GOOD MORNING.
IT'S THE THIRD DAY OF THE EVENT.
THIS MORNING WE HAVE THE GROUP
FROM EMORY WITH THE P.I.s, MIRKO
PAIARDINI AND ANDRES FINZI.
>> THANK YOU, I'M HAPPY IT
PRESENT THE COLLABORATORY AND IT
INCLUDES 16 INSTITUTION FROM
FIVE DIFFERENT COUNTRIES AND THE
END OF YEAR THREE WE EXTENDED
THE COLLABORATORY WITH U PEN.
SO AN IMPORTANT GOAL IS THE
TRAINING OF THE NEXT GENERATION
OF HIV CURE SCIENTISTS.
WE HAVE SCHOLARSHIP FOR HIV CURE
RESEARCH WITH THE SUPPORT FROM
THE EMORY SCHOOL OF MEDICINE AND
FIFTH YEAR WAS AWARDED AND YOU
SEE SOME OF THE WORK IN THE
PRESENTATION AND WE HAVE THE
SECOND ONE THE RFA JUST CAME
OUT.
AND THE INVESTIGATOR WORKED WITH
HIV AS YOU CAN SEE.
WE HAVE COMMUNITY OUTREACH AND
ENGAGEMENT THANKS ONE THE
COLLABORATION WITH SISTER LOVE
AND WE HAVE BEEN INVOLVED IN
POLICY SESSION AND WE HAVE AN 11
WEEK INTERNSHIP PROGRAM FOR
UNDERREPRESENTED MINORITY
STUDENT AND HAVE BEEN INVOLVED
IN THE COMMUNITY EVENT AND THE
25th ANNIVERSARY AND ORGANIZED A
COOK-OUT AND PARTICIPATED
WORKING AND PRESENT OUR WORK
BACK IN OCTOBER IN ATLANTA.
AND I'D LIKE TO THANK SISTER
LOVE WOMEN LIVING WITH HIV MORE
THAN 20 YEARS.
WE'VE ALSO BEEN SELECTED FOR THE
WORK THAT'S BEEN SHOWN LAST
MONTH IN OCTOBER IN LOS ANGELES
THE CONFERENCE WITH MORE THAN
12,000 ATTENDEES.
THIS IS FOCUSSED ON COMMUNITY
OUTREACH AND WE HAVE A VIDEO.
WE ORGANIZED AN EVENT FOR THE
WORLD AIDS DAY.
A GALLERY SHOWCASE OF PEOPLE
LIVING WITH HIV AND WE'LL SHARE
THE RESEARCH AS PART OF THIS
EVENT.
WE'RE ALSO ORGANIZED AN EVENT IN
EDUCATIONAL SYMPOSIUM IN SOUTH
AFRICA.
SO WITH THAT I'LL MOVE TO THE
ROOM PART WE'VE PRESENTED MANY
CONFERENCE AND HAVE 50 PUBLISHED
PAPERS.
WE ARE NOT COUNTING ALL THE
PAPER FROM ALL THE
COLLABORATORY.
THEY'RE FULLY SUPPORTED ON THE
PRIORITY OF HIV.
PUBLISHED IN JOURNAL AND THE
INDUCING LATENCY IN CELLS AND
MECHANISMS HAPPENING.
WE'VE BEEN DESCRIBING THE FUTURE
WITH POST-TREATMENT CONTROL IN
NONHUMAN PRIMATE AND VIRUS
REPLICATION AND DOING
INTERVENTION INCLUDING A STUDY
CHARACTERIZED THE COMPOUND AND
THE MECHANISM OF WORK AND
BLOCKED INFECTION AND INCLUDING
MACROPHAGES.
AND I WANT TO NOTE ON CURING HIV
I HELPED LEAD WITH A MULTIPLE
MEMBERS COLLABORATORIES.
I'LL TAKE A FEW MINUTES TO
DESCRIBE A COUPLE STUDIES
CONVENIENTLY.
ESTABLISHED.
ONE HAS BEEN CO-LED WITH MY LAB
IDENTIFYING EARLY AND
SIGNIFICANT EXPANSION OF TCF
CELLS THAT MARK STIMULI AND ALSO
MARKER OF DIFFERENTIATION LIKE
CD 39.
THE CELLS RESPOND AFTER
INFECTION IN MACAQUES AND PEOPLE
LIVING WITH HIV.
WEAR SHORTED WITH BETTER CONTROL
AND MORE OF THE CELLS AND
MECHANISTICALLY WE FOUND THE
CELLS EXPRESSED MORE THAN OTHER
CELLS AND LOCALIZED IN CLOSE
PROXIMITY TO THE CELLS AND IT'S.
SELECTED FOR THE JOURNAL FOR
RESEARCH BRIEFING.
CONSISTENTLY A STUDY WITH
COMMUNICATION THERE'S A
DIFFERENT MODEL.
NOW WE'LL TALK ABOUT POST
TREATMENT CONTROL IN MACAQUES
AND ONE OF THE KEY FEATURE OF
CONTROL WAS THE PRESENCE OF
CELLS AND THIS WAS AGAIN
ASSOCIATED WITH EXPRESSION OF
TCF1.
I WANT TO HIGHLIGHT A PAPER THAT
CAME OUT WEEKS AGO A
COLLABORATION WITH OUR INDUSTRY
PARTNER WHERE WE BROUGHT PD-1 IN
MACAQUES AND FOUND A PROLONGED
UP TO SIX MONTH CONTROL IN LARGE
MAJORITY OF THE ANIMAL DURING
THE TREATMENT IDENTIFIED AND WE
STILL HAVE REMAINING CHALLENGES
REGARDING THE SAFETY OF THE
SYSTEM AND LONGEVITY OF THE
RESPONSE.
WE HAVE ANIMAL STUDY FOCUSSING
ON THIS STUDY AND I CANNOT
PRESENT THE DATA TODAY BUT SEEMS
TO BE QUITE EXCITING.
SO WITH THAT I'LL INTRODUCE THE
SPEAKERS.
A KEY PRIORITY FOR HIV IS
UNDERSTANDING WHY INFECTED CELLS
SURVIVE AND BECOME A RESERVOIR
AND TRY TO TARGET THE MECHANISM
AND WE'LL DESCRIBE ONE OF THESE
MECHANISMS OF SURVIVAL AND THE
CLOSE CONFIRMATION THE HIV HAVE
TARGETING WITH COMPOUNDS.
MEMBERS OF THE COLLABORATORY IS
IDENTIFIED IN OTHER MECHANISMS
OF SURVIVOR OF INFECTED CELLS
AND WILL PRESENT HOW WE TARGET
AND IMPACT PERSISTENCE IN
NONHUMAN PRIMATES.
NOT ONLY THE INFECTED CELLS WHY
THEY SURVIVE BUT THE
INTERACTION.
AND WE'LL PRESENT ONE OF THE
UNIQUE CONTRIBUTION FOR HIV AND
THE ROLE OF CD 8 T CELLS AND
PRESENT MECHANISTIC INSIGHT HOW
THIS IS HAPPENING.
AND DESCRIBE THE FEATURES OF THE
CELLS BETTER ASSOCIATED
INCLUDING THE ROLE OF IL10 AND
PD 1 AND WE AND A REMAINING
CHALLENGE IS THAT MANY CD 8
CELLS DO NOT LOCALIZE TO THE
TISSUE AND YOU'LL SEE
PRESENTATION ON NEW STRATEGY
BASED TO REDIRECT CELLS TO THE
LYMPHOID TISSUE.
WITH THAT I'LL HAVE ANDRES START
HIS PRESENTATION.
>> THANK YOU.
I'M HAPPY TO BE HERE TO PRESENT
THE WORK WE'RE DOING WITHIN THE
HIV COLLABORATORY.
OUR GOAL IS TO DEVELOP NEW
STRATEGIES TO ELIMINATE INFECTED
CELLS.
WE LEARNED WE CAN DO THAT IF WE
OPEN THE ENVELOPE LIKE A PROTEIN
AT THE SURFACE AND GET TO THE
INFECTED CELLS FOR THE CURE.
WE HAVE SHOWN THE VIRUS DOES ALL
IT CAN TO RENDER THE IMMUNE
CELLS INVISIBLE TO THE IMMUNE
SYSTEM AND ONE KEEPS THE
ENVELOPE CLOSED AND THE
ANTIBODIES PRESENT AND THOSE
WITH HIV DO NOT RECOGNIZE AND
THEREFORE OPEN IT UP BY USING
MEMETICS AND THEY BEHAVE LIKE
CD4 AND OPEN AT THE TRIMER AND
RECOGNIZED BY ANTIBODIES AND CAN
RECRUIT THE CELLS AND THESE ARE
ELIMINATED BY THE DISEASE
IT'S ALWAYS A BIT MORE
COMPLICATED THAN IT LOOKS AND
OPEN UP THE TRIMER ENOUGH TO THE
ANTIBODIES SHOWN HERE IN BLACK
GET ENGAGED AND AFTER THE
BINDING IT FURTHER OPENS UP THE
TRIMER.
THERE'S A SEQUENTIAL OPENING OF
THE TRIMER TO ENGAGE ANTIBODIES
CALLED ANTI-CLUSTER ANTIBODIES.
YOU HAVE THE MEMETICS AND YOU
HAVE THIS COCKTAIL THE CELLS ARE
ELIMINATED EFFICIENTLY AND IF
YOU PUT THIS IN HUMANIZED MICE
YOU HAVE A SIGNIFICANT DELAY IN
VIRAL REBOUND AND DECREASE IN
THE SIZE OF THE VIRAL RESERVOIR.
THE QUESTION IS CAN WE DO
BETTER?
WE ARE OBSESSED WITH IMPROVING
THE POTENCY OF THE COCKTAIL.
ONE WAY IS TO IMPROVE THE
MEMETIC AND THIS IS WHAT THEY'RE
DOING.
AND.
THE DERIVATIVE WHICH IS MORE
POTENT AND MORE EFFICIENT WITH
THE COMBINATION OF ANTIBODIES OR
IN PLASMA OF PEOPLE LIVING WITH
HIV.
AND HOW DOES IT WORK IN HUMAN
MICE WITH THE MEMETICS AND THIS
IS WHAT YALE HAS BEEN DOING WITH
HUMANIZED MICE SUPPORTING
FUNCTION.
AND THEY NEED THE ANTIBODIES AS
THE CONTROL.
AND THIS PROVIDES THE
ANTIBODIES.
WE'RE PROVIDING AT THE TIME AND
MANY TOGETHER WITH ANTIBODIES
AND EVERY SINGLE ANIMAL SO IT'S
ONE INDIVIDUAL ANIMAL AND YOU
HAVE AROUND A FOUR WEEK DELAY IN
VIRAL REBOUND.
BUT WHAT WAS REALLY INTERESTED
IS WHEN YOU PROVIDE THE MEMETIC
COCKTAIL AT THE TIME OF ART
INITIATION YOU HAVE THREE TO
FIVE WEEKS ON DELAY OF VIRAL
REBOUND BUT IN FIVE ANIMALS YOU
SEE VIRAL CONTROL.
YOU ONLY SEE BLIPS.
IF YOU PUT IT TOGETHER IN THE
CONTROL ANIMALS VIRAL REBOUNDS
IMMEDIATELY AROUND FOUR WEEKS
DELAY IF YOU PROVIDER AT THE
TIME OF ART AND ACTUALLY HAVE
CONTROL WITH BLIPS IF YOU
PROVIDE AT THE TIME OF ART
INITIATION AND THIS IS
ASSOCIATED WITH DECREASING THE
SIZE OF THE VIRAL RESERVOIR AND
THE MEMETICS ALONE AND THE
DECREASE WHERE YOU PUT IT
TOGETHER WITH ANTIBODIES AND
PARTICULARLY POTENT IF YOU DO IT
AT THE TIME OF ART INITIATION.
THE QUESTION IS CAN WE DO
BETTER?
CAN WE KEEP IMPROVING THE
COCKTAIL?
