:26,560
THOSE HAVE NOT COME TO THE 

3559
02:55:26,560 --> 02:55:28,000
FOREFRONT.  IT IS A POSSIBILITY 

3560
02:55:28,000 --> 02:55:28,720
IF -- 

3561
02:55:28,720 --> 02:55:29,520
>>THANK YOU. 

3562
02:55:29,520 --> 02:55:30,120
>>YEAH. 

3563
02:55:30,120 --> 02:55:34,160
>>I HAVE A QUICK
QUESTION.  IS 

3564
02:55:34,160 --> 02:55:36,520
PSIRNA PART OF GAG RNA AS ONE 

3565
02:55:36,520 --> 02:55:39,480
PART OF IT OR SEPARATE RNA THAT 

3566
02:55:39,480 --> 02:55:42,000
IS -- YOU KNOW WHAT I MEAN?  

3567
02:55:42,000 --> 02:55:43,600
>>SORRY. 

3568
02:55:43,600 --> 02:55:45,600
>>THE PSIRNA. 

3569
02:55:45,600 --> 02:55:46,640
>>YES.  THAT REGION. 

3570
02:55:46,640 --> 02:55:49,080
>>IS IT PART OF THE
ENTIRE 

3571
02:55:49,080 --> 02:55:50,120
VIRAL RNA?  

3572
02:55:50,120 --> 02:55:50,560
>>YES. 

3573
02:55:50,560 --> 02:55:53,640
>>OKAY.  SO, THEN DURING 

3574
02:55:53,640 --> 02:55:54,880
INFECTION, THIS INFECTION, IS 

3575
02:55:54,880 --> 02:55:57,240
THERE -- YOU HAVE A MECHANISM 

3576
02:55:57,240 --> 02:56:01,120
YOU POSTULATE HOW IT LET'S GO OF

3577
02:56:01,120 --> 02:56:04,360
HOW GAG LET'S GO OF PSIRNA 

3578
02:56:04,360 --> 02:56:06,000
DURING INFECTION AND YOU HAVE A 

3579
02:56:06,000 --> 02:56:07,920
MECHANISM HOW IT GETS IT IN AND 

3580
02:56:07,920 --> 02:56:11,560
MECHANISM HOW IT GETS IT OFF?  

3581
02:56:11,560 --> 02:56:17,080
>>WELL, SO -- IT COMES
IN.  SO,

3582
02:56:17,080 --> 02:56:19,760
WHEN IT IS IMMATURE VIRAL 

3583
02:56:19,760 --> 02:56:22,240
PARTICLE IN THERE YOU WILL HAVE 

3584
02:56:22,240 --> 02:56:23,920
CLEAVAGE AND THAT PROTEIN AND 

3585
02:56:23,920 --> 02:56:25,920
GAG IS CLEAVED INTO MULTIPLE 

3586
02:56:25,920 --> 02:56:28,360
PARTS AND YOU WILL HAVE 

3587
02:56:28,360 --> 02:56:29,040
REORGANIZATION. 

3588
02:56:29,040 --> 02:56:31,000
SO, THEY ARE LOOKING AT HOW THAT

3589
02:56:31,000 --> 02:56:31,240
RE-ORG. 

3590
02:56:31,240 --> 02:56:34,520
>>I SEE.  IT IS IMAGE OF
GAG 

3591
02:56:34,520 --> 02:56:36,000
THAT IS BINDING. 

3592
02:56:36,000 --> 02:56:36,520
>>YES. 

3593
02:56:36,520 --> 02:56:38,800
>>PROCESS TO SEPARATE
BINDING? 

3594
02:56:38,800 --> 02:56:39,680
>>YES. 

3595
02:56:39,680 --> 02:56:41,080
>>I GET IT. 

3596
02:56:41,080 --> 02:56:44,120
>>GETS REVERSE
TRANSCRIBED AND 

3597
02:56:44,120 --> 02:56:45,400
BECOMES DNA. 

3598
02:56:45,400 --> 02:56:46,000
>>THANK YOU. 

3599
02:56:46,000 --> 02:56:50,240
>>LAST TALK IN THE
SESSION AND 

3600
02:56:50,240 --> 02:56:56,560
THEN LUNCH BREAK IS BY CHUEN-YEN

3601
02:56:56,560 --> 02:56:57,600
LAU.  

3602
02:56:57,600 --> 02:57:00,280
>>PRETTY GOOD. 

3603
02:57:00,280 --> 02:57:01,720
>>TALK IS INNATE IMMUNE 

3604
02:57:01,720 --> 02:57:04,520
CORRELATES OF CELL-ASSOCIATED 

3605
02:57:04,520 --> 02:57:09,160
HIV RNA AND DNA DURING LONG-TERM

3606
02:57:09,160 --> 02:57:10,080
SUPPRESSIVE ART. 

3607
02:57:10,080 --> 02:57:11,360
>>THANKS SO MUCH. 
EVERYONE, 

3608
02:57:11,360 --> 02:57:12,920
CAN YOU HEAR ME OKAY?  

3609
02:57:12,920 --> 02:57:13,520
>>YEAH. 

3610
02:57:13,520 --> 02:57:16,400
>>IS THIS A POINTER?  DO
YOU 

3611
02:57:16,400 --> 02:57:17,400
THINK IT IS?  

3612
02:57:17,400 --> 02:57:19,080
THAT IS GOOD.  

3613
02:57:19,080 --> 02:57:20,440
WELL, WHILE SHE IS PULLING UP 

3614
02:57:20,440 --> 02:57:22,160
THE SLIDE, I WILL TELL YOU I 

3615
02:57:22,160 --> 02:57:26,760
WILL SHARE WITH YOU A STORY THAT

3616
02:57:26,760 --> 02:57:28,960
WE HAVE TAKEN A LONG TIME TO 

3617
02:57:28,960 --> 02:57:31,480
COME TO TALKING ABOUT INNATE 

3618
02:57:31,480 --> 02:57:33,600
IMMUNE CORRELATES OF CELL 

3619
02:57:33,600 --> 02:57:37,080
ASSOCIATED HIVRNA IN PATIENTS 

3620
02:57:37,080 --> 02:57:39,120
THAT ARE LONG TERM ART. 

3621
02:57:39,120 --> 02:57:41,120
THIS IS EXCITING AND COMPLEMENTS

3622
02:57:41,120 --> 02:57:42,960
TALKS WE HAVE HEARD ALREADY 

3623
02:57:42,960 --> 02:57:45,360
ABOUT ROLE OF INNATE IMMUNITY IN

3624
02:57:45,360 --> 02:57:47,760
VIRAL INFECTIONS NO THE JUST 

3625
02:57:47,760 --> 02:57:47,960
HIV. 

3626
02:57:47,960 --> 02:57:51,800
JUST AS A REMINDER, MOST OF THIS

3627
02:57:51,800 --> 02:57:53,160
AUDIENCE IS FAMILIAR WITH THIS. 

3628
02:57:53,160 --> 02:57:56,440
WE ARE CONCERNED ABOUT HIV 

3629
02:57:56,440 --> 02:57:58,040
PERSISTENCE AS IMPEDIMENT TO 

3630
02:57:58,040 --> 02:58:00,480
CURING HIV.  WE DON'T HAVE 

3631
02:58:00,480 --> 02:58:03,480
REPLICATION DURING A LONG TERM 

3632
02:58:03,480 --> 02:58:06,640
SUPPRESSED INFECTION AND WE 

3633
02:58:06,640 --> 02:58:12,000
STILL HAVE PERSISTENCE OF CELLS 

3634
02:58:12,000 --> 02:58:14,800
AND THEY ARE DIVERSE AND HEAVY 

3635
02:58:14,800 --> 02:58:17,320
PORTION OF DEFECTIVE PROVIRUSES 

3636
02:58:17,320 --> 02:58:20,640
AND DON'T FULLY UNDERSTAND 

3637
02:58:20,640 --> 02:58:23,760
MECHANISMS DRIVING THIS 

3638
02:58:23,760 --> 02:58:25,560
FORMATION AND MAINTENANCE OF 

3639
02:58:25,560 --> 02:58:27,760
POPULATIONS AND PERSISTENCE 

3640
02:58:27,760 --> 02:58:30,400
ASSOCIATED WITH IMMUNE 

3641
02:58:30,400 --> 02:58:32,600
ACTIVATION IN INFLAMMATORY STATE

3642
02:58:32,600 --> 02:58:35,680
LEADING TO LONG-TERM MOBILITY 

3643
02:58:35,680 --> 02:58:37,560
AND MORTALITY AND PROVIRAL 

3644
02:58:37,560 --> 02:58:39,760
POPULATIONS THAT CAN EFFECT OR 

3645
02:58:39,760 --> 02:58:42,400
CLONE ALLEY EXPAND AND CAN 

3646
02:58:42,400 --> 02:58:46,920
EXPRESS RNA THAT CONTRIBUTES TO 

3647
02:58:46,920 --> 02:58:47,680
INFLAMMATORY STATE AND DON'T 

3648
02:58:47,680 --> 02:58:50,360
UNDERSTAND SOURCES OF IMMUNE 

3649
02:58:50,360 --> 02:58:52,880
ACTIVATION AND CHARACTERIZE 

3650
02:58:52,880 --> 02:58:54,360
RELATIONSHIP BETWEEN PERSISTENCE

3651
02:58:54,360 --> 02:58:58,000
AND INFLAMMATORY STATE TO HELP 

3652
02:58:58,000 --> 02:58:59,400
WITH CURE AND SOUGHT TO DEVELOP 

3653
02:58:59,400 --> 02:59:02,480
A COHORT OF LONG TERM SUPPRESSED

3654
02:59:02,480 --> 02:59:06,280
HIV PATIENTS AND WE HAVE 73 IN 

3655
02:59:06,280 --> 02:59:10,040
THE STUDY I WILL SHOW YOU DATA 

3656
02:59:10,040 --> 02:59:12,680
IN A SECOND MEASURING DNA AND 

3657
02:59:12,680 --> 02:59:17,440
RNA USING DDC PEL CR AND FOCUSED

3658
02:59:17,440 --> 02:59:23,680
ON LTR AND GAG GENES.  YOU WILL 

3659
02:59:23,680 --> 02:59:26,200
SEE 2LTRS PER GAG THAT IS 

3660
02:59:26,200 --> 02:59:28,240
CRITICAL WITH OUR ANALYSIS AND 

3661
02:59:28,240 --> 02:59:33,120
LOOKED AT RELATIVE LEVELS OF 

3662
02:59:33,120 --> 02:59:39,120
SITES BY FLOW FOTOMETRY. 

3663
02:59:39,120 --> 02:59:40,240
IDENTIFYING FACTORS ASSOCIATED 

3664
02:59:40,240 --> 02:59:44,320
WITH HIV, DNA AND RNA LEVELS AND

3665
02:59:44,320 --> 02:59:47,080
USED 13 CORRELATION REGRESSION 

3666
02:59:47,080 --> 02:59:50,800
AND CLASSIFICATION TESTS WITH 31

3667
02:59:50,800 --> 02:59:52,400
BIOMARKERS TO IDENTIFY 

3668
02:59:52,400 --> 02:59:54,880
PARAMETERS RELEVANT IN THE MOST 

3669
02:59:54,880 --> 02:59:57,280
TEST.  THEN WE TOOK PARAMETERS 

3670
02:59:57,280 --> 03:00:00,560
AND WE DID MULTILINEAR 

3671
03:00:00,560 --> 03:00:02,680
REGRESSION TO LOOK AT 

3672
03:00:02,680 --> 03:00:04,040
ASSOCIATIONS AND DID EXHAUSTIVE 

3673
03:00:04,040 --> 03:00:06,360
SEARCHES OF LINEAR MODELS WITH 

3674
03:00:06,360 --> 03:00:07,720
THOSE PARAMETERS OR JUST WITH 

3675
03:00:07,720 --> 03:00:09,680
TWO OR THREE SEPARATE PARAMETERS

3676
03:00:09,680 --> 03:00:12,920
TO LOOK AT A MODEL AND IDEA 

3677
03:00:12,920 --> 03:00:14,760
BEING AUTHENTIC BIOMARKERS WOULD

3678
03:00:14,760 --> 03:00:17,120
BE PRESENT IN MULTIPLE 

3679
03:00:17,120 --> 03:00:19,080
ALGORITHMS THAT THOSE WOULD BE A

3680
03:00:19,080 --> 03:00:20,320
DISCRIMINATORY FEATURE. 

3681
03:00:20,320 --> 03:00:22,280
HERE, YOU CAN SEE THE 

3682
03:00:22,280 --> 03:00:23,560
CHARACTERISTICS OF PATIENTS AND 

3683
03:00:23,560 --> 03:00:26,440
I WILL TELL YOU 73 OF THEM HAD 

3684
03:00:26,440 --> 03:00:27,720
DNA RESULTS. 

3685
03:00:27,720 --> 03:00:30,320
58 OF THOSE HAD RNA RESULTS 

3686
03:00:30,320 --> 03:00:33,360
ALSO.  THOSE GROUPS ARE FAIRLY 

3687
03:00:33,360 --> 03:00:34,680
SIMILAR.  THEY WERE ABOUT AROUND

3688
03:00:34,680 --> 03:00:38,160
50 YEARS OLD AND THEY WERE 

3689
03:00:38,160 --> 03:00:39,480
MOSTLY WHITE MALES. 

3690
03:00:39,480 --> 03:00:41,440
WE WERE UNDER-REPRESENTED IN 

3691
03:00:41,440 --> 03:00:43,440
TERMS OF FEMALES IN A LITTLE BIT

3692
03:00:43,440 --> 03:00:45,120
AND WE WERE OVERREPRESENTED IN 

3693
03:00:45,120 --> 03:00:47,080
WHITES AND BLACKS AND AFRICAN 

3694
03:00:47,080 --> 03:00:48,080
AMERICANS WERE ABOUT WHERE WE 

3695
03:00:48,080 --> 03:00:51,960
ARE IN THE EPIDEMIC IN TERMS OF 

3696
03:00:51,960 --> 03:00:53,680
PERCENTAGE AND THEY WERE LESS 

3697
03:00:53,680 --> 03:00:55,120
LATINX PEOPLE.  YOU CAN SEE FROM

3698
03:00:55,120 --> 03:00:56,640
THE -- LET'S SEE IF THIS -- 

3699
03:00:56,640 --> 03:00:59,520
WELL, OKAY.  I WILL WALK OVER 

3700
03:00:59,520 --> 03:01:01,160
HERE AND POINT TO IT.  YOU CAN 

3701
03:01:01,160 --> 03:01:04,160
SEE HERE THEY WERE PRETTY WELL 

3702
03:01:04,160 --> 03:01:06,560
RECONSTITUTED IN TERMS OF CD4 

3703
03:01:06,560 --> 03:01:07,760
COUNTS ABOUT YOU DOESN'T MEAN 

3704
03:01:07,760 --> 03:01:11,760
THEY HAVE FULLY NORMAL IMMUNE 

3705
03:01:11,760 --> 03:01:13,320
SYSTEMS AS YOU KNOW.  

3706
03:01:13,320 --> 03:01:15,760
LOOKING AT DNA RESULTS HERE I'M 

3707
03:01:15,760 --> 03:01:21,240
SHOWING YOU HISTOGRAMS OF THE 

3708
03:01:21,240 --> 03:01:25,840
LTRDNA AND GAG DNA. 

3709
03:01:25,840 --> 03:01:27,720
Y AXIS IS NUMBER OF PARTICIPANTS

3710
03:01:27,720 --> 03:01:31,720
AND YOU SEE THERE A BIT OF 

3711
03:01:31,720 --> 03:01:35,600
VARIATION IN LEVELS AMONGST 

3712
03:01:35,600 --> 03:01:36,520
PARTICIPANTS AND ALSO THAT THERE

3713
03:01:36,520 --> 03:01:41,480
ARE FEWER COPIES OF GAG THAN 

3714
03:01:41,480 --> 03:01:41,680
LTR. 

3715
03:01:41,680 --> 03:01:43,760
YOU CAN SEE IF YOU LOOK AT 

3716
03:01:43,760 --> 03:01:46,240
MEDIAN COPIES THERE IS 2.8 IN 

3717
03:01:46,240 --> 03:01:48,600
TERMS OF LOGS AND IN 3.4 IN 

3718
03:01:48,600 --> 03:01:52,080
TERMS OF LTR AND WE WILL LOOK 

3719
03:01:52,080 --> 03:01:54,840
AND TAKE CLOSER DIVE INTO THE 

3720
03:01:54,840 --> 03:01:55,960
DNA RESULTS. 

3721
03:01:55,960 --> 03:01:57,920
THINKING ABOUT EXPECTED RATIO 

3722
03:01:57,920 --> 03:02:00,680
SHOWING TWO LTRS PER GAG YOU SEE

3723
03:02:00,680 --> 03:02:03,680
YOU EXPECT A RATIO OF 2LTRS TO 

3724
03:02:03,680 --> 03:02:05,680
GAG THAT IS SHOWN ON Y AXIS AND 

3725
03:02:05,680 --> 03:02:08,920
ON HISTOGRAM YOU SEE THAT WE ARE

3726
03:02:08,920 --> 03:02:09,920
HEAVILY SHIFTED. 

3727
03:02:09,920 --> 03:02:13,120
THERE IS A LOT OF PEOPLE WHO 

3728
03:02:13,120 --> 03:02:15,480
HAVE MORE THAN EXPECTED -- WELL,

3729
03:02:15,480 --> 03:02:18,680
I GUESS YOU CAN SAY THEY HAVE 

3730
03:02:18,680 --> 03:02:21,120
MORE GAG DELETED PRO-VIRUSES AND

3731
03:02:21,120 --> 03:02:22,840
YOU MIGHT SAY YOU MIGHT UNTAP 

3732
03:02:22,840 --> 03:02:26,320
THE GAG AND YOU MISSED THAT AND 

3733
03:02:26,320 --> 03:02:27,760
SINGLE GENOME SEQUENCING WAS 

3734
03:02:27,760 --> 03:02:29,000
DONE TO SHOW PRIMERS ARE 

3735
03:02:29,000 --> 03:02:30,480
ACTUALLY RECOGNIZING THE TARGET 

3736
03:02:30,480 --> 03:02:33,920
AND WE DON'T THINK THAT IS WHAT 

3737
03:02:33,920 --> 03:02:35,280
IS RESPONSIBLE FOR THE RESULT 

3738
03:02:35,280 --> 03:02:37,720
AND IN THIS OTHER PLOT, YOU ARE 

3739
03:02:37,720 --> 03:02:42,320
LOOKING AT LTRDNA TO GAG DNA ON 

3740
03:02:42,320 --> 03:02:45,880
THE Y AXE YIGS AND LOOKING AT 

3741
03:02:45,880 --> 03:02:48,680
THE SLOPE IT IS DIFFERENT FROM 

3742
03:02:48,680 --> 03:02:50,960
EXPECTED SLOPE WITH USUALLE TWO 

3743
03:02:50,960 --> 03:02:53,360
LTRS TO GAGS AND IS PRETTY 

3744
03:02:53,360 --> 03:02:54,720
CONSISTENT THAT YOU SEE IT IS A 

3745
03:02:54,720 --> 03:02:58,160
GOOD FIT IN TERMS OF THE 

3746
03:02:58,160 --> 03:03:01,480
EQUATION.  HERE, I'M SHOWING 

3747
03:03:01,480 --> 03:03:03,640
AGAIN THAT GAG DELETED 

3748
03:03:03,640 --> 03:03:06,360
PROVIRUSES ARE PRESENT AT AN 

3749
03:03:06,360 --> 03:03:07,360
ALMOST CONSTANT RATE THAT IS 

3750
03:03:07,360 --> 03:03:09,600
ACTUALLY VERY INTERESTING TO US.

3751
03:03:09,600 --> 03:03:11,240
WHAT FACTORS ARE ACTUALLY 

3752
03:03:11,240 --> 03:03:14,120
ASSOCIATED WITH DNA LEVELS?  

3753
03:03:14,120 --> 03:03:18,080
IF YOU DO THE ANALYSIS THAT I 

3754
03:03:18,080 --> 03:03:19,720
HAD MENTIONED EARLIER AND THIS 

3755
03:03:19,720 --> 03:03:21,720
REGRESSION ANALYSIS AND YOU CAN 

3756
03:03:21,720 --> 03:03:24,880
SEE HERE THAT LOOKING AT GAG DNA

3757
03:03:24,880 --> 03:03:28,720
AND THE BEST FIT ONE PARAMETER 

3758
03:03:28,720 --> 03:03:31,760
MODEL HAD MEMORY CD8 CELLS AS 

3759
03:03:31,760 --> 03:03:33,760
THE BEST PREDICTOR. 

3760
03:03:33,760 --> 03:03:37,160
AND THAT HAD AN R VALUE OF .05. 

3761
03:03:37,160 --> 03:03:39,880
IF YOU LOOK FURTHER AT MORE 

3762
03:03:39,880 --> 03:03:41,640
PARAMETERS, WHAT WE FOUND WAS 

3763
03:03:41,640 --> 03:03:44,000
THAT A 2 PARAMETER SHOWED PRETTY

3764
03:03:44,000 --> 03:03:47,280
GOOD IMPROVEMENT OVER THE 1 

3765
03:03:47,280 --> 03:03:49,400
PARAMETER MODEL AND ADDING 

3766
03:03:49,400 --> 03:03:51,560
FACTORS DIDN'T HELP MUCH.  WE 

3767
03:03:51,560 --> 03:03:53,000
SETTLED ON TWO PARAMETER 

3768
03:03:53,000 --> 03:03:56,800
COMPOSITE MODEL WITH NADARCD4 

3769
03:03:56,800 --> 03:03:59,200
AND MEMORY CELLS AS BEST 

3770
03:03:59,200 --> 03:04:04,680
PREDICTORS AND R IMPROVED TO .6 

3771
03:04:04,680 --> 03:04:06,520
THAT IS SIGNIFICANT WITH BOND 

3772
03:04:06,520 --> 03:04:09,000
[INDISCERNIBLE] AND THAT IS DNA 

3773
03:04:09,000 --> 03:04:10,480
RESULTS.  YOU CAN SAY THAT IS 

3774
03:04:10,480 --> 03:04:13,000
JUST DNA.  WHAT ABOUT 

3775
03:04:13,000 --> 03:04:15,760
EXPRESSION?  RNA WE USE AS 

3776
03:04:15,760 --> 03:04:18,640
REPRESENTATION OF EXPRESSION.  

3777
03:04:18,640 --> 03:04:21,720
YOU CAN SEE HERE I'M SHOWING ON 

3778
03:04:21,720 --> 03:04:25,320
THIS SIDE BASICALLY MORE LTRNA 

3779
03:04:25,320 --> 03:04:27,160
THAN GAG RNA SAME GOING ON AS 

3780
03:04:27,160 --> 03:04:31,400
YOU SAW WITH DNA AND IN THIS TOP

3781
03:04:31,400 --> 03:04:34,360
PLOT OR TOP HISTOGRAM YOU HAVE 

3782
03:04:34,360 --> 03:04:37,880
THIS AND ON BOTTOM YOU HAVE GAG 

3783
03:04:37,880 --> 03:04:40,320
RNA PER MILLION CD4 CELLS YOU 

3784
03:04:40,320 --> 03:04:42,760
SEE AGAIN THE SHIFT IN THE PLOTS

3785
03:04:42,760 --> 03:04:45,760
AND MEDIAN FOR LTR IS MUCH 

3786
03:04:45,760 --> 03:04:47,760
HIGHER ON THE LOG SCALE THAN FOR

3787
03:04:47,760 --> 03:04:50,080
GAG.  OKAY.  THAT IS TOTAL.  

3788
03:04:50,080 --> 03:04:52,560
WHAT IF YOU LOOK AT EXPRESSION 

3789
03:04:52,560 --> 03:04:55,920
IN TERMS OF HOW MANY PROVIRUSES 

3790
03:04:55,920 --> 03:04:58,320
ARE PRESENT?  YOU HAVE SOME 

3791
03:04:58,320 --> 03:05:02,880
PROVIRUSES WITH TWO LTRS AND 

3792
03:05:02,880 --> 03:05:04,240
SOME PROVIRUSES -- SOME 

3793
03:05:04,240 --> 03:05:06,240
PROVIRUSES HAVE LTR AND GAG AND 

3794
03:05:06,240 --> 03:05:08,160
SOME WILL NOT HAVE GAG.  IF YOU 

3795
03:05:08,160 --> 03:05:10,000
LOOK AT TOTAL AMOUNT OF 

3796
03:05:10,000 --> 03:05:13,840
PROVIRUSES THAT IS LTRRNA OVER 

3797
03:05:13,840 --> 03:05:18,200
TOTAL PROVIRUSES ON TOP IS THE 

3798
03:05:18,200 --> 03:05:19,480
LEFT-HAND SIDE AND YOU COMPARE 

3799
03:05:19,480 --> 03:05:23,640
TO WHAT YOU HAD FOR GAG ARE.  NA

3800
03:05:23,640 --> 03:05:25,080
EXPRESSION PER GAG CONTAINING 

3801
03:05:25,080 --> 03:05:28,520
VIRUS IT IS PRETTY SIMILAR THAT 

3802
03:05:28,520 --> 03:05:29,600
SUGGESTS THERE IS COMPARABLE 

3803
03:05:29,600 --> 03:05:32,680
EXPRESSION AND ANOTHER WAY TO 

3804
03:05:32,680 --> 03:05:36,760
LOOK AT IT I PLOTTEDED 

3805
03:05:36,760 --> 03:05:41,720
PROPORTION OF THIS WITH HIV GAG 

3806
03:05:41,720 --> 03:05:44,200
RNA GAG CONTAINING VIRUSES AND 

3807
03:05:44,200 --> 03:05:45,720
LOOKING AT SLOPE HERE THIS SLOPE

3808
03:05:45,720 --> 03:05:48,360
IS ALMOST 1 THAT IS PRETTY 

3809
03:05:48,360 --> 03:05:50,080
INTERESTING SUGGESTING THAT 

3810
03:05:50,080 --> 03:05:53,280
RELATIVE LEVELS ARE COMPARABLE 

3811
03:05:53,280 --> 03:05:56,640
IN TERMS OF EXPRESSION. 

3812
03:05:56,640 --> 03:05:59,760
TAKING THAT A STEP FURTHER MEANS

3813
03:05:59,760 --> 03:06:01,040
TRANSCRIPTIONAL ELONGATION 

3814
03:06:01,040 --> 03:06:03,760
GENOME WE LOOKED AT 

3815
03:06:03,760 --> 03:06:06,360
TRANSCRIPTIONAL ELONGATION IS 

3816
03:06:06,360 --> 03:06:07,360
EXTENDING INTO GAG. 

3817
03:06:07,360 --> 03:06:09,240
WHAT IS REALLY ALSO KIND OF 

3818
03:06:09,240 --> 03:06:11,000
CURIOUS HERE IS IF YOU LOOK AT 

3819
03:06:11,000 --> 03:06:13,200
BLUE ARROWS YOU SEE HERE SOME 

3820
03:06:13,200 --> 03:06:16,960
PEOPLE ARE NOT REALLY ON THAT 

3821
03:06:16,960 --> 03:06:17,240
LINE. 

3822
03:06:17,240 --> 03:06:21,280
SOME PEOPLE HAVE MUCH, MUCH 

3823
03:06:21,280 --> 03:06:27,760
LOWER GAG LEVELS THAN LTRA.  I 

3824
03:06:27,760 --> 03:06:29,520
DON'T HAVE AN ANSWER YET BUT AT 

3825
03:06:29,520 --> 03:06:31,200
THE END OF THIS YOU MIGHT HAVE 

3826
03:06:31,200 --> 03:06:32,680
SUGGESTIONS FOR US TO LOOK INTO 

3827
03:06:32,680 --> 03:06:34,120
THAT AND OTHER THINGS AND WE 

3828
03:06:34,120 --> 03:06:41,080
WILL TAKE THE R NCHLT ANA A STER

3829
03:06:41,080 --> 03:06:43,760
AND SEE WHAT IMMUNE CORRELATES 

3830
03:06:43,760 --> 03:06:45,600
WOULD HELP US PREDICT WITH WHAT 

3831
03:06:45,600 --> 03:06:47,800
IS GOING ON WITH RNA SO YOU CAN 

3832
03:06:47,800 --> 03:06:50,000
KNOW AND TARGET THINGS 

3833
03:06:50,000 --> 03:06:53,320
DEVELOPING CURE STRATEGIES AND 

3834
03:06:53,320 --> 03:06:57,000
WHEN WE DID ANALYSIS THAT WAS 

3835
03:06:57,000 --> 03:07:02,560
BRIAN BUT ANYWAY WE HELPED AND 

3836
03:07:02,560 --> 03:07:04,200
YOU LOOK AT COMPOSITE FUNCTIONS 

3837
03:07:04,200 --> 03:07:07,760
PREDICTING WHAT YOU WILL SEE IN 

3838
03:07:07,760 --> 03:07:13,680
TERMS OF LTR RNA FOR PER TOTAL 

3839
03:07:13,680 --> 03:07:17,760
VIRUSES OR GAG RNA FOR GAG 

3840
03:07:17,760 --> 03:07:18,920
CONTAINING VIRUSES AND BOTH OF 

3841
03:07:18,920 --> 03:07:21,960
THOSE WERE RELATED TO PROPORTION

3842
03:07:21,960 --> 03:07:29,200
OF NK CELLS AND AGE.  THAT IS 

3843
03:07:29,200 --> 03:07:31,680
REMARKABLE.  RNA VALUES RELATE 

3844
03:07:31,680 --> 03:07:33,800
TO INNATE IMMUNITY AND WE DIDN'T

3845
03:07:33,800 --> 03:07:35,720
SEE THE SAME RELATIONSHIP WITH 

3846
03:07:35,720 --> 03:07:38,080
OTHER PARAMETERS WE WERE LOOKING

3847
03:07:38,080 --> 03:07:41,120
AT AND ALSO JUST AS AN ASIDE YOU

3848
03:07:41,120 --> 03:07:42,920
MIGHT LOOK AT THIS AND OKAY WHAT

3849
03:07:42,920 --> 03:07:46,640
CURVE IS ACTUALLY FITTING THIS? 

3850
03:07:46,640 --> 03:07:48,320
WELL, PROBABLY WHAT MAYBE THERE 

3851
03:07:48,320 --> 03:07:50,440
ARE DIFFERENT POPULATIONS. 

3852
03:07:50,440 --> 03:07:52,640
HERE, YOU KNOW, ON THE 

3853
03:07:52,640 --> 03:07:54,360
RIGHT-HAND SIDE OF THE CURVE, 

3854
03:07:54,360 --> 03:07:55,600
YOU HAVE A LITTLE ALMOST A 

3855
03:07:55,600 --> 03:07:57,240
FLATTER LINE THAT SEEMS TO 

3856
03:07:57,240 --> 03:07:59,040
REALLY SLOPE UP WHEN YOU GET TO 

3857
03:07:59,040 --> 03:08:01,080
THE LEFT-HAND SIDE AND MAYBE 

3858
03:08:01,080 --> 03:08:02,480
THERE IS DIFFERENT POPULATIONS 

3859
03:08:02,480 --> 03:08:05,280
AND I HAVE A FEW WRAP-UP SLIDES 

3860
03:08:05,280 --> 03:08:05,640
HERE. 

3861
03:08:05,640 --> 03:08:09,880
IN SUMMARY, THE LTR RNA PER 

3862
03:08:09,880 --> 03:08:13,160
TOTAL PROVIRUSES AND GAG RNA PER

3863
03:08:13,160 --> 03:08:16,920
GAG CONTAINING PROVIRUSES.  THAT

3864
03:08:16,920 --> 03:08:18,360
EXPRESSION IS COMPARABLE. 

3865
03:08:18,360 --> 03:08:20,560
THESE THINGS CORRELATE WITH 

3866
03:08:20,560 --> 03:08:23,760
PROPORTION OF NK CELLS OR INNATE

3867
03:08:23,760 --> 03:08:26,160
IMMUNITY AND AGE.  WE THINK THAT

3868
03:08:26,160 --> 03:08:30,000
HIV RNA IS A DRIVER OF INNATE 

3869
03:08:30,000 --> 03:08:31,760
IMMUNE ACTIVATION THAT IS 

3870
03:08:31,760 --> 03:08:34,240
SPECIFICALLY RNA NOT DNA. 

3871
03:08:34,240 --> 03:08:36,200
WE ARE VERY EXCITED ABOUT THE 

3872
03:08:36,200 --> 03:08:37,400
STATISTICAL APPROACHES THAT HAVE

3873
03:08:37,400 --> 03:08:40,080
BEEN USED TO IDENTIFY THESE 

3874
03:08:40,080 --> 03:08:40,360
COMPOSITES. 

3875
03:08:40,360 --> 03:08:43,080
IN TERMS OF THINKING OF THIS 

3876
03:08:43,080 --> 03:08:44,200
CONCEPTUALLY, HERE IS A MODEL 

3877
03:08:44,200 --> 03:08:46,320
FOR YOU TO KEEP IN YOUR MIND IF 

3878
03:08:46,320 --> 03:08:47,640
YOU CAN'T REMEMBER ALL THAT 

3879
03:08:47,640 --> 03:08:50,760
DATA.  SORRY.  I CAN'T REMEMBER 

3880
03:08:50,760 --> 03:08:51,920
DATA YOU PRESENTED BUT REMEMBER 

3881
03:08:51,920 --> 03:08:54,800
SOME OF IT.  IF YOU NEED A 

3882
03:08:54,800 --> 03:08:56,200
CONCEPTUAL MODEL YOU CAN SEE 

3883
03:08:56,200 --> 03:09:00,000
HERE IN A PERSON WHO IS INFECTED

3884
03:09:00,000 --> 03:09:02,720
INITIALLY STARTS WITH HIGH VIRAL

3885
03:09:02,720 --> 03:09:05,280
MODE LOTS OF PROVIRUSES GAG 

3886
03:09:05,280 --> 03:09:06,840
CONTAINING PROVIRUSES UP THERE 

3887
03:09:06,840 --> 03:09:10,280
YOU START THEM ON ART AND VIRAL 

3888
03:09:10,280 --> 03:09:11,400
LOAD COMES DOWN ASSUMING THEY 

3889
03:09:11,400 --> 03:09:14,000
ARE TAKING IT IN RESPONSE.  

3890
03:09:14,000 --> 03:09:16,440
VIRAL LOAD COMES DOWN AND 

3891
03:09:16,440 --> 03:09:18,920
PROVIRUSES START TO TRACK DOWN 

3892
03:09:18,920 --> 03:09:21,000
TOO.  BUT, YOU SEE GREATER 

3893
03:09:21,000 --> 03:09:23,160
DECREASES IN GAG CONTAINING 

3894
03:09:23,160 --> 03:09:25,480
PROVIRUSES THAN YOU SEE IN TOTAL

3895
03:09:25,480 --> 03:09:27,560
PROVIRUS AND AS YOU GET FURTHER 

3896
03:09:27,560 --> 03:09:29,360
ON AND LIKE IN OUR PARTICIPANTS 

3897
03:09:29,360 --> 03:09:30,960
WHO HAVE BEEN SUPPRESSED FOR A 

3898
03:09:30,960 --> 03:09:32,480
LONG TIME WHAT WE THINK IS GOING

3899
03:09:32,480 --> 03:09:34,520
ON IS YOU HAVE A BUNCH OF CELLS 

3900
03:09:34,520 --> 03:09:38,160
WITH PROVIRUSES AND SOME ARE 

3901
03:09:38,160 --> 03:09:41,000
EXPRESSING RNA AND THOSE 

3902
03:09:41,000 --> 03:09:43,480
EXPRESSING RNA ARE STIMULATING 

3903
03:09:43,480 --> 03:09:47,280
INNATE IMMUNITY IN PARTICULAR NK

3904
03:09:47,280 --> 03:09:47,760
CELLS. 

3905
03:09:47,760 --> 03:09:50,320
THIS MEANS THAT AGE-RELATED 

3906
03:09:50,320 --> 03:09:53,360
FACTORS I SHOWED IN THE PREVIOUS

3907
03:09:53,360 --> 03:09:56,760
PLOT AND AGE-RELATED FACTORS MAY

3908
03:09:56,760 --> 03:09:58,600
INFLUENCE EXPRESSION OF BOTH 

3909
03:09:58,600 --> 03:10:01,760
DELETED AND NON-GAG DELETED 

3910
03:10:01,760 --> 03:10:04,000
PROVIRUSES AND NK CELLS SENSING 

3911
03:10:04,000 --> 03:10:07,040
POPULATION OF RNA-CONTAINING 

3912
03:10:07,040 --> 03:10:08,560
CELLS AND EXPRESSION OF BOTH 

3913
03:10:08,560 --> 03:10:11,760
DELETED AND NON-DELETED 

3914
03:10:11,760 --> 03:10:13,720
PROVIRUSES STIMULATE INNATE 

3915
03:10:13,720 --> 03:10:16,520
IMMUNITY THAT HELPS TO DRIVE 

3916
03:10:16,520 --> 03:10:19,240
DYNAMICS OF PROVIRUS EXPRESSION 

3917
03:10:19,240 --> 03:10:22,240
AND VICE VERSA.  NOT A CYCLE.  

3918
03:10:22,240 --> 03:10:24,680
IT IS NOT ONE THING BOTH 

3919
03:10:24,680 --> 03:10:25,960
INFLUENCE EACH OTHER AND OTHER 

3920
03:10:25,960 --> 03:10:27,640
IMMUNE FACTORS INVOLVED AND IN 

3921
03:10:27,640 --> 03:10:29,120
TERMS WHERE WE GO WITH THIS AND 

3922
03:10:29,120 --> 03:10:31,560
WOULD LOVE TO HEAR INPUT AND 

3923
03:10:31,560 --> 03:10:32,800
SUGGESTIONS ALSO WE WANT TO 

3924
03:10:32,800 --> 03:10:34,480
PROCEED WITH FUNCTIONAL 

3925
03:10:34,480 --> 03:10:36,400
EVALUATION OF INNATE IMMUNE 

3926
03:10:36,400 --> 03:10:38,880
FACTORS INTERACTING WITH THE 

3927
03:10:38,880 --> 03:10:40,400
PROVIRUS AND FOR EXAMPLE WE 

3928
03:10:40,400 --> 03:10:43,600
MIGHT DO A STUDY WHERE WE GIVE A

3929
03:10:43,600 --> 03:10:46,240
MONOCLONAL ANTIBODY TO PATIENTS 

3930
03:10:46,240 --> 03:10:49,760
THAT MODULATES NK AND CD8 

3931
03:10:49,760 --> 03:10:51,880
EXPRESSION.  WE WILL ALSO DO 

3932
03:10:51,880 --> 03:10:53,880
LONGITUDINAL ASSESSMENTS FROM 

3933
03:10:53,880 --> 03:10:56,920
OUR POPULATIONS THAT HAVE BEEN 

3934
03:10:56,920 --> 03:10:58,840
INFECTED AND SUPPRESSED 

3935
03:10:58,840 --> 03:11:01,560
LONG-TERM AND LOOK AT PROVIRUS 

3936
03:11:01,560 --> 03:11:03,560
DURING TREATMENT INTERRUPTIONS 

3937
03:11:03,560 --> 03:11:06,560
AND I'M ENROLLING IN A STUDY 

3938
03:11:06,560 --> 03:11:08,200
DOING ANALYTIC TREATMENT 

3939
03:11:08,200 --> 03:11:09,560
INTERRUPTION FOR PATIENTS AND 

3940
03:11:09,560 --> 03:11:13,720
WILL COLLECT SAMPLES FROM 

3941
03:11:13,720 --> 03:11:16,320
ANO-TOMIC SITES AND PROIVERY AND

3942
03:11:16,320 --> 03:11:18,720
LOOK AT WHAT IS GOING ON WITH 

3943
03:11:18,720 --> 03:11:20,880
VIRUS THERE AND WILL LOOK AT RNA

3944
03:11:20,880 --> 03:11:22,920
AND DNA FROM THOSE AS WELL AND 

3945
03:11:22,920 --> 03:11:24,440
LOOK AT DIFFERENT POPULATIONS 

3946
03:11:24,440 --> 03:11:27,520
AND WE ARE JUST NOW 

3947
03:11:27,520 --> 03:11:31,880
COLLABORATING NOW WITH MAX WEISS

3948
03:11:31,880 --> 03:11:34,120
COHORT TO LOOK AT MORE 

3949
03:11:34,120 --> 03:11:35,600
REPRESENTATIVE SPECIMENS 

3950
03:11:35,600 --> 03:11:36,960
ESPECIALLY IN FEMALES. 

3951
03:11:36,960 --> 03:11:39,160
WITH THAT, THIS IS A COMMUNITY 

3952
03:11:39,160 --> 03:11:41,600
EFFORT AND IS AN EFFORT OF A 

3953
03:11:41,600 --> 03:11:43,200
LARGE GROUP OF PEOPLE THAT I 

3954
03:11:43,200 --> 03:11:45,360
STAND HERE REPRESENTING MY TEAM.

3955
03:11:45,360 --> 03:11:48,400
THEY HAVE BEEN FABULOUS.  

3956
03:11:48,400 --> 03:11:49,800
ESPECIALLY, YOU KNOW, FRANKS 

3957
03:11:49,800 --> 03:11:55,760
GROUP AND THE DRP AND NIAD OR 

3958
03:11:55,760 --> 03:11:58,520
EXTERNAL COLLABORATORS AND TUFTS

3959
03:11:58,520 --> 03:12:01,040
AND WALTER REID AND FREDERICK 

3960
03:12:01,040 --> 03:12:03,840
LAB WITH THE STATISTICIAN BRIAN 

3961
03:12:03,840 --> 03:12:07,320
LUKE WHO IS IN THERE AND STUDY 

3962
03:12:07,320 --> 03:12:09,360
PARTICIPANTS AND LOTS OF US 

3963
03:12:09,360 --> 03:12:11,760
COULDN'T DO WORK WE DO WITHOUT 

3964
03:12:11,760 --> 03:12:12,560
STUDY PARTICIPANTS AND WHAT THEY

3965
03:12:12,560 --> 03:12:15,840
GIVE US AND WITH THAT I INVITE 

3966
03:12:15,840 --> 03:12:19,560
YOU TO PROVIDE SUGGESTIONS AND 

3967
03:12:19,560 --> 03:12:26,160
COMMENTS AND THANK YOU VERY M

3968
03:12:26,160 --> 03:12:26,360
MUCH. 

3969
03:12:26,360 --> 03:12:29,640
>>NOT A SUGGESTION BUT A 

3970
03:12:29,640 --> 03:12:29,880
QUESTION. 

3971
03:12:29,880 --> 03:12:30,160
>>OKAY. 

3972
03:12:30,160 --> 03:12:32,400
>>YOU HAD CORRELATION FOR
NK 

3973
03:12:32,400 --> 03:12:33,080
AND AGE. 

3974
03:12:33,080 --> 03:12:33,360
>>YES. 

3975
03:12:33,360 --> 03:12:35,720
>>SO, IS THAT -- I GUESS
THE 

3976
03:12:35,720 --> 03:12:38,520
AGE AT THE TIME YOU SAMPLE OR 

3977
03:12:38,520 --> 03:12:39,840
DETERMINE NK COUNTS?  

3978
03:12:39,840 --> 03:12:40,520
>>CORRECT. 

3979
03:12:40,520 --> 03:12:43,640
>>AGE AND ACQUISITION AND
HIV 

3980
03:12:43,640 --> 03:12:46,280
DURATION AND ART AND HOW IT TIES

3981
03:12:46,280 --> 03:12:48,080
INTO IMMUNOLOGICAL AGING I 

3982
03:12:48,080 --> 03:12:48,320
GUESS. 

3983
03:12:48,320 --> 03:12:51,400
>>I STRUGGLE WITH THAT
ALL THE 

3984
03:12:51,400 --> 03:12:53,600
TIME.  YOU KNOW IT IS HARD TO 

3985
03:12:53,600 --> 03:12:55,320
DETERMINE WHEN EXACTLY SOMEONE 

3986
03:12:55,320 --> 03:12:58,240
WAS INFECTED LOOKING AT 

3987
03:12:58,240 --> 03:12:59,280
DIVERSITY OF PROVIRUS AND IF 

3988
03:12:59,280 --> 03:13:01,960
THEY TELL YOU OH, YEAH LIKE I 

3989
03:13:01,960 --> 03:13:05,080
ONLY HAVE ONE EXPOSURE THAT IS 

3990
03:13:05,080 --> 03:13:08,720
AT SUCH AND SUCH OF TIME AND 

3991
03:13:08,720 --> 03:13:12,160
BEING THAT IS NOT ALWAYS EXACT. 

3992
03:13:12,160 --> 03:13:14,240
WE TRIED TO PUT IT IN AND 

3993
03:13:14,240 --> 03:13:17,720
DURATION OF THERAPY INTO THE 

3994
03:13:17,720 --> 03:13:17,960
MODEL. 

3995
03:13:17,960 --> 03:13:20,360
AND THE -- THOSE TYPES OF 

3996
03:13:20,360 --> 03:13:21,520
THINGS, FIRST, WE DIDN'T THINK 

3997
03:13:21,520 --> 03:13:23,560
THEY WERE FULLY RELIABLE.  THEY 

3998
03:13:23,560 --> 03:13:26,200
DIDN'T REALLY PAN OUT LIKE AGE. 

3999
03:13:26,200 --> 03:13:28,040
BUT, BUT TIME -- YOU KNOW, THEY 

4000
03:13:28,040 --> 03:13:30,840
ARE TIME-RELATED FACTORS THAT 

4001
03:13:30,840 --> 03:13:32,440
ARE ALL TOGETHER.  YOU KNOW, IF 

4002
03:13:32,440 --> 03:13:36,520
WE HAD REALLY, REALLY ACCURATE 

4003
03:13:36,520 --> 03:13:38,280
DATA THAT IT WERE -- YOU KNOW, 

4004
03:13:38,280 --> 03:13:39,680
IT COULD BE SOMETHING THAT WE 

4005
03:13:39,680 --> 03:13:42,000
WOULD LOOK AT.  SO, WE DID SEE 

4006
03:13:42,000 --> 03:13:43,920
THAT THOSE THINGS CAME OUT.  

4007
03:13:43,920 --> 03:13:46,000
THEY WERE ALSO TIME-RELATED THAT

4008
03:13:46,000 --> 03:13:47,960
WE WRAPPED THEM TOGETHER IN AGE.

4009
03:13:47,960 --> 03:13:48,960
DOES THAT HELP?  

4010
03:13:48,960 --> 03:13:54,160
WHAT WOULD YOU HAVE DONE?  

4011
03:13:54,160 --> 03:13:58,280
>>THAT IS WHAT I'M
SAYING. 

4012
03:13:58,280 --> 03:14:00,560
>>OH, MY GOSH.  WE TRIED
BUT, 

4013
03:14:00,560 --> 03:14:04,280
YOU KNOW, I'M SURE WE MISSED 

4014
03:14:04,280 --> 03:14:04,800
SOMETHING.  

4015
03:14:04,800 --> 03:14:06,240
>>JUST QUESTIONS AND 

4016
03:14:06,240 --> 03:14:07,080
SUGGESTIONS KIND OF. 

4017
03:14:07,080 --> 03:14:08,640
>>YEAH.  

4018
03:14:08,640 --> 03:14:10,560
>>YOU SEE THIS NK
CORRELATION 

4019
03:14:10,560 --> 03:14:14,880
THAT SEEMS TO BE VERY 

4020
03:14:14,880 --> 03:14:15,160
CONVINCING. 

4021
03:14:15,160 --> 03:14:16,000
>>UH-HUH.  

4022
03:14:16,000 --> 03:14:18,320
>>THINKING ABOUT NK YOU
THINK 

4023
03:14:18,320 --> 03:14:20,320
OF ENVELOPE EXPRESSED ON SURFACE

4024
03:14:20,320 --> 03:14:23,040
OF CELLS AND PLANNING TO LOOK AT

4025
03:14:23,040 --> 03:14:24,400
ENVELOPE EXPRESSION AND ASSUMING

4026
03:14:24,400 --> 03:14:27,600
IF YOU SEE GAG EXPRESSION YOU 

4027
03:14:27,600 --> 03:14:28,440
ENVELOPE EXPRESSION AND DON'T 

4028
03:14:28,440 --> 03:14:30,320
THINK YOU COULD REALLY.  TWO 

4029
03:14:30,320 --> 03:14:31,800
THINGS COULD BE QUITE SEPARATED.

