GOOD MORNING, EVERYONE.
WELCOME AGAIN TO THE SIXTH
BIENNIAL HIV/AIDS CURE MEETING.
WE'RE GOING TO START OFF THIS
MORNING, IT'S GOING TO BE TH SAA
BRIDGES.
>> GOOD MORNING, EVERYONE.
I'M SANDRA BRIDGES, PROGRAM
OFFICER ALONG WITH ERIC FOR THE
REACH COLLABORATORY, AND I THINK
AS YOU CAN SEE ON THE SCREEN,
THAT STANDS FOR RESEARCH
ENTERPRISE TO ADVANCE A CURE FOR
HIV.
I'VE ASKED THEM FOR A SHORTER
NAME BUT THAT'S IT.
THIS IS REACH.
WE HAVE TWO -- WE HAVE CO-PIs
ON THIS COLLABORATORY.
THEY ARE BRAD JONES, WHO'S BASED
AT WEILL CORNELL MEDICINE, AND
MARINA CASKEY, WHO'S AT THE
ROCKEFELLER.
SO I THINK AT THIS POINT, I'LL
TURN IT OVER TO BRAD, AND HE'LL
CARRY ON.
THANK YOU.
IT'S A PLEASURE TO INTRODUCE THE
GROUP.
>> THANKS SO MUCH, SANDRA, AND
ERIC, FOR BEING SUCH SUPPORTIVE
PROGRAM OFFICERS.
IT'S MY PLEASURE TO GIVE THIS
OVERVIEW FOR REACH AND SEE IF I
CAN ADVANCE MY SLIDES ALSO.
SO AS SANDRA MENTIONED I CO-LEAD
THIS PROGRAM WITH MARINA CASKEY
AS WELL AS ADAM WARD.
THIS IS OUR EXECUTIVE COMMITTEE,
THEY SERVE A NUMBER OF IMPORTANT
ROLES.
WE'RE CHARGED WITH DYNAMICALLY
TRYING TO ALLOCATE RESOURCES TO
SUPPORT THE HIGHEST PRIORITY
SCIENCE AND WE DO THAT WITH THE
DISCUSSION AND VOTES OF OUR
EXECUTIVE COMMITTEE MEMBERS.
SO REACH IS LARGELY AN IMMUNE
BASED COLLABORATORY, WE'RE
TRYING TO HARNESS THE IMMUNE
SYSTEM TO CURE HIV OR ACHIEVE
REMISSION.
WE'RE MOSTLY FOCUSED ON
CD8 T-CELLS AND NATURAL KILLER
CELLS.
WE LOOK AT RESERVOIR DYNAMICS
AND HOW THESE RELATE TO T-CELL
RESPONSES, HOW T-CELLS CAN SHAPE
THE RESERVOIR EVEN UNDER
ANTIRETROVIRAL THERAPY.
WE HAVE A MAJOR FOCUS ON
UNDERSTUDIED POPULATIONS, IN
PARTICULAR A FOCUS ON RAKAI,
UGANDA AS YOU'LL SEE IN GUI'S
TALK.
RESEARCH FOCUS TWO, REMISSION,
WE'RE TRYING TO HARNESS BNABS IN
COMBINATION WITH CD8 PLUS
T-CELLS AND OTHER BIOLOGICS, AND
RESEARCH FOCUS 3, WE HAVE TWO
PARTS.
FIRST WE'RE TRYING TO ENHANCE
CTL AND NK CELL FUNCTION AND
ALSO OVERCOME MECHANISMS BY
WHICH SOME INFECTED CELLS RESIST
KILLING.
THAT'S A REALLY IMPORTANT AREA
OF FOCUS WITHIN REACH.
THE SECOND PART, WE'RE LOOKING
AT MECHANISMS OF LATENCY WITH A
FOCUS ON HOW THIS IS INFLUENCED
BY THE PROVIRAL INTEGRATION
SITE.
SO JUST TO FLASH THIS BRIEFLY, I
WANT TO MENTION THAT WE REALLY
PRIORITIZE TRYING TO FIND
SYNERGIES BETWEEN THESE
DIFFERENT RFs.
TO ME THAT'S ONE OF THE MOST
EXCITING PARTS OF THESE DELANEY
PROGRAMS, SO THIS IS SOMETHING
WE THINK ABOUT VERY CAREFULLY.
AND TO MENTION, WE ARE DOING A
LOT OF BASIC SCIENCE BUT WE'RE
LOOKING TOWARDS TRANSLATIONAL
OUTCOMES, AND POTENTIALLY TAKING
PROMISING APPROACHES AND
PARTNERING WITH THE ACTG, AND WE
HAVE ONE SUCH PARTNERSHIP SO
FAR.
THIS STUDY IS CALLED ACTG A5386.
THERE'S TWO ARMS.
THIS IS WITH OUR INDUSTRY
PARTNER IMMUNITY BIOTESTING A
SUPERAGONIST ALONE OR WITH
BROADLY NEUTRALIZING ANTIBODIES,
THEN THERE IS A TREATMENT
INTERRUPTION PHASE WHERE WE HOPE
WE SEE SOME SIGNAL OF REMISSION
THAT WAS SEEN IN NON-HUMAN
PRIMATES WITH THIS COMBINATION.
AND WE'RE ABOUT A THIRD OF THE
WAY THROUGH ACCRUAL FOR THIS
STUDY.
SO ONE OF THE WAYS WE LIKE TO
MEASURE OUR PROGRESS IS HOW WELL
WE'RE DOING AT BRINGING
DIFFERENT INVESTIGATORS TOGETHER
AND FORMING NEW CL COLLABORATIO.
SO WE DO THIS WITH THESE -- EACH
IS PROPORTIONATE TO THE NUMBER
OF CO-PUBLICATIONS WITH
INVESTIGATORS.
THIS IS WHERE WE STARTED AT THE
BEGINNING OF THE GRANT.
IT'S REWARDING TO SEE THIS IS
WHERE WE'RE AT 2 1/2 YEARS IN.
THERE'S A FEW NEW INVESTIGATORS
THAT HAVE BEEN ADDED BUT LARGELY
THIS DENSIFICATION IS DUE TO NEW
COLLABORATIONS, NEW PUBLICATIONS
WITH GROUPS OF INVESTIGATORS WHO
HADN'T WORKED TOGETHER
PREVIOUSLY, AS WELL AS NOW
BROADER LINES BETWEEN GROUPS WHO
HAD COLLABORATIONS.
IN THE LIMITED TIME I HAVE
TODAY, I PICKED JUST TWO AREAS
OF PROGRESS FROM THE FIRST TWO
YEARS TO HIGHLIGHT.
APOLOGIES TO THOSE WHO I LEFT
OUT.
WE'RE NOT FUNDING TRIALS IN
REACH BUT WE'VE HAD
OPPORTUNITIES TO CONTRIBUTE IN
REALLY IMPORTANT WAYS TO
EXISTING TRIALS.
ONE OF THESE IS THE ECLEAR
STUDY.
ONE OF THE CHALLENGES THAT WAS
DISCOVERED WITH THE TEAM IS THAT
ABOUT 51% OF THESE PEOPLE HAD
NON-SUBTYPE B HIV, SO APPLYING
INTACT PRO FIERL DNA ASSAYS WAS
A CHALLENGE.
SO WE WERE ABLE TO LEVERAGE OUR
EXPERIENCE IN ADAPTING TO
DIVERSE ISOLATES THAT GUIN WILL
TALK ABOUT AND DEVELOP 17 NEW
PRIMERS, 25 CUSTOM PROBES AND
MEASURE THE INTACT PRO VIRUS IN
EVERYONE IN THIS STUDY.
ONE OF THE THINGS THAT WE'VE
DONE IN LEVERAGING THE FLEXIBLE
ASPECTS OF THE DELANEY IS ADD
NEW INVESTIGATORS, SO OLE IS NOW
OFFICIALLY A REACH INVESTIGATOR
AND NOW WE'RE GOING TO
PRIORITIZE IN SUBSEQUENT YEARS
TRYING TO DISCERN MECHANISMS BY
WHICH SOME MEASURE OF CONTROL
WAS ACHIEVED IN THIS ECLEAR
STUDY AND OTHER TRIALS.
THE SECOND AREA I'LL HIGHLIGHT
IS THESE TWO STUDIES
CHARACTERIZING THE FEATURES OF
THE EXPANDED CLONES OF INFECTED
CELLS IN HIV RESERVOIRS, AND
APPROACHES FROM SOMEWHAT
DIFFERENT AN AGAINS, THEY
CONVERGED ON THE FINDING THAT
SOME OF THE RESERVOIR IS
HARBORED IN THESE CYTOTOXIC
CD4 T-CELL CLONES AND YET SHE
PROPOSED ONE OF THE REASONS
THESE MAY BE HARD TO KILL IS
THEY HAVE MECHANISMS FOR
DEFENDING THEMSELVES AGAINST
THEIR OWN CYTOTOXICITY.
SO ONE OF THE OTHER
INVESTIGATORS WE'VE ADDED GOING
INTO YEAR THREE IS FRAU, WHO HAS
A LARGE PANEL OF CLONES OF
INFECTED CELLS THAT WE CAN
REALLY PROBE FOR SOME OF THESE
FUNCTIONAL FEATURES.
WE HAVE A NUMBER OF POSTERS HERE
AT THE MEETING THAT I'LL
HIGHLIGHT HERE, AND CONGRATULATE
THE EARLY CAREER INVESTIGATOR
SCHOLARSHIPS THAT ARE
HIGHLIGHTED IN YELLOW.
I DON'T HAVE TIME TO READ
THROUGH ALL THESE OF PLEASE DROP
BY THE POSTERS AND SEE WHAT
WE'VE BEEN UP TO.
THEN OUR COMMUNITY PARTNER IS
AVAC, WE'LL HEAR MORE ABOUT
COMMUNITY ENGAGEMENT EFFORTS IN
HER UPCOMING TALK.
SO WITH THAT, I WILL WRAP UP AND
PASS OVER TO GUIN LEE, ONE OF
THE CO-LEADS OF RF 1 TO TELL BUS
ADAPTING INTACT VIRAL ASSAYS I.
>> GOOD MORNING, EVERYONE.
MY NAME IS GUIN LEE FROM WEILL
CORNELL MEDICINE.
TODAY I'LL SPEAK ON BEHALF OF MY
RF 1 COLEADS, AND OF COURSE ON
BEHALF OF THE ENTIRE TEAM TO
TALK ABOUT THE VIRAL RESERVOIR
IN RAKAI.
SO THE REACH RF 1 TEAM IS 15
INVESTIGATORS STRONG.
I'VE HIGHLIGHTED THE
INVESTIGATORS HERE WHO ARE
INVOLVED IN THE RAKAI PROJECT.
OUR OVERARCHING GOAL IN RF 1 IS
TO DEFINE A THREE-WAY
RELATIONSHIP BETWEEN COMPOSITION
DYNAMICS AND CD4 T-CELLS AND
REBOUND VIRUSES.
SO HERE TODAY I'M GOING TO TALK
VERY SPECIFICALLY ON NON-SUBTYPE
V HIV IN RAKAI.
SO THE PLAIN LANGUAGE SUMMARY.
THE KEY QUESTION HERE IS I WANT
TO ASK, ARE NON-SUBTYPE B HIV
DNA GENOMES, ARE THEY -- DO THEY
HAVE THE SAME COMPOSITION
RELATIVE TO WHAT WE KNOW ABOUT
SUBTYPE B TODAY, BECAUSE WE HAVE
A LOT OF RESERVOIR STUDIES IN
SUBTYPE B VIRUSES, BUT IS THE
RESERVOIR COMPOSITION THE SAME
IN NON-SUBTYPE B VARIANTS?
ARE WE ABLE TO ADAPT THE IPDA
ASSAY THAT IS DEVELOPED BASED ON
SUBTYPE B SEQUENCES ON THE
NON-SUBTYPE B VARIANTS?
SO WE FOUND THAT OUR KEY
FINDINGS IS THAT THE NON-SUBTYPE
B AND SPECIFICALLY SUBTYPE
A1 AND D PRO VIROME GENOMES,
THEY ACTUALLY SHARED A LOT OF
COMMONALITIES WITH SUBTYPE B.
SO FOR EXAMPLE, SUBTYPE B HAS A
LOT OF DEFECTIVE GENOMES WHEN
YOU LOOK AT THE PROVIRAL POOL
AND THE SAME IS TRUE FOR SUBTYPE
A AND D.
FOR EXAMPLE, WE HAVE SEEN CLONAL
EXPANSION OF SUBTYPE B VARIANTS,
ALSO SEEING EVIDENCE OF CLONAL
EXPRESSIONS OF TYPE A AND D.
WEEFL ALSO HAD PRELIMINARY DATA
TO SHOW THAT THE CD8 T-CELL
RESPONSES IN THE RAKAI
PARTICIPANTS BEING HIGHER THAN
THE AMERICAN -- THEIR AMERICAN
COUNTERPARTS.
SO THE NEXT STEP, SO WE HAVE
CURRENTLY INSTALLED OR IN THE
MID EVIDENTLY INSTALLING A DDPCR
PLATFORM IN RAKAI TO HELP
INSTALL THE DDPCR MACHINE ON
SITE.
SO THEN THE UGANDA SCIENTISTS
CAN ACTUALLY RUN THIS ASSAY
THERE.
SO MOVING FORWARD, WE WANT TO
APPLY THE DDPCR ASSAY TO ALL
STUDY PARTICIPANTS LONGITUDALLY
IN THE RAKAI COHORT, AND WE WANT
TO SEE WHETHER THERE'S
SIGNIFICANT CD8 T-CELL RESPONSES
CORRELATION WITH THE RESERVOIR
MEASUREMENTS.
SO TO INTRODUCE THE COHORT, THE
RAKAI LATENT RESERVOIR
LONGITUDAL COHORT HAS 19 STUDY
PARTICIPANTS.
IT'S HOUSED WITHIN A 30,000
REGIONAL HIV TREATMENT PROGRAM
COHORT WHERE THE CLINICAL AND
TREATMENT HISTORIES ARE
AVAILABLE, SO PARTICIPANTS WERE
ENROLLED MEDIAN SEVEN YEARS POST
TREATMENT.
PBMC AND PLASMA ARE COLLECTED
AND WE PERFORMED QVOA AND FRIP
SEQUENCING AND DDPCR ON THESE
STUDY PARTICIPANTS.
SO THE RAKAI RESERVOIR STUDY
REALLY STARTED WITH THIS
OBSERVATION THAT OUR OWN
DR. JESSICA SALZWEDEL MADE THAT
THE RAKAI RESERVOIR IS ACTUALLY
THREE FOLD LOWER IN TERMS OF IPD
VALUES COMPARED TO THE NORTH
AMERICAN COUNTERPARTS AND SO IT
SHOWS THAT THE NON-SUBTYPE B --
AT LEAST IN THIS POPULATION, IT
MIGHT NOT BE THE SAME AS WHAT
WE'VE USUALLY SEEN IN THE
SUBTYPE B COHORTS.
SO FURTHERMORE WE HAVE THE
LATEST PRELIMINARY DATA FROM THE
RF 1 THAT IF YOU LOOK AT PANEL
1, WE ARE COMPARING THE RAKAI
CTCD8 T-CELL RESPONSES TO A NORH
AMERICAN COHORT.
YOU CAN SEE THAT THE RAKAI STUDY
PARTICIPANTS HAVE HIGHER
INTERFERON GAMMA-SPECIFIC T-CELL
RESPONSES IN TERMS OF MAGNITUDE
RELATIVE TO THE NORTH AMERICAN
COUNTERPARTS.
SO THE -- IS ALSO HIGHER
SPECIFICALLY IN ENVELOPE AND
ALSO IN CMV IN THIS RAKAI
COHORT.
SO SOMETHING IS DIFFERENT AT
LEAST IN THE CD8 T-CELL
RESPONSES.
IN THE SECOND PANEL, CAN YOU SEE
THAT THE MAGNITUDE OF -- HAS AN
INVERSE CORELATION WITH THE IPD
MEASUREMENTS IN THIS RAKAI
COHORT.
WHAT THAT MEANS IS THE HIGHER
THE -- WE SEE A CORRELATION THAT
THERE'S A HIGHER -- RESPONSES
AND THERE'S A LOWER IUPM VALUES.
IT MEANS THAT WHEN THE T-CELL
MAGNITUDE RESPONSES IS STRONGER
IN THE CD8 NEF-SPECIFIC
RESPONSES, IT'S CORELATED WITH A
LOWER IUPM VALUES SO MAYBE THAT
SUGGESTED THAT THE CD8 T-CELLS
ARE MAKING A DENT ON THE
RESERVOIR, IS SHAPING THE
RESERVOIR PROFILE.
SO WE WANT TO STUDY THE SHAPES
OF THE RESERVOIR, WHAT IS INSIDE
THE RESERVOIR.
SO HERE WE HAVE MATCHING VIRAL
GENOME SEQUENCES OBTAINED FROM
20 TOLEDO NORS.
THERE ARE SUBTYPE A1 -- WE HAVE
FOUR INDIVIDUALS, NINE SUBTYPE D
INDIVIDUALS AND NINE INDIVIDUALS
WITH RECOMBINANT AD VIRUSES.
IF YOU LOOK AT THE RECOMBINANTS,
SO EACH VERTICAL ROW -- SORRY,
EACH HORIZONTAL ROW HERE
REPRESENTS A SINGLE INDIVIDUAL.
IF YOU LOOK AT THE BOTTOM STACK
THERE, THE RECOMBINANTS, THE
RECOMBINANT IN THIS COHORT IS
ACTUALLY VERY COMPLEX.
RED STANDS FOR SUBTYPE D AND
BLUE STANDS FOR SUBTYPE A, AND
YOU CAN SEE THAT THERE ARE A LOT
OF THESE INTERSUBTYPE REIMI
NANTZ THAT ARE CIRCULATING IN
THIS COHORT.
SOME OF THEM START WITH A
SUBTYPE A GAP AND THEN IT
BECOMES A SUBTYPE D PROTEASE AND
RT AND THEN IT BECOMES A SUBTYPE
A -- AGAIN, AND THEN IT TURNS
BACK INTO SUBTYPE D.
SO THE RECOMBINATION SITUATION
IN A COHORT LIKE THIS IS REALLY
COMPLEX, AND ALL OF THE
RECOMBINANT DONORS DON'T HAVE
THE SAME RECOMBINATION BREAK
POINTS.
FOR EXAMPLE IF A PERSON WALKS
INTO A CLINIC, YOU WOULD NOT BE
ABLE TO IMMEDIATELY KNOW WHETHER
THIS PERSON IS IMPACTED BY
SUBTYPE A OR SUBTYPE D VIRUSES,
AND PERHAPS THE ENVELOPE REGION
VERSUS THE G AK REGION WHICH ARE
THOSE TARGET SITES WOULD NOT
HAVE THE SAME SUBTYPE, AND SO WE
WANT TO DEVELOP A METHOD THAT
WOULD COVER BOTH SUBTYPES IN
THIS COHORT AND SO WE WILL BE
DOING A COHORT-SPECIFIC IPD
DEVELOPMENT APPROACH.
SO GOING BACK TO THE RESERVOIR,
SO IN THE STUDY WE'VE OBSERVED
THAT THE SUBTYPE A AND D
RESERVOIRS ARE VERY SIMILAR TO
SUBTYPE B IN THE SENSE THAT
THERE ARE VERY FEW INTACT
VIRUSES, AND THERE ARE A LOT OF
DEFECTIVE VIRAL GENOME
CATEGORIES VERY SIMILAR IN TERMS
OF HAVING THE LARGE TRUNCATIONS,
HAVING HYPERMUTATIONS, AND WE'VE
ALSO SEEN EVIDENCE OF CLONAL
EXPANSION.
SO HERE'S AN EXAMPLE OF A
REPRESENTATIVE INDIVIDUAL THAT
IS IMPACTED BY SUBTYPE A HIV.
SO YOU CAN SEE THAT THE DARK
BLUE STACKS OF BARS AT THE TOP
ARE THE INTACT VIRUSES.
AND ALL OF THE OTHER VIRAL
GENOMES AT THE BOTTOM WITH
LIGHTER COLORS ARE
GENOME-DEFECTIVE VIRUSES.
SO I'VE HIGHLIGHTED WITH
VERTICAL LINES OF THE IPDA SITE
AND ENVELOPE BINDING SITES.
HERE'S A SUBTYPE D DONOR.
AND YOU CAN ALREADY SEE THE
SIMILARITIES.
IT'S VERY SIMILAR TO WHAT WE SEE
USUALLY IN SUBTYPE B.
NOW, WHAT ABOUT THE IPDA BINDING
SITES?
SO IF YOU COUNT UP THE NUMBER OF
GENOMES THAT CONTAINS BOTH IPDA
BINDING SITES, WHICH IS A
PREDICTIVE MARKER FOR A GENOME
BEING INTACT, SO IF YOU HAVE
BOTH IPDA BINDING SITES, THE
GENE IS MORE LIKELY TO BE
INTACT.
SO OBVIOUSLY ALL OF THE INTACT
VIRUSES WOULD CONTAIN BOTH IPDA
BINDING SITES, BUT IF YOU COUNT
THE GENOME-DEFECTIVE VIRUSES, WE
SAW 95% WOULD EITHER HAVE ONE
MISSING OR MISSING BOTH IPDA
AND -- BINDING SITES.
THAT MEANS THAT WE HAVE 100%
SENSITIVITY AND 95% SPECIFICITY
IN TERMS OF IF WE JUST LOOK AT
THE LOCATIONS OF THESE PRIMER
AND PRO BINDING SITES, IF WE USE
THE ORIGINAL IPDA DESIGN ON THIS
COHORT.
BUT OF COURSE THE
SENSITIVITY/SPECIFICITY ISSUE IS
NOT JUST LIMITED TO WHERE THE
PRIMERS AND PROBES LOCATED.
SEQUENCE AND DIVERSITY ALSO
MATTERS.
SO LET'S LOOK AT A SEQUENCE
DIVERSITY.
ALL OF THE POLYMORPHISMS WE
IDENTIFIED -- THIS IS THE FIRST
REGION, AND THE BOTTOM FOUR ROWS
ARE THE RAKAI COHORT
OBSERVATIONS.
AND YOU CAN SEE THAT THE PSI
FORWARD AND REVERSE PRIMERS
PRETTY MUCH MATCH UP THE IPDA
WITH A FEW POLYMORPHISMS BUT THE
PSI PROBE HAS A LOT MORE
OBSERVED IN THE RAKAI COHORT.
THE SAME IS TRUE IN THE ENVELOPE
REGION.
THERE ARE -- WE SEE DIVERSITY.
AND SO HOW DO WE ACCOUNT FOR
THIS DIVERSITY?
FIRST LET'S SEE WHETHER THE
ORIGINAL IPDA DESIGN AND THE
ORIGINAL PRIMERS AND PROBE
SEQUENCES WOULD ACTUALLY BIND TO
THE SAMPLES IN THIS RAKAI
COHORT.
SO ON PANEL A HERE, WE SUBJECT A
SUBTYPE D SAMPLE THROUGH THE
ORIGINAL IPDA AND UNFORTUNATELY
IPDA ACTUALLY FAILED IN THE PSI
REGION AND IT ONLY PRODUCED
ENVELOPE SIGNALS.
BOTTOM THERE, WE USED AN
ADAPTIVE DESIGN, DESIGNED
SPECIFICALLY TO TAKE INTO
ACCOUNT FOR THE GENETIC
DIVERSITY AND WE WERE ABLE TO
RESCUE THE SIGNALS.
SO OUR APPROACH IS TO USE
DEGENERATIVE BASIS.
FOR EACH OF THE POLYMORPHIC
SITES THAT WE'VE DEVELOPED --
THAT WE'VE OBSERVED IN THIS IPDA
PRIMERS AND PROBES BINDING SITE,
WE INCORPORATED DEGENERATIVE
BASE IN THE REGION.
SO WHAT I MEAN BY
DEGENERATIVE-BASED APPROACH IS
THAT FOR EXAMPLE, IN A VERY
SPECIFIC SITE, IF WE SEE 50% --
OR WE SEE POLYMORPHISMS THAT
CONSIST OF 50% A AND 50% G, WE
DESIGN A PRIMER MIX THAT
CONTAINS WI 50% A NUCLEOTIDES AD
50% G, ALL MIXED UP AND PUT INTO
THE REACTION.
SO FOR COMPASS IN THE SPI PROBE
THERE WILL BE 60 VARIATIONS SO
IF YOU COUNT UP TO THE MATH,
THERE WILL BE 64 DIFFERENT
SPECIES OF THE PROBE SEQUENCE
THAT WILL BE IN THE MIX.
AND THIS ACTUALLY HAS SHOWN TO
BE ENOUGH TO PRODUCE A STRONG
SIGNAL TO DETECT THE SUBTYPE D
SAMPLES THAT RESCUE TO FAILURE.
SO WE ARE APPLYING THIS
TECHNOLOGY TO OTHER SAMPLES,
INCLUDING SUBTYPE A1 AND D AND
SUBTYPE A SAMPLES.
SO WE ARE ALSO VERY PROUD TO
ANNOUNCE THAT WE ARE
TRANSFERRING THE TECHNOLOGY TO
THE UGANDAN SCIENTISTS AND
INSTALLING A DDPCR MACHINE ON
SITE AND OUR TEAM IS CURRENTLY
ON SITE TO HELP WITH THE DDPCR
SETUP.
AND THIS IS ALSO THE FIRST DDPCR
MACHINE THAT IS INTRODUCED INTO
THE SUB-SAHARAN AFRICAN REGION
OUTSIDE OF SOUTH AFRICA.
SO WE'RE VERY PROUD OF THAT.
SO IN THE NEXT STEP, NOW THAT WE
HAVE AN ADAPTED IPDA ASSAY, WE
WANT TO USE THIS TO ENSURE
LONGITUDALLY THE RELATIVE
CHANGES OF GENOME INTACT
VIRUSES, DEFECTIVE VIRUSES, WE
ALSO HAVE THE IUPM VALUES FOR
THESE PARTICIPANTS AND WE ALSO
WANT TO CORRELATE THE T-CELL
RESPONSES IN THIS COHORT WITH
THE RESERVOIR DYNAMICS.
THIS IS A HUGE TEAM EFFORT.
IT'S NOT POSSIBLE WITHOUT ALL OF
THE TEAM MEMBERS HERE INVOLVED
IN THE STUDY, SO I THANK
EVERYONE AND OF COURSE ALL THE
RAKAI STUDY PARTICIPANTS WHO ARE
INVOLVED.
THANK YOU.
[APPLAUSE]
>> SO NOW I'M GOING TO TALK
ABOUT RF 2.
SO AS BRAD INTRODUCED, OUR
COLLABORATORY IS REALLY FOCUSED
ON IMMUNOLOGIC APPROACHES.
IN PART OF RF 2, WE ARE TRYING
TO LEVERAGE CLINICAL TRIAL
SAMPLES, ALL STUDIES WE HAVE
CONDUCTED OR ARE ONGOING THAT
ARE TESTING A COMBINATION OF B
NABS WITH OTHER STRATEGIES.
AND THEN HERE, THE POINT IS TO
TRY TO DETERMINE THEIR VIROLOGIC
AND IMMUNOLOGIC EFFECTS WITHIN
THE CONTEXT OF ACHIEVING
NEUROLOGIC CONTROL.
SO HERE ARE THE RF
2 INVESTIGATORS, AND THEN THE
STUDIES I'M GOING TO BE
DISCUSSING TODAY ARE STUDIES
THAT WE CONDUCTED AT ROCKEFELLER
AND STUDIES THAT WE ARE
CONDUCTING IN COLLABORATION WITH
OTHERS.
SO THE AIM OF THE RF 2 THAT I'LL
BE DISCUSSING STATES THE
FOLLOWING.
SO THE GOAL IS TO DEFINE
MECHANISMS OF CD8 OR NK CELL
MEDIATED CONTROL OF VIREMIA
FOLLOWING DIFFERENT IMMUNOLOGIC
STRATEGIES.
WE'RE TRYING TO LEVERAGE WHAT WE
CAN LEARN FROM DIFFERENT
CLINICAL TRIALS.
SO THIS FIGURE HERE, I'M TRYING
TO ILLUSTRATE STUDYS THAT WE ARE
CONDUCTING OR HAVE ACCESS TO,
WIDER STUDIES ARE STILL IN
DEVELOPMDEVELOPMENT, IN RED ARES
ONGOING AND IN BLUE ARE
COMPLETED STUDIES.
SO ACROSS THE SERIES OF STUDIES,
WE ARE TESTING BNABS IN
DIFFERENT CONTEXTS.
SO EITHER DOING ACUTE INFECTION,
CHRONIC INFECTION AT ART
INITIATION, ARTE ART RESTART, AE
OR IN COMBINATION WITH AGONISTS
OR IL15 SUPERAGONIST.
SO THIS IS A SUMMARY OF STUDIES
THAT WE'VE DONE AT ROCKEFELLER.
SO WHILE OUR STUDIES ARE SMALL,
WE'VE SHOWN THAT A COMBINATION
OF TWO ANTIBODIES ARE ABLE TO
MAINTAIN SUPPRESSION IN
INDIVIDUALS THAT HARBOR
SENSITIVE VIRUSES.
IN ADDITION TO THAT, WE STARTED
TO PROBE TO SEE IF THEY HAD
OTHER EFFECTS.
THE FIRST GRAPHIC COMES FROM THE
FIRST STUDY WE DID WHERE WE SHOW
AN INFUSION IN VIREMIC
INDIVIDUALS OR ART-SUPPRESSED
INDIVIDUALS LED TO INCREASE IN
THEIR AUTOLOGOUS
NEUTRALIZATION -- OVER THE
COURSE OF SIX MONTHS.
LOOKING AT THEIR T-CELL
RESPONSES IN A STUDY WHERE WE
DID THE TWO ANTIBODIES OVER THE
COURSE OF SIX WEEKS DURING ART
INTERRUPTION, WE ALSO SAW THERE
WAS AN INCREASE IN GAG-SPECIFIC
CD8 AND CD4 T-CELL RESPONSES
DURING THIS BNAB MEDIATED VIRUS
SUPPRESSION.
BUT THOSE CHANGES WERE
TRANSIENT.
MORE RECENTLY, A STUDY WE DID
WITH CHRISTIAN GAEBLER, HE USED
Q4PCR.
IN THIS STUDY THE PARTICIPANTS
RECEIVED ANTIBODIES OVER THE
COURSE OF FIVE MONTHS AND THEN
HE FOUND THAT THERE WAS THIS
SMALL BUT STATISTICALLY
SIGNIFICANT CHANGE IN THE NUMBER
OF INTACT PRO VIRUSES DURING
THIS COURSE OF SIX MONTHS IN
CONTRAST TO THE -- VIRUS.
SO PUTTING ALL OF THIS TOGETHER,
WE THINK THESE ARE SMALL SIGNALS
THAT THE ANTIBODIES MAY IN FACT
BE INTERFERING WITH HIV
PERSISTENCE IN VIVO.
HOWEVER NONE OF THESE CHANGES
HAVE BEEN SUFFICIENT TO PREVENT
RETURN OF VIREMIA CONSISTENTLY.
SO IT MAY BE THAT THESE STUDIES
WERE NOT INTERVENING AT THE
IDEAL CLINICAL TIME POINT.
SO COULD IT BE THAT ANTIBODIES
AT ART INITIATION OR PERHAPS AT
ARTEART RESUMPTION IS A BETTER E
TO INTERVENE.
SO THIS IS A STUDY THAT BRAD
DISCUSSED A LITTLE EARLIER THAT
WAS CONDUCTED BY OLE SOGA ARD.
, HERE HE ENROLLED INDIVIDUALS
TO RECEIVE -- REVERSING AGENT
AND THE POINT HERE WAS TO SEE IF
THIS INTERVENTION AT ART
INITIATION WOULD INTERFERE WITH
THE ESTABLISHMENT OF THE
RESERVOIR.
SO THE INTERVENTION TOOK PLACE
OVER SEVERAL WEEKS, AND THEN THE
PARTICIPANTS WENT OFF ART AT THE
END OF ONE YEAR.
WHAT'S INTERESTING IN THIS STUDY
IS THAT THE PARTICIPANTS THAT
RECEIVED THE ANTIBODY WITH OR
WITHOUT -- BUT HAD SENSITIVE
NEUTRALIZATION SENSITIVE VIRUSES
AT THE START, SO PLASMA VIRUSES
THAT WERE SENSITIVE TO THE
ANTIBODY, THEY MAINTAINED HIGHER
CD8 T-CELL RESPONSES THAN THE
OTHER GROUPS PRIOR TO ART DISTIN
WAITION.
DISCONTINUATION.
THEY ALSO EXPERIENCED VIRAL
REBOUND THAT WAS DELAYED AND
THEN SHOW THE DIFFERENT VIRAL
DYNAMIC WHEN ART WAS
DISCONTINUED IN COMPARISON TO
INDIVIDUALS WHO HAD RESISTANT
VIRUSES.
SO IT SEEMS THERE'S A SHIFT IN
HOW -- THE INTERFACE BETWEEN
IMMUNE RESPONSES AND VIRUSES
AFTER INTERVENTION.
SO WHEN WE LOOK ACROSS THE
STUDIES THAT WE HAVE COMPLETED,
WE SEE THE ANTIBODIES MAINTAIN
SUPPRESSION, WE HAVE THESE
INDICATIONS THAT PERHAPS THERE
IS INTERFERENCE WITH HIV
PERSISTENCE, AND ACROSS THESE
TRIALS, WE HAVE IDENTIFIED SIX
FULL OR PARTIAL POST
INTERVENTION CONTROLLERS, BUT WE
DON'T REALLY -- ASIDE OF THESE
CHANGES IN T-CELL RESPONSES, WE
DON'T REALLY HAVE A GOOD
UNDERSTANDING OF WHAT REALLY
DISTINGUISHING THEM FROM THE
ONES THAT WERE NON-CONTROLLERS.
SO AS BRAD TALKED EARLIER, WE
NOW ARE ALWAYS COMING OFFICIALLY
INTO THE COLLABORATORY AND WHAT
HE'S GOING TO BE FOCUSING ON IS
TO TRY TO UNDERSTAND THIS POST
INTERVENTION CONTROL OF
PARTICIPANTS THAT PARTICIPATE IN
OUR STUDIES AND HE'S GOING TO DO
THAT BY APPLYING A SERIES OF
MULTI-OMIC APPROACHES THAT ARE
GOING TO -- AIMING TO
CHARACTERIZE IMMUNE RESPONSES AT
THE TRANSCRIPTOMIC AND PHENOTYPE
LEVEL TO TRY TO UNCOVER PERHAPS
WHAT FEATURES ARE ARE
DISTINGUISHED CONTROLLERS FROM
NON-CONTROLLERS.
SO WE ALSO HAVE AN ONGOING
STUDY, THE CLINICAL TRIAL IS
FUNDED BY THE GATES FOUNDATION
THROUGH THE FRONTIERS PROGRAM.
THE STUDY IS BEING CONDUCTED IN
THE UK WITH FIDLER AND FRATER.
IT'S A PLACEBO CONTROLLED RAND
DOMMIZED STUDY WHERE INDIVIDUALS
STARTED ART DURING EARLY
INFECTION, RANDOMIZED 1 TO 1 TO
EITHER RECEIVE AN INFUSION OF
THE TWO ANTIBODIES OR PLACEBO.
AND THEY DISCONTINUED ART TWO
DAYS LATER.
SOME OF THE PARTICIPANTS RECEIVE
A SECOND DOSE OF THE ANTIBODY IF
THEY CONTINUE TO MAINTAIN
SUPPRESSION.
THE STUDY -- THE GOALS OF THE
STUDY IS TO SEE, NUMBER ONE, IF
THERE IS MAINTENANCE OF
SUPPRESSION LONG TERM WITH THIS
LONG-ACTING ANTIBODIES IN
COMPARISON TO PLACEBO.
AND THEN I'LL TALK ABOUT THE
MORE EXPLORATORY ARM OF THE
STUDY.
THE STUDY IS DESIGNED TO ENROLL
A TOTAL OF 72 PARTICIPANTS.
SO FAR 60 HAVE BEEN DOSED AND
THEN OUT OF THOSE, 37 HAVE BEEN
UNBLINDED, BUT THIS FIRST PHASE
OF THE STUDY REMAINS BLINDED.
SO WE WON'T BE TALKING FURTHER
ABOUT THIS.
BUT WE HAVE STARTED TO DO
ANALYSIS ON THE GROUP B STAGE
TWO PHASE OF THE STUDY.
SO AGAIN, PARTICIPANTS COME IN,
THEY RECEIVE PLACEBO,
DISCONTINUE ART.
ONCE ART -- ARE MET, THEN WE
KNOW THEY ARE UNBLINDED, THE
ONES THAT DID RECEIVE PLACEBO
ARE OFFERED TO RECEIVE AN
INFUSION OF THE TWO ANTIBODIES.
THE PROTOCOL WAS SUBSEQUENTLY
CHANGED TO OFFER -- TO HAVE A
SECOND DOSE AT 20 WEEKS LATER.
SO THE INFUSION IS GIVEN
TOGETHER WITH ART RESTART.
SIX MONTHS AFTER THE INFUSIONS
ARE GIVEN THEY COME OFF OF ART
FOR A SECOND TIME AND THEY ARE
MONITORED UNTIL VIRAL REBOWP.
REBOUND.
I SHOULD ALSO SAY THE
PARTICIPANTS WERE SELECTED FOR
SENSITIVITY AT LEAST AT A
SEQUENCE LEVEL TO 1074.
SO IN THIS OPEN LABEL PHASE OF
THE STUDY THERE ARE ONGOING
ANALYSIS OF THE RESERVOIR
REBOUND VIRUSES.
HERE I'M JUST GOING TO SHARE TWO
EXAMPLES TO ILLUSTRATE WHAT
WE'RE STARTING TO SEE.
SO IN THIS FIRST PARTICIPANT,
HERE I'M SHOWING THE VIRAL LOAD
CURVES ANTIBODY LEVELS OVER
TIME.
AND THEN THE TIME POINTS WHERE
SEQUENCING OF ENVELOPE TOOK
PLACE.
SO IF YOU SEE HERE, THIS
PARTICIPANT EXPERIENCED REBOUND,
THIS IS A PLACEBO RECIPIENT,
EXPERIENCED REBOUND WITHIN ABOUT
THREE WEEKS OF DISCONTINUING
ART, VIRAL LOADS REACHED ABOUT
200,000 AND THEN HE WAS
RESTARTED ON ART AND RECEIVED AN
ANTIBODY INFUSION AT THIS TIME.
WAS MAINTAINED ON ART FOR ABOUT
SIX MONTHS, ART WAS DISCONTINUED
DISCONTINUEDTHE SECOND TIME ANDA
RETURNS ABOUT SIX WEEKS AFTER
THE SECOND DISCONTINUATION OF
ART AND A TIME WHEN ANTIBODY
LEVELS WERE ABOUT 20 AND
30-MICROGRAMS PER ML SO THERE'S
STILL SOME ANTIBODY ON BOARD.
BUT UNLIKE WHAT HAPPENED AFTER
THE FIRST ATI PERIOD, HE
REBOUNDS TO A LOWER PEAK LEVEL
VIREMIA AND THEN HIS VIRAL LOADS
FLUCTUATE OVER THIS COURSE OF
ABOUT SIX MONTHS.
ONCE IT STARTS TO BE MORE
PERSISTENT, HE'S CLOSE TO
NEEDING ART -- SO WHAT WE ARE
LEARNING NOW FROM ANALYZING HIS
VIRUS, SO HERE THIS PHYLOGENETIC
TREE SHOWS SEQUENCES OBTAINED
FROM PBMCs AT BASELINE.
BLUE IS THE FIRST REBOUND TIME
POINT AND THEN GREEN AND ORANGE,
THE SECOND ATI OF THE PEAKS OF
VIRAL LOADS.
SO WE SEE THERE ARE DIFFERENT
VIRUSES THAT ARE EMERGING, AND
THE RESERVOIR, THERE WAS
SENSITIVITY TO BOTH ANTIBODIES
BUT THERE WAS ONE CLONE THAT HAD
RESISTANCE TO -- HIGHLIGHTED
HERE IN YELLOW.
THE FIRST REBOUND, A CLONE THAT
HAS PARTIAL OR RESISTANCE TO
3BMC ALSO EMERGES, AND AT THE
SECOND TIME POINT, THERE IS NOW
RESISTANCE TO BOTH ANTIBODIES
BECAUSE PROBABLY DURING THIS
PERIOD OF TIME, THERE WAS
MONOTHERAPY WITH 1074, BECAUSE
WE KNEW -- NOW WE KNOW THAT THE
PERSON HAD RESISTANCE TO 3BNC
THAT SELECTED RESISTANCE TO
1074.
BUT WHAT IS INTERESTING HERE
THAT DESPITE NOW HAVING
RESISTANCE TO BOTH ANTIBODIES,
THE VIRAL LOADS CONTINUE, THEY
ARE NOT REACHING THE SAME LEVEL
OF VIREMIA, OF REPLICATION AS IN
THE FIRST ATI PERIOD. SO WE
DON'T KNOW IF DESPITE HAVING
NEUTRALIZATION RESISTANCE,
PERHAPS THE ANTIBODIES STILL
HAVE A PARTIAL EFFECT, PERHAPS
THESE VIRUSES ARE LESS FIT OR
DURING THIS PERIOD OF TIME,
THERE IS AN ENGAGEMENT OF HOST,
CELL OR -- IMMUNE RESPONSES THAT
ARE SOMEHOW MODIFYING THIS VIRAL
REBOUND DYNAMIC.
THIS IS THE SECOND EXAMPLE.
THIS OTHER PARTICIPANT AGAIN
DISCONTINUES ART, EXPERIENCES
VIRAL REBOUND WITHIN ABOUT THREE
WEEKS OF ART DISCONTINUATION.
HIS PEAK VIREMIA IS LESS THAN
10,000.
HE RESUMES ART AFTER A PERIOD OF
SIX WEEKS OF VIRAL LOADS ABOVE
1,000, RECEIVES THE ANTIBODY
WHILE ON ART.
ART IS DISCONTINUED SIX MONTHS
LATER.
VIRAL REBOUND LIKE THE OTHER
PARTICIPANT STARTS TO EMERGE AT
ABOUT SIX WEEKS AFTER THE ART IS
DISCONTINUED.
IN THIS CASE, THE ANTIBODY
LEVELS WERE ABOUT 50 MI CROW 50S
PER ML.
ONCE AGAIN THE VIRAL LOAD
DOESN'T REACH THE SAME LEVEL OF
PEAK AS IN THE FIRST ATI.
HERE LEVELS ARE ABOUT 200 TO
300.
THESE VIRAL LOADS GO UP AND DOWN
FOR A PERIOD OF SIX MONTHS, AND
THEN HE FULLY SUPPRESSES AND
THEN CONTINUES TO DO SO NOW FOR
ABOUT 14 MONTHS AFTER THE SECOND
TIME THE ART WAS DISCONTINUED.
WE DON'T HAVE THE ENTIRE AND
BODY PK CURVE YET AND WE DON'T
HAVE THE SENSITIVITY RESULTS FOR
THE REBOUND VIRUSES.
BUT THE SEQUENCES OF THE
RESERVOIR VIRUSES IN FIRST
REBOUND THAT WERE THEN SELECTED
FOR TESTING WITH NEUTRALIZATION
SHOWS SENSITIVITY TO BOTH
ANTIBODIES.
IN ADDITION WHAT WE ARE ALSO
LEARNING FROM THIS PARTICIPANT,
AND THIS IS WORK THAT WAS DONE
IN JOHN'S LAB, WE'RE STARTING TO
LOOK AT HIS T-CELL RESPONSES,
AND IN THIS GRAPH HERE IT'S
SHOWING LONGITUDALLY CHANGES
IN -- SO CD8 T-CELLS TO
DIFFERENT HIV GENES, AND IN
PURPLE HERE IS THE VIRAL LOAD
CURVE AND THEN HERE ARE THE
DIFFERENT T-CELL RESPONSES.
AND AS EXPECTED, FOLLOWING THE
FIRST VIRAL REBOUND, THERE IS AN
INCREASE IN T-CELL RESPONSES,
THAT THOSE RESPONSES DECREASE
WHEN ART IS RESUMED AND THE
PERSON ACHIEVES VIRAL
SUPPRESSION.
ONCE AGAIN, THE T-CELLS START TO
COME UP AFTER THE SECOND PERIOD
OF VIREMIA, BUT WHAT'S
INTERESTING HERE, EVEN 20 WEEKS
OR SO AFTER THE PERSON
RESUPPRESSES ON HIS OWN, THESE
T-CELL RESPONSES REMAIN
ELEVATED.
WE DON'T KNOW IF THIS IS GOING
TO INCLUDE THE -- BECAUSE LATER
TIME POINTS HAVEN'T BEEN DONE
YET BUT WE FIND IT INTERESTING
THAT IT SEEMS THAT IN THIS CASE,
UNLIKE WHAT WE HAD SEEN IN OUR
EARLIER STUDY, THIS CHANGE IN
T-CELL RESPONSES ARE PERSISTING,
THEY'RE NOT AS TRANSIENT AS IN
OUR EARLIER STUDY.
THEN THE LAST THING I WANT TO
SHARE IS THAT WE ALSO HAVE A
STUDY THAT IS FUNDED THROUGH
A -- MECHANISM THAT IS ONGOING.
THIS IS AGAIN THE COMBINATION OF
3BNC AND 1074 PROVIDED BY OUR
PARTNER IMMUNITY BU BIO.
IT'S AN OPEN LABEL SINGLE ARM
STUDY WHERE WE ADMINISTER THE
ANTIBODIES, THE INTERVENTION
PERIOD IS OVER A PERIOD OF SIX
MONTHS DURING ATI SO ART IS
DISCONTINUED RIGHT AFTER THE
ANTIBODY INFUSIONS AND THEY'RE
MONITORED UNTIL REBOUND.
THE END POINTS ARE VIRAL
SUPPRESSION BY WEEK 24, BUT ALSO
WHAT'S MOST -- WHAT WE ARE MOST
INTERESTED TO SEE IS WHAT
HAPPENS DURING THIS PERIOD OF
BNAB -- OR BEYOND THE BNAB
WASHOUT PERIOD, ARE WE GOING TO
ABLE TO ACHIEVE VIROLOGIC
CONTROL.
WE NOW HAVE THOSE 17
PARTICIPANTS.
EIGHT ARE STILL IN THE
INTERVENTION PERIOD, FOUR HAVE
PROGRESSED INTO THE LONG-TERM
FOLLOW-UP OF ART, AND THEN FOUR
HAD MET ART -- CRITERIA AND ARE
IN STEP THREE.
WE HAVE NOW GIVEN 87 DOSES OF
N-803.
IN GENERAL PARTICIPANTS HAVE
EXPERIENCED WHAT'S BEEN
DESCRIBED IN THE PAST, LOCAL
INJECTION REACTIONS THAT HAVE
BEEN OF GRADE # AND 2.
ONE EXPERIENCED GRADE 3 MYALGIA
AND NOW HE REMAINS ON STUDY BUT
HE'S GOING TO RECEIVE REDUCED
DOSES OF N-803.
SO HOPEFULLY WE'LL HAVE DATA TO
SHARE WITH YOU NEXT TIME WE
MEET.
SO TO SUMMARIZE, THESE STUDIES
OF PASSIVELY ADMINISTERED
ANTIBODIES SHOW THERE SEEMS TO
BE SOME EFFECT ON -- BUT WE
HAVEN'T BEEN ABLE TO CLEARLY
DETERMINE IF THIS IS DUE TO A
VACCINAL EFFECT BUT PERHAPS MORE
IMPORTANTLY, THESE EFFECTS HAVE
NOT BEEN SUFFICIENT TO MEDIATE
LONG TERM VIROLOGIC CONTROL AT
LEAST CONSISTENTLY.
ALL OF THESE STUDIES HAVE BEEN
SMALL TO DATE.
RIO IS GOING TO BE A BIG STUDY
WHERE WE HAVE DATA FROM
72 PARTICIPANTS.
SO WE HOPE THAT WE WILL BE
LEARNING QUITE A BIT FROM THAT
STUDY.
BUT EVEN IN THEE FEW STUDIES, WE
WERE ABLE TO IDENTIFY SOME POST
INTERVENTIONAL CONTROLLERS AND
NOW GOING FORWARD, WE ARE GOING
TO ANALYZE IN GREATER DETAIL
USING DIFFERENT APPROACHES, SO
THAT WITH THE HOPE THAT WE'RE
GOING TO UNCOVER DIFFERENT
MECHANISMS OF CONTROL THAT COULD
HELP US SELECT OR REFINE FUTURE
CURE STRATEGIES.
AND THEN ANOTHER PART OF RF
2 THAT I DIDN'T HAVE TIME TO
TALK ABOUT, WHICH IS WORK THAT
HAS BEEN DONE BY UNIVERSITY OF
PITTSBURGH WITH AYA LI, IT'S
VERY CLEAR THAT ONE OF THE CHAL
CHALLENGES WITH BNAB IS IMMUNE
ESCAPE.
SO THEY'RE WORKING WITH NOVEL
THERAPEUTIC TOOLS TO PREVENT
IMMUNE ESCAPE IN ORDER TO
ACHIEVE VIROLOGIC CONTROL, AND
THEN TO DO THAT, THAT THEY'RE
DEVELOPING DIFFERENT BI AND
TRI-SPECIFIC MOLECULES THAT ARE
NOT ONLY ENGAGED WITH THE
ENVELOPE BUT ALSO EFFECTOR
CELLS.
WITH THAT I'LL ACKNOWLEDGE OUR
STUDY PARTICIPANTS THAT ENROLL
IN THESE VERY COMPLEX STUDIES
AND OUR VARIOUS COLLABORATORS,
ESPECIALLY ELE AND THEN JOHN.
THANK YOU.
[APPLAUSE]
>> RF 3 WE'RE FOCUSED ON
DIFFERENT WAYS BY WHICH INFECTED
CELLS MIGHT RESIST BEING KILLED,
SO THE SUMMARY IS WE'RE ASKING
THE QUESTION DO SOME HIV
INFECTED CELLS HAVE WAYS OF
PROTECTING THEMSELVES FROM BEING
KILLED, EVEN WHEN SEEN BY THE
IMMUNE SYSTEM?
WE FIND THAT YES, IMMUNE
RESISTANT POPULATIONS EXIST AND
NOW WE WANT TO OVERCOME THESE TO
ELIMINATE THE HIV RESERVOIR.
SO HERE'S HOW WE TEST TO SEE IF
SOME CELLS ARE RESISTANT TO
KILLING.
WE HAVE CELLS THAT ARE INFECTED
WITH EITHER A WILD TYPE HIV OR
AN HIV THAT HAS ONE POINT
MUTATION AND EPITOPE TARGETED BY
A T-CELL CLONE.
WE MIX THESE TOGETHER,
CO-CULTURE WITH THE T-CELL CLONE
THAT'S GOING TO TARGET THOSE
CELLS INFECTED WITH WILD TYPE
HIV, AND WE'RE GOING TO
POTENTIALLY SELECT FOR RESISTANT
POPULATION.
WE THEN COME IN WITH A SECOND
CTL CLONE THAT TARGETS AN
EPITOPE THAT'S INTACT IN BOTH
VIRUSES, SO IF THERE'S NO SUCH
THING AS CTL RESISTANCE IN THE
FIRST ROUND, WE'LL KILL OFF THE
WILD TYPE CELLS, AND IN THE
SECOND ROUND, WE'LL KILL BOTH
THE ONES THAT WEREN'T SELECTED
AND THE ONES THAT WERE EQUALLY.
IF THERE WAS A RESISTANT
POPULATION, THEN WHAT WE'LL SEE
IS EXACTLY WHAT WE SEE HERE.
THIS POPULATION THAT SURVIVED
THE FIRST ROUND OF KILLING ALSO
SURVIVES THE SECOND ROUND OF
KILLING, AND THE CELLS THAT
WEREN'T SELECTED IN THE FIRST
ROUND ARE KILLED OFF.
SO THE FIRST MECHANISM WHICH HAS
BEEN TALKED ABOUT A LOT IN THIS
MEETING IS BCL2 OVEREXPRESSION.
I'M GOING TO GO THROUGH THIS
QUICKLY FOR THE SAKE OF TIME.
WE SEE IT'S OVEREXPRESSED IN
CELLS THAT RESIST KILLING AND
SUBSEQUENTLY OTHER STUDI STUDIEN
CANCER SEE THIS IN TUMORS THAT
OVEREXPRESS BCL2.
THEY'RE IN PRE-CLINICAL AND
CLINICAL STAGE DEVELOPMENT.
WHAT REACH IS FOCUSING ON NOW IS
ADDING TO THIS PIPELINE.
SO DOING DISCOVERY SCIENCE AND
FINDING WHAT OTHER MECHANISMS
MAY BE TARGETABLE THAT WE CAN
BRING FORWARD INTO THESE
DIFFERENT APPROACHES.
SO THIS IS OUR SCHEMA AGAIN FOR
LOOKING AT RESISTANCE.
AGAIN WILD TYPE INFECTED CELLS,
CELLS INFECTED WITH AN ESCAPE
MUTANT HIV MIXED AND SUBJECTED
TO CTL KILLING.
NOW WE'RE USING MULTI-OMIC
PROFILING TO LOOK AT WHAT'S
DIFFERENT OF THESE INFECTED
CELLS THAT SURVIVE KILLING
VERSUS THESE ESCAPE MUTANT CELLS
IN THE EXACT SAME ENVIRONMENT
ALSO INFECTED WITH HIV THAT
WEREN'T JUST SUBJECT TODAY CTL
PRESSURE.
WE'RE SORT ON CELLS THAT EXPRESS
ENVELOPE BECAUSE WE'RE NOT
LOOKING AT LATENCY HERE, WE'RE
JUST LOOKING AT MECHANISMS BY
WHICH SOME CELLS CAN SURVIVE
KILLING.
HERE'S THE TRANSCRIPTIONAL PROAT
FILING.
WITHOUT ME VWHEN WE ADD CTL, WEE
TRANSCRIPTIONAL PROFILE OF BOTH
THE CELLS THAT ARE BEING
TARGETED AND THE CELLS THAT ARE
NOT BECAUSE THEY'RE IN AN
ENVIRONMENT WITH AN ACTIVATED
CTL.
WHAT'S IMPORTANT IS THAT THESE
ARE NOW DIFFERENT FROM EACH
OTHER.