OF COURSE WE CAN HAVE MORE
POTENT MEMETICS BUT CAN IMPROVE
THE ANTIBODY CONTENT OF THE
COCKTAIL.
AND WE'RE SAYING THAT BECAUSE
ALEXANDRA HAS BEEN LOOKING AT
PLASMA WITH PEOPLE WITH HIV AND
YOU HAVE 50 DIFFERENT
INDIVIDUALS LIVING WITH HIV AND
SEE IN ALL THE CASES WHETHER WE
HAVE THIS YOU GET OTHER
RECOGNITION BUT YOU CAN
APPRECIATE AND WANTED TO
UNDERSTAND WHY SOME PLASMA WAS
SUPERIOR THAN OTHERS IN THE
PRESENCE OF THE MEMETIC AND WE
WERE MISSING ONE FAMILY RESPONSE
AND WE MADE A COCKTAIL OF THAT.
WE WERE MISSING THE CLUSTER 1
REGION.
IN GRAY YOU CAN SEE IF YOU
PROVIDE THE TWO OR THREE
ANTIBODIES THERE'S NO MEMETIC IT
DOESN'T HAPPEN.
BUT IF YOU PROVIDE THE MEMETIC
IN BLUE IT GOES UP WITH EVERY
VIRUS WE TESTED AND THE
COMBINATION OF THREE ANTIBODIES
IS SUPERIOR.
THIS IS SUPERIOR TO EVERYONE WE
COMPARED.
THIS IS ACTIVITY AGAIN EVERY
COMBINATION OF BNAB AND SO FAR
THE COCKTAIL WE HAVE IS THE MOST
POTENT WE HAVE.
CAN WE DO BETTER?
SO ON TOP OF OF TRYING TO MAKE A
MORE POTENT COCKTAIL WE CAN HAVE
THE INFECTED CELLS TO ADDC.
AND WE HAVE DATA AND THIS WILL
GO UP AND OF COURSE WE STILL
HAVE A BIT MORE ENVELOPE SO YOU
HAVE MORE TARGET FOR THE
MEMETIC.
IF YOU USE PLASMA FROM
UNINFECTED INDIVIDUAL NO
RECOGNITION OF THE INFECTED CELL
AND PEOPLE WITH HIV YOU GET
RECOGNITION AND IN BLUE THE
RECOGNITION GOES HIGH AND EVEN
HIGHER WHEN YOU ADD BETA TO THE
TARGET AND TRUE WHEN YOU DO THE
COMBINATION COCKTAIL OF
ANTIBODIES.
AND THAT'S TRANSLATED TO ADCC.
WE HAVE ENHANCED WHEN WE COMBINE
AND THIS IS ALSO DUE WHEN YOU
HAVE DATA SOME LIGANDS GET
REGULATED SO THE INFECTED CELL
BECOMES MORE SUSCEPTIBLE TO
KILLING.
SOMETHING I LIKE ABOUT THIS IS
WE GO FROM IN VITRO TO EX VIVO.
WE HUMANIZE MICE AND NONHUMAN
PRIMATES HAVE A TIR -- CIRCLE
AND HOW'S IT LOOK IN NONHUMAN
PRIMATES?
AND THIS IS PREVIOUS COMBINATION
TOGETHER AND WE'LL HAVE TWO
GROUPS OF ANIMALS AND PROVIDE
THE COCKTAIL AT TIME OF ART
INITIATION AND THIS IS WHERE WE
ARE SO FAR.
THE STUDY IS ONGOING.
IT'S NOT COMPLETE.
WHEN YOU PROVIDE THE ANTIBODIES
ALONE AT THE TIME OF ART
INITIATION IT DOESN'T HAPPEN BUT
WITH MEMETIC YOU GET MORE OF A
VIRAL LOAD AND WANT TO KNOW IF
IT AFFECT THE SIZE OF THE
RESERVOIR THE ANIMAL WILL BE
TREATED AND WE'LL WAIT FOR TIME
TO VIRAL REBOUND AND MAKE SURE
THERE'S RESERVOIR.
WE HAVE THE AMOUNT TO THE
NONHUMAN PRIMATES AND I'D LIKE
TO THANK MY LAB AND
COLLABORATORS AND PARTICIPANTS
AND YOUR ATTENTION.
>> GOOD MORNING, EVERYONE.
IT'S GREAT TO BE HERE.
THANKS FOR ORGANIZING THIS AND
NIH COLLEAGUES.
IT WAS 10 YEARS AGO THAT I WAS
SITTING WITH ANDREW BAD LY
[AUDIO DIGITIZING]
AND WE WERE TALKING ABOUT
POTENTIAL BE NEW IDEAS TO CURE
HIV INFECTION AND THEY SAID,
GUIDO WE SHOULD TARGET WAYS TO
GET THE CELLS TO DIE OF
APOPTOSIS AND NOT JUST THE SHOCK
AND KILL.
WE EXPECT THE IMMUNE SYSTEM TO
COME IN AND DO THE JOB ONCE THE
VIRUS HAS BEEN REACTIVATED AND
WE INVENT THE MONIKER SHOCK AND
SUICIDE AND WERE TOLD IT'S
PROBABLY NOT GOOD LANGUAGE.
I THINK THE CONCEPT IS THERE.
AND IT'S NICE TO SEE YEARS LATER
ALMOST 10 YEARS LATER TO SEE
THE CONCEPT TAKING OFF.
FOR OUR COMMUNITY THE GOAL OF
THE STUDY WAS BLOCKING MOLECULES
HELPING INFECTED CD4 T CELLS TO
SURVIVE LEADING TO THE
ELIMINATION OF THE RESERVOIR.
WE'RE USING A PARTICULAR DRUG
AND PROMOTE CELL DEATH IN
INFECTED CELLS AND WHAT WE ARE
LEARNING IS WE CAN DO
EXPERIMENTS IN NONHUMAN PRIMATES
AND ASSESSING HOW THIS DRUG
IMPACT ON THE ESTABLISHMENT AND
MAINTENANCE OF THE RESERVOIR BUT
IN THE SETTING OF EARLIER
INITIATION OR CHRONIC ART AND
WHY IT'S IMPORTANT.
A REASONABLE APPROACH TO CURE
HIV INFECTION WILL INVOLVE
REDUCING THE RESERVOIR OF CELLS
WITH REPLICATION OF THE VIRUS
THAT PERSISTS UNDER ART.
SO, WHAT ANDY AND I DISCUSSED
DURING THAT MEETING IT WAS.
ING APPARENT WE'VE KNOWN FOR EYE
LONG TIME I THINK THERE'S
HUNDREDS OF PAPERS SHOWING
SURVIVAL OF LYMPHOCYTES IS
RELATED TO CHRONIC ABILITY TO
BLOCK THE MITOCHONDRIAL
APOPTOSIS THAT REALIZE ON CAS 9
AND OTHERS AND AT THAT TIME IT
BIOMEDICAL CLEAR THAT WE COULD
GO IN THAT DIRECTION AND HIGH
POSSIBLE -- HYPOTHESIZED WE
COULD PUSH THE APOPTOSIS OF
CELLS AND WE THOUGHT IT WAS
SPECIFIC ENOUGH TO GIVE IT A TRY
AND THERE WAS A STUDY OF CHRONIC
LEUKEMIA AND THERAPY FOR THAT
TYPE THAT HAD BEEN IN CLINICAL
TRIALS AND WHAT WE DECIDED TO DO
WAS TO SEE IF THIS BEAUTIFUL
CONCEPT BLOCK THIS AND REMOVING
THE BCL2 BLOCK EFFECTIVELY STOPS
THE MITOCHONDRIAL PATHWAY OF
APOPTOSIS AND GETTING RID OF THE
INFECTED CELLS IN THE STUDY OF
ART AND THOSE ARE THE TWO
STUDIES THAT HAVE EXPLORED THE
CONCEPT ONE WAS EXPLORED IN THE
HUMANIZED MOUSE MODEL AND DOING
RELATED WORK IN THE NONHUMAN
PRIMATE MODEL.
SO THIS IS THE FIRST STUDY BY
THOMAS IN THE BACK OF THE ROOM
AND IT WAS GIVEN TO MONKEYS
DURING EARLY ART AND YOU SEE THE
SCHEMATIC.
AND THERE'S A GROUP OF ANIMALS
AND ANOTHER GROUP GIVEN IT IN
THE DEPLETION AND THE CD 8
DEPLETION LEADS TO A MORE
LATENCY ENVIRONMENT IN THE CD4 T
CELLS AND IT'S EXCITING TO SEE
THE MECHANISM DECIPHERED FOR
THAT EFFECT.
SO THIS IS BY DESIGN.
I'D BE HAPPY TO ANSWER DETAILS
IN THE DISCUSSION.
AND CLEARLY THERE'S AN IMPORTANT
IMMUNOLOGIC RESPONSE OF THE AND
WE'VE SEEN THAT IN THE NEXT
STUDY THERE'S A DEPLETION OF CD4
CELLS AND THERE IS A GENERAL
PERTURBATION OF THE DYNAMIC OF
EXPRESSION YOU SEE REFLECTED ON
THE RIGHT SIDE BY MEASURING
EXPRESSION BY FLOW CYTOMETRY AND
YOU SEE THE BIOLOGICAL READOUTS
AND ONE IS THE CURB OF VIRAL
LOAD DECLINE OF ANTIVIRAL
THERAPY.
AND SOME OF US HERE IN THE ROOM
WEREN'T AROUND AT THIS TIME BUT
THE MODEL STILL STANDS BUT YOU
SEE THE COMBINATION OF CD 8
DEPLETION AND IT ALONE SEEMS TO
PERTURB THE SLOPE OF THE DECLINE
OF VIREMIA SUGGESTING A
DECREASED REDUCTION OF VIRUS OR
INFECTED CELLS AND WE CAN GO TO
THAT DURING THE DISCUSSION.
IT'S A COMPLEX OBSERVATION THAT
WOULD REQUIRE MORE THAN THE TIME
I'M ALLOTTED TODAY.
BUT IN TERMS OF THE RESERVOIR
WHAT'S IMPORTANT TO NOTE IS WHEN
YOU LOOK AT THE KINETIC OVER
TIME OF BOTH THE CELLS
EXPRESSING SHOWING INTEGRATED
DNA EITHER BY TOTAL COUNT OR
IPDA OR THE CELLS THAT ARE
EXPRESSING INFECTED WITH SIV DNA
EITHER AS A FRACTION OF THE CD4
CELLS OR THE ABSOLUTE COPIES OF
VIRUS PER ML BLOT.
DIFFERENT WAYS OF LOOKING AT THE
SAME PHENOMENON.
THERE'S A SIGNIFICANT DECLINE
YOU SEE THE LINES IN ORANGE AND
BLACK.
SIGNIFICANT FASTER DECLINE NA
PERSISTS OVER TIME OF THE
RESERVOIR IN THE ANIMAL TREATED
WITH IT ALONE OR WITH CD 8
DEPLETION COMPARED TO THE
CONTROL LINES WHICH IS THE BLUE.
AND THAT'S THE MAIN MESSAGE OF
THIS PARTICULAR EXPERIMENT THAT
AGAIN WE CAN DISCUSS MORE DURING
THE DISCUSSION.
THEN THE NEXT STUDY WAS TO TRY
IT UP COMBINATION WITH A LATENCY
APPROACH THE COMBINATION OF CD 8
DEPLETION AND IL15 SUPER AGONIST
AND A COCKTAIL OF SIV SPECIFIC
NEUTRALIZING ANTIBODIES.
THE IDEA IS TO SEE WHAT IT WOULD
DO IN THE SETTING OF ESTABLISHED
ART.
THESE ARE ANIMALS TREATED FOR
TWO YEARS WITH ANTIRETROVIRAL A
REAL SUPPRESSION IN HIV INFECTED
INDIVIDUALS OR PEOPLE LIVING
WITH HIV AND TREATED WITH ART.