4030
03:14:31,800 --> 03:14:35,800
>>I TRY TO MAKE THOSE
KINDS OF 

4031
03:14:35,800 --> 03:14:36,120
ASSUMPTIONS. 

4032
03:14:36,120 --> 03:14:37,680
>>SUGGESTION IS LOOK FOR
RNA 

4033
03:14:37,680 --> 03:14:39,600
EXPRESSION AND THAT COULD BE 

4034
03:14:39,600 --> 03:14:40,280
INTERESTING KIND OF. 

4035
03:14:40,280 --> 03:14:42,000
>>GREAT PLAN.  THANK YOU.

4036
03:14:42,000 --> 03:14:43,440
THANK YOU FOR THAT SUGGESTION. 

4037
03:14:43,440 --> 03:14:45,080
>>OKAY.  TWO QUESTION
SGLZ YES.

4038
03:14:45,080 --> 03:14:49,040
>>WHEN IS HOW BIG IS YOUR

4039
03:14:49,040 --> 03:14:51,120
MEASUREMENT AND CAN THEY DETECT 

4040
03:14:51,120 --> 03:14:53,040
OTHER MUTUAL VIRUS FOR FIRST 

4041
03:14:53,040 --> 03:14:54,120
QUESTION AND SECOND QUESTION DID

4042
03:14:54,120 --> 03:14:56,960
YOU MEASURE ADAPTIVE IMMUNITY?  

4043
03:14:56,960 --> 03:15:00,840
SO, IN THE MODEL, YOU ONLY 

4044
03:15:00,840 --> 03:15:02,840
COMPUTED INTO THE INNATE 

4045
03:15:02,840 --> 03:15:03,120
IMMUNITY. 

4046
03:15:03,120 --> 03:15:03,480
>>RIGHT. 

4047
03:15:03,480 --> 03:15:06,880
>>HOW MUCH IS ADAPT
IMMUNITY 

4048
03:15:06,880 --> 03:15:07,240
CONTRIBUTING?  

4049
03:15:07,240 --> 03:15:09,280
>>ALL RIGHT.  THAT IS A
REALLY 

4050
03:15:09,280 --> 03:15:10,840
GREAT QUESTION. 

4051
03:15:10,840 --> 03:15:13,120
WE DID PUT IN FACTORS FOR 

4052
03:15:13,120 --> 03:15:15,440
ADAPTIVE IMMUNITY. 

4053
03:15:15,440 --> 03:15:18,160
WE PUT IN THERE WERE 31 

4054
03:15:18,160 --> 03:15:19,960
BIOMARKERS AND I SHOWED YOU ONES

4055
03:15:19,960 --> 03:15:21,880
THAT ACTUALLY CAME OUT AS 

4056
03:15:21,880 --> 03:15:23,920
SIGNIFICANT IN EQUATIONS AND 

4057
03:15:23,920 --> 03:15:26,560
CERTAINLY THERE WERE, YOU KNOW, 

4058
03:15:26,560 --> 03:15:28,240
MANY -- THERE WERE MANY OTHER 

4059
03:15:28,240 --> 03:15:30,240
CELL TYPES WE LOOKED AT AND WE 

4060
03:15:30,240 --> 03:15:32,360
DIDN'T HAVE ANTIBODY LEVELS IN 

4061
03:15:32,360 --> 03:15:35,760
THERE.  YES.  WE DID CONSIDER 

4062
03:15:35,760 --> 03:15:37,040
ADAPTIVE IMMUNITY AND I'M HAPPY 

4063
03:15:37,040 --> 03:15:39,240
TO SHOW YOU AND GO THROUGH THE 

4064
03:15:39,240 --> 03:15:39,720
OTHER MODELS. 

4065
03:15:39,720 --> 03:15:44,160
THEY REALLY WEREN'T AS GOOD.  

4066
03:15:44,160 --> 03:15:46,280
SURE.  THANKS.  GOOD POINT. 

4067
03:15:46,280 --> 03:15:47,880
>>[INDISCERNIBLE]. 

4068
03:15:47,880 --> 03:15:50,040
>>OH, YES.  YOU KNOW, I
CAN'T 

4069
03:15:50,040 --> 03:15:52,080
FULLY ANSWER THAT QUESTION.  

4070
03:15:52,080 --> 03:15:55,160
MAYBE SOMEONE ELSE IN MY LAB CAN

4071
03:15:55,160 --> 03:15:58,280
HELP WITH THAT.  BUT, IT SHOULD 

4072
03:15:58,280 --> 03:16:01,120
BE SPECIFIC FOR HIV.  I DO NOT 

4073
03:16:01,120 --> 03:16:04,680
KNOW THE SPECIFIC SEQUENCES. 

4074
03:16:04,680 --> 03:16:06,360
>>OKAY.  GREAT. 

4075
03:16:06,360 --> 03:16:07,280
>>GREAT JOB. 

4076
03:16:07,280 --> 03:16:08,040
>>THANK YOU. 

4077
03:16:08,040 --> 03:16:12,000
>>YEAH.  I JUST WANT THE
TO 

4078
03:16:12,000 --> 03:16:13,800
MAKE A COMMENT AND SUGGESTION, I

4079
03:16:13,800 --> 03:16:17,440
GUESS.  ASSOCIATION IS NOT 

4080
03:16:17,440 --> 03:16:18,240
POSSESSION.  YOU MENTIONED THAT 

4081
03:16:18,240 --> 03:16:20,160
AT END AND FACT YOU SEE 

4082
03:16:20,160 --> 03:16:22,920
ASSOCIATION DOESN'T MEAN IT MAY 

4083
03:16:22,920 --> 03:16:26,320
BE THAT HIV RNA IS DRIVING THAT 

4084
03:16:26,320 --> 03:16:28,880
OR VICE VERSA AND WOULD SAY 

4085
03:16:28,880 --> 03:16:30,040
SUGGESTION PERHAPS MOVING 

4086
03:16:30,040 --> 03:16:32,560
FORWARD WHEN WE SAY SOMETHING 

4087
03:16:32,560 --> 03:16:34,320
CORRELATES WITH NK CELLS IS 

4088
03:16:34,320 --> 03:16:37,400
SAYING CORRELATES WITH STARS.  

4089
03:16:37,400 --> 03:16:39,080
CELLS HAVE DIFFERENT VARIETIES 

4090
03:16:39,080 --> 03:16:43,600
AND VERSIONS AND SOME ARE 

4091
03:16:43,600 --> 03:16:45,600
CYTOTOXIC AND OTHERS MAKING 

4092
03:16:45,600 --> 03:16:46,880
CYTOKINES AND MIGHT BE 

4093
03:16:46,880 --> 03:16:49,000
INTERESTING TO LOOK MORE IN 

4094
03:16:49,000 --> 03:16:50,280
DEPTH INTO EXACTLY WHICH NK 

4095
03:16:50,280 --> 03:16:52,120
CELLS WE ARE TALKING ABOUT HERE.

4096
03:16:52,120 --> 03:16:54,560
>>WE TOTALLY AGREE WITH
YOU ON 

4097
03:16:54,560 --> 03:16:55,840
THAT.  LOTS OF PEOPLE WILL WANT 

4098
03:16:55,840 --> 03:16:57,680
TO LOOK INTO THAT.  SO, WE ARE 

4099
03:16:57,680 --> 03:16:59,960
GOING TO TRY TO DO THAT. 

4100
03:16:59,960 --> 03:17:03,680
>>HAVE YOU LOOKED AT
MONOCYTES 

4101
03:17:03,680 --> 03:17:05,720
AND [INDISCERNIBLE] OR ANY OTHER

4102
03:17:05,720 --> 03:17:06,080
CYTOKINES?  

4103
03:17:06,080 --> 03:17:08,200
>>WE HAD MONOCYTES IN
THERE.  

4104
03:17:08,200 --> 03:17:12,560
WE DON'T HAVE IL15.  BUT, WE CAN

4105
03:17:12,560 --> 03:17:15,760
-- WE CAN LOOK MORE INTO THE 

4106
03:17:15,760 --> 03:17:16,080
CYTOKINES. 

4107
03:17:16,080 --> 03:17:18,520
THIS IS MOSTLY ON CELL TYPE. 

4108
03:17:18,520 --> 03:17:19,200
>>THANK YOU. 

4109
03:17:19,200 --> 03:17:20,800
>>THANK YOU SO MUCH,
EVERYONE. 

4110
03:17:20,800 --> 03:17:24,240
>>ALL RIGHT.  THANKS TO
ALL 

4111
03:17:24,240 --> 03:17:25,840
PARTICIPANTS THIS MORNING.  WE 

4112
03:17:25,840 --> 03:17:30,760
WILL GO TO LUNCH AND POSTER 

4113
03:17:30,760 --> 03:17:32,280
SESSIONS START AT 1 AND START 

4114
03:17:32,280 --> 03:17:34,280
BACK UP HERE WITH PRESENTING 

4115
03:17:34,280 --> 03:17:36,280
TALKS AT 2 AND GIVING EVERYBODY 

4116
03:17:36,280 --> 03:17:40,080
ANOTHER HAND.  POSTERS ARE NEXT 

4117
03:17:40,080 --> 03:17:44,360
DOOR OVER HERE.  

4118
03:17:44,360 --> 03:17:47,160
THE SECOND SESSION.  FIRST 

4119
03:17:47,160 --> 03:17:54,200
SPEAKER IS AIMÉE KREIMER.  SHE 

4120
03:17:54,200 --> 03:18:01,120
WILL GIVE AN UPDATE ON HPV. 

4121
03:18:01,120 --> 03:18:06,120
SHE IS NCI PRINCIPLE 

4122
03:18:06,120 --> 03:18:09,880
INVESTIGATOR ON SEVERAL 

4123
03:18:09,880 --> 03:18:15,200
PROPHYLACTIVE HPV VACCINES. 

4124
03:18:15,200 --> 03:18:18,880
RESEARCH INITIATIVES, ONE THAT 

4125
03:18:18,880 --> 03:18:21,680
HAS COME BY THE CANCER MOON SHOT

4126
03:18:21,680 --> 03:18:32,320
AND WILL LET AIMÉE TAKE OEVER. 

4127
03:18:32,320 --> 03:18:33,640
>>GOOD AFTERNOON,
EVERYONE.  

4128
03:18:33,640 --> 03:18:35,560
CAN YOU HEAR ME?  

4129
03:18:35,560 --> 03:18:42,760
I'M PRETTY LOUD.  EVERYONE CAN 

4130
03:18:42,760 --> 03:18:44,280
USUALLY HEAR ME.  I'M ALSO 

4131
03:18:44,280 --> 03:18:46,120
INFORMAL.  JUMP IN AND ASK 

4132
03:18:46,120 --> 03:18:47,320
QUESTIONS IF SOMETHING IS NOT 

4133
03:18:47,320 --> 03:18:51,920
CLEAR.  IT IS YOUR TALK.  I'M 

4134
03:18:51,920 --> 03:18:56,360
AIMÉE KREIMER, AN INFECTIOUS 

4135
03:18:56,360 --> 03:18:58,680
DISEASE EPIDEMIOLOGIST.  I'M SO 

4136
03:18:58,680 --> 03:19:02,480
FOCUSED ON HPV THAT I DON'T 

4137
03:19:02,480 --> 03:19:04,200
THINK I KNOW ANYTHING OTHER THAN

4138
03:19:04,200 --> 03:19:06,600
HPV.  I HAVE IT COVERED AND I'M 

4139
03:19:06,600 --> 03:19:11,120
NOT AN EXPERT IN HIV.  I DO SEE 

4140
03:19:11,120 --> 03:19:13,560
RELEVANCE TO HPV ASSOCIATED 

4141
03:19:13,560 --> 03:19:15,080
CANCERS AND I'M PREPARED TO TALK

4142
03:19:15,080 --> 03:19:16,200
ABOUT THAT. 

4143
03:19:16,200 --> 03:19:19,280
SO, JUST A LITTLE ABOUT MY TALK,

4144
03:19:19,280 --> 03:19:22,960
I WILL GO OVER EPIDEMIOLOGY OF 

4145
03:19:22,960 --> 03:19:26,760
HPV AND ASSOCIATED CANCERS AND 

4146
03:19:26,760 --> 03:19:28,920
WILL STRONGLY FOCUS ON HPV 

4147
03:19:28,920 --> 03:19:30,960
VACCINATION.  I THINK IT IS THE 

4148
03:19:30,960 --> 03:19:33,000
FUTURE.  FIRST PART OF TALK IS 

4149
03:19:33,000 --> 03:19:34,680
THE FUTURE AND NOW AND YESTERDAY

4150
03:19:34,680 --> 03:19:36,360
BUT ALSO THE FUTURE.  I WILL 

4151
03:19:36,360 --> 03:19:38,200
TALK ABOUT IT IN THE SETTING OF 

4152
03:19:38,200 --> 03:19:41,400
PEOPLE LIVING WITH HIV. 

4153
03:19:41,400 --> 03:19:45,440
SO, JUST TO REMIND EVERYONE WHY 

4154
03:19:45,440 --> 03:19:48,000
WE KEEP TALKING ABOUT HPV AND 

4155
03:19:48,000 --> 03:19:54,400
KEFSH CAL CANCER, IT IS A 

4156
03:19:54,400 --> 03:19:56,040
NECESSARY CAUSE OF IS CERVICAL 

4157
03:19:56,040 --> 03:20:00,040
CANCERS.  THEY HAVE HPV DRIVING 

4158
03:20:00,040 --> 03:20:01,560
TOWARDS CERV LOGICAL CANCER.  

4159
03:20:01,560 --> 03:20:04,200
THEY ARE NOW IN RESOURCE LIMITED

4160
03:20:04,200 --> 03:20:06,360
COUNTRIES AND LOW-INCOME 

4161
03:20:06,360 --> 03:20:07,640
COUNTRIES AND IS SECOND MOST 

4162
03:20:07,640 --> 03:20:10,440
COMMON CAUSE OF CANCER IN AFRICA

4163
03:20:10,440 --> 03:20:12,360
AND 4TH AMONG WOMEN WORLDWIDE 

4164
03:20:12,360 --> 03:20:15,200
AND IS AN ENORMOUS PROBLEM AND 

4165
03:20:15,200 --> 03:20:17,640
HALF OF WOMEN WHO GET CERVICAL 

4166
03:20:17,640 --> 03:20:19,480
CANCER IN LOW INCOME COUNTRIES 

4167
03:20:19,480 --> 03:20:21,760
DIE FROM IT.  FURTHER THING THIS

4168
03:20:21,760 --> 03:20:23,600
SLIDE DOESN'T CAPTURE IS TAKES 

4169
03:20:23,600 --> 03:20:26,120
WOMEN OUT AT THE PEAK OF WHEN IN

4170
03:20:26,120 --> 03:20:28,280
MOERJHOOD AND CENTER OF FAMILIES

4171
03:20:28,280 --> 03:20:30,840
COULD BE BREAD WINNERS AND IS 

4172
03:20:30,840 --> 03:20:32,080
NOT DESTRUCTIVE TO THE 

4173
03:20:32,080 --> 03:20:33,800
INDIVIDUAL BUT IS REALLY HARMFUL

4174
03:20:33,800 --> 03:20:36,560
TO FAMILY UNITS AND COMMUNITIES.

4175
03:20:36,560 --> 03:20:39,760
AND THIS IS A CANCER THAT IS OF 

4176
03:20:39,760 --> 03:20:41,480
INEQUALITY.  IT IS A CANCER 

4177
03:20:41,480 --> 03:20:43,760
WHERE 90% OF CASES AND DEATHS 

4178
03:20:43,760 --> 03:20:46,160
OCCUR IN LOW AND MIDDLE INCOME 

4179
03:20:46,160 --> 03:20:46,480
COUNTRIES. 

4180
03:20:46,480 --> 03:20:49,240
AND IT THAT IS BECAUSE WE REALLY

4181
03:20:49,240 --> 03:20:51,920
KNOW HOW TO PREVENT CERVICAL 

4182
03:20:51,920 --> 03:20:53,560
CANCER AND KNOW HOW TO VACCINATE

4183
03:20:53,560 --> 03:20:56,240
AND THAT THEY WORK AND KNOW HOW 

4184
03:20:56,240 --> 03:20:57,920
TO DO CERVICAL CANCER SCREENING.

4185
03:20:57,920 --> 03:21:00,880
IT IS NOT EFFICIENT AND REQUIRES

4186
03:21:00,880 --> 03:21:03,000
LOTS OF INFRASTRUCTURE, BUT IT 

4187
03:21:03,000 --> 03:21:03,400
WORKS. 

4188
03:21:03,400 --> 03:21:05,680
SO, I THINK THAT IS WHY AT THIS 

4189
03:21:05,680 --> 03:21:07,920
POINT SO MANY OF US ARE SO 

4190
03:21:07,920 --> 03:21:10,760
REALLY FOCUSED ON HPV.  WE SEE 

4191
03:21:10,760 --> 03:21:14,360
THE ENDGAME AND HOW TO, IN FACT,

4192
03:21:14,360 --> 03:21:16,320
REALLY CONTROL THESE CANCERS AND

4193
03:21:16,320 --> 03:21:20,120
IT IS NOT GETTING DONE YET.  WE 

4194
03:21:20,120 --> 03:21:21,920
KNOW FROM REAL-WORLD DATA THAT 

4195
03:21:21,920 --> 03:21:24,680
HAD HPV VACCINES REDUCE CERVICAL

4196
03:21:24,680 --> 03:21:27,560
CANCER BY 90%.  WE CAN TALK 

4197
03:21:27,560 --> 03:21:29,280
ABOUT TYPES AND VACCINE AND 

4198
03:21:29,280 --> 03:21:32,080
INCREASING VAILENCY.  LOW 

4199
03:21:32,080 --> 03:21:33,920
VAILENCY TIME YOU GET TO 

4200
03:21:33,920 --> 03:21:35,720
CERVICAL CANCER, THESE VACCINES 

4201
03:21:35,720 --> 03:21:37,120
JUST WORK AND SECONDARY 

4202
03:21:37,120 --> 03:21:39,000
PREVENTION SCREENING WORKS AND 

4203
03:21:39,000 --> 03:21:41,800
IF PEOPLE HAVE CERVICAL CANCER, 

4204
03:21:41,800 --> 03:21:43,400
THEY DESERVE THERAPY FOR THOSE 

4205
03:21:43,400 --> 03:21:44,160
CANCERS. 

4206
03:21:44,160 --> 03:21:45,920
SO, THERE WAS A CALL TO ACTION 

4207
03:21:45,920 --> 03:21:48,600
BY THE WHO THAT HAPPENED A FEW 

4208
03:21:48,600 --> 03:21:50,880
YEARS BACK.  MUCH LIKE NCI I 

4209
03:21:50,880 --> 03:21:53,000
FEEL HAS BEEN SAYING FOR A LONG 

4210
03:21:53,000 --> 03:21:55,520
TIME NOW WHICH IS TO SAY WE HAVE

4211
03:21:55,520 --> 03:21:56,800
TOOLS AND SHOULD MAKE AND 

4212
03:21:56,800 --> 03:21:58,840
CONTINUE TO IMPROVE ON THEM AND 

4213
03:21:58,840 --> 03:22:00,680
SHOULD ALSO MAKE USE OF THEM.  

4214
03:22:00,680 --> 03:22:03,440
THEY PUT FORTH A STRATEGY WITH 

4215
03:22:03,440 --> 03:22:05,480
THREE PILLARS AND WE SHOULD 

4216
03:22:05,480 --> 03:22:08,920
VACCINATE 98% OF GIRLS BY AGE 15

4217
03:22:08,920 --> 03:22:10,960
AND SCREEN 70% OF WOMEN AND 

4218
03:22:10,960 --> 03:22:12,040
MAKING A NOTE HERE ABOUT 

4219
03:22:12,040 --> 03:22:15,480
SCREENING THAT GETS ATTENTION ON

4220
03:22:15,480 --> 03:22:17,800
BIOMARKER AND UP FRONT PART OF 

4221
03:22:17,800 --> 03:22:19,400
SCREENING IS A RISK STRATIFIER 

4222
03:22:19,400 --> 03:22:22,480
AND LUMPS PEOPLE INTO HIGHER 

4223
03:22:22,480 --> 03:22:27,320
RISKS FOR CERVICAL PRECANCER AND

4224
03:22:27,320 --> 03:22:28,960
CANCER VERSUS LOWER RIFSHG AND 

4225
03:22:28,960 --> 03:22:32,080
DOESN'T REDUCE INCIDENTS OF 

4226
03:22:32,080 --> 03:22:33,560
CERVICAL CANCER BUT TREATING 

4227
03:22:33,560 --> 03:22:35,160
PEOPLE WITH SCREEN POSITIVE AND 

4228
03:22:35,160 --> 03:22:36,160
STANDING UP THAT TREATMENT AND 

4229
03:22:36,160 --> 03:22:38,440
SCREENING IS A PROCESS AND 

4230
03:22:38,440 --> 03:22:41,080
SCREEN FOR ANYTHING COLON OR -- 

4231
03:22:41,080 --> 03:22:45,040
IT IS NOT JUST BIOMARKER BUT 

4232
03:22:45,040 --> 03:22:46,240
DIAGNOSTICS AND TREATMENT OF 

4233
03:22:46,240 --> 03:22:48,560
PRECANCER THAT PULLS DOWN CANCER

4234
03:22:48,560 --> 03:22:51,000
AND WE SEE TIME AND AGAIN THAT 

4235
03:22:51,000 --> 03:22:54,320
EVEN IN US25% OF WOMEN SCREEN 

4236
03:22:54,320 --> 03:22:56,600
POSITIVE AND SHOULD GO ON FOR A 

4237
03:22:56,600 --> 03:22:57,880
TREATMENT WHO DON'T DO THAT IN 

4238
03:22:57,880 --> 03:23:00,360
THE US WHERE WE HAVE ALL 

4239
03:23:00,360 --> 03:23:02,920
RESOURCES IN THE WORLD AND LIKE 

4240
03:23:02,920 --> 03:23:04,240
TO OVERMANAGE PEOPLE FROM A 

4241
03:23:04,240 --> 03:23:06,480
MEDICAL PERSPECTIVE.  IT IS EVEN

4242
03:23:06,480 --> 03:23:09,280
MORE COMPLICATED IN COUNTRIES 

4243
03:23:09,280 --> 03:23:11,600
WHERE THERE IS A SINGLE PERSON 

4244
03:23:11,600 --> 03:23:13,440
TO TREAT THESE DISEASES, YOU 

4245
03:23:13,440 --> 03:23:16,600
KNOW?  

4246
03:23:16,600 --> 03:23:17,640
AND ALSO IN MY OPINION, NOT IN 

4247
03:23:17,640 --> 03:23:20,200
MY OPINION, IF YOU CAN'T OFFER 

4248
03:23:20,200 --> 03:23:21,920
FULL PROCESS FIND PEOPLE WITH 

4249
03:23:21,920 --> 03:23:25,040
HIGH RISK AND DIAGNOSE THEM AND 

4250
03:23:25,040 --> 03:23:25,840
SCREEN OR TREAT THEM 

4251
03:23:25,840 --> 03:23:30,880
APPROPRIATELY AND UNETHICAL TO 

4252
03:23:30,880 --> 03:23:31,760
HAVE BIOMARKER IF YOU CAN'T 

4253
03:23:31,760 --> 03:23:33,760
COMMIT TO THE WHOLE PROCESS.  

4254
03:23:33,760 --> 03:23:36,320
THIS STRATEGY AND GOAL IS TO BE 

4255
03:23:36,320 --> 03:23:39,760
PUT IN PLACE BY 2030. 

4256
03:23:39,760 --> 03:23:42,800
SO, WE WILL TALK ABOUT HPV 

4257
03:23:42,800 --> 03:23:45,560
VACCINATION AND GOAL IS 90% OF 

4258
03:23:45,560 --> 03:23:48,080
GIRLS UP TO AGE 15 VACCINATED BY

4259
03:23:48,080 --> 03:23:50,440
2030.  WE WILL SEE WHERE WE ARE.

4260
03:23:50,440 --> 03:23:53,440
VACCINES WERE LICENSED AND 

4261
03:23:53,440 --> 03:23:54,760
PROVEN TO BE SAFE AND 

4262
03:23:54,760 --> 03:23:56,920
EFFICACIOUS 16 YEARS AGO AND 

4263
03:23:56,920 --> 03:23:58,840
RECOMMENDED AND IS BOTH IN THE 

4264
03:23:58,840 --> 03:24:01,040
UNITED STATES AND GLOBALLY AT 

4265
03:24:01,040 --> 03:24:03,480
WHO LEVEL.  AT THIS POINT FAST 

4266
03:24:03,480 --> 03:24:06,800
FORWARD 16 YEARS AND GLOBAL 

4267
03:24:06,800 --> 03:24:08,360
COVERAGE OF AGE-APPROPRIATE 

4268
03:24:08,360 --> 03:24:11,800
GIRLS IS 13%.  IF WE RESTRICT 

4269
03:24:11,800 --> 03:24:14,440
THAT TO WOMEN OR GIRLS LIVING IN

4270
03:24:14,440 --> 03:24:16,760
LOW AND MIDDLE INCOME COUNTRIES,

4271
03:24:16,760 --> 03:24:19,000
IT IS 8%.  YOU CAN SEE, AGAIN, 

4272
03:24:19,000 --> 03:24:21,640
WE ARE TALKING ABOUT A CANCER 

4273
03:24:21,640 --> 03:24:23,960
THAT MARKS DISPARITY AND HEALTH 

4274
03:24:23,960 --> 03:24:25,640
INEQUALITY.  I CAN'T THINK OF A 

4275
03:24:25,640 --> 03:24:28,320
BETTER EXAMPLE THAN THIS.  

4276
03:24:28,320 --> 03:24:30,240
HIGH-INCOME COUNTRIES ARE 

4277
03:24:30,240 --> 03:24:33,440
MARCHING TO 80 OR 90% AND 

4278
03:24:33,440 --> 03:24:37,200
LOW-INCOME COUNTRIES IN BLUE ARE

4279
03:24:37,200 --> 03:24:39,520
AT VERY LOW PROPORTIONS AND WE 

4280
03:24:39,520 --> 03:24:43,040
NEED SOMETHING LIKE THAT TO MAKE

4281
03:24:43,040 --> 03:24:44,040
IT BETTER. 

4282
03:24:44,040 --> 03:24:45,760
WE TAKE PROPORTIONS AND WILL SAY

4283
03:24:45,760 --> 03:24:48,040
IT IS FIXED AND WE HAVE BEEN 

4284
03:24:48,040 --> 03:24:50,080
WORKING 16 YEARS TO GET THIS 

4285
03:24:50,080 --> 03:24:53,480
UPTAKE UP.  WE ARE AT 8% AT LMIC

4286
03:24:53,480 --> 03:24:56,000
WHICH IS IMPORTANT AND IS WHERE 

4287
03:24:56,000 --> 03:24:57,960
THE BURDEN OF CERVICAL CANCER 

4288
03:24:57,960 --> 03:25:00,040
IS.  WHAT HAPPENS WHEN WE FAST 

4289
03:25:00,040 --> 03:25:01,680
FORWARD THOSE NUMBERS?  

4290
03:25:01,680 --> 03:25:03,400
WE PROJECT OUT TO SEE HOW MANY 

4291
03:25:03,400 --> 03:25:05,760
LIVES WE WILL SAVE.  SO, OVER 

4292
03:25:05,760 --> 03:25:09,080
THE NEXT 65 YEARS, OF COURSE, IS

4293
03:25:09,080 --> 03:25:12,200
MODEL OR PROJECTS TO A HALF END.

4294
03:25:12,200 --> 03:25:15,000
WHEN WE LOOK AND ARE AGE GROUPS 

4295
03:25:15,000 --> 03:25:18,000
OF GIRLS IN 2014 WITHIN HIGH 

4296
03:25:18,000 --> 03:25:21,200
INCOME COUNTRIES AND UPPER 

4297
03:25:21,200 --> 03:25:26,920
MIDDLE INCOME LOW INCOME AND WE 

4298
03:25:26,920 --> 03:25:29,520
HAVE ESTIMATES OF CERVICAL 

4299
03:25:29,520 --> 03:25:30,600
CANCERS THAT WILL HAPPEN BEFORE 

4300
03:25:30,600 --> 03:25:33,200
AGE OF 75 AND LOWER MIDDLE 

4301
03:25:33,200 --> 03:25:34,880
INCOME COUNTRIES WE TALKED ABOUT

4302
03:25:34,880 --> 03:25:39,120
THIS GROUPING HAVING 80 TO 90% 

4303
03:25:39,120 --> 03:25:41,360
OF BURDEN OF CERVICAL CANCER AND

4304
03:25:41,360 --> 03:25:42,880
90% OF THE DEATHS. 

4305
03:25:42,880 --> 03:25:44,880
IF WE APPLY THAT VACCINATION 

4306
03:25:44,880 --> 03:25:49,280
PROGRAM THAT IS, YOU KNOW, AS IT

4307
03:25:49,280 --> 03:25:52,200
CURRENTLY IS, HOW MANY CERVICAL 

4308
03:25:52,200 --> 03:25:54,560
CANCERS AND DEATHS WILL WE 

4309
03:25:54,560 --> 03:25:56,040
AVERT?  IN TOTAL CURRENT 

4310
03:25:56,040 --> 03:25:58,120
VACCINATION STRATEGIES WILL 

4311
03:25:58,120 --> 03:26:02,480
AVERT 365,000 CASES AND 

4312
03:26:02,480 --> 03:26:02,760
$150,000. 

4313
03:26:02,760 --> 03:26:07,320
SO, WE NEED TO DO BETTER.  

4314
03:26:07,320 --> 03:26:10,600
WE HAVE BEEN WORKING USING HPV 

4315
03:26:10,600 --> 03:26:12,720
VACCINE FOR MANY YEARS NOW AND 

4316
03:26:12,720 --> 03:26:16,120
MY WORK IS IN COSTA RICA I WILL 

4317
03:26:16,120 --> 03:26:19,880
FOCUS ON MY WORK AND HAPPY TO GO

4318
03:26:19,880 --> 03:26:22,400
BIG PICTURE AS WELL AND JUST 

4319
03:26:22,400 --> 03:26:27,520
WITH A LITTLE BIT OF HISTORY HPV

4320
03:26:27,520 --> 03:26:29,200
WAS DISCOVER THE WITH CERVICAL 

4321
03:26:29,200 --> 03:26:31,600
CANCER IN THE 80S AND NCI I 

4322
03:26:31,600 --> 03:26:33,720
WASN'T PART OF IT OR AROUND BUT 

4323
03:26:33,720 --> 03:26:35,880
NCI WAS INSTRUMENTAL IN THAT AND

4324
03:26:35,880 --> 03:26:38,520
SAYING NOW THAT THEY KNOW HPV 

4325
03:26:38,520 --> 03:26:40,200
CAUSES CANCER WHAT DOES NATURAL 

4326
03:26:40,200 --> 03:26:42,640
HISTORY LOOK LIKE?  STUDIES 

4327
03:26:42,640 --> 03:26:45,440
LAUVENLGED ONE IN COSTA RICA TO 

4328
03:26:45,440 --> 03:26:48,760
DEFINE NATURAL HISTORY AND 

4329
03:26:48,760 --> 03:26:51,320
ONGOING AND DOCTORS WERE DOING 

4330
03:26:51,320 --> 03:26:54,720
ASSAYS FORMING FOUNDATION OF THE

4331
03:26:54,720 --> 03:26:58,680
VO OR VIRUS LIKE PARTICLE OF HPV

4332
03:26:58,680 --> 03:27:00,520
VACCINE AND ARE ONE OF THE 

4333
03:27:00,520 --> 03:27:02,160
INVENTORS OF THE VACCINE AND 

4334
03:27:02,160 --> 03:27:05,040
THROUGH COMMITMENT WE SAID 

4335
03:27:05,040 --> 03:27:07,640
VIRUS-LIKE PARTICLE VACCINES 

4336
03:27:07,640 --> 03:27:09,960
LICENSED TO PHARMACEUTICAL 

4337
03:27:09,960 --> 03:27:11,960
COMPANIES RAN PHASE 3 CLINICAL 

4338
03:27:11,960 --> 03:27:15,160
THEY DID PRECLINICAL AND 

4339
03:27:15,160 --> 03:27:15,960
CLINICAL TRIAL WORK AND FROM 

4340
03:27:15,960 --> 03:27:18,280
SUITABLE COMPANIES LOOKING AT 

4341
03:27:18,280 --> 03:27:20,120
THESE, WE THINK THERE SHOULD BE 

4342
03:27:20,120 --> 03:27:22,600
A PRIVATE OR NOT PRIVATE BUT 

4343
03:27:22,600 --> 03:27:24,360
PUBLIC EFFORT AS WELL.  AGAIN, 

4344
03:27:24,360 --> 03:27:29,920
NOT ME.  I'M STILL NOT HERE YET 

4345
03:27:29,920 --> 03:27:32,720
TO WLOOK AT THESE AND LAUNCHED 

4346
03:27:32,720 --> 03:27:34,760
THIS HPV VACCINE TRIAL THAT IS 

4347
03:27:34,760 --> 03:27:37,960
STILL ONGOING AND LOTS OF 

4348
03:27:37,960 --> 03:27:39,000
CONTRIBUTIONS TO SCIENCE AND WE 

4349
03:27:39,000 --> 03:27:40,400
PRESENT DATA ALL OVER THE WORLD 

4350
03:27:40,400 --> 03:27:42,760
AND ENCOURAGE COLLABORATIONS.  

4351
03:27:42,760 --> 03:27:44,200
IF ANYONE IS INTERESTED, WE WORK

4352
03:27:44,200 --> 03:27:47,640
WITH MANY PEOPLE IN THE ROOM AND

4353
03:27:47,640 --> 03:27:48,120
COME FIND ME. 

4354
03:27:48,120 --> 03:27:50,000
LET ME TELL YOU A LITTLE ABOUT 

4355
03:27:50,000 --> 03:27:52,720
IT.  WHY IS THIS COSTA RICA 

4356
03:27:52,720 --> 03:27:54,360
VACCINE TRIAL IMPORTANT?  

4357
03:27:54,360 --> 03:27:56,400
WE MADE A DISCOVERY THAT MAYBE 

4358
03:27:56,400 --> 03:27:59,720
ONE DOSE OF THE HPV VACCINE 

4359
03:27:59,720 --> 03:28:01,600
MIGHT BE ENOUGH.  WHEN I'M 

4360
03:28:01,600 --> 03:28:04,400
TALKING ABOUT 8% OF LMICS ARE 

4361
03:28:04,400 --> 03:28:07,000
VACCINATING, WE ARE THINKING 

4362
03:28:07,000 --> 03:28:16,400
ABOUT THEY ROLLED OUT AS 

4363
03:28:16,400 --> 03:28:19,280
THREE-DOSE REGIMENS AND SCALING 

4364
03:28:19,280 --> 03:28:20,920
THAT BACK TO 1 DOSE AND CUTS 

4365
03:28:20,920 --> 03:28:24,480
COST OF VACCINE BY 1/3 OR HALF 

4366
03:28:24,480 --> 03:28:27,520
IF IN ONE DOSE AND ALSO REALLY 

4367
03:28:27,520 --> 03:28:28,440
RELEASES REQUIRED INFRASTRUCTURE

4368
03:28:28,440 --> 03:28:30,960
THAT IS ASSOCIATED WITH A 

4369
03:28:30,960 --> 03:28:33,920
VACCINE PROGRAM.  THIS IS NOT AN

4370
03:28:33,920 --> 03:28:36,080
ADOLESCENT PLATFORM OR NOT WHERE

4371
03:28:36,080 --> 03:28:38,120
MOST PEOPLE -- MOST GET PART OF 

4372
03:28:38,120 --> 03:28:41,000
EPI PROGRAM AND GETTING VACCINES

4373
03:28:41,000 --> 03:28:43,480
UP TO AGE OF 2 WORLDWIDE.  THIS 

4374
03:28:43,480 --> 03:28:45,200
STICKS OUT AND GETTING IT DOWN 

4375
03:28:45,200 --> 03:28:47,600
TO A SINGLE DOSE MAKES IT 

4376
03:28:47,600 --> 03:28:50,560
AFFORDABLE AS WELL AS JUST 

4377
03:28:50,560 --> 03:28:51,440
REALLY DOABLE.  

4378
03:28:51,440 --> 03:28:56,120
SO, 2004, WE LAUNCHED THE COSTA 

4379
03:28:56,120 --> 03:28:57,200
RICA VACCINE TRIAL AND DIDN'T 

4380
03:28:57,200 --> 03:28:59,880
KNOW IT WAS SAFE.  THOUGHT SO.  

4381
03:28:59,880 --> 03:29:01,960
SAFETY AND EFFICACY WERE MAIN 

4382
03:29:01,960 --> 03:29:04,440
NAMES OF TRIAL AND RANDOMIZE THE

4383
03:29:04,440 --> 03:29:07,520
TO RECEIVE HEPATITIS A VACCINE 

4384
03:29:07,520 --> 03:29:15,120
OR CERVARIX ATHAVENTED WITH TLR 

4385
03:29:15,120 --> 03:29:17,160
AGONIST AND 18 TO 12 AND GIRLS 

4386
03:29:17,160 --> 03:29:20,880
OR WOMEN THAT WERE 18 TO 25 

4387
03:29:20,880 --> 03:29:24,400
YEARS AND WERE GETTING PREGNANT 

4388
03:29:24,400 --> 03:29:27,400
AND DON'T VACCINATE PREGNANT 

4389
03:29:27,400 --> 03:29:32,920
WOMEN AND HAD COLPOS COPY AND 

4390
03:29:32,920 --> 03:29:36,800
20% OF WOMEN RECEIVED FEWER THAN

4391
03:29:36,800 --> 03:29:41,760
THREE DOSES AND WE MADE THIS 

4392
03:29:41,760 --> 03:29:43,240
DISCOVERY USING WOMEN IN POST 

4393
03:29:43,240 --> 03:29:45,360
DOC WAY AND NOT RANDOMIZE THE 

4394
03:29:45,360 --> 03:29:47,600
WINDOWS HOPING THREE WOULD WORK 

4395
03:29:47,600 --> 03:29:50,360
AND THIS PROTECTS THE SAME AS 

4396
03:29:50,360 --> 03:29:53,000
TWO OR THREE DOSES SAYING WE 

4397
03:29:53,000 --> 03:29:54,560
HAVE TO CHECK NOW FOR DURABILITY

4398
03:29:54,560 --> 03:30:01,760
AND FOLLOWED THIS HPV ARM FOR 

4399
03:30:01,760 --> 03:30:06,040
VIER OL OJIC ENDPOINTS AND NOW 

4400
03:30:06,040 --> 03:30:07,680
FOLLOWING FOR IMMUNOLOGICAL 

4401
03:30:07,680 --> 03:30:12,400
ENDPOINTS AND I WILL SHOW RECENT

4402
03:30:12,400 --> 03:30:13,920
DA

4403
03:30:13,920 --> 03:30:14,120
DATA. 

4404
03:30:14,120 --> 03:30:16,440
WHEN CHECKING TO SEE IF ONE DOSE

4405
03:30:16,440 --> 03:30:18,240
STILL WORKS DOING A TRIAL 

4406
03:30:18,240 --> 03:30:19,600
LOOKING AT CUMULATIVE ENDPOINTS 

4407
03:30:19,600 --> 03:30:22,400
IN THE FOLLOWUP AND FOUR YEARS 

4408
03:30:22,400 --> 03:30:24,760
AND BLINDED RANDOMIZED PHASE IT 

4409
03:30:24,760 --> 03:30:26,880
WAS A CUMULATIVE ASSESSMENT AND 

4410
03:30:26,880 --> 03:30:27,960
ASKING THE QUESTION IS IT 

4411
03:30:27,960 --> 03:30:31,920
WORKING AT 10 YEARS, YOU DO AN 

4412
03:30:31,920 --> 03:30:33,440
ANALYSIS AT THAT POINT AND KEY 

4413
03:30:33,440 --> 03:30:35,720
QUESTION WE CAME OUT AND SAID, 

4414
03:30:35,720 --> 03:30:38,640
HEY, EVERYONE.  LOOK.  ONE DOSE 

4415
03:30:38,640 --> 03:30:41,320
WORKS AND WE WERE EXCITED THAT 

4416
03:30:41,320 --> 03:30:43,080
TWO DOSES WORKED AND EVERYONE 

4417
03:30:43,080 --> 03:30:46,480
SAID NO WAY THESE UNIT VACCINES 

4418
03:30:46,480 --> 03:30:48,320
MUST HAVE MULTIPLE DOSES IF YOU 

4419
03:30:48,320 --> 03:30:50,920
ARE -- WE SAID, OKAY.  DATA 

4420
03:30:50,920 --> 03:30:52,800
SHOWS IT REALLY WORKS AND ONCE 

4421
03:30:52,800 --> 03:30:56,160
WE PROVIDED ENOUGH DATA TO GET 

4422
03:30:56,160 --> 03:30:58,720
REALLY SOME TRACTION.  YEAH.  

4423
03:30:58,720 --> 03:31:00,400
TRACTION GOING THAT ONE DOSE 

4424
03:31:00,400 --> 03:31:03,560
WORKED THEY SWITCHED TO SAYING 

4425
03:31:03,560 --> 03:31:06,240
WE SEE IT WORKS IN SHORT-TERM 

4426
03:31:06,240 --> 03:31:08,640
BUT WON'T BE DURABLE OR AMOUNT 

4427
03:31:08,640 --> 03:31:11,280
TO ENOUGH ANTIBODIES.  

4428
03:31:11,280 --> 03:31:12,840
DURABILITY CHECKS HAVE BEEN 

4429
03:31:12,840 --> 03:31:14,520
IMPORTANT AND GOING QUICKLY 

4430
03:31:14,520 --> 03:31:15,880
THROUGH IT WE BENCHMARKED 

4431
03:31:15,880 --> 03:31:18,200
AGAINST THREE DOSES THAT IS 

4432
03:31:18,200 --> 03:31:19,520
STANDARD OF CARE IN WOMEN THIS 

4433
03:31:19,520 --> 03:31:21,760
AGE.  WE ARE ASKING HOW DOES ONE

4434
03:31:21,760 --> 03:31:23,800
DOSE COMPARE TO THREE DOSES?  

4435
03:31:23,800 --> 03:31:25,960
LOOKING AT VERY SMALL NUMBER OF 

4436
03:31:25,960 --> 03:31:27,760
ONE DOSE THAT WERE NOT 

4437
03:31:27,760 --> 03:31:29,640
RANDOMIZED AND THEY DIDN'T GET 

4438
03:31:29,640 --> 03:31:31,080
ADDITIONAL DOSE THEY WERE 

4439
03:31:31,080 --> 03:31:31,880
INTENDED TO GET AND HAVE DONE 

4440
03:31:31,880 --> 03:31:34,680
LOTS OF WORK TO SHOW BIAS 

4441
03:31:34,680 --> 03:31:35,600
DOESN'T DRIVE FINDINGS. 

4442
03:31:35,600 --> 03:31:38,240
I WON'T GET INTO IT NOW.  WE 

4443
03:31:38,240 --> 03:31:42,440
SHOWED HPV16 AND 18 TYPES IN 

4444
03:31:42,440 --> 03:31:45,040
BIVALENT HPV VACCINE.  

4445
03:31:45,040 --> 03:31:47,040
PROTECTION FOR 1 AND 3 DOSES IS 

4446
03:31:47,040 --> 03:31:48,520
THE SAME CONFIDENCE INTERVAL IS 

4447
03:31:48,520 --> 03:31:50,480
BIG HERE BECAUSE OF SMALL 

4448
03:31:50,480 --> 03:31:51,720
NUMBERS AND POINT ESTIMATES ARE 

4449
03:31:51,720 --> 03:31:54,200
THE SAME AND WE SHOWED AT 10 

4450
03:31:54,200 --> 03:31:56,600
YEARS IT THAT CROSS-PROTECTION. 

4451
03:31:56,600 --> 03:32:00,360
REMEMBER, VACCINES PROTECT 

4452
03:32:00,360 --> 03:32:01,840
AGAINST HOMOLOGOUS TYPES AGAINST

4453
03:32:01,840 --> 03:32:06,120
THE VACCINE AND TYPES FILO 

4454
03:32:06,120 --> 03:32:08,760
GENETICALLY RELATED TO 18 AND 16

4455
03:32:08,760 --> 03:32:11,760
AND WE SEE EVIDENCE OF 

4456
03:32:11,760 --> 03:32:12,160
CROSS-PROTECTION. 

4457
03:32:12,160 --> 03:32:15,320
SO, THESE ARE -- THESE DATA ARE 

4458
03:32:15,320 --> 03:32:17,680
BOLSTERED BY ANTIBODY PATTERNS 

4459
03:32:17,680 --> 03:32:20,840
AND SHOWING HPV16 HERE AND SHOW 

4460
03:32:20,840 --> 03:32:24,360
ON X AXIS TIME OUT TO 11 YEARS 

4461
03:32:24,360 --> 03:32:27,200
THIS ANTIBODY GMT THAT SAMPLES 

4462
03:32:27,200 --> 03:32:30,840
ARE TESTED AT FRED ERIC NATIONAL

4463
03:32:30,840 --> 03:32:35,080
LAB BY LISHA PINTO WHO RUNS THE 

4464
03:32:35,080 --> 03:32:36,760
LABORATORY AND DOES ALL OF THE 

4465
03:32:36,760 --> 03:32:38,600
ANTIBODY WORK.  WHAT WE SEE AND 

4466
03:32:38,600 --> 03:32:40,600
FIRST THING THAT GRABS YOU IS 

4467
03:32:40,600 --> 03:32:42,280
ONE DOSE STABLE OUT TO 11 YEARS 

4468
03:32:42,280 --> 03:32:44,600
WHICH WAS ABSOLUTELY UNEXPECTED 

4469
03:32:44,600 --> 03:32:47,000
AND IS ABOUT FOUR-FOLD LOWER 

4470
03:32:47,000 --> 03:32:50,120
THAN THAT ELICITED BY THREE 

4471
03:32:50,120 --> 03:32:52,760
DOSES BUT DON'T HAVE CORRELATIVE

4472
03:32:52,760 --> 03:32:54,200
PROTECTION AND DON'T KNOW 

4473
03:32:54,200 --> 03:32:57,000
MINIMUM ANTIBODY LEVEL IS THAT 

4474
03:32:57,000 --> 03:32:58,840
IS MAGIC NUMBER YOU GET 

4475
03:32:58,840 --> 03:33:01,120
PROTECTION OR NOT.  PAIRING UP 

4476
03:33:01,120 --> 03:33:03,600
WITH DATA ON PREVIOUS SLIDE WE 

4477
03:33:03,600 --> 03:33:06,080
CAN SAY LOWER ANTIBODY LEVELS 

4478
03:33:06,080 --> 03:33:09,360
DON'T ALWAYS EQUATE TO INFERIOR 

4479
03:33:09,360 --> 03:33:10,320
PROTECTION AND BENCHMARK AGAINST

4480
03:33:10,320 --> 03:33:13,320
NATURAL IMMUNITY THAT IS AGAINST

4481
03:33:13,320 --> 03:33:15,600
HPV IS WEAK.  IT IS NOT VERY 

4482
03:33:15,600 --> 03:33:18,200
STRONG BUT PROVIDES A BENCHMARK 

4483
03:33:18,200 --> 03:33:20,880
AND ONE-DOSE LEVELS ARE ABOUT AN

4484
03:33:20,880 --> 03:33:23,320
ORDER OF MAGNITUDE HIGHER AND WE

4485
03:33:23,320 --> 03:33:26,000
WILL FOLLOW TO 20 YEARS POST 

4486
03:33:26,000 --> 03:33:27,880
DOSE 1 ON THESE WOMEN.  WHY IS 

4487
03:33:27,880 --> 03:33:30,680
20 YEARS MAGIC NUMBER?  HPV 

4488
03:33:30,680 --> 03:33:33,200
VACCINES WE DON'T HAVE TO INDUCE

4489
03:33:33,200 --> 03:33:34,960
STERILIZING IMMUNITY.  DOESN'T 

4490
03:33:34,960 --> 03:33:37,960
ARE TO BE LIFELONG.  SEXUALLY 

4491
03:33:37,960 --> 03:33:38,800
TRANSMITTED INFECTION WE HAVE TO

4492
03:33:38,800 --> 03:33:41,240
COVER GIRLS WE CAN TALK BOYS TOO

4493
03:33:41,240 --> 03:33:44,040
BUT I'M FOCUSED ON GIRLS TODAY. 