AND AGAIN THESE ARE PRETTY
PRECISE CONTROLS SO THIS IS
TELLING US ABOUT THE FEATURES OF
CELLS THAT SURVIVED CTL KILLING.
THERE'S A LOT OF DIFFERENTIAL
GENES THAT WE CAN GO AFTER, SO
WE HAVE THE QUESTION OF WHAT TO
TACKLE AND AS YOU'LL SEE ONE OF
THE THINGS THAT WE'RE USING IN
OUR CRITERIA ARE PATHWAYS THAT
MAY HAVE THERAPEUTIC RELEVANCE.
WE ALSO SEE THIS AT THE SINGLE
CELL LEVEL, SO THIS IS
TRANSCRIPTOMICS.
THE SURVIVORS CLUSTER
DIFFERENTLY THAN THE BYSTANDERS.
WE THINK THERE'S MULTIPLE
MECHANISMS BY WHICH CELLS CAN
RESIST KILLING.
THIS IS SURFACE PROTEIN
EXPRESSION, THIS IS ONE OF THE
CITE-SEQ PANELS WITH 150
ANTIBODIES, SO YOU CAN SEE
REALLY HOW DIFFERENT THESE
SURVIVORS ACTUALLY ARE FROM THE
BYSTANDERS, REALLY CLUSTERING
VERY DISTINCT POPULATIONS.
OUR OLD FREN BCL2, WE SEE IT
HERE AGAIN, THE CELLS THAT
SURVIVE KILLING TEND TO
OVEREXPRESSION BCL2.
WHAT WE SEE WITH THE SINGLE CELL
DADATA IS THERE'S HETEROGENEITY
BUT THERE'S ALSO A LOT OF CELLS
THAT SURVIVE THAT ARE BCL2-LOW.
SO NOW WE CAN START TO TEASE
APART THIS HETEROGENEITY AND ASK
WHAT OTHER MECHANISMS MIGHT BE
AT PLAY.
THE FIRST MECHANISM THAT WE SEE
POINTS TO BIOPHYSICAL PROPERTIES
OF THE TARGET CELL, SOMETHING WE
WOULDN'T HAVE THOUGHT ABOUT
WITHOUT THESE RESULTS.
SO GENES INVOLVED IN ACTIVE
CYTOSKELETON ARE DOWN AS WELL AS
SOME LIPID COMPONENTS.
THIS ACTUALLY TIES INTO WHAT'S
KNOWN FROM THE TUMOR FIELD, SO
THE CYTOTOXIC T-CELL NEEDS TO
APPLY FORCE TO ITS TARGET CELL,
IT NEEDS TO STRETCH TO BE ABLE
TO INSERT INTO THE MEMBRANE.
ACTUALLY THE SQUISHIER THAT CELL
IS, THE LESS THAT CTL IS ABLE TO
KILL IT AND THIS IS AN ACTUALLY
PRETTY REMARKABLE EFFECT.
SO ARE SURVIVORS BIOPHYSICALLY
DIFFERENT FROM THE CELLS THAT
WERE BYSTANDERS? THE MOVIE IS
NOT GOING TO WORK UNFORTUNATELY
BUT WE USE A METHOD WHERE YOU
FORM A TETHER WITH TARGET CELLS
AND YOU PULL THE BEAD AWAY AND
YOU MEASURE THE FORCE IT TAKES
TO PULL THAT TETHER, WHICH TELLS
YOU ABOUT THE MEMBRANE TENSION.
LONG STORY SHORT, THESE INFECTED
CELLS THAT SURVIVE CTL KILL
HAVING LESS MEMBRANE TENSION
THAN THE BYSTANDERS THAT WERE IN
THE SAME WELL, SO WE ARE
SELECTING FOR CELLS THAT ARE,
FOR LACK OF A BETTER WORD,
SQUISHIER AND HARDER TO KILL.
IS THERE ANYTHING WE CAN DO
ABOUT THIS?
AGAIN THE CANCER FIELD HAS SOME
ANSWERS WE CAN LOOK TO.
THERE ARE WAYS TO STIFFEN CELL
MEMBRANES, BOTH IN VITRO AND IN
VIVO, IN PARTICULAR BY DEPLETING
CHOLESTEROL, SO CAN WE ENHANCE
KILLING OF HIV INFECTED CELLS
USING THIS APPROACH?
THAT'S SOMETHING WE WANT TO DO
NEXT.
THE OTHER MECHANISM THAT CAME
OUT IS WHAT WE CALL AVIDITY
ESCAPE.
MEANING A CTL HAS TO NOT ONLY
BIND TCR AND MHC1, THERE'S
ADHESION MOLECULES THAT NEED TO
INTERACT SO THE TARGET CELL HAS
ICAM-1.
ICAM-1 WAS DOWN ON SURVIVORS SO
HARDER FOR CTL TO GRAB ON TO
THESE TARGET CELLS AND WE
CONFIRM THIS BY FLOW CYTOMETRY,
THERE'S LESS ICAM-1 ON
SURVIVORS.
THEY'RE HARDER FOR THE CTL TO
GRAB ON TO.
AGAIN IN PARALLEL WITH RECENT
FINDING IN CANCER, ONE MECHANISM
OF IMMUNE EVASION IS THEY DON'T
UPREGULATE ICAM-1, THE CTL
CANNOT GRAB ON TO THESE CELLS.
IS THERE ANYTHING WE CAN DO
ABOUT IT?
THERE ARE SMALL MOLECULES UNDER
DEVELOPMENT TO ENHANCE
LFA1 ACTIVATION OR ICAM
EXPRESSION, SO MAYBE WE CAN MAKE
THESE CELLS STICKIER.
AND THERE'S EFFORTS TO ENGINEER
T-CELLS IN CARS WITH HIGHER
AVIDITY VERSIONINGS OF LFA1 THAT
CAN BIND TO JUST THE SMALL
AMOUNTS OF ICAM1 THAT MIGHT BE
LEFT ON THESE SURVIVORS, SO
THESE ARE TWO NEW APPROACHES.
THIS IS MORE JUST AN
ADVERTISEMENT FOR THE POSTER.
PLEASE SEE HIM AS WELL, BUT THE
OTHER THING WE SAW IS THAT
THERE'S A CLEAR METABOLIC
SIGNATURES OF CELLS THAT SURVIVE
KILLING.
THERE'S LESS METABOLICALLY
ACTIVE.
WE THINK THIS IS LINKED TO THE
FACT THAT REACTIVE OXYGEN
SPECIES ARE AN IMPORTANT
EXECUTER OF CTL KILLING AND
CT LS TARGET A CELL, THOSE
REACTIVE OXYGEN SPECIES WREAK
HAVOC.
SO IF A CELL IS NOT
METABOLICALLY ACTIVE AND DOESN'T
HAVE ENOUGH REACTIVE OXYGEN
SPECIES, IT'S GOING TO BE LESS
SUSCEPTIBLE TO KILLING.
PLEASE DO SEE ALBERTO'S POSTER
BECAUSE THERE'S A SAFE AND WELL
TOLERATED DRUG WHICH INCREASES
LEVELS OF REACTIVE OXYGEN
SPECIES, AND HE SHOWS THAT THIS
SENSITIZES THESE CELLS TO BEING
KILLED BY CYTOTOXIC T-CELLS.
SO CONCLUSIONS, HIV INFECTED
CELLS DO VARY IN THEIR
SUSCEPTIBILITY TO KILLING, WE
WANT TO OF COURSE
CROSS-REFERENCE THIS WITH THE
CHARACTERIZATION OF RESERVOIR
HARBORING CELLS SO WE'RE DOING
THAT IN THE COLLABORATORY.
RESISTANT CELLS HAVE DISTINCTIVE
PROPERTIES.
BCL2, BCL2 FAMILY MEMBERS ARE AN
IMPORTANT MECHANISM BUT THERE'S
OTHER MECHANISMS AS WELL.
MANY OTHER MECHANISMS THAT WE'RE
JUST SIFTING THROUGH NOW AND WE
HOPE TO OFFER MORE THERAPEUTIC
TARGETS, MORE WAYS TO ENHANCE
KILLING TO OUR FRIENDS THAT DO
TRANSLATIONAL RESEARCH AS WELL
AS DEVELOPING SOME OF THOSE
THINGS WITHIN REACH.
WITH THAT, I'LL WRAP UP.
[APPLAUSE]
>> SORRY.
THESE ARE MY ACKNOWLEDGMENTS.
>> SO I'M GOING TO PRESENT VERY
QUICKLY THE COMMUNITY PROGRAM
OVERVIEW JUST TO SAY THAT WE DO
HAVE SOME SPECIFIC AIMS, MAINLY
WHAT WE'RE TRYING TO DO IS BUILD
THE CAPACITY AND LIT ARE SEE OFO
ENGAGE MEAN AMINOING MEANINGFULE
CONVERSATION.
WE HAVE A REACH COMMUNITY
ADVISORY BOARD.
IT WAS ACTUALLY ESTABLISHED LAST
YEAR.
WE ORIGINALLY HAD AN ADVISORY
BOARD THAT WAS CONNECTED WITH
WEILL CORNELL MEDICINE THAT WAS
HIV-FOCUSED, BOTH IN THEIR
PREVENTION AND TREATMENT
PROGRAM, BUT DECIDED REACH
SHOULD HAVE ITS OWN.
SO BRANCHED OFF AND SO THESE ARE
SOME OF THEIR INITIAL MILEST
MILESTONES.
WE'VE HAD A NUMBER OF COMMUNITY
EVENTS AND WE'VE REALLY TRIED TO
ENGAGE A WIDE VARIETY OF
COMMUNITY IN THE NEW YORK CITY
AREA.
I'VE FOCUSED HERE ON JUST A FEW
BUT IN PARTICULAR, I THINK ONE
OF OUR MOST UNIQUE IS THAT WE
SPONSORED A RAVE, A BALL, TO
REACH THE BALLROOM COMMUNITY IN
NEW YORK CITY.
WE'VE ALSO GONE TO DIFFERENT
BURROUGHS, WE PARTNERED WITH THE
NEW YORK CITY LGBTQ CENTER SO A
VARIETY OF EVENTS THERE.
WE DO HAVE A FOCUS ON UGANDA.
SOME OF YOU HAVE SEEN
JOSEPHINE'S SERIES OF JOJO, WE
WERE ABLE TO SPONSOR THAT
THROUGH REACH, FIRST AS PART OF
THE ADD VO ADVOCACY COMMUNITY AN
CONTINUING ON THROUGH OUR
CUREROAR PROGRAM.
IN ADDITION HIGHLIGHTING ANOTHER
INDIVIDUAL WHO WAS SUPPOSED TO
BE HERE BUT UNFORTUNATELY
COULDN'T GET THEIR VISA TO COME,
BUT CHARLES BROWN AS WELL.
JUST TO HIGHLIGHT, ONE OF THE
THINGS THAT WE REALLY STRIVE FOR
IS TO INVEST INTO THE COMMUNITY
SO THEY CAN AGAIN MEANINGFULLY
ENGAGE AND PART OF THE ONE OF
THE METRICS WE WORK ON IS
THINKING ABOUT HOW OFTEN DO
PEOPLE ASK QUESTIONS AND WHAT
ARE THE QUALITY OF QUESTIONS
THAT THEY'RE ASKING AND SO
THINKING ABOUT CHARLES COMING IN
ALMOST TWO YEARS AGO ASKING WHAT
IS A VIRAL RESERVOIR TO NOW ON
THE ZOOM THAT WE HAD, THE RAVE
WE HAD OCTOBER 11TH JUST TWO
DAYS AGO FOR OUR COMMUNITY,
ASKING DR. JANET SILICANO ABOUT
THE DIFFERENCES IN VIRAL DANA
MDYNAMICS, ASKING QUESTIONS THAT
CAN REALLY TEASE OUT WHAT IS
MEANINGFUL FOR COMMUNITIES.
SO THOSE ARE THINGS THAT WE'RE
TRACKING AS WELL.
AGAIN VERY QUICKLY, I THINK A
LOT TO SAY AND WOULD LOVE TO
CHAT WITH OTHERS AFTER THE FACT
IF YOU HAVE MORE QUESTIONS, BUT
WE ARE REALLY THINKING ABOUT
AGAIN DIVERSIFYING OUR CAB, OUR
COMMUNITY ADVISORY BOARD IS
BASED IN NEW YORK CITY, SO WE DO
AGAIN HAVE THAT EXTENSION OF THE
UGANDA PROGRAM WHICH WE HAVE TO
KEEP SEPARATE FOR TIME ZONE
DIFFERENCES BUT OUR COMMUNITY
ADVISORY BOARD TO DEEPEN THAT
OUT.
WE'RE ALSO PARTNERING WITH THE
NEW YORK CITY DEPARTMENT OF
HEALTH FOR A WEBINAR SERIES LOOK
BEING AT INTRODUCTION, SEX AND
GENDER AND HOW DOES THE
ENVIRONMENT ACTUALLY -- JUST
LIKE YOU LEVERAGE THE SCIENCE,
WE ARE TRYING TO LEVERAGE OUR
COMMUNITY AND COLLABORATORY
PROGRAMS TO REALLY HEIGHTEN THAT
OUT AND THAT INCLUDES CROSS
COLLABORATORY LEARNING, IT
INCLUDES PARTNERING IN
AMPLIFYING EVENTS IN DIFFERENT
REGIONS AND PARTS OF THE WORLD
BUT ALSO REALLY TRYING TO AGAIN
STRENGTHEN THE KNOWLEDGE SHARING
AND BEST PRACTICE TO FIGURE OUT
WHAT WORKS IN NEW YORK CITY, CAN
IT ALSO WORK IN BOSTON, CAN IT
WORK IN ZIMBABWE AND E UGANDA, O
WEE REALLY TRIED TO TAKE THAT ON
AS PART OF THIS PROGRAM AS WELL.
I KNOW I'M OUT OF TIME.
HERE COMES SANDRA TO KICK ME
OFF.
SO THANK YOU ALL.
[APPLAUSE]
>> SINCE WE'RE A LITTLE BEHIND
FINAL WETIME WE'LL SKIP THE QUED
ANSWER PERIOD AND ASK YOU TO
PLEASE TALK TO THE MEMBERS OF
THE REACH COLLABORATORY DURING
THE COFFEE BREAK.
SO LET'S MOVE ON TO THE NEXT
GROUP.
>> BEFORE WE MOVE ON TO THE NEXT
COLLABORATORY, WE WANT TO LET
YOU KNOW THERE IS AN OVERFLOW
ROOM ACROSS THIS AUDITORIUM AND
ALSO FOR THE PEOPLE WATCHING
ONLINE, THERE IS SEND FEEDBACK
IF YOU HAVE QUESTIONS, THAT'S
ONE WAY TO SEND US THE
QUESTIONS.
THANK YOU.
>> THANK YOU.
GOOD MORNING, EVERYONE.
MY NAME IS TANIA LOMBO.
I'M A PROGRAM OFFICER IN THE
PREVENTION SCIENCE PROGRAM OF
THE DIVISION OF AIDS AT NIAID.
THIS MORNING I HAVE THE PLEASURE
TO INTRODUCE THE PEDIATRIC
ADOLESCENT VIRUS ELIMINATION
COLLABORATORY, OR PAVE.
THIS COLLABORATORY IS BASED IN
THE JOHNS HOPKINS UNIVERSITY AND
IS LTODAY YOU WILL HEAR PROGRESD
UPDATES FROM ALL THE RESEARCH
FOCI INCLUDING THE FOURTH
RESEARCH FOCUS THAT IS CLOSER
FOR THIS COLLABORATORY.
WE WANT TO EMPHASIZE THAT THIS
IS THE ONLY COLLABORATORY
FOCUSED ON HIV CURE RESEARCH IN
PEDIATRIC POPULATIONS.
WITH THAT, I WILL HAND IT OVER
TO YOU, DEBBIE.
>> GOOD MORNING.
THANK YOU, TANIA.
I'M GOING TO GET STARTED.
DO WE GET 5 MINUTES BACK?
SO AS TANIA SAID, THIS
COLLABORATORY IS THE FIRST
PEDIATRIC CURE COLLABORATORY AND
WE'RE REALLY, REALLY DELIGHTED
TO JOIN THE GROUP HERE.
SO I CO-LEAD WITH THIS ANN
CHAHROUDI.
SO TODAY WE'RE GOING TO PROVIDE
A HIGH LEVEL VIEW WITH SOME
HIGHLIGHTS IN TERMS OF THE
DIRECTION OF THE COLLABORATORY
AND SOME KEY FINDINGS TO DATE.
REALLY IN ORDER TO BE ABLE TO
SYNERGIZE OUR ACTIVITIES WITH
THE EXISTING ADULT
COLLABORATORIES.
AND SO I'LL GIVE AN OVERVIEW AND
ALSO AN UPDATE ON THE RESEARCH
FOCUS AREA ONE ON THE
PATHOGENESIS OF RESERVOIRS IN
CHILDREN, AND THEN ALSO THE
HUMAN DATA IN RF2 IN TERMS OF
CONTROL AND WHAT WE'VE LEARNED
OF CONTROL IN HIV CHILDREN
LIVING WITH PERINATAL HIV AND
THEN TURN IT OVER TO MAURICIO
MARTINS.
STUDYING -- TO END UP WITH A
SINGLE SHOT IN THE ARM FOR VIRUS
REPLICATION, FOLLOWED BY ANN
CHAHROUDI AND HER PIONEERING
WORK ON SURGE AND PURGE AND
VIROLOGIC CONTROL WITH DIFFERENT
MONOCLONAL ANTIBODIES.
AND THEN COME BACK TO A NEW
RESEARCH FOCUS AREA THAT'S
SPECIFIC TO THE PEDIATRIC
COLLABORATORY, RF 4, WHICH IS
REALLY DEVELOPING LABORATORY
ASSAYS TO PROBE GIVEN THE SMALL
BLOOD VOLUMES THAT ARE
OBTAINABLE.
THIS RF 4 IS CO-LED BY MYSELF
AND SUMITA AND OF COURSE OUR
COMMUNITY PARTNERSHIP WITH AVAC.
SO I WANTED TO START WITH OUR
MISSION TO THINK ABOUT WHAT
WE'RE TRYING TO DO, REALLY
CUTTING EDGE SCIENCE TO
ESTABLISH A DEEP AND BROAD
UNDERSTANDING OF THE
IMMUNOPATHOGENESIS OF PEDIATRIC
HIV RESERVOIRS.
AND A KEY COMPONENT ACROSS THE
AIDS SPECTRUM.
WE STUDY PERSISTENCE FROM THE
NEWBORN PERIOD THROUGH AGE 24 IN
THOSE LIVING WITH PERINATAL HIV
AND REALLY TO DEMONSTRATE SAFETY
AND EFFICACY IN THE NON-HUMAN
PRIMATE MODELS ON NOVEL AGENTS
TO PAVE THE WAY FOR
INTERVENTIONAL STUDIES SO WE
HOPE TO MOVE THESE CLINICAL
FINDINGS INTO CLINICAL TRIALS.
WITH THE VISION REALLY TO
ACHIEVE SUSTAINED ART-FREE
CONTROL OF HIV REPLICATION IN
PEDIATRIC POPULATIONS, THAT THIS
WILL BE POSSIBLE, WE BELIEVE,
WITH IMMUNE TARGETED APPROACHES.
I WANT TO START BY SAYING WE'RE
A LARGE COLLABORATORY AND WHAT
THIS FUNDING HAS DONE HAS REALLY
BROUGHT THE PEDIATRIC SPACE
TOGETHER.
THERE ARE MANY INDIVIDUALS WHO
HAVE BEEN WORKING IN ISOLATION
AND PEDIATRIC RESERVOIR
IMMUNOLOGIC BASIS OF PERSISTENCE
IN CHILDREN, SO WE'RE
44 INVESTIGATORS AND 18
INSTITUTIONS IN THE U.S., EUROPE
AND SOUTH AFRICA.
AND I WANT TO SAY AS PART OF THE
REQUIREMENT AS ALL OF YOU KNOW,
IT WAS A REQUIREMENT FOR
INDUSTRY PARTNERS, AND WE COULD
NOT HAVE DONE THIS WITHOUT THE
INVESTMENT OF OUR INDUSTRY
PARTNERS AND THEIR PIONEERING
WORK IN IPD ASSAY AND AS GUIN
LEE DISCUSSED, REALLY THE
CHALLENGES IN NON-SUBTYPE B IN
DEVELOPING THIS ASSAY.
IMMUNITYBIO, JEFF SAFRIT, AND
THEN A REALLY NOVEL
COLLABORATION IS WITH INIMMUNE,
A CANCER THERAPEUTIC PROGRAM
THAT ACTUALLY DEVELOPS PRODUCTS
FOR IMMUNOTHERAPY FOR CANCER,
AND SO WE BELIEVE INNATE IMMUNE
ENHANCERS SUCH AS THESE TLR
AGONISTS ARE GOING TO BE
CRITICAL FOR HIV SURGE AND PURGE
STRATEGIES AND THEN THE SMACK
MIMETICS THAT'S BEING STUDIED IN
THE ADULT SYSTEMS.
OUR SCIENTIFIC ADVISORY BOARD
HAVE BEEN REALLY TREMENDOUS IN
GUIDING AND SHAPING WITH
TERRIFIC FEEDBACK IN HOW WE CAN
DO BETTER IN WHAT WE DO.
A MAJOR COMPONENT OF OUR
COMMUNITY ENGAGEMENT IS ACTUALLY
OUR PARTNERSHIP WITH
STAKEHOLDERS, WITH GLOBAL -- A
GLOBAL FOOTPRINT SUCH AS
ELIZABETH GLAI SER PEDIATRIC
AIDS FOUNDATION, THE IMPACT
NETWORK, AVAC, FHI360.
SO I WANT TO FOCUS YOU TO A MAIN
PART OF THE PAVE MARTIN DELANEY
COLLABORATORIES RELIES ON --
ACCESS CLINICAL TRIAL COHORTS AS
MARINA DESCRIBED, WE BELIEVE
THAT TAKING ADVANTAGE OF THESE
BIOBANKS AND WELL KERIK TIRRIZED
COHORTS SHOULD BE YOUR STARTING
POINT FOR UNDERSTANDING BASIC
MECHANISMS OF PERSISTENCE.
SO WHAT YOU SEE ON THIS SLIDE AT
THE FAR LEFT, PARTNERSHIP WITH
THE IMPAACT NETWORK, THE 12
COUNTRIES WHERE WE'RE LOCATED,
HIV SUBTYPES, MOLECULAR TESTING,
KWAZULU-NATAL WILL PREVENT ON
THE COHORT AND EARLY INFANT
TREATMENT STUDY.
THE EPIICAL CONSORTIUM HAS BEEN
KEY BECAUSE THEY HAVE SUPPORTED
A LOT OF THE COHORT STUDIES
BEING DISCUSSED TODAY.
THTHE CHER COHORT STUDY SHOWING
EARLY TREATMENT IN INFANCY IS
LIFE-SAVING FOR CHILDREN.
SO I'M GOING TO NOW SWITCH TO RF
1 AND PEDIATRIC RESERVOIR LE, IM
GOING TO GIVE THE UPDATES ON
THIS.
AND REALLY THE KEY COMPONENT
HERE IS TO LOOK AT IN DEPTH
PROFILING OF HIV RESERVOIRS,
INCLUDING IN THE CENTRAL NERVOUS
SYSTEM, AND MECHANISMS --
UNDERSTANDING MECHANISMS OF
IMMUNE CONTROL AND SOURCES OF
REBOUND VIREMIA.
TO REALLY GAIN INSIGHTS INTO HIV
PERSISTENCE WITH LONG TERM
VIROLOGIC SUPPRESSION OF
PERINATAL INFECTION, RF 1 TEAM.
SO I'M GOING TO START WITH
REALLY VERY INTRIGUING FINDINGS
USING THE FLIP SEQ DEEP PROVIRAL
LANDSCAPE PROFILING IN LONG TERM
SUPPRESSED EARLY TREATED YOUNG
ADULTS.
SO THESE ARE YOUNG ADULTS WHO
ARE TREATED FROM INFANCY AND NOW
ARE ABOUT 20 YEARS OF AGE,
HAVEN'T BEEN SUPPRESSED FOR LONG
TIME.
SO THIS IS THE FIRST STUDY OF
ACTUALLY DOING LUKE PHORESIS IN
PERINATAL INFECTIONS.
THIS STUDY WAS CONDUCTED BY OUR
ITALIAN COLLABORATORS.
THEY ACTUALLY EMBARKED ON A
STUDY WHERE THEY DID
LEUKOPHORESIS ON NINE ADULTS
LIVING WITH HIV.
WHAT I WANT TO HIGHLIGHT IS THE
MEDIAN AGE IS 20 YEARS AT TIME
OF SAMPLING, MEDIAN AGE AT ART
WAS 4 MONTHS SUPPRESSED FOR 20
YEARS.
MOST OF THESE WERE ARE ACTUALLY
WOMEN.
NOT MEN.
AND THAT'S AN INTRIGUING
FINDING.
A LOT OF OUR STUDIES IN CHILDREN
IN COHORT STUDIES, THOSE
ENROLLED ARE MOSTLY WOMEN AND
GIRLS.
SO THE KEY FINDING HERE USING
MATHIAS' APPROACH, WHAT YOU SEE
IN RED IS THE LOCAL HIV COHORT,
TOTAL HIV DNA LEVELS ARE
SUBSTANTIALLY LOWER COMPARED
WITH LONG TERM TREATED ART
ADULTS.
WHAT YOU SEE ON THE RIGHT IS
ACTUALLY THE PROVIRAL -- INTACT
PROVIRAL DNA LEVEL IS EVEN LOWER
IN THESE YOUNG ADULTS.
CONFIRMING THAT EARLY EFFECTIVE
THERAPY WITH LONG TERM
SUPPRESSION WHICH MANY GROUPS
HAVE SHOWN IN DIFFERENT WAYS BY
MEASURING TOTAL HIV DNA REALLY
RENDERS HIV TO PERSIST WITH VERY
LITTLE RESERVOIRS WITH LONG TERM
SUPPRESSION.
WHAT I WANT TO SHOW YOU WITH
LEUKOPHORESIS, THIS STUDY WAS
DONE BY BEN BONE IN MATHIAS'
GROUP, THE NUMBER OF CELLS
ASSAYED, IN GENERAL WHAT YOU SEE
IS BY THE OPEN CIRCLES REPRESENT
TWO INDIVIDUALS IN WHOM INTACT
PRO VIRUSES WERE NOT IDENTIFIED.
BUT EVENTUALLY WITH SAMPLING
ENOUGH CELLS, MATHIAS' GROUP
COULD DETECT INTACT PROVIRAL
SEQUENCE IN THESE INDIVIDUALS.
SO WHAT I SHOW HERE ON THE SIDE
TO REALLY FOCUS YOUR ATTENTION
ON IS THE NUMBER OF CELLS THAT
WERE ANALYZED TO BE ABLE TO
DETECT INTACT PRO VIRUSES IN
THIS GROUP, AGAIN CONFIRMING
THAT EARLY LONG TERM SUPPRESSIVE
ART LEAVES EXCEEDINGLY LOW
RESERVOIRS IN CHILDREN AND
ADULTS.
SO IT WAS IN TREATING THIS
HAND-PICKED GROUP, 3 OF THE
9 PARTICIPANTS HAD HLA ALLELES
THAT HAVE BEEN REPORTED TO BE
PROTECTIVE IN ADULTS LIVING WITH
HIV.
I'M GOING TO QUICKLY SUMMARIZE
KEY FINDINGS FROM THE STUDY THAT
I HOPE I CONVINCE YOU FROM THIS
PROOF OF CONCEPT STUDY THAT THE
RESERVOIR IS SMALLER WITH LONG
TERM EARLY PERINATAL INFECTION
TO INDIVIDUALS HE WAS NOT ABLE
TO DETECT INTACT PRO VIRUSES,
THERE WERE SOME HLA PROTECTIVE
ALLELES THAT NEEDS TO BE
EXPLORED IN LARGER COHORTS.
THE OVERARCHING HYPOTHESIS IS
THERE'S IMMUNE-MEDIATED
MECHANISM OF CLEARANCE OF THESE
RESERVOIRS OVER TIME THAT'S
CONTRIBUTING TO RESERVOIR
DEPLETION WHICH WE BELIEVE WILL
INFORM THERAPEUTIC INTERVENTIONS
FOR LONG TERM SUPPRESSED
PERINATAL INFECTIONS.
THESE STUDIES WERE CARRIED OUT
BY BEN BONE AS THE MAIN
INDIVIDUAL IN MATHIAS' LAB.
SO I'M GOING TO SWITCH GEARS TO
THE SECOND AIM IN RF 1,
HARNESSING IMMUNOGENIC IMMUNOGEN
PURSUIT OF PEDIATRIC HIV
ERADICATION.
-- WENT OFF THERAPY AND HAS NOW
BEEN A POST TREATMENT CONTROL
FOR NOW 15 YEARS, WHICH
IDENTIFIED IN THAT ADOLESCENT
NOW IS THAT THERE WAS LOW LEVELS
OF CCR5 EXPRESSION, LOW LEVELS
OF IMMUNE ACTIVATION AND SOME
WEAK GAG-SPECIFIC CTL RESPONSES.
SO THE OVERARCHING PLAN HERE
ACROSS OUR COHORTS LISTED ON THE
BOTTOM OF THE SLIDE IS TO APPLY
THIS MULTIMODAL APPROACH WITH I
IMMUNOGENETICS TO REALLY
IDENTIFY CORRELATES OF SMALL
RESERVOIR SIZE AND IMMUNE
CONTROL.
NOW THE SECOND PART IS REALLY IN
THESE CHILDREN AND YOUNG ADULTS
WITH VERY LITTLE RESERVOIRS,
UNDERSTANDING WHAT CONTRIBUTES
TO REBOUND VIREMIA IS GOING TO
BE CRITICAL.
WE KNOW SOME OF THESE
INDIVIDUALS DO STOP THERAPY AND
DO REBOUND.
SO I DON'T KNOW THAT WE KNOW FOR
SURE THAT GETTING TO THIS
EXCEEDINGLY LOW LEVEL OF HIV
RESERVOIR SIZE IS ACTUALLY
PREDICTIVE OF REMISSION.
SO AS PART OF THIS, THIS GROUP
HAS OPTIMIZED IMMUNOCAPTURE
ASSAY AND ALSO ASSAYS TO
IDENTIFY PSEUDOVIRUS TESTING AND
TESTING THE SUSCEPTIBILITY OR
INFECTION CAPACITY IN PRIMARY
MACROPHAGES AND IN CELL LINES.
AND PRELIMINARY DATA TO DATE IN
THE REBOUND VIREMIA IN THE FAR
LEFT IN THE MISSISSIPPI BABY,
SHE HAS BEEN ABLE TO IDENTIFY --
AT THE TIME OF REBOUND VIREMIA.
SO THESE STUDIES WILL BE
EXPANDED TO OUR OTHER COHORTS
UNDERGOING ATI TO ASSESS FOR
REMISSION.
THE LAST PART FOR RF1 THAT I
WANT TO FOCUS ON AND WE RECEIVED
AN OAR SUPPLEMENT TO EXPAND THE
CNS STUDY.
IN A PILOT STUDY IN THE IMPACT
NETWORK LED BY ANN CHAHROUDI
AND -- WAGNER IDENTIFIED 72% OF
YOUNG ADULTS LIVING WITH
PERINATAL INFECTION WHO HAD
NEUROCOGNITIVE IMPAIRMENT, HAD
CELL ASSOCIATED DNA DETECTED IN
THE CSF.
THE CSF DNA QUANTITATION WAS
DONE IN DOUG RICHMOND'S
LABORATORY.
SO WE BELIEVE IT'S REALLY
CRITICAL TO UNDERSTAND THE
PERSISTENCE OF CELLS IN THE CNS.
SO AS PART OF THIS ORA
SUPPLEMENT, THE SHARE TRIAL
GROUP ACTUALLY RECEIVED THE
SUPPLEMENT TO BEGIN TO DO CSF
STUDIES IN CHILDREN IN SOUTH
AFRICA LIVING WITH PERINATAL HIV
AND LONG TERM PERINATAL HIV.
AND THE MAIN POINT HERE IS
ACTUALLY TO BE ABLE TO PERFORM
CSF ON CHILDREN AND TRYING TO
BREAK DOWN THAT BARRIER AND FEAR
OF DOING SPINAL TAPS.
IT'S A NEW NEUROTROPIC VIRUS.
FOR ANY OTHER DISEASE, WE DO
SPINAL TAPS, AND WITH THIS
SUPPLEMENT, THEY'VE ACTUALLY
BEEN ABLE TO ENROLL 22 OF THE 45
PARTICIPANTS WITHIN MONTHS AT
THE ONE SITE THAT WAS
IRB-APPROVED.
THE SECOND SITE WHERE THE 23
PARTICIPANTS ARE COMING FROM
JUST RECEIVED IRB APPROVAL.
AND SO THIS IS REALLY TO KIND OF
EMPHASIZE THAT THESE STUDIES CAN
BE CARRIED OUT, CNS STUDIES OR
CSF ANALYSIS CAN BE CARRIED OUT
IN PEDIATRIC PARTICIPANTS.
A BEAUTIFUL WAY OF ENGAGING THE
COMMUNITY AND PARTICIPANTS ON
HOW BEST TO DO THESE STUDIES, SO
THEY HAVE A WHOLE MEDITATION
PACKAGE AND A LOT OF GOODIES
THAT THEY GIVE TO THE
PARTICIPANTS TO MAKE IT A VERY
COMFORTABLE ENVIRONMENT POST
SPINAL TAP ANALYSES.
SO WITH THIS STUDY, WE HOPE TO
BE ABLE TO COMPARE -- DO AN
EXTENSIVE PROFILING OF THE
PLASMA AND BLOOD USING
MULTI-OMICS APPROACHES, SINGLE
CELL RNA SEQ, AND DNA QUANTITY
TAKES -- CHARACTERIZATION, ET
CETERA, TO UNDERSTAND THE ROLE
OF DETECTING CSF DNA AND ITS
IMPLICATION FOR HIV PERSISTENCE.
SO FROM THIS SUMMARY FOR RF 1, I
HOPE I'VE CO CONVINCED YOU THAT
THERE ARE EXCEEDINGLY LOW LEVELS
OF RESERVOIRS IN EARLY TREATED
ADOLESCENTS THAT WE BELIEVE MORE
COMPREHENSIVE STUDIES INCLUDING
HLA AND KIR PHENOTYPING IS GOING
TO BE CRITICAL FOR UNDERSTANDING
OUTCOMES IN CHILDREN.
AND TO SEE IF STUDIES OF CSF ARE
FEASIBLE IN OUR PEDIATRIC
COHORTS THAT WILL INFORM OUR
CURE CLINICAL TRIALS.
SO FOR THIS COLLABORATORY, WE
DID PUT THE PLAIN LANGUAGE
SUMMARY AT THE END OF THE SLIDE,
BUT WHAT OUR KEY QUESTIONS WAS
THE EFFECTS OF EARLY ART ON
RESERVOIR SIZE, WHETHER THE
VIRAL AND HOST IMMUNE FACTORS
THAT MAY CONTRIBUTE TO CONTROL,
AND CAN WE DETECT SPECIFIC
BIOMARKERS IN THE BLOOD AND CNS
TO HELP US IDENTIFY REALLY
PREDICTIONS OF REMISSION.
SO I THINK WHAT SHOULD BE
ENCOURAGED IS THAT DRK AND WHAT
I WANT TO EMPHASIZE IS THE
CHARACTERISTICS OF THE RESERVOIR
IN CHILDREN AND YOUNG ADULTS
LIVING WITH PERINATAL HIV IS
REALLY INDEED DISTINCT AND WE
BELIEVE A FAVORABLE PLATFORM FOR
CURE THERAPEUTICS.
SO I'M GOING TO SWITCH TO THE
NEXT TWO COMPONENTS, WHICH IS RF
2 AND CONTROL OF REBOUND IMOWN.
THIS IS LED BY FILL I.P.
GOULDER, AND NOW MAURICIO
MARTINS WHO YOU'LL HEAR FROM
NEXT.
THIS IS REALLY FOCUSED ON
ENHANCING PEDIATRIC HIV IMMUNITY
INCLUDING USE OF VECTORED BNAB
DELIVERY TO ACHIEVE POST
TREATMENT CONTROL.
WE HOPE TO GAIN INSIGHTS INTO
IMMUNE MEDIATED CONTROL OR
VIROLOGIC CONTROL OF PERINATAL
HIV INFECTION.
THIS IS THE RF 2 TEAM.
AND SO THE FIRST STORY THAT I'M
GOING TO TELL IS DATA FROM PHIL
GOULDER'S GROUP IN SOUTH AFRICA,
WHERE HE HAS A BABY CURE PROJECT
THAT IS FUNDED BY THE NIH, AND
WHERE HE'S IDENTIFIED EARLY LIFE
IMMUNE SEX DIFFERENCES IN
PERINATAL INFECTION.
SO THIS STUDY AS I SAID IS
CARRIED OUT IN NATAL, AND IN
THIS BABY CURE STUDY, HE
FOLLOWED CLOSE TO 300
MOTHER-INFANT PAIRS IN INFANTS
WHO HAD ACQUIRED INFECTION,
RECEIVED EARLY THERAPY IN 2015
BASED ON THE REPORT OF THE
MISSISSIPPI BABY.
SO TREATED WITHIN ONE TO 11 DAYS
OF LIFE WITH COMBINATION
ANTIRETROVIRAL TERRITORIMENT.
TREATMENT.HE FOLLOWED THESE INFR
TIME.
IN THIS STUDY WHAT THEY DID
IDENTIFY, AND THIS HAS BEEN
PUBLISHED WITH SEX DIFFERENCES
IN PERINATAL INFECTIONS.
SO INTERESTINGLY, IN THE SETTING
OF ACUTE INFECTION IN MOTHERS,
MALES ARE LESS SUSCEPTIBLE TO
VERTICAL TRANSMISSION AND HE'S
ACTUALLY CARRIED THESE STUDIES
IN TWIN STUDIES AND DEMONSTRATED
THAT IT ALSO EXISTS IN TWIN
PREGNANCIES.
AND HE'S ESTABLISHED THAT THIS
IS ACTUALLY DUE TO EARLY LIFE
INNATE IMMUNE SEX DIFFERENCES SO
GIRLS ARE MORE LIKELY TO BE
INFECTED IN UTERO, ALSO MORE
LIKELY TO BE INFECTED WITH
INTERFERON RESISTANT VARIANTS
WHEREAS BOYS LESS U.S.
SEPTEMBER -- WHAT HE IDENTIFIED
WAS VIRAL REBOUND IS LESS
FREQUENT IN ART NON-ADHERENT
MALES.
STHIS IS A VERY BUSY SLIDE, AGAN
THIS IS SORT OF A HIGH LEVEL
OVERVIEW.
THIS SHOWS THE FIVE MALE
PARTICIPANTS.
IF YOU COULD JUST FOCUS ON THE
RED TRIANGLES IN THE BOTTOM AND
THEN THE BLUE ARROWS GOING UP
AND DOWN, IT JUST SHOWS YOU THAT
THE VIRAL LOAD REMAINS
UNDETECTABLE IN ALL FIVE MALE
PARTICIPANTS, EVEN THOUGH THE
LEVELS OF LOPINAVIR WHICH IS
SHOWN IN THE BLUE LINE WITH THE
TRIANGLE FALLS BELOW THERAPEUTIC
LEVELS.
SO BASED ON THIS CONFIRMING BY
DRUG LEVEL MONITORING, THEY WERE
ABLE TO IDENTIFY FIVE MALES IN
THIS COHORT OF -- I THINK HE
REPORTED IT WAS 286 IN THE FINAL
ANALYSIS.
WHO EXPERIENCED THIS LACK OF
REBOUND IN THE SETTING OF
NON-DETECTABLE ARV
CONCENTRATIONS.
BASED ON THIS, HE'S CONCLUDING
THAT MALES ARE MORE LIKELY TO
ACHIEVE AVIREMIA WITH VERY EARLY
ANTIRETROVIRAL TREATMENT.
HE'S SHOWN -- IN AN INTEREST OF
TIME I DIDN'T SHOW THE DATA --
THAT THIS IS ACTUALLY ASSOCIATED
WITH TRANSMISSION OF LOW FITNESS
VIRUS IN THESE FIVE INFANTS.
SO ESSENTIALLY THE PRIMARY
CONCLUSION IS THAT EARLY LIFE
INNATE IMMUNE SEX DIFFERENCES DO
MODULATE VERTICAL TRANSMISSION
AND INFLUENCE OUTCOME POST
TRANSMISSION.
I DON'T THINK WE HAD CONSIDERED
SEX DIFFERENCES IN TERMS OF CURE
POTENTIAL PRIOR TO THESE
STUDIES.
I WILL SAY IN OUR IMPACT EARLY
TREATMENT WE FOUND SIMILARLY
GIRLS WERE LESS LIKELY TO
ACHIEVE VIROLOGIC SUPPRESSION BY
48 WEEKS, BY 2 YEARS OF AGE
COMPARED TO MALES.
SO THERE ARE EMERGING DATA IN
TERMS OF SEX DIFFERENCES WITH
RESPECT TO INFECTION
SUSCEPTIBILITY AND IN LONG-TERM
VIROLOGIC SUPPRESSION,
HIGHLIGHTING THE NEED TO
CONSIDER SEX-SPECIFIC
INTERVENTIONS TO OPTIMIZE CURE
POTENTIAL IN CHILDREN.
LASTLY, I WANT TO JUST KIND OF
HIGHLIGHT THE TISSUE RESERVOIR
STUDY.
SO WE'VE BEGUN STUDIES ON THE
CNS THROUGH CSF SAMPLING
OBVIOUSLY, BUT WE HAVE A REALLY
TERRIFIC GROUP WHO HAVE WORKED
FOR YEARS COLLECTING TONSILS.
WHEN YOU HAVE A BIOBANK OF
TONSILS, OVER 300 TONSILS FROM
CHILDREN AND ADULTS ONE YEAR OF
AGE TO 50-PLUS YEARS OF AGE
LIVING WITH AND WITHOUT HIV IN
SOUTH AFRICA.
SO A VERY RICH BIOBANK TO ASSESS
THE TONSIL TISSUE RESERVOIR IN
PERINATAL AND ADULT INFECTIONS,
SO PROVIDES A REALLY BEAUTIFUL
PLATFORM TO COMPARE ACROSS THE
AIDS SPECTRUM TISSUE RESERVOIRS.
AND SO PRELIMINARY DATA FROM
THIS GROUP, WHAT YOU SEE ON THE
FAR LEFT IS THAT THIS IS AGE AT
THE BOTTOM AND YOU CAN SEE
PERCENT CD4s ARE NOT DIFFERENT
IN TONSILS IN CHILDREN COMPARED
WITH ADULTS AS SHOWN IN GREEN.
BUT WHEN YOU LOOK AT T
FOLLICULAR HELPER CELLS IN THE
TONSILS, KIDS HAVE HIGHER
PROPORTIONS OF T FOLLICULAR
HELPER CELLS AND IN THE
CORRELATION PLOT, YOU CAN SEE
THIS IS DEFINITELY AN
AGE-DEPENDENT EFFECT, AND
ALSO -- BUT ADULTS HAD HIGHER
LEVELS OF CCR-5 EXPRESSION IN
THEIR TONSILS THAN IN PEDIATRIC
CASES.
THEY HAVE MULTIPLE STUDIES
PLANNED AND HOPEFULLY THE NEXT
STRATEGIES FOR CURE, WE'LL HAVE
SOME IN DEPTH RESULTS HERE, BUT
JUST TO SAY THAT THIS IS AN
EXTENSIVE PROJECT THAT WAS
ALSO -- RECEIVED A SUPPLEMENT,
OAR SUPPLEMENT FOR STUDIES.
SO OUR PLAIN LANGUAGE SUMMARY
FOR THIS, AND THEN I'LL TURN IT
OVER TO MAURICIO, IS WHAT ARE
THE KEY QUESTIONS, REALLY
OBVIOUSLY WHAT ARE THE IMMUNE
FACTORS THAT DRIVE SEX
DIFFERENCES IN HIV CONTROL IN
CHILDREN.
IS HIV LOCATED IN DIFFERENT
LYMPHOID TISSUE SITES IN
CHILDREN COMPARED TO ADULTS
LIVING WITH HIV, HOW DO THOSE
DIFFER, AND CAN WE ENHANCE
ANTIVIRAL IMMUNITY IN CHILDREN
THROUGH STUDYING ON THIS EXPLANT
MODEL, TONSILLAR MODEL FOR
IMMUNE INTERVENTIONS.
WE BELIEVE THESE STUDIES ALL
TOGETHER HIGHLIGHTING
DIFFERENCES IN PEDIATRIC AND
ADULT INFECTIONS REQUIRING
CONTINUED INVESTIGATION OF THESE
DIFFERENT AREAS OF HIV
PERSISTENCE.
THIS IS THE TEAM OF HENRY AND
ZACH, AND I'LL TURN IT OVER TO
MAURICIO TO TALK ABOUT AAV
EXPRESSION OF COMBINATION BNABS
AND VIROLOGIC CONTROL.
[APPLAUSE]
>> MY GROUP IS INTERESTED - -- E
MOLECULES WE'RE USING FOR THE
STUDY ARE THE B3 GLYCAN -- AND
THE I MEUB -- WE ALSO THINK OF
PASSIVE IMMY ?AITION HOLDS GREAT
PROMISE FOR TREATING PEDIATRIC
HIV INFECTION BECAUSE THESE
MOLECULES ARE SAFE, IN INFANTS,
INCLUDING -- CHILDREN INCLUDING
INFANTS AND ALSO THEY HAVE
DEMONSTRATED -- NOT ONLY IN HIV
STUDY BUS ALSO IN CLINICAL
STUDIES.
BUT THERE IS A CAVEAT.
THE MAIN ONE THAT WE THINK IS
BECAUSE THE CURRENT PARADIGM FOR
DELIVERING THESE MOLECULES
REQUIRE PASSIVE DELIVERY,
REPEATED PASSIVE DELIVERY WHICH
FACES BOTH LOGISTICAL AND
ECONOMICAL CHALLENGES FROM BROAD
SCALE IMPLEMENTATION.
WHAT IF WE COULD ENGINEER HOST
CELLS TO CONTINUOUSLY PRODUCE
THESE MOLECULES, THEREBY
OBVIATING THE NEED FOR THESE
REPEATED ADMINISTRATIONS.
SO THIS IS EXACTLY WHAT WE'RE
TRYING TO ACHIEVE WITH GENE
THERAPY USING AAV VECTORS.
WE'RE INTERESTED IN -- SKELETAL
CELLS BECAUSE THEY HAVE A VERY
LONG LIFESPAN, AND AS LONG AS
THE -- SO THE AAV GENOME
PERSISTS IN THE CELL NUCLEUS
FOR -- BASICALLY FOR AS LONG AS
THE CELL LIVES, SO IF YOU DON'T
HAVE ANY IMMUNE RESPONSE, IF
IT'S NOT TOXIC YOU CAN
ESSENTIALLY GET PERSISTENT --
FOR YEARS AND POSSIBLY DECADES.
OUR VISION IS FOLLOWING A SINGLE
DOSE OF AAV VECTORS, CHILDREN
LIVING WITH HIV WOULD DEVELOP
PERSISTENT ECK PRETION OF THESE
HIV BIOLOGICS AT SUFFICIENT
LEVELS TO PREVENT VIRUS REBOUND
AFTER ART INTERRUPTION.
SO TO TEST THIS, WE PARTNERED AT
THE OREGON NATIONAL HIGH PRAIT
CENTPRIMATECENTER, WE ENROLLED ,
SEVEN DAYS LATER THESE ANIMALS
WERE STARTED ON ANTIRETROVIRAL
THERAPY AND AT THE SAME TIME,
THEY RECEIVED FOUR INTRAMUSCULAR
INJECTIONS OF AAV9 VECTORS
ENCODING -- OR -- SO THESE
INTERVENTIONS WERE GIVEN AT DAY
SEVEN AND THEY WERE DELIVERED IN
FOUR INTRAMUSCULAR INJECTIONS.
THAT'S IT.
AT THE SAME LOCATION.
IN PARALLEL, WE ALSO INFECTED
THREE CONTROLS FOR VARIOUS
REASONS WE COULDN'T ADD
ADDITIONAL CONTROL ANIMALS IN
THE 2022 COHORT SO WE ADDED
THREE MORE THIS YEAR AND THESE
ANIMALS ARE BEING MONITORED.
SO LET'S LOOK AT THE PRE-ATI
PHASE.
I'M GOING TO BE SHOWING THESE
GRAPHS FOR THE NEXT FEW SLIDES
TO RED DOTS ARE PLASMA VIRAL
LOADS.
THE SHADED AREA CORRESPONDS TO
THE ANTIRETROVIRAL THERAPY
PHASE.
SO ART SUPPRESSED VIRAL LOADS IN
BOTH THE CONTROLS AND THE
EXPERIMENTAL ANIMALS.
I'M GOING TO SHOW YOU THE SERUM
CONCENTRATION LEVELS, YELLOW
DOTS WILL BE 10-1074, GREEN
DOTS -- SO ALL EXPERIMENTAL
ANIMALS DEVELOPED PERSISTENT
EXPRESSION -- WAS A BIT MORE
VARIABLE WITH A FEW INSTANCES OF
LOSS AND INTERESTINGLY REGAIN OF
EXPRESSION.
WHAT HAPPENED AFTER WE STOPPED
ART?
CONTROLS REBOUNDED, ALL THREE OF
THEM, VERY EASILY DETECTABLE.
VIRAL LOADS AT WEEK TWO, POST
INFECTION.
AND ALL ANIMALS MAINTAINED
EXPRESSION OF AT LEAST ONE OF
THE MOLECULES THROUGHOUT THE
POST ATI PHASE.
I'M GOING TO HE FOCUS ON SEVEN
ANIMALS BECAUSE THEY WERE
REMARKABLE.
THERE WAS NO REBOUND IN SEVEN OF
THEM FOR THE HUNDREDS OF TIME
POINTS THAT WE MEASURED SO FAR.
SO IN ALL CASES WHERE REBOUND
WAS PREVENTED OR DELAYED, IN THE
NEXT FEW CASES, BOTH ECD4IG AND
THE 1074 WERE STABLY EXPRESSED
WITH POST ATI AVERAGES IN EACH
ANIMAL WITH 15 TO 33 OR 19 TO 76
MICRO GRAMS PER ML FOR 10-1074.
THERE WAS THIS ONE ANIMAL THAT
EXPERIENCED CONSECUTIVE EPISODES
OF LOW LEVEL VIREMIA AT ABOUT
WEEK 30 POST ATI.
THEN VIRUS REBOUND COINCIDED
WITH A DROP -- ADJUVANT WAS
MAINTAINED THROUGHOUT THIS
PERIOD AND THAT PROBABLY HELPED
THIS ANIMAL REGAIN CONTROL IN
THE NEXT FEW TIME POINTS.
A FEW OF THE EXPERIMENTAL
ANIMALS EXPERIENCED REBOUND POST
ATI AND IN THOSE CASES ONLY --
BUT THAT MOLECULE, THE
PERSISTENT EXPRESSION PROBABLY
CONTRIBUTED TO REGAIN OF CONTROL
IN THOSE TWO INSTANCES.
TO OUR SURPRISE, 10-1074
EXPRESSION REBOUNDED IN THE TWO
ANIMALS AT WEEKS 2 TO 22 POST
ATI AND THIS INCREASE IN
CONCENTRATIONS OF 10-1074
COINCIDED WITH REGAIN OF
VIROLOGIC CONTROL.
SO WHEN WE PLOTTED THIS I,
PREVENTION OR DELAY OF VIRUS
REBOUND WAS STATISTICALLY
SIGNIFICANT.
SO WHEN YOU TRY AAV MEDIATED
GENE THERAPY WITH BROAD
NEUTRALIZING ANTIBODIES IN ADULT
MACAQUES, YOU OFTEN SEE -- TO
LIMIT THE EGGS PRETIO EGGS PRETE
MOLECULES.
THE HOST WILL DEVELOP ANTIBODIES
AGAINST THE AAV DELIVERED
MOLECULES.
BUT WE DON'T SEE THAT VERY
OFTEN.
ACTUALLY IN MOST CASES WE DON'T
SEE THAT AT ALL WITH INFANT
MACAQUES.
THE YOUNGER THEY ARE, THE LESS
LIKELY THEY ARE TO MAKE ADA
RESPONSES.
SO HERE EACH COLUMN CORRESPONDS
TO ONE ANIMAL.
AGAIN THE GREEN DOTS PLOTTED ON
THE LEFT, Y AXIS NOW, GREEN OR
YELLOW DOTS CORRESPONDS TO SERUM
CONCENTRATIONS OF EACH MOLECULE,
AND ON THE RIGHT Y AXIS, YOU
HAVE ABSORBANCE LEVELS OF
ANTIBODIES IN SERUM TARGETING
EACH BIOLOGIC.
AND THE ADAs IN THIS CASE ARE
PLOTTED IN BLACK DOTS.
THE HIGHER THE ADAs, TYPICALLY
THE LOWER EXPRESSION.
SO THESE LINES WERE FLAT IN THE
NEXT -- IN THE FIRST FIVE
ANIMALS THAT WE ANALYZED WITH
BRIEF INCREASES SHORTLY AFTER
INOCULATION BUT THEN THE ADAs
WENT BACK TO BASELINE.
WE SAW INSTANCES OF ADAs IN A
FEW ANIMALS, BUT INTERESTINGLY,
THEY DECAYED.
THEY FELL BACK TO BASELINE,
WHICH ENABLED A RECURRENCE IN
EXPRESSION LEVELS OF 10-1074 IN
THIS CASE.
SO THE VIROLOGIC CONTROL THAT I
JUST SHOWED YOU IS PROMISING BUT
WE NEED TO KEEP IN MIND THAT WE
STARTED ANTIRETROVIRAL THERAPY
VERY EARLY AFTER INFECTION ON
DAY 7 SO THAT PROBABLY LIMITS
THE SEEDING OF THE VIRAL
RESERVOIR.
WITH THAT IN MIND, WE'RE ASKING
IF EARLY ART INITIATION PLUS AAV
DELIVERY WILL ALSO EVENT VIRUS
REBOUND IN SHIV INFECTED
MACAQUES IN LARGER RESERVOIRS.