THE RESULTS OF THE STUDY IS THAT
WHILE WE CONFIRM THE ABILITY OF
THE TREATMENT TO EXTRAPOLATE AND
SEE THE THREE LINES IN ORANGE,
PURPLE AND GREEN AND THE
CONTROLS IN TERMS OF VIRUS
REACTIVATION AND THE ART BUT ON
THE RIGHT THE DNA COPIES PER
MILLION CD4 CELLS AND THERE'S A
HIGHLY SIGNIFICANT DECLINE AT
DAY 56 POST TREATMENT IN THE
GROUP OF ANIMALS THAT RECEIVED
THIS.
THERE'S A CONVERGENCE OF RESULTS
AND THOSE ARE THE MAIN
CONVERGENCE OF THE STUDY WHEN
IT'S GIVEN AT THE BEGINNING OF
ANTIVIRAL THERAPY AND THE
INHIBITION OF IL2 IS SUFFICIENT
TO PRODUCE AN INSTABILITY OF THE
RESERVOIR THAT TRANSLATES TO
LOWER LEVELS OF CELLS LAR HAVING
THE VIRUS OVER TIME.
I ACKNOWLEDGE THE FOLKS THAT
HAVE DONE THE WORK AND I'LL GIVE
IT BACK.
AND WE HAVE A NATURAL FUNCTION
THAT CAN INTERFERE WITH LRA
ACTIVE IN VIVO.
BY UNDERSTANDING HOW AND WHY
THEY CAN ACTIVATE ACTIVITY IT
CAN GIVE US THE ABILITY TO
DESIGN MORE EFFECTIVE
INTERVENTIONS WE CAN THEN USE
FOR HIV SHOCK AND KILL CURE
STRATEGIES.
IT'S BEEN WELL AND NOW THERE'S
EVIDENCE THEY HAVE A ROLE IN THE
CONTROL OF VIRAL REPLICATION.
THAT OF A NON-ANTIGEN SPECIFIC
ROW LATENCY MECHANISM.
THE NON CYTOLYTIC FUNCTIONS OF
CELLS CAN ACT SYNERGISTICALLY IN
THE ABSENCE OF ART.
SO ON ONE SIDE YOU HAVE THE
TARGETING OF PRODUCTIVELY
INFECTED CD4 T CELLS TO TARGET
FOR ELIMINATION AND ON THE OTHER
SIDE YOU HAVE A VIRAL SILENCE
MECHANISM.
SO THESE TWO MECHANISMS CAN HAVE
DIVERGENCE EFFECTS THAT CAN
BECOME MAGNIFIED AND A MECHANISM
TO SUPPORT HIV PERSISTENCE.
THE CURRENT UNDERSTANDING OF THE
MECHANISMS AND THE ROLE THEY
PLAY IN HIV CURE STRATEGIES IS
DISCUSSED IN MORE DETAIL IN AN
UPCOMING REVIEW IN NATURE REVIEW
IMMUNOLOGY.
OUR GOAL IS TO MECHANISTICALLY
DEFINE HOW THEY ESTABLISH
MAINTENANCE IN CD4 T CELLS.
WE IDENTIFIED HOW THEY REGULATE
METABOLISM TO ENHANCE THEIR
SURVIVAL, QUIESCENCE AND PROMOTE
HIV LATENCY.
SO IN THE STUDY WE ADAPTED OUR
IN VITRO HIV LATENCY MODEL TO
INCLUDE A CO-CULTURAL WITH CD 8
T CELLS AND ENRICHED CELLS FROM
HIV NAIVE INDIVIDUALS.
WE INFECT THE CELLS IN VITRO
WITH A REPLICATION COMPETENT HIV
AND CO-CULTURE THEM WITH CD 8 T
CELLS AND LOOK FOR THE IMPACT OF
HIV INFECTION.
ON THE TOP ROW WE'RE SHOWING
MEMORY CD4 T CELLS IN
MONOCULTURE AND SHOW WE SEE AN
INCREASE IN HIV GAG EXPRESSION
AND A DOWN MODULATION OF SURFACE
CD4.
IN THE BOTTOM ARE MEMORY CD4
TVRL T CELLS WITH AUTOLOGOUS
WITH A RATIO AND A LOSS OF HIV
EXPRESSION.
THE DATA SUPPORT USING THE IN
VITRO ASSAY AS A MODEL TO LOOK
AT THE MECHANISM OF THIS NON
CYTOLYTIC APPROACH.
USING AN RNA SEQ APPROACH WE
WANTED TO LOOK AT THE CHANGES IN
THE PROFILE OF THE CD4 T CELLS
ASSOCIATED WITH HIV EXPRESSION.
AND WHAT WE FOUND IS THAT
PATHWAYS ASSOCIATED WITH
CELLULAR METABOLISM EFFECTER
FUNCTION AND CELL SURVIVAL ARE
DOWN REGULATED IN CD4 T CELLS
AND THIS IS INDICATED BY THE
GREEN BOX.
THESE WERE COMPARED TO CD4 T
CELLS FROM MONOCULTURES FROM THE
SAME INDIVIDUALS INDICATED BY
THE ORANGE BARS.
IT'S IMPORTANT TO NOTE THE
SIGNALLING PATHWAYS THAT WERE
DOWN REGULATED ARE COMING FROM
IN THESE OBSERVATIONS ARE THE
ONES THAT ARE ASSOCIATED OR
CORRELATED WITH A DOWN
REGULATION OF HIV TRANSCRIPT
LEVELS.
BUT WE ALSO NOTICED THERE WERE
PATHWAYS UPREGULATED IN CD4 T
CELLS FROM CO-CULTURES AND THESE
WERE PATHWAYS ASSOCIATED WITH
QUIESENCE, MEMORY AND
DIFFERENTIATION AND IT'S THE UP
REGULATION OF THESE PATHWAYS
ASSOCIATED WITH A DECREASE IN
HIV TRANSCRIPT LEVELS.
I WANT TO POINT ONE WAS
DISCUSSED YESTERDAY IN A
PRESENTATION BY BRAD JONES WHERE
HE SHOWED IT'S IMPORTANT FOR CD4
T CELL SURVIVAL DURING HIV
INFECTION.
SO IN OUR ANALYSES WE IDENTIFIED
TWO PATHWAYS CRITICAL FOR THIS
CD 8 MEDIATED ACTIVITY.
THAT IS BETA SIGNAL AND WINT
STHIFT PROGRAMMING AND INDEED
WNT SHIFT ARE KNOWN TO CAME
PRETONE COMPLEX TO RECRUIT
COFACTORS.
ANOTHER INVESTIGATOR IN THE
RECENT COLLABORATORY FOLLOWED UP
WITH THIS DURING EPIGENETIC
PROFILING OF THE HIV PRIME LTR
IN CD4 T CELLS USING A
CO-CULTURE MODEL SIMILAR TO THE
ONE WE USED ON CD4 AND CD 8 T
CELLS IN VITRO AND LOOKED AT
CHIP QPCR AND LOOKED AT THE
ACETYLATION PROFILE AND FOUND NO
DIFFERENCE AT H3K9 AND H3K27
WHEN LOOKING AT THE METHYLATION
THE FOUND A DECREASE IN THE
METHYLATION ASSOCIATED WITH
ACTIVE PROMOTERS AND FOUND UP
REGULATION IN H3K9 AND K27
TRIMETHYLATION WHICH ARE MARKS
ASSOCIATED WITH INACTIVE
PROMOTERS AND LOOKED AT THE
CULTURE OF HIV TRANSCRIPTION AND
FOUND THERE WAS A SIGNIFICANT
DECREASE IN THE RECRUITMENT OF
TRANSCRIPTIONAL ACTIVATORS AND
SIGNIFICANT DECREASE IN
RECRUITMENT OF RNA POLYMERASE 2
AND KDK9 AND INTERESTINGLY AN
INCREASED RECRUITMENT OF THE
REPRESSIVE FACTOR UH1 TO THE
PROMOTER IN CD 8 T CELLS AND
CO-CULTURE.
AND THERE'S AN EPIGENETIC
REGULATOR THAT HELPS MAINTAIN
HISTOMODIFICATIONS AND DNA
METHYLATION.
TOGETHER WE HAVE INFORMATION
THAT SHOWS IF YOU ARE MODULATING
TGF BETA AND PATHWAYS THROUGH CD
8 MECHANISMS THIS IS IMPACTING
CHROMATIN ACCESSIBILITY
RESULTING IN A DECREASE IN DNA
HIV AND PROTEIN BUT IMPORTANTLY
NOT IMPACTING THE FREQUENCY OF
CELLS CARRYING INTEGRATED HIV
DNA.
TOGETHER OUR RESULTS HAVE
UNCOVERED A POTENTIAL FOR A
SHOCK AND KILL STRATEGY TO
TARGET THE REPRESSION MACHINERY
LIKE TO RELEASE VIRAL FROM THE
PRESENCE OF CD 8 T CELLS AND
THEN USED IN COMBINATION WITH AN
IMMUNOLOGICAL MODULATOR TO
AUGMENT THE CYTOTOXIC KILLING OF
CD 8 T CELLS WE CAN IMPACT THE
FREQUENCY.
I WOULD LIKE TO ACKNOWLEDGE THE
FORMER POSTDOC IN THE LAB WHO
LED THE STUDIES.
I THINK IT'S VERY IMPORTANT TO
ACKNOWLEDGE THE CONTINUING
SUPPORT OF NIH FOR STUDIES LIKE
THESE IN PARTICULAR NIAID.
PEOPLE LIVING WITH HIV IN THIS
WORLD ARE COUNTING ON US TO
CONTINUE OUR WORK NO MATTER WHO
THE PRESIDENT IS AND WE CAN'T
LED THEM DOWN.
THANK YOU.
S
>> I'LL DESCRIBE NEW WORK WE'VE
BEEN DOING WITH THE ERASE
COLLABORATORY AND TALKING ABOUT
CD 8 T CELLS AND THE GOALS OF
OUR STUDY ARE STARTING FROM
THECYTEEE -- CYTOTOXIC TISSUES
AND TARGET CYTOTOXIC CD 8 T
CELLS TO ULTIMATELY ELIMINATE
HIV INFECTED CELLS.
SO WHAT WE LEARNED IS THAT WE
CAN TARGET DIRECTLY CYTOTOXIC CD
8 T CELLS IN HUMANS, MICE AND
NONHUMAN PRIMATES AND TARGET
PROTEINS USING THE mRNA
TECHNOLOGY TO ENABLE THE IMMUNE
SYSTEM TO CONTROL OR AFFECT HIV
INFECTED CELLS IN TISSUES.
THE BACKGROUND IS THAT FULLY
DIFFERENTIATING THE CELLS DO NOT
MIGRATE TO TISSUES TO ELIMINATE
HIV RESERVOIRS AND THIS HAS BEEN
KNOWN FOR A LONG TIME THEY
DIFFERENTIATE TO CYTOTOXIC
EFFECTERS.
THEY LOSE THE EXPRESSION OF THE
HOMING MOLECULES BEING CD 62L
AND 7 THAT ALLOW THEM TO BE
ATTRACTED TO AND ENTER THE LYMPH
NODE AND SOME WAS WORK DONE BY
LUIS BACK THERE.
THE STUDY GOAL WAS TO FIGURE OUT
A WAY TO RE-EXPRESS ON
PERIPHERAL BLOOD TO ALLOW THEM
TO TRAFFIC IN LYMPHOID TISSUES
AND WE WANTED THIS TO WORK
ULTIMATELY BE SOMETHING THAT
COULD BE TRANSLATED INTO HUME
ZWRANZ AND SO OUR FIRST STEP
WHICH WAS BASICALLY TO DEVELOP A
PLATFORM TO TARGET HUMAN CTL TO
EXPRESS EXOGENOUS PROTEINS IN
VIVO AND WE HAVE TO WORK OUR WAY
TOWARDS THAT.