4494
03:33:44,040 --> 03:33:46,160
GIRLS FOR THOSE PEAK PERIODS AND

4495
03:33:46,160 --> 03:33:48,080
AGES OF SEXUAL ACQUISITION THAT 

4496
03:33:48,080 --> 03:33:54,440
IS SHORTLY AFTER SEXUAL DABU AND

4497
03:33:54,440 --> 03:33:56,440
HPV ACQUISITION EXPLODES AND 

4498
03:33:56,440 --> 03:33:58,480
STARTS TO COME DOWN AND 

4499
03:33:58,480 --> 03:34:00,240
PROTECTING 10 TO 30 YEAR OLDS WE

4500
03:34:00,240 --> 03:34:03,520
WILL REALLY INCREDIBLY REDUCE 

4501
03:34:03,520 --> 03:34:04,720
INCIDENCE OF CERVICAL CANCER.  

4502
03:34:04,720 --> 03:34:06,720
OF COURSE, IN THE US WE 

4503
03:34:06,720 --> 03:34:08,920
VACCINATE UP TO 45, SURE.  YOU 

4504
03:34:08,920 --> 03:34:10,720
KNOW, YOU WILL GRAB A FEW AND 

4505
03:34:10,720 --> 03:34:12,360
ALWAYS WE HAVE TO BE CAREFUL 

4506
03:34:12,360 --> 03:34:14,360
WHEN THINKING PUBLIC HEALTH THAT

4507
03:34:14,360 --> 03:34:16,640
IS TO SAY LET'S MAKE A VERY, 

4508
03:34:16,640 --> 03:34:18,440
VERY BIG IMPACT LET'S NOT BE AT 

4509
03:34:18,440 --> 03:34:19,800
THE INDIVIDUAL LEVEL THINKING 

4510
03:34:19,800 --> 03:34:21,480
ABOUT PERFECTION.  WE WILL MAKE 

4511
03:34:21,480 --> 03:34:24,360
THE BIG IMPACT FIRST AND CAN 

4512
03:34:24,360 --> 03:34:27,960
CLEAN UP EVERY SINGLE PERSON 

4513
03:34:27,960 --> 03:34:30,000
LATER WE HAVE FOUR CLINICAL 

4514
03:34:30,000 --> 03:34:32,280
TRIALS ONGOING LOOKING AT SINGLE

4515
03:34:32,280 --> 03:34:34,040
DOSE HPV VACCINATION THAT AT 

4516
03:34:34,040 --> 03:34:36,960
THIS POINT I HOPE I REALLY 

4517
03:34:36,960 --> 03:34:38,080
CONVINCED YOU HOW THIS COULD BE 

4518
03:34:38,080 --> 03:34:40,360
SOLUTION TO BARRIER OF POOR 

4519
03:34:40,360 --> 03:34:41,880
UPTAKE AFTER 16 YEARS BEING ON 

4520
03:34:41,880 --> 03:34:44,160
THE MARKET.  I TOLD YOU ABOUT 

4521
03:34:44,160 --> 03:34:47,280
THE COSTA RICA HPV VACCINE TRIAL

4522
03:34:47,280 --> 03:34:50,040
NOW IN 18TH YEAR FOLLOW UP AND 

4523
03:34:50,040 --> 03:34:52,160
WE MADE A DISCOVERY OF ONE DOSE.

4524
03:34:52,160 --> 03:34:54,160
I WOULD LIKE TO POINT OUT 1 DOSE

4525
03:34:54,160 --> 03:34:56,360
IS NOT POPULAR WITH 

4526
03:34:56,360 --> 03:34:57,560
PHARMACEUTICAL COMPANIES AND 

4527
03:34:57,560 --> 03:34:58,760
THEY DON'T WANT TO SELL LESS OF 

4528
03:34:58,760 --> 03:35:00,680
THEIR VACCINE.  I THINK THIS 

4529
03:35:00,680 --> 03:35:02,760
REALLY SPEAKS TO THE IMPORTANCE 

4530
03:35:02,760 --> 03:35:06,160
OF PUBLICALLY FUNDED EFFORTS 

4531
03:35:06,160 --> 03:35:11,560
WHERE ANALYSIS AND CONTROL IS IN

4532
03:35:11,560 --> 03:35:15,040
HANDS OF THE PUBLIC AND WE 

4533
03:35:15,040 --> 03:35:16,400
REALLY INTERROGATED THIS TRIAL 

4534
03:35:16,400 --> 03:35:17,880
LIKE WHAT OTHER PHARMACEUTICAL 

4535
03:35:17,880 --> 03:35:19,880
COMPANIES ARE POISE TODAY DO AND

4536
03:35:19,880 --> 03:35:21,200
MADE IMPORTANT HEALTH 

4537
03:35:21,200 --> 03:35:22,920
DISCOVERIES AS A RESULT AND WE 

4538
03:35:22,920 --> 03:35:26,160
CONSIDER OUR COSTA RICA HPV 

4539
03:35:26,160 --> 03:35:27,960
VACCINE TRIAL AS HYPOTHESIS 

4540
03:35:27,960 --> 03:35:29,280
GENERATING AND SHOWED YOU WOMEN 

4541
03:35:29,280 --> 03:35:31,400
WERE NOT RANDOMIZE TODAY GET ONE

4542
03:35:31,400 --> 03:35:33,320
DOSE AND THERE IS A SMALL 

4543
03:35:33,320 --> 03:35:34,760
NUMBER, YOU KNOW?  

4544
03:35:34,760 --> 03:35:38,000
WE LAUNCH THE ENORMOUS STUDY 

4545
03:35:38,000 --> 03:35:44,360
CALLED ESCUDDO TRIAL 

4546
03:35:44,360 --> 03:35:46,880
NONINFERIORITY TRIAL WITH 1 

4547
03:35:46,880 --> 03:35:50,160
VERSUS 2 DOSES. 

4548
03:35:50,160 --> 03:35:53,160
THAT IS THE AMERICA PRODUCT WITH

4549
03:35:53,160 --> 03:35:55,600
95% OF GLOBAL HPV VACCINE MARKET

4550
03:35:55,600 --> 03:35:57,960
SHARE AND NOT A GREAT THING AND 

4551
03:35:57,960 --> 03:36:00,360
HEALTHY MARKETS REQUIRE MULTIPLE

4552
03:36:00,360 --> 03:36:02,560
COMPETITORS, AS YOU KNOW.  THAT 

4553
03:36:02,560 --> 03:36:04,680
IS A SEPARATE TALK.  WE CAN TALK

4554
03:36:04,680 --> 03:36:06,360
ABOUT DEVELOPING COUNTRY 

4555
03:36:06,360 --> 03:36:07,440
MANUFACTURERS AND SERUM 

4556
03:36:07,440 --> 03:36:09,840
INSTITUTE AND THAT IS ALL ON THE

4557
03:36:09,840 --> 03:36:12,560
TABLE AND WE COMMENT ONE DOSE A 

4558
03:36:12,560 --> 03:36:18,360
COUPLE DIFFERENT WAYS PRIMAVERA 

4559
03:36:18,360 --> 03:36:20,000
IS IMMUNOBRIDGING TRIAL THAT 

4560
03:36:20,000 --> 03:36:21,920
GETS 1 DOSE SUCCESSFUL AND FOCUS

4561
03:36:21,920 --> 03:36:25,600
IS REALLY ON GIRLS NOW GETTING 

4562
03:36:25,600 --> 03:36:26,720
ONE-DOSE RECOMMENDATION TO GIRLS

4563
03:36:26,720 --> 03:36:30,120
BUT SEE HPV VACCINATION AS AN 

4564
03:36:30,120 --> 03:36:32,360
ACCELERATION PLAY.  WHEN WHO, 

4565
03:36:32,360 --> 03:36:34,600
FOR EXAMPLE, TALKS ABOUT 

4566
03:36:34,600 --> 03:36:35,800
CERVICAL CANCER ELIMINATION, 

4567
03:36:35,800 --> 03:36:38,840
THEY TALK ABOUT A 100-YEAR TIME 

4568
03:36:38,840 --> 03:36:42,640
SCALE TO THAT GOAL, WHICH IS A 

4569
03:36:42,640 --> 03:36:45,960
LONG TIME.  WE THINK IF YOU 

4570
03:36:45,960 --> 03:36:47,840
VACCINATE UP AN AGE RANGE WITH 

4571
03:36:47,840 --> 03:36:49,680
ONE DOSE IT REALLY PULLS THAT 

4572
03:36:49,680 --> 03:36:53,520
TIMELINE FASTER.  YOU TAKE HPV 

4573
03:36:53,520 --> 03:36:55,480
ENDOM NISTY AND CRUSHING IT.  

4574
03:36:55,480 --> 03:36:59,280
THIS WILL LOOK TO READ OUT LATER

4575
03:36:59,280 --> 03:37:02,880
ON IN THIS DECADE. 

4576
03:37:02,880 --> 03:37:05,520
WHAT TIME IS IT?  

4577
03:37:05,520 --> 03:37:07,360
OKAY.  I WILL PASS ALL TRIALS 

4578
03:37:07,360 --> 03:37:12,120
ARE IN CLINICAL TRIALS.GOV.  

4579
03:37:12,120 --> 03:37:14,200
I WANT TO FAST FORWARD A LITTLE 

4580
03:37:14,200 --> 03:37:16,880
BIT.  IN ADDITION TO OUR FOUR 

4581
03:37:16,880 --> 03:37:20,360
TRIALS SO THE WORLD HAS REALLY 

4582
03:37:20,360 --> 03:37:22,840
GOTTEN -- THIS HAS GOTTEN A LOT 

4583
03:37:22,840 --> 03:37:25,080
OF -- WHAT IS THE WORD?  

4584
03:37:25,080 --> 03:37:29,200
PEOPLE AROUND THE WORLD SEE 

4585
03:37:29,200 --> 03:37:32,640
POTENTIAL IN THIS AND HAVE 

4586
03:37:32,640 --> 03:37:34,520
SIMILARLY LAUNCHED STUDIES 

4587
03:37:34,520 --> 03:37:38,520
WORKING BACKWARDS UP THE SLIDE 

4588
03:37:38,520 --> 03:37:42,600
AGE-RAGE DOWN IN GAMBIA THAT IS 

4589
03:37:42,600 --> 03:37:45,960
A 4 AND EFFECTIVENESS THROUGH 

4590
03:37:45,960 --> 03:37:48,720
IMMUNOBRIDGING EASIER TO 

4591
03:37:48,720 --> 03:37:50,280
IMMUNOBRIDGE DOWN AGE RANGE AND 

4592
03:37:50,280 --> 03:37:52,880
YOU CAN SHOW IMMUNE LOGIC NOT 

4593
03:37:52,880 --> 03:37:56,000
INFERIORITY AND THERE IS AN 

4594
03:37:56,000 --> 03:37:57,320
EFFECTIVENESS STUDY IN THAILAND.

4595
03:37:57,320 --> 03:38:01,000
THIS IS THE FIRST STUDY WITH A 

4596
03:38:01,000 --> 03:38:02,080
SINGLE DOSE AMONG PEOPLE LIVING 

4597
03:38:02,080 --> 03:38:05,840
WITH HIV THAT IS GOING ON IN 

4598
03:38:05,840 --> 03:38:07,160
SOUTH AFRICA AND IS AN 

4599
03:38:07,160 --> 03:38:09,320
EFFECTIVENESS STUDY NOT EFFICACY

4600
03:38:09,320 --> 03:38:12,000
KEYS YOU INTO AN INDIVIDUAL 

4601
03:38:12,000 --> 03:38:12,600
LEVEL RANDOMIZATION AND 

4602
03:38:12,600 --> 03:38:18,080
EFFECTIVE N NGS STUDY CAN DO 

4603
03:38:18,080 --> 03:38:20,040
LARGER GROUPS OF PEOPLE NOT 

4604
03:38:20,040 --> 03:38:21,320
ROBUST TYPE OF EVIDENCE BUT 

4605
03:38:21,320 --> 03:38:22,720
OFTEN TIMES EASIER TO GET AT.  

4606
03:38:22,720 --> 03:38:24,680
THIS IS IMPORTANT.  IT IS A 

4607
03:38:24,680 --> 03:38:26,720
SINGLE DOSE STUDY LOOKING AT 8 

4608
03:38:26,720 --> 03:38:30,320
WOMEN LIVING WITH AND WITHOUT 

4609
03:38:30,320 --> 03:38:30,520
HIV. 

4610
03:38:30,520 --> 03:38:33,120
WE SAW PROGRESS THIS YEAR AND 

4611
03:38:33,120 --> 03:38:35,720
WHO SAGE PUT OUT PERMISSIVE 

4612
03:38:35,720 --> 03:38:37,320
RECOMMENDATION FOR ONE OR TWO 

4613
03:38:37,320 --> 03:38:41,440
DOSES OF HPV VACCINE THAT IS A 

4614
03:38:41,440 --> 03:38:44,560
HUGE ADVANCE. 

4615
03:38:44,560 --> 03:38:46,480
IT WILL NOW BE UP TO COUNTRIES 

4616
03:38:46,480 --> 03:38:48,360
TO SAY WHETHER THEY FEEL IT IS 

4617
03:38:48,360 --> 03:38:50,240
ROBUST ENOUGH.  TRIALS WILL 

4618
03:38:50,240 --> 03:38:51,920
CONTINUE TO READ OUT IN GOAL 

4619
03:38:51,920 --> 03:38:56,360
OVER NEXT 2 TO 3 YEARS IS PUSH 

4620
03:38:56,360 --> 03:38:58,680
TO A FULL RECOMMENDATION AND UK 

4621
03:38:58,680 --> 03:39:00,680
ALSO CAME OUT AND WENT WITH A 

4622
03:39:00,680 --> 03:39:01,480
FULL RECOMMENDATION AND THEY 

4623
03:39:01,480 --> 03:39:04,360
TEND TO BE BOLD AND PROGRESSIVE 

4624
03:39:04,360 --> 03:39:08,680
WHEN RECOMMENDING VACCINE POLICY

4625
03:39:08,680 --> 03:39:11,320
THEY WERE BOLD HERE AND IN BOTH 

4626
03:39:11,320 --> 03:39:12,960
INSTANCES PEOPLE WITH KNOWN 

4627
03:39:12,960 --> 03:39:15,480
STATUS OF HIV SHOULD CONTINUE TO

4628
03:39:15,480 --> 03:39:17,960
GET A THREE-DOSE SCHEDULE.  I 

4629
03:39:17,960 --> 03:39:20,480
WANT TO SHIFT AND TALK ABOUT HIV

4630
03:39:20,480 --> 03:39:21,960
AND CERVICAL CANCER AND THINK 

4631
03:39:21,960 --> 03:39:24,680
THE KEY THING WHEN I THINK ABOUT

4632
03:39:24,680 --> 03:39:27,320
HIV AND CERVICAL CANCER WHEN WE 

4633
03:39:27,320 --> 03:39:28,720
LOOK AT GLOBAL LEVEL PEOPLE 

4634
03:39:28,720 --> 03:39:32,360
LIVING WITH HIV CONTRIBUTE 5 OR 

4635
03:39:32,360 --> 03:39:35,560
6% TO TOTAL CERVICAL CANCER 

4636
03:39:35,560 --> 03:39:37,760
BURDEN THAT IS A RELATIVELY 

4637
03:39:37,760 --> 03:39:39,120
SMALL PROPORTION AND FLIPPING 

4638
03:39:39,120 --> 03:39:41,600
LOOKING AT SOME COUNTRIES SOUTH 

4639
03:39:41,600 --> 03:39:45,760
AFRICA AND COUNTRIES IN SUBIS A 

4640
03:39:45,760 --> 03:39:47,160
HARRANT AFRICA IT IS 

4641
03:39:47,160 --> 03:39:49,560
OVERWHELMING MAJORITY AND WE 

4642
03:39:49,560 --> 03:39:50,840
HAVE TO THINK ABOUT WOMEN LIVING

4643
03:39:50,840 --> 03:39:53,840
WITH HIV AND PROTECTING THEM AS 

4644
03:39:53,840 --> 03:39:56,040
WELL AND THIS WILL COME TWO WAYS

4645
03:39:56,040 --> 03:39:58,440
COMING DIRECTLY WITH VACCINATION

4646
03:39:58,440 --> 03:40:03,640
OF HPV AND INDIRECTLY BUILDING 

4647
03:40:03,640 --> 03:40:07,280
HERD IMMUNITY IN COMMUNITIES 

4648
03:40:07,280 --> 03:40:09,200
THEY LIVE.  I AM COGNIZANT OF 

4649
03:40:09,200 --> 03:40:11,080
THE TIME AND I WANT TO TALK 

4650
03:40:11,080 --> 03:40:13,280
ABOUT SOME OF THE DATA THAT HAVE

4651
03:40:13,280 --> 03:40:15,240
COME OUT.  I AM PUTTING IT UP.  

4652
03:40:15,240 --> 03:40:17,640
IN NO WAY DO I THINK YOU SHOULD 

4653
03:40:17,640 --> 03:40:21,000
BE ABLE TO READ THIS SLIDE BUT 

4654
03:40:21,000 --> 03:40:23,480
IS TO SAY THERE ARE MANY, MANY 

4655
03:40:23,480 --> 03:40:25,400
TRIALS LOOKING AT PROTECTION IN 

4656
03:40:25,400 --> 03:40:28,400
PEOPLE WITH KNOWN HIV STATUS, SO

4657
03:40:28,400 --> 03:40:31,800
WOMEN LIVING WITH HIV LOOKING AT

4658
03:40:31,800 --> 03:40:40,880
ZERO POSITIVITY AS AN ENDPOINT. 

4659
03:40:40,880 --> 03:40:43,480
WHEN WE THINK ABOUT THIS WE DO 

4660
03:40:43,480 --> 03:40:45,120
IN CONTEXT OF IN MY OPINION OF 

4661
03:40:45,120 --> 03:40:48,360
ONE DOSE AND PEOPLE WITH HIV ARE

4662
03:40:48,360 --> 03:40:49,920
MAKING A LESS ROBUST RESPONSE TO

4663
03:40:49,920 --> 03:40:55,200
THREE DOSES OF HPV VACCINE.  

4664
03:40:55,200 --> 03:40:57,960
THINKING ABOUT IMMUNE LEVELS 

4665
03:40:57,960 --> 03:40:59,760
SOLICITED BY ONE DOSE THOSE 

4666
03:40:59,760 --> 03:41:00,760
LEVELS OR THAT QUANTITY IS 

4667
03:41:00,760 --> 03:41:02,520
ENOUGH.  OF COURSE, THAT DOES 

4668
03:41:02,520 --> 03:41:03,960
NOTHING TO SPEAK OF THE QUALITY 

4669
03:41:03,960 --> 03:41:07,040
OF THE IMMUNE RESPONSE AND 

4670
03:41:07,040 --> 03:41:08,640
AINDIVIDUALITY OF ANY OF IT.  IT

4671
03:41:08,640 --> 03:41:12,000
THAT IS STILL AN OPEN QUESTION 

4672
03:41:12,000 --> 03:41:15,960
THAT WILL REQUIRE EFFICACY AS AN

4673
03:41:15,960 --> 03:41:17,280
ENDPOINT AND NEED TO KNOW 

4674
03:41:17,280 --> 03:41:20,360
WHATEVER ANTIBODIES THEY ARE 

4675
03:41:20,360 --> 03:41:21,960
GENERATING FROM A QUANTITY AND 

4676
03:41:21,960 --> 03:41:25,240
QUALITY PERSPECTIVE ARE 

4677
03:41:25,240 --> 03:41:26,240
SUFFICIENT TO PROTECT. 

4678
03:41:26,240 --> 03:41:29,080
THESE ARE TRIALS LISTED IN 

4679
03:41:29,080 --> 03:41:31,080
CLINICAL TRIALS.GOV THAT ARE 

4680
03:41:31,080 --> 03:41:33,920
GOING ON AND WE NOTE ONE 

4681
03:41:33,920 --> 03:41:38,400
EFFICACY TRIAL THAT IS A 

4682
03:41:38,400 --> 03:41:39,640
RELATIVELY SMALL SAMPLE THOUGH I

4683
03:41:39,640 --> 03:41:42,160
ASSUME THE ATTACK RATE IS QUITE 

4684
03:41:42,160 --> 03:41:44,640
HIGH AND 3 DOSES VERSUS PLACEBO 

4685
03:41:44,640 --> 03:41:46,520
IS LOOKING TO READ OUT NEXT 

4686
03:41:46,520 --> 03:41:51,120
YEAR.  THAT WILL BE REALLY, 

4687
03:41:51,120 --> 03:41:51,640
REALLY IMPORTANT. 

4688
03:41:51,640 --> 03:41:55,440
AND ONE OTHER STUDY IN RWANDA 

4689
03:41:55,440 --> 03:41:59,200
LOOKING AT QUADRO VAILANT 

4690
03:41:59,200 --> 03:42:00,440
VACCINE THEY HAVE 3 VERSE 2 

4691
03:42:00,440 --> 03:42:02,880
DOSES AND TRYING TO SEE IF WE 

4692
03:42:02,880 --> 03:42:06,440
CAN OBTAIN ADEQUATE PROTECTION 

4693
03:42:06,440 --> 03:42:09,160
WITH FEWER DOSES THAT ARE 2 NOT 

4694
03:42:09,160 --> 03:42:11,280
1 THAT IS WELL AND LOOKS AND IS 

4695
03:42:11,280 --> 03:42:13,000
A LARGE STUDY. 

4696
03:42:13,000 --> 03:42:15,120
SO, ONE KEY THING, AS I SAID, WE

4697
03:42:15,120 --> 03:42:17,680
HAVE MOVED THE NEEDLE NOW DOWN 

4698
03:42:17,680 --> 03:42:21,960
TO ONE OR TWO DOSE PERMISSIVE 

4699
03:42:21,960 --> 03:42:25,440
RECOMMENDATION GLOBALLY BY WHO. 

4700
03:42:25,440 --> 03:42:27,960
WE WILL NOW WAIT TO SEE IN THE 

4701
03:42:27,960 --> 03:42:30,280
NEXT YEAR OR 2 WHAT COUNTRIES 

4702
03:42:30,280 --> 03:42:31,320
PICK UP THIS RECOMMENDATION.  

4703
03:42:31,320 --> 03:42:34,120
LOTS OF QUESTIONS IN COUNTRIES 

4704
03:42:34,120 --> 03:42:37,320
ARE HIGH HIV BURDEN OR 

4705
03:42:37,320 --> 03:42:38,600
PREVALENCE ABOUT WHAT THEIR 

4706
03:42:38,600 --> 03:42:40,000
POPULATIONS ARE AND TWO WAYS TO 

4707
03:42:40,000 --> 03:42:42,240
THINK ABOUT THIS AND TWO 

4708
03:42:42,240 --> 03:42:43,080
POPULATIONS TO CONSIDER. 

4709
03:42:43,080 --> 03:42:45,360
THERE IS PEOPLE WHO -- THERE IS 

4710
03:42:45,360 --> 03:42:47,840
GIRLS WHO WILL GET HPV 

4711
03:42:47,840 --> 03:42:50,440
VACCINATION THAT IS AT 10 OR 11 

4712
03:42:50,440 --> 03:42:51,680
OR 12 OR WHENEVER THE 

4713
03:42:51,680 --> 03:42:53,000
RECOMMENDATION IS AND MAYBE UP 

4714
03:42:53,000 --> 03:42:56,360
TO 15.  IN COUNTRIES WHERE 

4715
03:42:56,360 --> 03:42:59,400
MEDIAN AGE OF HIV ACQUISITION IS

4716
03:42:59,400 --> 03:43:02,320
7 TAENOR LATER THEY WILL HAVE 

4717
03:43:02,320 --> 03:43:05,080
HPV VACCINATION AND ONBOARD 

4718
03:43:05,080 --> 03:43:07,800
ANTIBODIES PRIOR TO HPV 

4719
03:43:07,800 --> 03:43:10,400
ACQUISITION AND KEY QUESTION 

4720
03:43:10,400 --> 03:43:12,600
HARD TO GET AT IS WILL 

4721
03:43:12,600 --> 03:43:14,400
VACCINATION OF POPULATIONS PRIOR

4722
03:43:14,400 --> 03:43:18,800
TO HIV ACQUISITION, WHAT WILL 

4723
03:43:18,800 --> 03:43:20,000
ANTIBODY RESPONSE LOOK LIKE 

4724
03:43:20,000 --> 03:43:22,280
AFTER HIV ACQUISITION?  

4725
03:43:22,280 --> 03:43:24,200
FRANKLY, THAT IS THE BIGGER 

4726
03:43:24,200 --> 03:43:26,080
PICTURE QUESTION.  THAT IS WHAT 

4727
03:43:26,080 --> 03:43:27,320
WILL HAPPEN THE WORLD AROUND.  

4728
03:43:27,320 --> 03:43:30,080
THERE IS A SMALLER QUESTION OF 

4729
03:43:30,080 --> 03:43:31,680
HPV VACCINATION THAT IS AMONG 

4730
03:43:31,680 --> 03:43:33,760
PEOPLE LIVING WITH HIV AND I 

4731
03:43:33,760 --> 03:43:35,600
SHOWED YOU TRIALS THAT ARE IN 

4732
03:43:35,600 --> 03:43:37,880
FLIGHT TO LOOK AT THREE DOSES 

4733
03:43:37,880 --> 03:43:39,760
AND TRIAL IN FLIGHT TO LOOK AT 

4734
03:43:39,760 --> 03:43:41,560
TWO DOSES AND DON'T THINK WE 

4735
03:43:41,560 --> 03:43:43,120
WILL EVER GET TO ONE DOSE.  IF 

4736
03:43:43,120 --> 03:43:44,720
YOU STAND THERE LOOKING AT A 

4737
03:43:44,720 --> 03:43:47,560
WOMAN IN HIV CARE, WHY WOULD YOU

4738
03:43:47,560 --> 03:43:50,000
-- YOU KNOW, WHY WOULD YOU GIVE 

4739
03:43:50,000 --> 03:43:52,640
THE NEXT DOSE WOULD BE MY GUESS.

4740
03:43:52,640 --> 03:43:54,160
THAT IS THE MAIN POINTS I WANTED

4741
03:43:54,160 --> 03:43:57,960
TO TALK ABOUT.  THIS IS MY 

4742
03:43:57,960 --> 03:44:00,360
RESEARCH TEAM IN COSTA RICA AND 

4743
03:44:00,360 --> 03:44:04,280
PEOPLE I LEFT HERE.  HOPE I HAVE

4744
03:44:04,280 --> 03:44:07,840
LEFT ENOUGH TIME TO TALK A 

4745
03:44:07,840 --> 03:44:09,720
LITTLE BIT.  THANK YOU. 

4746
03:44:09,720 --> 03:44:20,240
>>ARE THERE ANY
QUESTIONS?  

4747
03:44:23,800 --> 03:44:27,880
>>I AM NOT AN
IMMUNOLOGIST. 

4748
03:44:27,880 --> 03:44:28,480
>>ME EITHER. 

4749
03:44:28,480 --> 03:44:31,560
>>NO.  I'M REALLY NOT. 
BUT, 

4750
03:44:31,560 --> 03:44:36,800
WHAT ABOUT IMMUNIZE -- WE 

4751
03:44:36,800 --> 03:44:38,120
IMMUNIZE BABIES AGAINST MANY 

4752
03:44:38,120 --> 03:44:39,520
VIRAL DISEASES, SO WHY IS THAT 

4753
03:44:39,520 --> 03:44:42,160
OUT OF THE QUESTION FOR HPV?  

4754
03:44:42,160 --> 03:44:44,120
>>THERE IS A COUPLE
ANSWERS TO 

4755
03:44:44,120 --> 03:44:45,280
YOUR QUESTION.  THEY DON'T HAVE 

4756
03:44:45,280 --> 03:44:48,560
A LOT TO DO WITH IMMUNOLOGY. 

4757
03:44:48,560 --> 03:44:50,120
FIRST ONE IS DURABILITY AND IF 

4758
03:44:50,120 --> 03:44:52,120
WE HAVE TO COVER PEOPLE FROM 

4759
03:44:52,120 --> 03:44:55,520
AGES OF MEDIAN AGE OF SEXUAL 

4760
03:44:55,520 --> 03:44:58,000
DEBUT WE WILL PICK IT AT 17 OR 

4761
03:44:58,000 --> 03:45:00,360
16 IN OUR COUNTRY IN LATER 

4762
03:45:00,360 --> 03:45:01,680
COUNTRIES AND NEED TO COVER THEM

4763
03:45:01,680 --> 03:45:05,680
YOU KNOW FOR AT LEAST 10 TO 15 

4764
03:45:05,680 --> 03:45:08,000
YEARS AFTER THAT DURING PEAK 

4765
03:45:08,000 --> 03:45:09,800
ACQUISITION AND IT ADDS ANOTHER 

4766
03:45:09,800 --> 03:45:12,160
DECADE OF ANTIBODIES AT THIS 

4767
03:45:12,160 --> 03:45:13,480
TIME WHERE NOTHING SHOULD BE 

4768
03:45:13,480 --> 03:45:15,960
HAPPENING AND THEY ARE NOT 

4769
03:45:15,960 --> 03:45:17,200
GETTING CHALLENGED BY HPV 

4770
03:45:17,200 --> 03:45:19,680
BETWEEN AGES OF 2 AND 12.  SO, 

4771
03:45:19,680 --> 03:45:24,360
THOSE ANTIBODIES ARE SUPERFLUOUS

4772
03:45:24,360 --> 03:45:26,440
AT THAT POINT IS ANSWER ONE.  

4773
03:45:26,440 --> 03:45:29,120
OTHER ANSWER IS EPI PROGRAM IS 

4774
03:45:29,120 --> 03:45:30,760
FILLED AND I THINK THAT THESE 

4775
03:45:30,760 --> 03:45:33,800
KIDS GET -- YOU KNOW, A ZILLION 

4776
03:45:33,800 --> 03:45:35,560
DOSES OF SHOTS WITHIN -- YOU 

4777
03:45:35,560 --> 03:45:38,880
KNOW, WITHIN 18 MONTHS.  AS I 

4778
03:45:38,880 --> 03:45:41,480
UNDERSTAND, PHARMACEUTICAL 

4779
03:45:41,480 --> 03:45:43,080
COMPANIES ARE NOT KEEN TO ADD 

4780
03:45:43,080 --> 03:45:44,560
MORE BURDEN TO THAT.  I THINK 

4781
03:45:44,560 --> 03:45:46,920
THAT THEY ARE ACTUALLY LOOKING 

4782
03:45:46,920 --> 03:45:49,240
FOR ANOTHER PLATFORM THAT IS NOT

4783
03:45:49,240 --> 03:45:52,280
EPI AGE.  I DON'T KNOW IF WILL 

4784
03:45:52,280 --> 03:45:56,560
BE AN ADOLESCENT PLAY.  OH, 

4785
03:45:56,560 --> 03:46:02,200
SORRY.  EARLY PROGRAM FOR 

4786
03:46:02,200 --> 03:46:04,000
IMMUNIZATIONS AND EARLY 

4787
03:46:04,000 --> 03:46:05,080
SOMETHING IMMUNIZATIONS AND 

4788
03:46:05,080 --> 03:46:06,400
DON'T REMEMBER BECAUSE WE ALL 

4789
03:46:06,400 --> 03:46:08,360
SAY IT.  CHILDHOOD VACCINATIONS 

4790
03:46:08,360 --> 03:46:10,640
THAT SUPPORTED THE WORLD AROUND 

4791
03:46:10,640 --> 03:46:12,200
IS THE PROGRAM WITHIN WHICH 

4792
03:46:12,200 --> 03:46:14,080
SOMEBODY NEEDS TO GOOGLE THAT.  

4793
03:46:14,080 --> 03:46:18,360
WITHIN WHICH ALL CHILDREN IN THE

4794
03:46:18,360 --> 03:46:21,320
GLOBE ARE VACCINATED. 

4795
03:46:21,320 --> 03:46:23,560
DURABILITY IS A QUESTION THAT IS

4796
03:46:23,560 --> 03:46:26,080
CONGESTED AND SO, YEAH.  HAVING 

4797
03:46:26,080 --> 03:46:27,960
SAID THAT, THERE IS A TRIAL.  

4798
03:46:27,960 --> 03:46:30,080
PEOPLE ARE THINKING OF A TRIAL 

4799
03:46:30,080 --> 03:46:33,200
RIGHT NOW TO LOOK AT ONE DOSE 

4800
03:46:33,200 --> 03:46:36,000
IN, YOU KNOW, TODDLERS AND 

4801
03:46:36,000 --> 03:46:37,240
ANOTHER PROBLEM WITH THAT -- 

4802
03:46:37,240 --> 03:46:38,840
EVEN WITH THE STUDY DESIGN YOU 

4803
03:46:38,840 --> 03:46:41,160
AGAIN NEED TO FOLLOW THOSE 

4804
03:46:41,160 --> 03:46:42,600
CHILDREN FOR 15 YEARS TO SEE IF 

4805
03:46:42,600 --> 03:46:44,720
IT WORKS AND WE DON'T LIKE TO DO

4806
03:46:44,720 --> 03:46:46,000
TRIALS FOR 15 YEARS. 

4807
03:46:46,000 --> 03:46:49,880
YOU LOSE THEM.  IT IS HARD TO 

4808
03:46:49,880 --> 03:46:50,120
TRACK.  

4809
03:46:50,120 --> 03:46:52,760
>>IS THE ESSENTIAL
PROGRAM 

4810
03:46:52,760 --> 03:46:53,160
[INDISCERNIBLE]. 

4811
03:46:53,160 --> 03:46:55,480
>>THANK YOU.  THERE IS
ZERO 

4812
03:46:55,480 --> 03:46:57,840
CHANCE I WOULD HAVE FOUND THE 

4813
03:46:57,840 --> 03:46:58,240
WORD ESSENTIAL. 

4814
03:46:58,240 --> 03:47:00,880
>>THERE MIGHT BE SOCIETAL

4815
03:47:00,880 --> 03:47:03,960
ARGUMENTS TO BE MADE FOR 

4816
03:47:03,960 --> 03:47:05,120
IMMUNIZING YOUNG GIRLS VERY 

4817
03:47:05,120 --> 03:47:08,160
YOUNG IN TERMS OF THIS IS MORE 

4818
03:47:08,160 --> 03:47:10,680
OF A SOCIAL CLINICAL QUESTION 

4819
03:47:10,680 --> 03:47:12,880
ABOUT PARENTS BEING RELUCTANT TO

4820
03:47:12,880 --> 03:47:15,720
ENCOURAGE THEIR 15 YEAR OLD 

4821
03:47:15,720 --> 03:47:18,560
GIRLS BEING SEXUALLY ACTIVE AND 

4822
03:47:18,560 --> 03:47:19,000
[INDISCERNIBLE]?  

4823
03:47:19,000 --> 03:47:21,360
>>YEAH.  UNLINKING IT TO
SOCIAL

4824
03:47:21,360 --> 03:47:25,480
STIGMA OF HPV IS A 

4825
03:47:25,480 --> 03:47:25,840
CONSIDERATION. 

4826
03:47:25,840 --> 03:47:28,440
I THINK THAT OUR -- FROM SURVEYS

4827
03:47:28,440 --> 03:47:31,760
THAT HAVE BEEN DONE, OUR GIRLS 

4828
03:47:31,760 --> 03:47:32,400
UNDERSTAND PROTECTION AGAINST 

4829
03:47:32,400 --> 03:47:35,240
ONE STI WHEN THERE IS A WHOLE 

4830
03:47:35,240 --> 03:47:36,360
HOST OF THEM STILL DOESN'T 

4831
03:47:36,360 --> 03:47:37,920
EFFECT BEHAVIOR.  YOU STILL HAVE

4832
03:47:37,920 --> 03:47:41,480
TO PROTECT YOURSELF AGAINST 

4833
03:47:41,480 --> 03:47:42,480
GONORRHEA AND CHLAMYDIA AND ALL 

4834
03:47:42,480 --> 03:47:45,800
OF THE OTHERS AND THEY DID A 

4835
03:47:45,800 --> 03:47:47,640
STUDY USING HARD ENDPOINT OF 

4836
03:47:47,640 --> 03:47:49,160
PREGNANCY AND SAID IF YOU HAVE 

4837
03:47:49,160 --> 03:47:51,960
HPV VACCINATION DID YOU HAVE 

4838
03:47:51,960 --> 03:47:53,360
HIGHER PREGNANCY BECAUSE YOU 

4839
03:47:53,360 --> 03:47:54,440
SUDDENLY WENT WILD?  

4840
03:47:54,440 --> 03:47:57,200
ANSWER IS NO.  IT WAS BALANCED. 

4841
03:47:57,200 --> 03:47:59,320
SO, THAT HAS BEEN BROUGHT UP 

4842
03:47:59,320 --> 03:48:01,120
OFTEN TIMES AND HASN'T BEEN BORN

4843
03:48:01,120 --> 03:48:05,480
OUT IN THE DATA. 

4844
03:48:05,480 --> 03:48:09,760
>>ANY DATA ON
[INDISCERNIBLE]. 

4845
03:48:09,760 --> 03:48:13,800
>>YEAH.  IT IS LICENSED
IN 

4846
03:48:13,800 --> 03:48:16,000
MALES FOR PREVENTION AND WAS 

4847
03:48:16,000 --> 03:48:17,560
ORIGINALLY LICENSED FOR 

4848
03:48:17,560 --> 03:48:21,120
PREVENTION OF ANAL CANCER WHERE 

4849
03:48:21,120 --> 03:48:22,760
STUDIES OBSERVED DIRECT EFFICACY

4850
03:48:22,760 --> 03:48:26,680
AND THEY SAW PROTECTION AGAINST 

4851
03:48:26,680 --> 03:48:29,480
COMPOSITE ENDPOINTS OF PEENILE 

4852
03:48:29,480 --> 03:48:33,360
HPV INFECTION AND RECENTLY ALSO 

4853
03:48:33,360 --> 03:48:34,840
HAD AN INDICATION AGAINST 

4854
03:48:34,840 --> 03:48:37,920
CANCERS CAUSED BY HPV IT THAT IS

4855
03:48:37,920 --> 03:48:41,160
FOR THREE DOSES IN THE UNITED 

4856
03:48:41,160 --> 03:48:44,160
STA

4857
03:48:44,160 --> 03:48:44,360
STATES. 

4858
03:48:44,360 --> 03:48:50,320
IN TERMS WHEN THE WHO MADE ONE 

4859
03:48:50,320 --> 03:48:51,080
DOSE RECOMMENDATION THEY THREW 

4860
03:48:51,080 --> 03:48:53,760
IN IN BOYS TOO.  25% OF THE 

4861
03:48:53,760 --> 03:48:57,360
WORLD DOES GENDER-NEUTRAL 

4862
03:48:57,360 --> 03:48:59,680
VACCINATION THAT HELPS A LOT AND

4863
03:48:59,680 --> 03:49:03,000
PEOPLE ARE SKEPTICAL OF 

4864
03:49:03,000 --> 03:49:04,160
GIRLS-ONLY VACCINATION GLOBALLY.

4865
03:49:04,160 --> 03:49:05,880
NOT IN THIS COUNTRY BUT PEOPLE 

4866
03:49:05,880 --> 03:49:08,120
QUESTION WHY ARE YOU JUST DOING 

4867
03:49:08,120 --> 03:49:10,120
MY GIRLS?  GENDER-NEUTRAL SEEMS 

4868
03:49:10,120 --> 03:49:11,960
TO HELP THERE.  WE ARE COMING 

4869
03:49:11,960 --> 03:49:14,720
OFF A VACCINE SHORTAGE THAT WAS 

4870
03:49:14,720 --> 03:49:16,720
PRETTY PROFOUND WHERE THERE JUST

4871
03:49:16,720 --> 03:49:19,240
WASN'T ENOUGH DOSES TO VACCINATE

4872
03:49:19,240 --> 03:49:21,520
THE GIRLS OF THE WORLD. 

4873
03:49:21,520 --> 03:49:25,120
SO, WHEN THAT HAPPENED AND THERE

4874
03:49:25,120 --> 03:49:30,120
WASN'T ENOUGH VACCINE WE ASKED 

4875
03:49:30,120 --> 03:49:31,880
COUNTRIES AND PUBLIC HEALTH 

4876
03:49:31,880 --> 03:49:33,280
PEOPLE TO CONSERVE THEIR DOSES 

4877
03:49:33,280 --> 03:49:37,120
FOR WOMEN.  FOR EXAMPLE, IN 

4878
03:49:37,120 --> 03:49:39,240
SUBIS A HARR AN AFRICA 

4879
03:49:39,240 --> 03:49:40,960
VACCINATING 100 LITTLE GIRLS YOU

4880
03:49:40,960 --> 03:49:43,840
WILL PREVENT ONE CASE OF 

4881
03:49:43,840 --> 03:49:45,000
CERVICAL CANCER BECAUSE 

4882
03:49:45,000 --> 03:49:46,960
INCIDENCE IN BIRTH IS SO HIGH 

4883
03:49:46,960 --> 03:49:48,440
AND UNITED STATES IF YOU 

4884
03:49:48,440 --> 03:49:50,880
VACCINATE 12 TO 16,000 LITTLE 

4885
03:49:50,880 --> 03:49:55,200
BOYS YOU WILL PREVENT 1 CASE OF 

4886
03:49:55,200 --> 03:49:57,360
ORO PHARYNX CANCER ROOM WITH 

4887
03:49:57,360 --> 03:49:59,640
STOCK PILE OF FIXED NUMBER OF 

4888
03:49:59,640 --> 03:50:02,120
DOSES USE METRICS NUMBERS NEEDED

4889
03:50:02,120 --> 03:50:05,040
TO PREVENT ONE CANCER TO HAVE 

4890
03:50:05,040 --> 03:50:06,680
DECISION MAKING AND WE ARE 

4891
03:50:06,680 --> 03:50:08,080
COMING OFF THE SHORTAGE RIGHT 

4892
03:50:08,080 --> 03:50:09,760
NOW AND ARE ACTUALLY FLIPPING.  

4893
03:50:09,760 --> 03:50:12,080
THAT WAS AN UNHEALTHY MARKET.  

4894
03:50:12,080 --> 03:50:13,720
WE DIDN'T HAVE ENOUGH AND 

4895
03:50:13,720 --> 03:50:15,240
DEVELOPING COUNTRY MANUFACTURERS

4896
03:50:15,240 --> 03:50:17,280
IN CHINA ARE COMING FORWARD WITH

4897
03:50:17,280 --> 03:50:21,600
TWO HPV VACCINES AND SERUM 

4898
03:50:21,600 --> 03:50:22,520
INSTITUTE IS COMING OUT WITH 

4899
03:50:22,520 --> 03:50:23,960
THEIRS AS WELL AND THEY CAN MAKE

4900
03:50:23,960 --> 03:50:26,600
LOTS OF DOSES AND WE WILL FLIP 

4901
03:50:26,600 --> 03:50:29,040
AND TOWARDS END OF DECADES WE 

4902
03:50:29,040 --> 03:50:30,880
WILL HAVE TREMENDOUS SURPLUS OF 

4903
03:50:30,880 --> 03:50:33,520
DOSES AND WE WILL SEE VERY 

4904
03:50:33,520 --> 03:50:35,720
QUICKLY ONE DOSE OR 

4905
03:50:35,720 --> 03:50:38,800
GENDER-NEUTRAL KIND OF THE WORLD

4906
03:50:38,800 --> 03:50:40,760
AROUND AND ALSO UP AN AGE RANGE 

4907
03:50:40,760 --> 03:50:42,920
AND WILL TELL YOU ONE VIGNETTE 

4908
03:50:42,920 --> 03:50:46,440
ABOUT COUNTRY-LEVEL DECISION 

4909
03:50:46,440 --> 03:50:48,520
MAKING.  I'M VERY CLOSE TO COSTA

4910
03:50:48,520 --> 03:50:50,080
RICA AND IN MODELING AGAIN WHEN 

4911
03:50:50,080 --> 03:50:56,000
YOU TRY TO SAY WE HAVE EXTRA 

4912
03:50:56,000 --> 03:50:57,400
DOSES COSTA RICA HAD EXTRA DOSES

4913
03:50:57,400 --> 03:50:59,760
-- GOING UP THE AGE RANGE WE 

4914
03:50:59,760 --> 03:51:01,120
WILL BRING MORE CANCER 

4915
03:51:01,120 --> 03:51:05,960
PREVENTION THAN DOING BOYS COSTA

4916
03:51:05,960 --> 03:51:08,480
RICA HAS ALWAYS DONE THEY DID 

4917
03:51:08,480 --> 03:51:09,760
VACCINATION FOR A COUPLE YEARS 

4918
03:51:09,760 --> 03:51:12,080
THAT IS GIRLS ONLY AGE 10 IN 

4919
03:51:12,080 --> 03:51:13,840
SCHOOLS AND COSTA RICA SAID 

4920
03:51:13,840 --> 03:51:16,360
THANK YOU.  WE SEE THE DATA AND 

4921
03:51:16,360 --> 03:51:18,200
EASIER WHEN SEEING GIRLS AGE 10 

4922
03:51:18,200 --> 03:51:20,680
TO DO JUST THE BOYS AND EVEN 

4923
03:51:20,680 --> 03:51:22,320
THOUGH PUBLIC HEALTH YIELD IS 

4924
03:51:22,320 --> 03:51:25,000
HIGHER DOING GIRLS AND BOYS OR 

4925
03:51:25,000 --> 03:51:26,760
DOING GIRLS AT AGE RANGE BECAUSE

4926
03:51:26,760 --> 03:51:29,000
OF FEASIBILITY OF DOING JUST 

4927
03:51:29,000 --> 03:51:31,000
GIRLS WE WILL DO OR GIRLS AND 

4928
03:51:31,000 --> 03:51:33,280
BOYS WE WILL DO THAT AND IS 

4929
03:51:33,280 --> 03:51:36,560
INTERESTING THERE IS 

4930
03:51:36,560 --> 03:51:38,280
EVIDENCE-BASED PART AND 

4931
03:51:38,280 --> 03:51:38,600
FEASIBILITY. 

4932
03:51:38,600 --> 03:51:42,120
>>MOST GIRLS GET HPV FROM
BOYS 

4933
03:51:42,120 --> 03:51:43,040
SO [INDISCERNIBLE] TRANSMISSION 

4934
03:51:43,040 --> 03:51:47,440
FROM VACCINATED OR UNVACCINATED 

4935
03:51:47,440 --> 03:51:50,480
BOYS TOO TO GIRLS. 

4936
03:51:50,480 --> 03:51:52,760
>>IF GIRLS HAVE
ANTIBODIES AND 

4937
03:51:52,760 --> 03:51:55,120
THEY WORK TO NEUTRALIZE 

4938
03:51:55,120 --> 03:51:57,280
INFECTION ALMOST 100% IT IS 

4939
03:51:57,280 --> 03:51:57,920
DIRECT PROTECTION. 

4940
03:51:57,920 --> 03:52:01,680
>>I UNDERSTAND.  I GUESS
WHAT 

4941
03:52:01,680 --> 03:52:04,760
I'M SAYING IS FEEN LOGICALLY IF 

4942
03:52:04,760 --> 03:52:06,840
YOU HAVE UNVACCINATED GIRLS AND 

4943
03:52:06,840 --> 03:52:08,320
UNVACCINATED BOYS THERE WILL BE 

4944
03:52:08,320 --> 03:52:10,000
SOME PROTECTION FOR GIRLS TOO?  