SO WE ARE ACTIVELY PURSUING THIS
THIS YEAR WITH ANIMALS PLACED ON
ANTIRETROVIRAL THERAPY NOW AT
WEEK 3 POST INFECTION, AND WHEN
THEY WERE TREATED WITH THE SAME
VECTORS GIVEN TO THE 2022
COHORT.
AND WE ALSO HAVE THREE ANIMALS
ENROLLED SO FAR.
AND AS OF NOW WE HAVE VIRAL
LOADS, THIS IS STILL VERY
PRELIMINARY WITH THE CONTROL
GROUP, ART IS WORKING, IT'S
SUPPRESSING VIRAL REPLICATION IN
THE CONTROL, AND EXPERIMENTAL
ANIMALS, AND WE ALREADY HAVE
SOME LEVELS OF EXPRESSION THAT
WE ARE ACTIVELY MONITORING.
SO JUST TO SUMMARIZE, EARLY ART
PLUS AAV VECTOR DELIVERY
PREVENTED OR SUBSTANTIALLY
DELAYED VIRUS REBOUND IN
PERINATALLY SHIV INFECTED
MACAQUES FOLLOWING ATI.
ANTI-DRUG ANTIBODIES WERE THE
MAIN FACTOR LIMITING TRANSGENE
EXPRESSION BUT THEIR IN INCIDENE
IN INFANTS WAS LOWER THAN THAT
SEEN IN OLDER MACAQUES.
THIS IS SHOWING DUE TO NEONATAL
TOLERANCE.
AND 10-1074 WAS PRIMARILY
AFFECTED, IN THE THREE INFANTS
THAT LOST EXPRESSION DUE TO
ADAs, SERUM CONCENTRATION OF
THIS MOLECULE EVENTUALLY
REBOUNDED CONCOMITANTLY WITH A
DECLINE IN ADAs, WHICH WE
RARELY SEE IN JUVENILES OR
ADULTS.
SO PLAIN LANGUAGE SUMMARY, THE
QUESTION WE ASKED WAS, COULD A
COMBINATION OF EARLY ART PLUS
AAV THEIR PEE WITH BIOLOGICS
ENABLE CONTROL -- THIS WORK
ADVANCES THE FIELD TOWARD A CURE
BECAUSE IT RAISES THE
POSSIBILITY THAT DURABLE
ART-FREE CONTROL OF PERINATAL
HIV INFECTION CAN BE ACHIEVED
THROUGH A SINGLE ADMINISTRATION
OF AAV VECTORS GIVEN
INTRAMUSCULARLY.
FOUR INJECTIONS, THAT'S ALL IT
TOOK FOR THIS STUDY.
AND WE ARE EXCITED ABOUT THIS
BECAUSE WITH ADEQUATE
INVESTMENT, I BELIEVE THAT AAV
VECTOR DELIVERY OF HIV -- CAN BE
A KEY TO SUSTAINED -- IN
CHILDREN IN A WRACT PRACT CAL
AND SCALABLE WAY.
SO I WANT TO GIVE THANKS TO THE
MEMBERS OF MY LAB WHO DID THE
ASSAYS AND HELPED ME WITH THESE
EXPERIMENTS, SPECIAL THANKS ALSO
TO NANCY AND ANN AND MEMBERS OF
THE TEAM FOR OVERSEEING THE
PRIMATE STUDIES.
THANK YOU.
[APPLAUSE]
>> HI, EVERYBODY.
MY NAME IS ANN CHAHROUDI, AND I
WILL BE TALKING TO YOU ABOUT
SOME OF THE WORK WE'RE DOING IN
RF 3 FOR PAVE.
SO IN RF 3, THE FOCUS IS
ERADICATION AS YOU ALL KNOW.
AND WE ARE WORKING TO DEFINE
PEDIATRIC-SPECIFIC FEATURES OF
VIRUS PERSISTENCE IN RESERVOIR
REACTIVATION TO INFORM
STRATEGIES TO SUCCESSFULLY
ELIMINATE VIRUS RESERVOIRS.
AND WE'RE REALLY FOCUSING ON HOW
WE CAN FACILITATE THE IMMUNE
SYSTEM AND ENHANCE IMMUNE SYSTEM
TO CLEAR THOSE RESERVOIRS.
I LEAD THIS RF WITH PAOLO PALMA.
THIS IS OUR RF 3 TEAM.
AND WHAT I'M GOING TO DO FOR THE
REMAINDER OF THIS TALK IS TO
PREVIEW A COUPLE OF INFANT
NON-HUMAN PRIMATE STUDYS THAT WE
HAVE AND THAT ARE STILL
HAPPENING THIS YEAR, AND THEN
TAKE YOU THROUGH A COMPLETED
STUDY THAT WE STARTED AT THE
BEGINNING OF THE PAVE PROJECT.
SO FIRST TO BUILD OFF OF
MAURICIO'S FANTASTIC RESULTS, WE
WANTED TO UTILIZE AAV DELIVERY
OF ECD4IG TO SEE IF WE COULD
DETERMINE WHETHER THERE WAS AN
EFFECT ON CLEARANCE OF INFECTED
CELLS.
AND SO THIS IS TAKING THE SAME
APPROACH YET USING AN IGG
1 VERSION OF ECD4IG AND THE
REASON FOR THAT IS TO IMPROVE
ANTIBODY EFFECTOR FUNCTIONS AND
SO HOPEFULLY HAVE ADCC AND OTHER
MECHANISMS OF CLEARING INFECTED
CELLS.
SO IN THIS STUDY THAT'S
CURRENTLY ONGOING, WE HAVE 20
ANIMALS, 10 CONTROLS AND 10
EXPERIMENTAL ANIMALS.
THE ANIMALS ARE ALL INFECTED
WITH SIV MAK251 ORALLY AT
4 WEEKS OF AGE AND THEN
ANTIRETROVIRAL THERAPY WAS
STARTED THREE WEEKS LATER.
AND AT THE SAME TIME IN THE
EXPERIMENTAL ANIMALS WHEN THEY
RECEIVED THE ANTIRETROVIRAL
THERAPY, THEY ALSO GET AN
INJECTION OF THE AAV9 ECD 4 IGG
1.
WE'RE FOLLOWING THEM THROUGHOUT
THIS PERIOD OF ART AND THEN WE
ARE ANTICIPATING THAT IN ORDER
TO CLEAR THE VIRAL RESERVOIRS OR
CLEAR THE INFECTED CELLS DURING
ART, WE WILL NEED A PERIOD OF
LATENCY REVERSAL.
SO THIS HAS NOT HAPPENED YET BUT
THE PLAN IS TO TREAT WITH THE
SMACK MIMETIC ECD 5582.
I WILL JUST CALL YOUR ATTENTION
TO A POSTER FROM A FELLOW IN MY
LAB.
HE GOES INTO MUCH GREATER DETAIL
ON HOW WE SELECTED THESE INFANT
MACAQUES IN TERMS OF THEIR
PRE-EXISTING ANTIBODIES TO AAV.
SO HERE ARE EARLY RESULTS.
SIMILAR TO WHAT MAURICIO HAS
SHOWN, WE ARE SEEING EXPRESSION
OF ECD 4, THE IGG 1 VERSION IN
ALL OF THESE ANIMALS.
THESE LAST WE HAVEN'T MEASURED
YET SO IT'S NOT ABSTINENCE, IT
JUST HASN'T BEEN MEASURED.
AND THEN JUST TO REMIND YOU OF
OUR LATENCY REVERSAL APPROACH,
SO THIS HAS BEEN TALKED ABOUT IN
SEVERAL TALKS ALREADY AT THIS
MEETING SO I WON'T GO INTO
DETAIL BUT WE'VE PUBLISHED ON IN
IT ADULTERY ADULT RECE RHESUS ML
AS -- AND IN PARTICULAR THEY
HAVE A LOT LESS VIRUS
REACTIVATION, ARE ON ART
VIREMIA.
WE'VE TAKEN THESE RESULTS AND
WORKED WITH UNC TO PERFORM PK
MODELING STUDIES TO HELP US
INFORM THE NEXT DOSE AND WE HAVE
SOME PILOT STUDIES AS WELL SO WE
FEEL PREPARED THAT WE SHOULD BE
ABLE TO ACHIEVE HIGHER LEVELS OF
LATENCY REVERSAL IN THE INFANTS
IN THE CURRENT STUDY.
SO THE NEXT PREYOU HAVE I WILL E
YOU IS A STUDY FROM THIS GROUP
LISTED ON THE SCREEN FROM WEILL
CORNELL MEDICINE WHERE THEY'RE
WORKING TO INDUCE BNABS, HIV
ENVELOPE TRIMER I NIGHIZATIO IM.
THIS IS ACTUALLY A PART OF RF 2,
BUT I THOUGHT I WOULD PRESENT IT
TODAY.
SO THE GOAL OF THESE IS TO
PRESENT MULTIPLE BNAB EPITOPES
IN WAYS THAT BEST MIMIC THEIR
PRESENTATION ON THE NATIVE
ENVELOPE SPIKE.
AND THE BG505 SOSIP IS DESCRIBED
HERE AN THE GT1.1 WHICH ENGAGES
A BROAD RANGE OF VRC01-CLASS C
D4 BINDING SITE PRECURSOR BNABS
IS SHOWN HERE AS WELL.
SO THIS IS ANOTHER -- THIS IS
ACTUALLY A STUDY THAT'S BEEN
COMPLETED BY ASHLEY NELSON, AND
THIS IS WHERE THEY USE THE BG50L
AND THE GT1.1 MODIFIED VERSION
IN INFANT RHESUS MACAQUES THAT
ARE NAIVE TO SIV SO THIS WAS AS
PART OF A PROPHYLACTIC VACCINE
STUDY.
AND THEY SHOWED THAT IT WAS ABLE
TO -- THEY WERE ABLE TO INDUCE
T TIER 1 AND TIER 2 NEUTRALIZING
ANTIBODIES WITHIN A YEAR OF THIS
INITIAL PROFILE AND THE
GT1.1 PRIMED INFANTS DISPLAYED
SUPERIOR ABILITY TO GENERATE
PRECURSORS TO CD4 BINDING SITE
NEUTRALIZING ANTIBODIES, SO YOU
CAN SEE HERE THE COMPARISON THAT
THEY MADE WITH INFANT MACAQUES
AND THE ADULT MACAQUES.
SO THIS IS THE STUDY THAT WEAR
DOINGWE'REDOING TAKING THAT APPD
APPLYING IT IN A THERAPEUTIC
VACCINE SPACE.
SO ANIMALS WERE INFECTED WITH
SHIV SF162P3.
THIS WAS DONE AT THE OREGON
PRIMATE CENTER.
THEY STARTED ANTIRETROVIRAL
THERAPY ONE WEEK AFTER INFECTION
AND THIS IS THE SCHEDULE OF
IMMUNIZATIONS.
THE SOSIP IMMUNIZATIONS ARE
BEING GIVEN WITH THE
TLR7/8 ADJUVANT 3M052.
SO THE HYPOTHESIS IS THAT
ADMINISTRATION OF GERMLINE
TARGETING SOSIP SHORTLY AFTER
INFECTION WILL LEAD TO
FOCUSED -- A FOCUSED ANTIBODY
RESPONSE, DRIVE THE
EXPANSION/MATURATION OF SPECIFIC
B CELL CLONAL LINEAGES WITH B
NABS GENERATED IN VIVO CAPABLE
OF DELAYING TIME TO REBOUND POST
ART INTERRUPTION.
WE'RE USING TWO DIFFERENT
METHODS, BOTH VECTOR DELIVERY
AND ACTIVE IMMUNIZATION TO
ACHIEVE BNAB EXPRESSION IN
INFANT RHESUS MACAQUES.
AND WE HAVE SOME ONGOING WORK
OBVIOUSLY TO DO AS THOSE
NON-HUMAN PRIMATE STUDIES ARE
STILL WORKING.
BUT WHAT IF WE TAKE A STEP BACK
AND THINK ABOUT PASSIVE
ADMINISTRATION OF BNABS IN
INFANTS?
THAT'S ACTUALLY WHERE WE STAR
STARTED.
SO THIS WORK WHICH WE'RE CALLING
SURGE AND PURGE AAPPROPRIATE,
THIS HAS BEEN DISCU --APROA. THD
AT THE TIME OF OUR INITIATION TO
ATTEMPT TO IMPEDE OR REDUCE
RESERVOIR ESTABLISHMENT.
THIS APPROACH IS PARTICULARLY
APPEALING FOR INFANTS AND
CHILDREN BECAUSE FOR MANY OF
THEM, WE KNOW WHEN THEY WERE
INFECTED AND WE CAN INTERVENE
EARLY WITH ANTIRETROVIRAL
THERAPY PLUS ADDITIONAL
IMMUNE-BASED INTERVENTIONS.
SO THE SURGE IS THE USE OF AN
IMMUNOSTIMULATORY AGENT DURING
THE PERIOD OF HIGH TURNOVER OF
INFECTED CELLS SO THIS IS DURING
ACUTE INFECTION, TO FURTHER
ENHANCE VIRAL ANTIGEN EXPRESSION
AS WELL AS PROMOTE T AND NK CELL
ACTIVATION TO ACCELERATE THE
CLEARANCE OF INFECTED
CD4 T-CELLS.
IN THE STUDY THAT I'LL BE
DESCRIBING WE USED N-803 AS OUR
SURGE AGENT.
THE PURGE IS TO USE PA CIVIL
ADMINISTERED ENVELOPE-SPECIFIC
ANTIBODIES THAT WILL WORK IN
CONCERT WITH INNATE IMMUNE CELLS
TO CLEAR INFECTED CD4 T-CELLS.
THE PURGE AGENTS WE USE ARE FOUR
RHESUS-SPECIFIC MONOCLONAL
ANTIBODIES DEVELOPED AT THE NIH.
SO HERE'S THE STUDY DESIGN.
WE HAD A GROUP THAT JUST HAD ART
ONLY AS CONTROLS, A GROUP THAT
RECEIVED MONOCLONAL ANTIBODIES
AND A GROUP THAT RECEIVED SIV
ANTIBODIES IN ADDITION TO N-803.
THEY WERE ALL INFECTED ORALLY,
STARTED ON ART WITHIN ONE TO TWO
WEEKS OF THAT INFECTION, AND
THEN RECEIVED THE ADDITIONAL
INTERVENTIONS AT THE SAME TIME
AS ART WAS INITIATED.
IN THIS STUDY, WE WERE ONLY ABLE
TO GIVE ONE DOSE OF N-803 DUE TO
ADVERSE EFFECTS.
SO WHAT DID WE SEE?
WE FOUND THAT IN ANIMALS THAT
RECEIVED N-803, WE SHOWED AN
INCREASE IN KI67 EXPRESSION ON
NK CELLS AND CD8 T-CELLS AT DAY
FOUR, WHICH IS SHOWN HERE.
CD4 T-CELLS DID NOT HAVE A
SIMILAR EE CREASE AND THE LEVELS
DECLINED BY DAY 7 SUCH THAT THEY
WERE SIMILAR TO THE OTHER
GROUPS.
SO THIS WAS PROOF OF CONCEPT
THAT N-803 WAS DOING WHAT WE
EXPECTED TO DO IN THESE ANIMALS.
HOWEVER WE SAW A SIMILAR DECLINE
OF VIREMIA ON ANTIRETROVIRAL
THERAPY IN ALL THREE OF THE
GROUPS, DESPITE THE
ADMINISTRATION OF THE ANTIBODIES
AS WELL AS THE N-8 O803, SO
ALTHOUGH THEY'RE DIFFERENT
AGENTS AND A DIFFERENT MODEL,
BUT IT'S DIFFERENT FROM THE
ECLEAR STUDY THAT MARINA CASKEY
JUST PRESENTED WHERE THEY SAW A
FASTER DECLINE IN VIREMIA WITH
ADMINISTRATION OF ANTIBODIES TO
ADULTS LIVING WITH HIV.
WE ALSO DID NOT FIND AN IMPACT
OF OUR INTERVENTIONS ON THE
IMPACTED CELLS, SO THIS IS
LOOKING AT GAG DNA CELLS IN
PERIPHERAL BLOOD AND LYMPH NODES
OVER TIME IN ALL GROUPS WHICH
EVERYTHING LOOKED SIMILAR.
AND WE ALSO LOOKED AT THE INTACT
SIV PROVIRAL RESERVOIR IN LYMPH
NODES, BLOOD AND RECTAL
BIOPSIES, AND THERE WAS NO
DIFFERENCE BETWEEN THE GROUPS.
SIMILARLY TO THESE LAST COUPLE
OF -- I'LL SHOW YOU WHAT
HAPPENED AFTER TREATMENT
INTERRUPTION.
ALL ANIMALS IN THE GROUPS
REBOUNDED AT A SIMILAR TIME AND
WE DID NOT HAVE ANY IMPACT ON
THE POST REBOUND DYNAMICS IN
TERMS OF SET POINT.
SO TO SUMMARIZE THIS STUDY, WE
SAW SIMILAR PLASMA VIRAL LOAD
DECAY ACROSS ALL GROUPS, WE DID
SEE AN INCREASE IN KI67 AT DAY
FOUR AFTER N-803 ADMINISTRATION,
AND OVERALL, WE SAW A DECLINE IN
CD4 T-CELL ASSOCIATED SIV DNA
INTACT VIRAL DNA OVER TIME IN
ALL GROUPS BUT WHEN WE LOOKED
CROSS-SECTIONALLY, THERE WAS NO
DIFFERENCE.
AND THEN FINALLY, I WILL JUST
CALL YOUR ATTENTION TO A POSTER
THAT'S BEING PRESENTED FROM THE
ROME GROUP, AND THEY'RE REALLY
DOING SOME VERY EXCITING STUDIES
TO DEVELOP A PREDICTIVE PLATFORM
FOR RESERVOIR REACTIVATION IN
VIRAL REBOUND THAT WE ARE
FEEDING DATA FROM THE ATACO
COHORT DEBBIE DESCRIBED EARLIER
AS WELL AS THE STUDIES OF SIV IN
INFANT RHESUS MACAQUES.
JOHN MARCOUX IS DEVELOPING A
MATH MACKALL MODEL FOR HELPING
US PREDICT VIRAL REBOUND IN
ANIMALS AND IN -- SO THE PLAIN
LANGUAGE SUMMARY.
THE KEY QUESTION WE WERE ASKING
IS CAN THE COMBINATION TREATMENT
WITH ART, -- IMMUNOSTIMULATORY
AGENTS RESTRICT RES VOR
ESTABLISHMENT, CLEAR PERSISTENT
RESERVOIRS AND/OR DELAY VIRAL
REBOUND IN INFANTS?
HOW DOES THIS WORK ADVANCE THE
FIELD TOWARD CURE OR CONTROL.
OUR EARLY EXPRESSION DATA FROM
THE ECD IGG 1 REINFORCES RESULTS
THAT PLEASTHAT MAURICIO PRESENTE
DELIVER OUR LATENCY REVERSING
AGENT.
THE ACTIVE IMMUNIZATION STRATEGY
WITH THE SOSIP SHOWS PROMISE FOR
INDUCTION OF BNAB PRECURSORS IN
INFANTS FROM THE SIV NAIVE STUDY
OR SHIV NAIVE STUDY.
AND THOUGH THE OUTCOMES OF OUR
SURGE AND PURGE STUDY WERE NOT
AS HOPED WE GAINED INSIGHT INTO
THE IMPACT OF COMBINATION
INTERVENTIONS IN INFANTS.
SO OVERALL WE THINK THAT THE
INFANT MONKEY MODEL IS USEFUL TO
HELP ADVANCE STRATEGIES FOR A
CURE, AND EQUALLY AS IMPORTANT,
IT TELLS US WHEN MORE RESEARCH
IS NEEDED BEFORE WE CONSIDER
ADVANCING A CERTAIN
INTERVENTIONAL APPROACH TO
CHILDREN.
THESE ARE THE ACKNOWLEDGMENTS
FOR THE SOSIP STUDIES, AS WELL
AS THE ACKNOWLEDGMENTS FOR THE
NON-HUMAN PRIMATE STUDIES WE DID
AT EMORY.
NOW I WILL TURN IT OVER TO
SAVITA TO TALK ABOUT RF 4.
THANK YOU.
[APPLAUSE]
>> GOOD MORNING.
I'M SAVITA PAHWA FROM THE
UNIVERSITY OF MIAMI.
I AM HERE TO INTRODUCE RF 4,
WHICH IS UNIQUE TO THE PAVE
COLLABORATORY.
THE OVERARCHING GOAL IS TO
OPTIMIZE CUTTING EDGE
TECHNOLOGIES TO STUDY HIV
PERSISTENCE IN CHILDREN.
IT HAS FOUR AIMS, AND ON THE
LEFT ARE THE -- AIMS 1 AND
2 DEAL WITH RESERVOIR DYNAMICS
AND INDUCIBILITY, WHICH WILL BE
DISCUSSED BY DEBBIE.
I WILL BE DISCUSSING AIMS 3 AND
4, AND STARTING WITH IMMUNE
PROFILING.
WHICH IS SHARED BETWEEN MIAMI
AND BOSTON LABS.
SO THE MAIN QUESTION IN
IMMUNOLOGIC PROFILING ASK WHAT
ARE THE IMMUNE RESPONSES AGAINST
HIV THAT ARE PRESENT, AND/OR ARE
EFFECTIVE IN THE INFANT IMMUNE
SYSTEM, BOTH PRE AND POST ART
INITIATION.
AND MOST OF THE ASSAYS IN OUR
TOOLBOX DEAL WITH PHENOTYPIC
STUDIES UTILIZING MULTIPARAMETER
FLOW CYTOMETRY AS WELL AS
FUNCTIONAL STUDIES.
AND THROUGH RF 4, WE HAVE
DEVELOPED MULTI-OMIC SINGLE CELL
ANALYSIS USING SINGLE CELL RNA
SEQ, AS WELL AS SMALL SCALE
FUNCTIONAL STUDIES TO DETERMINE
HOW IMMUNE CELLS REACT TO VIRAL
INFECTION AND OTHER STIMULI.
AND HERE ARE SOME OF THE
HIGHLIGHTS.
FIRST I WANT TO ACKNOWLEDGE THE
TARA COHORT WHICH IS A COHORT
DEVELOPED WITH COLLABORATOR
MARIA LANE IN MOZAMBIQUE.
IN INFANTS BORN TO HIV INFECTED
MOTHERS LEADING TO BIRTH OF HIV
EXPOSED INFECTED INFANTS, AND
HIV EXPOSED UNINFECTED
INASSISTANTS.
AND WHEN WE DID THE ECCITE-SEQ
ASSAY, WE FOUND THAT AT ONE
MONTH POST BIRTH, IN FOUR
INFANTS THEY EXHIBITED
ENRICHMENT OF NK AND CD8 T-CELL
CLUSTERS THAT WERE ABSENT IN
HEU, AND THOSE ARE SHOWN ON THE
LEFT ON THESE TWO DIAGRAMS.
THE RIGHT ONE BEING THE INFECTED
SHOWING THE CD8 AND THE NK
CELLS, AND ON THE LEFT ARE THE
UNINFEBUNINFECTED INFANTS WHO DT
HAVE THIS.
THEN ON THE EXTREME RIGHT BO
DBOTTOM, YOU SEE THE CTL CLONL
EXPANSION WAS NOT CORRELATED
WITH VIRAL LOAD.
SO SOME OF THE HIGHLIGHTS OF THE
OTHER PART IS THE SMALL SCALE NK
EFFECTOR CELL FUNCTION ASSAY, IN
WHICH WE ISOLATED NK CELLS FROM
3 MILLION PBMC AND CULTURED THEM
WITH HIV INFECTED CELL LINE HAD
THE UTT78 AS WELL AS WITH
UNINFECTED K562.
WHEN WE DID THE KILLING
EFFICIENCY OF NK CELLS AT ONE
MONTH PREART, WE FOUND THAT IT
WAS REALLY NEGATIVE LIQUOR LATED
LY CORRELATEDWITH VIRUS LOAD SHE
EXTREME RIGHT.
WHEN WE LOOKED AT THE
TRANSCRIPTIONAL PROGRAMS, WE
FOUND THAT THE NK CELLS INDUCED
DIFFERENT TRANSCRIPTIONAL
PROGRAMS IN RESPONSE TO THE HIV
INFECTED TARGET CELLS, AND THE
K562 UNINFECTED CELLS, WHICH ARE
SHOWN ON THE EXTREME RIGHT ON
THE BOTTOM.
SO FOR SUMMARY OF THIS PART, WE
CAN SAY THAT A COMPREHENSIVE
IMMUNE ANALYSIS IS POSSIBLE WITH
VERY FEW CELLS YOU CAN DO FLOW
CYTOMETRY, SINGLE CELL AND
EVERYTHING, WITH 5 MILLION
CELLS.
IF YOU WANTED TO TAKE A DEEPER
DIVE, THEN SINGLE CELL RNA SEQ
WITH EVEN SMALLER SAMPLES ARE
GOOD FOR SPECIFIC QUESTIONS.
EXAMPLE, HIGH AND LOW VIRAL
RESERVOIR AND CLINICAL RESPONSE
IN CLINICAL TRIALS.
EMERGING DATA ARE POINTING TO
EXPANSION OF SUBSETS OF NK AND
CD8 T-CELLS IN INFANTS WITH HIV
PRE-ART INFECTION AT ONE TO TWO
MONTHS OF AGE.
THE FUTURE DIRECTIONS ARE TO
DEVELOP THESE MULTI-OMIC RNA SEQ
ASSAYS AS WELL AS NK EFFECTOR
FUNCTIONS IN GREATER DEPTH, AND
TO PERFORM CROSS RF
COLLABORATIONS WHICH ARE REALLY
ONGOING WITH THE DIFFERENT
INVESTIGATORS LISTED HERE.
THE MAIN PLAYERS IN THE
UNIVERSITY OF MIAMI TEAM ARE
SHOWN IN CIRCLES.
LESLIE WHO'S IN THE AUDIENCE, IN
THE BACK, IN THE MIDDLE, AND TWO
GRADUATE STUDENTS, AKSHAY AND
VINH.
OF COURSE I HAVE TO BE THANKFUL
TO OUR COLLABORATORS IN MOAZ AM
BEAK AMOZAMBIQUE.
SYSTEM SEROLOGY PIPELINE IS
FOCUSED ON FINDING CORRELATES
BETWEEN ANTIBODY BINDING THROUGH
THE FAB DOMAIN, AS WELL AS TO
THE ANTIBODY EFFECTOR MEDIATED
FUNCTIONS WHICH ARE LEVERAGED
THROUGH THE FC DOMAIN, WHICH ARE
SHOWN IN THE BOTTOM BOX WITH ALL
THE DIFFERENT FUNCTIONS.
AND ON THE RIGHT SIDE IS THE
HEAT MAP SHOWING THAT YOU COULD
REALLY PROFILE THIS RESPONSE.
WE HAVE FOUR ORDERS OF MAGNITUDE
OF LINEAR RANGE OF DETECTION.
AND THESE ASSAYS ARE PERFORMED
IN BOSTON, IN THE LAB AT THE
INSTITUTE.
HERE THIS IS SHOWING THAT IN A
STUDY THAT WAS PERFORMED WITH
VACCINE RECIPIENTS OF HIV, OVER
A 72-MONTH PERIOD, THAT THE IGG
1 AND IGG 3 WERE POSITIVELY AND
INVERSE LIQUOR LATED
RESPECTIVELY WITH THE LATENT HIV
RESERVOIR SIZE.
AND HERE IS THE MODEL, SHOWING
ON THE TOP THAT THE IGG
3 RESPONSES ARE NEGATIVELY
CORRELATED, WHEREAS THE IGG
1 RESPONSES ARE POSITIVELY
CORRELATED WITH THE LATENT
RESERVOIR.
AND THIS IS THE TEAM OF RHINE RN
MCNAMERA.
THE QUESTION IS WHAT IS THE ROLE
OF ANTIVIRAL IMMUNITY IN VIRUS
CONTROL AND RESERVOIR DECAY IN
PRE-ART AND ART-TREATED
CHILDREN.
AND I THINK SOME OF THESE
TECHNOLOGIES WHICH WILL MINIMIZE
INPUT WILL HELP DRIVE EFFECTOR
MECHANISMS AGAINST HIV AND THE
SYSTEM SEROLOGY IS EXPLORING NEW
TOOLS TO ANALYZE RESERVOIRS.
AND THESE ARE ENCOURAGING
STUDIES BECAUSE THEY COULD
OVERCOME LIMITED BLOOD SAMPLING
IN PEDIATRIC POPULATIONS, AND,
THEREFORE, MOVE THE CURE FIELD
FORWARD.
YOAND THE FINAL AIM WAS AIM FOU,
WHICH IS IMMUNOPET IMAGING IN
NON-HUMAN PRIMATES FOR
VISUALIZING VIRAL RESERVOIRS.
USING ZIRCONIUM LABELED ANTIBODY
VRC07, YOU SEE PICTURES OF THESE
TWO ANIMALS TWO WEEKS POST
INFECTION AND 10 WEEKS POST ART,
AND YOU CAN SEE THESE
RESERVOIRS, THESE SITES OF VIRAL
REPLICATION REALLY LIGHT UP,
WHICH ARE MUCH GREATER IN THE
EARLY PHASE, AND MUCH SMALLER
AFTER ARV INSTITUTION AFTER 10
WEEKS.
SO THE SUMMARY IS THAT CAN WE
OPTIMIZE PRE-CLINICAL PET
IMAGING, AND YES, AND CAN THIS
BECOME COMPLEMENTARY TO
QUANTITATIVE ASSAYS TO ASSESS
VIRAL INFECTION?
AND FINALLY, THESE COULD REALLY
BE POSSIBLY OVERCOME INVASIVE
PROCEDURES SUCH AS BIOPSIES THAT
ARE NEEDED TO DETECT AND LOCATE
HIV REPLICATION IN TISSUES.
NOW I HAPPENED IT OVER TO DEB.
>> THANKS, SAVITA.
IN THE INTEREST OF TIME I'M
ACTUALLY GOING TO SKIP THE
RESERVOIR COMPONENT AND HAND IT
OVER TO JESSICA.
BUT JUST TO MAKE ONE POINT IN
TERMS OF THE THEME OF SEX
DIFFERENCES IN HIV RESERVOIR
SIZE, WE JUST COMPLETED A STUDY
IN A U.S. COHORT USING THE IPDA
ASSAY THAT WAS DESCRIBED IN THE
WELL MATCHED COHORT, THIS WORK
WAS DONE WHEN SHE WAS A MASTER'S
STUDENT IN MY LAB IN
COLLABORATION WITH A PEDIATRIC
FAK SCORE STUDY.
TIME OF VIROLOGIC SUPPRESSION IN
EARLY INFANCY OR CHILDHOOD
AROUND 14 MONTHS OF AGE, IN
ORANGE ARE THE GIRLS, SEX
ASSIGNED AT BIRTH AND IN PURPLE,
THE BOYS, AND IN THE LATE
SUPPRESSED GROUP, YOU CAN SEE
TOTAL HIV DNA IS ACTUALLY
INCREASING IN THE GIRLS.
IT HIGHER IN GIRLS VERSUS BOYS
AND EVEN DEFECTIVE HAVE A
DIFFERENT -- AND AGE OF
VIROLOGIC SUPPRESSION REALLY
MATTERS.
SUPPORTING ACTUALLY DEVELOPMENT
OF THE IPD ASSAY FOR APPLICATION
OF CROSS PEDIATRIC STUDIES.
THERE'S A POSTER IN TERMS OF
PROVIRAL LANDSCAPE ANALYSIS
OF -- INFECTIONS JUST SHOWING
HIGH BURDEN OF INTACT PRO
VIRUSES SO WE BELIEVE THESE ARE
ACTUALLY DEPLETED OVER TIME
PERHAPS BY SOME OF THE
MECHANISMS THAT SAVITA HAS
DESCRIBED.
SO I'M GOING TO TURN IT OVER.
I WANT TO THANK EVERYONE ON THE
TEAMS AND TURN IT OVER TO
JESSICA FOR THE COMMUNITY.
>> SO WE SEE THERE'S A LOT OF
REALLY GREAT SCIENCE AND IT'S
HARD TO CONDENSE THAT DOWN AND
THAT IS ONE OF THE THINGS THAT
THE COMMUNITY IS -- WHAT WE'RE
TRY TO REALLY LEAD IN THIS
PROGRAM.
SO DEBBIE ALREADY OUTLINED THAT
WE DO HAVE FOUR CORE PARTNERS AS
PART OF THE PAVE NETWORK.
SO JUST TO SAY WE DO HAVE A
COMMUNITY ADVISORY BOARD.
IT IS A GLOBAL ADVISORY BOARD,
WE DO HAVE A NUMBER OF COUNTRIES
REPRESENTED.
I DO WANT TO HIGHLIGHT MAYBE TWO
SPECIFIC PROJECTS, SO WORKING ON
A PERCEPTIONS PROJECT, ONE IS
LED BY TWO CORE MEMBERS FROM
NIGERIA AND UGANDA, AND THIS HER
CAMPAIGN OR WOMEN FOR HIV CURE
REALLY FEATURES YOUNG WOMEN
LIVING WITH PERINATAL HIV
TALKING ABOUT THEIR STORY AND
WHAT HIV CURE MEANS AND I'VE
SHOWN TWO TILES HERE.
WE'RE BEGINNING TO EXPAND THAT
OUT AND WE'LL BE CREATING A
VIDEO OUT OF THAT.
AND I ALSO WANT TO HIGHLIGHT
THAT WE'RE NOT JUST FOCUSING ON
THE ENGAGEMENT AND LITERACY
ELEMENT BUT ALSO AROUND THE
ENABLING ENVIRONMENT, SO WE
ACTUALLY HAVE HERE OUR CAB CHAIR
SPEAKING WITH THE UGANDA
NATIONAL SCIENCE AND TECHNOLOGY
COUNCIL ON PEDIATRIC HIV CURE
RESEARCH.
WE HAVE DONE AGAIN, THINKING
ABOUT THE METRICS, WE DID THE
SURVEY THROUGH THIS SOUTH
AFRICAN HIV CLINICIAN SOCIETY
AROUND WHAT THEIR KNOWLEDGE
LEVEL IS, AND WE'RE PLANNING ON
REPEATING THIS SURVEY TO AGAIN
THINK ABOUT HOW OUR PROGRAM AND
THE WEBINARS AND IN-PERSON
PROGRAMS THAT WE'VE DONE HAS
REALLY EXPANDED THAT KNOWLEDGE
OVER TIME.
WE'RE AGAIN THINKING ABOUT THIS
ENABLING ENVIRONMENT.
IT'S NOT ENOUGH TO JUST THINK
ABOUT LITERACY, WE ALSO REALLY
FOCUS ON BUILDING THE ADD SEW VY
SO INVEST BEING IN THE COMMUNI
TO GROW THE SCIENCE IN THE
REGION.
WE HAVE TWO HERE FOCUSING ON THE
CONGRESSIONAL DELEGATION HERE SO
WE'VE DONE TWO CONGRESSIONAL
LUNCHES AS WELL AS OUTREACH TO
THE FDA.
WE ALSO AGAIN HAVE A COMMUNITY
PERCEPTIONS PARTNERSHIP AND THIS
IS REALLY LEVERAGING A CROSS
COLLABORATORY PARTNERSHIP, BUT
I'VE JUST FOCUSED HERE ON SOME
OF THE PEDIATRIC AND ADOLESCENT
CONCERNS OF WHAT IT MEANS TO
CONTROL THE VIRUS AND NOT JUST
THINKING ABOUT ERADICATION, BUT
THINGS AS SIMPLE AS YOU KNOW,
WHO GETS TO DECIDE WHETHER I GO
BACK ON THERAPY, IS IT MYSELF OR
IS IT MY PARENTS.
AGAIN WE'RE ALSO THINKING ABOUT
THE SOCIAL SCIENCE AS PEACT, SO
PARTNERING TO THINK ABOUT AN
ETHICS PAPER THAT EXPANDS ON
SOME OF THE WORK THAT SHE HAS
DONE AND OTHERS IN THE COMMUNITY
ON SETTING THE RESEARCH AGENDA.
AND THEN SOME OF THE THINGS THAT
WE'RE REALLY LOOKING FORWARD TO
IS AGAIN THIS COMMUNITY VOICES
CAMPAIGN PARTNERING WITH
DIFFERENT GROUPS AND YOU'LL SEE
US POPPING UP AT SOME VARIOUS
CONFERENCES IN THE REGION.
THANK YOU.
[APPLAUSE]
>> THANK YOU, TO EVERYONE.
SPEAKERS, WE HAVE THE TIME FOR
ONE OR TWO QUESTIONS, SO IF YOU
HAVE ANY QUESTIONS, PLEASE COME
TO THE MIC.
>> HI.
I HAD A QUESTION TO DR. MARTINS.
FIRST OF ALL, AMAZING DATA, VERY
IMPRESSIVE.
I GUESS MY QUESTION RELATES TO
101074.
WOULD YOU SAY THAT IT'S DOING
MOST OF THE HEAVY LIFTING, SINCE
ONCE LEVELS DROPPED, ECD
4 ITSELF WAS ENABLED TO CONTROL
VIREMIA?
AND I GUESS THE SECOND QUESTION
WOULD BE WHETHER YOU HAVE ANY
EXPLANATION WHY TRANSGENE
EXPRESSION DROPPED AND THEN CAME
BACK UP LATER?
I THOUGHT THAT WAS REALLY
INTERESTING ON THOSE TWO
DIFFERENT MACAQUES.
>> THANK YOU.
VERY GOOD QUESTION.
SO YEAH, 101074 WAS DEFINITELY
REQUIRED FOR THE MAINTENANCE OF
VIROLOGIC CONTROL.
BUT WE DON'T KNOW IF IT WAS
SUFFICIENT BECAUSE IN ALL CASES,
THE EXPERIMENTAL ANIMALS HAD
PERSISTENT EXPRESSION OF ECD
4IG.
-- IF THEY HAD 1074 ONLY
BECAUSE AGAIN WE DIDN'T HAVE ANY
EXAMPLES OF ANIMALS WITHIN
10-1074 ONLY BUT NO ECD 4G.
BUT I THINK MY IMPRESSION IS WE
WILL NEED COMBINATION OF HIV
BIOLOGICS FOR MAINTAINING
STRINGENT CONTROL AND THAT'S
WHAT WE SHOULD BE PURSUING IN
THE FUTURE.
YOUR QUESTION ABOUT WHY ADAs
WANED IN THE INFANTS AND THEN
EXPRESSION RECURRED.
I DON'T KNOW THE ANSWER TO THAT.
I'M VERY INTERESTED IN STUDYING
THAT PHENOMENON.
IT SEEMS TO BE SOMETHING UNIQUE
TO INFANTS.
WE HAVE A MAJOR RESEARCH PROGRAM
IN MY LAB TRYING TO UNDERSTAND
MECHANISMS FOR EARLY LIFE
TOLERANCE AND I THINK IT HAS TO
DO WITH THAT.
>> THANK YOU.
>> SO I HAVE A QUESTION FOR
DEBBIE ABOUT STUDY ABOUT THE --
HOW MANY -- YOU DID?
>> I'M SORRY, I COULDN'T HEAR
YOUR QUESTION.
>> SO YOU MENTIONED YOU SEE THE
CNS -- HOW MANY DONORS YOU DID
FOR THAT?
IS IT DOMINANT OR JUST VERY FEW
CASE?
>> SO I ACTUALLY DIDN'T SHOW THE
ACTUAL DATA BECAUSE THIS WORK
WAS DONE IN CATHERINE'S GROUP
AND I KNOW IT WOULD GENERATE A
LOT OF QUESTIONS.
ESSENTIALLY WHAT SHE'S FOUND,
AND SHE'S NOT HERE TO ADDRESS
THE QUESTIONS WHICH IS WHY I
DIDN'T GO INTO DETAILS.
THE REALLY -- THE MAIN AIM RIGHT
NOW IS TO ESTABLISH
METHODOLOGIES TO REPRODUCIBLY DO
THE CAPTURE ASSAY AND ALSO THE
PSEUDOVIRUS NEUTRALIZATION AND
INFECTION ASSAYS, AND SO THE
PROOF OF CONCEPT IN A CHILD WITH
NO DETECTABLE PERIPHERAL BLOOD
RESERVOIR WHO THEN REBOUNDED,
SHE IDENTIFIED -- TROPIC IN
THOSE.
BUT I REALLY CAN'T ANSWER MORE
SPECIFIC ON IT.
>> I'M EXTREMELY INTERESTED ON
THAT BECAUSE WE DID -- WE DID
THE ANIMALS -- DIFFERENCE AND
ALSO IN HUMANS A DIFFERENCE OF
THE -- CNS, SO THE DIFFERENCE OF
THE MORPHOLOGY FOR THE --
>> WHAT I CAN DO IS PUT YOU IN
TOUCH WITH CATHERINE SO IT WOULD
BE GREAT FOR YOU GUYS TO DISCUSS
THIS.
>> SURE.
THANK YOU.
>> BECAUSE WE'RE ALWAYS LOOKING
FOR PEOPLE INTERESTED IN THE
SCIENCE TO BUILD OUR PROGRAM.
>> EXCELLENT.
ONE MORE QUESTION?
>> VERY EXCITING WORK.
WHY DON'T YOU THINK N-803 DID
ANYTHING?
IS IT LATENCY, LACK OF EXPOSURE,
WERE THE EFFECTS PERSISTENT?
WHAT ARE YOUR THOUGHTS ON THAT?
>> I THINK IT'S AN IMPORTANT
QUESTION.
AND IT'S ALL SPECULATION AT THIS
POINT, BUT YOU KNOW, I CAN'T SAY
THAT IT DIDN'T DO ANYTHING
BECAUSE WE DID SEE IMPACTS ON NK
CELLS AND CD8 T-CELLS.
IN THAT GROUP, IN THAT STUDY
JUST DUE TO ANIMAL AVAILABILITY,
WE DIDN'T HAVE AN N-8 O803 ONLY
GROUP SO IT WAS GIVEN WITH THE
ANTIBODIES, AND IT IS POSSIBLE
THAT WE -- SINCE WE ONLY GAVE
ONE DOSE THAT YOU WOULD NEED
REPEATED DOSES TO REALLY GET THE
EFFECT THAT HAS BEEN DESCRIBED
IN ADULT MONKEY STUDIES IN TERMS
OF TRAFFICKING TO LYMPH NODES
AND HAVING A BETTER EFFECT ON
THE RESERVOIR.
IT'S REALLY HARD TO SAY.
>> DO YOU KNOW HOW LONG THE
EFFECTS ON CELLS LASTED AFTER
SINGLE DOSE?
>> WELL, JUST LOOKING AT KI67 BY
DAY 7, THE LEVELS KIND OF HAD
NORMALIZED.
AND WE DIDN'T HAVE SORT OF AN
EARLY TIME POINT WHERE WE LOOKED
AT THE LYMPH NODES SO I'M NOT
ABLE TO KIND OF SAY, BUT IF YOU
LOOK AT -- BEFORE WE GIVE N-8 OH
N-803 AND 8 WEEKS AFTER THERE'S
NO DIFFERENCE IN THE CELL TYPES
OR ACTIVATION BUT THAT'S QUITE A
LONG --
>> THE ATI WAS HOW LONG AFTER
THE DOSE?
>> CLOSE TO A YEAR.
>> OKAY.
SO IT COULD HAVE WANED.
>> YEAH, FOR SURE.
>> OKAY.
THANK YOU SO MUCH TO EVERYONE.
AND I BELIEVE WE COME BACK AT
10:50.
>> ONCE AGAIN, THERE'S BEVERAGES
OUTSIDE SPONSORED BY FAES, THE
FOUNDATION FOR ADVANCED
EDUCATION SCIENCES.
PLEASE CHECK OUT THEIR FLYERS
WHICH IS OUT THERE.
THANKS AGAIN.
SO WE'LL BE STICKING TO TIME, WE
HAVE A PACKED AGENDA.
PLEASE COME BACK AT 10:50. THANK YOU.
SO HELLO, WE ARE
RESTARTING.
MY NAME IS BRIGITTE SANDERS,
PROGRAM OFFICER IN THE TARGETED
INTERVENTIONS BRANCH OF THE
DIVISION OF NIAID.
TOGETHER WITH MY COLLEAGUE, LEIA
NOVACK.
NEXT WE WILL HEAR A PRESENTATION
FROM THE I4C COLLABORATORY,
IMMUNOTHERAPY FOR HIV CURE.
THE I4C COLLABORATORY IS BASED
AT BETH ISRAEL DEACONESS MEDICAL
CENTER IN BOSTON AT THE
UNIVERSITY OF PITTSBURGH AND AT
THE MILITARY HIV RESEARCH
PROGRAM.
IN ADDITION TO DR. BAROUCH, WE
WILL HEAR PRESENTATIONS FROM DRY
VASAN, MILL MITCHELL WARN FROMH
THAT I'LL HAND IT OVER TO YOU,
DAN.
>> THANK YOU VERY MUCH.
IT'S A PLEASURE TO BE HERE TODAY
WITH ALL THE OTHER NINE
COLLABORATORIES.
THE GOAL OF I4C IMMUNOTHERAPY
FOR CURE IS TO ADVANCE OUR
SCIENTIFIC UNDER AND STAG OF THE
VIER RESERVOIR AND TO DEVELOP
IMMUNOLOGIC STRATEGIES FOR HIV
REMISSION AND ERADICATION BY A
HIGHLY COLLABORATIVE AND
MULTIFACETED RESEARCH PROGRAM
INVOLVING PARTNERSHIPS AMONG
ACADEMIA, INDUSTRY, GOVERNMENT
AND COMMUNITY.
THE THREE JOINT PIs OF THIS
PROGRAM ARE SANDY, JOHN AND
MYSELF AND A LARGE LIST OF
HIGHLY OUTSTANDING INVESTIGATORS
ARE LISTED BELOW.
OUR HYPOTHESIS IS THAT MULTIPLE
IMMUNOLOGIC STRATEGIES WILL NEED
TO BE EXPLORED AND COMBINED TO
ACHIEVE LONG TERM ART-FREE
VIROLOGIC CONTROL, AND/OR
COMPLETE VIRUS ERADICATION WITH
A GOAL OF SELECTING COMBINATION
REGIMENS TO ADVANCE INTO
CLINICAL DEVELOPMENT.
OUR RESEARCH FOCI INVOLVE
MECHANISTIC BASIS OF RESERVOIR
TARGETING PERSISTENCE, NOVEL
STRATEGIES FOR SUSTAINED VIRUS
CONTROL AND NOVEL STRATEGIES FOR
VIRUS ERADICATION, AND THESE
GOALS WILL BE DESCRIBED IN THE
COMING TALKS.
OUR PRINCIPAL IMMUNOLOGIC
STRATEGY HAS BEEN THE USE OF
BROADLY NEUTRALIZING ANTIBODIES
WITH I -- AS WELL AS SOME NEW
CELL AR APPROACHES INCLUDING
CAR-T CELLS, ENGINEERED B CELLS
AND ENHANCED NK CELLS.
NOW AT THE MIDPOINT OF THE
GRANT, SOME OF THE SELECTED
HIGHLIGHTS THAT WE'LL DISCUSS
TODAY INVOLVE ADVANCES IN BASIC
RESEARCH ON RESERVOIR
CHARACTERIZATION FROM A
VIROLOGIC, IMMUNOLOGIC AND
MULTI-HE MIBG PERSPECTIVE, THE
DEVELOPMENT OF BNABS THERAPEUTIC
VACCINES, CAR-T CELLS,
ENGINEERED B CELLS AND ENHANCED
NK CELLS FOR CURE STRATEGIES,
COMBINATION OF ACTIVE AND
PASSIVE IMMUNIZATION FOR BOTH
DELAYED VIRAL REBOUND AND
VIROLOGIC CONTROL IN NON-HUMAN
PRIMATE SWRELS ENS HANSED
COMMUNITY ENGAGEMENT AND CAB
ACTIVITIES.
SANDY V VASAN WILL DISCUSS RF 1,
MECHANISTIC BASIS OF VIRAL
PERSISTENCE, LEARNING LEARNINGI
STUDIES, JOHN MELLORS WILL SPEAK
ON EXPLORING INNOVATIVE
APPROACHES TO CONTROL AND
ELIMINATE HIV RESERVOIRS, I WILL
PROVIDE AN UPDATE ON RF 3, AND
JESSICA SALZWEDEL WILL DISCUSS
COMMUNITY ENGAGEMENT IN I4C.
WE'RE ALSO PROUD WE HAVE
SCHOLARSSCHOLARSHIP RECIPIENT HD
WHO HAVE POSTERS.
I WOULD ENCOURAGE YOU TO SPEND
TIME AT THOSE POSTERS AND THE
WORK OF THESE THREE OUTSTANDING
JUNIOR INVESTIGATORS, AS WELL AS
MANY OTHERS, ARE GOING TO BE
HIGHLIGHTED IN THE COMING TALKS.
AND WITH THAT, I'LL TURN IT OVER
TO SANDY.
>> THANKS, DAN.
SO RF 1 IS THE MECHANISTIC
FOCUS, I WON'T READ THE
HYPOTHESIS HERE VERBATIM, BUT
IT'S LED BY JOHN MELLORS, ALEX
AND MYSELF, AND WE ARE HONORED
TO HAVE A PHENOMENAL TEAM.
SO TO SUMMARIZE, THE NEXT 10
MINUTES WILL FOCUS ON TWO
APPROACHES OR TWO STORIES, I
SHOULD SAY.
THE FIRST IS TO STUDY THE
RESERVOIR, THE HIV RESERVOIR IN
PEOPLE WHO ARE LIVING WITH HIV
AND ARE WELL SUPPRESSED ON ART.
AND THE BOTTOM LINE OF WHAT
WE'RE FINDING IS THAT HOW EARLY
YOU START ART AFTER INITIAL
INFECTION DOES AFFECT THE
RESERVOIR, AND WITH EARLIER --
STARTING ART EARLIER, REDUCING
THE SIZE OF THE RESERVOIR, AND
THIS RESERVOIR, EVEN FOR PEOPLE
WHO ARE ON ART, VARIES OVER TIME
IN DIFFERING PATTERNS, WHICH IS
CONSISTENT WITH THE THEME OF
WHAT WE'VE BEEN HEARING OVER THE
LAST DAY AND A HALF.
AND THE STUDIES WE'VE CONDUCTED
TO DATE HAVE FOCUSED ON THE
BLOOD BUT WE'RE VERY EXCITED
THAT WE'RE NOW TURNING THESE
ANALYSES TO THE BRAIN TO SEE
WHETHER THOSE SAME PATTERNS
HOLD.
AND THEN THE SECOND PART OF THE
STORY IS ACTUALLY TO CO TO DO WE
CALL CORRELATES WORK, AND THAT'S
REALLY TO SEE IF WE CAN LOOK AT
PREDICTORS OF THE RESERVOIR OR
OTHER MARKERS THAT MAY
CORRESPOND TO THE TIME IT TAKES
FOR THE VIRUS TO COME BACK IN
THE BLOOD OR REBOUND AFTER
STOPPING -- A PARTICIPANT STOP
ART.
AND AGAIN WE LEVERAGE BOTH
ANIMAL AND HUMAN MODELS TO LOOK
AT THIS.
SO TO JUMP INTO THE FIRST STORY,
WHICH IS A COLLABORATION LED BY
BOB AND JANET SILICANO WITH DAN
BAROUCH AND LED BY DR. EMILY
FREY, 10 RHESUS MACAQUES WHO
WERE INFECTED WITH SIV MACK
231 WERE LEFT UNTREATED FOR 48
WEEKS BEFORE STARTING ART.
AND THAT'S IMPORTANT BECAUSE
BOTH FOR SCIENTIFIC REASONS AND
FRANKLY RESOURCE REASONS, MANY
OF THESE NHP STUDIES START ART
SOON AFTER INFECTION, BUT THIS
MODEL ACTUALLY BETTER
RECAPITULATES THE VAST MAJORITY
OF PEOPLE LIVING WITH HIV.
SO AFTER THAT 48 WEEKS, THEN
THEY WERE STARTED ON ART AND
MAINTAINING AND FOLLOWED FOR
FIVE YEARS SO THAT GAVE THE
INVESTIGATORS THE ABILITY TO
LOOK AT THE RESERVOIR IN DETAIL,
BOTH THROUGH QUANTITATIVE
MEASURES LIKE DIGITAL DROPLET
PCR AND QUALITATIVELY WITH
SINGLE GENOME SEQUENCING OVER
THE EXTENDED ART.
SO THE QUICK BOTTOM LINE HERE IS
THAT THE DECAY OF THESE INTACT
PRO VIRUSES ON ART WAS
MULTIPHASIC, IN THIS MODEL
TRIPHASIC SO YOU CAN SEE ACROSS
DIFFERENT NHPs THERE'S INITIAL
RAPID DECAY FOLLOWED BY SLOWER
DECAY AND ULTIMATELY MORE OF A
PLATEAU TYPE OF DECAY.
AND WHAT THIS MEANS TO US IS
THAT THERE IS A LABEL POPULATION
THAT GOES AWAY QUICKLY, AND THEN
A POPULATION THAT IS MORE
RELATED TO THE ANCESTRAL
VARIANTS OF INITIAL INFECTIONS
THAT PERSIST.
FURTHERMORE, THAT AS YOU CAN SEE
IN THE THIRD BULLET, THE
EVIDENCE FOR PROLIFERATION OF
THESE INFECTED CELLS BECOMES
MORE APPARENT OVER TIME, AND
WHAT THAT MEANS IS THAT THERE'S
MORE LIKELY TO BE PROLIFERATION
OF MORE CLONAL POPULATIONS OR
WHAT JOHN MIGHT CALL A
REPLICLONE AS YOU GO FURTHER OUT
INTO ART.
THIS SUGGESTS THAT THE RESERVOIR
IN ART IS BEING RECEDED THROUGH
THIS PROLIFERATIVE MECHANISM.
SO MOVING TO THE SECOND PART OF
THE RESERVOIR STUDY IN HUMANS
CON JECTED --LOOKING AT THE SAF
DECAY IN HUMANS ON
ACTG5321 WHICH IS AN ACTG COHORT
OF PEOPLE LARGELY SUBTYPE B
CHRONICALLY LIVING WITH HIV, AND
I APOLOGIZE BECAUSE THERE'S TWO
MORE FIGURES TO THIS PANEL THAT
DIDN'T COME THROUGH IN THE PDF
CONVERSION SO YOU'LL HAVE TO
TAKE MY WORD FOR IT OR FIND JOHN
OR JOSH AFTERWARDS, BUT
BASICALLY THAT THERE ARE VARYING
PATTERNS OF DECAY, AND AGAIN,
IT'S NICELY COMPLEMENTARY TO THE
MONKEY WORK I JUST SHOWED,
SHOWING THAT THERE CAN BE BOTH
THE SLOPE THAT YOU SEE THERE,
BUT THEN ALSO A SUBSET OF PEOPLE
WHO HAVE LATE INCREASES.