OUR STRATEGY WAS TO USE TARGETED
mRNA PARTICLES TO DELIVER TO
CTL.
THE FIRST CHALLENGE WAS HOW TO
TARGET THE CELLS.
AND WE SETTLED ON A REPRESENTER
CALLED CX3CR1 AND THIS IS A
RECEPTOR THAT IS ACTUALLY
EXPRESSED HIGHLY BY VASCULAR
CYTOTOXIC EFFECT AND HAS SOME
EXPRESSION OUTSIDE THE
HEMATOPOIETIC SYSTEM.
AND THERE'S A MEMBRANE THAT
STAYS ON THE INSIDE THE BLOOD
VESSEL OR COULD BE CLEAVED.
HOW WOULD WE THEN USE THE
ACCESS?
SO THERE'S A NUMBER OF DIFFERENT
WAYS YOU CAN TARGET LNP TO CELL
TYPES.
WE HEARD ABOUT SOME OF THEM IN
THE TALKS SO FAR THIS WEEK
INCLUDING MODIFYING THE LIPIDS
OR USING ANTIBODIES TO BIND TO
THE LNPs.
WE DECIDED TO TAKE A DIFFERENT
STRATEGY AND DIRECTLY CONJUGATE
THE LIGAND ON TO THE LNP IN A
DIRECT CONJUGATION THEM METHOD
AND AS OUR FIRST EXPERIMENT
BECAUSE IF THIS DIDN'T WORK
THERE WAS NO POINT IN GOING
FORWARD AND THEY ARE WERE
EXPRESSION THE REPORTER AND WE
INCUBATED THEM WITH PRIMARY
HUMAN PERIPHERAL BLOOD
LYMPHOCYTES AND THE FIRST
EXPERIMENT WAS A HOME RUN MORE
THAN EXPECTED.
ON THE LEFT PLOT WE'RE SEWING
PRIMARY HUMAN CD 8 T CELLS AND
SHOWING THE RECEPTOR WE WANT TO
TARGET ON THE Y AXIS AND ADD THE
LNPs AND INCUBATE THE CELLS FOR
ABOUT THREE DAYS.
WE CAN SEE ESSENTIALLY A MASSIVE
LOSS OF THE RECEPTOR AS IT'S
INDUCED TO ENDOCYTOSIS AND SEE
AN EXPRESSION OF GFP BY THE
CELLS WITHOUT ADDING
STIMULATION, CYTOKINE JUST
ADDING TO THE CD 8s AND PUTTING
THEM IN CULTURE.
JUST TO PROVE THIS IS TARGETING
THE CELLS WE WANTED, WE THEN
SUBSET MEMORY PHENOTYPES OF THE
CELLS AND CAN SHOW CLEARLY GFP
ON THE RIGHT FLOW PLOTS IS
GETTING EXCLUSIVELY EXPRESSED IN
THE EFFECTER MEMORY, NOT 100% OF
THEM BUT IMPORTANTLY THOSE CELLS
THAT EXPRESSED THE T CELLS THAT
EXPRESSED ON THE BOTTOM LEFT
WITHOUT AN LNP ADDED WE HAVE
EXPRESSION FROM THE CELLS 37
WHEN WE RAD THE LNP AND SEE XFP
EXPRESSION CELLS WE SEE
INDICATION WE'RE TARGETING
CYTOTOXIC CELLS AND NOT INDUCING
DEGRANULATION OF THE CELLS.
WE THEN WANTED TO TAKE IT IN
VIVO.
WE PUT IT INTO MICE AND LCMV
MODEL AND I DON'T HAVE TIME TO
TALK TOO MUCH ABOUT THE MODEL
PUT BASICALLY YOU CAN SEE EIGHT
DAYS AFTER LCM INFECTION WE ADD
LMP AND 24 HOURS LATER WE SEE A
MASSIVE UPTAKE INTO THE RECEPTOR
POSITIVE CELLS WITH AN 80%
TARGETING IN VIVO AFTER ONE DOSE
IN THE MICE.
WE THEN TOOK THIS WITH THE
MONKEYS BECAUSE WE'RE TRYING TO
GO FAST AND SO THIS IS A
TWO-ANIMAL EXPERIMENT.
I'M SHOWING FLOW DATA FROM ONE
REPRESENTATIVE ANIMAL AND NOW
WE'RE IN A REALISTIC SITUATION.
THE ANIMALS DON'T HAVE
EXPRESSION AND 15% OF THE
CIRCULATING CD 8s HAVE RECEPTOR
AFTER A SINGLE DAY WITH ONE DOSE
DELIVERED I.D. WE HAVE COMPLETE
LOSS OF THE RECEPTOR AND
EQUIVALENT LEVEL OF CELLS
PRODUCING GFP AND THIS PERSISTED
UNTIL DAY 7.
I'M NOT SHOWING DAY 10 AND EVEN
DAY 14 WE SEE RESIDUAL
EXPRESSION AND TARGETS 100% OF
THE SUBSET OF CELLS TARGETED IN
VIVO AND PERSISTS FOR HALF LIFE
OF GFP AS A CRITICAL ISSUE.
THE PERSISTS FOR A LONG TIME.
AND WE CAN SHOW THIS IS VERY
SPECIFICALLY TARGETING THE
EFFECTER CELLS IN THE MONKEYS AS
WELL AND I HAVEN'T TALKED ABOUT
NK CELLS BUT 100% OF THE
REFLECTOR CELLS AS WELL.
THIS IS AN IN VITRO.
WE'RE USING A CONSTRUCT mRNA
WITH A STEADY AND DEFICIENT
MUTANT SO THEY DON'T LOSE IT AND
THIS IS SHOWING HUMAN EXPRESSION
ON PRIMARY MACAQUE CELLS IN
VITRO.
YOU CAN SEE THEY'RE TRITATING
AND WE GET TRAFFICKING IN IN
VIVO IN A COUPLE WEEKS TEACHING
US THE PROTOCOLS AND DRIVING THE
STUDIES.
>> I'M JUST GOING TO CONCLUDE
WITH A COUPLE SLIDES AND YOU SAW
IN OUR TALKS WE IDENTIFIED
MULTIPLE MECHANISMS THAT PRO
PROMOTED THE LONG-TERM SURVIVAL
AND TRANSLATING THE DISCOVERY
FROM THE INSIGHT TO
INTERVENTION.
WE'RE MOVING TO THE NONHUMAN
PRIMATES AND THE INTERVENTION
WE'RE DOING PERFORMING DIFFERENT
PHASE OF THE COURSE OF THE
INFECTION IN THE ANIMALS AND THE
MECHANISTIC FACTION OF
INTERVENTION AND IDENTIFIED
INTERVENTION AT THE INITIATION
FOR EXAMPLE THE RATIONALE IS TO
ELIMINATE THE INFECTED CELLS
THAT OTHERWISE WOULD BE THE
RESERVOIR AND TESTING AND
CHARACTERIZING THE INTERVENTION
AND THIS IS WITH A STUDY TO
INDUCE REACTIVATION AND THE
RESERVOIR AND DOING INTERVENTION
OF THE BLOCKADE TARGETED
INTERACTION INTO NOW IMPROVING
THE ABILITY TO REBOUND THE
VIRUS.
REALLY WE HAVE INTERVENTION AND
BLOCKADE OF IL10 THAT IMPROVED
THE REBOUND.
AND THE HOPE WITH WE BE ABLE TO
LOWER THE RESERVOIR WITH THE
INITIATION IN THE FULLY
EXPRESSED ANIMAL AND LOWER THE
RESERVOIR AND INCLUDING THE
ABILITY OF THE ADMINISTRATION TO
CONTROL THE VIRUS AND HAVING THE
REMISSION OF HIV.
WHEN WE TALK ABOUT COMBINED
INTERVENTION IT'S IMPORTANT TO
REMEMBER THE NON-SPECIFIC
DELIVERY MAY CONTRIBUTE TO
TOXICITY OR ANTAGONISTIC EFFECT.
WE HAVE IDENTIFIED IS IT GOOD TO
HAVE STEM CELLS BUT CD4 CELLS
AND MANY THERE'S A SUBSET AND
THESE ARE THE IMMUNOCELLS.
IT'S IMPORTANT TO MOVE THROUGH
SELECTIVE DRUG DELIVERY TO
SPECIFIC DRUG SUBSET AND THIS IS
THE WORK WE'RE PLANNING TO DO IN
THE CONTINUATION IN THE NEXT FEW
YEARS AND THIS IS THE STRATEGY
WE'RE GOING TO MOVE IN THE
FUTURE AND ONE OF THE METHODS IS
USING mRNA CELL SPECIFIC
DELIVERY AND CELLS HAVE A
COMBINED STRATEGY IN NONHUMAN
PRIMATE AND CHARACTERIZED THE
INTERVENTION AND COMBINE THE
EFFICACY PROFILE AND TRANSLATE
THE MOST SAFE AND EFFECTIVE
STRATEGY.
SO WITH THAT I WOULD LIKE TO
ACKNOWLEDGE ALL THE MEMBER OF
THE COLLABORATORY THAT
PARTICIPATE IN THESE AND OTHER
STUDY.
I WANT TO THANK THE MEMBERS AND
SAB MEMBERS AND OF COURSE AND
ALL THE INSTITUTION AT NIH FOR
SUPPORT.
THANK YOU VERY MUCH.
>> WE DID AN EXPERIMENT WITH THE
CD 8 T CELLS AND PUT THE
CULTURES PACK IN TO LOOK AT
WHETHER WE CAN REACTIVATE THE
VIRUS AND 42 CD4s THAT WENT BACK
INTO CULTURE STAYED WITH THE LOW
LEVEL OR HIV EXPRESSION BUT IF
WE ACTIVATED THEM WE COULD
REACTIVATE THEM AS LONG AS THE
CD 8s WERE REMOVED.
THERE WAS AN EXPERIMENT TO SEE
COULD WE DO IT BUT THAT'S
SOMETHING WE NEED TO FOLLOW UP
WITH CAREEN SEE THE STABILITY OF
THE EPIGENETIC MARKS.
>> THANK YOU, SHARON LEWIN AND
ALL GREAT TALKS AND FABULOUS
WORK.
MY QUESTION IS FOR GUIDO.
WONDERFUL TO SEE THE MEDICATION
WORKING AT ART INITIATION.
THE DIFFERENCE BETWEEN THE VIRAL
LOAD CLEARANCE AND THE RESERVOIR
FINDINGS ARE VERY INTRIGUING AND
IT SHOULD SHORTEN THE SURVIVAL
OF AN INFECTED CELL AND EXPECTED
VIRAL LOAD CLEARANCE TO BE
GREATER.
IF YOU CAN ELABORATE ON THE
THINKING THERE.
THE SECOND QUESTION WAS THERE A
DIFFERENCE WITH IT ALONE FOR
WITH OUR LRA INTERVENTION.
HOW DO YOU DESIGN THE STUDIES
WAS HARD TO TELL.
DID THE LRA ADD ANYTHING TO IT
IN YOUR SECOND STUDIES?
>> THE SECOND STUDY I FORGOT TO
MENTION IS ALSO SUPPORTED BY AN
RO1 GRANT I RECEIVED TO CONTINUE
TO EXPLORE THE EFFECT OF CD 8
DEPLETION ON VIRUS REACT --
REACTIVATION.
DID -- IDEALLY WE SHOULD HAVE 12
GROUPS IN EVERY SINGLE POSSIBLE
COMBINATION.
WE COALESCED AROUND THE IDEA OF
KITCHEN SINK APPROACH THAT WHEN
WE ADD EVERYTHING WHAT REALLY
HAPPENS.
INTERESTINGLY ENOUGH WE NEED TO
DO MORE ANALYSIS BUT
INTERESTINGLY ENOUGH IT SEEMS
LIKE IT'S THE DIFFERENTIATOR AT
THE POINT PROBABLY BECAUSE THE
REVERSAL INDUCED AND KNEW FROM
THE NATURE PAPER REVERSAL OF
DEPLETION DOESN'T GO TO THE
HARDCORE RESERVOIR.