4945
03:52:10,000 --> 03:52:12,320
>>YEAH.  SO, IT THIS
VACCINE I 

4946
03:52:12,320 --> 03:52:14,880
TOOK IT OUT.  SORRY I CAN'T SHOW

4947
03:52:14,880 --> 03:52:17,520
YOU.  THIS VACCINE INDUCES MORE 

4948
03:52:17,520 --> 03:52:19,040
HERD IMMUNITY THAN EXPECTED IN 

4949
03:52:19,040 --> 03:52:22,480
THE US.  WHAT WE HAVE SEEN, 

4950
03:52:22,480 --> 03:52:25,560
AGAIN, IN GIRLS BUT IT WORKS TO 

4951
03:52:25,560 --> 03:52:28,360
BOYS TOO.  ONCE YOU IMPLEMENT 

4952
03:52:28,360 --> 03:52:30,160
HPV VACCINATION AND THEY 

4953
03:52:30,160 --> 03:52:31,920
IMPLEMENTED IN AUSTRALIA WITH 

4954
03:52:31,920 --> 03:52:34,240
VERY HIGH UPTAKE AND WITHIN A 

4955
03:52:34,240 --> 03:52:37,280
HANDFULL OF YEARS BEFORE THERE 

4956
03:52:37,280 --> 03:52:38,760
WAS A MALE VACCINATION THERE 

4957
03:52:38,760 --> 03:52:41,200
JUST WASN'T 16 AND 18 OR A POOL 

4958
03:52:41,200 --> 03:52:44,200
FOR IT TO BE IN.  IN US WE HAD 

4959
03:52:44,200 --> 03:52:47,120
60 OR 65% UPTAKE OR A COUPLE 

4960
03:52:47,120 --> 03:52:50,600
YEARS AGO WE STILL SEE 

4961
03:52:50,600 --> 03:52:52,360
TREMENDOUS AMOUNTS OF HERD 

4962
03:52:52,360 --> 03:52:54,480
IMMUNITY.  SO, BOYS GET 

4963
03:52:54,480 --> 03:52:56,200
PROTECTED AND IN FACT MODELING 

4964
03:52:56,200 --> 03:52:58,560
SHOWS IF UPTAKE IS HIGH IN GIRLS

4965
03:52:58,560 --> 03:53:00,600
BOYS WILL ALL GET PROTECTED 

4966
03:53:00,600 --> 03:53:02,160
EXCEPT FOR MEN WHO HAVE SEX WITH

4967
03:53:02,160 --> 03:53:04,160
MEN AND POCKETS OF THOSE AND 

4968
03:53:04,160 --> 03:53:09,160
THINKING OF, YOU KNOW, THERE -- 

4969
03:53:09,160 --> 03:53:12,000
TO ME I THINK ABOUT WE HAVE TO 

4970
03:53:12,000 --> 03:53:15,680
GET TO SUBIS A HARR AN AFRICA 

4971
03:53:15,680 --> 03:53:18,920
AND BURDEN IS ENORMOUS AND 

4972
03:53:18,920 --> 03:53:20,400
POCKETS ALSO WITH VERY HIGH 

4973
03:53:20,400 --> 03:53:24,600
RATES OF HPV-ASSOCIATED CANCERS 

4974
03:53:24,600 --> 03:53:26,480
GETTING THEM VACCINATED AS WELL 

4975
03:53:26,480 --> 03:53:28,160
IS ALSO IMPORTANT.  YES?  

4976
03:53:28,160 --> 03:53:33,280
>>HAVING ONE DOSE VACCINE
GETS 

4977
03:53:33,280 --> 03:53:34,160
MORE EFFICACIOUS AND DOES IT 

4978
03:53:34,160 --> 03:53:36,240
MAKE SENSE TO DO THAT IN 

4979
03:53:36,240 --> 03:53:39,960
COUNTRIES WHERE HIV IS MORE 

4980
03:53:39,960 --> 03:53:41,920
PREVALENT AND SUGGESTED IN 

4981
03:53:41,920 --> 03:53:43,480
RESPONSE EVEN WITH THREE DOSES 

4982
03:53:43,480 --> 03:53:45,320
AND IS NOT THAT GOOD?  

4983
03:53:45,320 --> 03:53:47,800
>>YUP.  SO, RIGHT.  SO,
JUST TO

4984
03:53:47,800 --> 03:53:50,120
BE CLEAR, WHEN WE ARE DOING ONE 

4985
03:53:50,120 --> 03:53:52,840
DOSE, IT IS JUST ONE DOSE OF THE

4986
03:53:52,840 --> 03:53:54,800
EXACT SAME VACCINE NOT DIFFERENT

4987
03:53:54,800 --> 03:53:57,320
FILE OR MORE ANTIGEN.  IT IS THE

4988
03:53:57,320 --> 03:53:59,280
EXACT SAME.  SO, I THINK THAT IF

4989
03:53:59,280 --> 03:54:01,200
YOU HAVE A WOMAN OR SOMEONE IS 

4990
03:54:01,200 --> 03:54:04,600
IN A CLINIC AND WOMAN HAS HIV 

4991
03:54:04,600 --> 03:54:05,920
DIAGNOSIS STANDING IN FRONT OF 

4992
03:54:05,920 --> 03:54:08,320
YOU YOU WILL CONTINUE TO DO 

4993
03:54:08,320 --> 03:54:10,280
MULTIPLE DOSES FOREVER AND 

4994
03:54:10,280 --> 03:54:12,280
BIGGER RESEARCH QUESTION OR 

4995
03:54:12,280 --> 03:54:15,320
PUBLIC HEALTH QUESTION -- 10, 

4996
03:54:15,320 --> 03:54:18,200
11, OR 12 GIRLS WHO AT AGE OF 18

4997
03:54:18,200 --> 03:54:20,720
ACQUIRE HIV YOU KNOW THEY ARE 

4998
03:54:20,720 --> 03:54:22,120
ALREADY PART OF A GLOBAL PROGRAM

4999
03:54:22,120 --> 03:54:23,640
AND DO YOU NEED TO GIVE THEM 

5000
03:54:23,640 --> 03:54:25,000
ANOTHER DOSE OR DO YOU NEED TO 

5001
03:54:25,000 --> 03:54:27,480
-- YOU KNOW, IS THAT SECOND DOSE

5002
03:54:27,480 --> 03:54:30,360
6 TO 8 YEARS LATER A BOOSTER 

5003
03:54:30,360 --> 03:54:33,520
THAT WILL HELP?  YOU KNOW, THAT 

5004
03:54:33,520 --> 03:54:36,080
IS WHERE PEOPLE ARE LOOKING TO 

5005
03:54:36,080 --> 03:54:39,320
IMPLEMENT RESEARCH AT THIS 

5006
03:54:39,320 --> 03:54:39,520
POINT.  

5007
03:54:39,520 --> 03:54:39,920
>>THANK YOU. 

5008
03:54:39,920 --> 03:54:43,960
>>THANK YOU, EVERYONE. 
IT WAS 

5009
03:54:43,960 --> 03:54:54,200
FUN TALKING.  

5010
03:55:01,600 --> 03:55:07,600
>>HI.  I'M SIDDHARTHA. 
OUR 

5011
03:55:07,600 --> 03:55:13,440
NEXT SPEAKER IS KRISTA DELL 

5012
03:55:13,440 --> 03:55:15,320
VIKZ-FRANKENBERRY TALKING ABOUT 

5013
03:55:15,320 --> 03:55:20,480
POTENT DUAL BLOCK TO HIV-1 

5014
03:55:20,480 --> 03:55:24,840
INFECTION USING LENTI VIRAL 

5015
03:55:24,840 --> 03:55:32,400
VECTORS EXPRESSING VIF RESIST 

5016
03:55:32,400 --> 03:55:36,120
APOBEC3G AND FUSION INHIBITOR 

5017
03:55:36,120 --> 03:55:44,480
PEPTIDE MC46.  

5018
03:55:44,480 --> 03:55:48,200
>>ALL RIGHT.  TREATMENT
FOR HIV

5019
03:55:48,200 --> 03:55:50,960
INFECTION WITH POE TENT -- CAN 

5020
03:55:50,960 --> 03:55:52,880
CONTROL VIRAL REPLICATION 

5021
03:55:52,880 --> 03:55:54,560
DELAYING ONSET OF AIDS AND WE 

5022
03:55:54,560 --> 03:55:55,920
KNOW THIS TREATMENT IS LIFELONG 

5023
03:55:55,920 --> 03:55:58,560
AND ASSOCIATED WITH HIGH MEDICAL

5024
03:55:58,560 --> 03:56:00,600
COSTS DRUG TOXICITIES AND 

5025
03:56:00,600 --> 03:56:02,640
SIDE-EFFECTS LEADING TO LACK OF 

5026
03:56:02,640 --> 03:56:05,800
ADHERENCE IN PATIENTS.  THERAPY 

5027
03:56:05,800 --> 03:56:10,000
INTERRUPTION CAN LEAD TO 

5028
03:56:10,000 --> 03:56:10,640
EMERGENCE OF DRUG RESISTANCE 

5029
03:56:10,640 --> 03:56:14,800
VIRUS AND REKINDLE INFECTION IN 

5030
03:56:14,800 --> 03:56:16,200
CELLS AND ALTERNATIVE FUNCTIONAL

5031
03:56:16,200 --> 03:56:18,600
CARE STRATEGIES ARE NEEDED FOR 

5032
03:56:18,600 --> 03:56:20,360
PATIENTS THAT ARE THERAPIES 

5033
03:56:20,360 --> 03:56:27,800
DEFINED AS THOSE CONTROLLING 

5034
03:56:27,800 --> 03:56:33,000
PYREMIA MAYBE USING CRISPR CAS9 

5035
03:56:33,000 --> 03:56:35,000
TO HAVE A PROVIRUS AND FOR TALK 

5036
03:56:35,000 --> 03:56:37,560
TODAY WE WILL LOOK AT WAYS TO 

5037
03:56:37,560 --> 03:56:40,000
HARNESS ANTIVIRAL ACTIVITY OF 

5038
03:56:40,000 --> 03:56:42,240
VIRAL RESTRICTION FACTORS AND 

5039
03:56:42,240 --> 03:56:43,760
OVERALL PROJECT GOAL IS ASKING 

5040
03:56:43,760 --> 03:56:46,800
WHETHER WE CAN ENGINEER T CELLS 

5041
03:56:46,800 --> 03:56:53,840
OR HEMOPOE ATTIC -- TO BLOCK 

5042
03:56:53,840 --> 03:56:55,480
HIV-1 REP MRIKS. 

5043
03:56:55,480 --> 03:57:01,480
THIS IS AN OVERALL SCHEMATIC 

5044
03:57:01,480 --> 03:57:03,920
SYNTHESIZING LENGTHY VECTOR AND 

5045
03:57:03,920 --> 03:57:06,320
PRODUCE VIRUS IN EX-VIVO TRANCE 

5046
03:57:06,320 --> 03:57:09,000
DEUCE PATIENT T CELLS OR STEM 

5047
03:57:09,000 --> 03:57:11,200
CELLS AND CELLS CAN BE REINFUSED

5048
03:57:11,200 --> 03:57:12,600
BACK INTO THE PATIENT WHERE THEY

5049
03:57:12,600 --> 03:57:15,440
CAN BE SELECTED AND EXPANDED AND

5050
03:57:15,440 --> 03:57:18,360
DEPENDING ON HIPV1 FACTOR WE 

5051
03:57:18,360 --> 03:57:20,480
HAVE CHOSEN THAT CAN PROTECT THE

5052
03:57:20,480 --> 03:57:23,760
CELL FROM HIV EVER INFECTING OR 

5053
03:57:23,760 --> 03:57:28,360
POST ENTRY FACTOR TARGETING CELL

5054
03:57:28,360 --> 03:57:30,680
TO REPLICATION AND BEGAN STUDIES

5055
03:57:30,680 --> 03:57:34,520
USING HOST RESTRICTION FACTOR 

5056
03:57:34,520 --> 03:57:37,480
KNOWN AS -- THAT WILL 

5057
03:57:37,480 --> 03:57:41,000
HYPERMUTATE AND INACTIVATE HIV-1

5058
03:57:41,000 --> 03:57:44,200
PROVIRUS AND INCLUDED IN VECTOR 

5059
03:57:44,200 --> 03:57:46,080
SELECTABLE MARKER IN ANIMAL 

5060
03:57:46,080 --> 03:57:47,840
STUDIES AND TISSUE CULTURE 

5061
03:57:47,840 --> 03:57:49,560
STUDIES AS WELL WE CAN SELECT 

5062
03:57:49,560 --> 03:57:56,040
AND EXPAND CELLS CARRYING HIV 

5063
03:57:56,040 --> 03:58:02,720
ANTI-V1 GENE AND APOE VEX BOX 

5064
03:58:02,720 --> 03:58:06,640
HIV-1 INFECTION AND ABSENCE OF 

5065
03:58:06,640 --> 03:58:09,760
VIF PROTEIN AND UPON SUBSEQUENT 

5066
03:58:09,760 --> 03:58:12,360
INFECTION INTO TARGET CELL IN 

5067
03:58:12,360 --> 03:58:16,000
REVERSE TRANSCRIPTION INSIDE 

5068
03:58:16,000 --> 03:58:23,320
CAPSI

5069
03:58:23,320 --> 03:58:25,480
CAPSID  APOEB /* APOBEC -- 

5070
03:58:25,480 --> 03:58:29,120
HOWEVER HIV HAS EVOLVED TO 

5071
03:58:29,120 --> 03:58:32,280
COUNTERACT APOBEC RESTRICTION 

5072
03:58:32,280 --> 03:58:34,320
FACTOR EXPRESSING VIRALLY 

5073
03:58:34,320 --> 03:58:37,680
ENCODED VIF PROTEIN THAT WILL 

5074
03:58:37,680 --> 03:58:40,760
BIND TO APOBEC AND THEREFORE 

5075
03:58:40,760 --> 03:58:43,560
EXCLUDE IT FROM VIRION AND VIRUS

5076
03:58:43,560 --> 03:58:46,800
CAN CONTINUE ON LIFECYCLE.  

5077
03:58:46,800 --> 03:58:48,680
HARNESSING THIS ACTIVITY SOMEHOW

5078
03:58:48,680 --> 03:58:51,000
MAKING APOBEC ALWAYS 

5079
03:58:51,000 --> 03:58:54,440
INCORPORATED INTO VIRUS WOULD 

5080
03:58:54,440 --> 03:58:57,360
INACTIVATE IT SO WE COULD USE AS

5081
03:58:57,360 --> 03:59:02,040
POTENTIAL THERAPY.  

5082
03:59:02,040 --> 03:59:04,360
THAT IS EXPRESSING APOBEC GENE 

5083
03:59:04,360 --> 03:59:08,040
AND INADVERTENTLY SOME AMOUNT OF

5084
03:59:08,040 --> 03:59:09,920
PROTEIN EXPRESSED FROM THIS 

5085
03:59:09,920 --> 03:59:12,320
VECTOR MENTIONING BEFORE THAT 

5086
03:59:12,320 --> 03:59:15,120
APOBEC WANTS TO BE NICELY 

5087
03:59:15,120 --> 03:59:19,040
INCORPORATED INTO VIRION AND 

5088
03:59:19,040 --> 03:59:21,960
VIRUS WILL CARRY THIS AND ALSO 

5089
03:59:21,960 --> 03:59:23,880
THIS HYPERMUTATION OR WE ARE 

5090
03:59:23,880 --> 03:59:26,160
ACTUALLY INACTIVATING A GENE WE 

5091
03:59:26,160 --> 03:59:28,560
WANT TO DELIVER AND NEED A WAY 

5092
03:59:28,560 --> 03:59:31,640
TO HAVE APOBEC3G IN HELPER CELL 

5093
03:59:31,640 --> 03:59:34,000
LINE IN INACTIVE FORM AND WHEN 

5094
03:59:34,000 --> 03:59:35,480
WE DELIVER TO TARGET CELL WE 

5095
03:59:35,480 --> 03:59:38,840
WOULD LIKE TO HAVE IT FULLY 

5096
03:59:38,840 --> 03:59:39,640
FUNCTIONING. 

5097
03:59:39,640 --> 03:59:41,280
TO DO THAT OUR LAB FOR A NUMBER 

5098
03:59:41,280 --> 03:59:43,720
OF YEARS STUDIED USING DIRECT 

5099
03:59:43,720 --> 03:59:45,960
REPEATS TO ACCOMPLISH THIS THAT 

5100
03:59:45,960 --> 03:59:49,680
IS A QUICK EXAMPLE USING GFP AND

5101
03:59:49,680 --> 03:59:51,960
WE CAN DUPLICATE INTERNAL 

5102
03:59:51,960 --> 03:59:54,320
PORTION OF ANY GENE OF CHOICE.  

5103
03:59:54,320 --> 03:59:57,360
WE HAVE GFFP JUST MAKING A 

5104
03:59:57,360 --> 03:59:59,080
DUPLICATION AND HELPER CELL LINE

5105
03:59:59,080 --> 04:00:00,520
IF WE HAVE ANY EXPRESSION FROM 

5106
04:00:00,520 --> 04:00:04,000
THE PROMOTER, THAT PROTEIN 

5107
04:00:04,000 --> 04:00:06,040
TRANSCRIBED AND TRANSLATED WOULD

5108
04:00:06,040 --> 04:00:08,880
BE NONGARBLE THE AND 

5109
04:00:08,880 --> 04:00:10,640
NON-FUNCTIONAL AND THIS VIRUS 

5110
04:00:10,640 --> 04:00:13,320
DELIVERING TO TARGET CELL DURING

5111
04:00:13,320 --> 04:00:14,440
REVERSE TRANSCRIPTION THAT 

5112
04:00:14,440 --> 04:00:16,200
DIRECT REPEAT IS DELETED ENDING 

5113
04:00:16,200 --> 04:00:20,120
UP WITH INTEGRATED PRO VIRUS IN 

5114
04:00:20,120 --> 04:00:22,320
TARGET CELL WITH FULLY 

5115
04:00:22,320 --> 04:00:24,800
FUNCTIONING GFP GENE AND WHAT WE

5116
04:00:24,800 --> 04:00:26,760
DID FOR APOBEC VECTORS AND IN 

5117
04:00:26,760 --> 04:00:29,160
THIS CASE WE CREATED A 

5118
04:00:29,160 --> 04:00:30,760
DUPLICATION IN INTERNAL PORTION 

5119
04:00:30,760 --> 04:00:33,880
OF THE GENE AND THIS CASE 900 

5120
04:00:33,880 --> 04:00:36,640
NUCLEOTIDES IN LENGTH AND A33G 

5121
04:00:36,640 --> 04:00:38,120
AND ANY TRANSCRIPTION OR 

5122
04:00:38,120 --> 04:00:41,080
TRANSLATION AND THAT PROTEIN IS 

5123
04:00:41,080 --> 04:00:44,120
NON-FUNCTIONAL AND VECTOR HAS 

5124
04:00:44,120 --> 04:00:47,160
P2A CLEAVAGE SITE AND THIS 

5125
04:00:47,160 --> 04:00:51,400
SELECTABLE MARKER TAGGED WITH 

5126
04:00:51,400 --> 04:00:55,000
GFP IN HELPER CELL AND VIRUS 

5127
04:00:55,000 --> 04:00:56,720
TARGET CELL -- TO DOUBLE 

5128
04:00:56,720 --> 04:00:58,680
STRANDED DNA DIRECT REPEAT IS 

5129
04:00:58,680 --> 04:01:01,000
DELETED WITH A FULLY FUNCTIONING

5130
04:01:01,000 --> 04:01:03,880
APOBEC IN TARGET CELLS THAT IS 

5131
04:01:03,880 --> 04:01:08,440
CLEAVED AWAY FROM GFP-TAGGED IS 

5132
04:01:08,440 --> 04:01:11,520
SELECTABLE MARKER AS NOTICED WE 

5133
04:01:11,520 --> 04:01:15,880
WON'T DELIVER WILD TYPE APOBEC 

5134
04:01:15,880 --> 04:01:18,680
TO TARGET CELLS -- SO, WE ARE 

5135
04:01:18,680 --> 04:01:21,040
USING POINT MUTANT NOTED AS 

5136
04:01:21,040 --> 04:01:24,320
THIS.  THIS IS KNOWN TO BE 

5137
04:01:24,320 --> 04:01:28,160
RESISTANT TO HIV-1 MEDIATED 

5138
04:01:28,160 --> 04:01:29,840
DEGRADATION.  THIS IS PROOF OF 

5139
04:01:29,840 --> 04:01:31,880
PRINCIPLE SHOWING DIRECT REPEATS

5140
04:01:31,880 --> 04:01:33,880
ARE DELETED WHEN WE SELECT FOR 

5141
04:01:33,880 --> 04:01:37,000
CELLS WITH MGMT SELECTION, WE 

5142
04:01:37,000 --> 04:01:40,040
CAN USE BASIC PCR ANALYSIS TO 

5143
04:01:40,040 --> 04:01:42,120
SHOW HERE THAT BOTTOM BAND WOULD

5144
04:01:42,120 --> 04:01:44,040
BE CORRECT SIZE IF DIRECT REPEAT

5145
04:01:44,040 --> 04:01:46,800
IS DELETED DON'T SEE UPPER BAND 

5146
04:01:46,800 --> 04:01:50,480
THAT IS INDICATIVE UNDELETED 

5147
04:01:50,480 --> 04:01:53,920
GENE WESTERN ANALYSIS NICE 

5148
04:01:53,920 --> 04:01:57,120
EXPRESSION OF THIS APOBEC3G GENE

5149
04:01:57,120 --> 04:02:00,120
THAT IS EXCISED AND CLEAVED AWAY

5150
04:02:00,120 --> 04:02:01,720
FROM THE SELECTABLE PROTEIN AND 

5151
04:02:01,720 --> 04:02:04,840
WENT AHEAD MAKING T CELL LINES 

5152
04:02:04,840 --> 04:02:08,160
EXPRESSING VECTOR.  WE HAVE 

5153
04:02:08,160 --> 04:02:09,680
APOBEC WITH SELECTABLE MARKER 

5154
04:02:09,680 --> 04:02:12,360
AND CELL LINES WITHOUT APOBEC 

5155
04:02:12,360 --> 04:02:14,480
AND ORIGINAL PARENTAL CELL LINES

5156
04:02:14,480 --> 04:02:17,160
AND ASKED OVERTIME BY MEASURING 

5157
04:02:17,160 --> 04:02:20,240
P24 CAPSID DO WE SEE ANY VIRAL 

5158
04:02:20,240 --> 04:02:20,560
REPLICATION?  

5159
04:02:20,560 --> 04:02:24,480
THIS IS SHOWING CEM CELLS AS 

5160
04:02:24,480 --> 04:02:26,680
EXPECTED IN GRAY IS PARENTAL 

5161
04:02:26,680 --> 04:02:28,960
CELL LINE AND ORANGE IS JUST 

5162
04:02:28,960 --> 04:02:30,480
EXPRESSING SELECTABLE MARKER AND

5163
04:02:30,480 --> 04:02:32,840
THOSE CELLS WERE EASILY INFECTED

5164
04:02:32,840 --> 04:02:36,160
BY NL43 AND SEE CULTURES CRASH 

5165
04:02:36,160 --> 04:02:38,760
OVER TIME AND VECTORS AND CELL 

5166
04:02:38,760 --> 04:02:44,360
LINES EXPRESSING APOBEC3G D28K 

5167
04:02:44,360 --> 04:02:46,960
BLUE LINE BELOW AFTER 41 DAYS IN

5168
04:02:46,960 --> 04:02:49,040
CULTURE WE SEE NO EVIDENCE FOR 

5169
04:02:49,040 --> 04:02:50,640
VIRAL REPLICATION AND TRUE FOR 

5170
04:02:50,640 --> 04:02:55,200
OTHER CELL LINES AND T LINES 

5171
04:02:55,200 --> 04:02:58,360
BLUE LINE ON BOTTOM 45 DAYS POST

5172
04:02:58,360 --> 04:03:01,920
INFECTION WE SEE NO EVIDENCE OF 

5173
04:03:01,920 --> 04:03:02,920
VIRAL REPLICATION. 

5174
04:03:02,920 --> 04:03:06,480
IT IS A POTENT INHIBITOR OF 

5175
04:03:06,480 --> 04:03:08,600
HIV-1 REPLICATION.  WE DON'T 

5176
04:03:08,600 --> 04:03:10,520
ONLY WANT TO DELIVER ONE HOST 

5177
04:03:10,520 --> 04:03:13,480
RESTRICTION FACTOR AND WOULD 

5178
04:03:13,480 --> 04:03:15,080
LIKE TO IMPROVE THERAPY.  WE 

5179
04:03:15,080 --> 04:03:17,720
WILL DO A DUAL BLOCK AND ADD A 

5180
04:03:17,720 --> 04:03:23,560
SECOND VAKTOR TO INHIBIT THAT IS

5181
04:03:23,560 --> 04:03:25,520
ENTRY TO PEPTIDE INHIBITOR THAT 

5182
04:03:25,520 --> 04:03:29,920
IS MC46 WHICH PEPTIDES CAN BLOCK

5183
04:03:29,920 --> 04:03:31,760
H1C FUSION AND SHOWN HERE WE 

5184
04:03:31,760 --> 04:03:33,800
KNOW THAT HIV ENVELOPE WILL BIND

5185
04:03:33,800 --> 04:03:37,320
TO TARGET CELLS CD4 AND 

5186
04:03:37,320 --> 04:03:39,720
CORECEPTOR WITH REARRANGEMENTS 

5187
04:03:39,720 --> 04:03:43,800
AND GP41 WILL EXPOSE EDGE AND 

5188
04:03:43,800 --> 04:03:46,800
TRIMERIC PEPTIDES AND THESE WILL

5189
04:03:46,800 --> 04:03:50,080
COME TOGETHER TO FORM OR ALLOW 

5190
04:03:50,080 --> 04:03:52,280
FOR FUSION.  WE CAN EXPRESS 

5191
04:03:52,280 --> 04:03:54,440
EXOGENOUS LITTLE C PEPTIDES THAT

5192
04:03:54,440 --> 04:03:56,640
COMBINE TO N TRIEM ERIC PEPTIDE 

5193
04:03:56,640 --> 04:03:59,320
AND BASICALLY BLOCK THIS 

5194
04:03:59,320 --> 04:04:01,680
REACTION.  THESE C PEPTIDES HAVE

5195
04:04:01,680 --> 04:04:03,280
BEEN STUDIED WITH DIFFERENT 

5196
04:04:03,280 --> 04:04:06,040
LINKS AND POSITIONS AND CAN BE 

5197
04:04:06,040 --> 04:04:08,240
DELIVERED EXOGENOUSLY AND ALSO 

5198
04:04:08,240 --> 04:04:10,920
THEY CAN BE MEMBRANE-BOUND AND 

5199
04:04:10,920 --> 04:04:12,200
EXPRESSED ON OUTSIDE OF YOUR 

5200
04:04:12,200 --> 04:04:16,680
TARGET CELL AND WE WILL USE THIS

5201
04:04:16,680 --> 04:04:19,760
C46 FOR THIS PURPOSE.  WE WENT 

5202
04:04:19,760 --> 04:04:22,200
AHEAD AND EMODIFIED VECTORS TO 

5203
04:04:22,200 --> 04:04:26,960
CARRY MC46 ALONE OR CARRY D128K 

5204
04:04:26,960 --> 04:04:30,120
AND P2A CLEAVAGE WE HAVE 

5205
04:04:30,120 --> 04:04:32,640
SELECTABLE MARKER ADDING A 

5206
04:04:32,640 --> 04:04:35,280
SECOND CLEAVABLE SELF-CLEAVING 

5207
04:04:35,280 --> 04:04:37,480
PEPTIDE TO EXPRESS MC46 AND 

5208
04:04:37,480 --> 04:04:42,320
CELLS WILL HAVE A DUAL BLOCK FOR

5209
04:04:42,320 --> 04:04:46,600
HIV-1 WE LOOKED HOW EFFICIENT 

5210
04:04:46,600 --> 04:04:50,240
NEW SYSTEM WAS AND MT4 CELLS 

5211
04:04:50,240 --> 04:04:53,360
PARENTAL CELLS NICELY EFFECTED 

5212
04:04:53,360 --> 04:04:56,000
WITH THESE AND CULTURES CRASH 

5213
04:04:56,000 --> 04:04:59,960
AND CELLS RED LINE EXPRESSING 

5214
04:04:59,960 --> 04:05:02,000
MC46 THAT BLOCKS ENTRY AND WE 

5215
04:05:02,000 --> 04:05:04,240
SEE NICE PROTECTION A MONTH OR 

5216
04:05:04,240 --> 04:05:06,680
MONTH AND A HALF LATER THERE IS 

5217
04:05:06,680 --> 04:05:09,160
A BLIPPO VIRUS WE SEE COMING UP 

5218
04:05:09,160 --> 04:05:11,920
THAT IS NOT SUPPORTED HAVING 

5219
04:05:11,920 --> 04:05:14,680
BOTH MC46 AND THIS, THE BLUE 

5220
04:05:14,680 --> 04:05:17,600
LINE, AGAIN, 45 DAYS POST 

5221
04:05:17,600 --> 04:05:19,160
INFECTION WE SEE STILL NO 

5222
04:05:19,160 --> 04:05:21,160
EVIDENCE OF VIRAL REPLICATION.  

5223
04:05:21,160 --> 04:05:22,600
THIS IS SHOWING THE EXPRESSION 

5224
04:05:22,600 --> 04:05:29,920
OF MC46 ON MEMBRANE-BOUND CELLS.

5225
04:05:29,920 --> 04:05:33,240
WE LOOKED AT OTHER T CELLS AND 

5226
04:05:33,240 --> 04:05:35,240
PARENTAL CELLS NICELY INFECTED 

5227
04:05:35,240 --> 04:05:36,760
AND WE SEE THESE CELLS IT THAT 

5228
04:05:36,760 --> 04:05:39,880
WERE ONLY EXPRESSING MC46 AND 

5229
04:05:39,880 --> 04:05:41,680
SEE ONE FLASK WHERE YOU GET A 

5230
04:05:41,680 --> 04:05:43,400
LITTLE OF THE SCAPE VIRUS AND 

5231
04:05:43,400 --> 04:05:46,040
AGAIN HAVING BOTH GENES PRESENT 

5232
04:05:46,040 --> 04:05:49,120
MC46 AND D128K WE DON'T SEE ANY 

5233
04:05:49,120 --> 04:05:51,560
REPLICATION AND FOR CEMS AGAIN 

5234
04:05:51,560 --> 04:05:53,240
PARENTALS ARE INFECTED AND IN 

5235
04:05:53,240 --> 04:05:55,720
THIS CASE WE SAW THREE OUT OF 6 

5236
04:05:55,720 --> 04:06:00,360
FLASKS WE HAD ESCAPED VIRUS AND 

5237
04:06:00,360 --> 04:06:04,200
AGAIN HAVING BOTH DUAL BLOCHL 

5238
04:06:04,200 --> 04:06:06,000
AND NO EVIDENCE FOR VIRAL 

5239
04:06:06,000 --> 04:06:07,560
REPLICATION.  ALL RIGHT.  WHY IS

5240
04:06:07,560 --> 04:06:08,960
IT IMPORTANT TO HAVE BOTH 

5241
04:06:08,960 --> 04:06:10,320
FACTORS PRESENT?  

5242
04:06:10,320 --> 04:06:13,680
SO, AGAIN, IN A NORMAL WILD TYPE

5243
04:06:13,680 --> 04:06:16,080
INFECTION HIV WON'T INFECT THE 

5244
04:06:16,080 --> 04:06:17,880
TARGET CELL AND PRODUCTIVE VIRUS

5245
04:06:17,880 --> 04:06:20,200
BEING RELEASED THAT IN TERN WILL

5246
04:06:20,200 --> 04:06:22,880
LEAD TO CELL DEATH.  IF WE ONLY 

5247
04:06:22,880 --> 04:06:25,600
INCLUDE HAVING D128K PRESENT 

5248
04:06:25,600 --> 04:06:27,760
THOSE CELLS CAN STILL BE 

5249
04:06:27,760 --> 04:06:30,760
INFECTED BY HIV-1 AND VIRUS 

5250
04:06:30,760 --> 04:06:38,000
COMING OUT WILL CARRY APOBEC -- 

5251
04:06:38,000 --> 04:06:41,360
WE WOULD HAVE TO REPLENISH 

5252
04:06:41,360 --> 04:06:43,040
GENETICALLY MODIFIED CELLS IF IT

5253
04:06:43,040 --> 04:06:45,560
WAS TO LEAD TO THAT THERAPY.  BY

5254
04:06:45,560 --> 04:06:49,080
ADDING MC46 PEPTIDE FUSION 

5255
04:06:49,080 --> 04:06:50,600
INHIBITOR, NOW CELLS ARE 

5256
04:06:50,600 --> 04:06:55,360
INITIALLY BLOCKED BY HIV-1 

5257
04:06:55,360 --> 04:06:55,680
INFECTION. 

5258
04:06:55,680 --> 04:06:57,640
IF WE HAVE ANY ESCAPE VIRUS 

5259
04:06:57,640 --> 04:07:00,560
GETTING THROUGH OR PASSED MC46 

5260
04:07:00,560 --> 04:07:02,560
BLOCK WE HAVE A BACKUP AND 

5261
04:07:02,560 --> 04:07:06,120
SECOND LINE OF DEFENSE AND 

5262
04:07:06,120 --> 04:07:08,360
APOBEC IS THERE READY TO BE 

5263
04:07:08,360 --> 04:07:10,400
INCORPORATED INTO THE VIRUS AND 

5264
04:07:10,400 --> 04:07:11,640
ACTIVATED ON SECOND ROUND OF 

5265
04:07:11,640 --> 04:07:13,520
INFECTION AND THAT WAY TO 

5266
04:07:13,520 --> 04:07:16,280
MAINTAIN LONGER CELLS FOR THESE 

5267
04:07:16,280 --> 04:07:17,720
GENETICALLY MODIFIED CELLS AND 

5268
04:07:17,720 --> 04:07:19,760
SHOWING THIS EXPERIMENTALLY AND 

5269
04:07:19,760 --> 04:07:21,760
IN TISSUE CULTURE WE WILL TAKE 

5270
04:07:21,760 --> 04:07:24,040
AND DO A MIXING EXPERIMENT 

5271
04:07:24,040 --> 04:07:27,760
MIXING 95% PARENTAL CEM CELLS 

5272
04:07:27,760 --> 04:07:30,720
WITH 5% EXPRESSING D128K ALONE 

5273
04:07:30,720 --> 04:07:35,680
OR D128K PLUS MC46 PEPTIDE 

5274
04:07:35,680 --> 04:07:39,120
INHIBITOR AND MONITOR OVER TIME 

5275
04:07:39,120 --> 04:07:45,160
POST NL4-3 INFECTION.  FOR TIME,

5276
04:07:45,160 --> 04:07:49,040
TLEEZ BLUE LINES HERE ARE 

5277
04:07:49,040 --> 04:07:52,840
PERCENT GFP AND 95% ARE PARENTAL

5278
04:07:52,840 --> 04:07:55,760
IMAGINE WITH NL4-3 INFECTION 

5279
04:07:55,760 --> 04:07:57,680
PARENTAL CELLS ARE KILLED AND 5%

5280
04:07:57,680 --> 04:07:59,960
ARE PROTECTED AND START TO GROW 

5281
04:07:59,960 --> 04:08:01,360
OUT IN CULTURE AND ARE 

5282
04:08:01,360 --> 04:08:03,920
MAINTAINED AND WE HAVE A 

5283
04:08:03,920 --> 04:08:05,360
PREFERENTIAL SURVIVAL OF CELLS 

5284
04:08:05,360 --> 04:08:09,600
WHEN THEY HAVE EXPRESSION OF 

5285
04:08:09,600 --> 04:08:12,960
MC46 AS WELL. 

5286
04:08:12,960 --> 04:08:15,920
IN CONCLUSION WE HAVE -- FOR 

5287
04:08:15,920 --> 04:08:22,600
EXPRESSION OF APOBEC3G D128K. 

5288
04:08:22,600 --> 04:08:25,120
WE HOPEFULLY CAN MOVE TO 

5289
04:08:25,120 --> 04:08:27,080
EXPERIMENTS IN MICE AND T CELLS 

5290
04:08:27,080 --> 04:08:29,560
TRANCE DEUCED WITH VECTORS 

5291
04:08:29,560 --> 04:08:31,920
EXPRESSING FUSION PEPTIDE 

5292
04:08:31,920 --> 04:08:37,920
INHIBITOR AND APOBEC3G D128K AND

5293
04:08:37,920 --> 04:08:40,120
PREVENTING ENTRY MORE 

5294
04:08:40,120 --> 04:08:43,360
IMPORTANTLY CONFERRED A 

5295
04:08:43,360 --> 04:08:45,480
SELECTIVE SURVIVAL ADVANTAGE AND

5296
04:08:45,480 --> 04:08:48,280
ACCUMULATION OF GENETICALLY 

5297
04:08:48,280 --> 04:08:50,360
MODIFIED CELLS AND DUAL BLOCK 

5298
04:08:50,360 --> 04:08:51,880
VECTORS SHOULD REDUCE 

5299
04:08:51,880 --> 04:08:55,840
PROBABILITY OF ESCAPE MUTANTS 

5300
04:08:55,840 --> 04:08:58,000
GAINING RESISTANCE AND HOPEFULLY

5301
04:08:58,000 --> 04:09:00,680
COULD PROVIDE NOVEL STRATEGY FOR

5302
04:09:00,680 --> 04:09:02,280
HIV-1 TREATMENT IN THE FUTURE 

5303
04:09:02,280 --> 04:09:07,280
AND WOULD LIKE TO THANK MENTOR 

5304
04:09:07,280 --> 04:09:08,920
AND MEMBERS OF THE LAB AND DR. 

5305
04:09:08,920 --> 04:09:10,960
WHO IS A CO-AUTHOR ON THE STUDY 

5306
04:09:10,960 --> 04:09:13,320
AND LAB MEMBERS IN HER LAB FOR 

5307
04:09:13,320 --> 04:09:16,560
HELPFUL SUGGESTIONS AND BRUCE 

5308
04:09:16,560 --> 04:09:18,320
AND KIP HERMAN FROM UNIVERSITY 

5309
04:09:18,320 --> 04:09:20,880
OF WASHINGTON WHO WILL HOPEFULLY

5310
04:09:20,880 --> 04:09:23,000
CONTINUE WITH MOUSE STUDIES TO 

5311
04:09:23,000 --> 04:09:26,040
VERIFY OUR FINDINGS. 

5312
04:09:26,040 --> 04:09:35,360
THANK YOU. 

5313
04:09:35,360 --> 04:09:37,480
>>THAT WAS A REALLY GOOD
TALK. 

5314
04:09:37,480 --> 04:09:41,120
VERY INTERESTING.  TRYING TO 

5315
04:09:41,120 --> 04:09:44,280
THINK THERAPIWISE, WOULD IT BE 

5316
04:09:44,280 --> 04:09:47,880
POSSIBLE IF CELLS WERE 

5317
04:09:47,880 --> 04:09:50,560
EXPRESSING MUTANT APOBEC ALL THE

5318
04:09:50,560 --> 04:09:54,080
TIME AND THAT WOULD ELIMINATE?  

5319
04:09:54,080 --> 04:09:56,600
OBVIOUSLY, IT COULD PREVENT HIV 

5320
04:09:56,600 --> 04:09:58,080
INFECTION AND PEOPLE THAT ARE 

5321
04:09:58,080 --> 04:10:00,920
HIV INFECTED WOULD IT ELIMINATE 

5322
04:10:00,920 --> 04:10:03,920
REPLICATION OR BE SOMETHING LIKE

5323
04:10:03,920 --> 04:10:07,760
CRISPR CAS SYSTEM WITH MUTANT 

5324
04:10:07,760 --> 04:10:10,120
APOBEC BE EXPRESSED ALL THE TIME

5325
04:10:10,120 --> 04:10:12,320
OR SOME BAD REASON FOR WHY YOU 

5326
04:10:12,320 --> 04:10:14,280
DON'T WANT TO DO THAT. 

5327
04:10:14,280 --> 04:10:16,240
>>INITIAL STUDIES
FLIPPING IN 

5328
04:10:16,240 --> 04:10:18,600
PUTTING D128K AS A NATURAL 

5329
04:10:18,600 --> 04:10:23,680
MUTATION IN THE CELLS AND DON'T 

5330
04:10:23,680 --> 04:10:24,160
KNOW IF THEY WILL HAVE 

5331
04:10:24,160 --> 04:10:25,080
IMMUNOLOGICAL EFFECTS OR NOT AND

5332
04:10:25,080 --> 04:10:26,760
SOMETHING TO THINK OF PUTTING 

5333
04:10:26,760 --> 04:10:29,280
POINT MUTATION IN THERE HIV IF 

5334
04:10:29,280 --> 04:10:30,760
IT INFECTS IT WOULD BE -- 

5335
04:10:30,760 --> 04:10:33,200
>>ONE OTHER THING, IF YOU
MAKE 

5336
04:10:33,200 --> 04:10:35,720
VIRUSES THAT PUT IN THIS APOBEC,

5337
04:10:35,720 --> 04:10:38,040
IS -- ARE THEY INTEGRATING INTO 

5338
04:10:38,040 --> 04:10:40,120
THE GENOME IN THE CELLS AND 

5339
04:10:40,120 --> 04:10:40,560
EXPRESSING THE -- 

5340
04:10:40,560 --> 04:10:42,920
>>YES.  THEY ARE
INTEGRATING. 

5341
04:10:42,920 --> 04:10:45,680
>>JUST WANTED TO MAKE
SURE.  

5342
04:10:45,680 --> 04:10:48,320
THANK YOU.  

5343
04:10:48,320 --> 04:10:56,040
>>DO YOU HAVE
[INDISCERNIBLE]. 

5344
04:10:56,040 --> 04:10:57,880
>>INTERESTING.  RIGHT. 
IN THE 

5345
04:10:57,880 --> 04:11:00,240
LITERATURE THERE IS NO ESCAPE 

5346
04:11:00,240 --> 04:11:02,520
MUTANTS.  ONE PERSON DID A 200 

5347
04:11:02,520 --> 04:11:05,040
DAY TISSUE CULTURE EXPERIMENT 

5348
04:11:05,040 --> 04:11:08,680
AND GOT ONE MUTANT 10% RESISTANT

5349
04:11:08,680 --> 04:11:12,040
AND 5 MUTATIONS.  WE ARE EXCITED

5350
04:11:12,040 --> 04:11:14,680
OR NOT EXCITED TO SEE ESCAPE TO 

5351
04:11:14,680 --> 04:11:16,840
IDENTIFY NEW MUTATIONS BUT WENT 

5352
04:11:16,840 --> 04:11:19,080
BACK AND SEQUENCED THE VIRUS.  

5353
04:11:19,080 --> 04:11:20,480
THERE IS NOTHING THERE.  NOT 

5354
04:11:20,480 --> 04:11:21,920
LIKE EVERYBODY IN THE CULTURE 

5355
04:11:21,920 --> 04:11:23,840
HAD A MUTATION AT POSITION 

5356
04:11:23,840 --> 04:11:25,800
FIFTEEN THAT WE COULD ACCOUNT 

5357
04:11:25,800 --> 04:11:28,360
FOR IT WAS ALL SINGLETS AND NOW 

5358
04:11:28,360 --> 04:11:29,640
WE ARE UNSURE AND THINK IT MIGHT

5359
04:11:29,640 --> 04:11:33,400
BE DUE TO THE FACT THAT THE CELL

5360
04:11:33,400 --> 04:11:35,440
MIGHT HAVE LOST EXPRESSION OF 

5361
04:11:35,440 --> 04:11:38,160
MC46 THAT GOT TURNED OFF 

5362
04:11:38,160 --> 04:11:40,840
ALLOWING THE VIRUS. 

5363
04:11:40,840 --> 04:11:41,560
>>[INDISCERNIBLE]. 

5364
04:11:41,560 --> 04:11:44,720
>>WE WOULDN'T THINK SO
BUT WITH

5365
04:11:44,720 --> 04:11:48,640
CM CELLS WE GOT 3 OUT OF 6 

5366
04:11:48,640 --> 04:11:52,000
CULTURES BUT WE DON'T -- 

5367
04:11:52,000 --> 04:11:56,880
>>REPASSAGE THAT VIRUS --

5368
04:11:56,880 --> 04:11:58,520
>>RIGHT.  WE HAVEN'T DONE
THAT 

5369
04:11:58,520 --> 04:12:02,360
OR GONE BACK TO TAKE THAT VIRUS 

5370
04:12:02,360 --> 04:12:05,400
REPASSAGING IT BUT IS SOMETHING 

5371
04:12:05,400 --> 04:12:08,240
WE WOULD LIKE TO DO. 

5372
04:12:08,240 --> 04:12:11,000
>>OKAY. 

5373
04:12:11,000 --> 04:12:19,320
>>THANK YOU. 

5374
04:12:19,320 --> 04:12:29,880
>>WE WILL HAVE OUR NEXT
SPEAK 

5375
04:12:31,160 --> 04:12:41,800
JIK JUAN YIQUAN WU.  

5376
04:12:51,760 --> 04:12:52,680
THE STAGE IS YOURS. 

5377
04:12:52,680 --> 04:12:54,360
>>GOOD AFTERNOON,
EVERYONE.  I 

5378
04:12:54,360 --> 04:12:56,160
WOULD LIKE TO THANK THE 

5379
04:12:56,160 --> 04:12:57,280
ORGANIZER GIVING ME AN 

5380
04:12:57,280 --> 04:12:59,720
OPPORTUNITY TO PRESENT MY WORK 

5381
04:12:59,720 --> 04:13:06,040
HERE.  ALSO, OF COURSE, FOR YOUR

5382
04:13:06,040 --> 04:13:16,440
STAYING HERE. 

5383
04:13:16,440 --> 04:13:23,760
[INDISCERNIBLE] ONCHOGENIC 

5384
04:13:23,760 --> 04:13:27,960
HERPES VIRUS COULD CAUSE 

5385
04:13:27,960 --> 04:13:35,200
[INDISCERNIBLE] P MULTI KRCENTR 

5386
04:13:35,200 --> 04:13:37,640
DISEASE.  THAT IL PATHWAY IS 

5387
04:13:37,640 --> 04:13:40,960
ACTIVE IN THE CELLS AND VERY 

5388
04:13:40,960 --> 04:13:45,280
IMPORTANT FOR RELATED MCD 

5389
04:13:45,280 --> 04:13:52,000
CURRENTLY IT HAS TREATMENTS AND 

5390
04:13:52,000 --> 04:13:58,440
[INDISCERNIBLE] CONVENTIONAL 

5391
04:13:58,440 --> 04:14:09,120
ANTIVIRUS THERAPY AS WELL JACKS 

5392
04:14:17,560 --> 04:14:21,600
JAK INHIBITORS HAVE BEEN PROVEN 

5393
04:14:21,600 --> 04:14:24,440
TO BE SAFE.  EVERYTHING HAPPENED

5394
04:14:24,440 --> 04:14:28,560
UNDER CLINICAL TRIALS OR FOR 

5395
04:14:28,560 --> 04:14:31,000
TREATMENT OF ADVANCED 

5396
04:14:31,000 --> 04:14:33,240
[INDISCERNIBLE] AND PURPOSE HERE

5397
04:14:33,240 --> 04:14:36,040
IS TO EXPLORE WHETHER JAK 

5398
04:14:36,040 --> 04:14:38,120
INHIBITORS CAN SERVE AS MORE 

5399
04:14:38,120 --> 04:14:39,240
EFFECTIVE AND LESS TOXIC 

5400
04:14:39,240 --> 04:14:41,600
TREATMENT FOR CASE ASSOCIATED 

5401
04:14:41,600 --> 04:14:51,960
WITH MCD OR KICS.  

5402
04:15:02,120 --> 04:15:05,600
5NJAK INHIBITORS CLINICALLY 

5403
04:15:05,600 --> 04:15:07,320
APPROVED OR IN CLINIC STAGE 

5404
04:15:07,320 --> 04:15:10,640
PICKED AND WERE TESTED.  HERE, 

5405
04:15:10,640 --> 04:15:16,920
WE CHOOSE THREE POC9S AND 

5406
04:15:16,920 --> 04:15:18,200
[INDISCERNIBLE] DIFFERENT DOSES 

5407
04:15:18,200 --> 04:15:23,480
OF THOSE INHIBITORS AND TESTED 

5408
04:15:23,480 --> 04:15:25,560
ON THESE [INDISCERNIBLE] YOU CAN

5409
04:15:25,560 --> 04:15:27,960
SEE HERE COMPARED WITH OTHER 

5410
04:15:27,960 --> 04:15:32,400
FOUR INHIBITORS SHOWS VERY 

5411
04:15:32,400 --> 04:15:36,960
IMPORTANT INHIBITION OF THE CELL

5412
04:15:36,960 --> 04:15:39,800
GROWTH.  