AND YOU'LL SEE THAT IN A
SUBSEQUENT SLIDE.
SO YOU DON'T HAVE TO JUST TAKE
MY WORD FOR IT.
BUT THE KEY QUESTIONS THAT WERE
ASKED WITH THIS PART OF THE
STUDY WAS THAT THE INFECTED CELL
CLONES, USING TWO DIFFERENT
MEASURES, PAINSTAKINGLY
CHARACTERIZING SOME OF THESE
CLONES BOTH BY IPDA AND THEN
THROUGH INTEGRATION SITE
ANALYSES, INCLUDING CUSTOMIZED
PRIMERS FOR THOSE CLONES THAT
WERE -- WHERE THE INTEGRATION
SITES WERE MAPPED CHARACTERIZE
THE PATTERN OF VARIABILITY OF
THESE CLONES OVER TIME.
AND THOSE WHO HAD PERSISTENT
CLONES.
AND SO FOCUSING HERE WITH JUST
ONE EXAMPLE OF TWO INDIVIDUALS
WHO WERE IN THAT LATE INCREASE
IN COHORT, WHICH WE ALSO HEARD
ABOUT A LITTLE BIT YESTERDAY,
THOSE INDIVIDUALS WERE BOTH
ANALYZED BY SINGLE COPY ANALYSIS
AND INTEGRATION SITE ANALYSIS,
AND THERE ARE MANY MORE
INDIVIDUALS WHO ARE BEING
CHARACTERIZED THIS WAY, BUT JUST
TO GIVE YOU A SNAPSHOT OF THIS
WORK IN PROGRESS, YOU CAN SEE
THAT THE FIRST PARTICIPANT,
THERE ARE TWO CLONES, BUT
THERE'S NOTHING THAT'S REALLY
PULLING OUT THAT'S DOMINANT,
WHEREAS THE SECOND PARTICIPANT,
THERE ARE MULTIPLE PROBABLE
CLONES AND IMPORTANTLY THE
INTEGRATION SITE ANALYSIS IS
PICKING UP CLONES THAT MIGHT NOT
HAVE BEEN PICKED UP BY IPDA.
AND IT JUST EMPHASIZES THE FACT
THAT WE NEED TO TAKE MULTIPLE
APPROACHES TO CHARACTERIZING THE
RESERVOIR RATHER THAN RELYING ON
ONE WINNER ASSAY.
SO THAT WORK WILL BE ONGOING,
AND YOU'LL HEAR MORE ABOUT IT AT
OUR NEXT UPDATE.
THIS THEN RELATES BACK TO THE
COHORTS THAT WE AT MHRP ARE ALSO
WORKING WITH.
I SERVE AS PROTOCOL CHAIR FOR
RV254, WHICH IS AN INCREDIBLE
COHORT OF PEOPLE IN THAILAND WHO
HAVE BEEN DIAGNOSED AND STARTED
ON ART VERY, VERY EARLY DURING
ACUTE OR EARLY HIV
IDENTIFICATION, AND THE
STATISTICS SPEAK FOR THEMSELVES
BUT THIS IS A LARGE COHORT OF
PEOPLE WHO HAVE -- WITH OVER 90%
RETENTION NOW GETTING INTO ITS
15TH YEAR WHO ARE JUST KIND
ENOUGH TO AGREE TO MULTIPLE
PROCEDURES, AND WE ARE NOW,
BASED ON THE DATA THAT YOU'VE
BEEN HEARING, EXTENDING THE
FOLLOW-UP IN THIS COHORT FROM 15
TO 20 YEARS SO THAT WE CAN
CONTINUE TO ASK SOME OF THESE
QUESTIONS.
IN THAT COHORT, AGAIN
AS COLLABORATIVE AND RECIPROCAL
VALIDATION.
NOW SWITCHING FROM THE RESERVOIR
STUDIES TO SOME OF THE ATI
CORRELATE STUDIES, THIS HAS ALSO
SERVED AS A BASIS FOR FOUR
SEPARATE ATI CLINICAL TRIALS TO
DATE WITH VARYING INTERVENTIONS
OR NO INTERVENTION IN THE CASE
OF THE FIRST STUDY.
ALL OF THESE STUDIES HAVE BEEN
PUBLISHED AND PRESENTED SO I'M
NOT GOING TO GO THROUGH THEM
HERE IN DETAIL, BUT RATHER USE
THIS SLIDE AS A BASIS TO TALK
ABOUT WHAT WE'RE DOING TO LOOK
IN AGGREGATE AT THE MAJORITY OF
THESE PARTICIPANTS IN ANALYZING
CORRELATES TO VIRAL REBOUND.
AND SO WHAT WAS JUST PUBLISHED
THIS YEAR IN THE LABORATORY AT
MHRP IS THAT IF YOU LOOKED AT
EARLY CLINICAL PREDICTORS YEARS
BEFORE THESE PEOPLE WENT ON ATI
BUT BEFORE THEY STARTED ART,
THAT PEOPLE WHO HAD HIGHER
INITIAL VIREMIA AND WHO TOOK
LONGER TO SUPPRESS POST ART WERE
MORE LIKELY TO REBOUND EARLIER,
WHICH WE BELIEVE IS A SURROGATE
TO THAT LARGER INITIAL SEEDING
OF THE RESERVOIR.
AND SO I SHOW THE PICTURES OF
THE INVESTIGATORS HERE BECAUSE
NOT ONLY TO ACKNOWLEDGE THEIR
WORK BUT ALSO BECAUSE THEY ARE
ALL HERE AND SO FOR THOSE OF YOU
ESPECIALLY THOSE IN THE
COMMUNITY WHO WANT TO LEARN
MORE, PLEASE I ENCOURAGE YOU TO
FIND THEM IN THE HALLWAYS IN THE
BREAKS BECAUSE THEY'LL BE
EXCITED TO TALK MORE ABOUT THEIR
WORK.
BUT BUILDING ON THIS, THEN,
WE'RE MOVING TO LOOK AT THE
POTENTIAL IMMUNOLOGIC, VIROLOGIC
AND OTHER LABORATORY CORRELATES
OF TIME TO VIRAL REBOUND.
AND SO IN COLLABORATION WITH
JOHN AND JOSH, WE UTILIZED THE
SINGLE COPY ASSAY TO LOOK AT
PRESENCE OF VIRUS ON PEOPLE BY
STANDARD CLINICAL MEASUREMENTS
WELL SUPPRESSED ON ART AND
FINDING, IF YOU FOLLOW THOSE RED
BARS ON THE LEFT PANEL, YOU CAN
SEE THAT PEOPLE WHO STARTED ART
IF LATER FIEBIG STAGES WERE MORE
LIKELY TO HAVE PROTECTIVE
VIREMIA ON A SINGLE COPY ASSAY
WHILE BEING SUPPRESSED ON ART BY
STANDARD MEASURES.
AND FURTHERMORE, THAT THAT
SINGLE COPY ASSAY PREATI
CORRELATES TO TIME TO VIRAL
REBOUND AS YOU CAN SEE ON THE
LEFT PANEL.
SO AS I MENTIONED IN THE
SUMMARY, WE'RE NOW LEVERAGING
THE NIMH-FUNDED COLLECTION OF
CSF AND CELLS IN SUPERNATEN WITH
SERENA AND LYDIE TO HOW THIS
MIGHT TRANSLATE TO THE
NEUROLOGIC COMPARTMENT.
AND THEN THE FINAL SLIDE I HAVE
IS TO BRING IT BACK, AGAIN, THIS
CORRELATES WORK IS AGAIN
COMPLEMENTARY TO THE WORK BEING
DONE BY MALIKA AID BOUDRIES,
PERIPHERAL BIOMARKERS OF VIRAL
REBOUND IN RHESUS MACAQUES, A
STUDY OF VARIOUS INTERVENTIONS
IN MACAQUES WHO BOTH HAD
CONTROLLERS AND REBOUNDERS, AND
JUST IN A BINARY WAY LOOKING AT
THOSE TWO SUBSETS AND
IDENTIFYING GENETIC SIGNATURES
THAT ARE PREDICTIVE OF REBOUND,
IN ADDITION TO CELLULAR MARKERS
POST STOPPING ART THAT THEN
PREDICTED REBOUND.
SO ALL OF THESE MEASURES ARE
TRYING TO HELP US UNDERSTAND THE
RESERVOIR, AND THE PATHOGENESIS
THAT CAN HELP US THEN DEVELOP
BETTER INTERVENTIONS TO ATTACK
CURE, WHICH TURNS US OVER TO RF
2.
[APPLAUSE]
>> IT'S REALLY A PRIVILEGE TO BE
ABLE TO PRESENT SOME INNOVATIVE
WORK LISTED HERE.
THE OBJECTIVES HERE ARE TO
ASSESS NEW TECHNOLOGIES,
RECOGNIZING THAT THEY HAVE RISK
BECAUSE THEY'RE UNPROVEN, BUT
HAVE THE PROMISE OF CONTROLLING
OR HELPING TO ERADICATE HIV.
THE SUMMARY IS SIMPLE.
A MULTIPRONGED APPROACH IS
LIKELY NEEDED TO CONTROL OR
ELIMINATE HIV.
THE QUESTION IS, CAN WE ENGINEER
T-CELLS, B CELLS, OR ENHANCE NK
CELLS TO CONTROL OR ELIMINATE
HIV?
SOME APPROACHES ARE PROMISING,
BUT REFINEMENT AND FURTHER PROOF
OF CON ACCEP CONCEPT IS NEEDED.
WE'RE AT A CRITICAL JUNCTURE
WITH THIS WORK WHERE WE'RE DOING
PROOF OF CONCEPT STUDIES IN NHP
MODELS.
SO FIRST JIM RILEY HAS LED A
GROUP TO ENGINEER T-CELLS BY
INTRODUCING VECTOR THROUGH
TRANSDUCTION WITH CD4 BEING THE
TARGETING MOLECULE, AND JIM
FOUND IN PRELIMINARY STUDIES
THAT TWO SIGNALING DOMAINS
NECESSARY FOR 1BB AND CD28, AND
ANIMALS UNINFECTED WERE INJECTED
WITH 200 MILLION ENGINEERED
CELLS.
THE RESULT WAS SOMEWHAT
DISAPPOINTING.
THERE WAS A VACCINE GIVEN TO TRY
TO BOOST PROLIFERATION EXPANSION
OF HIV-SPECIFIC CA CAR-T CELLS.
THE T-CELLS WERE IB FUSED AND ID
NOT PERSIST VERY LONG, AFTER
INFUSION AND WITH VACCINATION
DID NOT SEE AN INCREASE.
THE VACCINE WAS BIOACTIVE,
MEANING THAT IT INDUCED ANTIBODY
RESPONSES.
AND THE REASON FOR THIS IS
PRETTY CLEAR, THAT THE MACAQUE
GENERATED ANTIBODIES TO THE
HUMAN CD4 MOLECULE, AND AS YOU
CAN SEE HERE, THAT DEVELOPED IN
ASSOCIATION WITH CLEARANCE OF
THE ENGINEERED CAR-T CELLS
EXPRESSING HUMAN CD4.
SO THE NEXT STEP IS TO CLEARLY
SWITCH TO A RHESUS-BASED
CD4 CAR-T-CELL.
NEXT IS SOME REALLY INO INNOVATE
WORK DONE BY WEI LEI AND PAULA
CANNON TO EXPRESS BROADLY
NEUTRALIZING HEAVY CHAIN
ANTIBODIES.
HERE ARE THE ANTIBODIES THAT
WERE CREATED BY WEI LI TO MEET
THE CRITERIA OF HEAVY CHAIN
ANTIBODY OR SINGLE CHAIN FV IN
THE CASE OF PGT121, AND THEN
HUMANIZE J3 VHH AND CD4-MD1.22,
WHICH IS SINGLE DOMAIN CD4.
THEY RETAINED THEIR NEUTRALIZING
POTENCY, AND PAULA, THROUGH VERY
CLEVER DESIGN, INTRODUCED THE
DOMAIN INTO THE IGG 1 LOCUS, AND
BASICALLY SHOWS THAT YOU CAN GET
EFFICIENT TRANSDUCTION AND
EXPRESSION OF ANTIBO DEA THAT IS
NEUTRALIZING FROM HUMAN B CELLS
AND HAS NOW DONE THAT IN RHESUS
B CELLS, SO WE'RE RAPIDLY
APPROACHING THE TEST OF
TRANSDUCING CELLS EX VIVO,
RHESUS B CELLS, AND INFUSING
THEM INTO MACAQUES, BOOSTING
WITH TWO FORMS OF VACCINE TO SEE
IF WE CAN EXPAND B CELLS TO
PRODUCE THESE NEUTRALIZING HEAVY
CHAIN DOMAIN ANTIBODIES.
AND THAT STUDY IS JUST STARTING.
AND LASTLY, MARYANN CHECKLEY AND
JOHN CARNE ARE PIONEERING
EXPANDED NK CELLS USING A CELL
LINE THAT EXPRESSES
MEMBRANE-BOUND IL21.
MARY ANN IS HERE, SHE HAS A
POSTER, ALL THE OTHER
INVESTIGATORS I MENTIONED ARE
HERE.
I DON'T NEED TO TELL YOU THAT NK
CELLS COULD HAVE A ROLE IN
KILLING, RECOGNIZING KILLING
WITHOUT A ANTIBODY HIV INFECTED
CELLS BY EXPRESSION OF STRESS
LIGANDS ON THE INFECTED CELLS,
AND ALSO THE POTENTIAL FOR MORE
EFFICIENT KILLING WITH THE USE
OF A DIRECTED MONOCLONAL.
AND MARY ANN HAS REALLY DONE A
BEAUTIFUL JOB EXPANDING MK CELLS
WITH THIS CO-CULTURE, AND THE
FOLD INCREASE IS REALLY
REMARKABLE.
25,000 FOLD INCREASE IN CELLS,
AND YOU CAN SEE BY THE PIE CHART
ON THE FAR RIGHT, THE MAJORITY
ARE CD56 17 POSITIVE.
AND THESE CELLS IN THE
LABORATORY REDUCE VIRUS RELEASE
FROM INFECTED CELLS, AND REDUCE
INFECTED CELL NUMBER CARRYING
INTACT PRO VIRUSES.
AND REDUCE MRNA IN THOSE CELLS.
SO THEY'RE ACTIVE EX VIVO, THE
QUESTION IS, DO THEY HAVE ANY
EFFECT IN VIVO, AND WE HAVE AN
EXPERIMENT THAT HAS STARTED WITH
EXPANSION OF THESE CELLS, AND
THEY'LL BE INFUSED INTO ACUTELY
INFECTED MACAQUES VERSUS CONTROL
WITHOUT EXPANDED NKs AND WE'LL
SEE IF THEY HAVE EFFECT ON
INITIAL CONTROL OF VIREMIA.
WITH THAT, I'M GOING TO PASS IT
OVER TO DR. BAROUCH FOR RF 3.
[APPLAUSE]
>> OH IN RF 3, THEN, THE
NONTECHNICAL SUMMARY, THE
QUESTION WE'RE TRYING TO ADDRESS
IS, CAN WE COMBINE IMMUNE-BASED
STRATEGIES FOR HIV CURE, AND IS
IT POSSIBLE TO SHOW THAT A
COMBINED APPROACH MIGHT BE
BETTER THAN INDIVIDUAL
STRATEGIES ALONE.
IT'S BOTH A CONCEPTUAL QUESTION
AS WELL AS A PRACTICAL QUESTION
FOR SPECIFIC INTERVENTIONS.
SO WHY IS THIS WORK IMPORTANT
FOR CURE OR CONTROL?
WE THINK IT'S IMPORTANT BECAUSE
IF TWO OR MORE PARTIALLY
EFFECTIVE CURE STRATEGIES CAN BE
COMBINED, WE MIGHT BE ABLE TO
HAVE A GREATER CHANCE OF
DEVELOPMENT OF CLINICALLY
MEANINGFUL HIV CURE, SO WHY
SHOULD COMMUNITY BE EXCITED
ABOUT THE RESULTS AND PROGRESS
PRESENTED?
SO WE'LL SHOW DATA THAT IN
MACAQUES, THE COMBINATION OF
THERAPEUTIC VACCINES AND BROADLY
NEUTRALIZING ANTIBODIES RESULTS
IN MORE ANIMALS ACHIEVING
DURABLE VIROLOGIC CONTROL THAN
EITHER APPROACH ALONE FOLLOWING
ART DISCONTINUATION.
WE'RE ALSO PERFORMING PILOT
STUDIES WITH INNOVATIVE
CELL-BASED CONCEPTS THAT COULD
BE COMBINED WITH ONE OR OTHER OF
THESE IMMUNOLOGIC INTERVENTIONS
SHOULD THEY WORK.
SO IN FOCUS THREE, IN TERMS OF
THINKING ABOUT VIRUS
ERADICATION, OF COURSE IT'S A
VERY HIGH BAR, BUT OUR CONCEPT
IS TO ADOPT THE CLINICAL
STRATEGY FOR LEUKEMIA.
IN OTHER WORDS, INDUCTION
THERAPY FOLLOWED BY
CONSOLIDATION THERAPY, WITH THE
MODEST GOAL OR MODEST
RECOGNITION THAT IT IS
EXCEEDINGLY UNLIKELY THAT ANY
APPROACH THAT WE KNOW OF SHORT
OF BONE MARROW TRANSPLANTATION
WOULD TRULY ERADICATE THE ENTIRE
VIRAL RESERVOIR.
BUT WE THINK THAT THERE MIGHT BE
A WAY OF INDUCTION THERAPY FOR
THE RAPID ELIMINATION FOR AT
LEAST THE MAJORITY OF THE VIRAL
RES VOR WITH STRATEGIES SUCH AS
COMBINATION OF B NABS WITH
IMMUNE ACTIVATORS, COMBINATION
OF ENHANCED NK CELLS WITH OR
WITHOUT B NABS AND CAR-T CELLS
THAT WOULD TARGET MOLECULES LIKE
CCR5.
BUT THAT WOULD CERTAINLY NEED
SOME FORM OF ADDITIONAL
CONSOLIDATION THERAPY WHICH
ESSENTIALLY WOULD BE
IMMUNOSURVEILLANCE TO ELIMINATE
THE RESIDUAL VIRAL RESERVOIR,
SUCH AS THE USE OF THERAPEUTIC
VACCINE, ENGINEERED B CELLS OR
CAR-T CELLS TARGETING ENVELOPE
AND WE THINK PERHAPS A
COMBINATION OF THESE APPROACHES
MIGHT BE ABLE TO ACHIEVE VIRUS
ERADICATION OR AT LEAST MAKE
PROGRESS TOWARDS THAT LOFTY
GOAL.
SO WE STARTED INVESTIGATING
THERAPEUTIC VACCINES A NUMBER OF
YEARS AGO.
THIS WAS ACTUALLY IN THE CONTEXT
OF I4C 1.0, AND IN 2016, WE
PUBLISHED A STUDY IN WHICH WE
DEMONSTRATED THAT THE
THERAPEUTIC VACCINE WITH VECTORS
AT 26MVA TOGETHER WITH A
TLR7 AGONIST IN COLLABORATION
WITH GILEAD WAS ABLE TO LEAD TO
PARTIAL VIROLOGIC CONTROL
FOLLOWING ART DISCONTINUATION.
HERE YOU SATISFY ON THE LEFT
SEE ON THE LEFT ASUBSTANTIAL --E
MAGNITUDE AND THAT RESULTED IN
SUBSTANTIAL REDUCTION OF VIRAL
LOADS IN THE COMBINATION VAC
SEES PLUS VESATOLIMOD GROUP.
NOT SHOWN HERE WE ALSO
DEMONSTRATED A SUBSET OF THE
ANIMALS, IT WAS 3 OUT OF 12,
ACTUALLY HAD POST REBOND
VIROLOGIC CONTROLS TO
UNDETECTABLE LEVELS.
THE VACCINE APPEARED TO HAVE THE
PHENOTYPE OF POST REBOUND
VIROLOGIC CONTROL.
THIS WAS THEN TRANSLATED INTO
HUMANS WITH THE SAME VACCINE IN
HUMANS LED BY THE MHRP GROUP IN
THAILAND AND THE VACCINE
SIMILARLY WAS HIGHLY IMMUNOGENIC
IN EARLY ART -- OR EARLY
ART-TREATED HUMANS IN THAILAND
SHOWN AT THE BOTTOM.
THEN FOLLOWING A TREATMENT
INTERRUPTION, THEN THE VACCINE
LED TO A MODEST DELAY IN VIRAL
REBOUND THAT WAS A TREND IN THE
TOTAL COHORT AND WAS SIGNIFICANT
IF ONE CONTROLLER IN THE
PLACEBO -- ONE HLA FAVORABLE
ALLELE INDIVIDUAL IS POST HOC
EXCLUDED SO AT LEAST A TREND IN
THE RIGHT DIRECTION.
WE PUBLISHED A STUDY O ANTIBODIS
IN THE MACAQUE MODEL.
PG121 AGAIN WITH THE TLR AGONIST
RESULTED IN SUBSTANTIAL DELAY OF
VIRAL REBOUND FOLLOWING ART
DISCONTINUATION.
YOU SEE THE CURVE ON THE LEFT
DEMONSTRATING THAT
PD2121 PARTICULARLY WHEN GIVEN
WITH THE IMMUNE STIMULATOR
RESULTED IN A DELAY OF VIRAL
REBOUND, AND IN FACT, PREVENTION
OF REBOUND IN THE SUBSET OF THE
ANIMALS.
THESE BNABS HAVE ALSO BEEN
TRANSLATED TO THE CLINIC.
OUR GROUP HAVE MOVED THE
PGT121 TO FIRST IN HUMAN STUDIES
AS WELL AS OTHER ANTIBODIES, AND
WE SHOWED IN VIREMIC PERSONS
LIVING WITH HIV WITH SENSITIVE
VIRUS THAT WE SAW ABOUT A TWO TO
2 1/2 LOG DROP IN VIRAL LOADS
WITH A SINGLE INFUSION OF THIS
MONOCLONAL ANTIBODY.
NOT SURPRISINGLY, THIS WAS NOT
SEEN IN INDIVIDUALS WITH
RESISTANT VIRUS, AND WE MADE THE
CURIOUS OBSERVATION THAT PEOPLE
THAT NATURALLY HAD A VERY LOW
LEVEL OF VIRUS IN THE RIGHT
PANEL ACTUALLY HAD IN SOME CASES
LONG-TERM VIROLOGIC CONTROL
AFTER BNAB INFUSION THAT VASTLY
EXCEEDED THE HALF-LIFE OF THE
ANTIBODY.
NOW, I SHOULD CLARIFY THAT WE DO
NOT BELIEVE THIS IS A VACCINAL
EFFECT BECAUSE THE T-CELL
RESPONSES, MAGNITUDE, BREADTH,
FUNCTION, ANY WAY WE LOOK AT IT,
WERE UNCHANGED BY THE BNAB
ADMINISTRATION.
SO THERE IS IN SOME CASES LONG
TERM VIROLOGIC CONTROL AS A
RESULT OF BNAB ADMINISTRATION,
HOWEVER, IN OUR HANDS AND
MONKEYS AND HUMANS, IT IS NOT
DUE TO A VACCINAL EFFECT.
A STUDY THAT HAS RECENTLY BEEN
PUBLISHED THAT VICTORIA WALKER
SPERLING HAS A POSTER ON IT I
WOULD ENCOURAGE YOU TO SEE THAT
FOR MORE DETAILS IS TO LOOK AT
COMBINATION THERAPY WITH
ADD26/MVA VACCINATION IN
PGT121 IN SHIV INFECTED RHESUS
MACAQUES.
IT REALLY IS A CONCEPT OF
COMBINATION THERAPY AND IS IT
POSSIBLE TO SEE AN ADDITIVE,
SYNERGISTIC, OR ANTAGONISTIC
COMBINATION.
SO IN THIS STUDY, 51 RHESUS
MACAQUES WERE CHALLENGED
INTRARECTALLY AND TREATED
STARTING ON DAY 9, SO EARLY WITH
PREFORMULATED ART COMBINATION IN
COLLABORATION WITH GILEAD, AT
THE NOV --GROUP ONE INVOLVED THY
WITH VESATOLIMOD.
GROUP TWO WAS ONLY THE VACCINE,
GROUP THREE WAS ONLY THE
ANTIBODY AND GROUP FOUR WAS A
SHAM GROUP.
WE DO BELIEVE A GROUP OF AT
LEAST 12 MACAQUES ARE NEEDED FOR
ADD QA POWER.
YOU CAN SEE THE SCHEME OF THE
STUDY, BASICALLY IT'S FOUR SHOTS
OF VACCINATION AND/OR FIVE
INFUSIONS OF THE ANTIBODY WITH
VESATOLIMOD INTERSPERSED EVERY
TWO WEEKS IN THE LATTER PART OF
THE INTERVENTION SIGH KE. SO
CLEARLY NOT A CLINICALLY
FRIENDLY REGIMEN.
WE WOULD LOVE TO HAVE A ONE-SHOT
CURE BUT THIS WAS A PROOF OF
CONCEPT STUDY.
AFTER SHIV INFECTION, ALL THE
ANIMALS BECAME HIGH L HIGHLY VIE
REMEMO, NO EVIDENCE OF BLIPPING
FOR THE ENTIRE ART SUPPRESSION
AND INTERVENTION PERIOD.
WE ALSO SHOW VESATOLIMOD LED TO
A SIGNIFICANT ACTIVATION OF
CD4 POSITIVE T-CELLS AFTER EACH
ADMINISTRATION.
FOR THE MON CLONL ANTIBODY WE
SHOWED VERY GOOD PK IN THE
ANIMALS AFTER EACH OF THE FIVE
INFUSIONS WITH THE EXPECTED
JAGGED SAWTOOTH PATTERN AND
THAT'S NOT SHOWN HERE.
FOR THE GROUPS THAT DID RECEIVE
THE VACCINE, WE OBSERVED A
MASSIVE INCREASE IN THE
MAGNITUDE AND BREADTH OF C8 AND
CD4 T-CELL RESPONSES WITH
PARALLEL ICS DATA IN THE MANUAL
SCRIPT ESSENTIALLY SHOWING A
MASSIVE INCREASE IN CELLULAR
RESPONSES FOLLOWING BOTH THE AD
PRIMING AS WELL AS BOOSTING
COMPONENT.
THIS IS SHOWN IN THE MAGNITUDE
OF RESPONSES AS WELL AS A MAJOR
INCREASE IN THE NUMBER OF
RESPONDING SUBPOOLS WHICH IS OUR
SURROGATE MEASURE FOR BREADTH.
FOLLOWING -- SO WE FOLLOWED THE
ANIMALS FOR FOUR OR FIVE MONTHS
TO LET THE MONOCLONAL ANTIBODY
LEVELS DROP BELOW TO
UNDETECTABLE LEVEL SO IS WE
DON'T BELIEVE THERE WAS ANY
RESIDUAL ANTIBODY AT THE TIME OF
TREATMENT INTERRUPTION.
AFTER ART DISCONTINUATION THEN
WE LOOKED AT VIRAL REBOUND.
ALL THE ANIMALS IN THE SHAM
CONTROL GROUP REBOUNDED AND HAD
SET POINT VIREMIA.
OF IN THE ANIMALS THAT RECEIVED
THE VACCINE, IN THE BOTTOM LEFT,
ALL THE ANIMALS REBOUNDED IN A
VERY SIMILAR TIME COURSE, BUT
ABOUT A THIRD OF THEM APPEAR TO
HAVE POST REBOUND VIROLOGIC
CONTROL VERY SA SIMILAR TO OUR 6
PAPER AND, OVERALL AS A GROUP,
HAD LOWER SET POINT VIRAL LOADS.
IN THE ANIMALS THAT RECEIVED THE
ANTIBODY SHOWN IN THE UPPER
RIGHT, THEN THERE IS A DELAY IN
VIRAL REBOUND AND THERE WAS
SEVERAL ANIMALS THAT APPEARED
NOT TO REBOUND AT ALL.
AND IN THE COMBINATION GROUP
THAT RECEIVED BOTH THE ACTIVE
AND PASSIVE IMMUNIZATION IN THE
BOTTOM RIGHT, THEN WE OBSERVED
WHAT WE INTERPRETED AS AN
ADDITIVE EFFECT.
A LARGER NUMBER OF ANIMALS
REMAINED AVIE REMEMO AT THE END
OF THE STUDY PERIOD.
THIS WAS REALLY A MIXTURE OF
SOME ANIMALS THAT REBOUNDED AND
EXHIBITED POST ART VIROLOGIC
CONTROL, AND OTHER ANIMALS THAT
EXHIBITED A DELAYED REBOUND OR
NO REBOUND AT ALL.
SO IT REALLY APPEARS THAT NOW
WITH MULTIPLE LARGE SCALE
NON-HUMAN PRIMATE STUDIES, THE
VACCINE EFFECT IS REALLY NOT AN
EFFECT IN DELAYING OR PREVENTING
REBOUND, BUT IT REALLY APPEARS
TO RESULT IN POST REBOUND
VIROLOGIC CONTROL WHEREAS THE
BROADLY NEUTRALIZING ANTIBODY
APPEARS TO BE ABLE TO DELAY
REBOUND AND IN OCCASIONAL CASES,
PREVENT REBOUND IN CERTAIN
SETTINGS.
AND THE COMBINATION OF ACTIVE
AND PASSIVE IMMUNIZATION
RESULTED IN A MIXTURE OF THESE
PHENOTYPES AND THE TOTAL RESULT
IS THAT SEVEN OUT OF 10 ANIMALS
WERE AVIREMIC BY THE END OF THE
STUDY COMPARED WITH 5 OUT OF 12
AND 4 OUT OF 12 AND ZERO OUT OF
15 IN THE SHAM CONTROL GROUP.
SO THE OVERALL VIRUS IS SHOWN IN
THE LEFT, SHOWING THAT THE AT LT
ON A POINT ESTIMATE THE
COMBINATION GROUP HAD LOWER
MEDIAN VIRAL LOADS COMPARED WITH
THE INDIVIDUAL INTERVENTIONS AND
SUBSTANTIALLY LOWER THAN THE
SHAM CONTROL GROUP.
IF WE LOOK AT THE KAPLAN-MEIER
CURVES ON THE RIGHT FOR REBOUND,
THEN THE TWO GROUPS THAT RECEIVE
THE BROADLY NEUTRALIZING
ANTIBODY WERE CLEARLY THE TWO
GROUPS THAT SHOWED AN EFFECT ON
THE FRACTION OF ANIMALS THAT
REBOUNDED AND THE TIME FOR
REBOUND.
HOWEVER, IN TERMS OF VIROLOGIC
CONTROL, THERE WAS A CLEAR
CORRELATION WITH THE GROUPS THAT
RECEIVED THE VACCINE, AND THE
CELL MAGNITUDE AND BREADTH WAS A
IINVERSE LIQUOR LATED WITH VIRAL
LOADS AFTER ART DISCONTINUATION.
WE ARE EVALUATING WHETHER ART
PLUS BROADLY NEUTRALIZING
ANTIBODY THERAPY CAN BE USED IN
EARLY -- FOR EARLY TREATMENT OF
SHIV INFECTED RHESUS MACAQUES
AND GIVEN THE PREVIOUS RESULTS
WITH VESATOLIMOD SHOWING DELAY
OF -- WE WERE ASKING THE
QUESTION CAN COMBINATION THERAPY
AT THE TIME OF ART INITIATION
REDUCE RESERVOIR SEEDING, SO 36
MACAQUES WERE INFECTED
INTRARECTALLY WITH SHIV SF16
SF162P3 AND AT EARLY SET POINT
WITH EITHER ART ALONE, ART PLUS
PGT121, OR ART PLUS PGT121 PLUS
VESATOLIMOD AND THE STUDY IS
STILL IN PROGRESS.
FUTURE PLANS FOR THE I4C
2.0 OVERALL IS TO IMPROPER OUR
BASIC UNDERSTANDING OF THE VIRAL
RESERVOIR AND CORRELATES OF
REBOUND IN PRIMATES AND HUMANS,
TOO EVALUATE THERAPEUTICS AND
VACCINES -- AND WE'RE ALSO DOING
AS YOU HEARD A SERIES OF PILOT
STUDIES ON CELL-BASED APPROACHES
INCLUDING CAR-T CELLS ENGINEERED
B CELLS AND ENHANCED NK CELLS
AND BASED ON THE RESULTS OF ALL
OF THESE ONGOING STUDIES WE PLAN
TO DESIGN IN THE SECOND HALF OF
THE GRANT NEXT GENERATION
COMBINED IMMUNOTHERAPY STUDIES.
AND WITH THAT, I'LL TURN IT OVER
TO JESSICA FOR COMMUNITY
ENGAGEMENT.
[APPLAUSE]
>> HELLO AGAIN.
SO I'M GOING TO TALK ABOUT OUR
PROGRAM IN I4C.
SO WE DO HAVE THREE MAIN GOALS
HERE, AGAIN IT'S TO REALLY BUILD
THAT NETWORK OF CIVIL SOCIETY
AND COMMUNITY THAT CAN SPEAK IN
MEANINGFULLY ENGAGE IN THIS
WORK.
WE REALLY WANT TO HAVE DIRECT
FEEDBACK INTO THE PROGRAM AND AS
DAN WAS JUST MENTIONING, WE'VE
BEEN REALLY GEARING UP FOR THAT
AND I'LL HIGHLIGHT THAT IN THE
NEXT FEW SLIDES.
AND THEN WE WERE REALLY FOCUSING
AGAIN ON THE DIVERSITY OF OUR
ADVISORY BOARD.
AND WHAT'S UNIQUE IS I4C IS
INITY SECOND ITERATION SO WE
WERE ABLE TO ACTUALLY MAINTAIN
OUR COMMUNITY ADVISORY BOARD BUT
SINCE THEN WE'VE ALSO BEEN ABLE
TO GROW IT.
SO WE DO HAVE TWO NEW MEMBERS,
ONE OF WHICH IS IN THE ROOM, KIM
WILSON, AND THEN OUR OTHER
LONG-TERM MEMBER MARC WAGNER ARE
HERE REPRESENTING US.
ONE OF THE THINGS I WANT TO
HIGHLIGHT IS, SOMETHING THAT WE
REALLY VALUE AS FAR AS A METRIC
OF SUCCESS IS NOT JUST WHEN WE
ELEVATE AND CHAMPION OUR
PARTNERS, BUT WHEN THE FIELD
ELEVATES AND CHAMPIONS OUR
PARTNERS.
SO WE'RE REALLY EXCITED TO SEE
MARC WAGNER ON THE PANEL
YESTERDAY SPEAKING IN HIS OWN
EXPERTISE ON THE PRECISION
MEDICINE AND NEW GRANTS THAT ARE
COMING OUT.
SO THAT RECOGNITION BY THE FIELD
OF OUR PARTNERS AND THEIR
SUCCESS IS SOMETHING THAT WE
REALLY VALUE AS A METRIC THAT
WE'RE TRACKING OVER TIME.
WE HAVE BEEN ABLE TO BUILD THE
NUMBER OF LOCAL PARTNERSHIPS.
ONE IN PARTICULAR I WANTED TO
HIGHLIGHT WAS FENWAY HEALTH.
SO WE'VE REALLY BEEN WORKING
VERY STRATEGICALLY BUILDING THAT
BASE IN BOSTON, NOT JUST TO
THINK ABOUT HOW DO WE CONNECT
CURE IN THE LOCAL COMMUNITY, BUT
HOW DO WE BRIDGE IT IN THE
CONTEXT OF BOTH PREVENTION AND
TREATMENT, AND SO FENWAY HAS
BECOME A MAJOR PARTNER FOR US IN
THINKING ABOUT OUR EVENTS BUT
ALSO MOVING FORWARD HOW DO WE
BEGIN TO TRANSLATE THE MESSAGES
AND THE INFORMATION OF I4C OUT
INTO THE LARGER COMMUNITY.
AND THEN WE'VE ALSO -- WE DO
HAVE -- TANIA HENDERSON, OUR
CURE BOARD MEMBER WITH I4C IS
HERE AND SHE ACTUALLY DID SOME
LOCAL WORK IN BUILDING THIS OUT
IN A ANACOSTIA.
WE WERE ABLE TO HOLD A LOCAL
EVENT IN THE SOUTHEAST OF D.C. ,
IT'S REALLY AN UNDERSERVED
COMMUNITY, NOT JUST IN ITS
RESOURCES BUT -- JUST BUILT
THEIR FIRST CLINIC THERE IN
DECEMBER IT OPENED BUT THINKING
ABOUT ACKNOWLEDGMENT WHEN IT
COMES TO THIS INFORMATION.
SO WE'VE ALSO BEEN ABLE TO BUILD
LITERACY.
THERE'S A NUMBER OF REALLY
EXCITING TOOLS, JUST TO
HIGHLIGHT TWO IN PARTICULAR,
VICTORIA SPERLING WALKER IN
MARCH GAVE A FANTASTIC
PRESENTATION ON HOW TO
UNDERSTAND A SCIENTIFIC
PRESENTATION.
WHICH REALLY HAS OPENED UP A NEW
GATEWAY OF HOW DO WE THINK ABOUT
INNOVATIVE WAYS TO ENGAGE LAY
AUDIENCES IN THE SCIENCE.
AND AS SOMEBODY WHO IS NOT A
PH.D. OR AN M.D. MYSELF WHO
DOESN'T UNDERSTAND ALL THE
THINGS OF A HEAT MAP OR A
GENETIC DIVERSITY TREE, HAVING
SOMEBODY WALK THROUGH WHAT ARE
THE KEY AREAS ON THAT SLIDE THAT
I NEED TO UNDERSTAND IN ORDER TO
MEANINGFULLY ENGAGE IN THE
CONVERSATION HAS BEEN CRITICAL,
AND VICTORIA REALLY CREATED A
ROAD MAP THAT HAS BEEN ABLE TO
HELP US TAKE THOSE TOOLS AND
MOVE FORWARD.
WE ALSO HAVE A POCKET GUIDE.
AGAIN, YOU CAN FIND THESE, WE DO
HAVE AN INTERACTIVE PORTAL
CALLED ENGAGE.AVAC.ORG.
WE HAVE A SITE, IT'S COMPLETELY
FREE, A LEARNING MANAGEMENT
SYSTEM THAT HAS A NUMBER OF
TOOLS, PRESENTATIONS AND
RECORDED VIDEOS THAT CAN YOU
ACTUALLY TRACK AND DOWNLOAD AND
CREATE SOME OF THESE MATERIALS.
BUT THIS POCKET GUIDE IS MEANT
TO BE A PICTURE THAT CAN BE
PULLED UP ON A SMARTPHONE SO
THAT IF YOU'RE IN A PRESENTATION
OR A SESSION LIKE TODAY, YOU CAN
ACTUALLY JUST GO AHEAD AND
REFRESH YOURSELF ON WHAT THAT
SCIENCE MEANS.
SO WE'RE REALLY TRYING TO CREATE
BOTH INNOVATIVE TOOLS THAT CAN
BE USED IN A VARIETY OF SETTI
SETTINGS.
I WANTED TO SAY AGAIN, WHEN WE
THINK ABOUT THE INFLUENCE, IT'S
REALLY IMPORTANT THAT WE'RE NOT
JUST THINKING ABOUT LITERACY.
LITERACY IS ONE COMPONENT OF
COMMUNITY ENGAGEMENT, BUT THE
TREUP METRUE METRIC OF SUCCESS W
ARE WE PUSHING THAT ENVIRONMENT
TO GO EVEN FURTHER?
AND SO FOR US, CREATING THAT
ENABLING ENVIRONMENT HAS BEEN
KEY.
AND SO SOME OF THE WAYS IS WE'RE
THINKING AGAIN ABOUT THE
INTEGRATION WITH POLICY MAKERS,
AND SANDY JOINED US ON A PANEL
NEAR HIV VACCINE AWARENESS DAY
TO BRIDGE CURE INTO THE
CONVERSATIONS AROUND PREVENTION
AND TREATMENT WITH OUR
LAWMAKERS, AND SO THAT'S REALLY
IMPORTANT TO AGAIN THINKING
ABOUT HOW DO WE SUSTAIN FUNDING
AND HOW DO WE PUT A SPOTLIGHT ON
THE WORK THAT WE'RE DOING.
WE'VE ALSO DONE A LOT OF WORK
INTERVENING WITH CLINICIANS,
PEOPLE LIVING WITH HIV POST
INTERVENTION CONTROLLERS,
SPONSORS AND OTHERS TO NOT JUST
THINK ABOUT ERADICATION, BUT
WHAT DOES CONTROL MEAN AND WHAT
ARE THOSE CONSIDERATIONS.
AND THIS WORK WAS ACTUALLY LED
BY, AGAIN, ONE OF OUR CURE
MEMBERS, WHOSE PICTURE IS UP
THERE.
AND WE'VE JUST FOUND THAT THIS
HAS BEEN A FANTASTIC PROJECT,
AGAIN TO THINK ABOUT INFLUENCING
THE CONVERSATION AND THE
NARRATIVE MOVING FORWARD.
LAST THING I WANTED TO SAY IS,
YOU KNOW, WE'RE FOCUSED ON THE
SCIENCE, AND I FORESEE HAS
REALLY THOUGHT A LOT ABOUT THE
BENCH BUT WE'RE ALSO THINKING
WIABOUT HOW DO WE TRANSLATE THA,
HOW DO WE BRING THAT OUT NOW.
YOU HEARD A LOT O ABOUT THE
VARIOUS COHORTS AND THE WORK
BEING DONE IN MHRP AND THINKING
ABOUT THOSE BIO SAMPLES.
WE'RE THINKING ABOUT HOW DO WE
PLAN FROM THE TRANSITION FROM
THE BENCH REALLY INTO THOSE
LARGER SCALE CLINICAL TRIALS AS
THEY MOVE FORWARD.
SO WE'RE REALLY EXCITED THAT
WE'VE NOT ONLY HAD OUR CAB
MEMBERS BE AT THE ADVOCACY FOR A
CURE ACADEMY, BUT WE'VE ALSO
BEEN ABLE TO CREATE AN ENABLING
ENVIRONMENT IN OTHER WAYS.
WE'VE ACTUALLY CREATED A
JOURNALIST TRAINING THAT FOCUSES
ON COMMUNICATION THAT WAS A
YEAR-LONG ENDEAVOR WHERE
JOURNALISTS MET MONTHLY IN
ZIMBABWE, WHICH WAS
STRATEGICALLY CHOSEN FORTY
CONNECTION TO TWO UPCOMING FIRST
IN COUNTRY ATI TRIALS THAT ARE
HAPPENING THERE.
AND THROUGH THAT YEAR, WE MET
WITH JOURNALISTS, TRAINED THEM
ABOUT THE SCIENCE, HOW TO
COMMUNICATE IT, AND WHAT WERE
THE KEY MESSAGES, AND YOU CAN
SEE HERE A SMATTERING OF THE
PAPERS THAT THEY ALL WROTE,
STORIES THAT CAME OUT OF THAT
12-MONTH PROGRAM.
THAT PROGRAM IS NOW GOING TO BE
PILOTED OUT INTO OTHER COUNTRIES
CONDUCTING ATI CLINICAL TRIALS
AS WELL, SO THINK THINK ABOUT U,
SOUTH AFRICA AND KENYA, AND
AGAIN THE MATERIALS THAT WERE
CREATED BY THIS FELLOW, ANNA
MITI, REALLY HELPS TO BRING IN
AND DIVERSIFY, SHE ACTUALLY
TRANSLATED INTO TWO LOCAL
DIALECTS THAT ARE BEING USED NOW
IN THE ACTG5417 TRIAL SITE IN
SIB BAB WAY.
ZIMBABWE.
MANDISA DUKASHE -- AND BROUGHT
PARTNERS TO REALLY HELP MOVE
THAT WORK FORWARD.
THEN UDOM, OUR CAB MEMBER BASED
IN THAILAND HAS BEEN WORKING
WITH MHRP TO REALLY CREATE SOME
CURE-FOCUSED CABs, THINKING
ABOUT SOME OF THESE NEW
PROTOCOLS AND STUDIES THAT ARE
GOING OUT THERE.
SO REALLY EXCITE FOD ED TO SEE S
WORK MOVE FORWARD INTO THE NEXT
PHASE.
SO WITH THAT, I'M HAPPY TO TAKE
ANY QUESTIONS, AND REALLY LOOK
FORWARD TO THE WORK.
[APPLAUSE]
>> SO THANK YOU VERY MUCH.
WE ARE PERFECTLY ON TIME.
WE HAVE TIME FOR A FEW
QUESTIONS.
PLEASE COME TO THE MICROPHONE.
>> HI.
MY QUESTION IS FOR DR. VASAN.
EVERYBODY, THIS IS A GREAT TALK,
THANK YOU.
SO I THINK -- YOUR 50% OF THE
PARTICIPANTS WHO FAILED IPDA,
THEY WERE DEFECTS IN -- SHOULD I
KNOW THIS, JOHN?
>> SO MOST CLONES THAT WE KNOW
ARE DEFECTIVE --
>> IN -- OR PSI OR DO YOU KNOW?
>> IT LOOKS LIKE PSI.
>> OKAY.
SO DO YOU HAVE ANY -- ARE YOU
PLANNING TO DO PROVIRAL
SEQUENCING OR PSI SEQUENCING
BECAUSE YOU COULD -- IN TITAN
AND ECLEAR WE DESIGNED PRIMERS
AND PROBES SPECIFIC TO
PARTICIPANTS, EACH PARTICIPANT,
IT'S A HEADACHE BUT IT CAN BE
DONE IF YOU'RE GOING TO FOLLOW
THEM LONG TERM.
>> GOOD QUESTION.
SO LEIA BRANT IS IN THE
AUDIENCE.
WE ARE TAKING INDIVIDUAL PRO
VIRUSES, SEQUENCING THEM, AND
SEEING WHETHER THE SEQUENCE HAS
A RRE OR PSI BINDING REGION.
AND IF IT DOES, WHETHER IT'S
LIKELY TO READ OUT POSITIVE IN
THE IPDA BASED ON THE MATCH.
WHAT WE'RE FINDING IS THE VAST
MAJORITY OF CLONES, OF PRO
VIRUSES ARE DEFECTIVE.
THE ONES THAT WE'VE IDENTIFIED
SO FAR THAT ARE CLONAL AND NEAR
FULL LENGTH, A FEW ARE INTACT,
ABOUT 50% THAT WOULD BE DETECTED
BY THE IPDA, AND THE OTHER HALF
HAVE EITHER DELETION IN PSI
MOSTLY OR RRE.
>> OKAY, THANKS.
>> CHRIS PETERSON.
>> ALSO FOR JOHN.
WE'VE ALSO SEEN APT-CAR
ANTIBODIES OUTSIDE OF THAT HUMAN
CD4 DOMAIN, AND WE CAN SHOW IN
VITRO THAT THEY DO RESTRICT
FUNCTION, BUT IT'S NEVER LINED
UP IN VIVO, THAT WE'RE LOSING
CARS WAY BEFORE WE SEE THOSE
ANTIBODIES.
SO I'M WONDERING IF YOU HAVE ANY
CAUSATIVE EVIDENCE THAT THE
ANTIBODIES OR WHAT IS
RESTRICTING THE CAR FUNCTION IN
VIVO.
>> SO THE ANALYSES WERE JUST
INITIAL LOOK, AND DAN DID THOSE
ANALYSES.
SO CARs DISAPPEAR, ANTIBODY
APPEAR.
IS THAT CAUSAL?
WE DON'T -- WE DON'T KNOW THAT
FOR SURE.
IT'S CORRELATIVE.
THERE MAY BE OTHER MECHANISMS
WHEREBY CARs DON'T PERSIST.
AND JIM, PLEASE FEEL FREE TO GET
UP AND -- HE'S HAPPY WITH WHAT I
SAID.
[LAUGHTER]
>> I CAN ANSWER A FOLLOW-UP TO
THAT QUESTION ALSO.
WHEN WE INFUSE THE CAR-T CELLS
INITIALLY, THEN THE TWO
OBSERVATIONS ARE THAT THE CAR-T
CELLS DISAPPEARED CONCURRENTLY
WITH THE ANTICD4 ANTIBODIES
APPEARING, AND THEN WE ACTUALLY
DID ANOTHER PHASE OF THE STUDY
WHERE WE DID A SECOND INFUSION
OF CAR-T CELLS IN THE SAME
ANIMALS, AND IN THE SETTING OF
THE PRESENCE OF THOSE
ANTIBODIES, THERE WAS NO --
THERE WAS NOT EVEN AN EARLY
ACUTE TAKE, SO IT WAS A COMPLETE
BLOCKADE OF ANY CAR-T CELLS IN
THE PRESENCE OF THE ANTIBODIES.
>> PREINFUSION I TOTALLY AGREE,
BUT THE FIRST ONE, THAT'S WHAT
I'M CURIOUS ABOUT.
>> SO I THINK IT'S QUITE
CONVINCING EVIDENCE THAT THE
ANTIHUMAN CD4 ANTIBODIES WERE
INDUCED BY THE CAR-T CELLS AND
PREVENTED THE SECOND
ADMINISTRATION OF THEM.
>> THANK YOU FOR TALKING ABOUT
THE GLOBAL ENGAGEMENT PORTFOLIO
AND THE WONDERFUL WORK THAT
YOU'RE DOING IN AFRICA.
CAN YOU TALK A LITTLE ABOUT THE
PROCESS FOR INCORPORATING
COMMUNITY RECOMMENDATIONS INTO
CLINICAL TRIAL DESIGNS,
PARTICULARLY THOSE INVOLVING
ATIs, AND WHAT HAS THAT UPTAKE
BEEN LIKE?
>> THANKS, KARINE, FOR THE
QUESTION.
YOU KNOW, WHEN WE THINK ABOUT
THE GLOBAL PRESENCE, THIS
MEETING WAS IN JUNE.
SINCE THEN, THE STAKEHOLDERS
HAVE CONTINUED TO MEET, THIS
SMALL GROUP OF ADVOCATES HAVE
CONTINUED TO MEET MONTHLY TO
KIND OF TALK ABOUT THAT AND ARE
WORKING WITH THE CLINICAL TRIAL
PIs TO SEE HOW WE CAN
INCORPORATE THEIR THOUGHTS AND
FEEDBACK.
BECAUSE IT WAS DONE AFTER THE
PROTOCOL WAS SEALED, WE ARE
REALLY THINKING ABOUT HOW DO WE
PUSH FOR EITHER A STATEMENT
POSITION OR SOMETHING ELSE THAT,
AGAIN, IS LED BY THE ADVOCATES
THAT WERE IN THE ROOM ON WHAT
THEY WANT TO DO, BUT WHAT WE'VE
BEEN ABLE TO DO TO PUSH THEIR
FEELINGS IS THEY'VE HELD A LOT
OF SESSIONS IN CONJUNCTION WITH
U EQUAL U FORUMS TO TALK ABOUT
ATIs TO DELIVER THAT FEEDBACK,
AND WE'RE BEGINNING TO AGAIN
FEED THAT BACK INTO THE CLINICAL
TRIALS PROCESS WITH THE ACTG.
>> I'D LIKE TO ADD TO THAT
BRIEFLY BY JUST STATING THAT WE
AT LEAST FOR SOME OF OUR TRIALS
IN THAILAND, WE'VE BEEN WORKING
WITH GAIL HENDERSON AND HOLLY
PIA THROUGH AN R01 THAT WAS
FUNDED, ACTUALLY SOMEWHAT
QUANTITATIVE, ABOUT ANALYZING
PARTICIPANTS' ATTITUDES, FEAR,
CONCERNS AND WILLINGNESS TO
PARTICIPATE IN ATI STUDIES,
PARTNER PROTECTION AND ALSO
SHORT VERSUS LONG DURATION
ATIs.
A LOT OF THAT WORK IS NOW
PUBLISHED, AND HAS REALLY BEEN
INSTRUMENTAL IN GUIDING US IN
ADVANCE FOR THE DESIGN OF OUR
NEXT UPCOMING TRIAL THAT'S
OUTSIDE OF THE I4C BUT WE ARE
LEVERAGING THE I4C MECHANISM TO
ENGAGE THE CABs AND
SPECIFICALLY IN THIS CASE OUR --
CAB MEMBER.
AS WE TALKED ABOUT IN OUR
COMMUNITY MEETING YESTERDAY,
THERE ARE ASPECTS OF COMMUNITY
FEEDBACK THAT I THINK ARE
UNIVERSAL, AND THEN OTHERS THAT
ARE CULTURE-SPECIFIC AND WE NEED
TO BE SENSITIVE TO BOTH.
>> CAN YOU STATE YOUR NAME AND
AFFILIATION, PLEASE?
THANK YOU.
>> THANK YOU SO MUCH.
JOSEPHINE FROM UGANDA, REPRESENT
PEOPLE LIVING WITH HIV.
AND MY QUESTION IS ABOUT THE --
MOST TIMES WHEN YOU TALK ABOUT
THEM IN OUR COMMUNITY, WE STILL
MAKE A STATEMENT OF ATTITUDEMENT
HAS AN EFFECT ON THE SIZE OF THE
RESERVOIR, BUT MOST TIMES PEOPLE
ASK WHAT IS A ILI, IS THERE A
DEFINITION OF WHAT -- MEANS.
IS IT LIKE HOURS AFTER YOU'VE
BEEN INFECTED WITH HIV, IS IT
LIKE JUST YEARS AFTER YOU'VE
BEEN INFECTED WITH HIV?
THANK YOU.
>> THANKS FOR THAT QUESTION.
THERE'S A SYSTEM CALLED FEIBIG
STAGES THAT'S BASED ON THE
TIMING OF APPEARANCE OF
DIFFERENT LABORATORIES
ANTIBODIES, WESTERN BLOT, VIRAL
LOAD, AND SO REALLY WE'RE
TALKING ABOUT A PERIOD OF WEEKS
TO MONTHS IN TERMS OF ACUTE TO
EARLY.
AND THAT'S WHY WE ALSO KNOW THAT
THAT'S VERY DIFFICULT TO ACHIEVE
FOR MOST OF THE WORLD.
IRRESPECTIVE OF WHAT COUNTRY YOU
LIVE IN.