BUT BENITICLAX SEEMS TO DO MORE.
YOU'RE SPOT ON.
YOU PROBABLY SHOULD JOIN US AT
EMORY BECAUSE WE'VE BEEN TALKING
IN THE PAST THREE WEEKS THE
PREDICTION IS THE CELLS DIE
FASTER.
AND THE AFFECT OF VENETOCLAX IS
PUSHING IT TO HALF LIFE.
WE CAN TALK MORE BUT YOU'RE SPOT
ON.
THE SIMPLISTIC EXPECT WILL
RESULT WOULD HAVE BEEN A FASTER
DECLINE OF VIREMIA.
WE NEED TO PROBABLY RUN SOME
MOUSE MODELS WITH DIFFERENT
ASSUMPTIONS.
>> I'M CURIOUS DID YOU MIX CD4
AND 8 TOGETHER?
IF YOU MIX THE CELL WITH YOUR
CD4 DO YOU SEE THE SAME EFFECT?
>> SO THAT'S A GOOD QUESTION.
WE HAVEN'T DONE THAT EXPERIMENT
BUT I WILL SAY THAT IN CARRINE'S
MODEL SHE USES A SIMILAR CULTURE
SYSTEM BUT IT'S A SLIGHTLY
DIFFERENT ACTIVATION MECHANISM
SO WHERE THEY'RE NOT SEEING THE
EXPANSION OF THE CD 8 T CELLS AT
THE CO-CULTURE IT'S A BALANCED
DISTRIBUTION OF THE CELLS AND
THEY'RE STILL SEEING THIS IMPACT
ON EPIGENETICS.
IT'S A GREAT QUESTION BECAUSE
IT'S SOMETHING WE THOUGHT A LOT
ABOUT LIKE THE CD 8'S ARE
ACTIVATED AND WILL
PROLIFERATE -- WHAT'S THAT?
EXACTLY.
WE REPEATEDLY CHANGED MEDIA AND
REFRESHED EVERY DAY TO MAKE SURE
THERE'S LOTS OF NUTRIENTS SO
WE'RE NOT STARVING ANYBODY.
AND WE TRIED TO FIGURE OUT THAT
MECHANISM AND BECAUSE WE HAVE
THE ABILITY TO LOOK AT THE
NONHUMAN PRIMATE AND SEE THESE
ARE IN PARALLEL AND WE'RE NOT
SEEING AN IN VITRO RESULT THAT
JUST CAN'T BE RECAPITULATED IN
VIVO AND WE STARTED WITH AN IN
VIVO OBSERVATION AND LOOKED TO
SEE HOW TO MODEL IT IN VITRO.
>> THERE'S LOTS OF MECHANISMS.
HOW DOES THAT AFFECT THE
MECHANISMS WE'RE SEEING TO IN
VIVO FINDING SHOWING THE
INTERACTION AND REACTIVATION IS
KILLING THE HIV?
>> SO, I GUESS --
>> YOU NEED TO READ THE PAPERS.
WE HAVE PAPERS IN NATURE AND
IMMUNITY AND TWO BUT THE EASY
ANSWER IS YOU NEED TO PULL OUT
THE PAPERS.
I CAN SEND THEM TO YOU AND READ
THEM BECAUSE WE DISCUSS ALL THE
INTERACTION FOR THIS TYPE OF
INTERPRETATION.
IT'S A LONG STORY IT'S ABOUT 12
PAPERS BUT I DON'T KNOW IT'S A
GOOD USE OF TIME HERE TO
SUMMARIZE IT.
>> THANK YOU FOR TAKING US BACK
TO THE '90s BEFORE YOU WERE BORN
AND THE JAY LEEVY FACTOR.
HOW -- IT WAS GREAT YOU
EXPLAINED WHAT HAPPENED IN THE
CD4 CELLS AND LIKELY IT WOULD BE
ALSO GREAT IF YOU COULD TELL US
HOW THE CD 8 CELLS ARE DOING
THIS BECAUSE IT WOULD BE GREAT
TO BLOCK THAT TEMPORARILY
OPPOSED TO KILLING CD 8 T CELLS
WITH THE ANTIBODY.
DID YOU FIND THE FACTOR OR WHAT
IS IT THAT CD 8s ARE DOING THAT
CHANGES THE BIOLOGY OF THESE CD4
CELLS.
>> SO IT'S THE TGF BETA
SIGNALLING.
.
THE HYPOTHESIS OR WHAT WE'RE
CURRENTLY EVALUATING IS LOOKING
AT AN EXPRESSION BY CD 8 T CELLS
AND WE'RE SHOWING THE EXPRESSION
IS IMPORTANT IN ELITE
CONTROLLERS IN TERMS OF A
NON-CYTOLYTIC EXPRESSION AND SO
CONFIRMED BY OTHER GROUP AND
ESSENTIALLY BY MODULATING THAT
PARTICULAR PATHWAY WE'RE SEEING
UP REGULATION OF TGF BETA AND
INTERESTED IN AND AS GUIDO
MENTIONED IN THE NONHUMAN
PRIMATE WE'VE LOOKED AT THE CD 8
DEPLETION AND ONE THING WE'RE
INTERESTED IN IS PARTNERING WITH
BEING ABLE IT DELIVER MOLECULES
TO RELEASE REPRESSION TO HAVE CD
8 T CELLS AND BLOCK THE ROW
PRESSIVE MECHANISMS.
WE'RE CURRENTLY DOING STUDIES
WITH MERCK TO SCREEN FOR
COMPOUNDS AND DOING LIBRARY
SCREENS TO LOOK AT PATHWAYS TO
POTENTIALLY ALSO ALLEVIATE THE
EXPRESSION MECHANISM IN THE
PRESENCE OF CD 8s.
SO WE'RE GOING THROUGH THAT
SYSTEMATIC APPROACH TO LOOK AT
DIFFERENT MOLECULES TO BE ABLE
TO DO THAT WITHOUT THE CD 8
DEPLET
DEPLETION.
>> CD 8 CELLS ARE ONE TYPE OF CD
8 CELL EFFECTER MEMORY CELL
OR --
>> THAT'S A GOOD QUESTION AND
WE'RE IDENTIFYING THE CD 8 T
CELL SUBSET.
THERE'S CORRELATES IN THE CANCER
LITERATURE FOR A PARTICULAR T
CELL SUB POPULATIONS THAT HAVE
EXPRESSIVE ACTIVITY.
IN PARTICULAR LIKE FOR EXAMPLE
KNOWN TO IMPEDE A TUMOR
INFILTRATION AND WORKING ON
IMPEDING CYTOLYTIC TARGETS TO
CREATE THE EXPRESSION MECHANISM
BY CD 8s.
WE IDENTIFIED A FEW MARKERS THAT
SEEM TO BE CRITICAL FOR THE CD
8s TO HAVE IN ORDER TO PROMOTE
THE EXPRESSION ACTIVITY.
SO THE NEXT STEP IS TO BE ABLE
TO CORRELATE THAT WITH
EXPRESSION AND LOCALIZATION OF
THOSE CD 8 T CELLS IN THE
NONHUMAN PRIMATE MODEL TO BE
SABLE TO SAY WHERE ARE THE CELLS
AND WHEN THEY'RE INTERACTING
WITH THE CD4s AND INFECTION AND
FOLLOW-UP IN PEOPLE LIVING WITH
HIV AND THOSE CELLS.
>> AND THE REFERENCE TO JAY WAS
IMPORTANT BECAUSE HE WAS AN
INFLUENTIAL SCIENTIST FOR A LOT
OF US A PERSONAL FRIEND AND
ESTEEMED COLLEAGUE AND
EVERYTHING.
SO JAY LEEVY FAILED TO IDENTIFY
THE FACTOR AND I THINK IT'S
IMPORTANT WITH THE GROUP TO
DISCUSS AND WE DIDN'T HAVE THE
TECHNOLOGY WE HAVE NOW.
AND THE REASON NUMBER 2 I THINK
JAY GOT REALLY CONFUSED AND
STUCK IN THIS DICHOTOMY BETWEEN
SOLUBLE AND CELL TO CELL
CONTACT.
.
AND IT HAPPENED WHEN THE CELLS
ARE CLOSED.
WE GOT CAUGHT INTO THIS IS THIS
A SOLUBLE FACTOR BUT IN FACT
IT'S SOMETHING IN BETWEEN.
AND POINT NUMBER 3 IS THE OLDER
FOLKS IN THE ROOM WILL REMEMBER,
JAY THOUGHT THAT WAS THE REASON
THE LONG-TERM NON-PROGRESSERS
REMAINED LOW VIREMIC AND KNOW
THE EFFECT IS ALSO IN DONORS
THAT NEVER RECEIVED HIV AND A
LOT OF THIS IS RELATED TO THE
TECHNOLOGY THAT WASN'T AVAILABLE
AT THE TIME.
AND THE WHOLE THING STOPPED AND
WE WERE LUCKY TO RESURRECT IT.
ONCE YOU DEPLETE THE CD 8 IN
VIVO THERE'S A BIG REBOUND OF
VIREMIA SEEN IN 40 DIFFERENT
ANIMALS.
50 WHATEVER THE NUMBER IS.
>> I DIDN'T MEAN TO BE CRITICAL.
NOT AT ALL BUT THINGS HAPPENED A
LONG TIME AGO AND YOU KNOW.
>> WE CAN CONTINUE THE
DISCUSSION AT THE COFFEE BREAK.
>> THERE'S A QUESTION AND
CURIOUS ON THE GENETIC DATA ONE
THING THAT STOOD OUT TO ME WAS
IT SEEMED TO BE OPPOSITE TO
EVERYTHING ELSE GOING ON.
WONDERING IF YOU CAN COMMENT ON
THAT.
>> SO YEAH THERE'S A LOT OF
PATHWAYS WE HAVEN'T HAD A CHANCE
NO GET TO YET AND THAT'S ONE AND
STAT SIGNALLING IS ONE THAT
WE'RE VERY INTERESTED IN FOR A
LOT OF DIFFERENT MECHANISMS SO
ABSOLUTELY WILL FOLLOW-UP.
>> THIS IS FROM THE OVERFLOW
ROOM.
INTERESTING DATA ON THE DELIVERY
BY LNPs WHERE DO YOU THINK THE
CELLS WILL HOME TO NOW THAT YOUR
OVER EXPRESSION THE RECEPTOR AND
WHERE DO THEY TRAFFIC IN THE
MICE?
>> IN MICE WE'VE ONLY USED THE
GFP AND DIDN'T SEE TRAFFICKING
OF THE CELLS IN THE LYMPH NODES
PAUSE THEY DON'T HAVE THE HOMING
RECEPTORS.
OF COURSE ONCE WE DELIVER 60CD2L
WE HOPE THEY'LL BE ABLE TO ENTER
THE LYMPH NODES.
WE MAY NEED TO EXPRESS CD R7 AS
WELL BUT KNOW FROM PREVIOUS
LITERATURE FROM WAY BACK WHEN
AND IN COLLABORATION WITH TED
JUST EXPRESSION IT TOPICALLY IN
MICE ON ESSENTIALLY ALL CD 8 T
CELLS ALLOWS CONTINUAL ENTRY
INTO THE LYMPH NODE.
>> ALL RIGHT.
I'D LIKE TO INVITE THE CARE
SPEAKERS AND WHILE THEY'RE
APPROACHING THE STAGE REMINDER
IF YOU PLAN TO GET LUNCH ORDER
THROUGH CHOPPED YOU HAVE ABOUT
10 MORE MINUTES TO DO THAT MAYBE
A LITTLE BIT LESS.
9:45 IS THE ONLINE CUT OFF FOR
CHOPPED DROP THE WEBSITE AND QR
CODE IS OUTSIDE AT THE MAIN
DESK.