5413
04:15:39,800 --> 04:15:44,360
WE FURTHER EVALUATE INHIBITION 

5414
04:15:44,360 --> 04:15:49,960
EFFECT USING FLOW SYMMETRY AND 

5415
04:15:49,960 --> 04:15:55,640
THOSE CELLS WERE TREATED WITH 

5416
04:15:55,640 --> 04:15:58,560
DIFFERENT DOSES AND APOPTOSIS 

5417
04:15:58,560 --> 04:16:01,080
AND THIS WAS EVALUATING USING 

5418
04:16:01,080 --> 04:16:08,240
FLOW SYMMETRY.  YOU CAN SEE HERE

5419
04:16:08,240 --> 04:16:18,680
IT CAN INDUCE APOPTOSIS. 

5420
04:16:21,200 --> 04:16:24,480
THOSE DATA ARE INTERESTING ON 

5421
04:16:24,480 --> 04:16:27,400
WHY THIS IS SO DIFFERENT IN 

5422
04:16:27,400 --> 04:16:31,320
GROSS INHIBITION AND WITH 

5423
04:16:31,320 --> 04:16:35,200
COMPARISON WITH OTHER INHIBITORS

5424
04:16:35,200 --> 04:16:39,200
AWAY FROM THAT AND IRAQ 1 AND 

5425
04:16:39,200 --> 04:16:44,360
[INDISCERNIBLE] K4 MIGHT BE THE 

5426
04:16:44,360 --> 04:16:54,920
PLAYER CHOOSING INHIBITORS AND 

5427
04:16:55,200 --> 04:16:57,920
[INDISCERNIBLE] TO TEST THEM ON 

5428
04:16:57,920 --> 04:16:58,680
A DIFFERENT [INDISCERNIBLE]. 

5429
04:16:58,680 --> 04:17:02,480
AS YOU CAN SEE HERE, ONLY THESE 

5430
04:17:02,480 --> 04:17:07,560
FLT3 INHIBITORS SHOW SIMILAR 

5431
04:17:07,560 --> 04:17:11,240
INHIBITORY EFFECT AND TO FURTHER

5432
04:17:11,240 --> 04:17:14,680
CONFIRM THAT, WHICH WE PICK 

5433
04:17:14,680 --> 04:17:17,240
SEVERAL MORE DIFFERENT AND OTHER

5434
04:17:17,240 --> 04:17:19,040
INHIBITORS AND TO COMPARE EFFECT

5435
04:17:19,040 --> 04:17:20,640
WITH [INDISCERNIBLE]. 

5436
04:17:20,640 --> 04:17:26,600
AS YOU CAN SEE, THOSE FT3 

5437
04:17:26,600 --> 04:17:37,160
INHIBITORS INHIBITED CELL GR

5438
04:17:39,960 --> 04:17:40,120
GROWTH. 

5439
04:17:40,120 --> 04:17:43,320
WE FURTHER EXPLORE THEM. 

5440
04:17:43,320 --> 04:17:46,840
EFFECT ON CELL GROWTH.  SO, WE 

5441
04:17:46,840 --> 04:17:50,120
USE THIS LOCKDOWN OF THIS AND ON

5442
04:17:50,120 --> 04:17:52,880
LEFT PANEL SHOWS THIS EXPRESSION

5443
04:17:52,880 --> 04:18:03,400
DATA AFTER IT KNOCKED DOWN.  

5444
04:18:04,360 --> 04:18:10,040
DATA SHOWS COMPARISON OF LT AND 

5445
04:18:10,040 --> 04:18:15,400
THIS EXPRESSING SIMILAR GABA DH 

5446
04:18:15,400 --> 04:18:16,920
SHOWING POSITIVE CONTROL OF 

5447
04:18:16,920 --> 04:18:18,440
LOCKDOWN AND I WILL JUST -- I 

5448
04:18:18,440 --> 04:18:20,880
DON'T KNOW WHAT HAPPENED IN THE 

5449
04:18:20,880 --> 04:18:21,360
POWERPOINT.  

5450
04:18:21,360 --> 04:18:25,440
ON THE RIGHT IT SHOWS THIS 

5451
04:18:25,440 --> 04:18:31,520
VARIABILITY OF THE CELLS AFTER 

5452
04:18:31,520 --> 04:18:35,080
KNOCKDOWN OF FLT3.  YOU SEE RATE

5453
04:18:35,080 --> 04:18:42,040
OF CELLS HERE AND ALSO THE 

5454
04:18:42,040 --> 04:18:46,120
[INDISCERNIBLE] ARE REDUCED 

5455
04:18:46,120 --> 04:18:49,760
AFTER SIRNA KNOCKDOWN.  HAVING A

5456
04:18:49,760 --> 04:18:54,000
GLOBAL OVERVIEW OF THE GENE 

5457
04:18:54,000 --> 04:18:56,920
EXPRESSION AFTER TREATMENT WE 

5458
04:18:56,920 --> 04:18:59,360
PERFORM [INDISCERNIBLE] OF THE 

5459
04:18:59,360 --> 04:19:00,760
CELLS TREATED WITH 

5460
04:19:00,760 --> 04:19:03,680
[INDISCERNIBLE] AND ON RIGHT 

5461
04:19:03,680 --> 04:19:11,040
PANEL SHOWS GENE EXPRESSION 

5462
04:19:11,040 --> 04:19:14,560
PROFILE AND ALSO PASS RATE 

5463
04:19:14,560 --> 04:19:16,360
ENRICHMENT OF THE REGULAR GENES 

5464
04:19:16,360 --> 04:19:22,280
AND ON RIGHT SHOWS DATA FOR THE 

5465
04:19:22,280 --> 04:19:28,440
BCBL-1 CELL.  YOU CAN SEE A LOT 

5466
04:19:28,440 --> 04:19:30,840
OF THEM ARE HERE FALLING TO A 

5467
04:19:30,840 --> 04:19:34,880
CELL CYCLE OR CELL PROLIFERATION

5468
04:19:34,880 --> 04:19:37,640
OR CELL DIVISION.  RELATED AND 

5469
04:19:37,640 --> 04:19:40,120
SO IT IS OVERLAPPED IN TWO 

5470
04:19:40,120 --> 04:19:42,840
GROUPS.  

5471
04:19:42,840 --> 04:19:51,840
SO, THAT IS THE INDICATION. 

5472
04:19:51,840 --> 04:19:58,400
ELATED TO CELL PROLIFERATION 

5473
04:19:58,400 --> 04:20:00,000
DOWNREGULATED BY 

5474
04:20:00,000 --> 04:20:02,160
[INDISCERNIBLE]. 

5475
04:20:02,160 --> 04:20:04,320
WE ARE INTERESTED IN WHETHER 

5476
04:20:04,320 --> 04:20:07,200
SOME GENES ARE CRUCIAL FOR CELLS

5477
04:20:07,200 --> 04:20:11,880
SURVIVAL IN DISREGULATED GENES 

5478
04:20:11,880 --> 04:20:17,320
BY THIS ON LEFT SHOWS THIS AND 

5479
04:20:17,320 --> 04:20:20,960
ON UPSIDE IS DOWN-REGULATED 

5480
04:20:20,960 --> 04:20:31,400
GENES OF THE TWO GROUPS -- 

5481
04:20:35,800 --> 04:20:43,520
GROUPS WITH THIS [INDISCERNIBLE]

5482
04:20:43,520 --> 04:20:50,640
AND WE COMBINE IT WITH CRISPR 

5483
04:20:50,640 --> 04:20:53,920
[INDISCERNIBLE] THAT WAS 

5484
04:20:53,920 --> 04:20:57,920
PUBLISHED BEFORE.  SO, WE TRIED 

5485
04:20:57,920 --> 04:20:59,920
TO FIND OVERLAP GENES THAT CAME 

5486
04:20:59,920 --> 04:21:07,200
OUT WITH CERTAIN GENES THAT ARE 

5487
04:21:07,200 --> 04:21:10,720
PEL-SPECIFIC DEPENDENT GENES. 

5488
04:21:10,720 --> 04:21:14,440
IT SHOWS A RANK AND FULL CHANGE 

5489
04:21:14,440 --> 04:21:18,120
FOR OUR DATA.  SO, THOSE GENES 

5490
04:21:18,120 --> 04:21:20,920
ARE FURTHER TARGETED AND WE 

5491
04:21:20,920 --> 04:21:24,200
WOULD LIKE TO FURTHER EXPLORE 

5492
04:21:24,200 --> 04:21:26,600
AND BESIDES HOST GENES WE WOULD 

5493
04:21:26,600 --> 04:21:29,160
LIKE TO CHECK THESE GENES WITH 

5494
04:21:29,160 --> 04:21:31,760
RESPONSE TO THE TREATMENT AND 

5495
04:21:31,760 --> 04:21:37,080
THIS LEFT PANEL SHOWS DATA OF 

5496
04:21:37,080 --> 04:21:38,000
ACCOUNTS FOR [INDISCERNIBLE] 

5497
04:21:38,000 --> 04:21:41,080
GENES AND HERE SEX GENES ARE 

5498
04:21:41,080 --> 04:21:45,480
RELATIVELY MORE ABANDONED.  

5499
04:21:45,480 --> 04:21:52,280
AS YOU CAN SEE ON VIRAL RL6 AND 

5500
04:21:52,280 --> 04:21:56,360
[INDISCERNIBLE] IS NOT MUCH 

5501
04:21:56,360 --> 04:22:01,400
EFFECTED AND THIS IS K2 HERE AND

5502
04:22:01,400 --> 04:22:05,040
SLIGHTLY DECREASED AND OTHER 

5503
04:22:05,040 --> 04:22:08,400
THREE GENES ARE DOMINANT AND 

5504
04:22:08,400 --> 04:22:12,880
SIGNIFICANT AND KPCR ON RIGHT 

5505
04:22:12,880 --> 04:22:15,680
FURTHER INFORMATION WITH DATA 

5506
04:22:15,680 --> 04:22:19,560
USING SAME EXPERIMENT SUBMITTED 

5507
04:22:19,560 --> 04:22:23,920
FOR RSEC THAT IS REFLECTED SAME 

5508
04:22:23,920 --> 04:22:29,120
AS RESULTS IN RSEC DATA AND 

5509
04:22:29,120 --> 04:22:33,040
VIRAL F3 AND [INDISCERNIBLE] CAN

5510
04:22:33,040 --> 04:22:36,360
DOWNREGULATE IN RT AND ARE NOT 

5511
04:22:36,360 --> 04:22:37,560
MUCH EFFECTED AND ALSO 

5512
04:22:37,560 --> 04:22:40,880
[INDISCERNIBLE] IS NOT THAT MUCH

5513
04:22:40,880 --> 04:22:46,120
EFFECTED AND THE VIRO-6 CARRY 

5514
04:22:46,120 --> 04:22:49,520
INDUCE WHOM IO6 EXPRESSION AND 

5515
04:22:49,520 --> 04:22:53,720
PATIENT WITH MECD HAS HIGH MO6 

5516
04:22:53,720 --> 04:22:55,880
PRODUCTION AND PATIENTS CAN 

5517
04:22:55,880 --> 04:22:59,320
BENEFIT FROM TREATMENT OF IO6.  

5518
04:22:59,320 --> 04:23:01,760
IT WOULD LIKE TO SEE WHETHER 

5519
04:23:01,760 --> 04:23:04,760
[INDISCERNIBLE] CAN DOWNREGULATE

5520
04:23:04,760 --> 04:23:07,960
WITH [INDISCERNIBLE] AND IO6 

5521
04:23:07,960 --> 04:23:11,720
INDUCED PRODUCTION AND HERE WE 

5522
04:23:11,720 --> 04:23:14,920
CHOOSE MACROPHAGES THAT ARE ONE 

5523
04:23:14,920 --> 04:23:17,800
OF THE MAIN PRODUCER OF HUMAN 

5524
04:23:17,800 --> 04:23:20,640
IO6 AS OUR TARGETS. 

5525
04:23:20,640 --> 04:23:24,040
SO, HERE, WE CHOOSE TWO 

5526
04:23:24,040 --> 04:23:28,560
DIFFERENT MACROPHAGES.  THP1 AND

5527
04:23:28,560 --> 04:23:33,480
U937.  ON THE LEFT SHOWS 

5528
04:23:33,480 --> 04:23:34,600
VARIABILITY ASSAY WITH RESPONSE 

5529
04:23:34,600 --> 04:23:35,640
TO THE [INDISCERNIBLE] TREATMENT

5530
04:23:35,640 --> 04:23:43,680
AND ON THE RIGHT SHOWS DATA OF 

5531
04:23:43,680 --> 04:23:48,880
IO6.  BASICALLY, WE TREAT CELLS 

5532
04:23:48,880 --> 04:23:50,640
WITH IO6 AND [INDISCERNIBLE] AND

5533
04:23:50,640 --> 04:23:53,080
COLLECT THIS OF THE CELLS AND 

5534
04:23:53,080 --> 04:23:57,640
THIS VIRUS AND GOES IN THE 

5535
04:23:57,640 --> 04:24:07,640
ELIZA.  YOU CAN SEE 

5536
04:24:07,640 --> 04:24:10,960
[INDISCERNIBLE] INHIBIT IO6 

5537
04:24:10,960 --> 04:24:15,640
PRODUCTION IN NON-TOXIC DOSAGE 

5538
04:24:15,640 --> 04:24:25,440
THAT IS HIGHLIGHTED BY RESULTS. 

5539
04:24:25,440 --> 04:24:31,640
[INDISCERNIBLE] WE WOULD LIKE TO

5540
04:24:31,640 --> 04:24:34,040
SEE CHANGE OF KINASES IN CELLS 

5541
04:24:34,040 --> 04:24:37,680
AFTER TREATMENT AND CHOOSE HUMAN

5542
04:24:37,680 --> 04:24:40,960
FIRST [INDISCERNIBLE] AND TO 

5543
04:24:40,960 --> 04:24:47,200
TEST CHANGE IN THESE CELLS.  YOU

5544
04:24:47,200 --> 04:24:51,360
CAN SEE HIGHLIGHT IN THE SQUARE 

5545
04:24:51,360 --> 04:24:58,920
AND SO THESE ARE BOTH 

5546
04:24:58,920 --> 04:25:04,840
DOWNREGULATED IN THIS JSC-1 AND 

5547
04:25:04,840 --> 04:25:07,640
BCBL-1 AND THIS ACTIVATOR OF IO6

5548
04:25:07,640 --> 04:25:09,720
AND WAIT TO CONFIRM WITH WESTERN

5549
04:25:09,720 --> 04:25:12,920
BLOT AND YOU CAN SEE IN THESE 

5550
04:25:12,920 --> 04:25:18,880
CELLS BOTH IN JSC-1 AND BCBL-1 

5551
04:25:18,880 --> 04:25:26,320
AND STAGE 3 IS DOWNREGULATED AND

5552
04:25:26,320 --> 04:25:31,960
TARGETS START TO [INDISCERNIBLE]

5553
04:25:31,960 --> 04:25:33,800
THAT IS WHY WE WENT TO LOOK UP 

5554
04:25:33,800 --> 04:25:36,840
THE ACTIVITY.  SO, USING THIS 

5555
04:25:36,840 --> 04:25:41,760
PROTEIN ARRAY, WE FOUND THAT 

5556
04:25:41,760 --> 04:25:46,120
GENERALLY BIG ACTIVITY ARE 

5557
04:25:46,120 --> 04:25:51,680
INHIBITED IN THESE.  WE CHOOSE 

5558
04:25:51,680 --> 04:25:54,280
ONE MAIN COMPONENT OF GABA B 

5559
04:25:54,280 --> 04:25:57,840
COMPLEX AND P6 DEFINE AND CHECK 

5560
04:25:57,840 --> 04:25:59,520
PROTEIN EXPRESSION BY WESTERN 

5561
04:25:59,520 --> 04:26:02,600
BLOT.  IT IS LOUSY HERE BUT YOU 

5562
04:26:02,600 --> 04:26:06,600
CAN HAVE A GLANCE IN JC1 IT IS 

5563
04:26:06,600 --> 04:26:08,360
DOWNREGULATED BUT HAVE TO BE 

5564
04:26:08,360 --> 04:26:11,680
FURTHER CONFIRMED AND BASED ON 

5565
04:26:11,680 --> 04:26:13,560
DATA WE PROPOSE POSSIBLE 

5566
04:26:13,560 --> 04:26:15,280
MECHANISM OF ACTION OF 

5567
04:26:15,280 --> 04:26:18,560
[INDISCERNIBLE] RELATED MCD.  

5568
04:26:18,560 --> 04:26:22,200
SO, IN CASE INFECT AND PROMOTE B

5569
04:26:22,200 --> 04:26:25,240
CELLS DIFFERENTIATION IN PLASMA 

5570
04:26:25,240 --> 04:26:29,840
CELLS AND FURTHER INTO THESE MCD

5571
04:26:29,840 --> 04:26:38,880
PLASMA BLAST.  AND IN MRAZ MA 

5572
04:26:38,880 --> 04:26:43,280
BLAST VIRUS PRODUCER OF IO6 AND 

5573
04:26:43,280 --> 04:26:51,440
THOSE VIRAL IO6 AND 

5574
04:26:51,440 --> 04:26:53,160
[INDISCERNIBLE] IN MONOCYTES AND

5575
04:26:53,160 --> 04:27:00,360
YOU CAN SEE TARGETS OF THESE 

5576
04:27:00,360 --> 04:27:05,160
[INDISCERNIBLE] THEY CAN BE 

5577
04:27:05,160 --> 04:27:06,560
INHIBITED.  EXCUSE ME.  THEY CAN

5578
04:27:06,560 --> 04:27:11,000
BE INHIBITED BY THIS.  AND 

5579
04:27:11,000 --> 04:27:19,880
REDUCING THIS IO10 EXPRESSION.  

5580
04:27:19,880 --> 04:27:20,800
CONCLUSION IS [INDISCERNIBLE] 

5581
04:27:20,800 --> 04:27:24,280
TIME IN DEPENDENT INHIBITED CELL

5582
04:27:24,280 --> 04:27:26,840
GROWTH AND THIS MAY COUNT FOR 

5583
04:27:26,840 --> 04:27:29,880
[INDISCERNIBLE] CELL GROSS 

5584
04:27:29,880 --> 04:27:36,960
INHIBITION EFFECT.  

5585
04:27:36,960 --> 04:27:42,000
[INDISCERNIBLE] DOWNREGULATE A 

5586
04:27:42,000 --> 04:27:45,880
LOT OF GENES CELL CYCLE 

5587
04:27:45,880 --> 04:27:50,800
PROLIFERATION AND REDUCE MI 

5588
04:27:50,800 --> 04:27:56,360
EXPRESSION IT ALSO INHIBITS 

5589
04:27:56,360 --> 04:28:03,720
MULTIPLE DINACES INCLUDING THE 

5590
04:28:03,720 --> 04:28:08,560
STATS 3 AND GAMA B. 

5591
04:28:08,560 --> 04:28:12,680
IT MIGHT BE USEFUL FOR TREATMENT

5592
04:28:12,680 --> 04:28:18,000
AND FUTURE PLAN IS TESTING 

5593
04:28:18,000 --> 04:28:20,240
EFFECT OF CYTOKINE PRODUCTIONS 

5594
04:28:20,240 --> 04:28:24,960
AND EFFECT ON THESE PATHWAYS. 

5595
04:28:24,960 --> 04:28:30,600
NOW CURRENTLY PROTOCOL IS 

5596
04:28:30,600 --> 04:28:33,680
TREATING THIS AND BEING 

5597
04:28:33,680 --> 04:28:38,160
DEVELOPED BY OUR TEAM MEMBER.  

5598
04:28:38,160 --> 04:28:42,120
WITH THAT I WOULD LIKE TO THANK 

5599
04:28:42,120 --> 04:28:46,480
MENTOR DR. ROBERT AND OUR GROUP 

5600
04:28:46,480 --> 04:28:48,200
MEMBERS AND ALSO OUR BRANCH AND 

5601
04:28:48,200 --> 04:28:52,400
THANK YOU.  I WOULD LIKE TO TAKE

5602
04:28:52,400 --> 04:28:57,720
QUESTIONS. 

5603
04:28:57,720 --> 04:29:00,040
>>THANK YOU.  WE DON'T
HAVE 

5604
04:29:00,040 --> 04:29:03,640
ENOUGH TIME.  SO, NOW WE WILL 

5605
04:29:03,640 --> 04:29:08,880
MOVE TO THE NEXT.  UP NEXT, NEXT

5606
04:29:08,880 --> 04:29:13,680
SPEAKER IS TARA.  YEAH.  SO, THE

5607
04:29:13,680 --> 04:29:17,560
TITLE IS EXPRESSION OF HUMAN 

5608
04:29:17,560 --> 04:29:21,800
ENDOGENOUS RETROVIRUSES DUE TO 

5609
04:29:21,800 --> 04:29:24,240
DEFECTS IN CHROME ATTIN 

5610
04:29:24,240 --> 04:29:26,760
REMODELING IN CLEAR CELL 

5611
04:29:26,760 --> 04:29:30,640
MENINGIOMA.  SO, NOW IS YOUR 

5612
04:29:30,640 --> 04:29:30,840
STAGE. 

5613
04:29:30,840 --> 04:29:41,040
>>THANK YOU. 

5614
04:29:41,040 --> 04:29:43,520
>>GOOD AFTERNOON,
EVERYBODY.  

5615
04:29:43,520 --> 04:29:45,960
I HAVE NO DISCLOSURES TO REPORT.

5616
04:29:45,960 --> 04:29:50,240
SO, FIRST, I WILL TELL YOU A 

5617
04:29:50,240 --> 04:29:51,760
LITTLE ABOUT CLEAR CELL 

5618
04:29:51,760 --> 04:29:53,560
MENINGIOMA WHO IS EFFECTED WITH 

5619
04:29:53,560 --> 04:29:55,520
IT AND WHAT IS PROGNOSIS FOR 

5620
04:29:55,520 --> 04:29:59,680
THIS TUMOR.  MOST PATIENTS 

5621
04:29:59,680 --> 04:30:02,920
DIAGNOSED WITH CLEAR CELL 

5622
04:30:02,920 --> 04:30:05,120
MENINGIOMA ARE YOUNG AND RARE 

5623
04:30:05,120 --> 04:30:06,960
TUMOR AND ABOUT 100 PEOPLE IN 

5624
04:30:06,960 --> 04:30:08,360
THE UNITED STATES ARE DIAGNOSED 

5625
04:30:08,360 --> 04:30:10,080
WITH IT AND MAJORITY ARE YOUNG 

5626
04:30:10,080 --> 04:30:13,200
CHILDREN AND ADULTS DIAGNOSED 

5627
04:30:13,200 --> 04:30:15,400
ARE YOUNG IN AGE STILL.  PROBLEM

5628
04:30:15,400 --> 04:30:17,320
WITH THE TUMOR IS THERE IS NO 

5629
04:30:17,320 --> 04:30:19,720
GOOD TREATMENT FOR IT OTHER THAN

5630
04:30:19,720 --> 04:30:21,600
STANDARD OF CARE CIRCCAL 

5631
04:30:21,600 --> 04:30:22,560
[INDISCERNIBLE] AND THERE IS 

5632
04:30:22,560 --> 04:30:25,880
NOTHING THAT IS TARGETED.  SO, 

5633
04:30:25,880 --> 04:30:28,960
THE PROGNOSIS IS DISMAL FOR MOST

5634
04:30:28,960 --> 04:30:30,960
PATIENTS IT THAT GET THIS TUMOR.

5635
04:30:30,960 --> 04:30:33,280
SOMETHING THAT CHARACTERIZES THE

5636
04:30:33,280 --> 04:30:35,760
TUMOR IT HAS BEEN KNOWN SINCE 

5637
04:30:35,760 --> 04:30:44,080
2013 IS LOSS OF SMARKY PART 1.  

5638
04:30:44,080 --> 04:30:49,360
IN STUDY DONE IN 2016 THEY FOUNT

5639
04:30:49,360 --> 04:30:56,200
SMASHGE 1CHARACTERIZES THE TUMO 

5640
04:30:56,200 --> 04:30:56,840
BEEN KNOWN SINCE 2013 IS LOSS OF

5641
04:30:56,840 --> 04:30:57,480
SMARKY PART SMARCE1.  IN STUDY 

5642
04:30:57,480 --> 04:30:58,120
DONE IN 2016 THEY FOUNT SMASHGE 

5643
04:30:58,120 --> 04:30:59,200
SMAR

5644
04:30:59,200 --> 04:30:59,480
SMARCE1. 

5645
04:30:59,480 --> 04:31:02,560
IT IS A CHROMATIN REMODELING 

5646
04:31:02,560 --> 04:31:04,800
PROTEIN AND HAS TO BE IN NUCLEUS

5647
04:31:04,800 --> 04:31:07,000
TO DO ITS JOB.  IF NO 

5648
04:31:07,000 --> 04:31:08,080
EXPRESSION, THERE IS NO 

5649
04:31:08,080 --> 04:31:09,920
FUNCTION.  THIS TUMOR TYPE WAS 

5650
04:31:09,920 --> 04:31:11,840
INTERESTING TO ME.  WE WORKED ON

5651
04:31:11,840 --> 04:31:16,880
A PROJECT LOOKING AT ATYPICAL 

5652
04:31:16,880 --> 04:31:24,360
TERTOID TUMORS WITH KEY PART OF 

5653
04:31:24,360 --> 04:31:24,840
CHROMATIN REMODELING. 

5654
04:31:24,840 --> 04:31:27,120
THERE IS INTERESTING PARALLELS 

5655
04:31:27,120 --> 04:31:31,080
BETWEEN TWO TUMOR TYPES ONE THEY

5656
04:31:31,080 --> 04:31:41,600
BOENT HAVE INTEE STIT SHAL -- 

5657
04:31:48,440 --> 04:31:52,680
THE HUMAN ENDOGENOUS -- IT IS 

5658
04:31:52,680 --> 04:31:55,240
SPECIFIC TO HUMANS WITH OPEN 

5659
04:31:55,240 --> 04:31:57,120
READING FRAMES MAKING VIRAL 

5660
04:31:57,120 --> 04:31:59,000
PROTEINS ONE THAT SEEMS TO BE 

5661
04:31:59,000 --> 04:32:01,120
MOST PROBLEMATIC IS ENVELOPE.  

5662
04:32:01,120 --> 04:32:03,440
ENVELOPE CAN BE EXPRESSED IN 

5663
04:32:03,440 --> 04:32:07,000
MEMBRANE LIKE OTHER VIRAL 

5664
04:32:07,000 --> 04:32:08,640
PROTEINS AND OTHER VIRAL 

5665
04:32:08,640 --> 04:32:11,000
ENVELOPES I SHOULD SAY AND 95% 

5666
04:32:11,000 --> 04:32:14,960
OF AT/RT CASES PREDOMINANTLY IN 

5667
04:32:14,960 --> 04:32:16,640
YOUNG CHILDREN THERE WAS HIGH 

5668
04:32:16,640 --> 04:32:19,440
EXPRESSION OF HML-2 ENVELOPE 

5669
04:32:19,440 --> 04:32:22,880
PROTEIN AND SAW IN CELL LINES 

5670
04:32:22,880 --> 04:32:25,360
MADE IN CHILDREN'S HOSPITAL OF 

5671
04:32:25,360 --> 04:32:26,680
LOS ANGELES FROM TWO DIFFERENT 

5672
04:32:26,680 --> 04:32:29,280
PATIENTS IT WAS EXPORTED IN 

5673
04:32:29,280 --> 04:32:31,560
EXTRA CELLULAR VESICALS THAT WE 

5674
04:32:31,560 --> 04:32:36,840
SAW THEM BY ELECTRON MICROSCOPY.

5675
04:32:36,840 --> 04:32:41,880
WE SEE HML-2 ENVELOPE THAT IS IN

5676
04:32:41,880 --> 04:32:43,000
THE PARTICLES. 

5677
04:32:43,000 --> 04:32:49,200
HOW DOES IT RELATE TO CLEAR CELL

5678
04:32:49,200 --> 04:32:52,040
MENINGIOMA?  8 TUMORS BUNCH OF 

5679
04:32:52,040 --> 04:32:55,320
DIFFERENT INSTITUTIONS AND FOUND

5680
04:32:55,320 --> 04:33:00,280
EXPRESSION OF HERV-K.  THEY ARE 

5681
04:33:00,280 --> 04:33:01,280
SHARING MRAZ MA MEMBRANE AND 

5682
04:33:01,280 --> 04:33:04,520
WHERE ARROWS ARE YOU SEE ACTUAL 

5683
04:33:04,520 --> 04:33:06,280
EXTRA CELLULAR VESICLES WITH 

5684
04:33:06,280 --> 04:33:07,560
PROTEIN IN THEM AND CHECK TO 

5685
04:33:07,560 --> 04:33:12,000
MAKE SURE TUMORS HAD LACK OF 

5686
04:33:12,000 --> 04:33:13,520
SMASHGE SMARCE1 EXPRESSION.  

5687
04:33:13,520 --> 04:33:17,760
THEY DID AND LOOKED FOR MRURY 

5688
04:33:17,760 --> 04:33:28,680
POTENCY FACTOFACTOR OCT4. 

5689
04:33:45,440 --> 04:33:56,080
HML6 IS IN OLDER HERBV-K -- NEX 

5690
04:34:13,760 --> 04:34:16,760
STEP LOOKING AT COUPLE 

5691
04:34:16,760 --> 04:34:19,160
ENDOGENOUS RETRO VIRAL PROTEINS.

5692
04:34:19,160 --> 04:34:25,040
[INDISCERNIBLE] IS NOT ONLY ONE 

5693
04:34:25,040 --> 04:34:27,960
THAT CAN INTERSTITIAL CELLS.  

5694
04:34:27,960 --> 04:34:30,920
HEFSH K IS ACTUALLY BUT LESS IS 

5695
04:34:30,920 --> 04:34:34,800
KNOWN ABOUT THAT.  SIN CRITTIN 

5696
04:34:34,800 --> 04:34:45,680
SMARCE1 A -- SIN CRITTIN SMARCE 

5697
04:34:46,680 --> 04:34:57,360
AND SIN CRITTYNCY

5698
04:35:19,680 --> 04:35:24,040
 -- SO, IT COULD ACTUALLY BE A 

5699
04:35:24,040 --> 04:35:27,040
VERY BIG KEY FOR PROTECTION OF 

5700
04:35:27,040 --> 04:35:28,840
FETUS FROM MOTHER DURING 

5701
04:35:28,840 --> 04:35:30,200
DEVELOPMENT AND COULD BE 

5702
04:35:30,200 --> 04:35:32,600
CO-OPTED BY TUMOR TO HELP IT BE 

5703
04:35:32,600 --> 04:35:34,000
PROTECTED FROM THE IMMUNE SYSTEM

5704
04:35:34,000 --> 04:35:38,120
AND WANTED TO LOOK FOR CD63 A 

5705
04:35:38,120 --> 04:35:44,240
MARKER FOR EXOSOMES AND IF EXTRA

5706
04:35:44,240 --> 04:35:46,280
CELLULAR VESICLES WERE EXOSOEMS.

5707
04:35:46,280 --> 04:35:51,880
WE ARE CONFIDENCE THEY ARE 

5708
04:35:51,880 --> 04:35:54,440
EXOSOMES TRACKING WHAT WE HAVE 

5709
04:35:54,440 --> 04:35:57,120
SEEN IN ATYPICAL TUMORS AS WELL.

5710
04:35:57,120 --> 04:35:58,960
WE FOUND THAT WE COULD 

5711
04:35:58,960 --> 04:36:01,880
SIGNIFICANTLY INCREASE 

5712
04:36:01,880 --> 04:36:05,840
TRANSCRIPTION OF SYNCYTIN-11.  

5713
04:36:05,840 --> 04:36:06,680
NEXT THING TO TALK ABOUT I 

5714
04:36:06,680 --> 04:36:10,160
MENTIONED EARLIER LOOKING FOR 

5715
04:36:10,160 --> 04:36:20,640
OCT4 IN THESE TUMORS AND IF 

5716
04:36:21,400 --> 04:36:22,160
THERE ISL

5717
04:36:22,160 --> 04:36:32,720
THERE IS CORRELATION.  -- WE ARE

5718
04:36:47,280 --> 04:36:49,680
LOOKING FORWARD TO TESTING THEM 

5719
04:36:49,680 --> 04:36:54,000
TO SEE IF WE CAN PULL DOWN 

5720
04:36:54,000 --> 04:36:58,520
PROMOTERS USING OCT-4 ANTIBODY 

5721
04:36:58,520 --> 04:36:59,720
AND MIGHT WONDER WHAT ROLE OF 

5722
04:36:59,720 --> 04:37:04,840
THE VIRUSES IS IF IN PATHOGEN 

5723
04:37:04,840 --> 04:37:06,960
ESIS TUMOR AND QUESTION WE HAVE 

5724
04:37:06,960 --> 04:37:08,280
TO EXPLORE IS IF ONE OF TWO 

5725
04:37:08,280 --> 04:37:11,200
THINGS IS HAPPENING AND IF THESE

5726
04:37:11,200 --> 04:37:12,760
RETROVIRUSES ARE EXPRESSED IN 

5727
04:37:12,760 --> 04:37:13,960
DEVELOPMENT AND ARE IMPORTANT IN

5728
04:37:13,960 --> 04:37:15,920
PROCESS OF DEVELOPMENT IF 

5729
04:37:15,920 --> 04:37:18,240
TURNING THEM OFF PREMATURELY 

5730
04:37:18,240 --> 04:37:19,120
DEVELOPMENT WON'T PROCEED.  THEY

5731
04:37:19,120 --> 04:37:21,120
ARE REMAINING ON AFTER 

5732
04:37:21,120 --> 04:37:24,280
DEVELOPMENT OR GETTING TURNED 

5733
04:37:24,280 --> 04:37:26,680
BACK ON SOMEHOW UNDERSTANDING 

5734
04:37:26,680 --> 04:37:28,040
WHICH OF THE TWO POSSIBILITIES 

5735
04:37:28,040 --> 04:37:31,520
IS HAPPENING IS SOMETHING TO 

5736
04:37:31,520 --> 04:37:34,600
MODEL IN IN VIVO SYSTEM AND 

5737
04:37:34,600 --> 04:37:38,960
TELLING YOU MORE ABOUT THESE 

5738
04:37:38,960 --> 04:37:39,240
VIRUSES. 

5739
04:37:39,240 --> 04:37:41,200
THEY INTEGRATED INTO THE GENOME 

5740
04:37:41,200 --> 04:37:44,360
AND INTEGRATED INTO GERM LINE 

5741
04:37:44,360 --> 04:37:46,400
ANIMAL MOUSE OR HUMAN ANCESTORS 

5742
04:37:46,400 --> 04:37:48,720
AND ARE PASSED ON THEY ARE THE 

5743
04:37:48,720 --> 04:37:51,680
GERM LINE AND LIKE ANY OTHER 

5744
04:37:51,680 --> 04:37:53,240
MENDELIAN GENE AND LOTS OF TIMES

5745
04:37:53,240 --> 04:37:55,040
THEY HAVE BEEN THERE MILLIONS OF

5746
04:37:55,040 --> 04:37:56,960
YEARS AND CAN PICK UP MUTATIONS 

5747
04:37:56,960 --> 04:37:59,480
AND RECOMBINE AND YOU CAN END UP

5748
04:37:59,480 --> 04:38:02,320
WITH SOLO LTRS THAT ARE FLANKING

5749
04:38:02,320 --> 04:38:04,320
BITS OF THE VIRUS. 

5750
04:38:04,320 --> 04:38:06,520
AND LOTS OF OTHER CONSEQUENCES 

5751
04:38:06,520 --> 04:38:08,200
OF RECOMBINATION. 

5752
04:38:08,200 --> 04:38:10,000
BUT MOST IMPORTANT THING IS OPEN

5753
04:38:10,000 --> 04:38:12,160
READING FRAMES.  SO, ENVELOPE 

5754
04:38:12,160 --> 04:38:14,160
GENE HERE IS THE ONE I FOCUSED 

5755
04:38:14,160 --> 04:38:16,200
ON THE MOST TODAY.  THERE IS 

5756
04:38:16,200 --> 04:38:18,920
EVIDENCE FOR EXPRESSION OF OTHER

5757
04:38:18,920 --> 04:38:22,320
ENDOGENOUS RETRO VIRAL GENES AS 

5758
04:38:22,320 --> 04:38:26,800
WELL IN TUMORS. 

5759
04:38:26,800 --> 04:38:30,080
SYNCYTIN-1 IS IMPORTANT FOR 

5760
04:38:30,080 --> 04:38:40,480
MAMMALS AND PLACENTA. 

5761
04:38:43,600 --> 04:38:45,600
THIS IS SYNCYTIN-2 AND YOU SEE 

5762
04:38:45,600 --> 04:38:48,160
IT IN THE GENOME AND IT IS 

5763
04:38:48,160 --> 04:38:49,840
EXPRESSED EARLY IN DEVELOPMENT 

5764
04:38:49,840 --> 04:38:52,360
DAYS 6 TO 7 AND CONTINUES TO BE 

5765
04:38:52,360 --> 04:38:53,360
EXPRESSED THROUGHOUT DEVELOPMENT

5766
04:38:53,360 --> 04:38:56,240
AND MANY HAVE SLIGHTLY DIFFERENT

5767
04:38:56,240 --> 04:38:57,480
TIMINGS.   THEY ARE ALL 

5768
04:38:57,480 --> 04:38:58,640
EXPRESSED AT SOME POINT AND ARE 

5769
04:38:58,640 --> 04:39:00,800
MANY OF THEM.  KNOCKING ONE OF 

5770
04:39:00,800 --> 04:39:03,600
THEM DOWN OR OUT OTHERS COULD BE

5771
04:39:03,600 --> 04:39:05,560
THERE TO COMPENSATE AND OTHER 

5772
04:39:05,560 --> 04:39:08,960
THING INTERESTING TO NOTE IS 

5773
04:39:08,960 --> 04:39:11,560
SYNCYTIN-1 AND SYNCYTIN-2 

5774
04:39:11,560 --> 04:39:15,120
INTEGRATED SLIGHTLY DIFFERENT 

5775
04:39:15,120 --> 04:39:19,640
TIMINGS.  SYNCYTIN-1 IS KNOWN 

5776
04:39:19,640 --> 04:39:21,520
FOR IMMUNOSUPPRESSIVE PROPERTIES

5777
04:39:21,520 --> 04:39:23,080
AND [INDISCERNIBLE] ALTHOUGH IT 

5778
04:39:23,080 --> 04:39:25,120
IS NOT STRONGLY REFLECTED IN THE

5779
04:39:25,120 --> 04:39:26,320
LITERATURE AT THIS MOMENT. 

5780
04:39:26,320 --> 04:39:30,320
IN FUTURE, WE WANT TO REALLY 

5781
04:39:30,320 --> 04:39:36,280
UNDERSTAND HOW HERV EXPRESSION 

5782
04:39:36,280 --> 04:39:47,120
IS REGULATED AND OCTOBE-4 -- CAE

5783
04:39:50,840 --> 04:39:51,960
CONTRIBUTING TO EITHER 

5784
04:39:51,960 --> 04:39:55,920
DEVELOPMENTAL ISSUES OR CLEAR 

5785
04:39:55,920 --> 04:39:57,200
CELL MENINGIOMA SPECIFICALLY IN 

5786
04:39:57,200 --> 04:40:00,800
VIVO.  WITH THAT I WOULD LIKE TO

5787
04:40:00,800 --> 04:40:03,240
THANK PI AND TWO MEMBERS OF THE 

5788
04:40:03,240 --> 04:40:06,840
LAB THAT WORKED HARD ON THIS 

5789
04:40:06,840 --> 04:40:09,080
PROJECT AND COLLABORATORS THAT 

5790
04:40:09,080 --> 04:40:12,680
SENT SAMPLES FROM ALL ACROSS THE

5791
04:40:12,680 --> 04:40:15,600
COUNTRY AND OUR VERY ESTEEMED 

5792
04:40:15,600 --> 04:40:18,000
COLLEAGUE SOPHIE THAT WILL HELP 

5793
04:40:18,000 --> 04:40:20,320
WITH OUR CHICK EMBRYO MODEL AND 

5794
04:40:20,320 --> 04:40:24,240
WOULD BE HAPPY TO TAKE ANY 

5795
04:40:24,240 --> 04:40:27,520
QUESTIONS. 

5796
04:40:27,520 --> 04:40:29,880
>>ANY QUESTIONS?  

5797
04:40:29,880 --> 04:40:30,800
>>IS [INDISCERNIBLE]
SUPPRESSED

5798
04:40:30,800 --> 04:40:33,800
IN THE TUMORS AND OTHER THINGS 

5799
04:40:33,800 --> 04:40:35,640
YOU CALL EXOSOMES?  

5800
04:40:35,640 --> 04:40:37,440
>>WE CHECKED TO SEE IF
THEY 

5801
04:40:37,440 --> 04:40:41,160
WERE VLPS IN ATRT PROJECT.  THEY

5802
04:40:41,160 --> 04:40:46,480
DID NOT LOOK LIKE VLPS AT ALL.  

5803
04:40:46,480 --> 04:40:52,320
SO, I DOUBT THEY ARE VLPS AND 

5804
04:40:52,320 --> 04:40:58,200
COULD BE SOME GAG EXPRESSION I 

5805
04:40:58,200 --> 04:41:02,320
HAVEN'T STAINED FOR IT BUT 

5806
04:41:02,320 --> 04:41:06,280
ANTIBODIES FOR HEFSH K AND MAIN 

5807
04:41:06,280 --> 04:41:09,280
PROTEIN THEY EXPRESS IS 

5808
04:41:09,280 --> 04:41:10,480
ENVELOPE.  

5809
04:41:10,480 --> 04:41:20,840
>>[INDISCERNIBLE]. 

5810
04:41:21,320 --> 04:41:23,080
>>WE HAVEN'T CHECKED YET.
CAN 

5811
04:41:23,080 --> 04:41:25,800
YOU IN SOME LABS AND ONE POST 

5812
04:41:25,800 --> 04:41:29,440
DOC IS LOOKING AT THAT WITH ALS 

5813
04:41:29,440 --> 04:41:29,720
ACTUALLY. 

5814
04:41:29,720 --> 04:41:32,000
>>OTHER QUESTIONS?  

5815
04:41:32,000 --> 04:41:32,640
OKAY.  THANK YOU. 

5816
04:41:32,640 --> 04:41:43,040
>>HE HAS A QUESTION.  

5817
04:41:50,680 --> 04:41:53,880
>>IF YOU LOOK IN THE
TUMOR AND 

5818
04:41:53,880 --> 04:41:54,280
[INDISCERNIBLE]. 

5819
04:41:54,280 --> 04:41:57,120
>>NOT TO MY KNOWLEDGE. 
WE 

5820
04:41:57,120 --> 04:41:59,720
STARTED THE PROJECT A COUPLE 

5821
04:41:59,720 --> 04:42:02,360
MONTHS AGO AND LOOKING AT 

5822
04:42:02,360 --> 04:42:04,720
AVENUES AND I WAS THINKING ABOUT

5823
04:42:04,720 --> 04:42:06,360
E-MAILING AND ASKING HIM.  THAT 

5824
04:42:06,360 --> 04:42:08,520
IS ONLY ONE I KNOW OF THAT 

5825
04:42:08,520 --> 04:42:10,360
EXISTS AND WOULD BE USEFUL.  

5826
04:42:10,360 --> 04:42:12,800
THANK YOU.  

5827
04:42:12,800 --> 04:42:16,040
>>THANK YOU.  

5828
04:42:16,040 --> 04:42:21,560
>>NOW LET'S MOVE TO THE
NEXT 

5829
04:42:21,560 --> 04:42:22,760
SPEAKER.  

5830
04:42:22,760 --> 04:42:26,920
CHAD HOGAN.  TALK IS LOSS OF 

5831
04:42:26,920 --> 04:42:29,720
STAT3 IN B CELLS HEIGHTENS 

5832
04:42:29,720 --> 04:42:32,120
EXPRESSION OF ANTIVIRAL GENES 

5833
04:42:32,120 --> 04:42:36,480
AND REDUCES LATENCY OF MURINE 

5834
04:42:36,480 --> 04:42:40,520
GAMA HERPES VIRUS 68 IN VIVO. 

5835
04:42:40,520 --> 04:42:42,040
>>THANK YOU FOR STICKING
AROUND

5836
04:42:42,040 --> 04:42:44,240
FOR MY TALK AND ORGANIZERS FOR 

5837
04:42:44,240 --> 04:42:46,080
GIVING ME OPPORTUNITY TO SHARE 

5838
04:42:46,080 --> 04:42:54,240
MY WORK.  I'M CHAD HOGAN AND 

5839
04:42:54,240 --> 04:42:57,680
TODAY I WILL GIVE YOU A 

5840
04:42:57,680 --> 04:42:59,840
HIGHLIGHT OF MY DISSERTATION 

5841
04:42:59,840 --> 04:43:01,720
RESEARCH I'M CHARACTERIZING ROLE

5842
04:43:01,720 --> 04:43:08,120
OF STAT3 IN B CELLS IF IN 

5843
04:43:08,120 --> 04:43:10,160
GAMMAHERPESVIRUS LATENCY. 

5844
04:43:10,160 --> 04:43:13,240
I KNOW WE HAD HERPES VIRUS TALKS

5845
04:43:13,240 --> 04:43:15,400
EARLIER IN THE DAY.  REFRESHER, 

5846
04:43:15,400 --> 04:43:18,080
HERPES VIRUSES ARE LARGE DOUBLE 

5847
04:43:18,080 --> 04:43:20,520
STRANDED DNA VIRUSES CHARACTERED

5848
04:43:20,520 --> 04:43:22,000
BY ABILITY TO ESTABLISH 

5849
04:43:22,000 --> 04:43:24,360
LIFE-LONG INFECTION IN THE HOST 

5850
04:43:24,360 --> 04:43:26,920
TWO PHASES OF INFECTION.  LYTIC 

5851
04:43:26,920 --> 04:43:28,560
PHASE AND LINEAR GENE 

5852
04:43:28,560 --> 04:43:31,280
REPLICATION IN THE NUCLEUS AS 

5853
04:43:31,280 --> 04:43:33,400
WELL AS PRODUCTION OF INFECTIOUS

5854
04:43:33,400 --> 04:43:36,400
PARTICLES AND OTHER HAND LATENCY

5855
04:43:36,400 --> 04:43:39,520
A DORMANT OR QUIET STATE AND 

5856
04:43:39,520 --> 04:43:43,360
GENOME IS CENTERED IN NUCLEUS AS

5857
04:43:43,360 --> 04:43:44,960
EPISOME AND NO INFECTIOUS 

5858
04:43:44,960 --> 04:43:48,800
PARTICLES PRODUCED WE HAVE 

5859
04:43:48,800 --> 04:43:50,920
VACCINES AGAINST ONE VISA VEE AS

5860
04:43:50,920 --> 04:43:55,080
WELL AND ONE CLASS OF ANTIVIRAL 

5861
04:43:55,080 --> 04:43:55,400
DRUGS. 