SO THAT'S WHY STUDIES LIKE THE
ONE CONDUCTED BY DR. BAROUCH
HERE MODELING THE IMPACT OF THE
RESERVOIR ON PEOPLE WHO HAVE NOT
STARTED ART FOR YEARS AFTER
BEING EXPOSED TO HIV ARE EQUALLY
IMPORTANT.
>> DEBBIE
>> INTUITIVELY YOU WOULD THINK
IT'S BASED ON INFECTED CELL
FREQUENCY, THINK VIREMIA.
I WONDER GIVEN DATE DATA PRESED
YESTERDAY, HAVE YOU BEEN ABLE TO
LOOK AT AUTOLOGOUS
NEUTRALIZATION ANTIBODY AND TIME
IN RESET TO VIRAL ROAD TO KIND
OF TEASE OUT ARE THERE ANY
IMMUNE POTENTIAL MECHANISMS THAT
WE NEED TO CONSIDER WITH HIGH
LOAD VIREMIA, OR EVEN
SPECIFICALLY THE TIMING OF WHEN
TO STOP ATI IN TERMS OF A CELL
INFECTED -- INFECTED CELL
FREQUENCY?
>> THAT'S SPOT-ON.
WE'RE LOOKING AT THAT NOW.
WE DON'T HAVE THOSE DATA.
WE'RE ALSO COGNIZANT THAT WE'RE
LOOKING IN A SUBTYPE AE
POPULATION WHERE THE VIRUS IS
RELATIVELY MORE HO KNOWLEDGE
NUSS, SO I THINK THAT WARRANTS
REPLICATION ACROSS COHORTS.
>> JUST TO ADD TO THAT, THERE'S
OLD DATA THAT THE SINGLE BEST
PREDICTOR OF THE LEVEL -- THE
FREQUENCY AND LEVEL OF
PERSISTENT VIREMIA ON ART IS THE
PRE-ART VIRAL LOAD.
SO IT'S CONSISTENT THAT THE
NUMBER OF INFECTED CELLS AT THE
TIME OF STARTING ART AND THE
NUMBER OF EXPRESSING CELLS
PREDICTS HOW MANY INFECTED CELLS
WILL BE PRODUCING SOME VIRIONS
AFTER LONG-TERM ART.
AND THIS INITIAL EVIDENCE, AND
JOHN LOW PRESSUR LEE HAS SIMILA,
THAT THE LEVEL OF VIREMIA OR ITS
PRESENCE PREDICTS THE TIME TO
REBOUND.
THERE ARE MANY IMMUNOLOGIC
FACTORS THAT ADD NOISE TO THAT.
THE CORRELATION IS BEST IN
INDIVIDUALS WHO ARE TREATED
EARLY, BEFORE A BROAD
IMMUNOLOGIC RESPONSE IS
GENERATED.
>> SO JUST TO FOLLOW UP ON THAT,
JOHN, SOMETHING I NEVER COULD
QUITE UNDERSTAND IS WHY DOES
TREATMENT FOR 10 YEARS OR 20
YEARS NOT CHANGE THE VIRAL LOAD
SET POINT?
YOU KNOW, PEAK VIREMIA IS
USUALLY WHERE YOU STARTED OUT.
SO IT WOULD SUGGEST -- YOU'RE
SAYING THERE MIGHT BE SOME FIXED
BURSAES THAT'S DRIVING THAT
REBOUND.
SO FOR EXAMPLE, IN THE
MISSISSIPPI BABY AT REBOUND,
RECEIPT BOUND PEAK VIREMIA WAS
VERY SIMILAR TO THE TIME OF
DIAGNOSIS.
AND THAT'S BEEN SHOWN RELIABLY
IN THE FIELD, THAT WE DON'T
REALLY ALTER THAT PATTERN OF
REBOUND WITHOUT
IMMUNOTHERAPEUTICS OBVIOUSLY.
>> YEAH, I MEAN, I GUESS IF --
ART DOESN'T ALTER THE ABILITY TO
CONTROL, RIGHT?
IT CONTROLS VIREMIA AND VIRUS
PRODUCTION.
SO WITHOUT AN ADDITIONAL -- IN
SOME -- IT'S HETEROGENEOUS BUT
THE AVERAGE IS THAT IT DOESN'T
AFFECT IMMUNE CONTROL.
SO THUS THE NEED FOR
INTERVENTIONS AS YOU SUGGESTED.
>> AND TO CLARIFY THE STUDIES
THAT I PRESENTED REALLY JUST
LOOKED AT CORRELATES OF TIME TO
VIRAL REBOUND.
ALL OF THOSE EARLY ATI STUDIES,
WE STARTED PEOPLE BACK ON ART AS
SOON AS THEY HIT THEIR FIRST
INSTANCE OF 1,000 COPIES PER ML
IN PERIPHERAL BLOOD.
SO THAT'S WHERE TYING IN THE
EARLIER QUESTION, ALL OF THE
WORK WITH OUR COMMUNITIES TO
UNDERSTAND THE ACCEPTABILITY OF
BEING WILLING TO GO LONGER,
WHICH THEY GENERALLY ARE, WOULD
HELP US ANSWER THOSE QUESTIONS
IN FUTURE STUDIES.
>> OKAY.
ONE FINAL QUICK QUESTION, CAN
YOU STATE YOUR NAME, PLEASE?
>> HI.
MY NAME IS MADISON.
I'M A POSTBAC HERE AT THE VRC.
I HAD A QUESTION FOR DR. BAROUCH
REGARDING THE MULTIPRONG
STRATEGY FOR HIV SUPPRESSION IN
B INFECTED CELLS.
WOULD THIS BY CHANCE ENHANCE
POTENTIAL MUTATIONS WITH THE
INCREASED PRESSURE THE VIRUS IS
OBSERVING FROM THAT MULTIPRONG
STRATEGY?
AND THEN ALSO AS A FOLLOW-UP TO
THAT, WOULD YOU BE ABLE TO
UTILIZE YOUR BIOMARKER IN BLOOD
TO BETTER PROTECT WHEN VIRAL
REBOUND MIGHT OCCUR WITH THAT AS
WELL?
>> THANKS FOR YOUR QUESTIONS.
I THINK THAT THERE'S
CONCEPTUALLY TWO WAYS THAT WE
AND OTHERS ARE TRYING TO APPLY
INTERVENTIONS.
ONE IS DURING A PERIOD OF NO
VIRUS REPLICATION ON FULL ART
SUPPRESSION OR AS CLOSE TO THAT
AS WE CAN GET.
SUCH AS LONG TERM ART
SUPPRESSION IN MACAQUES OR
HUMANS, AND THEN PROVIDING
ANTIBODIES, VACCINES OR OTHER
INTERVENTIONS.
IN THAT SETTING, I THINK THAT
THE CHANCE OF MUTATIONS IS
RELATIVELY LOW.
BECAUSE THERE IS NO ONGOING
VIRUS REPLICATION.
THE SECOND WAY THAT PEOPLE ARE
LOOKING AT INTERVENTIONS IS TO
APPLY THEM EITHER AT THE TIME OF
ART INTERRUPTION OR SHORTLY
BEFORE OR SHORTLY AFTER.
IF THERE IS VIRAL REBOUND IN THE
CONTEXT OF LEVELS OF BROADLY
NEUTRALIZING ANTIBODIES OR OTHER
IMMUNE INTERVENTIONS, THEN I DO
THINK THAT THERE IS A CHANCE, IN
SOME CASES LIKELIHOOD TO DEVELOP
RESISTANCE.
SO I THINK THE ANSWER TO YOUR
QUESTION IS PROBABLY DEPENDENT
ON WHEN INTERVENTIONS ARE
APPLIED.
IF THEY'RE APPLIED IN THE
SETTING OF ONGOING VIRUS
REPLICATION, THEN SURE, THERE
COULD BE DEVELOPMENT OF
RESISTANCE.
IF THEY'RE APPLIED DURING A
PERIOD OF NO VIRUS REPLICATION,
THEN AT LEAST THEORETICALLY WE
WOULD NOT EXPECT A LOT OF
RESISTANCE.
AND SORRY, I FORGOT YOUR SECOND
QUESTION.
>> FOLLOWING UP ON WHEN YOU
COULD BETTER PREDICT REBOUND
USING THAT MULTIPRONGED APPROACH
UTILIZING YOUR BLOOD BIOMARKER
FOR THAT.
>> SO THOSE THAT WE RECENTLY
PUBLISHED ARE FOR A VERY NARROW
INDICATION, WHICH WAS EXTREMELY
EARLY ART INITIATION IN MACAQUES
PREVIREMIA, SO ESSENTIALLY DAY
ONE, DAY TWO, DAY THREE.
SO IT'S A VERY UNIQUE SITUATION,
AND I THINK, THEREFORE, THE
GENERALIZABILITY OF THOSE
BIOMARKERS, WHICH ARE
ESSENTIALLY BIOMARKERS OF
INFECTION, BECAUSE WE'RE PRETTY
CERTAIN THAT HALF THE ANIMALS
THAT DIDN'T REBOUND, THEY
WEREN'T CURED, THEY WERE
ACTUALLY NEVER INFECTED.
SO THERE'S SORT OF BIOMARKERS OF
OCCULT INFECTION, WHEN HALF THE
ANIMALS ARE INFECTED AND HALF
ARE NOT, AND YOU DON'T KNOW
WHICH IS WHICH.
SO WHETHER THEY'RE APPLICABLE TO
A SETTING OF EVERYONE BEING
INFECTED AND LOOKING FOR A
THERAPEUTIC EFFECT OF AN
INTERVENTION, I WOULDN'T MAKE
THAT JUMP.
WE ARE ACTUALLY LOOKING THROUGH
THIS PROGRAM AND OTHERS AT
BIOMARKERS IN A MORE GENERAL
SENSE.
SO I GUESS I WOULD SAY THAT THE
PUBLISHED DATA IS FOR A VERY,
VERY SPECIFIC INDICATION, AND WE
HAVE NOT PROVEN AND WOULD HE
PROBABLY WOULDN'T EVEN
ANTICIPATE THAT TO BE
GENERALIZABLE FOR INTERVENTIONAL
TYPE APPROACHES.
>> THANK YOU.
>> OKAY, THANK YOU VERY MUCH.
, I4C.
I'M HANDING IT OVER TO MY
COLLEAGUE TO MAKE SOME
ANNOUNCEMENTS.
>> THANKS A LOT.
I THINK WE JUST GO FOR THE
POSTER SESSION.
I JUST WANT TO REMIND YOU THERE
ARE SOME POSTERS IN THE BALCONY,
IF PEOPLE -- ADDITIONAL POSTERS,
AND THEN WE COME BACK AFTER
LUNCH AT 1:40 P.M., SO I WOULD
REQUEST YOU TO PLEASE COME A FEW
MINUTES EARLIER SO WE CAN GET
STARTED ON TIME.
THANK YOU.
A LITTLE BIT OF A LEARNING
CURVE, BUT I THINK WE'VE REALLY
HIT OUR STRIDE AND YOU'LL SEE
SOME OF THE GREAT WORK THAT OUR
TEAM MEMBERS ARE DOING.
SO I'M RUNNING THIS
COLLABORATORY IN COLLABORATION
WI,JUST A SHOUT OUT TO JEFF TAIR
TWO COULDN'T BE HERE BECAUSE OF
COVID, APPARENTLY HE GOT IT
STANDING IN LINE FOR HIS BOOSTER
SHOT, SO THERE YOU GO.
SO WE'RE GOING TO -- REALLY,
JEFF HAS BEEN DOING AN AMAZING
JOB AND WE'VE BEEN LEARNING A
LOT FROM HUM IN THE COMMUNITY
ENGAGEMENT SIDE.
OUR SCIENTIFIC ADVISORY BOARD
JUST HATS OFF TO THEM FOR GIVING
US AMAZING FEEDBACK, AND I
COULDN'T HOPE FOR A BETTER TEAM
OF SCIENTISTS TO WORK WITH TO
LEAD THIS EFFORT.
SO AS MENTIONED, OUR NAME IS RID
HIV, WHICH STANDS FOR REVERSING
IMMUNE DYSFUNCTION TO ACHIEVE A
CURE.
SO THE UNDERLYING PREMISE REALLY
IS THAT WHEN YOU HAVE AN ACUTE
INFECTION, THE INSULT ONTO THE
IMMUNE SYSTEM PRECLUDES THE
ABILITY OF THE IMMUNE SYSTEM TO
CONTROL VIREMIA DURING A CHRONIC
PHASE SO WE'RE TRYING TO
UNDERSTAND WHAT THOSE ARE AND
DEVELOP APPROACHES TO REVERSE
THEM.
AND WE'RE SPLITTING INTO 3RFs
AS MOST ARE.
THE FIRST RF IS REALLY OUR
EXPLORATORY RF.
A LITTLE ABOUT THE ROLE OF THE
HOST MICROBIOME ON INNATE
IMMUNITY AND THE ADAPTIVE
INTERFACE AND REALLY A NICE
STORY ON BILE ACIDS AND THEIR
IMPACT ON INNATE DYSFUNCTION AND
HIV PERSISTENCE.
THEY'RE ALSO USING A NUMBER OF
REALLY LEADING EDGE OMICS
EFFORTS, MULTI-SCALE OMICS TO
CHARACTERIZE THE COHORT THAT
JAVIER AND OTHERS HAVE
ESTABLISHED IN PEOPLE LIVING
WITH HIV WITH VERY HIGH AND VERY
LOW VIRAL RESERVOIRS TO SEE IF
THERE ARE REALLY IMMUNE LOGICAL
CORRELATES IN THE LOW RESERVOIR
INDIVIDUALS THAT WE CAN EXPLOIT
TO UNDERSTAND BOTH RESERVOIR
SEEDING AND CONTROL OF VIREMIA.
RF2 IS REALLY FOCUSING ON THE
RESTORATION TO HELP PRIME
CD8 CELLS TO CLEAR HIV INFECTED
CELLS DURING OR AFTER ATI, AND
SO A LOT OF THESE OMICS
APPROACHES THAT YOU'LL HEAR
ABOUT IS ALSO BEING USED TO DO
MULTI-SCALE ANALYSIS LOOKING AT
DIFFERENT KINETICS OF VIRAL
REBOUND AFTER ATI, AND THEN
YOU'LL HEAR ABOUT A COUPLE
PHARMACOLOGICAL APPROACHES
INCLUDING AN OFF THE SHELF TSCM
PRODUCT THAT'S BEEN KNOCKED OUT
FOR CCR5 TO PROVIDE CD4 HELP AND
TGF BETA INHIBITOR WHICH WE'VE
BEEN WORKING ON WITH MERCK TO
MOVE INTO NHP STUDIES EITHER
ALONE OR IN CONJUNCTION WITH
PD-1 ANTIBODIES, WHICH EXTENDS
THE WORK THAT RAFIQ AND HIS
GROUP HAVE BEEN DOING IN THAT
AREA.
RF3 FOCUSES MORE ON THE
CLASSICAL LATENCY REACTIVATION
AND KILL STRATEGIES, SO MY GROUP
ALONG WITH LARS IS WORKING ON
IMPROVING BUILDING NEXT
GENERATION SMACK MIMETICS, SO
INSTEAD OF TRYING TO TAKE CANCER
DRUGS AND SHOVE THEM INTO AN HIV
CURE REGIMEN, WE'RE DOING THE
CHEMISTRY FROM THE BEGINNING TO
DEVELOP A BESPOKE LATENCY
REVERSAL AGENT FOR HIV AS WELL
AS TRYING TO DEVELOP NOVEL
CLASSES OF LATENCY REVERSALS
USING HIGH THROUGHPUT SCREENING
AND PRIMARY PATIENT DERIVED
CELLS.
KILL STRATEGIES, YOU'LL HEAR,
CRISPR NK RECRUITMENT AND
SELL-BASED BNABs, AND THINK
ONE OF THE MORE ECK SIGHT THINGS
WE'RE DOING IS WORKING TO USE
MATH MODELING TO INTEGRATE ALL
OF THIS DATA AND TRY TO HAVE
SOME PREDICTIVE CAPACITY TO TELF
IMMUNE MODULATORS, LRAs AND
KILL STRATEGIES MIGHT BE MOST
EFFICIENT IN REDUCING THE
RESERVOIR AND ESTABLISHING
CONTROL OF VIREMIA.
SEW THE WAY WE DESIGNED OUR
GRANT, WE HAVE TWO TRANCHES OF
NHP STUDIES.
THE FIRST ONE WE'RE KIND OF
COMING UP TO AT THE END OF YEAR
TWO, AND SO WE'RE PROPOSING
RIGHT NOW THREE DIFFERENT
INTERVENTIONS SO ONE IS THE CCR.
YOU'LL HEAR FROM RAFIQ.
THE SECOND IS WITH TGF
INHIBITORS PLUS OR MINUS PD-1
AND THE THIRD IS USING NOVEL
SMACK MIMETICS THAT WE'VE
DEVELOPED IN THE GROUP TO LOOK
FOR LATENCY REVERSAL.
THIS IS MEANT TO BE A VERY IT
RIFF PROCESS WHERE ALL OF OUR
DATA WE'RE GENERATING GETS FED
INTO THESE INSILICO MODELS AND
THEN WILL BE USED TO REALLY
DRIVE WHAT THE EXPERIMENTS AND
THE INTERVENTIONS WE'RE GOING TO
FOCUS ON IN THE THREE PRIME END
OF THE GRANT.
SO WITH THAT, I'M GOING TO HAND
THINGS OVER TO HEAR ABOUT THE
WORK GOING ON IN RF 1.
>> I WILL FOCUS ON THE RF
1 UPDATES FOR OUR MDC.
THIS IS LED BY RAFICK AND THE
BACKBONE IS REALLY THE STATEMENT
THAT YOU ARE WHAT YOU EAT, AND
WHAT YOU EAT DRIVES YOUR IMMUNE
DYSFUNCTION IN HIV PERSISTENCE.
TO ADDRESS THAT POINT, WE HAVE
BEEN WORKING WITH GROUPS ACROSS
EUROPE AND THE U.S.
WE HAVE JAVIER AND MARIA IN
BARCELONA, ALL OF US AT EMORY.
THEN WE ARE WORKING WITH MERCK
AND AS SUMIT MENTIONED, IN
LOS ALAMOS.
NOW, THE SUMMARY SLIDE WHICH IS
THE NEXT SLIDE IS SORT OF
CHARACTERIZED WITHIN THIS
CARTOON HERE.
THE KEY QUESTION THAT WE WANT TO
ANSWER IS HOW DO THE METABOLITES
IMPACT THE HOST IMMUNE SYSTEM.
THEY CAN BE DIET RELATED, THEY
CAN BE METABOLIZED BY THE
MICROBIOME -- IN THE INNATE AND
ADAPTIVE IMMUNE SYSTEM THAT GET
ALTERED BY THIS MICROBIAL
METABALOME AXE AND LOOK AT HOW
THE CYTOKINE RESPONSES THAT
RESULT, PERSISTENCE OF THE HIV
REST VOYEUR.
THAT'S SUMMARIZED IN THIS SLIDE
HERE.
THE MAIN QUESTION -- ON THE
IMMUNE SYSTEM AND THE RESERVOIR,
AND WHAT WE HAVE DONE SO FAR IS
ACCRUED SAMPLES WITHIN THE
TREATMENT INTERRUPTION AND WE
HAVE LOOKED AT WHAT SORT OF
IMMUNE RESPONSES DISTINGUISH
THOSE PEOPLE AT HIGH RESERVOIR
VERSUS LOW RESERVOIR, AND WE
HAVE REALLY IDENTIFIED TWO
FAMILIES OF METABOLITE, THE
SHORT CHAIN FATTY ACIDS AND THE
BILE ACIDS AS DRIVERS OF IMMUNE
DYSFUNCTION AND PERSISTENCE OF
THE RESERVOIR, AND THIS IS
IMPORTANT BECAUSE WE WANT TO BE
ABLE TO MAKE THERAPEUTICS THAT
WOULD NOT ONLY CURB THE HIV
RESERVOIR BUT ALSO REJUVENATE
THE METABOLIC RESPONSE AND LEAD
TO OVERALL HEALTH IMPROVEMENT.
NOW AS I WAS SAYING, THE COHORTS
THAT WE HAVE RECRUITED, THEY
COME FROM EMORY IN ATLANTA AND
IN BOSTON, BUT WE ALSO HAVE
COHORT IN BARCELONA AND GENT
WITH JAVIER'S GROUP.
THESE COHORTS ARE EITHER
RETROSPECTIVE -- OR TREATED
COHORTS THAT THE DRAWI DURATIONT
CAN BE AS LONG AS 20 YEARS OR AS
SHORT AS ACUTE -- WE HAVE A
COUPLE OF COHORTS WHERE WE HAVE
ANALYTICAL TREATMENT
INTERRUPTION WHERE THE
PARTICIPANTS HAVE BEEN PULLED
OFF OF ART AND WE GET A CHANCE
TO LOOK AT THE DURATION TO BILE
REBOUND AND THE MAGNITUDE OF THE
VIREMIA UPON ANTIRETROVIRAL
TREATMENT INTERRUPTION.
ONE OF THESE COHORT WE WANTED TO
QUICKLY GO OVER IS CALLED THE
VOVIRET COHORT IN BARCELONA,
THIS IS A COHORT OF INDIVIDUALS
THAT HAVE BEEN ART-SUPPRESSED
FOR THREE OR MORE YEARS AND THE
RESERVOIR HAS BEEN QUANTIFIED IN
THESE PARTICIPANTS.
YOU CAN SEE ON THE Y AXIS, THE
RANGE OF THE RESERVOIR ON THE
LOG SCALE IS ABOUT 3 1/2 LOG
SCALE.
SO WITHIN THIS COHORT, THERE ARE
INDIVIDUALS THAT HAVE VERY HIGH
VIRAL RESERVOIR, AND THOSE THAT
HAVE VERY LOW VIRAL RESERVOIR,
AND ONE OF THE THINGS THAT WE
ARE DOING IS ATTEMPTING TO
CHARACTERIZE THE CLINICAL,
METABOLIC, IMMUNOLOGICAL AND
METABOLIC OUTCOMES THAT
DISTINGUISH THIS LOW RESERVOIR
GROUP FROM THE OTHER
INDIVIDUALS.
AND IN AN ATTEMPT TO DO THAT, WE
HAVE IDENTIFIED A SET OF
CLINICAL VARIABLES, 18 CLINICAL
SET FEATURE THAT DISTINGUISHES
THIS GROUP FROM THE OTHER
GROUPS.
NOW THAT'S JUST THE CLINICAL
OVERVIEW.
IN ADDITION TO THAT, WE ARE
DOING ALL OF THESE DIFFERENT
ASSAYS, BOTH ON THE IMMUNOLOGY
SIDE AND THE VIROLOGY SIDE.
IF YOU LOOK AT THE IMMUNOLOGY
SIDE, WE HAVE ASSAYS THAT ARE
FAIRLY HIGH THROUGHPUT.
YOU CAN -- WE RAN ABOUT A COUPLE
WEEKS AGO A THOUSAND SAMPLES FOR
PLASMA CYTOKINES.
THESE ASSAYS DOWN HERE, THEY
CHARACTERIZE THE SYSTEMIC MILIEU
AND THEN AS YOU GO UPWARDS AND
DO FLOW CYTOMETRY AND RNA
SEQUENCING AND SINGLE CELL
ASSAYS, YOU GET MORE GRANULARITY
WITHIN THE CELL LEVEL PATHWAYS.
ON THE BIOLOGICAL SIDE, THE SAME
AS IMENT EU NOLG, YOU START OFF
WITH BROAD VIRAL -- AS TOTAL --
LEVELS OR VIREMIA LEVELS AND
THEN YOU MOVE DOWN TO SINGLE
CELL ASSAYS THAT GIVE YOU
GRANULARITY INTO THE VIROLOGICAL
OUTCOMES.
OUR GOAL IS TO CAPTURE THE
INTEGRATION, TRANSCRIPTION,
TRANSLATION AND REPLICATION OF
THE VIRUS ALONG WITH THE HOST
METABALOME, THE IMMUNE RESPONSE
AND THE EPIGENETIC AND
TRANSCRIPTOME OUTPUT.
AND WE HAVE BEEN ABLE TO PUSH
THIS AGENDA FORWARD AT LEAST FOR
A COUPLE OF OUR COHORTS AND THIS
SLIDE CHARACTERIZES THE DRIVERS
OF THE HIGHEST RESERVOIR AT EACH
ONE OF OUR OMIC LEVELS, SO
MICROBIOME WISE WE SEE THAT
LACTOBACILLI DRIVE THE HIGHEST
REST VOYEUR, DOWNRESERVOIR, THED
ASSOCIATED SIGNALING IN
DYSFUNCTIONAL CD4 T-CELLS AS THE
DRIVER OF OUR HIGHEST RESERVOIR.
WE HAVE THE EX VIVO CORRELATE TO
FINISH OFF THE STORIES, WE HAVE
GONE INTO IN VITRO VALIDATION
ASSAYS.
THIS IS AN EXAMPLE OF THE WORK
THAT WE HAVE BEEN DOING ON THE
MICROBIOME, GIVEN THAT
LACTOBACILLI SPECIES CAME UP AS
A DRIVER OF HIGH RESERVOIR
HARBORING CELLS IN OUR ASSAYS,
WE DID DO IN VITRO ASSAYS IN
COLLABORATION WITH MERCK TO
UNDERSTAND WHAT LACTOBACILLI
PROMOTE THE SHORT CHAIN FATTY
ACIDS THAT DRIVE T-CELL
DYSFUNCTION AND RESERVOIR
PERSISTENCE AND WE'VE IDENTIFIED
THIS GROUP OF LACTOBACILLI,
THESE ARE RELATIVELY LOW
ABUNDANCE SPECIES THAT SEEM TO
PROMOTE THE ACCUMULATION OF
ALPHA KETOBUTYRATE.
IN ADDITION TO THE MICROBIOME,
THE BILE ACID WORK IS
DEMONSTRATED HERE.
WE HAVE BEEN LOOKING AT THE
METABOLITES IN AN UNBIASED WAY,
TO UNDERSTAND THE BIOLOGY OF
BILE ACIDS IN RESERVOIR
PERSISTENCE, WE CONDUCTED AN IN
VITRO ASSAY WHERE WE DID A
SCREEN OF 29 DIFFERENT BILE
ACIDS THAT SPAN PRIMARY AND
SECONDARY TYPES OF BILE ACIDS
THAT HAD EITHER NO CONJUGATION,
GLYCINE TAURINE CONJUGATION AND
ANY KIND OF SECONDARY
MODIFICATIONS, AND IN A GIST
WHAT WE SAW WAS THAT WHENEVER
YOU INCUBATE YOUR T-CELL WITH A
PRIMARY BILE ACID, YOU
UPREGULATE TGF BETA, BUT IF A
MICROBIOTA AND ASSOCIATED
CONVERSION TO SECONDARY BILE
ACID WAS AN OPTION, YOU GET AN
INCREASE IN INTERFERON BETA.
AND OVERALL THAT SUGGESTS TO US
THAT THE CD4 T-CELLS THAT ARE
GOING TO GET INFECTED AND ALLOW
THE HIV TO PERSIST WILL RESPOND
DIFFERENTLY IF YOU HAVE
MICROBIOME ASSOCIATED MILIEU
THAT IS IN THE PRESENCE OF
PRIMARY BILE ACIDS VERSUS
SECONDARY BILE ACIDS.
ON THE ONE HAND, THE PRIMARY
BILE ACIDS WILL PROMOTE HIGH
LEVELS OF TGF BETA AND ALLOW FOR
RESERVOIR PERSISTENCE, WHEREAS
THE SECONDARY PROMOTE TYPE I
INTERFERONS WHICH PREVENT
RESERVOIR SEEDING AND PREVENT
INFECTION.
SO THOSE ARE A FEW HIGHLIGHTS,
BUT GLOBALLY, WE HAVE BEEN ABLE
TO ESTABLISH THAT ALL OF THESE
FEATURES HERE, PRIMARY BILE
ACID, SHORT CHAIN FATTY ACID,
INCREASE IN T REGS AND
DYSFUNCTIONAL TCMs, SO TCMs
ARE DRIVERS OF HIGH RESERVOIR IN
OUR ANTIRETROVIRAL THERAPY
TREATED COHORTS, BUT IF YOU HAVE
INDIVIDUAL THS THAT ARE ABLE TO
MAINTAIN A MILIEU WITH INCREASED
INTERFERON -- TYPE 1 INTERFERON
OR IL-4, YOU SEE A REDUCTION IN
THE RESERVOIR, YOU OBSERVE THOSE
INDIVIDUALS HAVE LOWER
RESERVOIR.
AND WITH THAT, I'M GOING TO TURN
IT OVER TO RAFICK BUT BEFORE I
TO THAT, I JUST WANT TO
ACKNOWLEDGE THAT THIS WORK IS
BEING DONE ACROSS MULTIPLE
CONTINENTS.
WE HAVE THE TEAM IN GENDT AND
JAVIER'S TEAM IN BARCELONA AND
HAVE BEEN WORKING WITH OUR GROUP
AT EMORY LED BY RAFICK AND THE
PRIMATE CENTER AND VINCE
MARCONI'S GROUP AT UNIVERSITY
HOSPITALS AND VETERANS AFFAIRS
HOSPITAL AT EMORY, AND THEN
MERCK AND LAZAN ARE ALSO
INVOLVED.
THANK YOU.
[APPLAUSE]
>> GOOD AFTERNOON, EVERYONE.
BILE ACIDS ARE KNOWN TO PUT
PEOPLE TO SLEEP SO I WON'T TALK
TOO MUCH ABOUT BILE ACIDS, BUT
SO I THINK IT'S A GREAT THING TO
BE HERE AND PRESENT TO YOU WHAT
WE'VE BEEN DOING IN RF 2, LED BY
JAVIER AND VINCE MARCONI.
I'M TALKING ON BEHALF OF THEM
AND ON BEHALF OF THE WHOLE
GROUP.
SOMETHING WE'VE BEEN
BRAINSTORMING A LOT ABOUT FOR
MANY, MANY YEARS AND REALLY WE
WANT TO BE A LITTLE BIT
DIFFERENT OR MORE DIFFERENT THAN
WHAT EVERYBODY ELSE IS DOING,
AND REALLY TRY TO FOCUS ON WHAT
ARE THE MECHANISMS, THE MOST --
THAT CAN REGULATE COMMUNITY
CONSTITUTION AND ALSO -- SO IF
YOU LOOK AT THE WIDE SCOPE OF
BIOLOGY AND IMMUNOTHERAPY YOU
UNDERSTAND IN CANCER, THE
MICROBES AND METABOLITES ARE THE
ONES THAT REALLY REGULATE THE
RESPONSE IN ANTIPD-1, WHETHER
IBD OR CANCER, AGAIN THE FOCUS
ON HOW YOU CAN MODULATE THE
MICROBIOME, THE METABALOME,
OTHER IMMUNOTHERAPIES, THIS IS
WHERE THE CRUX IS.
AND IN FACT, YOU GO BACK --
PUBLISHED FOR MANY YEARS AGAIN
YOU UNDERSTAND THAT EVEN
PREVACCINATION, OR PREANY IMMUNE
INTERVENTION, THE STATE OF THE
HOST PREINTERVENTION, IS
CRITICAL TO WHETHER YOU'RE GOING
TO RESPOND TO IMMUNOTHERAPY.
THAT STATE IS REALLY DICTATED
AGAIN BY THE MICROBES AND THE
METABOLITES.
SO WITH THAT IN MIND, I THINK WE
WENT WITH -- WE HAD VERY MUCH
FORTUNE OF -- THAT ASHISH LISTED
BUT ON TOP WE ALSO HAD COHORTS
OF INDIVIDUALS THAT HAD
UNDERGONE SEVERAL DIFFERENT
TYPES OF IMMUNOTHERAPIES AND OUR
GOAL WAS TO TRY TO FIGURE OUT
WHETHER THERE WAS A COMMON
MECHANISM THAT ARE GOING TO
PREDICT WHO WAS GOING TO RESP
RESPOND, AND RESPONSES THEY'RE
LOOKING FOR IS WHETHER IT WAS
GOING TO LEAD TO DECAY OR ABLE
TO CONTROL -- THAT'S ESSENTIALLY
WHAT I'M GOING TO TALK TO YOU
ABOUT IN THE NEXT FEW MINUTES.
THE KEY QUESTIONS -- PERSISTENT
OR IN FACT THE REVERSE, IMPACT
ON ROOT HE SPONS TO
INTERVENTION, HOLISTIC APPROACH
IN ORDER TO DEFINE UNBIASED
WAYS -- NOVEL TARGETS THAT GIVES
US CLUES ON WHAT NOVEL TARGETS
CAN PURSUE -- I THINK IN TERMS
OF WHAT WE HAVE ACCOMPLISHED, I
THINK REALLY WHAT WE ARE REALLY
FOCUSED ON IS REALLY DEFINED
PATHWAY, THAT EXAMPLE I'M GOING
TO GIVE YOU IS THAT WE HAVE
GENERIC SIGNATURES THAT CAN
PREDICT A RESPONSE TO AT LEAST
THREE DIFFERENT TYPES OF
IMMUNOTHERAPIES.
THAT'S WHAT I REALLY WOULD LIKE
TO BUILD UPON TOGETHER, IN ORDER
TO BE ABLE TO EVEN ENHANCE -- I
WANT TO GO INTO HUMAN AS MUCH AS
POSSIBLE, I KNOW IT'S NOT PART
OF THIS, BUT MY GOAL IS REALLY
TO GO IN HUMAN.
THE TITLE OF OUR CONSORTIUM IS
IMMUNE CONSTITUTION,
IMMUNOTHERAPIES AND THAT'S
WHAT -- ABOUT AND IT'S IMPORTANT
BECAUSE YES THERE ARE LRAs,
THEY HAVE NOT SHOWN MUCH
SUCCESS.
I THINK I'LL SHOW YOU DATA THAT
AT LEAST SOME IMMUNOTHERAPIES
HAVE HAD SOME SUCCESS IN CURBING
THE RESERVOIR AND CONTROLLING
VIRAL LOAD.
SO TODAY I'M GOING TO SHOW YOU
THE STUDY THAT SUSAN AND MIRKO
HAVE SHOWN, GO BACK TO BILE
ACIDS AND SHOW HOW BILE ACIDS
MECHANISM IS ONE THAT TRIGGERS
THE RESPONSE TO DIFFERENT -- SO
YOU'VE SEEN THAT SLIDE EARLIER.
THIS IS I THINK A GROUNDBREAKING
STUDY THAT SUSAN LED TOGETHER
WITH THE GROUP WHERE WE TREATED
MONKEYS WITH ANTIPD-1 AND IL-10,
IT COMES FROM VERY HARD -- SO A
CONCEPT INITIALLY DONE BY
MICHAEL -- WHERE THE -- REGULATE
MANY DIFFERENT INNATE TYPE
MECHANISM THAT ARE ABLE TO
INTERACT, HELP PRIME THE IMMUNE
RESPONSE AND GET TO CONTROL
OF -- UP TO -- WEEKS AFTER
STOPPING ART THEY WERE ABLE TO
CONTROL VIRAL LOAD.
-- LEVELS AS COMPARED TO THE
ANTIIL-10 -- SO AGAIN IN THE
TRUE SPEESHT OF WHAT WE DO IN MY
GROUP, WE LOOKED AT WHAT ARE THE
PATHWAYS THAT -- PREDICT THE
CONTROL OF -- EVERYTHING WE DO
NOW IS PRE-ATI.
AMONG THE FIRST ONE, TOP ONE WAS
BILE ACIDS AND INTERFERON.
SO INTERFERON, THAT SHOWED THAT
WHEN YOU INFUSE INTERFERON, YOU
CAN CURB THE INFECTION BUT
ALSO -- REBOUND BUT WHY BILE
ACIDS?
BECAUSE BRIEFLY MENTIONED TO
YOU, BILE ACIDS ARE MODULATED BY
THE MICROBIOME SO AGAIN
INTERPLAY, THEY'RE THE ONES THAT
ARE ABLE TO TRIGGER --
INTERFERON.
IF IT'S IN A STATE OF -- BEFORE
VIRAL LOAD COMES BACK, WHEN YOU
STOP TREATMENT OF COURSE YOU
HAVE AN IMMUNE SYSTEM THAT'S
POISED AND ENHANCE IMMUNE
RESPONSE BECAUSE INTERFERON IS A
MAJOR ADJUVANT BUT ALSO IT
PROTECTS OLDER CELLS FROM
GETTING REINFECTED, SO I THINK
TO MAKE THE LAW OF LOGIC, THE
TWO ARE VERY MUCH INTERRELATED,
TO LEAD TO -- VIRAL REBOUND POST
ATI.
IN FACT WE IDENTIFY SEVERAL
INDIVIDUAL BILE ACIDS THAT ARE
NEGATIVELY CORRELATED TO
VIREMIA, PREATI AGAIN, SO THE
MORE THOSE BILE ACIDS, THELESS
IMMUNE, THE LESS VIRAL REBOUND
YOU'RE GOING TO GET.
SO THAT CAN BE A WHOLE TALK BUT
I JUST WANT TO GIVE THE GIST OF
IT WHICH AGAIN RELATES TO WORK
THAT WAS PUBLISHED ABOUT A YEAR
AGO WHERE IN FACT THAT THOSE
BILE ACIDS DO REALLY TO PRIME,
TO PUT THE INTERFERON LOCUS IN
A -- STATE.
SO WE DID SINGLE CELL SEQ AND
I'M SHOWING YOU HERE THE POISE
STATE OF FOUR GENES WHICH ARE IN
FACT THE GENES THAT REGULATE
INTERFERON RESPONSE, THE IRFs,
IRF7, MASTER REGULATOR OF IMMUNE
RESPONSES AND YOU SEE THAT THOSE
ARE ALL IN A POISE STATE AND
WHAT YOU SEE IN CIRCLES ARE THE
CD4 T-CELLS, SO YO THEY'RE ALREY
PROTECTED FROM GETTING INFECTED
BECAUSE ALL THE INTERFERON --
ALREADY AND THE ANTIVIRAL
INTERFERONS ARE BEING
UPREGULATED.
WHAT I DON'T SHOW YOU ALSO --
INNATE HUMAN CELLS -- TO FOLLOW
UP ON, WE SHOWED IN MACAQUES
WE'RE NOT ABLE TO CONTROL
VIREMIA, SHOWED YOU THE MAJOR
REGULATOR -- HUMAN DYSFUNCTION,
THAT IN MONKEYS WERE NOT ABLE TO
PROTECT THAT LOCUS IS OPEN.
SO IN MONKEYS WHICH ARE
PROTECTED IT'S OPEN, IN MONKEYS
THAT ARE NOT PROTECTED -- SO IT
GIVES YOU A VERY STRONG
MOLECULAR BASIS FOR THE EFFECT
THAT YOU ARE SEEING.
SO AT LEAST IN SUMMARY, WHAT THE
STUDY ALREADY SHOWS US IS THAT
IN FACT YOU HAVE A VERY STRONG
ROBUST INNATE RESPONSE EARLY ON
WHICH IS DOWNSTREAM OF BILE
ACIDS AND THOSE INTEGRATE
TOGETHER, ABLE TO PRIME THE
IMMUNE RESPONSE BUT ALSO TO
PROTECT -- SO THE NEXT STEP,
WHAT WE DID IS TO EXTEND OUR
PLANNINGS TO THREE ADVANCE
STUDIES.
ONE WHERE WE INFUSED INTO YOUR
HOST, IN ONE SUBJECT THAT WE
WERE ABLE TO SHOW OVER THREE
YEARS BUT ALSO IN SUBJECTS WE
WERE ABLE TO STOP ATI UPON
INFUSION, THE SUBJECTS WERE ABLE
TO CONTROL VIRAL LOAD FOR UP TO
SEVEN YEARS, ONE OF THEM AT
LEAST.
TWO OTHER STUDIES, ANTIPD-1 IN
PERSONS LIVING WITH HIV, ALSO
CANCER WE WERE ABLE TO SHOW
AGAIN THE STUDIES WITH SHARON
LEWIN AND STEVE ALSO HAVE --
WERE PART OF, THAT UPON THE
INFUSION, WE HAD CLEAR
SIGNATURE.
ONE DAY -- THAT PREDICT THE
OUTCOME TWO YEARS LATER, AND
AGAIN THE STUDY -- WHICH I JUST
SHOWED YOU, NOW WHEN YOU MERGE
ALL THESE DATA AND YOU TRY TO
FIGURE OUT WHETHER SIGNATURE
THAT IS COMING TO ALL THOSE
PRE-ATI OR IMMEDIATELY POST
INFUSION, AGAIN WHAT REALLY PANS
OUT IS INTERFERON -- THAT ARE
BEING CIRCLED OR SQUARED, ALL
THESE ARE -- SO THE MOTHER THAT
YOU HAVE IS WHATEVER IMMUNE
INTERVENTION, IS IT -- WHERE THE
INTERFERON LOCUS IS OPEN, YOU'RE
GOING TO HAVE PRIME CD4 T-CELLS
TO IN FACT PROVIDE HELP TO
CD8 T-CELLS, SO IF THERE'S NO
HELP, YOU WON'T GET PERSISTENT
CD8s AND YOU WILL GET
EXHAUSTION, BUT AT THE SAME
TIME, YOU'RE PROTECTING T-CELLS
OR OTHER CELLS FROM GETTING
INFECTED.
SO THIS IS REALLY A CONCEPT THAT
NOW WE WANT TO GO INTO NO NON-HN
PRIMATE, BUT ALSO IN HUMAN,
CLINICAL TRIALS, I'LL BE ABLE TO
PRESENT TO YOU IN THE NEXT
ITERATION OF THIS PROGRAM.
SO OF COURSE I JUST COLLECT THE
DATA AND THINK ABOUT THEM, AND I
HAVE AN AMAZING GROUP OF PEOPLE
THAT WORK WITH ME.
REALLY LEADERS IN THE FIELD.
AND WILL TAKE MY LEGACY FORWARD
AND THEN, OF COURSE, ALL THE
COHORT, MY COLLEAGUES, JAVIER,
NINOS AND THEIR COLLEAGUES, AND
SUMITA.
THANK YOU.
[APPLAUSE]
>> OKAY, SO I'M GOING TO GIVE
YOU A HIGH LEVEL TOUR THROUGH RF
3, COMBINING VARIOUS STRATEGIES
THROUGH RESERVOIR ELIMINATION.
WE HAVE REACTIVATION OF LATENT
GENOMES, WE HAVE A CRISPR-BASED
TECHNOLOGY TO DISRUPT YEE NOMES
AND WE -- BASEDON ADCC AND NSM .
AND HERE IS SHOWN THE DIVERSE
TEAM OF PEOPLE WHO ARE INVOLVED
IN THIS.
THIS IS LED BY MYSELF AND SUMIT.
SO A SUMMARY, CAN WE COMBINE
THESE VARIOUS TREATMENTS TO
REDUCE THE RESERVOIR?
WHAT WE'VE ACCOMPLISHED SO FAR,
WE'VE GOT NEW VERSIONS OF
LATENCY REVERSING DRUGS TO
ELIMINATE LATENT HIV, WE'VE GOT
PROGRESS, USING NATURAL KILLER
CELLS, B CELLS AND ANTIBODIES.
AND WE DEVELOPED GENE EDITING
TOOLS TO DIRECTLY ATTACK LATENT
HIV GENOMES.
OF COURSE THIS IS IMPORTANT AND
RELATES TO OUR AGENDA BECAUSE WE
BELIEVE WE'RE GOING TO NEED TO
REDUCE THE RESERVOIR TO ALLOW
THE IMMUNE THERAPIES THAT YOU'VE
HEARD ABOUT FOR THEM TO HAVE A
CHANCE TO WORK.
SO FIRST OF ALL THE WORK THAT'S
BEING DONE ON RESERVOIR
REACTIVATION MOSTLY DRIVEN BY
LARS AND SUMIT.
SO THE IDEA HERE IS THAT WE
RECOGNIZE LRAs ARE LIKELY TO
NEED REPEAT DOSING SO
OPTIMIZATION OF THEIR CHEMISTRY,
REDUCED TOXICITY AND DOSING
REGIMENS IS GOING TO BE
IMPORTANT.
SO THE TEAM HAVE DEVELOPED A
WHOLE SERIES OF NEW NOVEL SMACK
MIMETICS WHICH THE
CHARACTERISTICS ARE SHOWN IN THE
GRAPH ON THE LEFT.
THEY'RE ALL ABLE TO REACTIVATE
LATENT HIV IN JLAT CELLS.
IN ADDITION THEY HAVE A RANGE OF
DIFFERENT PK AND PD PROPERTIES,
SO ON THE RIGHT-HAND SIDE YOU'LL
SEE TWO DIFFERENT DRUGS,
CIAPAVIR AND SBP-6513 AND THEY
SHOW DIFFERENT CHARACTERISTICS
IN TIME OF ACTION.
AT THE SAME TIME WE'RE
INTERESTED IN IDENTIFYING
COMBINATIONINGS OF OTHER DRUGS
WE CAN COMBINE WITH THESE SMACK
MIMETICS.
SO HERE I'M SHOWING YOU A STUDY
WHERE CIAPAVIR IS BEING COMBINED
WITH TWO DIFFERENT SPEC
INHIBITORS.
THIS GIVES YOU DRUGS THAT ARE
FAR LESS TOXIC.
YOU'LL SEE ALL OF THEM SYNERGIZE
NICELY WITH CIAPAVIR.
AND THEN IN ADDITION, WE'RE ALSO
LOOKING FOR COMPLETELY NEW
LATENCY REACTIVATION DRUGS AND
WE'RE DOING THAT BY SCREENING
THE REFRAME LIBRARY WHICH IS
12,000 COMPOUNDS THAT ARE
FDA-APPROVED OR SORT OF NEAR
FDA-APPROVED, SOME FROM SORT OF
PRE-INDs.
IMPORTANTLY THEY'RE BEING
SCREENED NOT IN A CELL LINE
MODEL, BUT IN CD4 CELLS FROM
PEOPLE LIVING WITH HIV ON ART.
AND YOU'LL SEE ON THE GRAPH AT
THE BOTTOM THAT SHOWS SOME
INITIAL CHARACTERIZATION AND
SOME OF THE HITS THAT HAVE COME
OUT OF THIS.
SO WE'RE OPTIMISTIC THAT WE'LL
IDENTIFY BETTER, SAFER, POSSIBLY
COMBINATIONS OF LRAs THAT HAVE
BETTER PROPERTIES THAT FIT WITH
THE PROFILE FOR PEOPLE LIVING
WITH HIV.
MOVING ON TO SOME OF THE
APPROACHES WE'RE TAKING TO
ENHANCE IMMUNE CLEARANCE, I'M
GOING TO TELL YOU TWO STORIES,
HOW WE'RE RECRUITING MAs THIS,
IS WORK FROM JEFF MILLARD'S TEAM
AND MY WORK ON ENGINEERING B
CELLS.
SORE TRIKES RECOGNIZE BOTH --
THEY ALSO RECOGNIZE THE CD16
RECEPTOR ON NK CELLS.
THEREBY THEY DIRECT NK CELLS TO
AN INFECTED OR REACTIVATED CELL.
IN ADDITION, THEY ALSO HAVE
IL5-15 THAT SERVES TWO PURPOSES.
IT ACTIVATES THE NK CELLS AND
ALSO POTENTIALLY REACTIVATES
LATENT GENOMES.
JUST ONE PIECE OF DATA SHOWING
YOU THAT WE HAVE MADE TRIKES
THAT RECOGNIZE BOTH HIV AND SIV
AND CAN RECOGNIZE BOTH THE HUMAN
AND MACAQUE FORMS OF CD-16.
IN THE DATA I'M SHOWING YOU
HERE, THE LITTLE ARROWS POINT TO
THE ENHANCED KILLING THAT WE
ACHIEVE WHEN WE COMBINE NK CELLS
WITH TRIKES IN EITHER
REACTIVATED HIV OR SIV INFECTED
CELLS.
MY GROUP IS WORKING ON AND YOU
ALSO HAD A LITTLE BIT OF THIS
EARLIER FROM JOHN MILLARD SO WE
ARE TAKING B CELLS AND ENG
FEARING THEM TO MAKE COMPLETELY
CUSTOMIZED MOLECULES.
AND THE IDEA HERE IS THAT WE
COULD THEN PUT THEM INTO AN
ANIMAL OR A HUMAN AND THEN
VACCINATE WITH GP120 BECAUSE
UNLIKE EXPRESSING AN ANTIBODY
FROM, SAY, MUSCLE, AND IF YOU
EXPRESS THE ANTIBODY FROM THE
AUTHENTIC ANTIBODY LOCUS,
IMMUNOGLOBULIN LOCUS IN B CELLS,
YOU HAVE THE POTENTIAL FOR THAT
ANTIBODY TO RESPOND TOITY
VACCINTO ITSVACCINE AND PROVIDEM
SECRETION OF THE ANTIBODY.
BECAUSE WE'RE USING AN SIVMAC
239 MODEL, WE HAD TO DEVELOP
CANDIDATE ANTIBODIES THAT WOULD
WORK IN THIS SYSTEM.
SO USING THE SERIES OF BNABs
RECENTLY IDENTIFIED BY MARIO, WE
DERIVED OUR OWN VERSION OF
ITS103 THAT'S SHOWN ON THE LEFT,
AND WE ALSO PLAYED AROUND WITH
ECD4IG AND DID A SORT OF MIX AND
MATCH AND FOUND THE BEST VERSION
OF THE MOLECULE THAT WORKED
AGAINST SIVMAC 239.
BUT THEN IMPORTANTLY WE WERE
ALSO ABLE TO COMBINE THIS
THROUGH OUR EDITING TECHNOLOGY
WITH CHANGES IN THE FC PORTION
OF THE ANTIBODY.
SO WE'VE INCORPORATED SOME
MUTATIONS THAT ARE KNOWN TO
ENHANCE ADC SEQ KILLING BY NK
CELLS AND THE GRAPH SHOWS YOU
DOWN AT THE BOTTOM IN RED, THIS
IS OUR SORT OF OPTIMIZED
ANTIBODY THAT ALSO CONTAINS
THESE MUTATIONS.
THE FINAL COMPONENT OF RF 3 IS
USING BASE EDITORS WHICH ARE A
POTENTIALLY SAFER FORM OF
CRISPR/CAS 9 TO TARGET THE HIV
GENOME, AND THIS IS WORK DONE
WITH ROSS WILSON.
SO WE'VE IDENTIFIED A COUPLE OF
SEQUENCES, WE REALLY LIKE THE
TATTER BOX AND THE LTRs IN
BOTH HIV AND SIEVE A SIV AS A SO
TARGET.
OUR APPROACH, TRYING TWO
DIFFERENT WAYS OF THINKING ABOUT
DELIVERING THESE BASE EDITORS IN
VIVO.
ONE APPROACH IS TO PACKAGE THEM
INTO A RETROVIRAL PARTICLE OR A
VLP.
AND THE SECOND APPROACH IS TO
MAKE THEM AS A KIND OF
RECOMBINANT COMBINATION PROTEIN
AND YOU'LL SEE HERE I'M SHOWING
YOU THE LEVEL OF EDITING WE CAN
GET WHEN WE ADD EITHER THE
VLPs TO DELIVER THE BASE
EDITORS OR THE RECOMBINANT
PROTEIN.
WITH THE RECOMBINANT PROTEIN, WE
ALSO SIGNIFICANTLY INCREASE ED
ILTING WHEN WE ADD A CELL
PENETRATING PEPTIDE.
THEN OF COURSE MOST IMPORTANT
THE DIFFICULT AND CHALLENGING
THING IS HOW THE HECK DO WE
TARGET A CD4 T-CELL IN VIVO.
SO TO THAT END, WE'RE TRYING TWO
DIFFERENT APPROACHES WITH THESE
TWO DIFFERENT DELIVERY SYSTEMS,
AND FOR EXAMPLE, I'M SHOWING
HERE THAT WE ARE ABLE TO
EXQUISITELY TARGET RESTING
CD4 T-CELLS WITH OUR RETROVIRAL
PARTICLES, AND WE HAVE WORK IN
PROGRESS MAKING THE COMBINATION
TO TARGET T-CELLS BY ADDING A
LIGAND TO THOSE.
WITH THAT, I WILL FINISH.
THESE ARE THE NAMES OF THE
PEOPLE INVOLVED IN THE FOUR
DIFFERENT PROJECTS AND I'M HAPPY
TO PASS ON TO OUR COMMUNITY
ENGAGEMENT REPRESENTATIVE.
[APPLAUSE]
PRAWSH
>> GOOD AFTERNOON, EVERYONE.
I'M JEFF TAYLOR.
YOU MAY NOT RECOGNIZE ME BECAUSE
I SHAVED MY BEARD.
AS YOU'VE HEARD, JEFF IS NOT
WITH US UNFORTUNATELY TODAY, BUT
I AM ANDY CATES, ONE OF THE
CO-CHAIRS OF THE RID HIV
COLLABORATORY, COMMUNITY
ADVISORY BOARD, AND HELLO.
THERE'S A WIND UP HERE.
SO RID HIV, WE'RE KIND OF A FUN
CAB.
WE HAVE DONE SOME PRETTY NEAT
THINGS TOO.
SO THE MDC CAB LANGUAGE
GUIDELINES, WE HAD PRESENTED AT
IAS LANGUAGE AS YOU'LL HEAR IS
SOMETHING THAT WE'VE CONTINUALLY
BEEN HARPING ABOUT FOR MANY,
MANY YEARS, AND ALSO BRIDGETTE
PICOU PRESENTED AT USCHA ON A
HALF DAY CURE SESSION WITH DARE,
CRISPR FOR CURE AND THE REUNION
PROJECT.
THEN WE DID A LONG TERM SURVIVOR
WEBINAR SERIES, WHICH I THINK
YOU'VE HEARD A LOT ABOUT.
THERE'S BEEN SEVERAL
COLLABORATORIES THAT HAVE
PRESENTED THAT.
BACK TO LANGUAGE, BEFORE I
REALLY DIG INTO THIS, I WONDER
IF YOU'D KIND OF INDULGE ME FOR
A SECOND, MAYBE LOOK AROUND THE
ROOM AT WHO'S IN HERE, JUST KIND
OF LOOK AROUND THE ROOM AND
IMAGINE YOU'RE THE ONLY PERSON
IN HERE THAT IS NOT AN INFECTED
SUBJECT.