THIS IS THE FINAL COLLABORATORY
PRESENTATION SO IMMEDIATELY
FOLLOWING THIS SESSION WE'LL
BREAK UNTIL 11:00 AND HAVE TWO
PANEL DISCUSSION.
WE'RE LOOKING FORWARD TO THAT.
I HOPE YOU CAN STAY AROUND FOR
THOSE DISCUSSIONS.
THIS IS THE THIRD ITERATION OF
THE CARE GROUP LED BY THE
UNIVERSITY NORTH CAROLINA CHAPEL
HILL.
>> THANKS TO THOSE IN THE ROOM
REMAINING TO THE END.
I'M PRETTY TIRED.
I HOPE I CAN DO MY JOB.
I WOULD LIKE TO FIRST THANK ALL
THE INVESTIGATORS IN CARE.
UNFORTUNATELY WE WON'T HAVE TIME
TO PRESENT EVERYONE'S WORK
TODAY.
I'M JUST GOING TO TRY TO GIVE AN
OVERVIEW OF WHERE WE'RE GOING
WITH HIGHLIGHTS TO DELVE INTO IN
MORE DETAIL.
I DON'T NEED TO TALK ABOUT THE
SLIDE.
IT'S THE OVER ALL CONCEPTUAL
IDEA.
AS WE TALKED ABOUT OTHER
APPROACHES AND OTHER IDEAS OVER
THE MEETING AND WE'RE
INCORPORATING ADVANCES AND
PERHAPS THE FUTURE WILL LOOK
SOMEWHAT DIFFERENT THAN THIS BUT
THIS IS WHAT WE'VE BEEN MOVING
TOWARDS.
I WANTED TO START WITH OUR
EFFORTS WITH THE COMMUNITY.
WE HAVE THREE COMMUNITY PARTNERS
AND THE CARE GROUP THE COMMUNITY
ADVISORY BOARD OF CARE AND
OTHERS HAVE COLLABORATED WITH
THESE PARTNERS AS YOU CAN SEE
APPEARING AT THEIR VARIOUS
EVENTS AND BRINGING THE IDEA OF
CARE AND CURE RESEARCH INTO OUR
COMMUNITY.
I THINK UNLIKE MANY OF THE
COLLABORATORY LOCATIONS, WE ARE
MOSTLY IN PART OF THE SOUTHEAST
HIV EPIDEMIC IN THE U.S. WHICH
IS DIFFERENT POPULATIONS.
WE HAVE SORT OF CITIES BUT NOT
BIG CITIES.
PEOPLE COME FROM DISTANCES AND
THE SETTING IS PRETTY DIFFERENT
THAN A LOT OF OTHER PLACES WHERE
CURE RESEARCH IS GOING ON.
IN ADDITION TO WORKING WITH
THESE GROUPS, WE'VE ALSO GONE
OUT INTO VARIOUS RELEVANT
COMMUNITY EVENTS AND INTERACTED
WITH PEOPLE DEVELOPING BOTH WHAT
WE INVITED THE COMMUNITY TO AND
INFORMATION AND BROCHURES WE'RE
NOW USING TO HELP US INTERACT
AND BRING THIS INFORMATION
FORWARD.
FOR THIS COMING YEAR WE HAVE AN
UPCOMING EVENT AT THE GOVERNOR'S
MANSION AND THE GROUP HAS SPENT
TIME LOOKING AT WHAT WE ARE
DOING AND HOW WE'RE DOING IT TO
EVALUATE HOW WE CAN BE IMPACTFUL
IN THE DIFFERENT COMMUNITIES WE
SERVE GOING FORWARD.
I LOOK FORWARD TO ENACTING WITH
OTHER COMMUNITY MEMBERS AND
LOOKING AT THE BIOLOGY OF
LATENCY TO INFORM US HOW TO MOVE
FORWARD INTO PEOPLE WITH THIS
INFORMATION TO DEVELOP
THERAPEUTIC STRATEGIES.
AND ONE WITH A GROUP AND OTHERS
AND I'M SURE YOU'RE WELL AWARE
OF IS THIS IDEA WHILE VIREMIA IS
DIFFERENT THROUGH THE COURSE OF
INFECTION THE VIRUSES THAT END
UP IN THE RESERVOIR APPEAR IN
MOST PEOPLE TO MOSTLY EMANATE
FROM EXPANSION AND YOU CAN SEE
WHILE SOME OF THE OLD VIRUSES IN
RED OR OTHER COLORS ARE IN THE
RESERVOIR IN SOME PEOPLE MOST
THE VIRUSES IN MOST PEOPLE COME
FROM MORE RECENTLY CIRCULATING
VIRUSES WITHIN THE LAST YEAR
PRIOR TO ART INITIATION.
SO WHERE PEOPLE WERE BASHING ON
INFECTION AND DURABLE EXPRESSION
THIS OFFERED A NEW WINDOW TO
ATTACK THE RESERVOIR EARLY AT
THE INITIATION OF ART.
YOU CAN SEE IT MOVE FORWARD WITH
MULTIPLE STUDY SOME OF WHICH
WERE DISCUSSED IN THE
PRESENTATION OTHERS DONE IN
CARE.
SARA WILL HAVE DATA SOON FROM 10
WOMEN IN THE COHORT WHO FOR
VARIOUS REASONS INTERRUPTED ART
AND WE'LL SEE WHERE THE REBOUND
VIRUSES COME FROM IF THEY COME
FROM THE MORE RECENT OR MOVE
DISTANT RESERVOIR OR SOME MIX.
FURTHER, SOME OBSERVATIONS
SUGGESTS THE PRESENCE OF THE
INHIBITOR MAY IMPEDE THE
DEVELOPMENT OF THE RESERVOIR.
SO JUMPING OVER THE ANIMAL
MODELS WE WERE ABLE TO GO TO THE
ACTG AND DEVELOP A PILOT HUMAN
CLINICAL TRIAL STILL IN
DEVELOPMENT BUT SLATED TO
POTENTIALLY OPEN THIS COMING
YEAR INTERNATIONALLY.
A LARGE GROUP LOOKING AT HIV
PERSISTENCE IN TISSUE.
THE MERCK GROUP HAS CONTRIBUTED
SIGNIFICANTLY TO THIS AND I'LL
SHOW OTHER PIECES OF DATA AS AN
OVERVIEW.
THIS IS WORK FROM NADIA ROME YOU
HEARD SOME OF HER OTHER WORK
THIS WEEK AND HER HIV PREPS
ASSAY ABLE TO DETECT THE mRNA
CELLS BY SEQ AND SHOW MOST BUT
NOT ALL CELLS ARE POSITIVE FOR
THE ANTIGEN.
GUIDO FERRARI'S GROUP AT DUKE
HAS BEEN ABLE TO ACCESS TISSUE
FROM THE HOPE TRANSPLANT
PROGRAM.
IT'S A PROGRAM OF HIV POSITIVE
DONORS FOR HIV POSITIVE
TRANSPLANTS.
A TRANSPLANT FOR INSTANCE WHEN A
KIDNEY IS REMOVED, LOCAL LYMPH
NODES ARE AVAILABLE AND HE'S
BEEN ABLE TO ACQUIRE ALL LYMPH
NODES FROM PEOPLE EXPRESSED AND
SEE WIDE VARIETY OF CELLS
CHANGED BY THE EXPOSURE.
THIS IS ALSO ILLUSTRATED IN THIS
FIGURE IN A DIFFERENT WAY
SHOWING BEFORE AND AFTER IN THE
DIFFERENT POPULATIONS IN THE
PRESENCE OF SEVERAL DIFFERENT
ART, LOVE RA COMBINATIONS.
INTERESTINGLY -- LRA
COMBINATION.
WHEN YOU LOOK AT THE CELLS THAT
BECOME POSITIVE FOR RNA IN THE
EXPERIMENT YOU SEE MOST OF THESE
CELLS HAVE A TFH AND THAT IS AN
OBSERVATION THAT CAN BE
REFLECTED ON OTHER STUDIES
EARLIER IN THE WEEK THAT NEEDS
FURTHER DEVELOPMENT.
LAST YEAR COLLABORATORS
INCLUDING VERY IMPORTANTLY THE
LAST GIFT COHORT SHOWED
DEFINITIVELY THE MICROGLIA SHOW
THEIR CLEARLY DIFFERENT THAN LRA
RESPONSES IN T CELLS AND SOME
OBSERVATIONS WILL BE COMING OUT
IN THE LITERATURE RELATIVELY
SOON.
THE LAST PART OF THE BIOLOGY OF
LATENCY LOOKS DIRECTLY AT THE
DEVELOPMENT OF LRAs.
AS YOU KNOW WE RESERVED LATENCY
SOME TIME AGO AND WE CONTINUED
TO WORK IN DIFFERENT AREAS
DEVELOPING NEW LRAs PARTICULARLY
THOSE THAT MIGHT SYNERGIZE WITH
PREVIOUSLY DESCRIBED ONES.
SOME WORK I DON'T HAVE TIME TO
PRESENT HERE, CAT PRESENTED HER
POSTER YESTERDAY AND YOU GOT TO
SEE THAT AND IMPORTANTLY THERE
WAS A CRISPR SCREEN LOOKING FOR
LRA TARGETS FOR THOSE THAT MIGHT
SYNERGIZE WITH NON-CANONICAL
SIGNALLING.
THE NEXT PART IS DEVELOPING
IMMUNE MODULATION APPROACHES OR
IMMUNOTHERAPIES TO CONTROL VIRAL
REBOUND.
ONE EFFORT THAT'S GONE ON IS THE
DELIVERY OF INHIBITERS BY AAV
LED BY MATT GARNER AND MICHAEL
FARSAN.
ORIGINALLY THIS WAS MOSTLY
LOOKING AT DELIVERY OF ECA4
WRAPPED YOU WORK IN PAVE WITH
THE VECTORS.
THE VECTORS ARE BEING IMPROVED
AND DEVELOPED FOR FUTURE ANIMAL
EXPERIMENTS.
ANOTHER MAJOR ADVANCE IS THE
IDEA OF DEVELOPING WAYS TO
TARGET HIV INFECTED CELLS
PRESENTING ON THE PEP SIDE IN
THE HLE COMPLEX.
THIS IS A VERY COMPLEX IDEA.
IT'S GOING TO BE BEAUTIFULLY
EXPLAINED IN A PRESENTATION
SHORTLY.
SO I WON'T DO A BAD JOB OF
TRYING TO DO THAT.
AND THEN FINALLY THIS STEP
BEFORE GOING INTO HUMAN STUDIES
IS THE WORK IN THE ANIMAL
MODELS.
WE'VE CONTINUED TO ITERATIVELY
STUDY WORK IN HUMANIZED MOUSE
MODEL AND PRIMATE AND GUIDO IS
GOING TO GO THROUGH MANY OF
THOSE RECENT STUDIES.
SO NOW WE'LL MOVE TO CARLEY.
THANKS VERY MUCH.
6:
>> HI, EVERYONE.
I'M A Ph.D. GRAD AND I'LL
PRESENT MY WORK DONE IN
COLLABORATION WITH CARE.
ONE OF OUR GOALS IS IMPROVING
LATENCY REVERSAL FOR HIV CURE
AND THE SHOCK SIDE OF THE SHOCK
AND KILL APPROACH.
SO TO DO THIS WE WOULD FIRSTLY
LIKE TO IMPROVE UPON EXISTING
REVERSAL LATENCY AGENT BY
CONTROLLING LATENCY.
SECONDLY WE WOULD LIKE TO
INCREASE POTENCY AND SPECIFICITY
OF REVERSAL AND IDENTIFY
DRUGGABLE TARGETS.
AND SO WE HAVE SEVERAL LATENCY
REVERSAL AGENT TO REACTIVATE
CELLS BUT THEY LACK SPECIFICITY
AND LACK THE RESERVOIR.
SO ONE STRATEGY BEEN TO PAIR
DIFFERENT LRAs WITH DIFFERENT
MECHANISM OF ACTION THAT
UPREGULATED THE NON-CANONICAL
PATHWAY AND ONE THAT INCREASES
THE AVAILABLE PFT.