5862
04:43:55,400 --> 04:43:59,600
OF THREE SUBFAMILIES OF HUMAN 

5863
04:43:59,600 --> 04:44:01,960
HERPYS VIRUSES OUR LAB IS 

5864
04:44:01,960 --> 04:44:08,560
FOCUSED ON GAMMA VIRUSES EBV AND

5865
04:44:08,560 --> 04:44:09,880
EPSTEIN VIRUS BECAUSE OF -- THEY

5866
04:44:09,880 --> 04:44:12,440
ARE ASSOCIATED WITH CANCERS AND 

5867
04:44:12,440 --> 04:44:14,280
INFECT A LARGE PORTION OF THE 

5868
04:44:14,280 --> 04:44:16,200
GLOBAL POPULATION AND BECAUSE OF

5869
04:44:16,200 --> 04:44:20,960
IT THAT OUR LAB FOCUSES ON GAMMA

5870
04:44:20,960 --> 04:44:21,760
HERPESVIRUSES MY PROJECT IN 

5871
04:44:21,760 --> 04:44:25,120
PARTICULAR FOCUSED ON HOST 

5872
04:44:25,120 --> 04:44:27,560
PROTEIN STAT3 TRANSCRIPTION 

5873
04:44:27,560 --> 04:44:30,360
FACTOR.  WE CAN TRANSLOCATE TO 

5874
04:44:30,360 --> 04:44:32,120
NUCLEUS TO ACT AS TRANSCRIPTION 

5875
04:44:32,120 --> 04:44:36,440
FACTOR REGULATING PROCESSES 

5876
04:44:36,440 --> 04:44:37,440
PROLIFERATION SURVIVAL AND NO 

5877
04:44:37,440 --> 04:44:40,040
SURPRISE IT IS A MAJOR PLAYER IN

5878
04:44:40,040 --> 04:44:42,640
CANCER AND IN FACT IS STAT3 

5879
04:44:42,640 --> 04:44:44,320
ACTIVATION IS FOUND IN MANY 

5880
04:44:44,320 --> 04:44:45,600
HUMAN CANCERS INCLUDING THOSE 

5881
04:44:45,600 --> 04:44:51,320
THAT ARISE DUE TO EPV AND KSHV 

5882
04:44:51,320 --> 04:44:57,600
AND STAT3 IS ACTIVATED ON GAMA 

5883
04:44:57,600 --> 04:44:59,440
HERPES VIRUS ACTIVATION AND 

5884
04:44:59,440 --> 04:45:01,440
BENEFIT AND MULTIPLE FRONTS ON 

5885
04:45:01,440 --> 04:45:04,280
CELL SURFACE AND DIRECTLY IN 

5886
04:45:04,280 --> 04:45:06,360
NUCLEUS FOR TRANSCRIPTIONAL 

5887
04:45:06,360 --> 04:45:10,000
ACTIVITY AND DRIVING QUESTION OF

5888
04:45:10,000 --> 04:45:12,280
MY RESEARCH IS WHAT IS ROLE OF 

5889
04:45:12,280 --> 04:45:15,360
STAT3 IN GAMA HERPES VIRUS 

5890
04:45:15,360 --> 04:45:17,760
LATENCY ESTABLISHMENT?  

5891
04:45:17,760 --> 04:45:21,920
TO STUDY THAT ROLE WE UTILIZE 

5892
04:45:21,920 --> 04:45:28,600
THIS HERPES VIRUS THIS MODEL 

5893
04:45:28,600 --> 04:45:32,800
PATHOGEN AND HOMOLOGS OF MASS 

5894
04:45:32,800 --> 04:45:34,880
GENES AND -- REPLICATION AND 

5895
04:45:34,880 --> 04:45:37,440
LATENCY.  REAL POWER OF OUR 

5896
04:45:37,440 --> 04:45:40,320
MODEL COMES WITH THE ABILITY TO 

5897
04:45:40,320 --> 04:45:42,240
INFECT IN NATURAL LIVE HOST AND 

5898
04:45:42,240 --> 04:45:43,840
TO OBSERVE PRIMARY INFECTION TO 

5899
04:45:43,840 --> 04:45:46,040
LOOK AT HOST DETERMINANTS OF 

5900
04:45:46,040 --> 04:45:46,840
ESTABLISHMENT OF INFECTION THAT 

5901
04:45:46,840 --> 04:45:51,200
IS HARDER TO DO WITH HUMAN GAMA 

5902
04:45:51,200 --> 04:45:53,640
HERPES VIRUSES THEMSELVES AND 

5903
04:45:53,640 --> 04:45:57,360
PREVIOUS RESEARCH IN LAB SHOWED 

5904
04:45:57,360 --> 04:46:02,880
NO ROLE IN REPLICATION AND IN 

5905
04:46:02,880 --> 04:46:09,440
LUNGS OF MICE IN THE MEMORY OR B

5906
04:46:09,440 --> 04:46:10,920
CELL IN GENERAL AND DETERMINING 

5907
04:46:10,920 --> 04:46:13,880
THIS ROLE SPECIFICALLY IN B 

5908
04:46:13,880 --> 04:46:15,840
CELLS WE NEED A MODEL TO KNOCK 

5909
04:46:15,840 --> 04:46:20,560
OUT PROTEIN SPECIFICALLY IN THAT

5910
04:46:20,560 --> 04:46:22,720
COMPARTMENT AND WE HAVE THIS 

5911
04:46:22,720 --> 04:46:26,880
DOWNSTREAM OF INDIGENOUS 

5912
04:46:26,880 --> 04:46:28,040
PROMOTER KNOCKING OUT THIS AND 

5913
04:46:28,040 --> 04:46:30,480
FOR ALL EXPERIMENTS SHOWING YOU 

5914
04:46:30,480 --> 04:46:32,880
UTILIZING MICE THAT WOULD BE 

5915
04:46:32,880 --> 04:46:34,280
CONSIDERED WILD TYPE MICE AND 

5916
04:46:34,280 --> 04:46:37,280
HAVE STAT 3 IN B CELLS AND AS 

5917
04:46:37,280 --> 04:46:41,520
WELL WE ARE UTILIZING FLOW 

5918
04:46:41,520 --> 04:46:44,000
CITOMETRY TO TRACK PHENOTYPE AND

5919
04:46:44,000 --> 04:46:46,080
CELLS AND WE HAVE A REPORTER 

5920
04:46:46,080 --> 04:46:49,200
VIRUS AND ABLE TO TRACK 

5921
04:46:49,200 --> 04:46:51,280
PERCENTAGE OF INFECTED B CELLS 

5922
04:46:51,280 --> 04:46:54,200
IN STAT 3 WILD TYPE I WILL REFER

5923
04:46:54,200 --> 04:46:56,840
TO THEM AS AND YOU CAN SEE WE 

5924
04:46:56,840 --> 04:47:00,480
HAVE A SIGNIFICANT FREQUENCY OF 

5925
04:47:00,480 --> 04:47:02,360
POSITIVE B CELLS IN IN TWO 

5926
04:47:02,360 --> 04:47:04,680
DISTINCT STRAINS OF STAT 3 

5927
04:47:04,680 --> 04:47:05,840
KNOCKOUT MICE THAT WAS FIRST 

5928
04:47:05,840 --> 04:47:08,360
INDICATION TO US THAT STAT 3 IS 

5929
04:47:08,360 --> 04:47:10,600
PLAYING ROLE IN VIRAL LATENCY 

5930
04:47:10,600 --> 04:47:11,640
ESTABLISHMENT AND MENTIONING IN 

5931
04:47:11,640 --> 04:47:14,760
DATA NOT SHOWING NOW BUT DEFECT 

5932
04:47:14,760 --> 04:47:17,560
VALIDATED BY LIMITING DILUTION 

5933
04:47:17,560 --> 04:47:20,200
PCR DIDN'T SEE FURTHER 

5934
04:47:20,200 --> 04:47:22,440
REACTIVATION DEFECT WITH THESE 

5935
04:47:22,440 --> 04:47:23,320
MICE.  

5936
04:47:23,320 --> 04:47:30,720
SO, ONE IMPORTANT ASPECT -- 

5937
04:47:30,720 --> 04:47:34,040
GERMINAL CENTER IS MICRO 

5938
04:47:34,040 --> 04:47:35,960
STRUCTURE IN -- ACTIVATED B 

5939
04:47:35,960 --> 04:47:40,960
CELLS GO TO MUTATE B CELL 

5940
04:47:40,960 --> 04:47:45,080
RECEPTOR AND GET TESTED. 

5941
04:47:45,080 --> 04:47:48,360
SO, HERE -- IT IS KNOWN THAT 

5942
04:47:48,360 --> 04:47:50,360
WITH THIS YOU NEED A PROPER 

5943
04:47:50,360 --> 04:47:53,120
GERMINAL CENTER FORMATION FOR 

5944
04:47:53,120 --> 04:47:55,200
VIRUS TO ACTUALLY PERSIST.  HERE

5945
04:47:55,200 --> 04:47:58,800
I'M UTILIZING TWO MARKERS TO DEN

5946
04:47:58,800 --> 04:48:03,520
OAT GERMINAL CENTER B CELLS AND 

5947
04:48:03,520 --> 04:48:05,400
SUBPOPULATION AND TO SURPRISE WE

5948
04:48:05,400 --> 04:48:06,920
SAW INCREASE IN KNOCKOUT MICE 

5949
04:48:06,920 --> 04:48:10,360
THAT IS OPPOSED TO DECREASE IN 

5950
04:48:10,360 --> 04:48:11,760
LATENCY THAT WE ACTUALLY SAW. 

5951
04:48:11,760 --> 04:48:15,600
IN ORDER TO GET A BETTER -- FLOW

5952
04:48:15,600 --> 04:48:16,680
CITOMETRY IS REPRESENTATIVE OF 

5953
04:48:16,680 --> 04:48:18,880
THE POPULATION WE WANT TO LOOK 

5954
04:48:18,880 --> 04:48:21,000
AT OVERALL STRUCTURE AND 

5955
04:48:21,000 --> 04:48:22,760
ARCHITECTURE OF SPLEENS AND WITH

5956
04:48:22,760 --> 04:48:27,840
THE LAB AND NIAD WE HAD NAÏVE 

5957
04:48:27,840 --> 04:48:30,080
INFECTED SPLEENS OF KNOCKOUT 

5958
04:48:30,080 --> 04:48:31,280
MOOIS TO DO [INDISCERNIBLE] AND 

5959
04:48:31,280 --> 04:48:33,480
YOU CAN APPRECIATE IN PURPLE I 

5960
04:48:33,480 --> 04:48:37,320
HAVE B CELL MARKER B220 DENOTING

5961
04:48:37,320 --> 04:48:42,400
A FOLLICULAR REGION OF GERMINAL 

5962
04:48:42,400 --> 04:48:44,240
CENTERS APPRECIATING IN NAÏVE 

5963
04:48:44,240 --> 04:48:46,400
CASE COMPARING WILD TYPE AND 

5964
04:48:46,400 --> 04:48:50,040
KNOCKOUT FOLLICLES THAT ARE 

5965
04:48:50,040 --> 04:48:51,600
FRAGMENTED AND SMALLER IN WILD 

5966
04:48:51,600 --> 04:48:53,720
TYPE CASE AND UPON EXPRESSION WE

5967
04:48:53,720 --> 04:48:59,640
SEE EXPRESSION OF ACTIVATION OF 

5968
04:48:59,640 --> 04:49:01,560
WILD MARKER.  GERMINAL CENTER B 

5969
04:49:01,560 --> 04:49:04,040
CELLS THAT ARE TYPICAL AND 

5970
04:49:04,040 --> 04:49:06,680
EXPRESSION OF MARKER IS MORE 

5971
04:49:06,680 --> 04:49:08,480
DISBURSED AND OUT OF NORM AND 

5972
04:49:08,480 --> 04:49:10,040
NOT REALLY COMPACT AND AGAIN IS 

5973
04:49:10,040 --> 04:49:12,160
AN INDICATION TO US THERE IS 

5974
04:49:12,160 --> 04:49:13,120
SOMETHING WRONG WITH STRUCTURE 

5975
04:49:13,120 --> 04:49:16,280
OF GERMINAL CENTERS IN THESE 

5976
04:49:16,280 --> 04:49:16,960
MICE. 

5977
04:49:16,960 --> 04:49:19,560
SO, BECAUSE WE ARE SEEING 

5978
04:49:19,560 --> 04:49:23,240
DISREGULATION OF GERMINAL CENTER

5979
04:49:23,240 --> 04:49:25,600
ITSELF WE LOOK AT DOWNSTREEMENT 

5980
04:49:25,600 --> 04:49:28,360
EFFECTS OF THAT AND WE SEE A 

5981
04:49:28,360 --> 04:49:31,840
SIGNIFICANT DECREASE IN THIS 

5982
04:49:31,840 --> 04:49:39,080
POPULATION IN KNOCKOUT MICE. 

5983
04:49:39,080 --> 04:49:43,680
WE COLLECT SERUM AND IN LAB 

5984
04:49:43,680 --> 04:49:46,000
UNIVERSITY OF ARKANSAS MEDICAL 

5985
04:49:46,000 --> 04:49:49,040
SCHOOL THERE IS DECREASE IN 

5986
04:49:49,040 --> 04:49:51,680
ANTIBODIES AND CAPACITY TO 

5987
04:49:51,680 --> 04:49:53,800
NEUTRALIZE VIRUS IN COMING 

5988
04:49:53,800 --> 04:49:55,080
KNOCKOUT MICE AND AS WELL 

5989
04:49:55,080 --> 04:49:57,640
LOOKING AT OTHER ARM OF ADAPTIVE

5990
04:49:57,640 --> 04:50:00,280
RESPONSE AND T CELLS 42 DAYS 

5991
04:50:00,280 --> 04:50:03,240
POST INFECTION WE SEE 

5992
04:50:03,240 --> 04:50:06,400
SIGNIFICANT INCREASE IN VIRUS 

5993
04:50:06,400 --> 04:50:09,720
SPECIFIC T CELLS FIRST 

5994
04:50:09,720 --> 04:50:11,880
RESPONDERS TO INFECTION CLEAR 

5995
04:50:11,880 --> 04:50:13,480
INFECTION AND DIE OFF AND 

5996
04:50:13,480 --> 04:50:14,760
MINIMAL ACTIVE REPLICATION WE 

5997
04:50:14,760 --> 04:50:18,040
SEE INCREASE IN THIS POPULATION 

5998
04:50:18,040 --> 04:50:20,120
AND SO FROM TWO SORT OF THINGS I

5999
04:50:20,120 --> 04:50:22,240
HAVE SHOWN SO FAR WE HAVE 

6000
04:50:22,240 --> 04:50:25,720
DISFUNCTION IN B AND T CELL 

6001
04:50:25,720 --> 04:50:27,120
RESPONSES WITH INFECTION AND 

6002
04:50:27,120 --> 04:50:29,040
WANTED TO SEE IF REDUCTION IN 

6003
04:50:29,040 --> 04:50:30,760
LATENCY IS DUE TO IMMUNE 

6004
04:50:30,760 --> 04:50:32,280
RESPONSE OR WHAT IS NECESSARY IN

6005
04:50:32,280 --> 04:50:37,040
B CELL ITSELF FOR VIRUS TO GO 

6006
04:50:37,040 --> 04:50:47,480
LATENT WE TAKE B CELLS WITH STAT

6007
04:50:47,480 --> 04:50:49,160
3 AND COMBINE TO HOST AND THAT 

6008
04:50:49,160 --> 04:50:51,840
WAY WE HAVE A COMPETITIVE MODEL 

6009
04:50:51,840 --> 04:50:53,640
WE CAN DETERMINE WHETHER OR NOT 

6010
04:50:53,640 --> 04:50:55,240
STAT 3 IS NECESSARY WHILE CELLS 

6011
04:50:55,240 --> 04:50:57,440
ARE RESPONDING TO SAME IMMUNE 

6012
04:50:57,440 --> 04:50:57,720
RESPONSE. 

6013
04:50:57,720 --> 04:51:00,200
IN ORDER TO DO THIS, WE LAYERED 

6014
04:51:00,200 --> 04:51:05,520
ON TOP OF THE ORIGINAL STAT3 

6015
04:51:05,520 --> 04:51:07,600
MUTATION TOMATO RED FLUORESCENT 

6016
04:51:07,600 --> 04:51:12,240
PROTEIN UNDER REGULATION OF 

6017
04:51:12,240 --> 04:51:13,400
PRECOMBIN NANT -- KNOCKOUT STAT 

6018
04:51:13,400 --> 04:51:16,800
3 AND TURN ON THIS NICE RED 

6019
04:51:16,800 --> 04:51:19,520
PROTEIN AND FLOW CITOMETRY WE 

6020
04:51:19,520 --> 04:51:24,320
CAN TAKE ADVANTAGE OF THE MARKER

6021
04:51:24,320 --> 04:51:25,960
AND KNOCKOUT IN POSITIVE CELLS 

6022
04:51:25,960 --> 04:51:30,000
LOOKING AT FREQUENCY OF THIS.  

6023
04:51:30,000 --> 04:51:32,960
WE SAW SIGNIFICANT DECREASE IN 

6024
04:51:32,960 --> 04:51:35,320
LATENCY ESTABLISHMENT AND NOT 

6025
04:51:35,320 --> 04:51:36,800
SHOWING DATA HERE BUT WERE 

6026
04:51:36,800 --> 04:51:39,520
VALIDATED BY OTHER MEANS HERE AS

6027
04:51:39,520 --> 04:51:41,320
WELL.  KNOCKING IMPORTANT 

6028
04:51:41,320 --> 04:51:42,600
TRANSCRIPTION FACTOR AND NEXT 

6029
04:51:42,600 --> 04:51:46,280
IDEA SEEING WHAT IS HAPPENING TO

6030
04:51:46,280 --> 04:51:47,560
TRANSCRIPTIONAL LANDSCAPE IN 

6031
04:51:47,560 --> 04:51:50,720
ABSENCE OF STAT3 AND TOOK 

6032
04:51:50,720 --> 04:51:52,320
POPULATIONS UTILIZING THESE 

6033
04:51:52,320 --> 04:51:54,080
MARKERS SORTING WILD TYPE 

6034
04:51:54,080 --> 04:51:56,840
KNOCKOUT UNINFECTED AND ENFEKTED

6035
04:51:56,840 --> 04:52:02,000
CELLS PERFORMING RNA SEQUENCING 

6036
04:52:02,000 --> 04:52:07,200
PRINCIPLE COMPONENT -- AND 

6037
04:52:07,200 --> 04:52:10,040
PERFORMING GENE CENTER 

6038
04:52:10,040 --> 04:52:11,640
ENRICHMENT ANALYSIS WITH 

6039
04:52:11,640 --> 04:52:14,520
KNOCKOUT WILD TYPE CELLS WE SEE 

6040
04:52:14,520 --> 04:52:16,400
SOME PATHWAYS THAT MAKE SENSE 

6041
04:52:16,400 --> 04:52:19,040
MTOR AND MIXED SIGNALING THAT 

6042
04:52:19,040 --> 04:52:21,280
HAVE GROWTH PATHWAYS AND SEE 

6043
04:52:21,280 --> 04:52:24,320
INCREASE IN INFLAMMATION AND 

6044
04:52:24,320 --> 04:52:26,360
INFLAMMATORY PATHWAYS AND IT IS 

6045
04:52:26,360 --> 04:52:29,800
KNOWN THAT IT HAS MECHANISMS FOR

6046
04:52:29,800 --> 04:52:31,080
DAMPENING THIS RESPONSE AND 

6047
04:52:31,080 --> 04:52:34,320
LOOKING AT WHAT IS GOING ON IN 

6048
04:52:34,320 --> 04:52:36,360
THIS CASE.  HERE I'M SHOWING YOU

6049
04:52:36,360 --> 04:52:40,080
A COMPARISON OF INFECTED AND 

6050
04:52:40,080 --> 04:52:41,480
UNINFECTED WILD TYPE GERMINAL 

6051
04:52:41,480 --> 04:52:44,160
CELLS AND WE ARE SEEING NEGATIVE

6052
04:52:44,160 --> 04:52:45,720
ENRICHMENT SCORE THAT MEANS THAT

6053
04:52:45,720 --> 04:52:48,600
GENES INVOLVED IN TYPE 1 

6054
04:52:48,600 --> 04:52:49,960
INTERFERON RESPONSE ARE 

6055
04:52:49,960 --> 04:52:53,720
DOWNREGULATED IN INFECTED CELLS 

6056
04:52:53,720 --> 04:52:54,840
COMPARED TO WILD TYPE 

6057
04:52:54,840 --> 04:52:56,880
COUNTERPARTS AND THAT THIS 

6058
04:52:56,880 --> 04:52:59,320
RESPONSE IS DAMPENED AND ON 

6059
04:52:59,320 --> 04:53:01,560
OTHER HAND COMPARING WILD TYPE 

6060
04:53:01,560 --> 04:53:03,680
INFECT TODAY KNOCKOUT INFECTED 

6061
04:53:03,680 --> 04:53:06,520
CELLS POSITIVE ENRICHMENT SCORE 

6062
04:53:06,520 --> 04:53:09,360
I SEE AND GENES ARE HEIGHTENED 

6063
04:53:09,360 --> 04:53:10,440
ACTUALLY IN EXPRESSION. 

6064
04:53:10,440 --> 04:53:13,520
AND SO IT IS KNOWN THAT STAT3 

6065
04:53:13,520 --> 04:53:17,800
CAN PLAY A ROLE IN DAMPENING OF 

6066
04:53:17,800 --> 04:53:20,200
THIS COMPLEX A MAIN DRIVER OF 

6067
04:53:20,200 --> 04:53:24,520
ISGS IF IN TYPE 1 INTERFERON 

6068
04:53:24,520 --> 04:53:25,960
RESPONSE REGULATION HAS 

6069
04:53:25,960 --> 04:53:28,920
COMBINING WITH OTHER STATS AND 

6070
04:53:28,920 --> 04:53:32,320
REPRESSION ON IRF9 AND MADE A 

6071
04:53:32,320 --> 04:53:34,560
MODEL WITH LOSS OF STAT 3 LEADS 

6072
04:53:34,560 --> 04:53:36,280
TO INCREASE IN SIGNALING 

6073
04:53:36,280 --> 04:53:38,760
MOLECULES LEADING TO OVERALL 

6074
04:53:38,760 --> 04:53:40,080
INCREASE IN FORMATION OF THIS 

6075
04:53:40,080 --> 04:53:42,240
COMPLEX AND LEADING TO INCREASED

6076
04:53:42,240 --> 04:53:44,760
ISGS THAT ARE ACTUALLY EFFECTING

6077
04:53:44,760 --> 04:53:46,960
VIRAL OR VIRUS ITSELF IN MANY 

6078
04:53:46,960 --> 04:53:50,480
DIFFERENT ASPECTS OF LIFECYCLE 

6079
04:53:50,480 --> 04:53:53,120
HOST KRENSING AND DIRECT EFFECTS

6080
04:53:53,120 --> 04:53:55,640
ON VIRAL GENOME AND HERE TO THE 

6081
04:53:55,640 --> 04:53:56,960
RIGHT I'M SHOWING THIS DATA IT 

6082
04:53:56,960 --> 04:53:59,920
THAT IS VALIDATING ISGS IT THAT 

6083
04:53:59,920 --> 04:54:01,680
WE FOUND MOST INTERESTING AND 

6084
04:54:01,680 --> 04:54:06,240
AGAIN WE ARE -- GPPS ARE GENES 

6085
04:54:06,240 --> 04:54:11,520
POINTED OUT TO US MOST HEAVILY. 

6086
04:54:11,520 --> 04:54:14,800
SO, NEXT, WE WANTED TO ALSO 

6087
04:54:14,800 --> 04:54:16,960
VALIDATE ANOTHER ISG THAT WE HAD

6088
04:54:16,960 --> 04:54:20,360
IN OUR HIT THAT ARE IF IT 

6089
04:54:20,360 --> 04:54:22,720
PROTEINS AND IF 1, 2, AND 3 HAVE

6090
04:54:22,720 --> 04:54:24,400
DIFFERENT ANTIVIRAL ACTIVITIES 

6091
04:54:24,400 --> 04:54:27,640
THAT ARE KNOWN AND FOUND THAT IF

6092
04:54:27,640 --> 04:54:30,640
IT 3 WAS ISG HEAVILY UPREGULATED

6093
04:54:30,640 --> 04:54:33,440
IN KNOCKOUT CELLS THEMSELVES AND

6094
04:54:33,440 --> 04:54:37,640
IN COLLABORATION WITH NANCY 

6095
04:54:37,640 --> 04:54:41,440
REISH LAB AT STONEY BROOK 

6096
04:54:41,440 --> 04:54:43,840
UNIVERSITY IF [INDISCERNIBLE] 

6097
04:54:43,840 --> 04:54:46,880
YOU BLOCK REPLICATION OF MHV68 

6098
04:54:46,880 --> 04:54:50,320
IN THIS DATA YOU SEE SHOWING A 

6099
04:54:50,320 --> 04:54:52,920
24-HOUR TIME COURSE.  SO, IN 

6100
04:54:52,920 --> 04:54:54,880
CONCLUSION, LOSS OF STAT 3 AND B

6101
04:54:54,880 --> 04:54:57,680
CELLS LEADS TO GLOBAL IMMUNE 

6102
04:54:57,680 --> 04:55:00,920
DEFECTS ON B AND T CELL 

6103
04:55:00,920 --> 04:55:02,680
RESPONSES IN TWO DISTINCT ANIMAL

6104
04:55:02,680 --> 04:55:06,880
STRAINS AND THERE IS INTRINSIC 

6105
04:55:06,880 --> 04:55:10,080
REQUIREMENT FOR THESE FOR -- AS 

6106
04:55:10,080 --> 04:55:12,720
WELL THIS INFECTION OF GERMINAL 

6107
04:55:12,720 --> 04:55:17,720
CELL B CELLS ALTERED 

6108
04:55:17,720 --> 04:55:19,480
TRANSCRIPTIONAL LANDSCAPE AND 

6109
04:55:19,480 --> 04:55:21,720
UPREGULATION OF GROWTH OF 

6110
04:55:21,720 --> 04:55:22,520
PATHWAYS AND [INDISCERNIBLE] 

6111
04:55:22,520 --> 04:55:25,480
RESPONSE AND SILENCING OF TYPE 1

6112
04:55:25,480 --> 04:55:27,520
INTERFERON RESPONSE AND THESE 

6113
04:55:27,520 --> 04:55:29,960
STUDIES I COVERED SOME NOVEL 

6114
04:55:29,960 --> 04:55:33,040
PROVIRAL RULES FOR STAT 3 WE ARE

6115
04:55:33,040 --> 04:55:35,240
LOOKING FURTHER INTO IN HOPES OF

6116
04:55:35,240 --> 04:55:37,680
PREVENTING LATENCY AND BY THAT 

6117
04:55:37,680 --> 04:55:40,680
WAY PREVENTING VIRUS DRIVEN 

6118
04:55:40,680 --> 04:55:41,640
MALIGNANCIES FROM OCCURRING AND 

6119
04:55:41,640 --> 04:55:43,960
WITH THAT I WOULD LIKE TO THANK 

6120
04:55:43,960 --> 04:55:45,840
MY LAB AND BRANCH AND MANY 

6121
04:55:45,840 --> 04:55:47,080
COLLABORATORS THAT HELPED TO PUT

6122
04:55:47,080 --> 04:55:49,080
THIS WORK TOGETHER.  WITH THAT, 

6123
04:55:49,080 --> 04:55:58,520
I WILL TAKE ANY QUESTIONS. 

6124
04:55:58,520 --> 04:55:59,640
>>QUESTIONS?  

6125
04:55:59,640 --> 04:56:02,160
>>OKAY.  I HAVE A
QUESTION.  

6126
04:56:02,160 --> 04:56:04,760
>>WE HAVE.  THAT ACTUALLY
WAS 

6127
04:56:04,760 --> 04:56:05,960
NOTHING.  THERE WAS NEVER 

6128
04:56:05,960 --> 04:56:07,600
ANYTHING THAT CHANGED BETWEEN 

6129
04:56:07,600 --> 04:56:10,040
THEM BETWEEN WILD TYPE AND 

6130
04:56:10,040 --> 04:56:11,880
KNOCKOUT MICE.  GOOD QUESTION.  

6131
04:56:11,880 --> 04:56:16,920
>>OKAY.  SO, I GUESS WE
CAN 

6132
04:56:16,920 --> 04:56:19,400
MOVE TO THE NEXT SPEAKER. 

6133
04:56:19,400 --> 04:56:21,640
>>FOR THE LAST TALK IN
THE 

6134
04:56:21,640 --> 04:56:26,120
SESSION BEFORE OUR LITTLE BREAK,

6135
04:56:26,120 --> 04:56:28,920
GABRIEL STARRETT WILL TALK ABOUT

6136
04:56:28,920 --> 04:56:31,160
OR TELL US ABOUT VIROMES OF 

6137
04:56:31,160 --> 04:56:34,080
BLADDER CANCERS OF SOLID ORGAN 

6138
04:56:34,080 --> 04:56:36,160
TRANSPLANT RECIPIENTS AND PEOPLE

6139
04:56:36,160 --> 04:56:46,720
LIVING WITH HIV REFLECT RELATIVE

6140
04:56:49,040 --> 04:56:59,280
DISEASE RISK.  

6141
04:57:03,560 --> 04:57:05,080
>>THANKS FOR STICKING
AROUND 

6142
04:57:05,080 --> 04:57:06,800
BEFORE THE BREAK.  INTERESTING 

6143
04:57:06,800 --> 04:57:11,000
STORY TO SHARE WITH YOU TODAY.  

6144
04:57:11,000 --> 04:57:14,360
WHAT EMERGED AS A PILLAR OF 

6145
04:57:14,360 --> 04:57:16,840
CANCER VIROLOGY IS 

6146
04:57:16,840 --> 04:57:18,640
IMMUNOSUPPRESSED PEOPLE 

6147
04:57:18,640 --> 04:57:20,240
TRANSPLANT RECIPIENTS OR PEOPLE 

6148
04:57:20,240 --> 04:57:23,440
LIVING WITH HIV/AIDS ARE IN HIGH

6149
04:57:23,440 --> 04:57:25,440
RISK OF RESOLVING NUMEROUS TYPES

6150
04:57:25,440 --> 04:57:29,120
OF CANCERS THAT IS MOST WELL 

6151
04:57:29,120 --> 04:57:32,320
SEEN WITH [INDISCERNIBLE] SORE 

6152
04:57:32,320 --> 04:57:36,320
COMBA AND MERC CELL CARCINOMA 

6153
04:57:36,320 --> 04:57:38,840
AND FREQUENCIES OF POPULATIONS 

6154
04:57:38,840 --> 04:57:41,880
AND STUDIES LOOKING AT VARIOUS 

6155
04:57:41,880 --> 04:57:43,760
CANCERS THAT INCREASED RISK FOR 

6156
04:57:43,760 --> 04:57:46,400
FURTHER HAVE CONFIRMED THIS 

6157
04:57:46,400 --> 04:57:47,880
SHOWING THAT THIS SARCOMA YOU 

6158
04:57:47,880 --> 04:57:51,000
HAVE AT TOP AND INCLUDES HPV 

6159
04:57:51,000 --> 04:57:52,600
CANCERS WE HEARD ABOUT 

6160
04:57:52,600 --> 04:57:54,080
PREVENTION TODAY AND OTHER 

6161
04:57:54,080 --> 04:57:54,880
CANCERS DOWN HERE THAT DON'T 

6162
04:57:54,880 --> 04:57:57,440
HAVE CLEAR ASSOCIATIONS WITH 

6163
04:57:57,440 --> 04:58:00,040
INFECTIOUS DISEASE AND INCREASED

6164
04:58:00,040 --> 04:58:03,520
INCIDENCE WITHIN POPULATION 

6165
04:58:03,520 --> 04:58:05,520
SUGGEST THEY MIGHT BE WITH 

6166
04:58:05,520 --> 04:58:06,720
INFECTIOUS AGENT AND GOING ALONG

6167
04:58:06,720 --> 04:58:10,200
WITH THIS FOCUSING ON KIDNEY 

6168
04:58:10,200 --> 04:58:12,760
TRANCE CRIPPENTS AND PATIENTS 

6169
04:58:12,760 --> 04:58:15,400
WITH PREVIOUS HISTORY OF 

6170
04:58:15,400 --> 04:58:17,760
VIEREMIA ARE A FURTHER INCREASED

6171
04:58:17,760 --> 04:58:19,280
RISK FOR DEVELOPING BLADDER 

6172
04:58:19,280 --> 04:58:20,600
CANCER SUGGESTING THAT THIS 

6173
04:58:20,600 --> 04:58:23,880
PARTICULAR VIRUS IS ASSOCIATED 

6174
04:58:23,880 --> 04:58:25,000
WITH DEVELOPMENT OF THIS TYPE OF

6175
04:58:25,000 --> 04:58:27,600
CANCER AND THERE IS A CONFUSING 

6176
04:58:27,600 --> 04:58:29,080
RESULT AS WELL AND LOOKING AT 

6177
04:58:29,080 --> 04:58:32,040
PEOPLE LIVING WITH HIV AIDS AND 

6178
04:58:32,040 --> 04:58:34,240
RISK FOR DEVELOPING KIDNEY OR 

6179
04:58:34,240 --> 04:58:35,400
SPECIFICALLY BLADDER CANCER SEEM

6180
04:58:35,400 --> 04:58:39,320
TO BE AT A LOWER RISK FOR 

6181
04:58:39,320 --> 04:58:40,080
DEVELOPING BLADDER CANCER AND 

6182
04:58:40,080 --> 04:58:42,000
OTHER STUDIES HAVE SHOWN THEY 

6183
04:58:42,000 --> 04:58:44,160
HAVE NO INCREASED RISK FOR 

6184
04:58:44,160 --> 04:58:45,280
DEVELOPING BLADDER CANCER.  WHAT

6185
04:58:45,280 --> 04:58:48,080
DOES IT MEAN FOR ASSOCIATION OF 

6186
04:58:48,080 --> 04:58:50,200
BEING CAUSED BY INFECTIOUS 

6187
04:58:50,200 --> 04:58:51,320
AGENT?  THAT IS GIST WHAT I WILL

6188
04:58:51,320 --> 04:58:53,840
TALK ABOUT TODAY.  THIS IS 

6189
04:58:53,840 --> 04:58:55,200
COVERING TWO CASE SERIES.  ONE 

6190
04:58:55,200 --> 04:58:58,040
OF WHICH IS 43 CASES FROM 

6191
04:58:58,040 --> 04:58:59,400
TRANSPLANT RECIPIENTS FROM 

6192
04:58:59,400 --> 04:59:01,520
VARIOUS TYPES OF ORGANS AND WE 

6193
04:59:01,520 --> 04:59:05,280
WERE ABLE TO COLLECT 43 PRIMARY 

6194
04:59:05,280 --> 04:59:08,320
TUMORS AND TISSUES MATCHED WITH 

6195
04:59:08,320 --> 04:59:11,280
15 CASES HERE AND MET AFT ASEIZE

6196
04:59:11,280 --> 04:59:13,920
AND 15 PRIMARY TUMORS FROM 

6197
04:59:13,920 --> 04:59:16,160
PEOPLE LIVING WITH HIV AND AIDS.

6198
04:59:16,160 --> 04:59:19,200
I WANT TO HIGHLIGHT THIS IS 

6199
04:59:19,200 --> 04:59:20,800
RETROSPECTIVE AND ARCHIVED AND 

6200
04:59:20,800 --> 04:59:24,240
WE HAVE DONE TOTAL RNA 

6201
04:59:24,240 --> 04:59:25,960
SEQUENCING AND GENOME SEQUENCING

6202
04:59:25,960 --> 04:59:27,800
AND GIVING PATIENT 

6203
04:59:27,800 --> 04:59:29,600
CHARACTERISTICS OF POPULATIONS 

6204
04:59:29,600 --> 04:59:32,440
TO HIGHLIGHT CAVEATS AND HOW TO 

6205
04:59:32,440 --> 04:59:35,040
INTERPRET THIS.  MEDIAN AGE 

6206
04:59:35,040 --> 04:59:37,600
SIMILAR 65 AND 59 AND GENERAL 

6207
04:59:37,600 --> 04:59:39,480
BLADDER CANCER IS INCREASED 

6208
04:59:39,480 --> 04:59:42,280
FREQUENCY IN MEN THAT IS 3 TO 4 

6209
04:59:42,280 --> 04:59:44,720
OR 1 TO WOMEN AND TRANSPLANT 

6210
04:59:44,720 --> 04:59:47,120
RECIPIENT POPULATION IS FAIRLY 

6211
04:59:47,120 --> 04:59:48,760
REPRESENTATIVE OF BEING 7 TO 3 

6212
04:59:48,760 --> 04:59:51,040
AND HIV POPULATION IS ABOUT 13 

6213
04:59:51,040 --> 04:59:55,480
TO 1.  IT IS SKEWED VERY MUCH TO

6214
04:59:55,480 --> 04:59:56,960
MALE AND MAJOR DIFFERENCE 

6215
04:59:56,960 --> 04:59:58,640
BETWEEN TWO GROUPS WE HAVE 

6216
04:59:58,640 --> 05:00:01,560
TOGETHER IS WE HAVE HIV POSITIVE

6217
05:00:01,560 --> 05:00:03,520
POPULATION THAT SKEWS TOWARDS 

6218
05:00:03,520 --> 05:00:05,400
HAVING MORE ADVANCED DISEASE.  

6219
05:00:05,400 --> 05:00:07,280
THESE ARE MORE -- SO, IN 

6220
05:00:07,280 --> 05:00:10,080
GENERAL, THEY HAVE SIMILAR 

6221
05:00:10,080 --> 05:00:13,120
PROPORTIONS TO INVASIVE BLADDER 

6222
05:00:13,120 --> 05:00:15,280
CANCERS VERSUS NONINVASIVE AND 

6223
05:00:15,280 --> 05:00:18,320
SKEWED TOWARDS METASTATIC AND 

6224
05:00:18,320 --> 05:00:21,520
DEEPER INVADING TUMORS AND IN 

6225
05:00:21,520 --> 05:00:24,360
GENERAL WE HAVE HIGHER-GRADE 

6226
05:00:24,360 --> 05:00:26,880
TUMORS WITHIN THIS COHORT VERSUS

6227
05:00:26,880 --> 05:00:29,520
ORGAN TRANSPLANT RECIPIENTS IN 

6228
05:00:29,520 --> 05:00:30,720
GENERAL REFLECTS WHAT LARGER 

6229
05:00:30,720 --> 05:00:33,200
STUDIES HAVE DONE LOOKING AT 

6230
05:00:33,200 --> 05:00:34,960
OVERALL EPIDEMIOLOGY OF THE TWO 

6231
05:00:34,960 --> 05:00:37,440
DIFFERENT GROUPS AND ADDITIONAL 

6232
05:00:37,440 --> 05:00:39,040
CHARACTERISTICS THAT MIGHT BE 

6233
05:00:39,040 --> 05:00:42,680
RELEVANT HERE AND COUNTS ON 

6234
05:00:42,680 --> 05:00:45,960
AVERAGE WERE 493 CELLS PER MIL. 

6235
05:00:45,960 --> 05:00:49,920
AS WELL AS HIV VIRAL LOAD THAT 

6236
05:00:49,920 --> 05:00:51,720
WAS AT 50.  OTHER IMPORTANT 

6237
05:00:51,720 --> 05:00:55,080
POINT IS ALL PATIENTS WERE ON 

6238
05:00:55,080 --> 05:00:56,760
ANTIVIRAL THERAPY AT TIME THEY 

6239
05:00:56,760 --> 05:00:59,240
WERE DIAGNOSED WITH BLADDER 

6240
05:00:59,240 --> 05:01:01,080
CANCER AND IN GENERAL 

6241
05:01:01,080 --> 05:01:03,920
TRANSPLANTED POPULATION MOSTLY 

6242
05:01:03,920 --> 05:01:07,000
KIDNEY TRANSPLANT RECIPIENTS 

6243
05:01:07,000 --> 05:01:09,240
HEART AND OR LUNG TRANSPLANT 

6244
05:01:09,240 --> 05:01:10,480
RECIPIENTS IS GENERAL WORK FLOW 

6245
05:01:10,480 --> 05:01:13,200
HOW TO PROCESS SAMPLE AND EVERY 

6246
05:01:13,200 --> 05:01:15,520
SAMPLE HAD SECTIONS SENT OFF FOR

6247
05:01:15,520 --> 05:01:20,320
DNA ISOLATION AND RNA ISOLATION 

6248
05:01:20,320 --> 05:01:29,320
AND DID WHOLE GENOME AND TOTAL 

6249
05:01:29,320 --> 05:01:33,560
SEQUENCING [INDISCERNIBLE]. 

6250
05:01:33,560 --> 05:01:36,040
SO, I WILL SHOW THIS TO 

6251
05:01:36,040 --> 05:01:37,200
BASICALLY BRIEFLY GLOSS OVER IT 

6252
05:01:37,200 --> 05:01:40,040
THAT COULD BE SUMMARIZE THE IN 

6253
05:01:40,040 --> 05:01:42,320
THIS PIE CHART THAT IS SHOWING 

6254
05:01:42,320 --> 05:01:47,440
OVER 50% OF TUMORS FROM SOLVENT 

6255
05:01:47,440 --> 05:01:52,080
TRANSPLANT RECIPIENTS CONTAIN 

6256
05:01:52,080 --> 05:01:56,360
THIS AS A RESORT AND SEEMS BK 

6257
05:01:56,360 --> 05:01:58,520
MAY PLAY A ROLE WITHIN THESE.  I

6258
05:01:58,520 --> 05:02:00,040
WILL SHOW ADDITIONAL EVIDENCE 

6259
05:02:00,040 --> 05:02:04,080
FOR THAT AS WELL.  

6260
05:02:04,080 --> 05:02:05,520
NEXT MOST ABUNDANT WERE 

6261
05:02:05,520 --> 05:02:07,440
INTERESTING SINGLE-STRANDED 

6262
05:02:07,440 --> 05:02:10,920
VIRUSES CALLED YELLOW VIRUSES 

6263
05:02:10,920 --> 05:02:15,200
MOST ABUNDANT VIRUSES IN US OR 

6264
05:02:15,200 --> 05:02:22,320
OUR BLOOD STREAM INCREASING 

6265
05:02:22,320 --> 05:02:27,800
FREQUENCY OF [INDISCERNIBLE] AND

6266
05:02:27,800 --> 05:02:28,960
[INDISCERNIBLE] PAPILLOMA 

6267
05:02:28,960 --> 05:02:31,200
VIRUSES AS WELL IN THE TUMORS AS

6268
05:02:31,200 --> 05:02:33,280
WELL.  HIV AND PEOPLE LIVING 

6269
05:02:33,280 --> 05:02:35,440
WITH HIV POPULATION, THERE WERE 

6270
05:02:35,440 --> 05:02:38,360
VERY FEW VIRUSES AND TWO 

6271
05:02:38,360 --> 05:02:38,960
PATIENTS BOTH HAD 

6272
05:02:38,960 --> 05:02:41,160
[INDISCERNIBLE] VIRUSES IN THEM 

6273
05:02:41,160 --> 05:02:43,320
AND MORE THAN ONE VIRUS WITHIN 

6274
05:02:43,320 --> 05:02:45,200
EACH TUMOR AND IT IS EXTENT OF 

6275
05:02:45,200 --> 05:02:48,160
IT VIRIONS OF THESE POPULATIONS 

6276
05:02:48,160 --> 05:02:50,000
LOOK STRIKINGLY DIFFERENT THIS I

6277
05:02:50,000 --> 05:02:53,480
WILL TRY TO ARGUE MAY REFLECT 

6278
05:02:53,480 --> 05:02:55,320
INCREASED RISK WE SEE AT 

6279
05:02:55,320 --> 05:02:57,840
EPIDEMIOLOGICAL LEVEL.  I WANT 

6280
05:02:57,840 --> 05:03:04,080
TO TAKE A MOMENT TO TALK ABOUT 

6281
05:03:04,080 --> 05:03:06,360
[INDISCERNIBLE] VIRUSES WHICH 

6282
05:03:06,360 --> 05:03:08,760
ARE DOUBLE STRANDED CIRCULAR 

6283
05:03:08,760 --> 05:03:12,360
VIRUSES AND WE ARE COVERED IN 

6284
05:03:12,360 --> 05:03:15,960
THEM AND IN GENERAL WITH -- THEY

6285
05:03:15,960 --> 05:03:18,120
DON'T CAUSE PROBLEMS IMMUNE 

6286
05:03:18,120 --> 05:03:19,440
SUPPRESSION COMING INTO PICTURE 

6287
05:03:19,440 --> 05:03:21,640
YOU CAN HAVE VARIOUS SKIN 

6288
05:03:21,640 --> 05:03:23,440
DISEASES OR FATAL BRAIN 

6289
05:03:23,440 --> 05:03:26,480
INFECTION AND MORE COMMONLY WHAT

6290
05:03:26,480 --> 05:03:32,320
WE KNOW ARE NEVER ROP OJY AND 

6291
05:03:32,320 --> 05:03:39,320
CYSTITIS AND AMERICALE CELL 

6292
05:03:39,320 --> 05:03:42,120
POLYOMA VIRUS WHICH IS EMERGING 

6293
05:03:42,120 --> 05:03:43,480
ONCOGENIC VIRUS.  WE ARE COVERED

6294
05:03:43,480 --> 05:03:46,160
IN THESE THINGS AND THEIR 

6295
05:03:46,160 --> 05:03:47,960
INFECTIONS ARE LIFELONG AND 

6296
05:03:47,960 --> 05:03:49,560
SUBCLINICAL AND USUALLY 

6297
05:03:49,560 --> 05:03:53,160
INFECTION HAPPENS SOMETIMES IN 

6298
05:03:53,160 --> 05:03:55,440
EARLY CHILDHOOD. 

6299
05:03:55,440 --> 05:03:57,920
YOU HAVE INLT MITTIENT SHEDDING 

6300
05:03:57,920 --> 05:04:01,080
OF VIRUSES DEPENDING WHAT TISSUE

6301
05:04:01,080 --> 05:04:02,480
THEY ARE IN. 

6302
05:04:02,480 --> 05:04:05,240
SKIN VIRUSES COMING OUT OF 

6303
05:04:05,240 --> 05:04:07,240
YOU'RIN AND 10% OF PEOPLE ARE 

6304
05:04:07,240 --> 05:04:09,280
SHEDDING SOME SF THE VIRUSES AND

6305
05:04:09,280 --> 05:04:12,320
SHEDDING INCREASES AND VIRUS 

6306
05:04:12,320 --> 05:04:13,760
REPLICATION INCREASES DURING 

6307
05:04:13,760 --> 05:04:15,560
IMMUNE SUPPRESSION AND INCLUDING

6308
05:04:15,560 --> 05:04:18,400
PREGNANCY AND ALSO HIV AND 

6309
05:04:18,400 --> 05:04:20,560
INCLUDING DRUGS AND AGING 

6310
05:04:20,560 --> 05:04:22,480
INCREASING VIRAL SHEDDING AND 

6311
05:04:22,480 --> 05:04:24,320
WHEN WE TEND TO SEE AMERICALE 

6312
05:04:24,320 --> 05:04:27,200
CELL CARCINOMA IS CANCER WITH 

6313
05:04:27,200 --> 05:04:30,760
PEOPLE WITH VERY ADVANCED AGE 

6314
05:04:30,760 --> 05:04:33,160
AND POLYOMA VIRUSES ARE SMALL 

6315
05:04:33,160 --> 05:04:35,640
SINGLE STRANDED DNA VIRUSS THAT 

6316
05:04:35,640 --> 05:04:37,440
ARE SIMPLE YOU CAN DIVIDE GENOME

6317
05:04:37,440 --> 05:04:40,280
INTO THREE PIECES EARLY REGION 

6318
05:04:40,280 --> 05:04:43,600
VIRAL T ANTIGENS AND YOU HAVE 

6319
05:04:43,600 --> 05:04:47,520
SAME FUNCTIONS OF THESE THAT HPV

6320
05:04:47,520 --> 05:04:51,080
HAS AND THEY CONTAIN VIRAL 

6321
05:04:51,080 --> 05:04:52,680
HELICASE THAT HAS THIS AND 

6322
05:04:52,680 --> 05:04:56,160
CAPSID PROTEINS AND NONCODING 

6323
05:04:56,160 --> 05:04:58,000
CONTROL REGION BIDIRECTIONAL 

6324
05:04:58,000 --> 05:04:59,480
PROMOTER THAT CONTROLS BOTH OF 

6325
05:04:59,480 --> 05:05:03,040
THESE AND NOW LOOKING AT THIS 

6326
05:05:03,040 --> 05:05:04,320
TRANSPLANT RECIPIENT POPULATION 

6327
05:05:04,320 --> 05:05:05,840
LOOKING SPECIFICALLY AT 

6328
05:05:05,840 --> 05:05:08,320
CONFIRMATION OF THE GENOME WE 

6329
05:05:08,320 --> 05:05:12,680
SEE PRETTY HETEROGENOUS BOTH RNA

6330
05:05:12,680 --> 05:05:14,360
EXPRESSION AND WHAT IS 

6331
05:05:14,360 --> 05:05:15,040
REPRESENTATIVE OF THIS WITHIN 

6332
05:05:15,040 --> 05:05:19,320
SOME OF THE TUMORS AND WHAT WE 

6333
05:05:19,320 --> 05:05:22,080
SEE IN LIKE THIS TUMOR IS WE SEE

6334
05:05:22,080 --> 05:05:24,600
VERY, VERY HIGH AND CONSISTENT 

6335
05:05:24,600 --> 05:05:27,240
COVERAGE OF THIS VIRUS GENOME 

6336
05:05:27,240 --> 05:05:28,680
ACROSS THE BOARD AND SEE HIGH 

6337
05:05:28,680 --> 05:05:30,200
EXPRESSION OF BOTH OF THE LATE 

6338
05:05:30,200 --> 05:05:32,800
AS WELL AS EARLY REGIONS AND 

6339
05:05:32,800 --> 05:05:35,040
WHAT WAS UNUSUAL WITHIN TUMOR IS

6340
05:05:35,040 --> 05:05:38,680
1% OF TUMORS EXPRESSED T ANTIGEN

6341
05:05:38,680 --> 05:05:41,360
WE COULD SEE AND ADDITIONAL 

6342
05:05:41,360 --> 05:05:43,120
AMOUNTS SUGGEST THIS IS A 

6343
05:05:43,120 --> 05:05:45,360
PRIMARY TUMOR INFECTED WITH BK 

6344
05:05:45,360 --> 05:05:47,200
THAT DOESN'T CONTAIN INTEGRATED 

6345
05:05:47,200 --> 05:05:49,280
FORM THAT WE WOULD EXPECT WITH 

6346
05:05:49,280 --> 05:05:51,920
HPV ASSOCIATED CANCERS AND OTHER

6347
05:05:51,920 --> 05:05:54,480
HAND HAVE THIS TUMOR THERE IS 

6348
05:05:54,480 --> 05:05:56,360
DRASTIC DIFFERENCES IN COVERAGE 

6349
05:05:56,360 --> 05:05:58,680
PLOTS IN THIS GENOME AND LARGE 

6350
05:05:58,680 --> 05:06:00,080
DELETION IN MIDDLE OF THIS.  