THEN FLIP THAT AND THINK ABOUT
EVERYBODY ELSE IN THIS ROOM
BEING AN INFECTED SUBJECT, AND
YOU'RE THE ONLY ONE THAT'S NOT
INFECTED.
DID THAT, LIKE, REGISTER?
I MEAN, I'M HOPING IT KIND OF
GAVE PEOPLE A VISCERAL REACTION.
I DIDN'T INTEND TO, LIKE, BRING
THINGS THIS DIRECTION, BUT ONE
OF THE CAB MEMBERS SHOWED ME
THIS FLYER THAT'S OUTSIDE.
AND THE INCLUSION CRITERIA FOR
THIS RESEARCH STUDY IS THE VERY
FIRST BULLET, HIV-1 INFECTED
THIS IS FROM THE NIH, AND THE
NIH IS THE ONE THAT'S BEEN
TELLING US NOT TO USE THIS
LANGUAGE.
SO ANYWAY, FOOD FOR THOUGHT.
MOVING ON.
SO WE DID UPDATE THE COMMUNITY
PREFERRED LANGUAGE, AND THAT'S,
AS YOU KNOW, A GOAL OF MAKING
PEOPLE FEEL, WELL, HUMAN.
AND NOT INFECTED OR SUBJECTED.
I WILL LEAVE IT AT THAT BECAUSE
I THINK MY POINT IS MADE.
SORRY TO BE A DRAG AFTER LUNCH.
THIS IS THE WEBINAR SERIES THAT
I'M SURE EVERYBODY HAS SEEN
ENOUGH TIMES THAT YOU'VE
MEMORIZED THE DATES AND YOU'RE
GOING TO JOIN US IN THE NEXT
ONES.
THE NEXT ONE IS OCTOBER 24TH,
AND THAT'S THE PARTICIPANT
EXPERIENCES IN RESEARCH, WHERE
WE'RE GOING TO HAVE PAUL
EDMONDS, MATT SHARPE AND TOM
VILLA ALONG WITH GAIL GRAHAM
TALKING ABOUT THEIR EXPERIENCES
IN RESEARCH.
I KNOW TIME IS KIND OF SHORT FOR
US, SO IN MY LAST SLIDE, I WILL
GO OVER OUR FUTURE COMMUNITY
ENGAGEMENT ACTIVITIES THAT WE'VE
GOT PLANNED.
SO MANY OF YOU HOPEFULLY ALL OF
YOU HAVE HEARD OF THE LAST GIFT
STUDY, WHICH IS SOMETHING THAT
HAS GENERATED AN AWFUL LOT OF
GREAT DATA.
ALL COMING FROM AMAZINGLY AL
TRUE IS ALTRUISTIC PARTICIPANTST
JOINED THIS STUDY.
IT'S CONTINUING TO GO ON AND ON
NOVEMBER 6TH, WE'RE GOING TO
HAVE A COMMUNITY CONSULTATION
EVENT WHERE THE COMMUNITY, WHO
IS A LARGE, LARGE PART OF THIS
STUDY, WE HELPED FORM THE STUDY,
WE WERE CONSULTED EVERY SINGLE
STEP OF THE WAY AND NOW WE'RE
BEING CONSULTED AGAIN.
SO IT IS DEFINITELY ONE OF THOSE
THINGS THAT IS FOR US, WITH US.
THEN ON WORLD AIDS DAY, WE'VE
GOT THE TIMOTHY RAY BROWN
COMMUNITY CURE SYMPOSIUM.
THIS WILL BE THE SECOND ONE THAT
WE'VE DONE.
DR. CANNON AND CHANDA WILL BE
HERE, OR THERE IN PALM SPRINGS.
WE'LL ALSO HAVE JOHN ZAIA FROM
THE CITY OF HOPE AND OUR OWN
PAUL EDMONDS, THE CITY OF HOPE
PATIENT.
THEN WE HAVE A CONTINUING VIRAL
RESERVOIR WEBINAR SERIES ALSO
DONE WITH DARE AND CRISPR AND
CURE TREATMENT -- CURE AND THE
TREATMENT ACTION GROUP.
THESE ARE REALLY WELL, WELL
ATTENDED WEBINARS.
YOU'VE HEARD SOME OF THE NUMBERS
BEFORE BUT THERE'S PEOPLE
LOOKING AT THESE WEBINARS FROM
ALL OVER THE WORLD.
IT'S REALLY HEARTENING.
THEN WE DO A PRECROI COMMUNITY
CURE WORKSHOP.
THAT'S SOMETHING THAT'S BEEN
HAPPENING FOR YEARS.
WE GET SOME OF THE MOST
IMPRESSIVE PRESENTATIONS
DIRECTLY TO THE COMMUNITY PRIOR
TO THE DAY BEFORE CROI.
WE'VE ALSO COME UP WITH THE IDEA
OF DOING A SPANISH LANGUAGE
RESERVOIR, AND IT'S GOING TO
FEATURE THE LONDON PATIENT, ADAM
CASTILLEJO, SO THAT'S KIND OF
COOL.
WE DO HAVE SPANISH IN THIS WORLD
AND IT'S ABOUT TIME THAT WE'VE
STARTED REALLY REACHING OUT TO
FOLKS THAT SPEAK SPANISH
LANGUAGES AND WE'RE GOING TO BE
DOING THAT -- I'M NOT EXACTLY
SURE ON THE DATE BUT IT COMING
UP FAIRLY SOON.
AND THEN THE LONG TERM SURVIVOR
WEBINAR SERIES CONTINUES.
WITH MORE COLLABORATIONS FROM
DARE, CHRIS TER FO CHRIS TE CRID
THAT'S GOING TO BE GOING ON IN
THE WILL END OF THE YEAR.
SO ANYWAY I'VE GOT ABOUT
26 SECONDS TO LEAVE YOU WITH,
AND I THANK YOU FOR YOUR
ATTENTION.
[APPLAUSE]
>> THANK YOU, TEAM RID, EXACT
TIME, 40 MINUTES.
SO I APPRECIATE THAT.
THE SESSION IS NOW OPEN FOR
QUESTIONS AND ANSWERS.
GO YOU A HEAD.
>> HI, KIRA FROM UMASS.
I CAN'T SEE YOUR NAME TAG FROM
HERE.
I THINK IT'S ASHISH.
CLARIFICATION ON ONE OF YOUR
SLIDES.
WHEN YOU TALKED ABOUT THE LACTO,
I THOUGHT THAT WAS REALLY
INTERESTING.
IS THE LACTO IN THE PLASMA OR IS
IT THE LACTO IN THE GUT THAT
CORRELATED WITH --
>> NO, SO WE DID PAT SEQ, IT'S A
PLASMA QUANTIFICATION -- WHICH
WAS A PLASMA QUANTIFICATION OF
MICROBIAL READS, AND WE MAP THAT
TO THE LACTOBACILLUS GENUS, AND
THEN TO BREAK DOWN THE SPECIES
CLUSTER, WE DID AN UNBIASED
SCREEN OF ALL KNOWN GUT
LACTOBACILLI.
THE TOP 14.
WE SAW THE ONES KNOWN TO BE LESS
ABUNDANT IN HUMANS WERE THE ONES
THAT PROMOTED TGF BETA
PRODUCTION AND IMMUNE
DYSFUNCTION.
>> SO YOU'RE ASSUMING THAT COMES
FROM THE BACTERIUM THAT'S IN THE
PERIPHERY, IN THE BLOOD, AM I
CORRECT?
>> NO, THEY'RE JUST MICROBIAL
READS, SO THEY'RE AN ARTIFACT OF
THE CROSSTALK BETWEEN THE IMMUNE
SYSTEM AND THE BACTERIA AT THE
MUCOSA.
>> OKAY, PERFECT.
>> SO QUESTION FOR RAFICK.
IN THE INTERFERONS, DID YOU SEE
ANY DIFFERENCE BETWEEN THE ALPHA
ISOTYPES AND BETA WHEN IT CAME
TO THE INTERFERON SIGNATURE, AND
THEN THE SECOND PART IS, IS IT
ALL COMING FROM THE MYELOID CELL
OR ARE THERE OTHER CELLS
CONTRIBUTING TO THE TYPE I
INTERFERON PRODUCTION?
>> SO THE FIRST PART OF YOUR
QUESTION, IT'S MOST LEEWAY TA,
ALPHA.
IN VITRO, THE -- BUT TO MEASURE
IN VITRO WE SEE CLEAR ALPHA
VERSUS BETA SIGNATURE.
THERE'S HUGE OVERLAP BETWEEN
ALPHA AND BETA SIGNATURE, BUT
WHAT WE KNOW IS IT'S REALLY A
BETA WHICH -- REALLY DRIVING
BETA INTERFERON AND -- SO THAT'S
THE FIRST QUESTION.
THE SECOND ONE WAS?
ANY CELL CAN MAKE IT.
-- HAVE SHOWN THAT -- CAN
TRIGGER -- KEYSTONE MEETING
WHERE AGAIN THERE WAS A HUGE
EMPHASIS -- CAN BE SENSORS OF --
OR BACTERIA, SO IT CAN BE --
CELLS, BUT WE HAVE TO
DEMONSTRATE THAT POINT BUT WE
ALSO SHOW THAT IN VITRO, AT
LEAST, BILE ACID CAN TRIGGER --
INTERFERON BETA BOTH IN
DIFFERENT -- AND EVEN IN NAIVE
CELLS, NAIVE T-CELLS.
SO IN VIVO, I THINK WE NEED T
TO -- TO DEMONSTRATE THAT.
>> WE CAN TAKE A FEW MORE
QUESTIONS.
>> QUICK QUESTION FOR
DR. CANNON.
I WAS REALLY CURIOUS ON YOUR B
CELL EDITING APPROACH.
I KNOW YOU'RE DELIVERING THE
REPAIR TEMPLATE WITH AN AAV AND
ELECTROPLATING CRISPR, BUT CAN
YOU TALK MORE ABOUT THOSE CELLS?
DO THEY STILL HAVE TO GO THROUGH
SOME TYPE OF -- I'M CURIOUS
EXACTLY ABOUT THE STRATEGY THE
THERE.
>> SORRY, I DIDN'T QUITE GET
WHAT YOU SAID TOWARDS THE END.
>> I WAS JUST WONDERING ONCE YOU
BASE KR HAVE YOUR TEMPLATE, GOT
YOUR CRISPR, YOU TARGET THE B
CELL LOCUS AND INTRODUCE YOUR
ANTIBODY, ONCE THAT B CELL IS
THEN PUT BACK INTO AN ANIMAL, IS
THAT ANTIBODY -- DOES THAT GO
THROUGH -- DOES IT GO THROUGH --
BASICALLY, ONCE YOU'VE MODIFIED
THE B CELL LOCUS IN THAT
PARTICULAR WAY?
>> OKAY.
SO THAT'S OUR THINKING, IS THAT
BY INSERTING A B CELL INTO THE
AUTHENTIC IMMUNOGLOBULIN LOCUS,
WE CAN HOPEFULLY RESERVE ALL THE
SORT OF NATURAL FEATURES OF B
CELLS AND ANTIBODY PRODUCTION.
SO WHAT WE'VE SEEN IS WE TAKE
THE B CELLS AND DIFFERENTIATE
THEM TOWARDS PLASMA CELLS, TYPE
OF B CELL THAT CHURNS OUT
ANTIBODIES, THEY CHURN OUT THE
ANTIBODIES.
WE CAN ALSO PUT THEM INTO --
THERE'S A NICE MODEL OF
IMMUNIZATION IN VITRO WHICH IS
BASED ON TONSIL ORGANOIDS FROM
MARK DAVIS' GROUP, WITH ARE A
VACCINE BASICALLY GP120, THE
ENGINEERED CELLS RESPOND AND
EXPAND AND DIFFERENTIATE WHAT
ANTIBODIES DO, AND INDEED WE SEE
SIGNATURES OF SOMATIC
THAT EXPERIMENT WAS ALSO
PUBLISHED VERY RECENTLY, IT TOOK
US A LITTLE BIT MORE THAN THREE
YEARS, I SHOULD SAY, TO COMPLETE
THIS BECAUSE WE HAVE TO REPEAT
MULTIPLE TIMES AND THEN THE RATE
OF THE SUCCESS OR NO REBOUND
INCREASED UP FOR CLOSE TO 50% OR
MORE.
SO THIS ALL TOGETHER IN
COLLABORATION WITH ANOTHER
GROUP, WE STARTED USING
NON-HUMAN PRIMATE.
AND THEN THE RESULT OF THAT
EXPERIMENT SHOWS THAT IN THE
LARGER GROUP OF ANIMAL SHOW THAT
AGAIN WHAT WE'VE GOT EARLIER WAS
REPRODUCIBLE AND THEN THE RESULT
IN THE DISSOLUTION OF THE VIRUS
CRISPR IN ALMOST EVERY TISSUE
AND ORGANISM BROAD RANGE
DISTRIBUTION AND FUNCTIONAL
INACTIVATION OF THE VIRUS.
SO WITH THAT INFORMATION, WE
DEVELOPED THE PROGRAM, MARTIN
DELANEY, WHICH COMPRISE THREE
RESEARCH FOCUS THAT THEY'RE --
MY COLLEAGUE DESCRIBED THAT, DO
YOU WANT TO PRESENT THIS ONE
BECAUSE IT'S A CONTINUATION OF
THE NEXT ONE.
>> WE ARE A NEW COLLABORATORY.
WE HAVE AS EVERYONE ELSE THREE
RESEARCH FOCI, AND YOU CAN SEE
THE INTERACTIONS OF RESEARCH
FOCUS.
I THINK WE'RE A LITTLE BIT
SMALLER.
DELANEY AS FAR AS PI NUMBERS
THAN SOME OF THE OTHERS.
BUT VERY INTERACTIVE.
BASICALLY I WANTED TO GIVE A
LITTLE BIT OF OVERVIEW ON SOME
OF THE MODEL SYSTEMS THAT WE'RE
USING.
WE START FROM INSILICO, SO THIS
INCLUDES BIOINFORMATICS AND
COMPUTER BASED MODELING.
WE USE A LOT OF IN VITRO CELL
LINES, EX VIVO CLINICAL SAMPLES,
AND TWO DIFFERENT MICE MODEL, AN
IN VIVO HUMANIZED AN MO MODEL
AND ALSO A NOVEL MOUSE MODEL
WHICH I'LL TALK A LITTLE ABOUT
WHEN I TALK IN RETROVIRAL 2.
I'M IN OF COURSE NON-HUMAN
PRIMATES.
SO AS YOU WOULD GUESS FROM THE
NAME OF OUR COLLABORATORY, A LOT
OF OUR TECHNOLOGIES ARE BASED ON
CRISPR.
WE DO A LOT OF DIFFERENT THINGS
WITH CRISPR.
ONE IS FOR CRISPR MODIFICATION
OF IMMUNE CELLS AND THAT'S IN
RETROVIRAL 2, AND THEN
RETROVIRAL 3 IS REALLY LOOKING
AT THE ELIMINATION OF THE VIRAL
RESERVOIR.
SO WE TAKE KIND OF A MULTIPLEX
APPROACH IN ALL OF THESE WHERE
WE LOOK AT CRISPR MODIFICATION,
SELECTION OF THE GUIDE RNAs
AND THAT'S WHAT GIVES US THE
SPECIFICITY.
WE LOOK AT A NUMBER OF OFF
TARGET ASSESSMENTS AND THEN DO
EX VIVO EVALUATIONS OF
EFFICIENCY AND SPECIFICITY.
THIS INCLUDES BARCODED VIRAL
ANALYSIS WHICH WE USED IN
RETROVIRAL 1.
AGAIN WE USE AN AAV DELIVERY
SYSTEM AND IN RF3, AND WE HAVE
OUR IN VIVO ANALYSES.
SO I WANTED TO GIVE A LITTLE
ABOUT WE'RE A NEW COLLABORATORY
BUT THESE PAPERS WERE DIRECTLY
FUNDED OR PARTIALLY FUNDED BY
THE CRISPR FOR CURE
COLLABORATORY, SO AS CLEARLY
ALLUDED TO, THE PAPER LOOKING AT
CRISPR EDITING BETWEEN CCR5 AND
HIV, AS WELL AS WE DID ANOTHER
STUDY LOOKING AT THE CRISPR
EDITING OF PROTEIN COSMOGS AND
THEN SOME OTHER STUDIES YOU CAN
SEE AS WELL.
I JUST WANTED TO BRING UP OUR
CORPORATE PARTNER WHICH IS
EXCISION BIOTHERAPEUTICS.
WE DID A PAPER WITH THEM ABOUT
THE RECLINICAL SAFETY FOR SAB
NON-HUMAN PRIMATES AND THAT WAS
NOT FUNDED BY THE DELANEY.
AS ALLUDED TO, THEY HAVE
RECEIVED FDA APPROVAL FOR USING
CRISPR IN PEOPLE WITH HIV.
NOW I'M GOING TO INVITE BEN, ONE
OF OUR EARLY STAGE
INVESTIGATORS FROM THE LAB.
[APPLAUSE]
>> THANK YOU.
I'D LIKE TO GIVE A BRIEF
OVERVIEW, KEY QUESTION BEING
WHETHER OR NOT RNA AND DNA
METHODS FOR MEASURING HIV
RESERVOIRS CAN BE ADAPTED TO
SIV -- CAN BE EVALUATED IN AN
SIV INFECTED RHESUS MACAQUE
MODEL.
SOME KEY FINDINGS, WE AND OTHERS
HAVE BEEN SUCCESSFUL FOR
ADAPTING THESE MEASUREMENT
TECHNIQUES FOR HIV RESERVOIRS
ADAPTIVE FOR SIV.
THIS IS IMPORTANT BECAUSE DOING
RESERVOIR MEASUREMENTS OF SIV
WILL HELP EVALUATE POTENTIAL
ERADICATION STRATEGIES THAT WE
HOPE CAN EFFICIENTLY BE APPLIED
TO HIV.
WE'RE EXCITED ABOUT THIS BECAUSE
WE NOW BASE BACEICALLY HAVE MANY
OF THE TOOLS WE WOULD NEED TO
SHOW SIGNIFICANT REDUCTION IN
HIV RESERVOIRS ON A PATH TOWARDS
EVENTUALLY GETTING SOMEONE OFF
OF THERAPY OR AT LEAST HAVING
THERAPY INTERRUPTION, BUT AN TAI
WOULD NOT BE NEEDED BECAUSE
THESE TECHNIQUES ARE SO
SENSITIVE TO SEE WHETHER OR NOT
WE HAVE A REDUCTION IN THE
RESERVOIR AND IF IT'S SAFE TO
CONTINUE.
SO TODAY I'LL BE DESCRIBING OUR
METHOD FOR DETECTING HIV
PROVIRUSES USING A DIGITAL PCR,
AND THIS IS A METHOD WE
DEVELOPED PRIOR TO THE
PUBLICATION OF THE MORE WIDELY
ADOPTED IPDA.
IT'S USING A SLIGHTLY DIFFERENT
APPROACH BUT YIELDS VERY SIMILAR
RESULTS.
HERE ARE THE BINDING SITES FOR
OUR PRIMER PROBE SETS IN AFN
ASSAY WE CALL THE POTENTIALLY
INTACT PROVIRAL LOAD ASSAY OR
PIPL FOR SHORT.
YOU CAN SEE IN COMPARISON WITH
THE IPDA.
SO WE WERE ABLE TO USE THIS
ASSAY TO SHOW IN VITRO SOME
REDUCTIONS OF HIV RESERVOIRS
AFTER TREATMENT WITH CYTOTOXIC
NK CELLS THAT WERE EXPANDED IN
OUR LABORATORY AND WORKED WITH
MARY ANN AND THAT'S GOING TO BE
PUBLISHED LATER THIS YEAR.
SO ALL HIV CELLS AS YOU KNOW
CONTAIN A COPY OF THE HIV GENOME
SHOWN HERE INTEGRATED INTO THEIR
DNA BUT MOST PROVIRUSES IN
PEOPLE LIVING WITH HIV ARE
DEFECTIVE DUE TO LARGE
DELUSIONS, SO AN IMPORTANT PART
OF FINDING AN HIV CURE IS TO
DETERMINE HOW MANY OF THESE
PROVIRUSES ARE ACTUALLY INTACT
SINCE THIS IS AT LEAST ONE
REQUIREMENT TO MAKING A
REPLICATION COMPETENT VIRUS THAT
CAN SPREAD TO OTHER CELLS AND
INCREASE THE VIRAL RESERVOIR.
SO IN OUR ASSAY, THE DNA IS
EXTRACTED FROM CD4 T-CELLS AND
THEN MIXED WITH PCR REAGENTS AND
PRIMERS AND PROBE FOR GAG AND
ENVELOPE AND THESE ARE SPREAD ON
TO A MICRO CHIP IN SOLUTION WITH
ABOUT 20,000 WELLS PER CHIP AND
THIS IS DONE WITHOUT MAKING ANY
OIL-BASED DROP LETS.
AFTER THERMAL CYCLING AND
SCANNING FOR FLUORESCENCE, ONE
CAN SEE PROVIRUS IS DETECTED
ONLY WITH GAG OR ENVELOPE
PRIMERS, AND SO THESE SINGLE
POSITIVES ARE CONSIDERED
DEFECTIVE, COMPARED TO THE MORE
RARE DOUBLE POSITIVES RECOGNIZED
BY BOTH SETS OF PRIMERS, WHICH
WE WOULD CONSIDER TO BE
POTENTIALLY INTACT.
AGAIN THIS IS PROBABLY BASED ON
RESULTS PUBLISHED USING THE IPDA
METHOD.
SO SHOWN HERE ARE SOME IMPORTANT
CONTROLS FOR THIS ASSAY, WHICH
WOULD BE TRUE OF ANY IPDA.
SO THE DNA FROM HIV NEGATIVE
CELLS HELP ESTABLISH THE
BACKGROUND LEVELS OF
FLUORESCENCE THAT WE CAN EXCLUDE
AND WHEN THIS DNA IS MIXED WITH
A MOLECULAR CLONE OF HIV, THIS
REPRESENTS A 100% INTACT
PROVIRUS AND IN THIS CON TECH,
WITHIN ACCESS OF HIV NEGATIVE
DNA THERE'S NO FALSE DETECTION
OF DEFECTIVE SINGLE POSITIVE
PROVIRUSES DUE TO ANY PCR
INHIBITION OR ERRORS, AND SO ALL
THAT WE SEE ARE DETECTED AS
INTACT WITH THIS APPROACH.
ON THE RIGHT IS AN EXAMPLE OF
MEMORY CD4 T-CELLS DNA FROM A
PERSON WITH HIV ON ART.
THIS ILLUSTRATES THE ABUNDANCE
OF DEFECTIVE PROVIRUSES DETECTED
WITH OUR ASSAY VERY SIMILAR TO
THE IPDA IN THESE SINGLE
POSITIVES AND ONLY A RARE
PROPORTION IS ACTUALLY A DOUBLE
POSITIVE THAT WOULD BE
CONSIDERED POTENTIALLY INTACT,
IN THIS CASE ONLY 4%.
SO BASED ON MY EXPERIENCE WITH
DOING THESE KINDS OF ASSAYS, I
WAS RECRUITED BY THE CRISPR FOR
CURE TO GET SOME OF THE
PUBLISHED SIV IPDAs UP AND
RUNNING WITH OUR EQUIPMENT SO WE
COULD EVALUATE IN RHESUS
MACAQUES.
SO THE LOCATIONS AND PRIMERS OF
THE PROBES USED IN THE SIV ARE
SHOWN HERE IN COMPARISON WITH
THE HIV, AND AGAIN THIS WAS
DEVELOPED FROM BOB SILICANO'S
LAB, TO SEE WHERE THE DELETIONS
TEND TO OCCUR, AND SO THEY
DETERMINED THAT POLE, AN
ENVELOPE WHERE THE BEST TARGETS
TO PROBE FOR.
AGAIN WE'RE GOING TO ADAPT THIS
APPROACH USING OUR MICRO
CHIP-BASED DIGITAL PCR.
I HIT A BUTTON.
HOW DO I GET BACK TO -- THIS IS
NOT -- SO HERE'S HOW THE SIV
IPDA IS LOOKING.
WITH OUR EQUIPMENT, AGAIN, THIS
IS NOT BASED ON A DIGITAL
DROPLET BUT IT'S A SIMILAR IDEA.
ATION YOU CAN SEE, THE CONTROL
WITH SIV NEGATIVE CELLS HAS VERY
LITTLE BACKGROUND, COMES OUT
VERY CLEAN, AND SO ON THE RIGHT,
I TESTED CD4 T-CELL DNA FROM
SHIF INFECTED RHESUS MACAQUE AND
THIS IS CLEARLY DETECTING
DEFECTIVE PROVIRUSES IN BLUE AND
RED DOTS COMPARED TO THE
POTENTIALLY INTACT PROVIRUSES
SHOWN IN GREEN.
SO SWITCHING GEARS NOW, WE CAN
ALSO DETECT SPLICED HIV MRNA AS
A WAY TO QUANTIFY POTENTIAL
RESERVOIR, SO IN RESPONSE TO HIV
AT THAT TIME, IT'S TRANSCRIBED
AND SPLICED, REHE MOV REMOVING E
SECTION ON THE LEFT OR DOUBLY
SPLICED REMOVING THIS REGION ON
THE RIGHT, OR UNSPLICED, AND ALL
THE SPLICED RNAs USE A MAJOR
SUPPLIES DONOR SITE D1 AND THOSE
THAT DO NOT REMAIN UNSPLICED.
SO THE CELLS THAT CAN PRODUCE
SPLICED HV RNAs ARE NOT
ENTIRELY DEFECTIVE BECAUSE HIV
AT THAT TIME IS PRESENT,
SUPPLIES ACCEPTOR SITES ARE
PRESENT, SO WE CONSIDER THAT
THESE CELLS ARE MORE LIKELY TO
EXPRESS HIV PROTEINS, POSSIBLY
RELEASE HIV, AND CONTRIBUTE TO
CHRONIC IMMUNE CELL EXHAUSTION.
HOWEVER, NOT ALL OF THESE CELLS
NECESSARILY HAVE INTACT
PROVIRUSES THAT COULD INCREASE
THE SIZE OF THE RESERVOIR, AND
LATENTLY INFECTED CELLS ALSO
WOULD NOT BE ABLE TO EXPRESS
THESE RNAs EVEN IF THE
PROVIRUSES WE DETECT ARE INTACT.
SO IT'S BEEN SHOWN -- THIS GOT A
LITTLE MESSED UP BUT IT'S FINE.
IT'S BEEN SHOWN THAT VAST
MAJORITY OF SINGLY AND DOUBLY
SPLICED RNAs SPLICED FROM THIS
DONOR 1 SITE TO EITHER ACCEPTOR
4 OR 5, ESPECIALLY WITH A VERY
HIGH PREFERENCE FOR ACCEPTOR 5,
1 THING THAT I NOTICED IS THAT
ALL OF THESE RNAs WHICH ENCODE
FOR ENVELOPE, REV AND NEF, THEY
ALL SHARE THIS COMMON SEQUENCE R
4 SITE.
SO WHAT THIS MEANS IS THAT BY
PRIMING ON EITHER SIDE OF THIS
JUNCTION, BETWEEN DONOR 1 AND
ACCEPTOR 5, IT POSSIBLE TO
DETECT ALL OF THESE RNAs, AT
LEAST THEORETICALLY BY RTPCR, SO
PREVIOUSLY QPCR METHODS THAT
RELIED ON A MORE TWO-STEP
APPROACH, ONE ROUND FOLLOWED BY
A NESTED QPCR, BUT WITH MY
PROTOCOL AND THE PRIMERS THAT
I'VE MADE, IT'S ACTUALLY
POSSIBLE -- IT'S ACTUALLY
SENSITIVE ENOUGH TO DETECT THESE
RNAs BY A SI SINGLE ONE STEP
DIGITAL PCR SO THIS GIVES A
SIGNIFICANT ADVANTAGE BECAUSE
WITH DIGITAL PCR, YOU CAN
DIRECTLY COUNT THE RNA MOLECULES
THAT ARE SPREAD ON TO THE PCR
MICRO CHIP WITHOUT THE NEED FOR
STANDARD CURVE OR ANY REFERENCE.
SO THIS IS A POWERFUL TOOL.
IT'SIT'S VERY HIGHLY SPECIFIC TO
DETECTION OF RNA WITH VERY
LITTLE BACKGROUND IN UNAFFECTED
CELLS AND IT'S HIGHLY
QUANTITATIVE, WHICH I'M ABLE TO
SHOW WITH A SERIAL DELUSION OF A
KNOWN NUMBER OF HIV-POSITIVE
CELLS DELIVERED WITH HIV
NEGATIVE CELLS IN THIS RANGE OF
ABOUT 128 TO 512 CELLS PER
MILLION.
AND AGAIN THIS IS QUANTITATIVE,
VERY LINEAR RELATIONSHIP, AND
THE ASSAY IS SENSITIVE ENOUGH TO
DETECT INDUCIBLE HV RNA IN
PRIMARY CELLS, SO CD4 T-CELLS
FROM A PERSON LIVING WITH HIV,
AND THAT WE HAVE IN VITRO
STIMULATED OVERNIGHT AND SHOW
THE UPREGULATION OF HIV RNA.
WE CAN LITERALLY COUNT THESE
RNAs IN THE UNIT BEING THE
NUMBER OF RNA MOLECULES PER
MICROGRAM OF RNA.
TOTAL RNA.
SO I ALSO MODIFY THIS ASSAY TO
DETECT SIV RESERVOIRS IN RNA
FROM CD4 T-CELLS, INFECTED
RHESUS MACAQUES HERE SHOWING A
SIMILAR PRIMING STRATEGY, AND SO
HERE IS THE DATA THAT I GET FROM
THIS ASSAY, AGAIN THERE'S
NEGATIVE CELL RNA PUT INTO THE
ASSAY SO WE CAN DEFINE THE
BACKGROUND LEVEL OF FLUORESCENCE
TO FIND A THRESHOLD AND WITH
ACUTELY AFFECTED CELLS WE CAN
SHOW A HE HAVE HIGH LEVEL OF RNA
DETECTED AND ALSO ILLUSTRATING
THE DYNAMIC RANGE OF THIS ASSAY,
SO OVER 200,000 RNA MOLECULES
CAN BE DETECTED PER MICROGRAM
WITHOUT SATURATION.
AND THEN MORE IMPORTANTLY, USING
CD4 T-CELLS FROM AN SIV INFECTED
RHESUS MACAQUE WE'RE ABLE TO
DETECT EVEN IN AN UNSTIMULATED
STATE SIV MRNAs THAT ARE
SPLICED, AND THEN WHEN WE TREAT
THESE CELLS OVERNIGHT WITH A --
STIMULUS, WE CAN ALSO SAMPLE
THOSE AND SEE INDUCTION OF SIV
RNA AND SHOW THAT THERE WAS
LATENCY IN THIS SYSTEM.
SO IN CONCLUSION, I THINK I'M
ABLE TO CONVINCE YOU THAT WE'RE
ABLE TO DETECT -- RNAs
DIRECTLY BY ONE STEP
ADDITIONAL -- PCR.
THIS ASSAY IS HIGHLY SPECIFIC,
QUANTITATIVE, SENSITIVE ENOUGH
THAT YOU CAN DETECT RESERVOIRS
IN PRIMARY SAMPLES AND ALSO I
CAN SHOW SIV LATENCY IN RHESUS
MACAQUES.
SO OUR PLAN IS TO APPLY THIS
KIND OF APPROACH TO SAMPLES FROM
SIV INFECTED RHESUS MACAQUES ON
ART WITH OR WITHOUT A CRISPR
MEDIATED ERADICATION STRATEGY.
AND JUST LIKE TO GIVE THANKS TO
BRANDON KEEL WHO'S MADE A
BARCODED VERSION OF SIV THAT
YOU'LL HEAR MORE ABOUT LATER,
AND THE SAMPLES WE GET FROM
RHESUS MACAQUES PROVIDED BY
TRISHA BURDOW.
THANKS TO JONATHAN KARN FOR
MENTORSHIP AND THANKS FOR THE
FUNDING FROM THE CRIP CRISPR FE
AND OUR LOCAL CFAR.
THANK YOU VERY MUCH.
[APPLAUSE]
>> NEXT I'M GOING TO TALK ABOUT
SOME OF OUR WORK WITH RF2.
SO I WANT TO SAY THAT RCHT
F2 HAS A NUMBER OF DIFFERENT
PROJECTS AND I'M ONLY GOING TO
BE TALKING ABOUT ONE OF THE
OBJECTIVES IN THIS PROJECT.
THERE'S A LOT OF PEOPLE THAT ARE
INVOLVED IN THESE STUDIES.
SPECIFICALLY SOME OF THE PIs
AT TEMPLE OR MYSELF,
DR. KAMINSKI, DR. SHANE IS
INVOLVED IN THE MR. G STUDIES,
DR. KARN AND HIS GROUP AND THEN
WE WORK WITH EXCISION
BIOTHERAPEUTICS AND DR. JERRY
ZACK.
I WON'T BE SHARING ANY OF THE
MONKEY STUDIES BUT THOSE ARE
DONE WITH MARK -- SO HERE'S MY
PLAIN LANGUAGE SUMMARY.
WHAT I'M GOING TO BE TALKING
ABOUT IS CAN WE USE GENE EDITING
TO REMOVE THE HIV RECEPTOR
CCR5 TO STOP HIV FROM ENTERING
CELLS.
SO KEY FINDINGS WERE CRIP PER
TECHNOLOGIES HAVE SHOWN
PROMISING RESULTS IN CELL
CULTURE, BLOOD AND MOUSE MODEL.
AND WHY IS THIS IMPORTANT?
SO PAST STUDIES HAVE SHOWN THAT
WHEN WE TRANSFER BONE MARROW
CELLS MISSING A PART OF THE CC
RMPLECCR5, WHICH WE CALL DELTA ,
IT CAN LEAD TO A CURE.
WHY SHOULD WE BE EXCITED ABOUT
THIS?
THIS IS NOVEL RESEARCH WITH THE
GOAL OF REMOVING CCR5 TO BLOCK
HIV INFECTION.
AND A LOT OF PEOPLE HAVE TALKED
ABOUT DOING THIS HIV BLOCKING
CCR5 IN THE PAST COUPLE DAYS,
BUT OUR STRATEGY IS REALLY TO DO
AN IN VIVO GENE EDITING PROCESS.
SO AGAIN THE OBJECTIVE FOR THIS
IS TO KNOCK OUT CCR5 BY USING
CRISPR/CAS 9 GENE EDITING AND
THIS WILL LIMIT BORROW SPREAD
AND INFECTION AND POTENTIALLY
PROVIDE HELPER CELL FUNCTION.
SO REALLY OUR STRATEGY IS TO
PRODUCE TWO GUIDE RNAs, WE USE
TWO GUIDE RNAs TO COMPLETELY
REMOVE A SECTION OF THE CCR5 AND
RENDER IT INCAPABLE OF HAVING
HIV INFECT CELLS.
SO I'M NOT GOING TO TALK A LOT
ABOUT OUR PAST STUDY, BUT I DO
WANT TO MAKE A NOTE OF OUR PAPER
DONE IN COLLABORATION WITH
DR. GENDELMAN AND DR. CALILI.
I WAS AN AUTHOR ON THERE AS
WELL, BUT IT'S A BIG GROUP OF
PEOPLE LOOKING TO LOOK AT CRISPR
GENE EDITING OF CCR5, AND WE DID
THIS IN COMBINATION WITH A --
USING HIV CRISPR.
SO AGAIN WE SHOWED AT THE BOTTOM
A KIND OF OVERALL VIEW OF THE
STUDY.
SO THE MICE WERE ON ART, AND SO
RED OR -- THIS KIND OF GREY OR
ORANGE COLOR IS WHEN WE HAD
REBOUND AND WHITE IS WHEN WE DID
NOT HAVE REBOUND.
SO AS YOU CAN SEE, AS WE USED A
SINGLE CRISPR CCR5 OR IF WE USED
HIV CRISPR, WE HAD SOME ANIMALS
THAT DID NOT REBOUND AFTER AN
ATI, BUT WHEN WE USED BOTH THE
ART AND THE TWO CRISPRS, THE
CCR5 AND HIV, WE FOUND ONE
STUDY, 50% AND THE OTHER 67% OF
ANIMALS DID NOT REBOUND AFTER AN
ATI.
SO KIND OF THIS RENDITION HERE,
THIS WAS CALLED OUR GENERATION
1.0, SO THE TWO GUIDE RNAs
THAT WERE USED FOR CCR5 IN THOSE
STUDIES WERE A AND B, BUT REALLY
OUR STUDIES, WE WANTED TO LOOK
AT POSSIBLE GUIDE RNAs THAT
WOULD WORK IN BOTH RHESUS AND
HUMAN BECAUSE AS YOU'LL SEE FROM
THE DATA, THE A AND B GUIDES DID
NOT WORK VERY WELL IN RHESUS.
SO WE DECIDED TO LOOK AT A
SECOND GENERATION OF GUIDES THAT
NOW WITH THE NEWER TECHNOLOGY,
WE THOUGHT WE COULD DESIGN MORE
EFFECTIVE GUIDES.
SO WORKING WITH OUR PARTNERS
EXCISION BIOTHERAPEUTICS, WE DID
INSILICO TO LOOK THE A NOMINATED
OFF TARGET SITES AND THIS IS
BASICALLY TO SEE IS THERE ANY
POTENTIAL SITES IN EITHER THE
HUMAN GENOME OR THE MACAQUE
GENOME THAT WERE CLOSE TO OUR
CCR5 GUIDES.
AND AS YOU CAN SEE FROM THIS
CHART, WE NEEDED AT LEAST TWO TO
THREE MISMATCHES BEFORE WE HAD
ANY GENES THAT WERE SIMILAR.
SO THIS REALLY IS THE FIRST
LEVEL OF OUR OFF-TARGET
ANALYSIS.
WE'RE ALSO LOCKING AT GUIDE SEQ,
CAS SEQ, AND ALL OF THESE
STUDIES BUT THIS IS THE FIRST
INSILICO METHODS.
SO NEXT WE WANTED TO LOOK AT IF
A SINGLE GUIDE RNA COULD CUT, SO
WHAT WE DID IS A SINGLE GUIDE
RNA INDEL ANALYSIS.
WE TOOK OUR GUIDE RNA AND WE
TOOK CAS9 AND WE SENT THAT OFF
TO SINTENGO AND THEY'D GIVE US A
PERCENT I NDEL, EITHER INSERTION
OR DELETION.
WE FOUND FROM HERE THAT THREE
AB8 AND 653 WERE BOTH HIGHLY
EFFICIENT WITH GIVING UP TO 93%
INDELLS.
BUT SINCE WE WANTED TO DO THIS
NOT JUST LOOKING AT SINGLE
INDELS, WE WANTED TO HAVE TWO
GUIDE RNA PAIR, WE THEN DID DUAL
CCR5 GUIDED RNA EXCISION.
SO IN ALL OF THESE, YOU WILL SEE
THE FULL LENGTH PORTION.
THIS IS A PCR FULL LENGTH
PORTION.
YOU'LL SEE THE PORTION OF THE
GEL AFTER THE CRISPR WAS THERE,
SO THIS WAS THE CUT SECTION
AFTER IT WAS REMOVED AND THEN WE
DID SEQUENCING SO YOU CAN SEE
THE PART THAT'S ROW MOVED, AND
HERE YOU CAN SEE THE BREAK
POINT.
SO AS IT COMES BACK TOGETHER.
SO THESE ARE ALL
SEQUENCE-VERIFIED.
SO WE DID BOTH HUMAN AND MONKEY
CELL LINES.
AND FOUND THAT 388 AND 653, THAT
COMBINATION WAS EFFICIENT.
SO AGAIN THIS IS JUST A SUMMARY
OF A LOT OF DATA THAT WE HAD
DONE BECAUSE EVERYTHING HAS BEEN
REPEATED MULTIPLE TIMES.
THE A AND B THAT WAS USED IN THE
PAPER IN PNAI IN HUMAN WORKS
VERY WELL BUT IN MONKEY, THE
EFFICIENCY WAS VERY LOW.
SO AS YOU CAN SEE HERE, 388 AND
653 IS THE PAIR WE'RE MOVING
FORWARD WITH.
SO NEXT WE WANTED TO LOOK AT
THAT SAME -- THOSE SAME PAIRS
BUT USING EX VIVO ANALYSIS OF
BOTH MONKEY PMCs AND HUMAN
PBMCs, AND WE SAW THAT THESE
TWO GUIDE RNAs WERE REMOVED A
SECTION OF CCR56789 AND THAT WAS
CONFIRMED BY SEQUENCING AS YOU
CAN SEE IN THE MISSING REGION
WHERE OUR TWO GUIDE RNAs HIT.
SO OUR NEXT STUDIES ARE REALLY
TO LOOK AT THIS IN A DIFFERENT
MOUSE MODEL, SO THE MR. G MOUSE
MODEL.
SO IN COLLABORATION WITH LEEHAN
SHANE OF WASHINGTON UNIVERSITY
IN ST. LOUIS, HE DEVELOPED WHAT
WE CALL MR. G MOUSE MODEL.
SO THIS MOUSE MODEL IS REALLY
INTERESTING BECAUSE IT HAS
MYELOID CELLS, B CELLS, T-CELLS
AND NK CELLS THAT ARE ALL HUMAN,
AND IT'S VERY CLOSE TO WHAT WE
SEE IN HUMAN POPULATION.
SO AS YOU CAN SEE HERE, WE HAVE
ABOUT 18% CD14 AND ABOUT 9% NK
CELLS, SO THIS MODEL IS ABLE TO
HAVE HUMAN CELLS.
SO THE NEXT THING WE DID IS JUST
TO LOOK AT CCR5 EXPRESSION ON
CD4 T-CELLS AND THIS MR. G MOUSE
MODEL, AND YOU CAN SEE CONTROL
ANIMALS ARE IN BLUE AND INFECTED
ARE IN RED.
AS YOU CAN SEE OVER TIME WE HAVE
EXPRESSION OF CCR5 -- WE'VE
STARTED PRELIMINARY STUDIES AND
THE FIRST EXPERIMENT WE DID WAS
TO PACKAGE THOSE GUIDE RNAs
THAT WE CHOSE INTO AV # AND
AAV6.
AND THEN WE DELIVERED THOSE TO
AN ANIMAL AT LOW DOSE, 10 TO
11AAV PER MASS.
AS YOU CAN SEE FROM THE RESULTS
HERE, WE LOOKED AT DAY THREE AND
DAY 10 AFTER AAV.
AND PRELIMINARY RESULTS SHOW
THAT WE DO HAVE A SIGNIFICANT
DECREASE IN CCR5 SO WE DO HAVE
EDITING AND REMOVAL OF CCR5.
THIS IS PRIMARY DATA SO NOW
WE'RE LOOKING AT A HIGHER DOSE
AND ALSO GOING TO DO SOME MORE
EXTENSIVE STUDIES BUT THIS IS
JUST TO SHOW THAT IT IS WORKING
IN THIS MODEL.
SO FUTURE STUDIES WILL USE THESE
CCR5S AND THE MISTRG MOUSE MODEL
AND ALSO POTENTIALLY IN THE
NON-HUMAN PRIMATE MODEL IF IT
MEETS OUR GO/NO-GO CRITERIA.
AGAIN I SAID WE'RE USING A
NUMBER OF OTHER TARGETS IN
RETROVIRF2 AND THOSE INCLUDE PD5
AND CD16.
SO LOOKING AT NK AND
CD8 MODERATION.
SO I'M GOING TO PASS IT OVER TO
DR. KHALILLI, WHO WILL TALK
ABOUT RF3.
>> MY NEXT SLIDE IS PLAIN
LANGUAGE SUMMARY, BASICALLY
ILLUSTRATING -- CAN ELIMINATE
THE VIRUS FROM THE WHOLE
CHROMOSOME BY THE CRISPR, AND AS
MENTIONED EARLIER, THAT IT SEEMS
THAT AT LEAST IN THE
EXPERIMENTAL ANIMALS, LARGE AND
SMALL ANIMAL, IT'S POSSIBLE TH
THAT -- TO THE CURE.
THE PROBLEM THAT WE ARE FACING
WITH THE HIV IN MY VIEW IN THAT
APPROACH IS THE PRESENCE OF THE
INCORPORATED VIRAL DNA.
SO BASICALLY, IF YOU CAN THINK
THAT THE INFECTIOUS DISEASE
SPACE CHANGES, BECOME LIKE A
GENETIC DISEASE, IF THAT IS THE
GENETIC APPROACH, NOW YOU HAVE A
BAD GENE IN YOUR CHROMOSOME,
YOU'VE GOT TO FIND A WAY TO
INACTIVATE THE BAD GENE.
SO THAT CAN BE ACCOMPLISHED BY
THE CHRIS CRISPR TECHNOLOGY, BE
CRISPR/CAS 9 IS BASICALLY IN THE
NUCLEUS BUT CRISPR/CAS
9 BASICALLY APPROPRIATE FOR THIS
KIND OF STUDY IS THE GUIDE
RNAs.
RNAs WHICH BASICALLY EDUCATE
IN THE NUCLEUS THAT -- TO CUT
WITHOUT ANY COLLATERAL DAMAGE
THE OTHER PART OF THE CELLULAR
GENE.
AND THIS CLEAVAGE SHOULD BE VERY
EFFICIENT AND SPECIFIC.
SO RF3 IS VERY MUCH FOCUSING ON
THE DEVELOPING OF THE GUIDE
RNAs, WHICH IS APPROPRIATE FOR
THE CLEAVAGE OF THE SIV, SIV
1 FOR THE STUDIES IN THE MONKEY,
AND THE HIV-1 FOR STUDIES IN
NON-HUMAN PRIMATE, -- MICE WHICH
MENTIONED ABOUT THAT.
AND THAT IS MISTRG MICE
DEVELOPED BY RF2 MEMBERS.
WITH THAT KNOWING, I'M GOING TO
SHOW YOU THE MAP FIRST FOR THE
SRV THAT WE ARE USING FOR
DEVELOPING OF THOSE GUIDE
RNAs.
SO WE WE IDENTIFY THE GROUP OF
REGIONS WITHIN THE BARCODE SIV
WHICH COULD BE USED FOR THE
TARGETING AND DEVELOPMENT OF THE
GUIDE RNA.
AS I MENTIONED EARLIER, OUR
APPROACH IS USING MULTIPLEX OF
THE GUIDE RNA IN ORDER TO EXCISE
THE SEGMENTS OF THE -- GENOME.
WL THAT APPROACH THEN YOU CAN
ELIMINATE AN INTRODUCTION AND
MUTATIONS WHICH CAUSES BASICALLY
MUTANT VIRUS COMING OUT LATER ON
FROM THE CELL.
BUT IF THE BARCODE ALSO SIV, THE
CHALLENGE IS THAT WE HAVE TO USE
AREAS OF THE VIRUS WHICH DOES
NOT REMOVE OUR BARCODE SEQUENCE.
THAT IS IMPORTANT BECAUSE THAT
BARCODE HELPS US UNDERSTAND
ABOUT THE RESERVOIR.
THE VIRUS IS COMING UP FROM THE
RESERVOIR.
NICHE LE THEN WE STARTED USING
SINGLE GUIDE RNAs, REGION
WITHIN THE BARCODED SIV ONE
WHICH CAN BE USED FOR AT LEAST
ONE GUIDE RNA AND THEN WITH THE
HIGH EFFICIENCY OF THE INDEL
MUTATIONS.
AND THEN WE IDENTIFY THOSE
REGION AS YOU SEE BY THE ARROWS
ON THE TOP OF THE BARS, AND WE
USED THE PAIR, THAT ONE, WITH
THE SECOND ONE WHICH HAS ALSO
HIGH EFFICIENCY OF THE INDEL
MUTATION.
THEN WE -- WHETHER OR NOT YOU
HAVE AN EXCISION OF THE DNA
FRAGMENT FROM THE CHROMOSOMES OF
THE GENES, INCORPORATED THE
EXAMPLE OF THAT ONE IS -- THIS
IS BASICALLY FULL LENGTH AND
SOME OF THEM ARE OBVIOUSLY --
IT'S AN INDEL MUTATION, AND THIS
IS THE EC EXCISION ASSAY, NOT TE
EXCISE FRAGMENT.
THE FRAGMENT WHICH REMAINS AFTER
EXCISION -- SO YOU SEE THAT ONE,
AND THEN I WENT THROUGH THE
WHOLE SCREENING BASED ON THE
INFORMATION FOR INSILICO
ANALYSIS TO IEND GUY THE -- GAG
AS POTENTIAL FOR THE MOVING
FORWARD FOR THE IN VIVO STUDIES.
SO BASED ON THAT STUDY, WE
IDENTIFIED THAT 31% OF THE CELLS
THAT WE USE HAS A COMPLETE
EXCISION REMOVAL OF THE REGION
WITHIN THE -- WITHOUT ANY
COLLATERAL DAMAGE OR TOXICITY
ASSOCIATED WITH THE EXCISION.
SO NOW WE HAVE A PRODUCT.
THAT PRODUCT RIGHT NOW IS IN
PROCESS OF BEING PA PACKAGED ON
AAV9, T-CELL TROPHIC.
THIS IS THE AREA OF THE
RF3 WHICH IS BASICALLY PERFORMED
BY HARUN CHAN AND ALSO MIKE
PARSON, AND THEN THEY'LL
COLLABORATE WITH US AND THEY'RE
TRYING TO MAKE AAV9 WHICH HAS A
HIGH AFFINITY FOR CD4 CELLS.
SO ONCE THE PACKAGE IS DONE,
WE'RE GOING TO MOVE FORWARD WITH
THE MACAQUE STUDIES.
IN THE PARALLEL, WE ALSO -- THE
SAME KIND OF ROAD MAP FOR THE
MICE STUDIES.
IN THIS CASE OBVIOUSLY WE'RE
USING HIV-1.
AND THE FIRST ONE WE DID WAS
THAT THEY IDENTIFY SEVERAL
REGIONS WITHIN THE HIV WHICH CAN
BE TARGETED FOR THE EXCISION
BASED ON THE PRESENCE OF THE --
BASED ON THE PRESENCE OF THE PAM
SEQUENCE.
AND WHEN YOU ALIGN THOSE
REGIONS, WHICH IS ABOUT 500,
WITH THE SEQUENCES FROM THE
LOS ALAMOS STUDIES, YOU IDENTIFY
14 OF THEM PROBABLY PROVIDE THE
POTENTIAL FOR THE TARGETING BY
THE CRISPR/CAS 9.
AND THEN ALTHOUGH THAT'S 14, WE
USE SOME OF THEM, AND BASICALLY
THE INDEL MUTATIONS, AND AS YOU
SEE HERE, AND THEN SELECTED THE
FOUR OF THEM FOR THE SUBSEQUENT
STUDIES WHICH IS ECK VEE VO.
I'M GOING TO STOP HERE, I'M
GOING TO INVITE DR. SARIYER TO
TALK ABOUT THE EX VIVO
EXPERIMENT.
THANK YOU.
[APPLAUSE]
>> COMING DOWN TO FOUR PRIMARY
GUIDE RNAs THAT WE THINK MIGHT
BE USEFUL FOR MOVING FORWARD
WITH THE IMMUNOSTUDIES.
SO ANOTHER IMPORTANT PART OF OUR
WORKFLOW IS EX-A VERY VO
EDITING.
SO THIS STARTS WITH THE DONOR
PBMCs AND WE ARE IN
COLLABORATION WITH DREXEL
UNIVERSITY.
WE FORM OUR COHORTS, AND IN THIS
EXAMPLE YOU SEE 34 DONOR CELLS,
FRESHLY OBTAINED FROM THE
DONORS, AND OUR WORKFLOW
INVOLVES ISOLATING CD4 T-CELLS
AND EXPANSION OF THOSE T-CELLS
FOR SEVEN DAYS BY INDUCING THEM
AND ALSO BEFORE THE UTILIZATION
FOR EX VIVO ANALYSIS, IT WAS --
THE EXPANSIONS.
AND THEN ONCE THOSE CELLS ARE
EXPANDED, WE UTILIZED THEM FOR
INDEL AS WELL AS EXCISION
ANALYSIS TO TEST FOR GUIDE RNA
ACTIVITIES.
SO AGAIN THESE ARE OUR FOUR
CANDIDATE GUIDE RNAs FOR
SCREENING IN EX VIVO, AND OUR
WORKFLOW INVOLVED RMB
RIBONUCLEAR PROTEIN -- T-CELLS
ARE VERY HARD TO TRANSFECT OR
TRANSDUCE PRIMARY T-CELLS, SO WE
FOUND THAT RMP IS THE BEST
METHOD USING RECOMBINANT CASS #
PROTEIN INTRODUCING TO THE CELLS
USING EITHER -- ELECTRO -- AND
GOING FROM THEREFORE INDEL AND
EXON ANALYSIS.
I NEED TO NOTE HERE THAT THE
GENOMIC DATA OBTAINED FROM THOSE
STUDIES ALSO MOVES TO --
APPROACH THE FULL -- SEQUENCING,
GUIDE COMPATIBILITY ASSAYS AND
VARIOUS ALGORITHMS FOR ON AND
OFF TARGET ANALYSIS USING GUIDE
SEQ, AND THOSE STUDIES ARE ALSO
LED BY DR. WIGDAL'S GROUP AT
DREXEL UNIVERSITY.
SO THIS IS AN EXAMPLE OF INDEL,
IT INVOLVES OUR TARGET SITE
SEQUENCING AND RUNNING THROUGH
THE -- ANALYSIS.
THIS GIVES US VERY NICELY WHAT
INDELS AND YOU KNOW EDITS ARE
FORMED -- FOR THIS PARTICULAR
CANDIDATE GUIDE RNA WHICH IS THE
LTR REGION OF THE HIV, AND BASED
ON THIS, WE GET A PERCENT INDEL
ACTIVITY, WHICH IS HERE 21%.
AFTER SECRETING ALL THE RNA
CANDIDATES WITH 16 DONORS IN
THIS TABLE AS AN EXAMPLE, WE GET
VARIOUS ACTIVITIES RANGING FROM
A FEW PERCENT TO 98%, DEPENDING
ON THE DONOR SEQUENCE.
TO GIVE YOU AN IDEA ABOUT HOW
THESE PARTICULAR GUIDE RNAs
PERFORM, QUANT QUANTITATIVE EXCN
OR INDEL ACTIVITIES TO MAKE A
FULL DECISION.
SECOND APPROACH IS MENTIONED,
TWO GUIDE RNAs TO REMOVE A
CHUNK OF HIV, NOT GIVING HIV A
CHANCE TO REPLICATE OR REABT
VAIT.