AND WE SEE SYNERGY REVERSAL.
THE COMBINATION WAS BROUGHT INTO
AN EX VIVO SYSTEM WHERE CELLS OF
PEOPLE TAKING WIN HIV WERE
REACTIVATED AND THERE WAS AN
ADDITIONAL ELONGATION BLOCK.
WHERE WE CAN UNDERSTAND HOW THE
LRAs ARE WORKING ON THEIR OWN
AND TOGETHER THERE'S STILL
BLOCKS WE CANNOT PREDICT AND SO
THE EMMERMAN LAB SOUGHT A WAY TO
ACTIVATE THE BLOCKS.
TODAY I'LL TELL THE STORY OF
IMPROVING ON THE ACD AND LRA
COMBINATION SPECIFICALLY.
WE USE A CRISPR SCREEN TO
REACTIVATE AND CAN INTRODUCE A
LIBRARY OF KNOCKOUTS WITH THE
HIV CRISPR VECTOR TO TARGET THE
HIV LATENCY FACTOR SO THE UP
TERM PROVIRUS IS ACTIVATE AND
BECAUSE HOW THE VECTOR WAS
DESIGN WITH THE HIV LTRs IT TOO
IS REACTIVATED AND PACKAGED SO
IT ACCUMULATES AND THIS IS A
STRATEGY TO CLEARLY LINK THE
KNOCKOUT TO THE REACTIVATION
PHENOTYPE AND THERE'S LITTLE
BACKGROUND IN THE SYSTEM.
AND BY SEQUENCING THE VIRAL
SUPER NATE ENT IN THE CELLS WE
CAN USE THE RATIO OF THE GUIDES
ENRICHED TO GENERATE A MAGIC
SCORE WITH GENES HIGHLY
ENRICHED.
AND THE SCREEN CAN BE PERFORMED
IN THE ABSENCE OR PRESENCE OF
LRAs.
AND TO SHOW THE RESULTS IN THE
TIME POINT ON THE Y AXIS WE
PERFORMED THE SCREEN WITH AZD
AND ON THE X AXIS PERFORMED WITH
DMSO AND THE UNTREATED CONDITION
AND I REVEALED THE GENE HITS IF
WE FOCUS ON THE OPEN CIRCLES AT
THE BOTTOM YOU CAN SEE WHEN WE
KNOCKOUT THE NON TARGETING
CONTROLS WE SEE LITTLE
ENRICHMENT.
HOWEVER, EVERY GENE HIT ABOVE
THERE KNOCKOUT IS PREDICTED TO
REVERSE LATENCY.
SO SOME OF THOSE HITS REVERSE
LATENCY IN THE ABSENCE OF LRAs
AND SOME PREDICTED TO IMPROVE.
I WANT TO DRAW YOUR ATTENTION TO
THE PREDICTIVE TO IMPROVE THE
TREATMENT WHEN KNOCKED OUT.
AND ADDITIONALLY I WANTED TO
HIGHLIGHT ING3 WHICH IS A FACTOR
WHEN KNOCK DOWN HAS BEEN SHOWN
TO I AM IMPROVE.
SO WHAT IS -- IMPROVE THIS.
AND THE INTEGRATOR IS A GENOME
WIDE ATTENUATOR OF
NON-PRODUCTIVE TRANSCRIPTION.
THE COMPLEX CAN DETECT ABERR
ABERRANCES FROM THE
TRANSCRIPTION TO ELONGATION AND
IT HAS TWO MODULES.
A PHOSPHOTASE AND A CLEAVAGE
MODULE WITH WHICH TO CLEAVE AND
TERMINATE TRANSCRIPTION AND THE
ELONGATION STEP IS WHERE IT WAS
SEEN IN THE PRIMARY CELL SYSTEM.
SO OUR HYPOTHESIS THE INTEGRATOR
COMPLEX IS BLOCKING HIV
TRANSCRIPTION AT THE ELONGATION
LEVEL AND THEREFORE KNOCKING OUT
INTS12 SHOULD INCREASE
TRANSCRIPTION.
ONE ASSAY WE USED TO VALIDATE
THIS IS TOTAL RNA SEQ AND TOOK
THE CELLS TREATED AND/OR KNOCKED
OUT OF CRISPR AND WE DID THIS IN
BIOLOGICAL TRIPLICATE AND
MEASURES HOW UP OR DOWN
REGULATED VARIOUS GENES ARE AND
MEASURED HOW EXPRESSED THE GENES
ARE.
HIGHLY EXPRESSED ON THE RIGHT.
AND WE CAN SEE THAT FROM AZD
TREATMENT ALONE WE SEE THE
ROBUST INDUCTION OF HIV SO
THERE'S A LOG TWOFOLD CHANGE AND
HIGHLY EXPRESSED.
AND OF THE HOST GENES AFFECTED
THERE'S 80 UPREGULATED AND 306
DOWN REGULATED.
MOST OF THOSE UP OR DOWN
REGULATED ARE NOT HIGHLY
EXPRESSED.
SO HIV IS THE MOST EFFECTIVE
FROM THE TREATMENT AND SPECIFIC.
EXCITINGLY WHEN WE LOOKED AT OUR
INTS 12 KNOCKOUT WE SEE IT ALSO
INDUCES HIV TO SIMILAR LEVELS AT
A TWOFOLD CHANGE AND LESS
DYSREGULATION OF THE HOST AND
COULD BE A GOOD CANDIDATE FOR
LRAs.
WE SEE A FURTHER INDUCTION OF
HIV AND MORE DYSREGULATION OF
THE HOST BUT COMPARED TO A TOXIC
ACTIVATOR WE SEE THOUSANDS OF
HIGHLY EXPRESSED GENES
DYSREGULATED IN THAT CASE AND
HERE WE'RE ONLY SEEING ABOUT
200.
AND SO WE BELIEVE THAT WE NOT
ONLY SEE A POTENT INCREASE FROM
THE KNOCKOUT BUT OUR RESULTS ARE
FAIRLY SPECIFIC.
SO IN COLLABORATION WITH THE
BROWN LAB AND THIS SHOULD SAY
THE ARCHIN LAB WE BROUGHT IT
INTO AN EX VIVO SYSTEM AND TOOK
CELLS AND KNOCKED THEM OUT FOR
NON-TARGETING CONTROL AND
REACTIVATED THEM AND MEASURED
RNA IN THE SUPER LATENT.
WHEN I SHOW THE RESULTS FROM
THREE DONORS AND WE LOOK AT THE
NON-TARGETING CONTROL IN TWO OF
THE THREE WE SEE REACTIVATION
FROM KNOCKING IT OUT ON ITS OWN
WHICH IS EXCITING TO SEE AND THE
DONOR ON THE LEFT COMPARING OURA
ZZ AND KNOCKOUT WE SEE THE
ELONGATION KNOCK OUTWHERE THE
COMBINATION IS NOT WORKING WELL
AND WHEN PAIRED WE SEE ROBUST
ACTIVATION OF HIV.
AND LOOKING AT OTHER DONORS THE
ONE IN THE MIDDLE HAS A SMALLER
RESERVOIR SO THE VALUES ARE A
BIT MORE MESSY BUT SEE AN
INCREASE FROM THE KNOCKOUT.
THIS IS EXCITING BECAUSE IT
INDICATED OUR SCREENING WAS ABLE
TO PREDICT A BLOCK THAT EXISTS
IN PRIMARY CELLS.
SO TO SUMMARIZE I'VE SHOWN HIV
TRANSCRIPTION IS BLOCKED AT THE
HIV LEVEL.
IF YOU'D LIKE MORE MECHANISTIC
DETAILS WE'LL HAVE A DETAIL IN
BIO ARCHIVE AND THERE WILL BE
MORE WHEN IT'S PUBLISHED AND
THERE'S A VIABLE DRUG TARGET FOR
IMPROVING LRAs AND THE LABS ARE
DEVELOPING INHIBITORS TO ING3
AND INTS12 SHOULD BE EXPLORED
FURTHER AND ADDITIONALLY DRUGS
MAY BE IDENTIFIED TO TARGET
INTS12 TO IMPROVE LATENCY AND
WITH THAT THANK YOU AND I'LL LET
THE NEXT SPEAKER COME TO THE
PODIUM.
SO I HAVE MY LAB'S EFFORTS TO
TRY TO FIND NEW THINGS THAT
REGULATE HIV.
PARTICULARLY FOCUSSING ON TWO
THINGS THAT CHEMICAL JEANS AND
WE LOOK FOR GENES THAT REGULATE
LATENCY AND HAVE DONE SCREENS
WITH CHEMICALS AND WITH CRISPR
TO TRY TO FIND THESE THINGS AND
FOUND TWO THINGS.
WE THINK ETS 1 IS REPRESSING AND
WE THINK SEDT2 CAN REPRESS AND
WE HAVE A BROUGHT REACTIVATION
OF THE RESERVOIR AND WE DID AN
OMICS EXPERIMENT TAKE BEING HIV
INFECT WILL CD 8 T CELLS AROUND
COMBINED SINGLE CELL ATAC SEQ
AND YOU GET THE CHROMATIN
STRUCTURE AND WE CAN IDENTIFY
DIFFERENTLY EXPRESSED GENES
ACROSS THE POPULATION AND
DYNAMIC CHROMATIN PEAKS AND LOOK
AT THE BINDING SITES IN THE OPEN
CRHROMATIN AND WE CORRELATED WIH
THE EXPRESSION.
WHICH THINGS ARE CORRELATED WITH
HIV RNA LEVELS AND THEY'RE
LIKELY TO BE REGULATORS OF HIV.
SO THERE'S ABOUT 300 THINGS
CORRELATED WITH HIV.
AND THEN WE WORKED WITH THE
EMERMAN LAB AND DID A CRISPR
SCREEN KELLY DESCRIBED.
WE DID THE SCREEN IN 10.6 CELLS.
TO CUT A LONG STORY SHORT THESE
ARE THE HITS HERE.
AND I DON'T HAVE TIME TO GO
THROUGH ALL THE PIHITS.
THE THINGS ABOVE ARE WHEN YOU
KNOCK IT OUT YOU GET MORE HIV
BEING RELEASED.
SO ETS1 IS A TRANSCRIPTION
FACTOR HIGHLY EXPRESSED IN T
CELLS AND THERE'S A BUNCH OF
PAPERS INDICATING A POSITIVE
FACTOR FOR HIV EXPRESSION.
WE'RE SURPRISED TO SEE IT SHOW
UP AS A REPRESSIVE FACTOR.
BUT FOLLOWED UP ON THIS AND
PROBABLY THE MOST INTERESTING
EXPERIMENT WAS TO KNOCK IT OUT
IN CELLS WITH PEOPLE WITH HIV.
WE HAVE CD4 T CELLS FROM
DIFFERENT DONORS AND CITES
CRISPR KNOCKOUT AND WE GET A
BONA FIDE REPRESSOR IN PEOPLE
WITH HIV.
WE'RE STILL TRYING TO FOLLOW UP
ON THE MECHANISM.
I DO RNA SEQ AND WE PROFILED
CELLS AND PE LOOKED AT GENES
GOING UP AND DOWN.
I DON'T HAVE TIME TO GO THROUGH
ALL THE DETAILS BUT WE FOUND ONE
GENE THAT WENT UP AND IT'S A
LONG CODING RNA PREVIOUSLY
PUBLISHED AS A POSITIVE FACTOR
FOR HIV EXPRESSION AND
POSITIVELY REGULATED SO MAYBE
THIS IS HOW THE KNOCKOUT WORKS
YOU KNOCKOUT AND IT PROMOTES
HIV.
TO TEST THAT HYPOTHESIS WE DID A
DOUBLE KNOCKOUT IN A PRIMARY
MODEL MY LAB USES.
WE TAKE T CELLS AND EXPRESS THEM
WITH A CLONE OF HIV AND INFECT
THE CELLS IN THE LAB.