6351
05:06:00,080 --> 05:06:01,760
THIS IS CONSISTENT WITH WHAT YOU

6352
05:06:01,760 --> 05:06:05,560
WOULD SEE WITH HPV INTEGRATED 

6353
05:06:05,560 --> 05:06:09,320
INTO CERVICAL CANCER AND THERE 

6354
05:06:09,320 --> 05:06:10,440
IS A BREAK POINT WITH 

6355
05:06:10,440 --> 05:06:12,800
DUPLICATIONS AND THIS LEADS TO 

6356
05:06:12,800 --> 05:06:15,240
VERY HIGH EXPRESSION OF T 

6357
05:06:15,240 --> 05:06:18,360
ANTIGEN REGION INACTIVATES 

6358
05:06:18,360 --> 05:06:20,320
HELICASE AS WELL WRU HAVE A 

6359
05:06:20,320 --> 05:06:22,000
JUFRPGS HERE AND IN THIS TUMOR 

6360
05:06:22,000 --> 05:06:25,280
AND OTHER ONE WE SEE 100% OF 

6361
05:06:25,280 --> 05:06:27,240
TUMORS EXPRESSING VIRAL LARGE 

6362
05:06:27,240 --> 05:06:29,520
ANTIGEN SUGGESTING THAT THIS 

6363
05:06:29,520 --> 05:06:31,280
VIRUS IS VERY IMPORTANT FOR 

6364
05:06:31,280 --> 05:06:32,320
DEVELOPMENT OF THIS TUMOR 

6365
05:06:32,320 --> 05:06:33,600
FURTHER SUPPORTING IT THIS WE 

6366
05:06:33,600 --> 05:06:37,000
HAVE A PRIMARY AND METASTATIC 

6367
05:06:37,000 --> 05:06:39,200
TUMOR PAIR WE SEE A SIMILAR 

6368
05:06:39,200 --> 05:06:41,240
THING AND MAINTENANCE OF THIS 

6369
05:06:41,240 --> 05:06:44,360
VIRUS DNA AS WELL AS RNA 

6370
05:06:44,360 --> 05:06:45,440
EXPRESSION THAT IS IDENTICAL 

6371
05:06:45,440 --> 05:06:47,000
BETWEEN THESE WITH 

6372
05:06:47,000 --> 05:06:47,720
REARRANGEMENTS AND DELETIONS 

6373
05:06:47,720 --> 05:06:49,960
THAT IS HARD TO SEE ON THIS.  

6374
05:06:49,960 --> 05:06:51,920
THESE HAVE VERY DIM BROWN STAIN 

6375
05:06:51,920 --> 05:06:55,080
FOR LARGE T ANTIGEN AND THESE 

6376
05:06:55,080 --> 05:06:58,040
INCREASE A LITTLE IN INTENSITY 

6377
05:06:58,040 --> 05:06:59,680
FOR THIS FURTHER SUGGESTING 

6378
05:06:59,680 --> 05:07:02,880
COURSE OF METASTASIS AND THESE 

6379
05:07:02,880 --> 05:07:04,840
ANTIGENS MIGHT BE IMPORTANT FOR 

6380
05:07:04,840 --> 05:07:05,960
SURVIVAL OF THE TUMOR AND WE 

6381
05:07:05,960 --> 05:07:09,680
WERE ABLE TO GO THROUGH AND 

6382
05:07:09,680 --> 05:07:11,800
CHARACTERIZE NUMEROUS 

6383
05:07:11,800 --> 05:07:13,280
INTEGRATION SITES SOME TUMORS 

6384
05:07:13,280 --> 05:07:15,400
HAD MANY INTEGRATION SITES AND 

6385
05:07:15,400 --> 05:07:18,080
OTHERS HAD SINGLE INTEGRATION 

6386
05:07:18,080 --> 05:07:19,840
SITE WE COULD SEE WITHIN THEM 

6387
05:07:19,840 --> 05:07:22,840
AND THESE INTEGRATIONS ALSO TEND

6388
05:07:22,840 --> 05:07:25,320
TO OVERLAP WITH AMPLIFICATIONS 

6389
05:07:25,320 --> 05:07:27,360
OF HOST GENOME INDICATING YOU 

6390
05:07:27,360 --> 05:07:29,840
GET BREAKS AND REARRANGEMENTS IN

6391
05:07:29,840 --> 05:07:32,480
VIRAL GENOME AND BREAKS AND 

6392
05:07:32,480 --> 05:07:34,040
REARRANGEMENTS IN AMPLIFICATIONS

6393
05:07:34,040 --> 05:07:36,840
OF HOST DNA CLEARLY SHOWN HERE 

6394
05:07:36,840 --> 05:07:39,720
EXAMPLE OF CHROMOSOME 1 AND 

6395
05:07:39,720 --> 05:07:42,360
WHERE THIS POLYOMA VIRUS IS 

6396
05:07:42,360 --> 05:07:44,400
INTEGRATED AND 11 COPIES OF THIS

6397
05:07:44,400 --> 05:07:47,120
SECTION OF HUMAN GENOME AND 8 

6398
05:07:47,120 --> 05:07:49,960
COPIES HERE AND BLUE LINE IS 

6399
05:07:49,960 --> 05:07:52,560
DIPLOID COPY OF HUMAN ADJACENT 

6400
05:07:52,560 --> 05:07:54,200
DNA AND SHOWN FOR THIS TUMOR 

6401
05:07:54,200 --> 05:07:56,280
THIS IS SIMILARLY SIZE THE 

6402
05:07:56,280 --> 05:07:59,400
REGION AND SINGLE COPY GAIN AND 

6403
05:07:59,400 --> 05:08:01,480
LARGE REGION WITH TWO-COPY GAIN 

6404
05:08:01,480 --> 05:08:04,800
WITH 200 KILOBASES AND DON'T 

6405
05:08:04,800 --> 05:08:09,520
KNOW FUNCTION WITHIN THESE 

6406
05:08:09,520 --> 05:08:11,560
TUMORS DON'T SEE DISTINCTION IN 

6407
05:08:11,560 --> 05:08:15,560
THIS -- THESE CAN CREATE 

6408
05:08:15,560 --> 05:08:16,760
SUPERENHANCERS CHANGING -- THAT 

6409
05:08:16,760 --> 05:08:19,200
CAN EFFECT TUMOR BIOLOGY AND 

6410
05:08:19,200 --> 05:08:20,640
FUTURE WORK BY MY GROUP IS 

6411
05:08:20,640 --> 05:08:22,800
UNDERSTANDING HOW BK CAN CAUSE 

6412
05:08:22,800 --> 05:08:26,840
CANCER THROUGH SOME OF THE OTHER

6413
05:08:26,840 --> 05:08:27,400
MECHANISMS.  

6414
05:08:27,400 --> 05:08:29,080
AND MY LAST LITTLE POINT THAT IS

6415
05:08:29,080 --> 05:08:31,280
KIND OF SUPPORTING FACT THAT 

6416
05:08:31,280 --> 05:08:32,840
THIS VIRUS IS PLAYING A VERY 

6417
05:08:32,840 --> 05:08:36,280
LARGE ROLE IN TUMORS OF THESE 

6418
05:08:36,280 --> 05:08:38,480
TRANSPLANT RECIPIENTS IS SEEING 

6419
05:08:38,480 --> 05:08:41,080
FINGERPRINTS OF LARGE T ANTIGEN 

6420
05:08:41,080 --> 05:08:42,440
ACTIVITY BRIEFLY TALKED ABOUT 

6421
05:08:42,440 --> 05:08:44,680
THAT IS IMPORTANT FUNCTIONS IN 6

6422
05:08:44,680 --> 05:08:48,280
AND 7 AND IT BINDS AND 

6423
05:08:48,280 --> 05:08:51,720
INACTIVATES P53 AND RB AND SEE 

6424
05:08:51,720 --> 05:08:53,600
STRONG WITHIN BK POSITIVE TUMORS

6425
05:08:53,600 --> 05:08:57,120
HERE IN RED WE SEE DRASTIC 

6426
05:08:57,120 --> 05:08:58,640
EFFECTS ON CELL CYCLE GENES THAT

6427
05:08:58,640 --> 05:09:01,800
ARE RELATED TO TRANSCRIPTION 

6428
05:09:01,800 --> 05:09:04,080
FACTORS CONTROLLED BY RB-LIKE 

6429
05:09:04,080 --> 05:09:06,680
FAMILY MEMBERS AND GOT TALK 

6430
05:09:06,680 --> 05:09:09,680
ABOUT APO BECK 3 THAT IN WORK IS

6431
05:09:09,680 --> 05:09:12,000
SHOWN TO BE SUPPRESSED BY THE 

6432
05:09:12,000 --> 05:09:13,720
DREAM COMPLEX THAT IS VERY 

6433
05:09:13,720 --> 05:09:16,960
HIGHLY EXPRESSED AND WANT TO 

6434
05:09:16,960 --> 05:09:20,280
HIGHLIGHT THAT IS THE DOMINANT 

6435
05:09:20,280 --> 05:09:22,080
MUTATION SIGNATURE WITHIN 

6436
05:09:22,080 --> 05:09:23,640
BLADDER CANCER AND SUGGESTING 

6437
05:09:23,640 --> 05:09:25,920
THAT, THAT IS A POTENTIAL 

6438
05:09:25,920 --> 05:09:28,680
MECHANISM FOR HOW THE VIRUS IS 

6439
05:09:28,680 --> 05:09:30,680
CONTRIBUTING TO CARCINOGEN ESIS 

6440
05:09:30,680 --> 05:09:33,040
AND CONCLUDING THIS TALK AND SO 

6441
05:09:33,040 --> 05:09:35,840
REALLY THE MAIN TAKEAWAY IS DNA 

6442
05:09:35,840 --> 05:09:39,080
VIRUSES ARE RELATIVELY COMMON 

6443
05:09:39,080 --> 05:09:42,680
BLADDER CANCERS WITH TRANSPLANT 

6444
05:09:42,680 --> 05:09:44,360
RECIPIENTS RARELY IN PEOPLE WITH

6445
05:09:44,360 --> 05:09:46,720
HIV AND PROVIDING EXPLANATION 

6446
05:09:46,720 --> 05:09:48,400
WHY THERE IS SIFRNS IN OVERALL 

6447
05:09:48,400 --> 05:09:50,640
RISK WITHIN POPULATIONS FOR 

6448
05:09:50,640 --> 05:09:52,360
DEVELOPING BLADDER CANCER AND 

6449
05:09:52,360 --> 05:09:54,280
SUPPORTING THIS IDEA THAT 

6450
05:09:54,280 --> 05:09:55,880
VIRUSES CAN CAUSE BLADDER CANCER

6451
05:09:55,880 --> 05:09:59,400
WITHIN OUR COHORTS WE ARE SEEING

6452
05:09:59,400 --> 05:10:02,800
MAINTENANCE WHAT INTEGRATE VIRAL

6453
05:10:02,800 --> 05:10:06,080
GM IN METASTATIC LEGIONS AND 

6454
05:10:06,080 --> 05:10:07,280
MECHANISMS SIMILAR TO WHAT WE 

6455
05:10:07,280 --> 05:10:10,440
SEE FOR HPV AND VIRUS MEDIATED 

6456
05:10:10,440 --> 05:10:14,040
CANCERS AND ALSO WANT TO SAY WE 

6457
05:10:14,040 --> 05:10:17,920
SAW WITHIN ONE HPV -- PRIMARY 

6458
05:10:17,920 --> 05:10:20,520
AND METASTATIC TUMOR AND NOW I 

6459
05:10:20,520 --> 05:10:23,640
WANT TO PAUSE FOR QUESTIONS TO 

6460
05:10:23,640 --> 05:10:25,840
EVERYONE IS SOMETHING THEN 

6461
05:10:25,840 --> 05:10:27,280
INTRINSIC ALLEY DIFFERENCE IN 

6462
05:10:27,280 --> 05:10:28,560
IMMUNE SUPPRESSION BETWEEN TWO 

6463
05:10:28,560 --> 05:10:30,640
POPULATIONS EXPLAINING THIS 

6464
05:10:30,640 --> 05:10:31,600
PHENOMENON?  WE KNOW THERE ARE 

6465
05:10:31,600 --> 05:10:33,640
DIFFERENCES AND IS IT ENOUGH TO 

6466
05:10:33,640 --> 05:10:35,720
EXPLAIN WHY PEOPLE LIVING WITH 

6467
05:10:35,720 --> 05:10:38,960
HIV WE DON'T SEE SAME TYPES OF 

6468
05:10:38,960 --> 05:10:40,400
VIRUSES WE SEE IN THIS OTHER 

6469
05:10:40,400 --> 05:10:41,360
POPULATION OR SOMETHING 

6470
05:10:41,360 --> 05:10:43,000
DIFFERENT WITH THE WAY THAT WE 

6471
05:10:43,000 --> 05:10:46,160
SURVEIL THESE PATIENTS I SHOW 

6472
05:10:46,160 --> 05:10:48,960
DIFFERENCE IN ADVANCE BETWEEN 

6473
05:10:48,960 --> 05:10:51,600
TUMORS IN THESE POPULATIONS AND 

6474
05:10:51,600 --> 05:10:54,680
ACTIVELY SCREENED FOR IN 

6475
05:10:54,680 --> 05:10:58,080
INDIVIDUALS THAT ARE SOLVENT 

6476
05:10:58,080 --> 05:11:02,080
TRANCE SIPPENT -- IS THERE A 

6477
05:11:02,080 --> 05:11:06,040
GREATER ROLE OF TUMOR VIRUS AS 

6478
05:11:06,040 --> 05:11:07,480
CROSS THE BOARD WITH BLADDER 

6479
05:11:07,480 --> 05:11:11,440
CANCER I ARGUE PROBABLY 

6480
05:11:11,440 --> 05:11:14,480
HOPEFULLY EVERYTHING TURNS OUT 

6481
05:11:14,480 --> 05:11:16,040
WITH RESEARCH. 

6482
05:11:16,040 --> 05:11:17,440
ACKNOWLEDGING THOSE IN MY GROUP 

6483
05:11:17,440 --> 05:11:20,360
AS WELL AS CLOSE COLLABORATORS 

6484
05:11:20,360 --> 05:11:22,080
ESPECIALLY ERIC WHO IS 

6485
05:11:22,080 --> 05:11:23,520
EPIDEMIOLOGISTS I WOULDN'T HAVE 

6486
05:11:23,520 --> 05:11:25,200
GOTTEN ANY SAMPLES WITHOUT HIM 

6487
05:11:25,200 --> 05:11:30,120
AND VERY USEFUL RESOURCES FROM 

6488
05:11:30,120 --> 05:11:32,360
BIOWOLF OUR SEQUENCING 

6489
05:11:32,360 --> 05:11:34,920
FISTILITIES AND COLLABORATORS AT

6490
05:11:34,920 --> 05:11:37,080
HOSPITALS THROUGHOUT THE US THAT

6491
05:11:37,080 --> 05:11:38,760
HELPS US GET THESE SAMPLES AND 

6492
05:11:38,760 --> 05:11:43,680
WITH THAT I WILL TAKE QUESTIONS.

6493
05:11:43,680 --> 05:11:44,920
>>[APPLAUSE]. 

6494
05:11:44,920 --> 05:11:50,680
>>[INDISCERNIBLE]. 

6495
05:11:50,680 --> 05:11:59,320
>>THAT WOULD BE
INTERESTING TO 

6496
05:11:59,320 --> 05:12:01,200
LOOK AT IN GENERAL POPULATIONS 

6497
05:12:01,200 --> 05:12:03,680
IN ABSENCE OF CANCER AND WITHIN 

6498
05:12:03,680 --> 05:12:06,280
POPULATIONS WE DIDN'T SEE A 

6499
05:12:06,280 --> 05:12:07,840
GREATER ENRICHMENT OF MALE 

6500
05:12:07,840 --> 05:12:09,400
TUMORS HAVING MORE OF A 

6501
05:12:09,400 --> 05:12:10,800
PARTICULAR VIRUS THAN WHAT WE 

6502
05:12:10,800 --> 05:12:15,360
SAW IN FEMALE TUMORS THAT WAS 

6503
05:12:15,360 --> 05:12:20,160
SURPRISINGLY EVEN. 

6504
05:12:20,160 --> 05:12:22,600
YEAH.  

6505
05:12:22,600 --> 05:12:30,920
>>[INDISCERNIBLE]. 
VIRENIA IS 

6506
05:12:30,920 --> 05:12:36,480
NOT IN HEALTHY PEOPLE.  VIRURIA 

6507
05:12:36,480 --> 05:12:40,080
IS ABOUT 10-ISH PERCENT OF THE 

6508
05:12:40,080 --> 05:12:42,920
POPULATION AT ANY GIVEN MOMENT. 

6509
05:12:42,920 --> 05:12:46,840
>>FAIRLY INTERESTING
TRANSPLANT

6510
05:12:46,840 --> 05:12:54,040
RECIPIENTS HAVE [INDISCERNIBLE].

6511
05:12:54,040 --> 05:12:55,840
>>I SKIMMED OVER THAT A
LITTLE 

6512
05:12:55,840 --> 05:12:59,480
BIT AND LONG TIME THIS IS 

6513
05:12:59,480 --> 05:13:02,080
EMERGING HYPOTHESIS IN KIDNEY 

6514
05:13:02,080 --> 05:13:04,360
TRANCE PLANTS AND THESE VIRUSES 

6515
05:13:04,360 --> 05:13:06,920
REMAIN PERSISTENT AND SEEMS IT 

6516
05:13:06,920 --> 05:13:09,400
IS QUITE POSSIBLE A NEW VIRAL 

6517
05:13:09,400 --> 05:13:11,640
GENOTYPE INTRODUCED FROM THE 

6518
05:13:11,640 --> 05:13:13,960
GRAFT IS WHAT CAN INCREASE RISK 

6519
05:13:13,960 --> 05:13:15,800
FOR THAT PERSON DEVELOPING 

6520
05:13:15,800 --> 05:13:18,040
BLADDER CANCER AND HOLDS UP WITH

6521
05:13:18,040 --> 05:13:22,360
THAT HYPOTHESIS SHOWS TRUE FORM 

6522
05:13:22,360 --> 05:13:27,840
OF NEVER OPATHY MAKES SENSE.  IT

6523
05:13:27,840 --> 05:13:30,240
CAN REPLICATE AND LOSE THE 

6524
05:13:30,240 --> 05:13:31,720
KIDNEY AND DOESN'T HOLD UP FOR 

6525
05:13:31,720 --> 05:13:33,560
BLADDER CANCER.  ALSO WHAT WAS A

6526
05:13:33,560 --> 05:13:36,360
BIG ADVANTAGE OF THE STUDY IS IT

6527
05:13:36,360 --> 05:13:41,000
WASN'T JUST KIDNEY TRANSPLANT 

6528
05:13:41,000 --> 05:13:43,160
RECIPIENTS PREVIOUS CASE STUDIES

6529
05:13:43,160 --> 05:13:45,240
FOCUSED ON WE HAVE HEART LUNG 

6530
05:13:45,240 --> 05:13:46,440
AND HEART LIVER AND COUPLE ARE 

6531
05:13:46,440 --> 05:13:49,800
FROM HEART LUNG ONE IS A LIVER 

6532
05:13:49,800 --> 05:13:51,200
TRANSPLANT RECIPIENT AND THEY 

6533
05:13:51,200 --> 05:13:53,200
DON'T FULLY EXPLAIN IDEA OF 

6534
05:13:53,200 --> 05:13:55,360
INTRODUCTION OF NEW GENOTYPE 

6535
05:13:55,360 --> 05:13:58,080
FROM THE GRAFT ORGAN AS FAR AS 

6536
05:13:58,080 --> 05:13:59,960
WE UNDERSTAND THIS VIRUS IT 

6537
05:13:59,960 --> 05:14:03,880
DOESN'T JUST RESIDE WITHIN THE 

6538
05:14:03,880 --> 05:14:04,120
ORGANS. 

6539
05:14:04,120 --> 05:14:11,360
>>THANK YOU. 

6540
05:14:11,360 --> 05:14:12,440
>>THANK YOU. 

6541
05:14:12,440 --> 05:14:13,840
>>[APPLAUSE]. 

6542
05:14:13,840 --> 05:14:19,360
>>SHORT BREAK.  BE BACK
AT 

6543
05:14:19,360 --> 05:14:24,080
4:10. 

6544
05:14:24,080 --> 05:14:29,600
IT IS MY PLEASURE TO INTRODUCE 

6545
05:14:29,600 --> 05:14:33,480
DR. IRINI SERETI WHO IS THE NEXT

6546
05:14:33,480 --> 05:14:38,200
SPEAKER AND SENIOR INVESTIGATOR 

6547
05:14:38,200 --> 05:14:43,880
AND CHIEF OF -- AT NIAD. 

6548
05:14:43,880 --> 05:14:49,400
SO, SHE GOT HER MD IN ATHENS 

6549
05:14:49,400 --> 05:14:57,720
GREECE AT UNIVERSITY OF NATIONAL

6550
05:14:57,720 --> 05:15:01,200
CAPODISTRIAN UNIVERSITY AND 

6551
05:15:01,200 --> 05:15:03,280
COMPLETED MHS AT DUKE UNIVERSITY

6552
05:15:03,280 --> 05:15:08,680
AND CAME TO THE NIAD IN 

6553
05:15:08,680 --> 05:15:10,240
INFECTIOUS DISEASES FELLOWSHIP 

6554
05:15:10,240 --> 05:15:15,440
AND STAYED ON AS A CLINICAL 

6555
05:15:15,440 --> 05:15:16,560
INVESTIGATOR RECEIVING HER 

6556
05:15:16,560 --> 05:15:19,040
TENURE IN 2015 AND PUBLISHED 

6557
05:15:19,040 --> 05:15:22,800
MORE THAN 200 PAPERS AND 

6558
05:15:22,800 --> 05:15:25,640
RECENTLY WAS NAMED AN EXECUTIVE 

6559
05:15:25,640 --> 05:15:30,480
LEADERSHIP IN ACADEMIC MEDICINE 

6560
05:15:30,480 --> 05:15:31,840
FELLOW THIS YEAR. 

6561
05:15:31,840 --> 05:15:36,560
SHE IS AN UPCOME AGO ASSOCIATE 

6562
05:15:36,560 --> 05:15:38,160
EDITOR IN INFECTIOUS DISEASES 

6563
05:15:38,160 --> 05:15:41,520
AND EXECUTIVE MEMBER OF NIH 

6564
05:15:41,520 --> 05:15:43,400
OXFORD CAMBRIDGE SCHOLARS 

6565
05:15:43,400 --> 05:15:47,560
PROGRAM AND ASSOCIATED 

6566
05:15:47,560 --> 05:15:51,840
INFLAMMATION AND IN BOTH CLINIC 

6567
05:15:51,840 --> 05:15:53,480
AND LABORATORY.  

6568
05:15:53,480 --> 05:15:56,800
WELCOME.  WE LOOK FORWARD TO 

6569
05:15:56,800 --> 05:16:00,200
YOUR TALK. 

6570
05:16:00,200 --> 05:16:10,760
>>I WILL GET MY FACE OUT
OF IT.

6571
05:16:13,000 --> 05:16:14,880
>>THAT IS A GREAT
PICTURE. 

6572
05:16:14,880 --> 05:16:16,560
>>I HAVE THE NAME OF THE
PERSON

6573
05:16:16,560 --> 05:16:18,880
WHO TOOK IT.  IT WAS FROM HERE 

6574
05:16:18,880 --> 05:16:20,360
FROM NIH. 

6575
05:16:20,360 --> 05:16:22,280
GREAT.  THANKS FOR THE KIND 

6576
05:16:22,280 --> 05:16:24,960
INTRODUCTION AND SO MUCH FOR THE

6577
05:16:24,960 --> 05:16:28,320
INVITATION FOR SUCH A WONDERFUL 

6578
05:16:28,320 --> 05:16:30,320
MEETING.  I GOT IMPOSTER 

6579
05:16:30,320 --> 05:16:31,520
SYNDROME AND FELT I SHOULD BE 

6580
05:16:31,520 --> 05:16:34,000
ACROSS THE HALL IN THE 

6581
05:16:34,000 --> 05:16:36,960
IMMUNOLOGY MEETING.  ANYWAY, 

6582
05:16:36,960 --> 05:16:40,200
FORGIVE ME FOR BEING 

6583
05:16:40,200 --> 05:16:42,360
UNAPOLOGETICALLY CLINICAL IN 

6584
05:16:42,360 --> 05:16:44,320
IMMUNOLOGY THAN VIROLOGY I WILL 

6585
05:16:44,320 --> 05:16:46,200
DISCUSS INFLAMMATORY SYNDROMES 

6586
05:16:46,200 --> 05:16:49,640
WE SEE IN PEOPLE WITH ADVANCED 

6587
05:16:49,640 --> 05:16:52,200
HIV STARTING ANTIRETROVIRAL 

6588
05:16:52,200 --> 05:16:54,280
THERAPY AND WAYS FOR 

6589
05:16:54,280 --> 05:16:56,960
INTRODUCTION REMINDING WHERE WE 

6590
05:16:56,960 --> 05:17:01,280
ARE IN HIV EPIDEMIC.  

6591
05:17:01,280 --> 05:17:03,920
HALF OF THEM ARE WOMEN AND GIRLS

6592
05:17:03,920 --> 05:17:08,000
AND IN TREATMENT CASCADE, WE ARE

6593
05:17:08,000 --> 05:17:11,640
TRYING TO REACH -- AND ARE 

6594
05:17:11,640 --> 05:17:14,920
CLOSER TO 85, 73, 66 AT THE 

6595
05:17:14,920 --> 05:17:15,680
MOMENT AND IMPORTANTLY 

6596
05:17:15,680 --> 05:17:19,920
POPULATION WITH HIV IS AGING AND

6597
05:17:19,920 --> 05:17:22,560
ESTIMATED THAT ABOUT 75% OR 73% 

6598
05:17:22,560 --> 05:17:27,280
WILL BE OVER 50 YEARS OF AGE BY 

6599
05:17:27,280 --> 05:17:30,680
2030.  

6600
05:17:30,680 --> 05:17:31,880
UNFORTUNATELY, WE KNOW THAT THE 

6601
05:17:31,880 --> 05:17:34,840
BEST OUTCOMES IN HIV ARE WHEN 

6602
05:17:34,840 --> 05:17:39,520
PEOPLE GET STARTED ON THERAPY AT

6603
05:17:39,520 --> 05:17:40,800
HIGH -- CURRENT TREATMENT 

6604
05:17:40,800 --> 05:17:44,560
GUIDELINES INCLUDING WHO ARE TO 

6605
05:17:44,560 --> 05:17:47,120
START THERAPY AT CD4 COUNTS OF 

6606
05:17:47,120 --> 05:17:50,000
500 AND UPON HIV DIAGNOSIS 

6607
05:17:50,000 --> 05:17:51,920
BASICALLY.  WE ARE DEALING WITH 

6608
05:17:51,920 --> 05:17:54,800
A PERSISTENT PROBLEM OF LATE 

6609
05:17:54,800 --> 05:17:56,560
PRESENTATION TO CARE AND PEOPLE 

6610
05:17:56,560 --> 05:17:58,040
PRESENTING WITH ADVANCED DISEASE

6611
05:17:58,040 --> 05:18:00,720
THAT ARE DATA FROM EUROPE 

6612
05:18:00,720 --> 05:18:03,680
ACTUALLY SHOWING 50% OF PATIENTS

6613
05:18:03,680 --> 05:18:06,400
ACCOUNT FOR LESS THAN 350 AND 

6614
05:18:06,400 --> 05:18:07,680
START THERAPY AND IF YOU THINK 

6615
05:18:07,680 --> 05:18:10,600
IT IS BETTER, YOU ARE WRONG AND 

6616
05:18:10,600 --> 05:18:14,360
MEDIAN CD4 CURRENTLY ARE FAIRLY 

6617
05:18:14,360 --> 05:18:17,240
RECENT DATA FROM FEW YEARS AGO 

6618
05:18:17,240 --> 05:18:18,760
PEOPLE THAT ARE 50 YEARS OR 

6619
05:18:18,760 --> 05:18:21,360
OLDER AND CLOSE TO 400 FOR 

6620
05:18:21,360 --> 05:18:23,040
PEOPLE YOUNGER THAN 50 YEARS OF 

6621
05:18:23,040 --> 05:18:23,440
AGE. 

6622
05:18:23,440 --> 05:18:25,240
SO, THAT OBVIOUSLY MATTERS AND 

6623
05:18:25,240 --> 05:18:27,560
THIS IS ALSO DATA FROM THE CDC 

6624
05:18:27,560 --> 05:18:30,400
AND FROM THE US THAT IS SHOWING 

6625
05:18:30,400 --> 05:18:32,840
A VERY -- AGAIN, PERSISTENT 

6626
05:18:32,840 --> 05:18:34,200
PROPORTION THAT IS CLOSE TO 20% 

6627
05:18:34,200 --> 05:18:35,880
OF PEOPLE PRESENTING WITH STAGE 

6628
05:18:35,880 --> 05:18:38,600
3 OR AIDS CLASSIFICATION. 

6629
05:18:38,600 --> 05:18:42,360
AND THIS EFFECTS MORE MINORITIES

6630
05:18:42,360 --> 05:18:44,800
THAT ARE COMPARED TO WHITE 

6631
05:18:44,800 --> 05:18:47,360
PATIENTS NOT HISPANIC PATIENTS 

6632
05:18:47,360 --> 05:18:49,560
AND ARE PEOPLE THAT WE STUDY IN 

6633
05:18:49,560 --> 05:18:51,840
THE CLINIC AND THAT HAVE AN 

6634
05:18:51,840 --> 05:18:55,440
INTEREST IN ADVANCED HIV DISEASE

6635
05:18:55,440 --> 05:18:58,480
AND I COLLABORATE CLOSELY WITH 

6636
05:18:58,480 --> 05:19:02,840
BOB'S GROUP AND RAMASWANI'S 

6637
05:19:02,840 --> 05:19:05,640
GROUP AND PATIENTS WITH RISK FOR

6638
05:19:05,640 --> 05:19:09,080
ACUTE INFLAMMATORY RESPONSES 

6639
05:19:09,080 --> 05:19:10,080
STARTING INTRAVIRAL THERAPY AND 

6640
05:19:10,080 --> 05:19:13,920
CALL THIS IRIS AND IMMUNE 

6641
05:19:13,920 --> 05:19:14,720
RECONSTITUTION INFLAMMATORY 

6642
05:19:14,720 --> 05:19:16,560
SYNDROME THAT ARE PARADOXICAL 

6643
05:19:16,560 --> 05:19:17,840
REACTIONS HAPPENING IN PEOPLE 

6644
05:19:17,840 --> 05:19:21,400
WITH HIV WHO START ANTIVIRAL 

6645
05:19:21,400 --> 05:19:23,360
THERAPY AND HAVE AN UNDERLYING 

6646
05:19:23,360 --> 05:19:25,440
INFECTION OR TUMOR AND CALL THEM

6647
05:19:25,440 --> 05:19:28,520
PARADOXICAL AND EXPECTATION IS 

6648
05:19:28,520 --> 05:19:29,480
WHEN PEOPLE START UNDER THIS 

6649
05:19:29,480 --> 05:19:32,400
THERAPY EVERYTHING GETS BETTER 

6650
05:19:32,400 --> 05:19:34,160
AND IN THIS CASE, THEIR 

6651
05:19:34,160 --> 05:19:36,240
INFECTION OR MANIFESTATIONS OF 

6652
05:19:36,240 --> 05:19:39,280
INFECTION OR TUMORS MAY GET A 

6653
05:19:39,280 --> 05:19:41,680
LOT WORSE AFTER STARTING 

6654
05:19:41,680 --> 05:19:44,680
ANTIVIRAL THERAPY AND INCIDENTS 

6655
05:19:44,680 --> 05:19:46,320
CAN BE APPROXIMATELY 20% WITH 

6656
05:19:46,320 --> 05:19:49,720
LOW CD4 COUNTS STARTING THERAPY 

6657
05:19:49,720 --> 05:19:51,520
AND THEY HAPPEN EARLY WITHIN 

6658
05:19:51,520 --> 05:19:56,040
FIRST 6 MONTHS OF ART AND 

6659
05:19:56,040 --> 05:19:58,000
SUCCESSFUL HIV VIER LOGIC 

6660
05:19:58,000 --> 05:19:59,440
SUPPRESSION AND UNDERLYING 

6661
05:19:59,440 --> 05:20:03,760
INFECTION SEEMS TO BE UNDER 

6662
05:20:03,760 --> 05:20:07,640
CONTROL IF HAVE TUBERCULOSIS 

6663
05:20:07,640 --> 05:20:11,520
CULTURE IS MORE NEGATIVE AND 

6664
05:20:11,520 --> 05:20:14,600
THREE MAJOR CLINICAL PREDICTORS 

6665
05:20:14,600 --> 05:20:17,080
IDENTIFIED ARE HAVING LOW CD4 

6666
05:20:17,080 --> 05:20:19,520
COUNTS AND HAVING PREEXIST 

6667
05:20:19,520 --> 05:20:21,640
OPPORTUNISTIC INFECTION IF IT IS

6668
05:20:21,640 --> 05:20:24,360
A CLINICAL SUCH AS TUBERCULOSIS 

6669
05:20:24,360 --> 05:20:26,520
FOR EXAMPLE AND PRETREATING 

6670
05:20:26,520 --> 05:20:28,040
INFECTION FOR SHORTER PERIOD OF 

6671
05:20:28,040 --> 05:20:31,040
TIME PRIOR TO STARTING ANTIVIRAL

6672
05:20:31,040 --> 05:20:34,280
THERAPY OR IMMUNOLOGICAL TERMS 

6673
05:20:34,280 --> 05:20:36,200
HIGHER ANTIGEN LOAD AND WHAT IT 

6674
05:20:36,200 --> 05:20:38,560
LOOKS LIKE IN CLINIC AND 

6675
05:20:38,560 --> 05:20:43,040
PATIENTS WE HAVE SEEN AT NIH AND

6676
05:20:43,040 --> 05:20:45,440
WOMAN WITH RECURRENT CERVICAL 

6677
05:20:45,440 --> 05:20:46,280
[INDISCERNIBLE] AND WOULD 

6678
05:20:46,280 --> 05:20:49,280
CONTINUE TO ACCUMULATE WITH 

6679
05:20:49,280 --> 05:20:53,680
NEGATIVE CULTURES FOR MTB AND 

6680
05:20:53,680 --> 05:20:58,200
THIS PERSON FROM MEXICO HAD 

6681
05:20:58,200 --> 05:21:02,880
HISTOPLASMA IRIS AND AFRICAN 

6682
05:21:02,880 --> 05:21:04,760
AMERICAN PATIENT HERE AND 

6683
05:21:04,760 --> 05:21:08,520
ANOTHER PATIENT WHO HAD MAC -- 

6684
05:21:08,520 --> 05:21:12,240
AND THIS WAS A PATIENT WITH JC 

6685
05:21:12,240 --> 05:21:14,440
VIRUS PROGRESSIVE 

6686
05:21:14,440 --> 05:21:17,800
[INDISCERNIBLE] WHO DEVELOPED AN

6687
05:21:17,800 --> 05:21:21,920
IRIS AFTER STARTING ANTI VIRAL 

6688
05:21:21,920 --> 05:21:22,680
THERAPY.  I WILL SUMMARIZE 

6689
05:21:22,680 --> 05:21:25,160
PREVIOUS OVENGSS AND WE DID 500 

6690
05:21:25,160 --> 05:21:29,840
PATIENT STUDY IN US, KENYA AND 

6691
05:21:29,840 --> 05:21:33,520
THAILAND AND IRIS WAS 

6692
05:21:33,520 --> 05:21:35,240
INDEPENDENT PREDICTOR OF 

6693
05:21:35,240 --> 05:21:37,600
MORTALITY.  MOST WAS ABROAD.  3%

6694
05:21:37,600 --> 05:21:41,360
IN US AND CLOSER TO KENYA AND 

6695
05:21:41,360 --> 05:21:43,800
THAILAND AND IN ALL THREE 

6696
05:21:43,800 --> 05:21:46,200
COUNTRIES ACTUAL INCIDENTS OF 

6697
05:21:46,200 --> 05:21:48,760
VIRUS WAS IDENTICAL.  23% FROM 

6698
05:21:48,760 --> 05:21:54,080
ALL COUNTRIES AND LOW HEMOGLOBIN

6699
05:21:54,080 --> 05:21:54,960
WAS [INDISCERNIBLE] WHICH WAS 

6700
05:21:54,960 --> 05:21:56,960
EASILY DONE CLINICAL LABORATORY 

6701
05:21:56,960 --> 05:21:59,680
TESTING AND DEATHS LOW BMI SO 

6702
05:21:59,680 --> 05:22:03,440
LOW BODY MASS INDEX AND HIGH 

6703
05:22:03,440 --> 05:22:05,560
REACTIVE PROTEIN AND D DIMER 

6704
05:22:05,560 --> 05:22:07,600
WERE CLOSELY ASSOCIATED WITH 

6705
05:22:07,600 --> 05:22:09,040
DEATH AND FOUND FROM LABORATORY 

6706
05:22:09,040 --> 05:22:11,280
ASPECT WE AND OTHERS HAVE SHOWN 

6707
05:22:11,280 --> 05:22:14,480
EXPANSION OF ACTIVATED CD4 

6708
05:22:14,480 --> 05:22:16,800
POSITIVE ANTIJ ENSPECIFIC CELLS 

6709
05:22:16,800 --> 05:22:18,720
RECOGNIZING UNDERLYING INFECTION

6710
05:22:18,720 --> 05:22:23,000
AND UNDERLYING TB OR MAC THAT 

6711
05:22:23,000 --> 05:22:26,760
SEEM TO BE KEY COMPONENT OF 

6712
05:22:26,760 --> 05:22:29,280
PATHOGEN ESIS AND EFFECTIVE 

6713
05:22:29,280 --> 05:22:31,920
PHENOTYPE AND CYTOTOXIC 

6714
05:22:31,920 --> 05:22:33,440
PHENOTYPE MAKING LARGE AMOUNTS 

6715
05:22:33,440 --> 05:22:37,120
OF GAMA AND TNF AND WE DO IT BY 

6716
05:22:37,120 --> 05:22:40,360
SIMULATION THAT I WILL SHOW YOU 

6717
05:22:40,360 --> 05:22:43,280
AN EXAMPLE OF WE HAVE ALSO FOUND

6718
05:22:43,280 --> 05:22:47,960
IN PREVIOUS WORK THERE IS A 

6719
05:22:47,960 --> 05:22:49,800
HYPERMETABOLIC STATE IN PATIENTS

6720
05:22:49,800 --> 05:22:52,840
AND EXPRESSION ON CD4 CELLS AND 

6721
05:22:52,840 --> 05:22:54,520
MONOCYTES AND UPTAKE THAT COULD 

6722
05:22:54,520 --> 05:22:59,040
BE VISUALIZED IN CLINIC WITH FTG

6723
05:22:59,040 --> 05:23:02,600
PET SCANNING AND FINALLY I WILL 

6724
05:23:02,600 --> 05:23:04,640
DELVE FURTHER INTO THIS AND 

6725
05:23:04,640 --> 05:23:06,600
THERE IS SIGNIFICANT MYELOID 

6726
05:23:06,600 --> 05:23:09,040
CELL ACTIVATION PRONOUNCED IN 

6727
05:23:09,040 --> 05:23:14,520
IRIS AND BOTH LOOKING AT PLASMA 

6728
05:23:14,520 --> 05:23:16,880
BIOMARKERS AND INTERLEUKIN 18 

6729
05:23:16,880 --> 05:23:19,320
AND INTERFERON AND GAMA AND 

6730
05:23:19,320 --> 05:23:23,440
FOUND HIGH PROPORTION OF 

6731
05:23:23,440 --> 05:23:25,120
INFLAMMATORY MONOCYTES.  

6732
05:23:25,120 --> 05:23:27,080
I WILL SHOW YOU SOME DATA THAT 

6733
05:23:27,080 --> 05:23:29,320
IS ON WHAT WE ARE FINDING NOW 

6734
05:23:29,320 --> 05:23:32,960
THAT IS ROLE OF NRP3 

6735
05:23:32,960 --> 05:23:35,720
INFLAMMATORY ACTIVATION AS WELL 

6736
05:23:35,720 --> 05:23:38,160
AS CLASSICAL COMPLEMENT 

6737
05:23:38,160 --> 05:23:41,200
ACTIVATION IN PEOPLE WHO DEVELOP

6738
05:23:41,200 --> 05:23:42,320
MICROBACTERIALIZE SPECIFICALLY 

6739
05:23:42,320 --> 05:23:44,520
AND IS AN EXAMPLE WHAT WE FIND 

6740
05:23:44,520 --> 05:23:47,560
WHEN WE DO T CELL STIMULATIONS 

6741
05:23:47,560 --> 05:23:51,160
IN LAB IN VITRO AND PERSON THAT 

6742
05:23:51,160 --> 05:23:53,880
PRESENTED WITH THIS AND THIS IS 

6743
05:23:53,880 --> 05:23:56,560
LYMPHOID OPATHY FOR THOSE NOT 

6744
05:23:56,560 --> 05:24:00,840
USE TOTD SEEING CAT SCANS AND 

6745
05:24:00,840 --> 05:24:02,920
TUBERCULOSIS WAS IN LYMPH NODES 

6746
05:24:02,920 --> 05:24:07,600
HERE AND AFTER STARTING 

6747
05:24:07,600 --> 05:24:10,040
ANTIVIRAL THERAPY PATIENT 

6748
05:24:10,040 --> 05:24:12,600
DEVELOPED THIS.  THIS IS BIGGER 

6749
05:24:12,600 --> 05:24:14,320
AND DESPITE FACT THAT CULTURES 

6750
05:24:14,320 --> 05:24:17,280
WERE NOW NEGATIVE AND 

6751
05:24:17,280 --> 05:24:19,760
STIMULATING THIS FOR T CELLS IN 

6752
05:24:19,760 --> 05:24:23,600
VITRO USING TB ANTIGENS YOU CAN 

6753
05:24:23,600 --> 05:24:25,480
SEE IS ACTUALLY SIGNIFICANT TNF 

6754
05:24:25,480 --> 05:24:27,440
IN PRODUCTION OF BASELINE THAT 

6755
05:24:27,440 --> 05:24:30,040
IS THE NORM OF THESE PERCENTAGE.