SO IN THIS EXAMPLE, VERIFYING
THAT THERE IS EXCISION ACTIVITY.
THE TABLE HERE SUMMARIZES THOSE
RESULTS FROM 16 DONORS, AND
GIVES US A RANGE BETWEEN 8 TOLL
75% EXCISION ACTIVITY AMONG THE
16 DONORS.
WITH THIS, I WOULD LIKE TO
ACKNOWLEDGE ALL THE
COLLABORATORS FOR RF3.
DREXEL GROUP, HARVARD GROUP,
WASHINGTON UNIVERSITY, OUR
TEMPLE GROUP AND EXCISION
THERAPEUTICS.
THANK YOU.
[APPLAUSE]
>> HI, EVERYONE.
I'M KATE, THE COMMUNITY
ENGAGEMENT COORDINATOR FOR
CRISPR FOR CURE.
I AM GOING TO FLY THROUGH THIS A
BIT QUICKLY BECAUSE WE ARE
RUNNING OUT OF TIME.
THE MISSION OF OUR COMMUNITY
ENGAGEMENT COMPONENT IS TO
FOSTER AND MAINTAIN PARTNERSHIPS
AND OPEN COMMUNICATION BETWEEN
COMMUNITY MEMBERS AND RESEARCHER
WITHIN THE CRISPR FOR CURE
NETWORK AND ALSO TO ENHANCE HOW
THE WORK CAN TARGET GENETIC
MATERIAL FOR HIV EDUCATION,
PREVENTION, TREATMENT AND
RESEARCH ACTIVITIES REFLECTING
BOTH INVESTIGATORS' INTERESTS
AND COMMUNITY ENGAGEMENT.
SO THE YEAR TWO MILESTONES.
WE CREATED AND PASSED THE CAB
BYLAWS.
WE HAVE A NEW COMMUNITY PARTNER,
WILLIAM WEY, LGBTQ COMMUNITY
CENTER.
WE HAVE INITIATED THE PROJECT OF
GLOSSARY OF SCIENTIFIC TERMS,
AND WE ALSO ARE IN THE PROCESS
OF EDITING DOWN THE COFFEE WITH
CRISPR FOR CURE VIDEO, AS WELL
AS PARTICIPATION IN THE LTS
STUDY.
COMMUNITY ADVISORY BOARD.
SO WE DID HAVE OUR FIRST BOOK
CLUB MEETING.
HELD AT THE WILLIAM WAY CENTER.
IT BRINGS TOGETHER RESEARCHERS
AND COMMUNITY MEMBERS IN
DISCUSSING CODE BREAKER, THE
BOOK.
WE DID PARTICIPATE IN THE U.S.
CHA IN D.C. THIS YEAR, AND THEN
WE ALSO SPONSORED THE
RESTORATIVE JUSTICE WORKSHOP IN
COLLABORATION WITH THE
RESTORATIVE PRACTICES AT PNN AS
WELL AS MYSELF FACILITATING A
COMMUNICATIONS WORKSHOP AND THEN
OBVIOUSLY THE VIDEO.
SO THE BOOK CLUB.
SESSION ONE, WE DISCUSSED PARTS
ONE AND TWO OF CODE BREAKER.
WE BROUGHT EVERYBODY IN, WE
SERVED FOOD AND WE'RE GOING TO
BE DOING OUR SECOND SESSION.
THE BOOK CLUB IS MODERATED BY
ONE OF OUR CAB MEMBERS.
AND THEN THE RESTORATIVE JUSTICE
AND COMMUNICATION WORKSHOP,
RESTORATIVE PRACTICES IS A
COMMUNITY DEVELOPMENT FRAMEWORK
THAT FOCUSES ON BUILDING
RELATIONSHIPS THROUGH ONGOING
SUSTAINED INTERACTIONS.
CAB LEADERS AND CAB MEMBERS ARE
BROUGHT INTO COMMUNITY
DISCUSSIONS LEARNING HOW TO BE
BETTER COMMUNICATORS AND MORE
PURPOSEFUL PARTICIPANTS IN THEIR
OWN WORK.
THESE WORKSHOPS AND
PRESENTATIONS ARE SKILL-BASED
OFFERINGS REQUESTED BY THE
ACTUAL CAB MEMBERS.
SO THE CREATION OF THE COFFEE
WITH CRISPR FOR CURE VIDEO IS
JUST CONVERSATIONS, VERY CASUAL
CONVERSATIONS BETWEEN THE
COMMUNITY MEMBERS AND
RESEARCHERS ABOUT HIV CURE
RESEARCH WITH THE FOCUS ON
CRISPR.
WE'RE GOING TO BE -- TO LAUNCH
DISCUSSIONS ABOUT HIV CURE AND
CRISPR.
WE ALSO PARTICIPATED IN THE LONG
TERM SURVIVOR STUDY AND OUR
COMMUNITY PARTNERS.
WE ARE NOW PARTNERED WITH THE
FREE LIBRARY OF FILL DEFINITELYY
YAL COLORS ORGANIZATION, AND THE
WILLIAM WAY COMMUNITY CENTER.
CHALLENGES AND SUCCESSES.
I THINK RECRUITMENT AND
RETENTION HAS BEEN DIFFICULT FOR
US.
WE'RE TRYING TO -- THERE'S --
DUE TO THE PRESENCE OF AS IT
STATES, BECAUSE THERE'S SO MANY
CABS IN PHILADELPHIA, THERE'S A
LOT OF CROSS POLLINATION IN THE
CABS AND WE'RE TRYING TO ATTRACT
NEW MEMBERS, YOUNGER MEMBERS,
MEMBERS OF VARYING IDENTITIES.
I DO THINK THAT WE HAVE
BENEFITED BY THE PRESENCE OF TWO
MDCs IN PHILADELPHIA AND WE'LL
BE WORKING TO COLLABORATE TO PUT
SOMETHING TOGETHER WITH THE BEAT
HIV.
WE ALSO HAVE FANTASTIC
LEADERSHIP WITHIN THE CAB, AND
WE DO HAVE INNOVATIVE IDEAS AND
RESEARCH SUPPORT THAT'S ALWAYS
AVAILABLE.
WE ARE A VERY INTERACTIVE
RESEARCH TEAM.
PLANS FOR YEAR THREE.
THE COMMUNITY HIV CURE RETREAT
DURING THE SUMMER OF 2024, PLAN
TO INVITE OTHER MDC MEMBERS IN
ADDITION TO THE PHILADELPHIA
COMMUNITY, AS WELL AS EXPAND AND
DISSEMINATE THE CRISPR FOR CURE
GLOSSARY OF TERMS.
THAT'S IT.
[APPLAUSE]
>> THANK YOU.
WE ARE A LITTLE BEHIND BUT WE
HAVE TIME FOR A FEW QUESTIONS IF
ANYBODY HAS ANY.
I HAVE ONE.
PAULA.
>> HI.
I SUPPOSE I WOULD ADDRESS THIS
TO DR. KHALILLI.
YOU MENTIONED YOU ARE USING AAVI
THINK ABOUT AAV9 AS BEING T-CELL
TROPIC.
BUT OF COURSE AAV9 GOES INTO
LIVER, BRAIN, MUSCLE, HEART,
LUNGS, KIDNEY, PAP K PANCREAS, T
BASICALLY GOES EVERYWHERE IN THE
BODY, SO I WONDER IF YOU'RE
CONCERNED ABOUT THAT OR IF YOU
HAVE IDEAS TO MAKE MORE TARGETED
DELIVERY TO T-CELLS.
>> WE DO -- WE ARE IN PROCESS OF
WORKING WITH MIKE FARZAN AND HIS
GROUP TO IMPROVE THE AAV9 FOR
TRANSDUCING T-CELLS AND MYELOID
CELLS, HUMAN AS WELL AS IN THE
MONKEY.
SO THAT PROCESS IS GOING ON.
BUT ONE OF THE THINGS WHICH
WAS -- WE WERE VERY ENCOURAGED
WAS IN ANIMAL MODELS, IN SIV AND
ACTUALLY IN THE MACAQUE AS WELL
AS IN HUMAN IS MICE.
WE SAW THAT THE VERY -- IN
TRANSDUCTION OF THE CD4 CELLS IN
VIVO.
WE DON'T SEE STRONG -- IN THE
CELL CULTURE BUT IT SEEMS
SOMEHOW THE AAV9 FINDS THE WAY
TO GET INTO THE CD4 CELLS IN THE
IIN VIVO CYST TE. WE DON'T KNOW.
WE DON'T KNOW WHAT THE REASON
FOR THAT, WHAT CAUSES THE HIGH
EFFICIENCY IN THE TRANSDUCTION
IN VIVO BUT IT HAPPENS.
>> I GUESS IT'S MORE THE OFF
TARGET THINGS I WOULD BE KIND OF
CONCERNED ABOUT OFF TARGET OR
THE DELUSION EFFECT OF GOING
INTO SO MANY OTHER TISSUES IN
VIVO.
AS YOU KNOW, AAV9 IS USED AS A
GENE THERAPY VEHICLE TO GO INTO
MUSCLE.
SO IT'S REALLY NOT T-CELL TRO
TROPIC.
>> AS I SAID, WE ARE TRYING TO
FIND A WAY TO IMPROVE INCREASE
THE EFFICIENCY OF THE AAV9 IN
THE -- TO THE -- IT MAY NOT --
INCREASE EFFICIENCY.
>> THANK YOU.
>> EDWARD FROM YOE BEGAN DA,
RAKAI AND JOHNS HOPKINS.
HOW WELL DO THE SINGLE GUIDE RNA
WORK WITH AAV HIV SUBTYPES?
>> CAN YOU REPEAT --
>> THE SVRNAs, ARE THEY BEST
ON B SUBTYPE OR MULTIPLE
SUBTYPES AND RECOMBINANTS?
HOW WELL DO THEY WORK IN --
>> RIGHT NOW WE ARE BASICALLY
USING THE CLINICAL SAMPLE WHICH
I THINK -- SUBTYPE B.
WE HAVEN'T STARTED ANY OTHER
SUBTYPE.
>> A COUPLE QUESTIONS.
ONE IS CAN YOU TALK ABOUT WHAT
YOUR METHODOLOGY IS FOR LACKING
FOR CHROMOSOMAL TRANSLOCATIONS
USING MULTIPLE GUIDES?
>> YES.
>> SECOND QUESTION IS, I THINK
THE -- ASSAY IS FIND FOR YES/NO
BUT I'M CURIOUS WHERE YOU STAND
ON COMING TO MORE QUANTITATIVE
READOUTS FOR HOW EFFICIENTLY
YOU'RE EDITING THESE LOCI.
>> YES, WITH RESPECT TO THE
CHROMOSOMAL -- WE STARTED -- WE
DEVELOPED ACTUALLY THE METHOD
FOR THE SO-CALLED CAS SEQ FOR
LOOKING AT THE CHROMOSOMAL
ARRANGEMENT AS A RESULT OF THE
EXCISION, LET'S SAY TWO COPIES
ARE ON TWO DIFFERENT CHROMOSOME
BUT THEY ARE NOT ELIMINATION OF
THOSE SEGMENT OF THE PRO -- DNA,
BRINGS THOSE TWO CHROMOSOMES
TOGETHER, WHICH IS OBVIOUSLY --
IT'S A GENOTOXICITY ASSOCIATED
WITH THE EXCISION.
WE DIDN'T SEE SOMETHING LIKE
THAT, BUT WE HAVE ALREADY
DEVELOPED THE METHOD BASED ON
THE PUBLISHED STUDIES WAS DONE
BY OTHERS IN OUR LABORATORY AND
WE ARE IN PROCESS OF EXAMINING
THAT ONE.
SO WHAT WAS YOUR SECOND
QUESTION?
OH, EFFICIENCY IS -- WE ARE
USING A DDPCR TO ASSIST
EFFICIENCY OF THE EXCISION, OR
CLEAVAGE OF THE VIRAL DNA.
>> ONE FINAL QUESTION?
>> SO ONE COMMENT ANDY READ FROM
NIAID.
I PERSONALLY THINK ANY CURE
MODALITY IS GOING TO NEED TO
REQUIRE SOME SORT OF GENE I
EDITING SO IT'S EXCITING TO SEE
THAT MOVING FORWARD.
AND MY QUESTION, THOUGH, IS, FOR
THE MACAQUE ANALYSIS THAT YOU
GUYS HAVE DONE WITH YOUR ASSAY,
YOU KNOW, BOB SILICANO'S PAPER
SHOWED THE RESERVOIR IN THE
MACAQUES LOOKS PRETTY DIFFERENT
THAN WHAT WE SEE IN HUMANS WITH
A LOT MORE INTACT PROVIRUSES.
AND ONE QUESTION IS, ARE YOU
GUYS SEEING THE SAME THING WITH
YOUR ASSAYS, AND ALSO DO YOU
KNOW IF ANYONE HAS EVER LOCKED
IN THINGS LIKE AFRICAN GREEN
MONKEYS ON THERAPY TO SEE WHAT
THEIR RESERVOIR LOOKS LIKE?
AND I'M JUST CURIOUS.
>> I HAVE VERY LIMITED DATA ON
THAT MYSELF, BUT THAT'S
CERTAINLY SOMETHING THAT WE'LL
BE LOOKING INTO.
SO FAR I'VE ONLY TESTED
BASICALLY ONE MONKEY THAT HAD A
FAIRLY HIGH VIRAL LOAD AS WELL
FOR DIFFERENT REASONS.
WENT OFF THERAPY BRIEFLY.
SO MAY OVERREPRESENT THE NUMBER
OF INTACT PROVIRUSES THAT WE'LL
FIND IN THAT SYSTEM.
BUT I THINK IT HAS BEEN
DESCRIBED THAT THERE'S
COMPLETELY DIFFERENT LANDSCAPE
OF PERCENT PROVIRUSES IN SIV.
>> YOU'RE ABSOLUTELY RIGHT.
AND SO WE'RE WORKING HERE WITH
SIV MACK 239M2 WHICH I IS A
BARCODED VIRUS BUT WE'VE ALSO
DONE A NUMBER OF STUDIES WITH
DIFFERENT SHIV VIRUSES AND I
HAVE A SEPARATE R01 LOOKING AT
SHIV D WITH KATIE BARR SO WE'RE
DOING -- TO LOOK AT THE VIRAL
RESERVOIR.
SO YEAH.
>> ALL RIGHT.
LET'S THANK OUR CRISPR FOR CURE
SPEAKERS.
WE HAVE ONE FINAL SESSION COMING
UP, A PANEL DISCUSSION ABOUT
EXPANDING HIV CURE RESEARCH
GLOBALLY.
WE'RE GOING TO SHORTEN OUR BREAK
SO THAT WE CAN MAKE SURE
EVERYBODY HAS A CHANCE TO SEE
THIS EXCITING PANEL DISCUSSION,
SO PLEASE COME BACK AT 3:40. THANKS.
AND WE AT NIH ALSO ARE VERY
INTERESTED IN THIS AT NIAID IN
PARTNERSHIP WITH NIDDK AND NIMH,
WE'VE PUBLISHED A NOTICE OF
SPECIAL INTEREST OR NOSI ON HIV
CURE RELATED RESEARCH IN DIVERSE
POPULATIONS.
SO WE'RE TRYING TO ATTRACT MORE
GRANT APPLICATIONS TO DO HIV
CURE RESEARCH IN MORE DIVERSE
POPULATIONS.
AND SO WE THOUGHT IT WOULD BE
GREAT TO HAVE A PANEL IN THIS --
AT THIS MEETING TO DISCUSS WHAT
REALLY IS NEEDED TO MOVE INTO
MORE DIVERSE STUDIES IN HIV CURE
RESEARCH.
TOM QUINN WILL MODERATE THE
SESSION.
>> THANK YOU, KARL, AND WELCOME
TO THE FINAL SESSION OF THIS
FANTASTIC CONFERENCE.
IN THE PANEL DISCUSSION, WE WANT
TO HEAR FROM EACH OF THESE YOUNG
AFRICAN COLLABORATIVE
INVESTIGATORS AS TO WHAT THE
SCOPE OF CURE RESEARCH SHOULD BE
ON THE CONTINENT OF AFRICA, AND
WE CAN EXPAND TO ASIA, LATIN
AMERICA AND OTHER PLACES.
AS KARL JUST MENTIONED, SOME OF
THE COLLABORATORIES WE'VE HEARD
FROM ARE ALREADY -- HAVE ALREADY
NICINITIATED A NUMBER OF STUDIES
WORKING IN COLLABORATION FROM
SOME OF THE SCIENTISTS YOU'RE
ABOUT TO HEAR FROM.
BUT MORE NEEDS TO BE DONE.
REMEMBER THERE'S 39 MILLION
INFECTED PEOPLE IN THE WORLD,
CLOSE TO 70% RESIDE IN THE
CONTINENT OF AFRICA.
CLADE B MAKES UP ONLY A SMALL
PERCENT OF ALL THE SUBTYPES
CIRCULATING IN THE WORLD.
SUBTYPE C MAKES UP FROM 9%.
HOW MUCH WORK HAS BEEN DONE ON
SUBTYPE C?
AND IF YOU GO TO EAST AFRICA,
AND PARTS OF WEST AFRICA, YOU
SEE SUBTYPES A, D, REI RECOMBIN,
ALL OF THE OTHER SUBTYPES ARE
PRETTY MUCH REPRESENTED IN THAT
CONTINENT.
AND YET MOST OF THE WORK AS
WE'VE HEARD ALL OVER THIS PAST
TWO DAYS HAS BEEN FOCUSED A LOT,
AND EXCITING WORK, ON SUBTYPE B.
AND WHILE THAT'S RELEVANT AND
WILL PROVIDE US INSIGHT, WE NEED
TO START THINKING ABOUT
DIVERSIFYING SOME OF THIS AS TO
HOW IT CAN BE EFFECTIVE WITH
OTHER SUBTYPES AND EVALUATING
THOSE IN AFRICA, IN OTHER AREAS
OF THE WORLD, SO THAT WE HAVE A
REAL GLOBAL EFFORT AT HIV CURE.
SO ASSEMBLED BEFORE YOU ARE
INDIVIDUALS, SCIENTISTS,
INVESTIGATORS WHO HAVE REALLY
BEEN INVOLVED IN THE RESEARCH,
LEADING TOWARDS CURE.
THEY'VE COLLABORATED WITH SOME
OF YOU, THEY'VE SENT SPECIMENS
ABROAD BACK TO THE U.S.
SOME OF THE WORK IS STARTING TO
TAKE PLACE IN AFRICA, AND THAT
CONTEXT IS EXTREMELY IMPORTANT
THAT WE START LOOKING AT
INFRASTRUCTURE, WE START LOOKING
AT THE SCIENTISTS EDUCATING
THEM, MENTORING THEM AND HAVING
THEM PERFORM THE STUDIES WHERE
THE PARTICIPANTS ARE RESIDING.
, VERIFY THAT FROM CARL'S
REMARK, THE INSTITUTE IS VERY
INTERESTED IN AN INTERNATIONAL
EFFORT FOR FINDING A CURE FOR
HIV.
AND THAT GOES ALL THE WAY FROM
DAIDS TO THE INTRA MURAL
PROGRAM, AND I WILL SAY WITH THE
NEW LEADERSHIP WHO STARTED THIS
CONFERENCE, DR. GENIE JENANNE.
SO THIS WILL CLOSE OUT THE
CONFERENCE AND WE HOPE TO HEAR
FROM YOU AFTER EACH OF THE
PANELISTS HAVE GIVEN THER THEIR
PERSPECTIVE ON WHAT CURE SHOULD
BE LOOKING LIKE IN AFRICA.
AND SO I'M GOING TO ASK EACH ONE
OF THEM TO TAKE THREE, FOUR
MINUTES, GOING TO HAVE TO KEEP
IT SHORT BECAUSE WE WANT TO HEAR
FROM THE AUDIENCE, AND IF IT
GOES BEYOND FIVE, I'M GOING TO
HAVE TO CUT YOU OFF, BUT I WILL
START WITH ZAZA, IF YOU COULD
INTRODUCE YOURSELF, AND GIVE US
YOUR PERSPECTIVES ON WHAT NEEDS
TO BE DONE, WHAT LIES AHEAD IN
THE FUTURE FOR RESEARCH AND CURE
IN AFRICA.
AND PLEASE, AS WE GO DOWN THE
LINE, JUST GIVE A FULL
INTRODUCTION, WHAT YOU HAVE BEEN
DOING IN THIS AREA AND THEN WHAT
YOUR THOUGHTS ARE FOR THE
FUTURE.
THANKS.
>> ALL RIGHT.
THANK YOU VERY MUCH.
AND THANK YOU VERY MUCH FOR THIS
FANTASTIC OPPORTUNITY TO BE
INVITED HERE AND TO GIVE
PERSPECTIVES ABOUT HIV CURE ON
THE CONTINENT.
SO MY NAME IS ZAZA NDHLOVU, I'M
A VIRAL IMMUNOLOGIST BY
TRAINING.
I OBTAINED MY PH.D. AT JOHNS
HOPKINS AND DID MY POSTDOC WITH
BRUCE AT HARVARD.
I HAVE MY LAB WITH INTEREST IN
VIRAL RESERVOIRS IN TISSUES, AND
IMMUNE RESPONSES, TRYING TO FIND
WAYS IN WHICH WE CAN PINCH THE
VIRUS IN THE TISSUES.
SO RELATED TO HIV CURE RESEARCH
BEING DONE ON THE CONTINENT,
PARTICULARLY BASIC SCIENCE
RESEARCH, INCLUDING
INTERVENTIONS THAT HAVE ONLY
BEEN -- INTERVENTIONS THAT HAVE
BEEN DONE ON THE CONTINENT SO
FAR, DESPITE BEARING THE BIGGEST
BURDEN.
SO VERY FEW AFRICANS THAT ARE
PIs AND DIRECTLY FUNDED ON THE
CONTINENT, AND THERE'S VERY
LIMITED KNOWLEDGE IN THE
COMMUNITY, INCLUDING THE
POLITICIANS OR STAKEHOLDERS.
THE POLITICIANS, PEOPLE LIVING
WITH HIV, CAREGIVERS KNOW VERY
LITTLE ABOUT WHAT CURE RESEARCH
IS, WHAT WE'RE TRYING TO ACHIEVE
AND WHETHER THEY ARE EVEN PART
OF THAT.
SO THE LACK OF OWNERSHIP IS
REALLY A BIG PROBLEM.
SO I THINK WHAT WE NEED TO DO IS
REALLY TO CREATE AN HIV CURE
RESEARCH ON THE CONTINENT THAT
IS EQUITABLE AND FAIR AND
INCLUDES ALL STAKEHOLDERS.
SO WE NEED TO ENCOURAGE PEOPLE
IN THE CONTINENT TO WORK WITH
EACH OTHER, SO WE NEED TO CREATE
LEADERSHIP ON THE CONTINENT, AND
THAT LEADERSHIP WILL BE ABLE TO
SHARE POLICY AND WAYS IN WHICH
TO CONDUCT CURE RESEARCH IN A
SAFE AND MEANINGFUL WAY.
REMEMBER HIV CURE RESEARCH IS
VERY COMPLEX.
IF YOU COME TO BASIC SCIENCE,
YOU NEED LARGE BLOOD VOLUME, WE
NEED TISSUES OR THESE ARE
UNUSUAL WAYS OF DOING RESEARCH
COMPARED TO WHAT WE DID BEFORE.
SO YOU NEED SPECIAL REGULATION
AND YOU NEED MORE RESOURCES.
AND MORE IMPORTANTLY, ON THE
CONTINENT OF AFRICA FOR THOSE
THAT ASKED, THE COST OF DOING
BASIC SCIENCE RESEARCH IS
EXTREMELY HIGH.
SO FOR EVERY REAGENT WE GET,
THAT WOULD COST YOU $100 A YEAR,
WOULD COST YOU $300 IN AFRICA.
THE COST OF RUNNING REAGENTS AND
THE TIME AROUND TO GET THOSE
REAGENTS ARE VERY EXPENSIVE, AND
SO EVEN PEOPLE THAT HAVE THE
IDEAS AND CAN CONDUCT RESEARCH,
BECAUSE THEY ARE FORCED TO
COLLABORATE WITH SOMEBODY HERE
IN THE U.S. OR U.K. AND SHIP
THEIR SAMPLES, IT'S A LOT
EASIER, IT'S CHEAPER AND SO WE
ARE LAGGING BEHIND IN THAT VEIN,
AND SO WE NEED TO REALLY -- THE
SOLUTION IS TO FIND AND MOBILIZE
LEADERSHIP.
PEOPLE THAT CAN TALK TO THE
POLITICIANS, PEOPLE THAT CAN
COMMUNICATE POLICY, PEOPLE THAT
CAN COME UP WITH A COHERENT
PROGRAM OF HIV CURE RESEARCH
THAT IS REALLY TARGETED AT
ADDRESSING THOSE SUBTYPES THAT
MOSTLY CIRCULATE ON THE
CONTINENT.
>> THANK YOU.
EDWARD?
>> TH THANK YOU.
SO A POSTDOC AT JOHNS HOPKINS IN
TOM QUINN'S RAB QUINN'S LAB, W
UGANDA.
I WAS THE MOST -- IN THE DAY OF
THE HIV IN UGANDA, AND WE LOST
MANY PEOPLE TO HIV.
FAST FORWARD, MY INTEREST IN
CURE RESEARCH STARTED AFTER I
COMPLETED MEDICAL SCHOOL AND
STARTED PROVIDING CLINICAL CARE
IN RAKAI.
THAT'S WHEN I STARTED GETTING
MULTIPLE DISCLOSURES FROM MANY
FAMILY MEMBERS ABOUT THEIR
STATUS AND IF THERE WAS ANY HOPE
THAT THIS THING COULD GO AWAY.
SO I STARTED LOOKING FOR
OPPORTUNITIES AND THAT'S HOW I
APPLIED TO THE IAS RESEARCH FOR
CURE ACADEMY AND HAD THE
OPPORTUNITY TO HAVE SHARON AND
STEVE AND TUMBE AND -- WHERE IS
KAREN?
AND THEM TRAIN US, GIVE US
REALLY THAT INTRODUCTION WHICH
WAS MY ENTRY TO THIS FIELD, AND
SHORTLY AFTER COLLABORATORS OF
RAKAI, DR. RED, ANDREW, AND
DR. JESSICA, I THINK THEY'RE
PROBABLY AROUND.
ACTUALLY INTRODUCING NEW
POTENTIAL PROJECT THAT I APPLIED
FOR AND THAT LED TO MY TRAINING
IN CANADA, HOW TO ANALYZE THIS,
AND BIOSTATISTICS AND
EPIDEMIOLOGY TRAINING.
SO THIS WAS TO GET THAT KIND OF
TRAINING.
EVENTUALLY IT LED TO MY CURRENT
POSTDOCTORAL FELLOWSHIP.
AT JOHNS HOPKINS IN TOM QUINN'S
LAB.
SO IT BEEN QUITE A JOURNEY FOR
ME BUT AN INTERESTING ONE.
NOW, IT IS TEMPTING TO MAKE MANY
DEMANDS OF YOU, BUT FORGET ABOUT
ON RESPONSIBILITIES, I THINK I
WOULD LIKE TO START WITH
OURSELVES.
WE HAVE A SAYING, IF YOU POINT
AT SOMEONE THREE FINGERS ARE
POINTING BACK AT YOU.
SO IN OUR OWN CASE, WE HAVE TO
OWN UP THIS PROBLEM.
AND THE WORK.
THE LARGEST BURDEN OF THE
DISEASE IS ON OUR CONTINENT, BUT
SOMETIMES WHEN WE'RE IN THIS THE
COLLABORATIONS, THIS IS A BIT
EMBARRASSING TO SAY BUT IT HAS
TO BE SAID, IN SOME CASES WE ARE
NOT VIEWED AS SERIOUS
CONTRIBUTORS TO THIS WORK.
AND SOMETIMES TRULY SO.
BUT WE HAVE TO MAKE THAT EXTRA
EFFORT TO PUT IN EXTRA EFFORT
EVEN WHEN YOU DO NOT HAVE THE
EXPERTISE, THERE ARE THINGS YOU
CAN DO FOR YOUR COLLABORATORS TO
KNOW THAT THIS IS A SERIOUS
PERSON THAT WE CAN WORK WITH.
AND SECONDLY, OUR GOVERNMENTS
ALSO NEED TO DO SOMETHING ABOUT
THIS.
IT SAYS IF YOU HAVE SOMEONE CRY
WITH YOU, THIS IS IN MY TRIBE,
IF YOU HAVE SOMEONE CRY WITH
YOU, YOU HAVE TO CRY LOUDER. LON
THAT PERSON.
SO WE HAVE GOODWILL OF OUR
FRIENDS, BUT WHAT ARE WE DOING?
WE MAY NOT HAVE THE SAME AMOUNT
OF MONEY, BUT IS THERE SOMETHING
SMALL THAT WE CAN ACTUALLY
CONTRIBUTE TO THIS WORK.
TIME WILL COME FROM FRIENDS ARE
NOT ABLE TO HELP US.
MAYBE NOT WITH HIV BUT WITH A
DIFFERENT PROBLEM.
IT DID HAPPEN DURING COVID IN
THE MIDDLE OF THE PANDEMIC.
EVERYBODY WAS HOLDING VACCINES,
AND WERE OUT IN THE COLD.
WHAT DO WE DO IN SUCH IPS
STANCE?
SO IN OUR CASE, THE GOVERNMENT
OF UGANDA DID SOMETHING I'VE
NEVER SEEN BEFORE.
I THINK RESEARCH INNOVATION
FUND, IT WAS I THINK AROUND
$20,000 PER PERSON THAT THE
GROUP FUNDED TO HEY, GUYS, DO
SOMETHING, DO SOMETHING ABOUT
THIS THING.
NOW WE DON'T NEED TO WAIT FOR
TOUGH TIMES LIKE THAT TO COME.
WE NEED TO ACTUALLY START DOING
THESE THINGS AS AFRICAN PEOPLE,
AS PEOPLE IN OTHER LMICs SO
THAT IN CASE WE ARE IN SUCH A
SITUATION EVER AGAIN, WE'RE ABLE
TO DO SOMETHING ON OUR OWN.
SHOULD I PAUSE THERE?
>> YES.
>> THANK YOU.
>> WE'LL BE ABLE TO COME BACK
AFTERWARDS.
IMMACULATE?
>> GOOD AFTERNOON, EVERYONE.
MY NAME IS IMMACULATE NANKYA.
I'M BASED IN UGANDA AT THE JOINT
CLINICAL RESEARCH CENTRE,
CO-DIRECTOR OF THE RUST BUILD
SAFER, COLAB RANGE OF MOTION
BETWEEN THE UNIVERSITY AND
UNIVERSITY OF PITTSBURGH, SO I
WORK IN COLLABORATION WITH JOHN
I'M A MOLECULAR BIOLOGIST, I'M A
MEDICAL BIOLOGIST VIROLOGIST
BASICALLY, AND BASICALLY I WAS
IN THE HIV RESISTANCE AND THEN
MOVED INTO HIV CURE WITH THE
PEOPLE HAVE MENTIONED, AND THE
ISSUE AT HAND CURRENTLY IS YES
THERE IS A LOT OF WORK THAT HAS
BEEN DONE IN THE SUBTYPE B, AND
THESE ARE PREDOMINANTLY MALE
COHORT, SO THERE IS A NEED TO
DIVERSIFY TO LOOK AT WHAT IS OUT
THERE, WHAT IS MAINLY IN AFRICA,
THEY ARE MORE PREDOMINANTLY
FEMALE, HETEROSEXUAL COMMUNITY,
THEY ARE MORE DIVERSE
POPULATIONS AND DIVERSE
SUBTYPES, AS YOU KNOW MOST OF
THE SUBTYPES IN AFRICA, AND
PRECISELY IN UGANDA, WE HAVE
SUBTYPE A, D, C, AND THEN THE
RECOMBINANTS.
SO -- AND AS WE ALL KNOW THAT
ALREADY MUCH OF THE WORK IS DONE
IN SUBTYPE B AND THERE IS NEED
TO OPTIMIZE SO THE KEY THING
HERE IS TO OPTIMIZE ASSAYS FROM
THE B TO THE NON-Bs.
AND ALSO RIGHT NOW WE'RE DOING
THAT KIND OF WORK.
BECAUSE I WORK IN COLLABORATION
WITH THIS HERE, SO OPTIMIZATION
ALSO BRINGS ALONG TRAINING, SO
WE HAVE PEOPLE COMING FROM
UGANDA TO COME HERE IN THE U.S.
AND THEY'RE TRAINED IN THE
OPTIMIZATION, GAINING ALSO THE
EXPERTISE.
AND THIS IS VERY CRUCIAL BECAUSE
YOU CAN'T DO THIS WORK WHEN YOU
DON'T HAVE THE EXPERTISE.
SO ONCE THESE PEOPLE ARE
TRAINED, THEN ALSO THERE IS NEED
TO -- THIS IS CAPACITY BUILDING,
SO THE CAPACITY BUILDING THEN
NOW MEANS THAT THERE IS ALSO
TECHNOLOGY TRANSFER, SO
BASICALLY IN THIS KIND OF WORK,
WE REALLY NEED TO BUILD THAT
CAPACITY TO DO THIS WORK, SO
THAT WE CAN CLEARLY UNDERSTAND
WHAT WE HAVE, THE RESEARCH WE'RE
DOING RIGHT NOW IS STILL AT --
WE ARE TRYING TO UNDERSTAND THE
ACTUAL DYNAMICS OF THE RESERVOIR
IN THE NON-Bs AND IT NEEDS A
LITTLE CHARACTERIZATION, IS
NEEDS A LOT OF -- ALL THESE
ASSAYS, BUT ALSO THE ASSAYS COME
WITH EQUIPMENT, SO WE FIND THAT
IN THIS -- OUR COUNTRIES, MOST
OF IT IS NOT AVAILABLE.
FOR MOST OF THE WORK WE HAVE
DONE PREVIOUSLY, WE HAVE BEEN
DOING SOME PART OF THE WORK IN
OUR COUNTRIES LIKE IN UGANDA,
AND THEN SHIP THE SAMPLES TO
HERE.
SO THAT THE LAST PART OF THE
ASSAYS, THE MEASUREMENT ASSAYS
ARE DONE HERE.
SO WE WILL NOT BE ABLE TO REALLY
SUCCESSFULLY DO THIS WORK WHEN
WE DON'T HAVE THE EQUIPMENT.
THEN ONCE WE HAVE -- WE MAY NOT
BE -- I MAY NOT HAVE ALL THE
EQUIPMENT, I MAY NOT HAVE THE
DROPLET PCR AND THEN THE
NANOPOLE AND ALL THESE THINGS,
BUT AS MAYBE COLLABORATIONS ARE
REALLY VERY IMPORTANT FOR US, SO
IF WE CAN ALSO -- LIKE WE DO THE
NORTH TO SOUTH COLLABORATIONS,
IT ALSO IMPORTANT WITHIN
COUNTRY, WITHIN THE AFRICAN
CONTINENT TO HAVE
COLLABORATIONS.
SOMETIMES YOU TEND THAT WE FIND
TO KEEP OR YOU KNOW LIKE YOU
HIDE YOUR EQUIPMENT, YOU DON'T
WANT TO SHARE IT WITH SOMEONE
ELSE, AND THAT ALSO HINDERS OUR
PROGRESS IN RESEARCH.
SO REALLY I'D ADVOCATE FOR US TO
BE MORE OPEN TO COLLABORATIONS.
SOMETIMES WHEN I HAVE AN IDEA,
SOMEONE ELSE WILL NOT TAKE IT UP
BECAUSE THEY DON'T WANT TO WORK
WITH ME, THEY WOULD PREFER TO
WORK WITH SOMEONE IN THE NORTH
THAN SOMEONE IN THE SOUTH.
SO IT'S REALLY IMPORTANT AS WE
GO INTO THIS, NOT THAT -- SOUTH
TO SOUTH, WITHIN CO COUNTRY, WIN
THE CONTINENT IS IMPORTANT IF WE
ARE TO GO FARTHER IN THE CURE
AGENDA.
THANK YOU VERY MUCH.
>> THANK YOU, IMMA IMMACULATE.
JULIE?
>> I'M JULIE AKE, DIRECTOR OF
THE U.S. MILITARY HIV RESEARCH
PROGRAM.
WHICH MEANS I WORK IN KENYA AND
UGANDA AND IN TANZANIA, AND
TIAMU IN NIGERIA AS WELL AS
DR. SORCHI, IN THAILAND AND
INCREASINGLY WORKING IN THE
PHILIPPINES.
I'VE LEARNED MORE FROM THOSE
INDIVIDUALS IN THE COURSE OF MY
LIFE AND MY CAREER REALLY THAN
ANY OF THE TERRIFIC MENTORS I'VE
HAD HERE IN THE STATES, BECAUSE
OF THE REALLY OUTSTANDING WORK
THAT THEY DO IN THEIR LOCAL
COMMUNITIES, AND WE ALL LEARN
HOW TO DO CLINICAL TRIALS RIGHT
FROM THESE EXPERTS IN LOW AND
MIDDLE INCOME SETTINGS.
I WOULD ADD, AT MHRP, WE ALWAYS
DO THE BULK OF OUR RESEARCH
INTERNATIONALLY.
IT HOW I GREW UP.
I'VE ALWAYS SEEN THAT THE
POSSIBLE IS ALWAYS THERE IN
INTERNATIONAL SETTINGS.
PROBABLY CONDUCTED IN MY
EXPERIENCE, OFTEN BETTER.
AND SO WE SHOULD ALWAYS EXPECT
MORE.
GO FORTH BOLDLY IN THIS AREA AND
EXPECT SUCCESS.
WE'VE ONLY EVER SEEN IT IN TERMS
OF BEING ABLE TO OPERATIONALIZE
VERY COMPLEX STUDIES IN THESE
SETTINGS.
IT GIVES ME A HUGE AMOUNT OF
CONFIDENCE IN TERMS OF THE
DIRECTION THAT THE FIELD IS
TAKING.
I'LL SHARE MY OWN EXPERIENCE,
WE'VE ALWAYS DONE A LOT OF
VACCINE WORK INTERNATIONALLY,
BUT MORE RECENTLY, COMPLETED A
STUDY WHERE WE GAVE VRC01 DURING
ACUTE INFECTION SO OFTEN WITHIN
21 DAYS OF A NEGATIVE TEST IN
UGANDA, KENYA, TANZANIA AND
THAILAND ADMINISTERING
VRC01 OBVIOUSLY UNDERGOING
INFORMED CONSENT, THE SITES AND
THE LOCAL INVESTIGATORS ALSO
WERE ABLE TO TRAIN UP AND
PERFORM A NUMBER OF TISSUE
SAMPLING PREA DEURS.
THE LOCAL CLINICIANS, THEY SAY
SURE, YOU CAN TRAIN ME TO DO A
LYMPH NODE BIOPSY, I'M ALREADY
CREDENTIALED.
THEY CAN ALSO TAKE OUT MY
APPENDIX AND DELIVER MY BABY,
RIGHT?
I MEAN, WE SHOULD NEVER
UNDERESTIMATE WHAT IS CAPABLE IN
THAT SETTING, BUT THEY ALSO,
WITH THE GUT BIOPSIES THEY
CAPABLY PERFORMED, GENERATED
REALLY IMPORTANT DATA ON THE
PRESENCE OF VRC01 AND I'M GOI
GOING -- AMINO INFLAMMATORY
MARKEMARKERS, THEY DID AN OUTSTG
JOB SO I'M EXCITED WE HAVE AN
OPPORTUNITY TO REALLY SORT OF
STEP ON THE GAS FOR WORKING IN
INTERNATIONAL POPULATIONS AND
WITH THE SUPPORT THAT NIAID IS
INCREASINGLY PROVIDING WITH OUR
PARTNERS THAT I'VE MENTIONED,
ALSO WITH COLLEAGUES IN THE
PHILIPPINES, WE'RE LAUNCHING AN
INITIATIVE WE CALL DELIVER,
WHICH IS DEVELOPING LEADERSHIP
AND INNOVATION IN VIRAL
ERADICATION RESEARCH, REALLY
WITH AN AIM TOWARDS DOING MORE
MULTISITE IMPACTFUL CURE TRIALS,
CAPITALIZING ON THE ABILITY TO
INTERVENE AT THE TIME OF HIV
DIAGNOSIS, AND CHALLENGING
OURSELVES TO SEE IF -- NOT JUST
THROUGH THE COHORTS WE'VE BEEN
WORKING ON FOR YEARS BUT THROUGH
OUR PEPFAR PROGRAM PLATFORM, CAN
WE REALLY INTEGRATE WITH PUBLIC
HEALTH CASE FINDING STRATEGIES
TO WORK WITH THESE POPULATIONS
AND START TO DELIVER TRIALS TO
THE POPULATIONS GLOBALLY AS
THESE DIAGNOSES ARE BEING MADE.
REALLY EXCITED ABOUT THIS
EFFORT.
THAT'S WHAT WE'RE ALL HO HERE F,
ISN'T IT?
THANK YOU.
>> THANKS, JULIE.
AND NEXT IS HANEEFA, WHO WILL
FILL US IN ON SOME OF THESE
OPPORTUNITIES.
>> THANKS.
I'M REALLY EXCITED TO BE HERE.
MY NAME IS HANEEFA SALEEM, JOHNS
HOPKINS BLOOMBERG SCHOOL OF
PUBLIC HEALTH.
ONE OF THE ROLES THAT I ALSO
HOLD IS DIRECTOR OF THE INTERC
SUB-SAHARAN AFRICA WORKING
DWREUP AND I'M ALSO THE PROGRAM
LEAD FOR A NEW INITIATIVE THAT
WE JUST LAUNCHED, NIH FUNDED
CFAR AFRICURE PROGRAM.
WE'VE HEARD OF THE NEED TO
DIVERSIFY CURE RESEARCH AND PART
OF THAT IS DIVERSIFYING THE
WORKFORCE.
SO THE CFAR AFRICARE PROGRAM IS
INTENDED TO ADVANCE HIV CURE
RESEARCH IN AFRICA IN PARTICULAR
BY PROVIDING MENTOR
DEVELOPMENTAL AWARDS TO
INVESTIGATORS BASED IN AFRICA
WHO CAN ADDRESS SOME OF THE
ISSUES SPECIFIC FOR AFRICA.
THROUGH THIS PROGRAM, WE'RE
AIMING TO PROVIDE SMALL DEVEL
DEVELOPMENT AWARDS REALLY TO
INVEST IN THE PEOPLE WHO
HOPEFULLY WILL DO THIS WORK.
WE HEARD FROM SOME OF OUR OTHER
COLLEAGUES ON THE PANEL IN TERMS
OF THE NEED FOR INDEPENDENT
INVESTIGATORS IN AFRICA DOING
THIS TYPE OF WORK, SO WE'RE
REALLY TRYING TO PUSH FOR THAT
BY BUILDING CAPACITY LOCALLY.
THERE ARE SEVERAL ELEMENTS OF
THE PROGRAM.
FIRST THERE'S OBVIOUSLY THE
AWARD, BUT MORE IMPORTANTLY
THERE'S THE MENTORSHIP, SO
AWARDEES WILL BE MENTORED BY
SENIOR INVESTIGATORS ACROSS THE
CFARs, BUT THEN THERE ARE ALSO
LOCAL INVESTIGATORS IN AFRICA
WHO ARE DOING THIS WORK AND PART
OF THAT IS TO BUILD WHAT
IMMACULATE MENTIONED, SOME OF
THESE REGIONAL COLLABORATIONS
AND COLLABORATIONS WITHIN THE
CONTINENT.
SO WE'RE REALLY EXCITED ABOUT
THIS PROGRAM.
WE HAD A FLYER THAT WAS UP
EARLIER, BUT I'M HAPPY TO TALK
MORE ABOUT THIS PROGRAM, AND
WE'RE HOPING -- WE'RE LOOKING
FORWARD TO RECEIVING APPLICANTS
AND REALLY LAUNCHING THIS
PROGRAM, AND I WANT TO ENCOURAGE
ALL OF YOU WHO MAY BE WORKING
WITH INVESTIGATORS, MAY HAVE
COLLEAGUES IN AFRICA TO SPREAD
THE WORD OF THIS PROGRAM,
BECAUSE IT'S REALLY PART OF THIS
PRIORITY TO DIVERSIFY HIV
RESEARCH TO OTHER POPULATIONS.
>> GREAT, THANKS, HANEEFA.
LASTLY, WE'RE GOING TO HEAR FROM
THE AFRICAN COMMUNITY AND THAT'S
ELINA, IF YOU COULD INTRODUCE
YOURSELF.
>> THANK YOU VERY MUCH.
MY NAME IS ELINA MWASINGA.
I'M FROM MALAWI.
I LEAD AN ORGANIZATION CALLED
THE NATIONAL ASSOCIATION FOR
YOUNG PEOPLE LIVING WITH HIV.
HIV CURE RESEARCH ADVOCATE AND
I'M REALLY EXCITED TO BE HERE.
SO MY PERSONAL EXPERIENCE STEMS
FROM MY PERSONAL CHALLENGES THAT
I'VE FACED AS A PERSON LIVING
WITH HIV THE SO THE IMPACTS
FIRSTHAND LOOKING AT STIGMA
DISCRIMINATION, IT WAS REALLY
HARD, AND ALSO DEALING WITH THE
THE STRUGGLES OF THE PILL -- I
KNOW IT'S SOMETHING YOU JUST
HAVE TO ACCEPT BUT IT DOESN'T
GET ANY EASIER.
SO TO BE IN THIS SPACE TO LEARN
THAT THERE IS HOPE FOR HIV CURE
REALLY MEANS A LOT.
AND FOR THE YOUNG PEOPLE I
REPRESENT, SOMETIMES YOU MEET A
YOUNG PERSON ON THE VERGE OF
COMMITTING SUICIDE.
EVEN IF YOU TELL THEM THEY HAVE
TO TAKE THE DRUGS FOR THE REST
OF YOUR LIFE, IT DOESN'T BECOME
EASIER, BUT WHEN YOU TELL THEM
THAT, OH, THERE'S SOME
BREAKTHROUGHS, WE'VE GOT PEOPLE
BEING CURED OF HIV, THAT'S WHAT
GIVES THEM HOPE.
SO I REALLY APPRECIATE THE WORK
THAT THE RESEARCHERS ARE DOING
AND ALL THE KEY PLAYERS ARE
DOING.
I THINK YOU REALLY DESERVE A
ROUND OF APPLAUSE BECAUSE YOU
ARE DOING GREAT WORK.
AND BEING IN THIS SPACE IS SUCH
A GREAT OPPORTUNITY, SO I'M
REALLY, REALLY LOOKING FORWARD
TO THE MORE OUTCOMES OF THE WORK
THAT'S BEING DONE IN THE LAB, AS
WELL AS IN THE COMMUNITIES.
SO MY WORK IN HIV CURE RESEARCH
STARTED ABOUT A YEAR AGO, WHEN I
WAS ENGAGED WITH AVEC, AND I'VE
BEEN WORKING A LOT WITH JESSICA,
SANDRA, I'VE BEEN EXPOSED TO
THE -- AT FIRST IT'S REALLY
DIFFICULT TO EVEN UNDERSTAND
WHAT AN HIV RESERVOIR IS, BUT
I'M GLAD THAT I WAS VERY
FAMILIAR IN THIS ROOM WITH A LOT
OF WORDS AND I COULD RELATE TO A
LOT OF THE PRESENTATION.
SO I THINK LOOKING AT AFRICA IN
TERMS OF THE COMMUNITY, IN TERMS
OF HIV CURE, MY RESEARCH, AND
WE'RE ALSO DEALING WITH MYTH,
FOR EXAMPLE, THERE'S MYTH THAT
IF YOU SLEEP WITH A VIRGIN
YOU'RE GOING TO BE CURED.
SO I BELIEVE AS WE TALK ABOUT
HIV CURE RESEARCH, IT'S
IMPORTANT THAT WE START TO
EMPOWER COMMUNITIES WITH THIS
KNOWLEDGE.
I THINK WE LEARN A LOT FROM
COVID-19.
WHEN THE VACCINE CAME OUT, THERE
WAS SO MUCH UNRESPONSIVENESS
BECAUSE THERE WAS NOT THAT QUICK
KNOWLEDGE, BUT IF WE START NOW
AND WHEN THE CURE COMES, I THINK
WE WON'T SPEND MUCH TIME
CONVINCING PEOPLE WHO ALREADY
HAVE -- KNOWLEDGE, SO I THINK
THE TIME IS NOW TO START
BUILDING UP THIS IN OUR
COMMUNITIES AND WE NEED TO
ENSURE THAT -- CLAB RAYTIVE
EFFORTS AND PLATFORMS WHERE
RESEARCHERS CAN ALSO ENGAGE WITH
THE COMMUNITIES.
AND I THINK EARLIER WE TALKED
ABOUT THE INFRASTRUCTURES IN
AFRICA, SO ALREADY AFRICA
DEPENDS SO MUCH ON DONOR FUNDED
LOOKING AT PEPFAR AND GLOBAL
FUND LIKE ALMOST 80% GOES
TOWARDS COMMUNITIES AND OUR
GOVERNMENTS DO MAKE COMMITMENTS
TO CONTRIBUTE A CERTAIN
PERCENTAGE BUT THAT NEVER
HAPPENS, SO I THINK AS ALREADY
MENTIONED, IT'S IMPORTANT THAT
WE ALSO HOLD OUR GOVERNMENT
ACCOUNTABLE TO START PLANNING
FOR DOMESTIC RESOURCES TOWARDS
HIV CURE RESEARCH.
I'LL END HERE FOR NOW.
THANK YOU.
[APPLAUSE]
>> I WANT TO THANL THE PANELISTS
FOR BEING BRIEF SO WE HAVE
PLENTY OF TIME BUT I'M GOING TO
DO A BRIEF SUMMARY.
I WANT TO STIMULATE SOME OF YOU
OUT IN THE AUDIENCE BEFORE YOU
LEAVE THIS CONFERENCE, AND ALSO
THE PANELISTS.
SO LET ME JUST SUMMARIZE WHAT
SOME OF THE THEMES THAT I HEARD.
FIRST IS THAT THERE IS A DIRE
NEED FOR MORE INTENSIVE TRAINING
IN THIS FIELD OF CURE RESEARCH.
IT'S HIGHLY TECHNICAL, AND THERE
NEEDS TO BE A LOT OF
COLLABORATION NORTH-SOUTH AND
SOUTH-SOUTH.
AND ACTUALLY, THE
COLLABORATORIES ARE THE PERFECT
EXAMPLE OF THAT TYPE OF
COLLABORATION.
I'VE SEEN IT INDIVIDUALLY WITH
THE DIFFERENT COLLABORATORIES
I'VE WORKED WITH OR HAVE BEEN
AFFILIATED WITH.
HOW YOU REACH OUT ACROSS
DIFFERENT INSTITUTIONS.
THAT COMPETITIVE SCIENTISTS GET
TOGETHER TO ACTUALLY WORK ON A
PARTICULAR PROBLEM AND FORGE
FORWARD.
SO I DO BELIEVE THAT THE CURE
COLLABORATORIES ARE PROBABLY THE
BEST SCENARIO IN WHICH WE CAN
EMBRACE THE PROBLEMS
INTERNATIONALLY ON CURE RESEARCH
AND HAVE THIS TYPE OF
COLLABORATION.
THE COLLABORATORIES NEED TO NOT
JUST BE IN ONE CITY AND MOST OF
THEM ARE NOT, THEY'RE MULTIPLE
CITIES IN THE U.S., BUT NOW THEY
NEED TO REACH OUT, HELP WITH THE
TRAINING OF OF REALLY EXCITING
SCIENTISTS, WELL EDUCATED BUT
NEED THE TRAINING IN SPECIFIC
TECHNIQUES AND HOW TO MOVE THAT
FORWARD.
I ALSO HEARD THAT WE NEEDED A
GREATER FOCUS OF THESE
COLLABORATORIES, THE ONES THAT
WE'VE ALL HEARD FROM, ON NON-B
SUBTYPES.
THEY MAKE UP A SMALL PROPORTION
OF THE GLOBAL PROBLEM THAT WE
FACE.
AND SO THAT'S A CHALLENGE TO ALL
OF YOU.
START THINKING OUT OF THE BOX.
GET SOME CLADE Cs, SOME Ds,
SOME As, SOME RECOMBINANTS.
CAN YOU DO IPDA EASILY, SO THAT
YOU CAN MEASURE THE RESERVOIRS
EFFECTIVELY WHEN YOU'RE DEALING
WITH NON-CLADE Bs.
SO THAT WAS ONE OF THE THINGS
BROUGHT UP.
I ALSO HEARD THAT CLINICAL
RESEARCH IS VERY POSSIBLE, THAT
THE COMMUNITY EMBRACES THAT,
THAT THOSE WHO WORK IN AFRICA,
WHETHER IT'S GETTING INTESTINAL
BIOPSIES OR IT'S DOING TREATMENT
INTERRUPTIONS, OTHER TYPES OF
INVESTIGATIONS.
ALL OF THAT IS SOMETHING THAT
CAN BE DONE IN AFRICA, DOESN'T
HAVE TO JUST BE DONE IN THE U.S.
AND I THINK THE COMMUNITY WANTS
TO BE INVOLVED IN THAT, THAT THE
SCIENTIFIC LEADERS CAN REALLY
TAKE ON SOME OF THESE
INITIATIVES, SO EVEN THOUGH
WE'RE TALKING ABOUT CRISPR AND
WHAT WE'RE DOING WITH CRISPR IN
U.S. SCIENCE LABORATORIES, I
THINK SOME OF THAT CAN BE DONE
WITH THE NON-CLADE Bs AND IT
CAN BE DONE IN AFRICA I AND THE
COHORTS CAN BE BUILT IN THE
MEANTIME TO EFFICIENTLY GO
FORWARD FOR THOSE TYPES OF
INVESTIGATIONS.
I HEARD A NEED FOR
INFRASTRUCTURE.
THAT THE TYPE OF EQUIPMENT YOU
ALL USE IS NOT IN AFRICA.
IN VERY FEW PLACES.
MAYBE SOUTH AFRICA'S GOT SOME IN
CAPETOWN, MAYBE IN JOHANNESBURG,
BUT CERTAINLY NOT IN THE EASTERN
CAPE WHERE I'VE WORKED.
IT CERTAINLY JUST STARTING TO
COME INTO UGANDA.
THE FIRST DIGITAL DOP L DROPLETR
JUST MAKING ITS WAY INTO UGANDA.
SO THERE'S A REAL NEED TO
LOOKING AT THAT TECHNOLOGY.
YOU CAN TRAIN SOMEONE IN YOUR
LAB, PUT THEM BACK IN AFRICA AT
THEIR HOME WITH THEIR COMMUNITY,
AND THEY MAY OR MAY NOT BE ABLE
TO FOLLOW THROUGH ON SOME OF
THESE UNLESS THERE'S AN INVEST M
IN INFRASTRUCTURE.
AND EDWARD SAID THE AFRICAN
GOVERNMENTS AND THEIR FUNDING
AGENCIES NEED TO PULL A LITTLE
BIT OF WEIGHT IN THAT PROCESS.
WHETHER THAT'S THESIBLE OR NOT,
THESE FEASIBLE ORNOT, I'M GOINGO
EDWARD AND THE COMMUNITIES TO
RAISE THAT.
WE HEARD THAT THERE IS A FUNDING
OPPORTUNITY.
DEADLINES, NOVEMBER 10TH.
CALLED AFRCURE.
YOU SAWED ADD.
READ THROUGH IT.
IT'S A MENTORSHIP RELATIONSHIP
BUT IT'S WHAT STARTS THE PROC
PROCESS.
AND CAN BRING A LOT OF RICHES TO
THE HOST LABORATORIES THAT ARE
MENTORING TO THE ONES TAKING
PLACE IN VARIOUS COUNTRIES OF
AFRICA.
AND WE HEARD FROM THE COMMUNITY
THERE'S A REAL NEED FOR THIS
TYPE OF RESEARCH TO MOVE
FORWARD.
I WOULD SAY 20 YEARS AGO, NO ONE
OR VERY FEW PEOPLE FELT THAT WE
WERE GOING TO BE ABLE TO BRING
OUR BRAND NEW TRIPLE THERAPY
ANTIRETROVIRAL DRUGS TO AFRICA.
AND LO AND BEHOLD, YES, IT'S 20
YEARS LATER, BUT WE HAVE, IN THE
RANGE OF ABOUT 30 MILLION PEOPLE
ON TREATMENT, THE VAST MAJORITY
OF THAT NUMBER IS IN AFRICA, AND
THE VIRAL SUPPRESSION RATES IN
SOME PLACES LIKE RAKAI OR IN
MALAWI AND SOME OTHER PLACES IS
ACTUALLY BETTER THAN IT IS IN
THE SOUTH OF THE U.S.
IT'S A HUGE SUCCESS, AND IT
WOULD BE ASHAMED TO BE WAITING
FOR SO LONG TO START ENGAGING
THE CURE RESEARCH ON THE
CONTINENT.
SO LET ME STOP A BIT ON
SUMMARIZING SOME OF THE POINTS
THAT I JUST HEARD.
THERE WERE OTHER POINTS MADE,
BUT I'M GOING TO THROW A
CHALLENGE OUT TO THE AUDIENCE.
WHY DO RESEARCH IN AFRICA?
WHAT'S THE MOTIVATION?
WHAT'S THE RESEARCH QUESTIONS?
AND I THINK EACH ONE OF YOU WILL
HAVE TO THINK ABOUT THAT, BUT
LET ME SUMMARIZE SOME THAT CARL
AND HIS COLLEAGUES HAVE COME UP
WITH AND IF THEY'RE THINKING
ABOUT IT, YOU DEFINITELY SHOULD
BE THINKING ABOUT IT FOR FUTURE
FUNDING.
SO WHAT ARE SOME OF THE KEY
UNKNOWNS OUT THERE?
WHAT DIFFERENCES EXIST AMONG THE
DIFFERENT HIV SUBTYPES, AND THE
DIFFERENT POPULATIONS?
WITH RESPECT TO THE RESERVOIR
COMPOSITION, ITS CLONALITY, IT'S
DECAY, ARE DYNAMICS DIFFERENT
WITH THESE OTHER SUBTYPES?
WHAT ARE THE RATES OF POST
TREATMENT CONTROL?
WHAT'S THE EFFECTIVENESS OF
CURATIVE STRATEGIES AS YOU START
TESTING THESE IN THE U.S.?
WHAT ROLE DOES SEX, AGE,
COMORBIDITIES, COMORTALITIES,
COINFECTION, GENETICS,
ENVIRONMENTAL FACTORS, AND
GEOGRAPHY AT LARGE, PLAY IN
THOSE DIFFERENCES? SO LOTS OF
THINGS TO THINK ABOUT.
THAT'S JUST SORT OF THE TIP OF
THE ICEBERG WITHOUT GETTING TOO
TECHNICAL, BUT ONE COULD EASILY
GO INTO THE TECHNICALITIES OF
THOSE TYPES OF ISSUES.
SO I WILL DEFINITELY STOP THERE,
THAT'S MY FIVE-MINUTE SPIEL.
I SEE JESSICA AT THE MICROPHONE,
AND ALSO OVER THERE, I CAN'T SEE
AS WELL, BUT LET ME OPEN UP THE
MICS BECAUSE I WANT YOU TO
ENGAGE WITH THE PANELISTS AND
HEAR FROM YOU AS TO WHAT YOU
THINK IS FEASIBLE, HEAR FROM THE
PANELISTS WHAT THEY FEEL WOULD
BE THE BEST WAY FORWARD FOR THEM
AND THEIR COLLEAGUES WORKING IN
AFRICA.
>> I'LL START.
SO I HAVE A QUESTION FOR THE
PANEL.
I'M INTERESTED TO HEAR HOW MUCH
YOU FEEL IT IS A BARRIER TO
RESEARCH ON THE CONTINENT,
AVAILABILITY OF FUNDING THAT CAN
BE HELD BY AFRICAN PIs.
SO THIS QUESTION STEMS FROM MY
OBSERVATION THAT NOT ONLY IS IT
THAT FREQUENTLY THE SAMPLES ARE
COLLECTED IN E UGANDA WHERE I WK
AND SHIPPED BACK TO NORTH
AMERICA.
I'M IN CANADA, ALSO MY
COLLABORATORS IN THE UNITED
STATES, BUT ALSO THE MONEY AND
THEN THE PAPERS TEND TO GO THAT
WAY.
SO AS A CANADIAN, OUR LARGE
FUNDING ORGANIZATION IS CIHR FOR
HEALTH RESEARCH, AND YOU HAVE TO
BE AT A CANADIAN INSTITUTE TO
APPLY FOR THAT FUNDING.
AND I KNOW THE NIH IS MORE OPEN
AND YOU CAN APPLY
INTERNATIONALLY TO NIH GRANTS,
BUT IT'S HARD TO COMPETE FOR
THEM.
AND SO WITH THE LACK OF
AVAILABILITY OF LOCAL NATIONAL
FUNDING, I'LL SPEAK SPECIFICALLY
FOR UGANDA LOCALLY, IT HARD FOR
MY UGANDAN COLLEAGUES TO COMPETE
FOR NIH FUNDING AND THEY SIMPLY
CAN'T, FOR CHR FUNDING.
SO THEN WE HAVE THIS SITUATION
WHERE THE CANADIAN IS APPLYING
FOR THE GRANT, HOLDING THE
GRANT, AND THEN TRANSFERS A
SUBAWARD.
THE SAMPLES ARE COLLECTED THERE,
AND THEN THE SAMPLES COME BACK
AND ISN'T IT SO FRUSTRATING WHEN
THE LAST PERSON WHO TOUCHES THE
SAMPLE IS THE LAST AUTHOR OR THE
FIRST AUTHOR ON THE PAPER.
AND THAT PA PARADYNAMIC, I WONDD
HOW WE CAN SHIFT THAT.
I THINK THE AFRICARE -- WE CAN
HAVE MORE PEOPLE TRAINED,
COMPETE FOR NIH GRANTS FOR
HPIs.
THESE ARE MY OWN THOUGHTS BUT
I'M INTERESTED HOW THE PANEL
VIEWS THAT, DO YOU VIEW THAT AS
BEING A MAJOR BARRIER AND WHAT
MIGHT WE BE ABLE TO DO TO
ADDRESS THAT?
>> I CAN TAKE A STAB AT THAT.
SO LET ME START FROM A POSITIVE
ASPECT OF THIS.
I THINK AFRICA HAS SO MUCH
POTENTIAL AND CAN COMPETE AND BE
AN EQUAL PARTNER ON THE TABLE TO
SHIFT THE HIV AGENDA.
WE DEMONSTRATED DURING COVID, WE
LED THE WORLD IN CHARACTERIZING
SARS-COV-2 2, THE VARIANTS AND
CONTRIBUTED SIGNIFICANT RI TO
THE DEVELOPMENT OF PROTECTIVE
VACCINES THAT HELPED THE WORLD.
SO THAT'S A CLEAR DEMONSTRATION.
IN PLACES WHERE YOU HAVE
LEADERSHIP, THEY UNDERSTAND THE
PROBLEMS, THEY CAN REACH OUT TO
THE STAKEHOLDERS, TO EVEN
MOBILIZE LOCAL RESOURCES.
I CAN GIVE AN EXAMPLE OF
TANZANIA, THE GOVERNMENT OF
TANZANIA HAS PUT UP 20 MILLION
U.S. DOLLARS IN RESEARCH FOR
SICKLE CELL ANEMIA, GENE THERAPY
RESEARCH IN SICKLE CELL ANEMIA.
SO THERE IS THAT.
SO WHAT WE ARE LACKING IN TERMS
OF THE HIV CURE PROGRAM IS
LEADERSHIP, AND OWNERSHIP.
AND GETTING BACK TO YOUR
QUESTION, WHEN THE GRANT IS
WRITTEN BY A CANADIAN WITH -- IN
AFRICA, WHOSE IDEA IS THAT?
WHO CONCEPTUALIZED THE IDEA?
IS IT THE CANADIAN INVESTIGATOR
OR AFRICAN INVESTIGATOR?
WHEN THE FUNDING KOMEN COMES TH,
WHERE DO THE BULK OF THE MONEY
GO, THE OVERHEADS AND
EVERYTHING?
AND WHAT IS CONTAINED IN THE
SUBAWARD?
SO IF YOU GET A MILLION DOLLARS
AND YOU SUBAWARD 100,000, TO
ACTUALLY DO ANY MEANINGFUL BASIC
SCIENCE RESEARCH, IN THE GIPPING
I SAID THAT.
THE COST OF DOING RESEARCH ON
THE CONTINENT IS MUCH, MUCH
HIGHER.
SO THE BIGGEST BARRIER IS
RESOURCES TO BEGIN WITH.
BECAUSE THERE'S FEWER RESOURCES,
WE HAVE TO DEPEND ON THE WEST.
THE SOLUTION TO THAT IS DIRECT
FUNDING, OPPORTUNITIES TO FUND
AFRICA DIRECTLY BEING INVOLVED
IN THE CONCEPTUALIZATION OF THE
IDEA SO THAT THE IDEA TAKES INTO
ACCOUNT THE REALITY ON THE
GROUND.
>> I'M GOING TO KEEP THIS MOVING
BECAUSE THE LINE IS BUILDING AND
THAT WAS AN EXCELLENT RESPONSE.
NEXT QUESTION.
>> THANKS.
I'M MOHETH FROM WEILL CORNELL.
I WORK IN DR. GUIN LEE'S LAB,
AND I HAD A COUPLE COMMENTS.
FIRST I AGREE WITH ZAZA THAT
RESEARCH IN AFRICA OR LIKE
OUTSIDE OF THE AMERICAN
CONTINENT AND EUROPE, IT COSTS A
LOT.
I WAS ABOUT TO ASK YOU IF YOU
HAD ANY PLANS TO -- I MEAN,
ANCHORAGE MANUFACTURING AND ALSO
QUALITY ANALYSIS AND CERTIFYING
YOUR OWN REAGENTS SO THAT THE
COSTS COULD GO DOWN AS MUCH AS
YOU CAN POSSIBLY BRING IT DOWN.
AND WOULD THAT ACTUALLY HELP YOU
IN ANY WAY TO CONDUCT MORE
MEANINGFUL RESEARCH?
I UNDERSTAND THAT TRAINING IS
IMPORTANT, BUT WITHOUT
RESOURCES, YOU'RE NOT GOING TO
BE ABLE TO DO A LOT OF
MEANINGFUL RESEARCH FOR YOU TO
EVEN REACH FOR THE INCENTIVES
LIKE WAS MENTIONED.
IF YOU'RE NOT ACTUALLY ABLE TO
DO MEANINGFUL RESEARCH HOW ARE
YOU EVEN GOING TO APPLY FOR
THESE AWARDS AND FELLOWSHIPS
WITHOUT RESOURCES?
SO MY QUESTION IS HOW ARE YOU
PLANNING ON ADDRESSING THE
MANUFACTURING AND THE
ACCESSIBILITY TO REAGENTS?
>> SO THAT IS A MUCH BIGGER
PROBLEM THAT ONE INVESTIGATOR
CANNOT SOLVE.
SO IT'S A BUSINESS PROBLEM.
WE CANNOT ORDER REAGENTS
DIRECTLY FROM THE MANUFACTURERS
IN THE U.S.
THERE'S A MIDDLEMAN.
AND THE MIDDLEMAN PUTS UP A BIG
MARKUP FOR US TO GET THE REAGENT
TO YOUR LAB, YOU HAVE TO GO
THROUGH A LOCAL SUPPLIER, AND
YOU DEPEND ON THEM.
FOR THEM THEY WANT TO MAKE A
PROFIT SO THEY CANNOT SHIP AN
ANTIBODY FOR YOU BECAUSE THEY
WON'T MA MAKE A PROFIT SO YOU'LL
HAVE TO WAIT FOR THEM TO MAKE
VOLUMES, SOMETIMES THEY ARE WAY
EXAGGERATED AND I THINK THAT
BUSINESS IS UNREGULATED.
THE SOLUTION TO THAT IS THAT THE
FUNDERS NEED TO COME TOGETHER,
THE NIH, THE WELLCOME TRUST, THE
BILL GATES FOUNDATION TO
NEGOTIATE ON OUR BEHALF TO THESE
COMPANIES TO FIND A WAY IN WHICH
WE CAN LOWER THE COST, AND IT
HAS TO BE A CONDITION LIKE IF
YOU'RE GOING TO BUY A FLOW SIGHE
YOU A COMPETITIVE PRICE.
SO IT'S A MUCH BIGGER PROBLEM
THAT REQUIRES THE FUNDERS, THE
GOVERNMENTS, ON THE GROUND AND
MOBILIZATION OF LARGER GROUP OF
PEOPLE.
AGAIN WITH THEM IT'S ABOUT
VOLUMES.
IF MORE PEOPLE ARE PIEI BUYING R
THEM LIKE FOR INSTANCE, IF WE'RE
COLLABORATING LIKE MY COLLEAGUE
SAID FROM UGANDA, ZAMBIA, SOUTH
AFRICA, WE'RE ALL DOING SIMILAR
RESEARCH, WE CAN NEGOTIATE UP
FRONT WITH A COMPANY TO LOWER
THE COST BECAUSE WE CAN
GUARANTEE BUSINESS BECAUSE WE
KNOW WE ARE FUNDING AND WE'RE
GOING TO BE BUYING CONSTANTLY
FROM THEM.
SO THAT'S SOMETHING THAT HAS
BEEN IDENTIFIED AND SOLUTION
NEEDS TO BE FOUND.
IF WE'RE GOING TO HAVE
MEANINGFUL BASIC SCIENCE
RESEARCH ON THE CONTINENT, WE
NEED TO FIND A WAY TO LOWER THE
COST OF DOING BUSINESS ON THE
CONTINENT.
>> A SMALL FOLLOW-UP, HAVE YOU
THOUGHT OF APPROACHING INDIAN
LABORATORIES WHERE THEY MIGHT
HAVE ACCESS TO THESE RESOURCES
AND CAN MAYBE PROVIDE IT FOR
CHEAPER?
BECAUSE I DON'T SEE A LOT OF
REPRESENTATION OF INDIAN COHORTS
IN MOST OF THE STUDIES AND I
WOULD LIKE TO BRING UP THAT
CONVERSATION TOO.
THANKS A LOT FOR YOUR ANSWER.
>> LET'S MOVE THIS FORWARD.
I WILL JUST MAKE THE COMMENT
THAT THIS RESOURCE ABOUT THE
REAGENTS AND OTHER THINGS WAS
THE BIGGEST OBSTACLE FOR ARVs
COMING TO AFRICA.
BUT THE CLINTON FOUNDATION, THE
U.N., UN AIDS, WHO, NIH, THERE
WERE LOTS OF EFFORTS WHERE THEY
CAME TOGETHER.
SO MAYBE WE CAN USE THAT AS A
PARADIGM GOING FORWARD, BUT I
THINK BTHANK BOTH QUESTIONERS O.
NEXT.
>> THANK YOU FOR THIS PANEL.
THIS IS A REALLY CRITICAL TOPIC
FOR ALL OF US.
I THINK WE'VE BEEN TALKING ABOUT
HOW TO ENGAGE A GLOBAL EFFORT IN
HIV RESEARCH FOR A LONG TIME.
BUT I WOULD MAKE TWO POINTS.
ONE, I WOULD SORT OF -- I WANT
TO AGREE THAT RESOURCES IS A
MAJOR DRIVER FOR ENGAGEMENT.
AND 20 YEARS AGO WITH THE ONSET
OF THE CPRA PROGRAM, I THINK
THAT WAS A REALLY VISIONARY
INVESTMENT ON INFRASTRUCTURE AND
TRAINING THAT LED TO TRIALS AND
EVEN TODAY WE'RE STILL USING
SAMPLES FROM THAT PROGRAM THAT
LED TO LEADERSHIP GROWTH, THAT
LED TO NETWORKS, WHERE THAT WERE
EVENTUALLY PICKED UP BY THE ACTG
AND I THINK MAYBE IT'S TIME THAT
WE REVISIT THAT INVESTMENT AGAIN
IN CURE CENTERS OF RESEARCH
GLOBALLY.
AND MAYBE INFUSE RESOURCES FOR
THE PURPOSES OF ACHIEVING WHAT
WE ALL WANT, WHICH IS A GLOBAL
ENGAGEMENT.
THE SECOND POINT, I'VE BEEN IN
STUDY SECTION FOR 25 YEARS AND
I'VE SEEN MANY APPLICATIONS AS
ALREADY NOTED THAT ARE NOT
COMPETITIVE BECAUSE THESE STUDY
SECTION MEMBERS ARE NOT AS AWARE
OF THE OBJECTIVES OF A GLOBAL
ENGAGEMENT MISSION.
SO IF THERE'S GOING TO BE
INVESTMENTS IN GLOBAL
ENGAGEMENT, WE REALLY NEED TO
EMPHASIZE SPECIAL PANELS THAT
BRING EMPHASIS FROM THE GLOBAL
ENVIRONMENT TO THAT REVIEW
SESSION BECAUSE I THINK THAT MAY
ALSO BE A VERY DIRECT WAY TO
MAKE SURE THAT THE CREDITS OF
THE APPLICATIONS ARE DISCUSSED
WITHIN THE CONTEXT OF THEIR
ENVIRONMENTS AND THAT'S
SOMETHING TO CONSIDER.
THANK YOU.
>> EXCELLENT COMMENT, AND I SEE
KARL MAKING NOTES.
NEXT, DEBBIE.
>> I HAD ACTUALLY A QUESTION AND
A SIMILAR COMMENT AND THEN SOME
CONSIDERATION.
SO HANEEFA THANK YOU FOR LEADING
THIS EFFORT.
YOU USED THE WORD SMALL MONEYS
AND I THINK WHEN WE HAD INTERNAL
CONVERSATIONS ABOUT WHAT MONEY
SHOULD BE IN TERMS OF INVESTMENT
IN A GIVEN INDIVIDUAL.
WHAT I RECALL, THERE WAS A
SIZABLE AMOUNT, SO AN
INVESTIGATOR -- A MID CAREER
LEVEL INVESTIGATOR COULD HAVE A
REASONABLE AMOUNT OF MONEY.
IT'S STILL NOT SUFFICIENT, BUT
TO AT LEAST GET STARTED.
SO I THINK IT WOULD BE IMPORTANT
TO CLARIFY WHAT THAT DOLLAR
AMOUNT IS AS WE THINK ABOUT AN
APPLICATION AND THE GOALS.
AND SECONDLY, YOU KNOW, IN
WORKING WITH OUR COLLEAGUES IN
AFRICA, AND APPLYING FOR GRANTS,
EXACTLY WHAT WAS SAID, THE BAR
AND THE ASSESSMENT FOR RANKING
APPLICATIONS IS SO HIGH THAT OUR
AFRICAN COLLEAGUES GET VERY
DISCOURAGED WHEN A SMALL
APPLICATION IS TURNED DOWN.
SO I THINK WE NEED TO KIND OF
THINK THROUGH A FRAMEWORK FOR
SUCCESS OF THIS PROGRAM INSTEAD
OF THIS SORT OF CONVENTIONAL WAY
OF YOU SUBMIT YOUR APPLICATION
AND WHAT'S THE SCIENCE BUT
REALLY DO YOU HAVE THE RIGHT
MENTORSHIP ENVIRONMENT, IS THIS
PERSON GOING TO REALLY -- IS
THIS A TRUE INVESTMENT, OR JUST
WE'RE GOING TO DO THIS FOR THIS
INDIVIDUAL, AND I WOULD
ENCOURAGE YOU TO REALLY THINK
THROUGH TWO LEVELS, SOMEONE
THAT'S ADVANCED AS IMMACULATE IN
TERMS OF BEING ABLE TO GET
SIGNIFICANT FUNDING BUT THINK
ABOUT THE YOUNG PEOPLE, THE
EARLY INVESTIGATORS, I GET
REACHED OUT ALL THE TIME, I WANT
TO GET INVOLVED IN CURE
RESEARCH, HOW CAN I GET FUNDED
AND THERE'S REALLY NO MECHANISM
TO GET SOMEONE STARTED.
SO THINKING THROUGH A TWO-TIER
PROCESS SO YOU HAVE A CONTINUOUS
PIPELINE TO KEEP THAT GROWING.
AND THEN MY THIRD FOR
CONSIDERATIONS IS, ZAZA AND --
EXCELLENT LABORATORIES, AND AS
TOM SAID A LOT OF THE
COLLABORATORIES HAVE
INVESTIGATORS IN
RESOURCE-CONSTRAINED SETTINGS,
SO WHY DON'T WE START WITH WHERE
THE INFRASTRUCTURE EXISTS TO
MAKE THE PROGRAM SUCCESSFUL IN
ITS FIRST ROUND.
THAT'S JUST FOR CONSIDERATION.
>> THAT'S WHERE SOUTH TO SOUTH
COLLABORATION CAN REALLY TAKE
OFF.
ESTABLISH A COUPLE CENTERS OF
EXCELLENCE IN CURE RESEARCH WITH
AFRICAN INVESTIGATORS AT THE
LEAD, AND THEN DO SOUTH TO SOUTH
WITHIN THE CONTINENT.
, I THINK
WOULD BE A GREAT WAY.
I WISH THERE WAS A LOT MORE TIME
BECAUSE WE COULD ASK YOU ABOUT
YOUR EXPERIENCE WITH IMPACT AND
HOW WELL THAT FUNCTIONED WITHIN
AFRICA AND SOME OF THE STUDIES
THAT YOU PRESENTED EARLIER.
BUT WE'LL SAVE THAT TO
AFTERWARDS, DEBBIE.
I'LL SEE HER BACK IN BALTIMORE.
NEXT.
>> YES, HELLO.
THANK YOU FOR BEING HERE.
I'M A COMMUNITY REPRESENTATIVE
OF THE REACH COLLABORATORY IN
NEW YORK.
FIRST I WOULD LIKE TO REMIND
EVERYBODY THAT THE REACH
COLLABORATORY ASSISTED THE RAKAI
HEALTH SCIENCE PROGRAM WITH
INSTALLATION OF A NEW DDPCR.
THIS IS PERHAPS AT THE BEGINNING
OF SOME KIND OF A MORE CLOSE
COLLABORATION, TECHNICAL
ASSISTANCE, WHATEVER -- HOWEVER
WE NEED TO GO.
I'M A COMMUNITY REPRESENTATIVE
AND I KNOW AND I REMEMBER THAT
HIV HAS BEEN IDENTIFIED ABOUT 40
YEARS AGO I WOULD LIKE TO KNOW
AS A COMMUNITY REPRESENTATIVE,
HOW DOES THE COMMUNITY FEEL
ABOUT CURE?
IN YOUR COMMUNITIES, --
EXTENDING RESEARCH AND CLINICAL
TRIALS HELP POPULARIZE HIV CURE
AND WOULD THE PEOPLE IN YOUR
COMMUNITIES PARTICIPATE?
>> ELINA, CAN YOU ADDRESS THAT,
PLEASE?
GREAT QUESTION.
>> I THINK IT EXTENDS TO WHAT'S
THE REACH ON THE GROUND IN THE
HIV CURE RESEARCH.
I THINK WHEN WE BRING OUT THAT
UNDERSTANDING, THAT'S WHERE WE
START TO DEFINE.
I KNOW WE COME TO UNDERSTAND OF
THE DIFFERENT STRATEGIES ON CURE
RESEARCH THAT ARE THERE, BUT I
THINK WHAT WE BRING TO THE
COMMUNITY TO GO OVER JUST THE
SENSE BUT I THINK WE ATTACH IN
REAL LIFE STORIES, AND I THINK
WE EXPLAIN THAT, THAT'S WHEN I
THINK WE'RE LOOKING INTO THE
COMPONENT OF IF YOU'RE ABLE
TO -- WE'RE STARTING WITH THE
BASIC -- DOES IT GO TO YOU AND
WE UNDERSTAND YOU CANNOT
TRANSMIT AND THEN YOU'RE
STARTING TO BRING IN THE
DEFINITION OF CURE AND STAGE SO
I THINK IT BRINGS IN A DIFFERENT
CONTEXT AND DIFFERENT BACKGROUND
OF THE COMMUNITIES, AND ENGAGING
THE COMMUNITIES, I THINK IT'S
ABOUT STARTING FROM STEP ONE.
SO WE MOVE -- I HEARD -- WITH
THE COMMUNITY THAT THERE'S
INFORMATION TO MAKE SURE THE
COMMUNITIES ARE FULLY ENGAGED AS
WELL AS TO ADVOCATE.
>> THANK YOU.
>> MY FAMILY HAS PARTICIPATED IN
THIS COHORT FOR 30-SOMETHING
YEARS.
THIS IS THEIR HOPE, WHAT SOMEONE
TOLD ME.
THEY BELIEVE BY GIVING THEIR
BLOOD, EVERY TIME, SOMETHING
GOOD EVENTUALLY WILL COME OUT OF
THIS.
THAT'S THE BIGGEST MOTIVATOR FOR
THEM TO KEEP DOING THIS.
>> THANK YOU.
>> WE NEED TO MOVE ON.
>> THANK YOU SO MUCH.
THIS IS JUST A COMMENT, COMING
FROM WHAT I SEE IN MY COUNTRY,
THAT'S UGANDA, IS THAT I THINK
THERE IS NEED FOR US IN AFRICA
AS WELL TO COME UP WITH, I DON'T
KNOW, MAYBE LIKE A CONTINENTAL
ANALYSIS OF WHAT IS ACTUALLY --
WHAT IS THIS TRICK THAT WE HAVE
AS A -- COUNTRY IN TERMS OF HIV
CURE RESEARCH, WHAT ARE OUR
WEAKNESSES, BECAUSE I FEEL LIKE
SOMETIMES WHEN WE LOOK AT A
COUNTRY, INSTITUTIONS ARE ALL
DOING DIFFERENT THINGS, THEY
HAVE PROBABLY DIFFERENT -- AND
THEY HAVE PROBABLY DIFFERENT
MACHINE, SO HOW TO ENSURE THAT
ALL OUR RESEARCHERS IN A COUNTRY
KNOW WHAT IS HAPPENING AT
INSTITUTION A SO THAT WHEN THEY
NEED ANYTHING, THEY CAN EASILY
GO THERE AND THEY DON'T HAVE TO
DUPLICATE OR EVEN FIND MORE
EXPENSES AND ALL THAT, SO MAYBE
AS COUNTRIES, WE HAVE TO LOOK AT
LIKE MAYBE LIKE INSTITUTIONAL
SORT ANALYSIS AND THEN THAT CAN
COME UP TO COUNTRY AND THEN
MAYBE IT CAN EVEN COME UP TO THE
CONTINENT.
AND THEN ALSO I JUST WANT TO
MAKE A COMMENT ON WHAT THE
COMMUNITY THINKS ABOUT HIV CURE.
IT IS DIFFERENT ACCORDING TO
EACH.
MY MOTHER WOULD WANT AN HIV CURE
BECAUSE SHE'S CURRENTLY HAVING A
HEART DISEASE, SO PROBABLY THOSE
ISSUES OF HEART FAILURE, LIVER
FAILURE AND ALL THAT ARE GIVING
HER MORE REASON FOR AN HIV CURE.
I WANT AN HIV CURE BECAUSE I'M
TIRED OF MEDICATION.
SO I THINK THE REASONS ACCORDING
TO AGE OR SEX ARE DIFFERENT.
THANK YOU.
>> I'VE GOT TO ASK, ZAZA, DO YOU
WANT TO COMMENT ON THAT?
MAYBE IMMACULATE?
>> I THINK A QUICK COMMENT ON
THAT.
IT'S VERY, VERY TRUE THAT
RESEARCH EVERYWHERE IS SILOED.
INCLUDING HERE IN THE U.S.
IN AFRICA IT'S EVEN MORE SILOED
BECAUSE YOU ARE ONLY ALIGNED
WITH PEOPLE THAT YOU WORK WITH
AND WHERE YOU'RE GETTING YOUR
FUNDING TO DO YOUR RESEARCH, AND
MOSTLY YOU'LL FIND THAT THE
PEOPLE THAT YOU ARE WORKING WITH
TO FUND YOUR RESEARCH WHO ARE
HELPING YOU ARE PEOPLE FROM
THE -- AND THOSE ARE THE PEOPLE
YOU INTERACT WITH.
BUT THERE IS NEED LIKE YOU SAY
TO HAVE SOUTH TO SOUTH
COLLABORATION.
SO HOW DO WE DO THAT?
WE NEED TO INCENTIVIZE THAT.
THE ONLY WAY YOU CAN I INCENTIVE
THAT IS SAY YOU FUND AN AFRICAN
COLLABORATORY.
AND THOSE PEOPLE ARE FORCED TO
WORK TOGETHER BECAUSE EVERYONE
NOW HAS A SKIN IN THE GAME.
THE NEED TO DELIVER ON THE
OBJECTIVES OF THE STUDY AND THEN
YOU'LL FIND WHO HAS STRENGTH IN
COHORT FORMULATION, WHO HAS
STRENGTH IN RESERVOIR ASSAYS,
WHO HAS STRENGTH IN IMMUNOLOGY,
CAN WE ALL COME TOGETHER, AND
PEOPLE BEGIN TO TALK TO EACH
OTHER, THE STUDENTS NEED TO
INTERACT AND NEED TO WORK AS A
TEAM AND FOR ME, THAT'S THE WAY
FORWARD.
IF THERE IS FUNDING MODALITIES
THAT ATTRACT -- FORCES PEOPLE TO
WORK TOGETHER TO SAY YOU NEED TO
COME TOGETHER AND YOU ARE MORE
LIKELY TO GET THIS FUNDING IF
YOU ACTUALLY BAND TOGETHER AS
AFRICAN INVESTIGATORS, I THINK
THAT WILL GET US SOMEWHERE.
SO MOSTLY IN SOUTH AFRICA,
WITHIN SOUTH AFRICA, PEOPLE
WORKING IN JOHANNESBURG DON'T
EVEN TALK TO PEOPLE WORKING IN
CAPETOWN, SO ON AND SO FORTH AND
THE SAME THING IN MALAWI, THE
SAME THING IN UGANDA.
IF WE CAN HAVE FUNDING THAT
ACTUALLY TRIES TO BREAK THOSE
SILOS, I THINK WE CAN MAKE
HEADWAY.
>> GREAT.
WE HAVE THREE PEOPLE AT THAT
MICROPHONE.
I'M GOING TO HAVE YOU EACH ASK
YOUR QUESTION.
LET'S GET ALL THREE QUESTIONS UP
BECAUSE THEN WE HAVE TO CLOSE
THE PANEL.
OR COMMENT.
DOESN'T HAVE TO BE A QUESTION.
>> I'LL TRY TO BE VERY FAST.
I'M GUIN LEE FROM WHI WEILL COR.
SO I JUST WANT TO SHARE A STORY
MAYBE AND A PERSONAL EXPERIENCE
OF KNOWLEDGE TRANSFER, AND SO
I'M FUNDED BY AN R01 THAT
INVOLVES WORKING WITH A COHORT
IN UGANDA, AND SO I MADE SURE TO
WRITE IN A KNOWLEDGE TRANSFER
COMPONENT IN THE R01, IT'S MY
SOLO R01 SO NOT RELATED TO
REACH, BUT WRITING IN A
KNOWLEDGE TRANSFER COMPONENT IN
THE R01 SO NOW I'M CONNECTED TO
A MENTEE THERE, AND SO WE SET UP
WEEKLY MEETINGS, SO I WOULD TALK
TO THIS MENTEE EVERY WEEK AND I
WILL TEACH THE MENTEE HOW TO,
FOR EXAMPLE, USE GRAPH PRISSMM,
HOW TO, FOR EXAMPLE, USE EXCEL,
BUT ALSO TO ANALYZE DATA SO DRY
ANALYTICAL SKILLS CAN BE PASSED
ON VIRTUALLY.
SO WE HAVE BEEN CONTINUING ON
WITH THO THOSE WEEKLY MEETINGS R
OVER A YEAR AND THE MENTEE HAS
SUCCESSFULLY PRODUCED -- SO
THESE ARE LITTLE THINGS WE CAN
DO TO TRANSFER THE KNOWLEDGE AND
IT DOESN'T HAVE TO BE WET LAB
AND REAGENT FOCUSED, JUST LITTLE
THINGS, A LITTLE AT A TIME, I
THINK.
THAT'S WHAT I WANT TO SHARE.
THANKS.
>> THANKS, GREAT PANEL.
I JUST HAVE A COMMENT.
I'M WEARING MY IAS HAT HERE AND
THAT IS WH I THINK THERE'S A NUF
SIMILAR EFFORTS.
BRILLIANT TO SEE GETTING BEHIND
FUNDING RESEARCH, SOME OTHER
EFFORTS OBVIOUSLY THROUGH THE
EIS AND TRAINING THROUGH THE
RESEARCH ACADEMIES AIDS FUND AND
GATES ARE ABOUT TO INVEST
HEAVILY IN ADVOCACY FOR CURE IN
AN AFRICAN-LED INITIATIVE
TOGETHER WITH AVAC AND IAS, AND
I THINK IN THE END WHAT WE WANT
IS AFRICAN-LED, AFRICAN-FUNDED
SCIENCE.
SO WE NEED A BIT OF MORE
COHERENT ADVOCACY VOICE WITH
FUNDERS AND LEADERS IN AFRICA,
AND I JUST WONDER WHETHER WE HAD
A BIT MORE COORDINATION AROUND
SOME OF THESE EFFORTS.
WE COULD GET TOGETHER A BIT OF
NARRATIVE FOR GREATER ADVOCACY
AND I'VE BEEN INVOLVED IN SOME
EFFORTS AIMED AT THIS, AND ONE
OF THOSE INVOLVED JOHN KANGESAN
BEFORE HE MOVED TO PEPFAR, IT
WAS JUST IN THE LAST TWO MONTHS
OF HIM AT THE AFRICAN CDC.
AND HE WAS VERY RECEPTIVE TO THE
WHOLE CONCEPT OF WHY CURE
RESEARCH NEEDS TO HAPPEN IN
AFRICA, WHY THERE NEEDS TO BE
KNOWLEDGE AMONGST THE
COMMUNITIES AND HE COULD ALSO
SEE THE ECONOMIC ARGUMENT FOR
LEADERS IN THE AFRICAN CONTINENT
TO INVEST IN THIS FOR THEMSELVES
ECONOMICALLY.
SO I THINK JOHN WOULD BE A
REALLY GOOD PERSON TO ENGAGE AS
BOTH FROM A PEPFAR POINT OF VIEW
AND KNOWLEDGE OF THE CDC AND IAS
CAN HELP PLAY A ROLE BUT I THINK
WE DO NEED A COORDINATED EFFORT
AROUND WHAT ARE THE NEEDS, WHAT
ARE THE CURRENT OPPORTUNITIES,
AND HOW ARE WE REALLY GOING TO
GET TO SOMETHING THAT'S
AFRICAN-LED AND FUNDED, AND A
WAY OF ENGAGING AFRICAN
LEADERSHIP.
AND THE START COULD BE CDC AND
PEPFAR.
>> GREAT COMMENT.
TOTALLY AGREE.
LAST ONE.
>> MY NAME IS JUSTINE FROM
UGANDA.
I WORK WITH THE -- PROJECT
MOSTLY COLLABORATING WITH THE
U.S. MHRP AND I WANTED TO JUST
TALK ABOUT THE TIME THAT WE
PROCESS THE LYMPH NODES AND
BIOPSIES FOR CURE RESEARCH, HIV,
AND FOR THE GUT BIOPSIES.
WHAT WE DID WITH STAINING THEM,
AND LOOKING AT THE DATA USING
THE FLOW CYTOMETERS, WE
DEMONSTRATED WE HAVE -- LIKE IT
IS VERY POSSIBLE TO CHARACTERIZE
REALTIME ET RESERVOIR IN LOW AND
MIDDLE INCOME COUNTRIES, SO
NEEDS WITHIN TRAINING RESOURCES,
ESPECIALLY GRANT-WRITING SKILLS,
AND THE RELEVANT EQUIPMENT.
THANK YOU.
>> THANK YOU.
[APPLAUSE]
>> WE'RE AT THE END OF OUR
ALLOTTED TIME, BUT I WANT TO SEE
IF ANY OF THE PANELISTS, BECAUSE
WE JUST HAD SOME COMMENTS, IF
ANY OF YOU VERY QUICKLY WANT TO
GIVE A FINAL WORD TO THIS
AUDIENCE?
YOU DON'T GET THIS OPPORTUNITY
VERY OFTEN.
SO ANYONE DOWN THE LINE.
EDWARD WANTS TO GO FIRST, JULIE.
ZAZA, YOU'RE NOT GOING TO SAY
ANYTHING?
NO, NO, EDWARD IS FIRST.
>> FIRST I WOULD LIKE TO SAY
THANK YOU TO THE AMERICAN
PEOPLE.
YOUR GENEROSITY HAS SAVED
MILLIONS OF LIVES OVER THE LAST
20 YEARS.
AND TWO, THE NIH AND THE OTHER
INSTITUTIONS THAT HAVE PROVIDED
TRAINING FOR PEOPLE FROM LOW AND
MIDDLE INCOME COUNTRIES ACROSS
THE SPECTRUM, THANK YOU.
AND NOW TH THE INCREASING
COMMITMENT THAT WE ARE SEEING
TARGETING SUPPORTING RESEARCHERS
AND COMMUNITY PEOPLE AND
ADVOCATES TO DO THIS WORK IN
AFRICA IS MOVING IN THE RIGHT
DIRECTION.
SO SO FAR, YOU'VE GIVEN US --
YOU'VE TAUGHT US HOW TO FISH,
AND YOU'RE BEGINNING TO GIVE US
SOME FISHING HOOKS.
THE NEXT THING I THINK WE WANT
TO SEE IS INCREASING -- IS YOU
TEACHING US ACTUALLY HOW TO MAKE
THE FISHING HOOKS OURSELVES SO
THAT WHEN THAT TIME COMES, WE
CAN HELP OURSELVES MUCH BETTER.
THANK YOU.
[APPLAUSE]
>> MAYBE JUST ONE POINT THAT WE
DIDN'T JUST POINT OUT BECAUSE
THE PROBLEM IS MULTI-LAYERED, SO
THERE'S THE ISSUE OF ALSO
ATTRACTING YOUNG TALENT, LIKE
EDWARD HERE.
SO I'VE BEEN WORKING IN SOUTH
AFRICA FOR MORE THAN 10 YEARS
NOW, AND THE KEY TO, YOU KNOW,
THE SUCCESSFUL PROGRAM IS
ATTRACTING YOUNG TALENT, AND SO
TO ATTRACT AND RETAINING THE
TALENT.
SO WE'VE DONE VERY WELL TO
ATTRACT, YOU'VE DONE VERY WELL
TO TRAIN, BUT YOU'VE DONE VERY
POORLY AT RETAINING.
MORE THAN 90% OF PEOPLE WITH
PH.D.s I'VE TRAINED MYSELF
HAVE LEFT THE CONTINENT, AND
THAT IS A PROBLEM, AND I DON'T
KNOW WHAT THE SOLUTION IS TO
THAT, BUT AS LONG AS WE KEEP
LOSING GOOD TALENT TO THE WEST,
THEY COME FOR VISITING THE LAB
AND END UP STAYING.
IT'S ALWAYS GOING TO BE
DIFFICULT AND THAT'S SOMETHING
THAT ALSO NEEDS TO BE THOUGHT
ABOUT IN TERMS OF CAREER
PROGRESSION, AND WHEN PEOPLE AT
THE END OF THEIR TRAINING, THEY
COME TO YOU AND SAY WHAT NEXT,
YOU DON'T HAVE AN ANSWER,
THERE'S NO FACULTY POSITION,
THERE ARE NO -- THE LIMITED
OPPORTUNITIES FOR PEOPLE IN
SCIENCE TO HAVE A CAREER ON THE
CONTINENT AND TO PROGRESS.
THERE ARE VERY FEW PEOPLE LIKE
ME WHO CAME AND GOT A GOOD
EDUCATION IN THE U.S. AND WENT
BACK AND MADE A MEANINGFUL
CAREER OUT OF IT.
IT'S NOT BEEN EASY BUT IT'S VERY
RARE.
THERE ARE FEW PEOPLE THAT HAVE
DONE THAT, BUT MOST PEOPLE FAIL
TO DO THAT AND ESPECIALLY
OUTSIDE SOUTH AFRICA, IT'S
EXTREMELY DIFFICULT, SO IT'S THE
IDEA OF CAPACITY BUILDING AS
HAPPENED QUITE A BIT ABOUT
TRAINING PEOPLE BUT THE
RETENTION AND PATHWAY TO BEING
INDEPENDENT INVESTIGATOR ON THE
CONTINENT IS NOT VERY
WELL-DEFINED AT THE MOMENT.
THANK YOU.
>> THANK YOU, EVERYONE, WHO HAS
STAYED AROUND TO THE END.
APPRECIATE YOUR TIME.
I JUST HAD JUST A FEW COMMENTS.
I WAS JUST LOOKING AT THE
NOSIs THAT HAVE COME OUT AND I
SEE THERE'S SO MUCH OPPORTUNITY
IN THERE.
THERE'S SO MUCH THAT CAN BE
DONE, THERE'S SO MUCH THAT --
AND WHEN YOU LOOK AT ALL THESE,
THERE'S SO MUCH, MYSELF, I'M
LIKE OKAY, ME AND MY GROUP ARE
PLANNING TO PUT IN MAYBE LIKE
TWO OF THEM, BUT I'M LIKE OKAY,
SO WE PUT IN, DO WE STAND A
CHANCE?
MOST TIMES, IS IT LIKELY THAT
THE ONES -- THE PLAYERS ARE THE
ONES WHO ARE GOING TO GET THEM
OR IS THERE AN OPPORTUNITY THAT
NEW KIDS ON THE BLOCK ARE
GETTING THESE OPPORTUNITIES,
BECAUSE IT'S REALLY SO DIVERSE,
BUT IF OPPORTUNITIES ARE OPEN
NOT TO EVERYONE BUT WHO IS ABLE,
I THINK THERE IS MUCH FOR
EVERYONE.
AND I'M ALSO LOOKING AT AN
OPPORTUNITY LIKE IS THERE A
CHANCE OF HAVING AFRICAN GRANTS
FOR AFRICANS?
BECAUSE NOW THIS IS LMICs BUT
YES, CAN WE HAVE THE OPPORTUNITY
TO PUT IN AND CONSIDERED SO AS
WE GET THIS, WE ARE BUILDING
CAPACITY.
WHEN YOU GET A GRANT, IT REALLY
BRINGS -- IT JUST TAKES YOU
FORTH INTO SOMETHING ELSE AND
MORE AND TO MORE AND TO MORE.
ALSO THE OTHER THING WOULD MAYBE
BE AS THESE GRANTS ARE BEING
AWARDED, IS THERE AN OPPORTUNITY
OF EXPLAINING THE DEVELOPMENTAL
AWARDS, THESE ARE SMALL GRANTS
THAT CAN HELP NEWER PEOPLE COME
ON BOARD AND THEN EXPAND THEIR
EXPERTISE.
SO IF YOU HAVE MORE
DEVELOPMENTAL GRANTS, THEN
YOU'LL HAVE MORE PEOPLE HAVING
MORE OPPORTUNITIES TO WRITE EVEN
BIGGER GRANTS, AND THIS WILL
EXPAND THE EXPERTISE ON
CONTINENT.
THANK YOU.
>> ANY OTHER COMMENTS?
JULIE, HANEEFA?
>> I DID ORIGINALLY BUT MY
COLLEAGUES SAID SO MANY
IMPORTANT THINGS.
MAYBE I WOULD JUST COMMENT THAT
A REALLY KEY IMPORTANT AUDIENCE
ARE NOT OUR COLLEAGUES IN
MINISTRIES OF HEALTH BUT ALSO IN
THE MINISTRIES OF FINANCE.
IT IS PEOPLE LIKE THAT WHO
UNDERSTAND THAT VERY WELL AND SO
I THINK THAT IS A REALLY
IMPORTANT PIECE OF ADVICE THAT
WE JUST HEARD FROM, FROM SHARON.
AND MAYBE THE LAST THING I WOULD
SAY IS THAT WE ARE SO INDEBTED
TO THE VOLUNTEERS THAT HAVE --
AND PARTICIPANTS IN STUDIES WHO
HAVE TAKEN US SO FAR IN THE
EARLY PHASE, MAYBE THE END OF
THE BEGINNING, RIGHT, OF HIV
CURE RESEARCH, PRIMARILY HERE
BASED IN THE U.S.
FOR EVERY ONE OF THROWS VALU THD
PARTICIPANTS, THERE ARE
THOUSANDS OF PEOPLE GLOBALLY
WHOSE VOICE MAY NOT BE HEARD
BECAUSE OF THEIR PERSONAL
CIRCUMSTANCES OR JUST THE
SETTING IN WHICH THAT THEY LIVE.
THESE INITIATIVES, THESE FOCUSED
COORDINATED EFFORTS TO REALLY
ELEVATE NOT JUST CLINICAL, I
SHOULD SAY ALSO THE KEY
IMPORTANCE OF THE OUTCOME BASIC
RESEARCH BEING DONE IN LOW AND
MIDDLE INCOME SETTINGS, THIS IS
REALLY ELEVATING RAISING THOSE
VOICES.
I MEAN, INCREDIBLY IMPACTFUL,
SOME OF THE MOST IMPORTANT WORK
WE CAN POSSIBLY BE DOING AS A
COMMUNITY, EVERYONE IN THIS
ROOM, IT'S JUST REALLY
FULFILLING TO BE HAVING THIS
DISCUSSION AT THIS TIME.
>> OKAY, LAST WORDS DOWN THERE
AT THE END OF THE PANEL HERE.
>> I JUST WANT TO BE QUICK.
JUST SORT OF REITERATE THAT WE
DO HAVE THE CFAR AFRICA PROGRAM.
IT'S NOT GOING TO ADDRESS ALL OF
THE PROBLEMS AND ALL OF THE
CHALLENGES, BUT IT IS ONE STEP
TO REALLY INVEST IN NEW
INVESTIGATORS, EARLY CAREER
INVESTIGATORS, AND IT REALLY
TARGETING INVESTIGATORS WHO ARE
BASED IN AFRICA WHO HAVE
AFFILIATIONS IN AFRICAN
INSTITUTIONS TO TRY TO AVOID
SOME OF THAT BRAIN DRAIN OR AT
LEAST TRY TO MITIGATE SOME OF
THAT BRAIN DRAIN.
SO WE'RE REALLY EXCITED TO GET
STARTED ON THIS INITIATIVE, AND
REALLY FOCUS ON INVESTING IN
THOSE EARLY STAGE INVESTIGATORS.
>> I'LL ALSO BE BRIEF.
I THINK WE TALKED A LOT ABOUT
THE FUNDING OPPORTUNITIES.
I THINK I'M ALSO LOOKING AT
SPECIFICITY OF AS WE'RE TALKING
ABOUT THE HIV CURE RESEARCH
FUNDING WE SHOULD ALSO THINK OF
COMMUNITY-SPECIFIC, I KNOW WE
ONLY TALK ABOUT -- WE ONLY TALK
SO MUCH ABOUT COMMUNITY
ENROLLMENT, FOLLOW UP SHOULD
ALSO BE SPECIFIC AND STANDALONE
COMMUNITY RESOURCES.
AND I'M ALSO THINKING THERE ARE
MANY GLOBAL COMMITMENTS THAT
GOVERNMENT AND HEAD OF STATES
MAKE.
I THINK IT'S ALSO ABOUT TIME WE
START MAKING COMMITMENTS TOWARDS
HIV CURE RESEARCH AS WELL AS --
AND RESOURCES.
I THINK THIS IS SOMETHING THAT
WE CAN EASILY FOLLOW UP IF IT'S
DOCUMENTED AS WELL.
THANK YOU.
>> THANK YOU TO THE WHOLE PANEL.
[APPLAUSE]
I TURN IT OVER TO OUR
COLLEAGUES, KARL.
>> THANKS A LOT.
APPRECIATE IT.
SO JUST A FEW CLOSING REMARKS
BEFORE I HAND IT OVER TO KARL.
SO WE HAD TWO DAYS OF FA FANTASC
SCIENTIFIC TREAT.
THIS WOULD NOT HAVE BEEN
POSSIBLE WITHOUT THE SUPPORT OF
OUR LEADERSHIP.
I WANT TO THANK THE DIRECTOR OF
NIAID, ESPECIALLY FOR AGREEING
TO GIVE OPENING REMARKS, AND
KARL DIEFFENBACH, DIRECTOR OF
THE DIVISION OF AIDS FOR SUPPORT
OF THE CURE PROGRAM AND DIRECTOR
OF BASIC SCIENCE PROGRAM,
DR. DIANA FINZI FOR GUIDING US
THROUGH THIS PROCESS, AND OF
COURSE KARL FOR TRUSTING US TO
RUN THIS PROGRAM AND THIS
MEETING THIS WOULD NOT HAVE BEEN
POSSIBLE WITHOUT THE PROGRAM
MANAGEMENT TEAM WHICH CONSISTS
OF PROGRAM OFFICERS FROM OTHER
ICs, BUT I'M ESPECIALLY
THANKFUL TO MY COLLEAGUES IN MY
BRANCH, PATHOGENESIS AND
THERAPEUTICS INTERVENTIONS
BRANCH, WITHOUT THEIR HELP, IT'S
A TEAM EFFORT, SO I'M GLAD I
WOULD CALL THIS AS A GREAT
SUCCESS.
AND I JUST WANT TO THANK THE
CO-SPONSORS ICs WHO HAVE
SUPPORTED THIS PROGRAM.
AND ESPECIALLY THE MEMBERS OF
THE COLLABORATORY.
WITHOUT THEIR SCIENTIFIC
PRESENTATION, THIS WOULD NOT
HAVE BEEN COMPLETE.
I THANK EVERY ONE OF THEM WHO
CAME HERE ALL THE WAY TO MAKE
THIS A GREAT EVENT.
SO WE ARE ABOUT 503 REGISTRANTS
AND 30 ON SITE, AND THERE WERE
ABOUT 350 PEOPLE WATCHING IT
VIRTUALLY ON NIH VIDEOCAST.
WE THANK THEM ALL.
AND FINALLY, I WANT TO THANK THE
SPONSORS.
WE DID NOT KNOW WHETHER WE WOULD
HAVE THE CA CAFETERIA OPEN IN TE
LAST TWO DAYS BUT WE DID, WE
WERE PERSISTENT, WE MADE THEM
OPEN AT LEAST FOR THESE TWO DAYS
AND FOR THE COFFEE SERVICE THAT
WE HAD FREE PROVIDED BY THE
FAES, AND I WANT TO THANK THE
NIH EVENTS STAFF FOR FANTASTIC
SUPPORT, THE CONFERENCE PEOPLE,
THE GUY IN THE BOOTH, THANK YOU,
AND MILES HERE.
FANTASTIC.
IT'S BEEN WONDERFUL SUPPORT,
REALLY APPRECIATE THE NIH VIDEO
STAFF.
THEY'VE BEEN TELECASTING THIS,
AND I GET WONDERFUL RESPONSE
FROM THEM, FROM THE PEOPLE
WATCHING WORLDWIDE.
IT'S WONDERFUL.
AND I WANT TO THANK THE NIAID
EVENTS PEOPLE WHO ARE
RESPONSIBLE FOR CREATING THE
WEBSITE.
AND THE CONFERENCE SERVICES,
LUMINA, THOSE ARE THE LADIES WHO
WERE AT THE REGISTRATION DESK,
THEY DID A PHENOMENAL JOB,
FANTASTIC SUPPORT SERVICE.
WITH THAT I WANT TO HAND IT OVER
TO KARL.
THANK YOU ALL.
[APPLAUSE]
>> I JUST WANT TO THANK UDAI FOR
LEADING THE ORGANIZATION OF THE
MEETING THIS YEAR, DID A
FANTASTIC JOB ALONG WITH HIS
COLLEAGUES, AS WELL AS ALL THE
OTHER PROGRAM STAFF.
SO THANKS, UDAI, FOR DOING A
GREAT JOB.
WE DON'T HAVE A DATE YET FOR THE
NEXT ITERATION OF THE STRATEGIES
FOR A CURE IN 2025 PRESUMABLY,
BUT WE'LL BE SENDING OUT SOME
SURVEYS AND WE WELCOME ALL
FEEDBACK ON HOW WE CAN MAKE THIS
MEETING BETTER AS WELL AS WHAT
THE NEXT JOINT MDC MEETING
SHOULD BE FOR NEXT YEAR.
SO SAFE TRAVELS, EVERYONE, AND
THANK YOU FOR YOUR
PARTICIPATION.
[APPLAUSE]