6756
05:24:30,040 --> 05:24:33,280
DURING THE IRIS EVENT THIS IS 

6757
05:24:33,280 --> 05:24:35,640
TRULY SKUBERRANT AND HIGHER WHAT

6758
05:24:35,640 --> 05:24:37,640
WE SEE WITH POSITIVE CONTROL AND

6759
05:24:37,640 --> 05:24:39,680
WE USE IT A LOT OBVIOUSLY AND 

6760
05:24:39,680 --> 05:24:43,080
OTHER GROUPS HAVE DESCRIBED THIS

6761
05:24:43,080 --> 05:24:46,800
SKUBERRANT DISREGULATED T CELL 

6762
05:24:46,800 --> 05:24:48,240
ACTIVATION DURING IRIS AND WE 

6763
05:24:48,240 --> 05:24:50,480
FOUND NOT VERY HELPFUL IS THAT 

6764
05:24:50,480 --> 05:24:53,600
EVEN IF OBVIOUSLY WE USE IMMUNE 

6765
05:24:53,600 --> 05:24:56,960
SUPPRESSION WHEN THINGS 

6766
05:24:56,960 --> 05:24:59,440
OBVIOUSLY GO AND WHEN 

6767
05:24:59,440 --> 05:25:01,800
SYMPTOMATOLOGY IS TOO INTENSE 

6768
05:25:01,800 --> 05:25:03,800
AND TREAT PATIENTS CLOSELY AND 

6769
05:25:03,800 --> 05:25:07,680
IF YOU PUT THEM ON COURTI CO 

6770
05:25:07,680 --> 05:25:09,880
STEROIDS FOR EXAMPLE EX-VIVO 

6771
05:25:09,880 --> 05:25:12,280
THEY WOULD HAVE HIGH T CELL 

6772
05:25:12,280 --> 05:25:14,160
STIMULATION AND STIMULATING THEM

6773
05:25:14,160 --> 05:25:16,320
WITH ANTIGENS AND WE WANTED TO 

6774
05:25:16,320 --> 05:25:19,240
LOOK AS I MENTIONED AT MYELOID 

6775
05:25:19,240 --> 05:25:21,720
CELLS AND HAD A VERY CLEAR 

6776
05:25:21,720 --> 05:25:24,480
SIGNAL BY HIGH LEVELS OF IL1 AND

6777
05:25:24,480 --> 05:25:26,560
18 THAT WAS INFLAMMATORY 

6778
05:25:26,560 --> 05:25:29,960
ACTIVATION IN PATIENTS AND QUICK

6779
05:25:29,960 --> 05:25:31,640
REMINDER FOR INFLAMMATORY 

6780
05:25:31,640 --> 05:25:32,960
ACTIVATION THERE ARE SIGNALS 

6781
05:25:32,960 --> 05:25:35,920
FROM PATHOGENS AND DAMAGE 

6782
05:25:35,920 --> 05:25:39,000
ASSOCIATED MOLECULAR PATTERNS 

6783
05:25:39,000 --> 05:25:45,560
AND ONE OF THE RECEPTORS IS THE 

6784
05:25:45,560 --> 05:25:47,400
NLRP3 THAT IS CLASSIC 

6785
05:25:47,400 --> 05:25:49,920
[INDISCERNIBLE] THAT ACTIVATES 

6786
05:25:49,920 --> 05:25:52,520
FURTHER COMBINING APOPTOSIS 

6787
05:25:52,520 --> 05:25:54,920
ASSOCIATED SPECK-LIKE PROTEIN 

6788
05:25:54,920 --> 05:25:58,720
CONTAINING CARD THAT THEY CREATE

6789
05:25:58,720 --> 05:26:00,960
ALC COMPLEX FURTHER ACTIVATING 

6790
05:26:00,960 --> 05:26:05,560
CAL SPACE 1 THAT CONVERTS PRO-IO

6791
05:26:05,560 --> 05:26:08,840
TEAM TO ACTIVE CYTOKINES AND 

6792
05:26:08,840 --> 05:26:11,760
IMPORTANTLY IO1 BETA CAN LEAD TO

6793
05:26:11,760 --> 05:26:14,520
CLINICAL MANIFESTATIONS SUCH AS 

6794
05:26:14,520 --> 05:26:17,680
FEVER AND PRODUCTION OF IL-6 AND

6795
05:26:17,680 --> 05:26:20,520
CLP AND IT IS CRITICAL FOR 

6796
05:26:20,520 --> 05:26:22,400
ACTIVATION THAT WE KNOW HAPPENS 

6797
05:26:22,400 --> 05:26:28,680
IN IRIS AND GAM INTERFERON 

6798
05:26:28,680 --> 05:26:32,040
ACTIVATION AND SO THE SPECKS AND

6799
05:26:32,040 --> 05:26:34,440
AFC SPECKS ARE CONSIDERED REALLY

6800
05:26:34,440 --> 05:26:36,920
A HALLMARK OF INFLAMMATORY 

6801
05:26:36,920 --> 05:26:38,600
ACTIVATION IF YOU VISUALIZE 

6802
05:26:38,600 --> 05:26:42,840
THEM.  YOU CAN USE OBVIOUSLY 

6803
05:26:42,840 --> 05:26:45,200
PHOTON MICROSCOPY AND WE USE THE

6804
05:26:45,200 --> 05:26:48,400
IMAGE STREAM ANALYSIS A LOT THAT

6805
05:26:48,400 --> 05:26:50,800
COMBINES VISUALIZATION 

6806
05:26:50,800 --> 05:26:53,600
ADVANTAGES AND PHOTON MICROSCOPY

6807
05:26:53,600 --> 05:26:55,680
BACK WITH ADVANTAGE OF FLOW 

6808
05:26:55,680 --> 05:26:56,880
CITOMETRY AND CAN YOU MEASURE 

6809
05:26:56,880 --> 05:26:59,680
HOW MANY CELLS HAVE AFC SPECKS 

6810
05:26:59,680 --> 05:27:02,320
OPPOSED TO JUST FINDING THEM 

6811
05:27:02,320 --> 05:27:03,560
QUALITATIVELY AND WHAT WE FOUND 

6812
05:27:03,560 --> 05:27:06,600
WAS THAT BY LOOKING AT THE CELLS

6813
05:27:06,600 --> 05:27:09,040
THAT HAVE THESE SPECKS AND THESE

6814
05:27:09,040 --> 05:27:12,080
SPECKS I NEED TO MENTION THAT 

6815
05:27:12,080 --> 05:27:16,760
FLICA IS A SUBSTRATE FOR CAS 

6816
05:27:16,760 --> 05:27:19,320
SPACE 1 AND THIS MEANS THEY HAVE

6817
05:27:19,320 --> 05:27:21,600
ACTIVATED CAS SPACE 1 AND WE 

6818
05:27:21,600 --> 05:27:23,240
HAVE EVIDENCE OF HIGH LEVELS OF 

6819
05:27:23,240 --> 05:27:28,120
THE MONOCYTES THAT ARE BOTH ASC 

6820
05:27:28,120 --> 05:27:34,080
SPECK POSITIVE AND YOU SEE THEY 

6821
05:27:34,080 --> 05:27:37,720
COLOCALIZE IN CITES HERE AND 

6822
05:27:37,720 --> 05:27:39,360
MONOCYTES AND THAT INTERESTINGLY

6823
05:27:39,360 --> 05:27:41,480
ENOUGH WAS A BIG PLUS FOR US AND

6824
05:27:41,480 --> 05:27:45,040
WHEN WE TREATED PATIENTS WITH 

6825
05:27:45,040 --> 05:27:47,400
COURTI CO STEROIDS THAT 

6826
05:27:47,400 --> 05:27:49,440
ALLEVIATED PRESENCE OF THESE 

6827
05:27:49,440 --> 05:27:49,760
COMPLEXES. 

6828
05:27:49,760 --> 05:27:51,400
WE WERE ABLE TO SEE THERE WAS 

6829
05:27:51,400 --> 05:27:55,040
FOR EXAMPLE RESPONSE TO THERAPY 

6830
05:27:55,040 --> 05:27:57,720
WHICH IS IMPORTANT FOR OUR 

6831
05:27:57,720 --> 05:28:00,000
PURPOSES AND WE FOUND THAT ALSO 

6832
05:28:00,000 --> 05:28:03,640
BY USING THIS RP3 INHIBITOR THAT

6833
05:28:03,640 --> 05:28:07,880
IS HERE THE MCC950, WE WERE ABLE

6834
05:28:07,880 --> 05:28:12,120
TO ABROW GATE RELEASE OF 

6835
05:28:12,120 --> 05:28:14,200
INTERLEUKIN 1.  ALSO, WE COULD 

6836
05:28:14,200 --> 05:28:17,840
BLOCK THAT BY BLOCKING POTASSIUM

6837
05:28:17,840 --> 05:28:19,360
INFLUX THE IMPORTANT SECOND 

6838
05:28:19,360 --> 05:28:21,040
SIGNAL FOR INFLAMMATORY 

6839
05:28:21,040 --> 05:28:24,600
ACTIVATION AND WE SHOWED IT WAS 

6840
05:28:24,600 --> 05:28:27,000
AN RP3 INFLAMMATORY THAT IS 

6841
05:28:27,000 --> 05:28:31,360
INVOLVED IN PATIENTS WITH MICRO 

6842
05:28:31,360 --> 05:28:35,080
BACTERIAL VIRUS AND CELLS WITH 

6843
05:28:35,080 --> 05:28:39,480
FLICA EXPRESSIONS AND ACTIVATED 

6844
05:28:39,480 --> 05:28:41,800
KAS 1 HAS POSITIONS AND EVIDENCE

6845
05:28:41,800 --> 05:28:44,880
OF COMPLEMENT ACTIVATION IN 

6846
05:28:44,880 --> 05:28:47,160
PATIENTS ALONG WITH CAS SPACE 1 

6847
05:28:47,160 --> 05:28:49,400
AND INFLAMMATORY ACTIVATION. 

6848
05:28:49,400 --> 05:28:53,920
SO, WHAT I -- WHAT WE -- OUR 

6849
05:28:53,920 --> 05:28:56,360
MODEL SO FAR WE HAVE ACTIVATED 

6850
05:28:56,360 --> 05:28:58,160
MYELOID CELLS THAT PRODUCE 

6851
05:28:58,160 --> 05:29:02,440
CERTAIN BIOMARKERS AND 

6852
05:29:02,440 --> 05:29:03,320
INFLAMMATORY CYTOKINES AND 

6853
05:29:03,320 --> 05:29:05,440
EXPANSION OF ANTIGEN SPECIFIC 

6854
05:29:05,440 --> 05:29:07,840
CELLS THAT PRODUCE MASSIVE 

6855
05:29:07,840 --> 05:29:11,160
AMOUNTS OF INTERFERON AND GAMMA 

6856
05:29:11,160 --> 05:29:13,680
AND WERE STILL SEEING IN CLINIC 

6857
05:29:13,680 --> 05:29:15,720
SUBSET OF PATIENTS THAT HAVE 

6858
05:29:15,720 --> 05:29:17,400
MORE SEVERE DISEASE 

6859
05:29:17,400 --> 05:29:19,640
MANIFESTATIONS AND WERE ONES 

6860
05:29:19,640 --> 05:29:22,960
THAT HAD MORE PERSISTENT SIM 

6861
05:29:22,960 --> 05:29:24,320
TOMORROWTOLOGY THAT REQUIRED 

6862
05:29:24,320 --> 05:29:27,400
PROTECTIVE COURSES OF COURTI CO 

6863
05:29:27,400 --> 05:29:29,760
STEROIDS REMINDING US OF 

6864
05:29:29,760 --> 05:29:32,400
PATIENTS WITH SYNDROME OF HLH 

6865
05:29:32,400 --> 05:29:36,760
THAT IS A HEMOPHAGOCYTIC HISTORY

6866
05:29:36,760 --> 05:29:38,880
OFCYTOSIS THAT IS PRIMARY IN 

6867
05:29:38,880 --> 05:29:42,560
PEOPLE WHO HAVE MUTATIONS IN 

6868
05:29:42,560 --> 05:29:45,280
CYTOTOXIC GENES AND SECONDARY TO

6869
05:29:45,280 --> 05:29:47,320
INFECTIONS AND TO AUTO IMMUNE 

6870
05:29:47,320 --> 05:29:51,840
DISEASES AND YOU HEAR THE TERM 

6871
05:29:51,840 --> 05:29:53,640
MICROPHAGE ACTIVATION SYNDROME 

6872
05:29:53,640 --> 05:29:57,160
AND COHORT OF 80 PATIENTS WITH 

6873
05:29:57,160 --> 05:30:00,720
MICRO BACTERIAL DISEASE AND WE 

6874
05:30:00,720 --> 05:30:03,400
WENT BACK AND APPLIED CRITERIA 

6875
05:30:03,400 --> 05:30:07,640
FOR HLH AND THOSE PRESENTING 

6876
05:30:07,640 --> 05:30:10,040
EVENTUALLY FOLLOWING THEM 

6877
05:30:10,040 --> 05:30:11,760
LONGITUDINALLY WITH IRIS 

6878
05:30:11,760 --> 05:30:13,200
FEATURES AND WERE ABLE TO 

6879
05:30:13,200 --> 05:30:15,320
CLASSIFY THOSE WHO PRESENTED 

6880
05:30:15,320 --> 05:30:18,640
WITH SAY REGULAR IRIS OR SIMPLE 

6881
05:30:18,640 --> 05:30:23,120
IRIS AND MEETING HLH CRITERIA 

6882
05:30:23,120 --> 05:30:29,040
AND ONE IS HIGH FERA TEEN AND 

6883
05:30:29,040 --> 05:30:32,080
OTHER CRITERIA WITH CRYTOPINA 

6884
05:30:32,080 --> 05:30:33,280
AND [INDISCERNIBLE] AND WANTED 

6885
05:30:33,280 --> 05:30:36,840
TO SEE IF THAT RETROSPECTIVELY 

6886
05:30:36,840 --> 05:30:37,480
APPLIED CLASSIFICATION THAT 

6887
05:30:37,480 --> 05:30:39,800
WOULD HELP US TO IDENTIFY MORE 

6888
05:30:39,800 --> 05:30:42,760
UNIQUE PATHOPHYSIOLOGY OR WORSE 

6889
05:30:42,760 --> 05:30:46,360
OUTCOMES OF PATIENTS THAT SO 

6890
05:30:46,360 --> 05:30:49,920
HAPPENED THEY WERE EVENLY SPLIT 

6891
05:30:49,920 --> 05:30:54,600
BETWEEN THREE GROUPS AND NO IRIS

6892
05:30:54,600 --> 05:30:57,400
SIMILARLY IN THESE ACCOUNTS AND 

6893
05:30:57,400 --> 05:31:00,320
STRIKINGLY DIFFERENT IN PATIENTS

6894
05:31:00,320 --> 05:31:03,440
THOSE FOR HLH THAT REQUIRED MUCH

6895
05:31:03,440 --> 05:31:06,120
MORE FREQUENTLY WERE REQUIRING 

6896
05:31:06,120 --> 05:31:07,600
COURTI CO STEROID TREATMENT AND 

6897
05:31:07,600 --> 05:31:09,200
DON'T USE TREATMENT FOLLOW THEM 

6898
05:31:09,200 --> 05:31:11,400
AND USE N SETS FOR EXAMPLE AND 

6899
05:31:11,400 --> 05:31:14,000
THEY DEFINITELY NEEDED MORE 

6900
05:31:14,000 --> 05:31:17,440
CORTICO STEROIDS AND NEEDS 

6901
05:31:17,440 --> 05:31:19,640
ADDITIONAL IMMUNOSUPPRESSION AT 

6902
05:31:19,640 --> 05:31:23,680
TIMES AND NEEDED MORE PROTECTED 

6903
05:31:23,680 --> 05:31:25,480
AND MORE SEVERE COURSE THAT 

6904
05:31:25,480 --> 05:31:28,560
LASTED LONGER AND IN QUEST TO 

6905
05:31:28,560 --> 05:31:31,640
TRY TO FIND BIOMARKERS TO 

6906
05:31:31,640 --> 05:31:34,720
PREDICT OR IDENTIFY PATIENTS AT 

6907
05:31:34,720 --> 05:31:37,080
BASELINE BEFORE STARTING 

6908
05:31:37,080 --> 05:31:38,360
ANTIVIRAL THERAPY WE WANTED TO 

6909
05:31:38,360 --> 05:31:41,320
LOOK AT MARKERS EASILY DONE IN 

6910
05:31:41,320 --> 05:31:43,240
CLINICAL LABORATORIES LOTS OF 

6911
05:31:43,240 --> 05:31:46,400
PATIENTS ARE IN RESOURCE LIMITED

6912
05:31:46,400 --> 05:31:47,720
SETTINGS IN LOW AND MIDDLE 

6913
05:31:47,720 --> 05:31:51,120
INCOME COUNTRIES AND FINDING 

6914
05:31:51,120 --> 05:31:52,760
HEMOGLOBIN AND FER ACONTINUE WE 

6915
05:31:52,760 --> 05:31:54,880
HAD A DECISION TREE ANALYSIS TO 

6916
05:31:54,880 --> 05:31:56,760
IDENTIFY MOST PATIENTS THAT 

6917
05:31:56,760 --> 05:32:00,920
WOULD GO ON TO DEVELOP HLH TYPE 

6918
05:32:00,920 --> 05:32:01,720
OF IRIS. 

6919
05:32:01,720 --> 05:32:04,720
NOW, IMPORTANTLY ALSO WHEN THEY 

6920
05:32:04,720 --> 05:32:09,480
PRESENTED WITH IRIS WE FOUND HLH

6921
05:32:09,480 --> 05:32:11,800
IRIS HAD A VERY CLEAN 

6922
05:32:11,800 --> 05:32:14,600
DISTINCTION BASED ON THIS WHICH 

6923
05:32:14,600 --> 05:32:17,800
IS GAMMA INTERFERON BIOMARKER 

6924
05:32:17,800 --> 05:32:20,280
AND THIS HAPPENS TO BE OF COURSE

6925
05:32:20,280 --> 05:32:22,840
ONE OF THE CRITERIA OF HLH THAT 

6926
05:32:22,840 --> 05:32:27,840
ARE USED AND ALSO SIGNIFYING 

6927
05:32:27,840 --> 05:32:31,480
REALLY MOSTLY T CELL 

6928
05:32:31,480 --> 05:32:40,280
PROLIFERATION AND ACTIVATION. 

6929
05:32:40,280 --> 05:32:43,040
ALTHOUGH THIS WAS STATISTICALLY 

6930
05:32:43,040 --> 05:32:46,800
SIGNIFICANT AND CLEARLY IT WAS A

6931
05:32:46,800 --> 05:32:48,720
VERY CLEAN DISTINCTION OF HLH 

6932
05:32:48,720 --> 05:32:50,520
GROUP AND IMPORTANTLY WE HAD 

6933
05:32:50,520 --> 05:32:54,840
ALWAYS PUZZLED AND WERE ALWAYS 

6934
05:32:54,840 --> 05:32:57,000
VEXED NOT FINDING ANYTHING WITH 

6935
05:32:57,000 --> 05:32:58,920
REGULATORY T CELLS IN IRIS AND 

6936
05:32:58,920 --> 05:33:01,240
NOW THAT WE DISTINGUISH MORE 

6937
05:33:01,240 --> 05:33:03,560
SEVERE TYPE WE FIND 

6938
05:33:03,560 --> 05:33:04,880
PARADOXICALLY THEY HAD LOWEST 

6939
05:33:04,880 --> 05:33:07,040
PROPORTION OF T. REX AND AREA WE

6940
05:33:07,040 --> 05:33:08,880
ARE MORE INTERESTED TO LOOKING 

6941
05:33:08,880 --> 05:33:12,040
FURTHER INTO WHY THAT IS THE 

6942
05:33:12,040 --> 05:33:17,600
CA

6943
05:33:17,600 --> 05:33:19,760
CASE. 

6944
05:33:19,760 --> 05:33:21,560
LOOKING AT ANALYSIS BIOMARKERS 

6945
05:33:21,560 --> 05:33:26,200
AND PHENOTYPES GOOD SDICHGS 

6946
05:33:26,200 --> 05:33:28,840
PEOPLE DEVELOPING THIS AND 

6947
05:33:28,840 --> 05:33:30,680
COMPARING IRIS AND NO IRIS AT 

6948
05:33:30,680 --> 05:33:33,560
ALL AND EVERYBODY HAD 

6949
05:33:33,560 --> 05:33:36,640
MICROBACTERIAL DISEASE WHEN 

6950
05:33:36,640 --> 05:33:40,760
INCLUDED IN COHORT I DON'T HAVE 

6951
05:33:40,760 --> 05:33:42,760
DATA HERE BUT LOOK AT GENETICS 

6952
05:33:42,760 --> 05:33:46,480
OF HLH AND PATIENTS DEVELOPING 

6953
05:33:46,480 --> 05:33:49,560
IRIS HAVE A HIGHER PROTEIN 

6954
05:33:49,560 --> 05:33:54,520
VARIANCE IN GENES RELATED TO HLH

6955
05:33:54,520 --> 05:33:57,440
AND WE FOUND SIGNIFICANT 

6956
05:33:57,440 --> 05:34:00,720
DIFFERENCE 20% OF PATIENTS 

6957
05:34:00,720 --> 05:34:06,680
DEVELOPING IRIS HAD LOW HLH 

6958
05:34:06,680 --> 05:34:10,000
VARIANCE AND MENTIONED WE USE 

6959
05:34:10,000 --> 05:34:13,920
THE COURTI CO STEROIDS TO TREAT 

6960
05:34:13,920 --> 05:34:19,080
THE PATIENTS AND TREATING 

6961
05:34:19,080 --> 05:34:21,720
MICROBACTERIA PATIENTS WITH 

6962
05:34:21,720 --> 05:34:23,560
CORTICO STEROIDS WE SAW 

6963
05:34:23,560 --> 05:34:24,640
EMERGENCE OF [INDISCERNIBLE] 

6964
05:34:24,640 --> 05:34:27,160
SARCOMA NOT SUSPECTED AT 

6965
05:34:27,160 --> 05:34:28,960
BASELINE AND WE SCREENED ALL 

6966
05:34:28,960 --> 05:34:34,120
PATIENTS COMING IN WITH LOW CD4 

6967
05:34:34,120 --> 05:34:36,840
COUNTS WITH PCR TO MAKE SURE WE 

6968
05:34:36,840 --> 05:34:38,840
DON'T GET THESE SURPRISES AND 

6969
05:34:38,840 --> 05:34:40,960
INTERESTING ABOUT KS HERPES 

6970
05:34:40,960 --> 05:34:45,120
VIRUS THAT I WILL MENTION IS 

6971
05:34:45,120 --> 05:34:48,720
REALLY PRELIMINARY WORK WE ARE 

6972
05:34:48,720 --> 05:34:50,320
DOING WITH THIS GROUP AND 

6973
05:34:50,320 --> 05:34:54,560
INTERESTING THING ABOUT KS IS IT

6974
05:34:54,560 --> 05:34:56,720
CAN CAUSE INFLAMMATORY RESPONSES

6975
05:34:56,720 --> 05:34:59,760
AND SYNDROMES IN PEOPLE WITH HIV

6976
05:34:59,760 --> 05:35:01,600
THAT COULD BE SOMETIMES 

6977
05:35:01,600 --> 05:35:04,200
DIFFICULT TO DISTINGUISH FROM 

6978
05:35:04,200 --> 05:35:08,360
WHAT WE SEE IN OTHER INFECTIONS 

6979
05:35:08,360 --> 05:35:09,920
THAT ARE A VIER YUGS AND YOU HAD

6980
05:35:09,920 --> 05:35:13,800
A FEW TALKS TALKING ABOUT KSHV. 

6981
05:35:13,800 --> 05:35:15,280
THANKFULLY I DON'T HAVE TO GO 

6982
05:35:15,280 --> 05:35:16,360
THROUGH SPECIFICS. 

6983
05:35:16,360 --> 05:35:17,960
IF YOU HAVE QUESTIONS ABOUT 

6984
05:35:17,960 --> 05:35:23,000
VIRUS YOU CAN ASK BOB.  WHAT IS 

6985
05:35:23,000 --> 05:35:24,960
FASCINATING ABOUT KSHV MASSIVE 

6986
05:35:24,960 --> 05:35:26,960
AMOUNT OF OPEN READING FRAMES.  

6987
05:35:26,960 --> 05:35:29,960
I THINK OVER 80.  WHAT IS 

6988
05:35:29,960 --> 05:35:32,880
FASCINATING IS HAS AT LEAST 14 

6989
05:35:32,880 --> 05:35:35,080
CELLULAR HOMOLOGS AND VIRUS 

6990
05:35:35,080 --> 05:35:38,960
ITSELF PRODUCES IL-6 AND 

6991
05:35:38,960 --> 05:35:43,600
CHEMOKINDS AND PRODUCES BCL2. 

6992
05:35:43,600 --> 05:35:46,160
INTERESTINGLY IT CAN ACTIVATE 

6993
05:35:46,160 --> 05:35:48,720
CAPPA B AND CELLS FURTHER 

6994
05:35:48,720 --> 05:35:51,680
PRODUCE INFLAMMATORY CYTOKINES 

6995
05:35:51,680 --> 05:35:53,440
AND SPECTRUM OF DISEASES ARE 

6996
05:35:53,440 --> 05:35:55,600
BROAD AND RANGE EVERYWHERE FROM 

6997
05:35:55,600 --> 05:35:59,560
SKIN DISEASE IN OUR PATIENTS TO 

6998
05:35:59,560 --> 05:36:00,760
MULTICENTRIC CASTLEMAN'S DISEASE

6999
05:36:00,760 --> 05:36:03,240
THAT ALREADY HAS BEEN MENTIONED 

7000
05:36:03,240 --> 05:36:05,520
AND KICKS THAT IS INFLAMMATORY 

7001
05:36:05,520 --> 05:36:07,760
SYNDROME WITH KS AND PRIMARY 

7002
05:36:07,760 --> 05:36:10,320
INFUSION LYMPHOMA IS ONLY AND 

7003
05:36:10,320 --> 05:36:12,400
BOB CAN CORRECT ME TRUE CANCER. 

7004
05:36:12,400 --> 05:36:17,320
MOST OF THESE CAN BE -- MOST ARE

7005
05:36:17,320 --> 05:36:21,000
POLYCLONAL AND ANGIOPER 

7006
05:36:21,000 --> 05:36:23,960
LIVERATIVE OPPOSED TO MONOCLONAL

7007
05:36:23,960 --> 05:36:26,000
DISEASE AND WE WERE INTERESTED. 

7008
05:36:26,000 --> 05:36:27,800
CLEARLY PATIENTS CAN SOMETIMES 

7009
05:36:27,800 --> 05:36:29,440
NOT SOMETIMES BUT MANY TIMES 

7010
05:36:29,440 --> 05:36:31,040
COME FROM AFRICA AND THEY DO 

7011
05:36:31,040 --> 05:36:35,320
HAVE -- WE SEE LOTS OF KS AND WE

7012
05:36:35,320 --> 05:36:37,120
DON'T SEE LOTS OF BRIGHT PEOPLE 

7013
05:36:37,120 --> 05:36:41,200
BUT LOTS OF KS BECAUSE OF 

7014
05:36:41,200 --> 05:36:42,520
AFRICAN ORIGIN PATIENTS AND 

7015
05:36:42,520 --> 05:36:46,840
DECIDED TO DO SOME STUDIES THAT 

7016
05:36:46,840 --> 05:36:48,640
WR DONE MICRO BACTERIALIZE NTD 

7017
05:36:48,640 --> 05:36:52,160
PATIENTS WITH KS AND MALIGNANCY 

7018
05:36:52,160 --> 05:36:55,440
BRANCH WITH OPPORTUNITY TO STUDY

7019
05:36:55,440 --> 05:36:57,240
PATIENTS ASSOCIATED DISORDERS 

7020
05:36:57,240 --> 05:37:00,600
AND HIV PATIENTS CONTROLLED IN 

7021
05:37:00,600 --> 05:37:01,880
ANTIVIRAL THERAPY AND DIDN'T 

7022
05:37:01,880 --> 05:37:03,480
HAVE THESE INFLAMMATORY 

7023
05:37:03,480 --> 05:37:05,280
SYNDROMES YOU CAN SEE ARE FAIRLY

7024
05:37:05,280 --> 05:37:08,480
SIMILAR WITH RESPECT TO OVERALL 

7025
05:37:08,480 --> 05:37:10,560
CD4 COUNTS AND VIRAL LOAD. 

7026
05:37:10,560 --> 05:37:12,720
SO, WE DECIDED TO DO EXACTLY THE

7027
05:37:12,720 --> 05:37:14,680
SAME ANALYSIS AND LOOK AT 

7028
05:37:14,680 --> 05:37:16,160
EVIDENCE IF THERE IS ANY 

7029
05:37:16,160 --> 05:37:18,240
EVIDENCE OF INFLAMMATORY 

7030
05:37:18,240 --> 05:37:20,480
ACTIVATION IN PATIENTS WITH 

7031
05:37:20,480 --> 05:37:23,360
CAPPA ASSOCIATED DISORDERS, ONE.

7032
05:37:23,360 --> 05:37:26,040
2, IF THERE IS ANYTHING THAT CAN

7033
05:37:26,040 --> 05:37:27,720
DIFFERENTIATE THE DIFFERENT 

7034
05:37:27,720 --> 05:37:29,320
GROUPS AND CLEARLY WHAT 

7035
05:37:29,320 --> 05:37:30,800
ONCOLOGISTS ARE STRUGGLING WITH 

7036
05:37:30,800 --> 05:37:35,600
IS WHO HAS PRIMARY INFUSION 

7037
05:37:35,600 --> 05:37:36,880
LYMPHOMA REALLY WHERE THE 

7038
05:37:36,880 --> 05:37:39,040
DIFFERENCE OF TREATMENT AND 

7039
05:37:39,040 --> 05:37:41,680
PROGNOSIS COMES IN DIFFERENCE TO

7040
05:37:41,680 --> 05:37:44,800
A GREAT EXTENT AND FOUND HIGH 

7041
05:37:44,800 --> 05:37:46,760
LEVELS OF THIS AND OF EXPRESSION

7042
05:37:46,760 --> 05:37:49,120
ON MONOCYTES BOTH SUGGESTING 

7043
05:37:49,120 --> 05:37:53,160
THERE IS INFLAMOSOME ACTIVATION 

7044
05:37:53,160 --> 05:37:58,640
IN PATIENTS WITH THIS KHV 

7045
05:37:58,640 --> 05:37:59,680
ASSOCIATED DISORDERS AND WE 

7046
05:37:59,680 --> 05:38:02,120
APPLIED SAME TECHNIQUES WITH 

7047
05:38:02,120 --> 05:38:03,840
IMAGE STREAM ANALYSIS AND FOUND 

7048
05:38:03,840 --> 05:38:06,560
REALLY MASSIVE AMOUNTS OF 

7049
05:38:06,560 --> 05:38:09,160
MONOCYTES THAT ARE EXPRESSING 

7050
05:38:09,160 --> 05:38:11,200
SPECKS AS WELL AS 

7051
05:38:11,200 --> 05:38:11,680
[INDISCERNIBLE] BEING 

7052
05:38:11,680 --> 05:38:12,680
[INDISCERNIBLE] POSITIVE 

7053
05:38:12,680 --> 05:38:14,720
COMPARED TO HEALTHY CONTROLS AND

7054
05:38:14,720 --> 05:38:17,160
YOU KNOW WE THOUGHT WELL THESE 

7055
05:38:17,160 --> 05:38:18,960
PATIENTS HAVE ALSO HIV.  

7056
05:38:18,960 --> 05:38:21,240
ALTHOUGH THEY ARE TREATED THEY 

7057
05:38:21,240 --> 05:38:24,520
MIGHT HAVE INFLAMOSOME 

7058
05:38:24,520 --> 05:38:26,240
ACTIVATION AND WENT TO COMPARE 

7059
05:38:26,240 --> 05:38:29,360
WITH HIV PATIENTS AND THEY WERE 

7060
05:38:29,360 --> 05:38:32,160
HIGHER AND MICRO BACTERIA 

7061
05:38:32,160 --> 05:38:34,640
PATIENTS WITH IRIS WERE LOWER 

7062
05:38:34,640 --> 05:38:36,320
THAN THOSE WITH KS DISEASE AND 

7063
05:38:36,320 --> 05:38:38,720
THERE IS CLEARLY MASSIVE 

7064
05:38:38,720 --> 05:38:41,360
INFLAMOSOME ACTIVATION IN THESE 

7065
05:38:41,360 --> 05:38:43,120
PATIENTS AND THIS IS AGAIN 

7066
05:38:43,120 --> 05:38:45,000
SHOWING COMPARISON WITH 

7067
05:38:45,000 --> 05:38:48,640
SUPPRESSED HIV NOT ONES WITH 

7068
05:38:48,640 --> 05:38:50,720
MICRO BACTERIAL IRIS I SHOWED 

7069
05:38:50,720 --> 05:38:53,560
YOU BEFORE AND THERE IS 

7070
05:38:53,560 --> 05:38:55,160
SIGNIFICANT DIFFERENCE AND 

7071
05:38:55,160 --> 05:38:57,000
TREATED HIV DIDN'T SEEM 

7072
05:38:57,000 --> 05:38:59,160
DIFFERENT FROM HEALTHY CONTROLS 

7073
05:38:59,160 --> 05:39:01,120
AND WE FOUND THERE WAS 

7074
05:39:01,120 --> 05:39:02,600
SIGNIFICANT ASSOCIATION IN 

7075
05:39:02,600 --> 05:39:06,160
INFLAMOSOME ACTIVATION 

7076
05:39:06,160 --> 05:39:09,520
PREDOMINANTLY WITH KS HV VIRAL 

7077
05:39:09,520 --> 05:39:11,720
LOAD AND NOT HV VIRAL LOAD.  

7078
05:39:11,720 --> 05:39:13,440
NOW, UNFORTUNATE THING IS WE 

7079
05:39:13,440 --> 05:39:15,840
COULD NOT REALLY DISTINGUISH 

7080
05:39:15,840 --> 05:39:17,520
BETWEEN DIFFERENT KS SYNDROMES 

7081
05:39:17,520 --> 05:39:20,120
AT ALL.  IT WAS REALLY A BLUR AS

7082
05:39:20,120 --> 05:39:22,480
YOU CAN SEE HERE.  SO, WE PUT 

7083
05:39:22,480 --> 05:39:25,960
ALL INFLAMMATORY MARKERS AND 

7084
05:39:25,960 --> 05:39:28,080
MONOCYTE INFLAMOSOME MARKERS AND

7085
05:39:28,080 --> 05:39:33,720
COULD NOT REALLY DISTINGUISH WHO

7086
05:39:33,720 --> 05:39:35,240
HAD PRIMARY LYMPHOMA VERSUS SKIN

7087
05:39:35,240 --> 05:39:36,600
KS AND KEEP IN MIND THERE IS 

7088
05:39:36,600 --> 05:39:39,600
LOTS OF OVERLAP AND THAT SOME 

7089
05:39:39,600 --> 05:39:43,440
PATIENTS HAVE BOTH SKIN KS'S AND

7090
05:39:43,440 --> 05:39:46,680
MULTICENTRIC CASTLEMAN'S DISEASE

7091
05:39:46,680 --> 05:39:49,320
AND WE SEE THOUGH LOTS OF 

7092
05:39:49,320 --> 05:39:51,560
INFLAMMATORY SIGNAL IS COMING 

7093
05:39:51,560 --> 05:39:54,520
AND IN RED IS PATIENTS WITH 

7094
05:39:54,520 --> 05:39:56,480
MULTICENTRIC CASTLEMAN'S DISEASE

7095
05:39:56,480 --> 05:39:58,560
AND THEY TEND TO CLUSTER BASED 

7096
05:39:58,560 --> 05:40:00,600
ON DIFFERENT MARKERS COMING TO 

7097
05:40:00,600 --> 05:40:02,080
INFLAMMATORY MARKERS THAT ARE 

7098
05:40:02,080 --> 05:40:04,200
SHOWN HERE TOWARDS THE END WITH 

7099
05:40:04,200 --> 05:40:08,640
CRP AND IL18 AND PHEROCONTINUE 

7100
05:40:08,640 --> 05:40:11,000
IN I LICHLT 1. 

7101
05:40:11,000 --> 05:40:13,480
NOW, WE WERE THOUGH VERY 

7102
05:40:13,480 --> 05:40:15,280
RELIEVED WHEN WE SAW THAT WE 

7103
05:40:15,280 --> 05:40:18,120
COULD SEE A SIGNAL OF 

7104
05:40:18,120 --> 05:40:19,600
DIFFERENTIATION BETWEEN PATIENTS

7105
05:40:19,600 --> 05:40:22,800
WITH MICROBACTERIAL IRIS AND 

7106
05:40:22,800 --> 05:40:25,280
PATIENTS WITH INFLAMMATION OR 

7107
05:40:25,280 --> 05:40:26,960
INFLAMMATORY SYNDROMES RELATING 

7108
05:40:26,960 --> 05:40:30,120
TO KS AND SEEMING THAT KS WAS 

7109
05:40:30,120 --> 05:40:34,160
MORE IL18 RELATED AND MICRO 

7110
05:40:34,160 --> 05:40:36,600
BACTERIAL IRIS WAS MORE GAMMA 

7111
05:40:36,600 --> 05:40:41,600
INTERFERON ASSOCIATED THAT IS 

7112
05:40:41,600 --> 05:40:43,520
BECAUSE PATIENTS DEVELOP IRIS 

7113
05:40:43,520 --> 05:40:47,000
WITH A T CELL RESPONSE AND 

7114
05:40:47,000 --> 05:40:50,160
DRIVES PATHOLOGY HERE AND 

7115
05:40:50,160 --> 05:40:56,640
PATIENTS HAVE MORE OF IT PURE 

7116
05:40:56,640 --> 05:40:59,440
INFLAMOSOME WITH IL-6 ON TOP OF 

7117
05:40:59,440 --> 05:41:03,800
CYTOKINES AND CHEMOKINDS OF THE 

7118
05:41:03,800 --> 05:41:04,240
VIRUS. 

7119
05:41:04,240 --> 05:41:08,840
I SHOWED WE HAVE FOUND SYSTEMIC 

7120
05:41:08,840 --> 05:41:09,440
INFLAMMATORY ACTIVATION IN 

7121
05:41:09,440 --> 05:41:13,400
INDIVIDUALS WITH HIV WITH 

7122
05:41:13,400 --> 05:41:15,720
MICROBACTERIAL IRIS AND KHV 

7123
05:41:15,720 --> 05:41:19,600
ASSOCIATED CONDITIONS AND SEVERE

7124
05:41:19,600 --> 05:41:28,320
MICRO BACTERIAL VIRUS WITH 

7125
05:41:28,320 --> 05:41:32,520
UNIMPOSED T CELL REGULATIONS. 

7126
05:41:32,520 --> 05:41:35,280
THAT CASE HB IS POTENTIALLY 

7127
05:41:35,280 --> 05:41:36,920
DRIVING INFLAMMATION DUE TO 

7128
05:41:36,920 --> 05:41:42,200
STRONG ASSOCIATION WITH THIS 

7129
05:41:42,200 --> 05:41:45,600
ACTIVATION WITH IL18 AND CURIOUS

7130
05:41:45,600 --> 05:41:47,600
DIGGING INTO MECHANISM OF IT AND

7131
05:41:47,600 --> 05:41:50,120
OPEN READING FRAME OF KS SEEMS 

7132
05:41:50,120 --> 05:41:55,840
TO INHIBIT NLRP1 AND NLRP3 AND 

7133
05:41:55,840 --> 05:41:59,360
BIT OF A CONUNDRUM THERE AND 

7134
05:41:59,360 --> 05:42:03,400
WORTH DIGGING INTO THAT AND WE 

7135
05:42:03,400 --> 05:42:05,160
SEE MULTICENTRIC CASTLEMAN'S 

7136
05:42:05,160 --> 05:42:06,720
DISEASE DRIVING THIS PROFILE AND

7137
05:42:06,720 --> 05:42:10,680
CAN HAVE DISTINCT SIGNATURE TO 

7138
05:42:10,680 --> 05:42:12,400
DIFFERENTIATE BETWEEN DIFFERENT 

7139
05:42:12,400 --> 05:42:17,600
CASE AND KS SYNDROMES AND IN 

7140
05:42:17,600 --> 05:42:22,640
CONTRAST TO THAT WE FOUND MACRO 

7141
05:42:22,640 --> 05:42:27,840
BACTERIAL CASE AND INFLAMMATORY 

7142
05:42:27,840 --> 05:42:36,680
SYNDROMES AFRICAN POPULATIONS. 

7143
05:42:36,680 --> 05:42:39,280
TREATMENTS ARE VERY DIFFERENT. 

7144
05:42:39,280 --> 05:42:42,480
I WOULD LIKE TO FINISH THANKING 

7145
05:42:42,480 --> 05:42:45,480
MY TEAM AND SYLVIA IS AN EXPERT 

7146
05:42:45,480 --> 05:42:48,120
IN THE GROUP AND JOE IS 

7147
05:42:48,120 --> 05:42:49,760
INFECTIOUS FELLOW WITH LOTS OF 

7148
05:42:49,760 --> 05:42:54,600
WORK AND ANALYSIS I SHOWED YOU 

7149
05:42:54,600 --> 05:42:57,040
AND CLINICAL PEOPLE AND BOB'S 

7150
05:42:57,040 --> 05:42:59,280
GROUPS THAT WERE INCREDIBLE 

7151
05:42:59,280 --> 05:43:00,920
COLLABORATORS AT THE BEDSIDE AND

7152
05:43:00,920 --> 05:43:09,040
ALSO IN THE BENCH.  THANK YOU. 

7153
05:43:09,040 --> 05:43:10,040
>>VERY NICE.  

7154
05:43:10,040 --> 05:43:13,560
WHAT HAPPENS IF YOU BLOCK CAS 

7155
05:43:13,560 --> 05:43:17,160
SPACE 1 WITH INHIBITORS OR IL-1 

7156
05:43:17,160 --> 05:43:18,840
BETA WITH INHIBITORS?  

7157
05:43:18,840 --> 05:43:20,360
>>VERY GOOD QUESTION. 
THAT 

7158
05:43:20,360 --> 05:43:22,640
HASN'T BEEN DONE YET IN THE 

7159
05:43:22,640 --> 05:43:23,920
CLINIC.  WE DO THINK THAT, THAT 

7160
05:43:23,920 --> 05:43:25,440
IS ONE OF THE DIRECTIONS THAT WE

7161
05:43:25,440 --> 05:43:30,440
WILL BE LOOKING AT.  

7162
05:43:30,440 --> 05:43:32,240
YEAH.  THERAPIUTICALLY SPEAKING.

7163
05:43:32,240 --> 05:43:32,480
>>OKAY. 

7164
05:43:32,480 --> 05:43:35,920
>>AND JAK INHIBITORS
MENTIONED 

7165
05:43:35,920 --> 05:43:37,680
IN A TALK BEFORE MIGHT BE 

7166
05:43:37,680 --> 05:43:38,640
ANOTHER WAY TO GO. 

7167
05:43:38,640 --> 05:43:41,520
>>THANK YOU. 

7168
05:43:41,520 --> 05:43:46,880
>>THANK YOU. 

7169
05:43:46,880 --> 05:43:51,560
>>HI.  IS THERE DATA WITH

7170
05:43:51,560 --> 05:43:53,760
[INDISCERNIBLE] WITH IRIS AND 

7171
05:43:53,760 --> 05:43:56,320
GLOBAL DEPLETION IN BLOOD. 

7172
05:43:56,320 --> 05:43:58,080
>>SORRY?  

7173
05:43:58,080 --> 05:44:03,840
>>OCCURRENCE OF IRIS
PATIENTS 

7174
05:44:03,840 --> 05:44:07,080
WITH GLUTEA THIGH OWN DEPLETION 

7175
05:44:07,080 --> 05:44:07,480
IN BLOOD?  

7176
05:44:07,480 --> 05:44:11,680
>>IF HAPPENS DURING IRIS
YOU 

7177
05:44:11,680 --> 05:44:11,880
MEAN. 

7178
05:44:11,880 --> 05:44:15,320
>>OCCURRENCE OF IRIS IS
WITH 

7179
05:44:15,320 --> 05:44:15,600
DEPLETION. 

7180
05:44:15,600 --> 05:44:17,600
>>GOOD QUESTION.  WE
HAVEN'T 

7181
05:44:17,600 --> 05:44:20,080
DONE IN MICRO BACTERIALIZE AND 

7182
05:44:20,080 --> 05:44:23,240
WE FOUND IT IN COVID AND DID 

7183
05:44:23,240 --> 05:44:25,320
SIMILAR STUDIES LOOKING AT 

7184
05:44:25,320 --> 05:44:27,360
INFLAMMATORY ACTION IN PATIENTS 

7185
05:44:27,360 --> 05:44:32,480
AND FOUND SIGNIFICANT DEPLETION.

7186
05:44:32,480 --> 05:44:36,360
>>IT OCCURS IN VITRO
INFECTION.

7187
05:44:36,360 --> 05:44:37,680
>>THAT IS GOOD. 

7188
05:44:37,680 --> 05:44:39,680
>>WE HAVEN'T DONE FOR
THESE 

7189
05:44:39,680 --> 05:44:42,880
PATIENTS YET BUT COVID COHORT 

7190
05:44:42,880 --> 05:44:45,960
AND REMARKABLE FOUND OXIDATIVE 

7191
05:44:45,960 --> 05:44:47,120
STRESS AND [INDISCERNIBLE] SO WE

7192
05:44:47,120 --> 05:44:49,840
HAVEN'T REPEATED THAT WITH OUR 

7193
05:44:49,840 --> 05:44:50,440
-- 

7194
05:44:50,440 --> 05:44:54,160
>>MOST PREDOMINANT
ANTIOXIDANT.

7195
05:44:54,160 --> 05:44:55,400
>>GREAT SUGGESTION. 
THANKS 

7196
05:44:55,400 --> 05:44:55,920
VERY MUCH. 

7197
05:44:55,920 --> 05:44:58,320
>>YEAH. 

7198
05:44:58,320 --> 05:44:58,960
>>THANK YOU. 

7199
05:44:58,960 --> 05:45:09,520
>>>>OKAY.  GREAT. 
THANK YOU. 

7200
05:45:18,720 --> 05:45:29,160
>>SORRY.  I JUST HAVE TO
DO 

7201
05:45:34,720 --> 05:45:42,440
THIS.  

7202
05:45:42,440 --> 05:45:47,800
OKAY.  SO, I JUST WANT TO END BY

7203
05:45:47,800 --> 05:45:50,800
THANKING EVERYONE WHO 

7204
05:45:50,800 --> 05:45:52,600
CONTRIBUTED TO MAKING THIS DAY 

7205
05:45:52,600 --> 05:45:55,520
SO EXCITING AND FUN DAY WITH A 

7206
05:45:55,520 --> 05:45:58,960
LOT OF GREAT TALKS AND FIRST OF 

7207
05:45:58,960 --> 05:46:03,600
ALL WANT TO THANK MY 

7208
05:46:03,600 --> 05:46:05,320
CO-ORGANIZER CINDY WHO HAS BEEN 

7209
05:46:05,320 --> 05:46:08,760
A PLEASURE TO WORK WITH HER IN 

7210
05:46:08,760 --> 05:46:10,480
ORGANIZING THIS IN THE LAST FEW 

7211
05:46:10,480 --> 05:46:14,920
MONTHS AND THANKING INVITED 

7212
05:46:14,920 --> 05:46:15,240
SPEAKERS. 

7213
05:46:15,240 --> 05:46:19,440
AND ALL OF THE ORAL AND POST 

7214
05:46:19,440 --> 05:46:23,440
REPRESENTERS WHO SUBMITTED 

7215
05:46:23,440 --> 05:46:25,320
ABSTRACTS SHARING THEIR STUDIES 

7216
05:46:25,320 --> 05:46:27,360
I THINK WITHOUT THEM THIS 

7217
05:46:27,360 --> 05:46:29,000
WOULDN'T BE SUCCESSFUL. 

7218
05:46:29,000 --> 05:46:30,760
ALSO, I WANT TO THANK ALL OF THE

7219
05:46:30,760 --> 05:46:35,400
PEOPLE WHO ATTENDED IN PERSON 

7220
05:46:35,400 --> 05:46:36,560
AND VIRTUALLY. 

7221
05:46:36,560 --> 05:46:39,400
FINALLY, I WANT TO THANK THE 

7222
05:46:39,400 --> 05:46:41,080
ADMINISTRATIVE STAFF WHO 

7223
05:46:41,080 --> 05:46:42,600
SUPPORTED US DURING THE 

7224
05:46:42,600 --> 05:46:44,200
ORGANIZATION, PARTICULARLY 

7225
05:46:44,200 --> 05:46:47,600
JACKIE AND JULIA LAM AND TERRY 

7226
05:46:47,600 --> 05:46:53,000
AND VALERIE TURN KWIFT.  AND THE

7227
05:46:53,000 --> 05:46:56,480
ONLY THING THAT REMAINS THEN IS 

7228
05:46:56,480 --> 05:47:00,960
ANNOUNCING TRAVEL AWARD WINNERS.

7229
05:47:00,960 --> 05:47:03,840
SO, DRUM ROLL, PLEASE. 

7230
05:47:03,840 --> 05:47:07,800
OKAY.  SO, THE FIRST FOR THE 

7231
05:47:07,800 --> 05:47:11,360
ORAL PRESENTATIONS, THE WINNERS 

7232
05:47:11,360 --> 05:47:15,800
ARE IN NO PARTICULAR ORDER 

7233
05:47:15,800 --> 05:47:26,280
RAMONA MOLES AND TRINYIN LAU, 

7234
05:47:29,640 --> 05:47:40,120
AND KRISTA A /* FRANKEN BERRY 

7235
05:47:40,120 --> 05:47:44,520
AND FOR THE POSTER 

7236
05:47:44,520 --> 05:47:51,800
PRESENTATIONS, THE WINNERS ARE 

7237
05:47:51,800 --> 05:48:02,280
UTAH AND ALEX FLINE PETER AND 

7238
05:48:02,280 --> 05:48:04,800
SARCAS SARCAS. 

7239
05:48:04,800 --> 05:48:08,560
OKAY.  CONGRATULATIONS, 

7240
05:48:08,560 --> 05:48:09,480
EVERYONE.  

7241
05:48:09,480 --> 05:48:11,800
I SHOULD NOTE THAT PARTICULARLY 

7242
05:48:11,800 --> 05:48:14,040
SINCE KRISTA AND I ENDED UP 

7243
05:48:14,040 --> 05:48:15,560
WINNING THAT I WASN'T INVOLVED 

7244
05:48:15,560 --> 05:48:17,600
IN THE DECISION-MAKING PROCESS 

7245
05:48:17,600 --> 05:48:19,720
AND WE HAD A NUMBER OF JUDGES 

7246
05:48:19,720 --> 05:48:22,520
THAT RANKED ALL OF THE TALKS 

7247
05:48:22,520 --> 05:48:22,720
AND. 

7248
05:48:22,720 --> 05:48:26,080
>>THANK YOU TO THE
JUDGES. 

7249
05:48:26,080 --> 05:48:28,360
>>THANK YOU TO THE JUDGES
FOR 

7250
05:48:28,360 --> 05:48:31,120
ALL OF THE HARD WORK AND OKAY.  

7251
05:48:31,120 --> 00:00:00,000
BYE, EVERYBODY.  SEE YOU NEXT
YEAR