WHEN YOU KNOCKOUT YOU SEE RNA
LEVELS GO DOWN AND WHEN I DO A
DOUBLE KNOCKOUT TOGETHER IT
ABROGATES THE ABROGATES THE
KNOCKOUT AND PART OF THE EFFECT
IS THROUGH UP REGULATING.
THIS IS OUR MODEL.
WE THINK IT'S REPRESSING CELLS
AND IT POSITIVELY ACTIVATES HIV.
AND THIS IS A TRANSFERASE.
IT CREATES THE TRIMETHYL MARK
HERE AND THIS WAS INTERESTING.
THIS MARK IS ABUNDANTLY FOUND ON
THE ACTIVELY TRANSCRIBED GENES.
THE TRI METHYL IS A KEY
INDICATION FACTOR FOR HIV.
WHAT HAPPENS IF YOU REMOVE THE
TRI METHYL?
HOW DOES IT CHANGE THE WAY HIV
GETS EXPRESSED.
WE HAVE AN INHIBITOR AND WE
INFECT WITH HIV AND SEE NOTHING
LAND.
IT DOES NOT SEE THE TRIMETHYL
HAS ANOTHER WAY TO INFECT AND IT
DOESN'T DEPEND AND WE PRE
TREATED WITH THIS INHIBITER.
THE INTEGRATION SITES CHANGED.
HIV LIKES TO ACTIVATE WITH THE
ACTIVELY TRANSCRIBED GENES AND
WE HAVE CHROMATIN MODEL BASED ON
THE MARKS.
WHEN YOU HAVE THE DEPLETION YOU
SEE FEWER INTEGRATION IN THE
ACTIVELY TRANBY BY --
TRANSCRIBED GENES AND THEY MOVE
HERE TO LIKE A DIFFERENT
NEIGHBORHOOD.
WE LOOKED AT LATENCY.
WE SOMEWHERE THE MODEL TO INFECT
CELLS AND ENRICH FOR ACTIVELY
INFECTED CELLS AND CULTURE THEM
FOR A PERIOD OF TIME.
YOU CAN SEE CELLS AT TRANSITION
REMAINING POSITIVE TO NEGATIVE
AND COUNT THE YELLS BEING --
CELLS AND MEASURE AND IN THE
PRESENCE OF THE INHIBITOR WE SEE
MORE LATENTLY INFECTED CELLS AND
CELLS SHUT DOWN AND THE ACTIVITY
IS REQUIRED TO KEEP HIV ON AN
ACTIVELY TRANSCRIBED STATE.
I THINK IT'S DIFFERENT FROM THE
INTEGRATION SITE PHENOMENON.
I DON'T HAVE TIME TO GO TO THE
DETAILS LATER.
WE LOOKED AT TOTAL RNA LEVELS
AND WE SAW IT CHANGES LYSINE.
WE SEE MORE UNSPLICED VIRAL RNA.
SOMEHOW THE HISTONE AFFECT THE
EXPRESSION OF HIV.
THAT'S OUR BEST GUESS FOR HOW
THIS WORKS.
ANOTHER THING THAT WAS
POTENTIALLY USEFUL TAKING LATE
ENLY INFECTED CELLS YOU GET MORE
BANG FOR YOUR BUCK FROM CERTAIN
LRAs AND HYPERSENSITIZE THE
INHIBITORS.
YOU CAN KNOCK DOWN HIV
EXPRESSION AND HERE YOU GET A
BROADER EXPRESSION AND I'LL PASS
IT OFF NEXT TO HONGBING.
>> AND IT'S GREAT TO COME HERE
TO SHARE AN PRESENT OUR WORK.
AND IT IS POSSIBLE FOR
IMMUNOTHERAPY FOR HIV
ERADICATION.
SO KILLER T CELLS PLAY A ROLE IN
CONTROLLING HIV REPLICATION.
AND THE KILLER CELLS RECOGNIZE
INFECTED CELLS THROUGH A SMALL
PIECE OF HIV PRESENTED BY A
MOLECULE CALLED HLA-A-B OR C.
BECAUSE OF THE GLOBAL DIVERSITY
OF THE MOLECULE AND COVER THE
WHOLE POPULATION.
THE T CELLS CAN ALSO RECOGNIZE
HIV THROUGH ANOTHER MOLECULE
CALLED E.
AND THIS IS A NON-POLYMORPHISM.
AND THE T CELLS CAN AFFECT THE
IMMUNE CELLS AND THERE'S
POTENTIAL THROUGH THE T CELLS.
THERE'S A GREAT ADVANTAGE OF
IMMUNOTHERAPY AND IT'S
POLYMORPHIC SO THERE'S A
POSSIBILITY OF UNIVERSAL
IMMUNOTHERAPY AND HIV INFECTION.
E IS NOT DOWN REGULATED.
HOWEVER, THE HLA-A, B OR C ARE
DOWN REGULATED.
WE RECOGNIZED PEPTIDE AND ONE
CLONED T CELLS FOR ALL THREE
ACTORS.
SO HERE I JUST SHOW AN EXAMPLE
OF IL-9 CLONE AND AFTER PRIMING
WE CAN DETECT POSITIVE RESULTS
AND THE CLONE WITH THIS AND IT'S
LOW COMPARED TO T CELLS BECAUSE
THE BINDING AFFINITY OF TO THE
PEPTIDE IS MUCH LOWER THAN
CLASSIC T CELL.
AND AT DUKE THEY GENERATED
POTENT ANTIBODY.
SO VO 9 IS A SELF-HOST PEPTIDE
ORIGINATING FROM THE OTHER
MOLECULES.
AND WE USED THE VIRAL EXPRESSION
ASSAY.
BRIEFLY THE CD4 T CELLS FROM
HEALTHY DONOR WERE INFECTED WITH
HIV VIRUS AND CLONED FOR FIVE
DAYS AND QUANTIFIED THE INFECTED
CELLS AND I GIVE YOU TWO
EXAMPLES HERE.
THE MIDDLE ONE IS ONE OF OUR
IL-9 CLONE COMPARED TO THE
INFECTED CELLS ALONE WITHOUT T
CELL CLONE WE SEE REDUCTION OF
P24 POSITIVE CELLS IS OVER 87%
OF KILLING AND THE SECOND
EXAMPLE IS IL-9 CLONE.
AND THIS ONE SHOWED EVEN MORE
POTENT KILLING ACTIVITY.
IT'S NEARLY 97% INHIBITION.
AND WE THEN PERFORMED EXPRESSION
ASSAY.
THE GRAPH SHOWED THE EXAMPLE OF
TWO IL-9 ACTORS IN THE YELLOW
BARS.
AND IN THIS ASSAY WE AND THIS IS
A WELL STUDIED AND POTENT
FUNCTION.
SO YOU CAN SEE THE TRANSDUCTANTS
SHOWED POTENT INHIBITION ALMOST
CLEARING THE INFECTED T CELLS
BUT WORKED BEAUTIFULLY ON THE
DONORS ON THE POSITIVE AND WITH
THE ACCIST -- ACTIVE DONORS
THERE'S NO EFFECT BUT FOR THE
TCR WORKED FOR ALL DONORS.
THAT'S AN EXAMPLE OF THE
NON-POLYMORPHISM OF THE TCR.
NOW I'M TALKING ABOUT THE
FUNCTION.
WE TESTED THE ANTIBODY AND SO
ACTUALLY WE PRESENTED THIS
PEPTIDE TO THE MOLECULE
EXPRESSED MAINLY ON NK CELLS OR
SOME SUBSET OF CD 8 T CELLS.
SO TO INITIATE INHIBIT THE
SIGNAL TO BLOCK THE KILLING THE
ANTIBODY CAN BLOCK THE
INHIBITORY SIGNAL.
IF THEY CAN RESTORE THE KILLING
FUNCTION SO WHAT WE USED IS ONE
OF OUR CLONE SO IT SHOWED IN THE
BLUE BAR.
THIS CLONE HAS SHOWN MODEST
INHIBITION AND WE ADD THE
ANTIBODY AND YOU CAN SEE
SIGNIFICANT INCREASE ON THE
KILLING ACTIVITY WHICH SHOWED IN
THE PINK BOX.
SO SUMMARIZE WHAT WE HAVE DONE
SO FAR WE HAVE DEMONSTRATED FOR
THE FIRST TIME THAT THE E
RESTRICTED HIV CELLS CAN BE
PRIMED IN VITRO AND RECOGNIZE
NATURALLY PRESENTED HIV ACTORS
AND INFECTED CELLS.
AND IT IS VERY ENCOURAGING THAT
THE TCR INTO THE CD 8 T CELLS
WERE EFFECTIVE IN REDUCING VIRUS
REPLICATION AND TOGETHER WITH
THE ENHANCEMENT OF KILLING OF
THE ANTIBODY COULD OFFER A NOVEL
THERAPEUTIC APPROACH TO HIV
ERADICATION.
OUR HYPOTHESIS IS THE
E-RESTRICTED LOW AFFINITY T
CELLS MAY BE LESS SUSCEPTIBLE TO
CELL DEATHS IN VIVO AND COULD BE
VERY IMPORTANT IN THERAPY
PERSISTENCE IN HIV ERADICATION.
AND SO FINALLY I WOULD LIKE TO
THANK ALL MY COLLEAGUES AT
OXFORD AND OUR COLLABORATORS AT
UNC, DUKE AND UAB FOR THE GREAT
COLLABORATION WORK.
THANK YOU.
>> IT'S GOOD TO BE HIRE.
THE -- HERE.
THE COLLABORATORY HAS BEEN
EXCITING AND TRIED TO GIVE A
GENERAL SENSE OF WHERE WE ARE.
I'VE BEEN ONLY BEEN INVOLVED IN
THE LAST TWO ITERATIONS.
THE WORK THAT WE'LL BE
DISCUSSING AND THIS IS THE PLAIN
LANGUAGE SUMMARY THE IMPORTANCE
OF USING THE NONHUMAN PRIMATE
MODEL AND USING THE PARTICULAR
LATENCY REVERSAL AGENT ALONE OR
IN COMBINATION WITH OTHER AGENT
THAT PROMOTE AND THE KEY
COMPONENT OF THE SHOCK AND KILL
APPROACH IS THE LATENCY AGENT I
MENTIONED THE CONVERSATION 10
YEARS AGO.
THIS ONE WAS A CONVERSATION I
THINK WAS EIGHT OR NINE YEARS
AGO AND WE UNDER IN THE BLUE
JACKET AND I WAS CALLED UP AND
GOT THE AMAZING COMPOUND THAT
REVERSES LATENCY TO A LEVEL I'VE
NEVER SEEN BEFORE.
AND WE DECIDED AND STARTED
PUTTING IT INTO MONKEYS AND THE
IDEA IS THAT A STRONG CELL
SPECIFIC IMMUNE CELL SPECIFIC
LATENCY REVERSING CAN BE
OBTAINED BY USING THE CONCEPT OF
MEMETICS.
THOSE ARE ACTIVATOR OF THE
PATHWAYS AND INHIBITORS OF
APOPTOSIS AND SHOWED LATENCY
REVERSE ACTIVITY AND OUR WORK IN
MONKEYS THEY WERE VERY EFFECTIVE
AT REVERSING LATENCY BUT WE'LL
COME BACK TO THAT.
THIS IS SOMETHING I ALLUDED TO
BEFORE.
MONKEY STUDIES IN WHICH WE ADD
SOMETHING TO THE ANTIVIRAL
THERAPY TO DISRUPT THE RESERVOIR
ARE IN STUDIES WHERE WE IMPACT
THE ESTABLISHMENT OF THE
RESERVOIR AND GIVEN AT THE TIME
OF THE STUDIES THAT IMPACT ON
THE PERSISTENCE OF THE RESERVOIR
AND GIVE SO-CALLED PURE
INTERVENTION AFTER A PROLONGED
PERIOD OF ART.
I'LL FOCUS FIRST ON A STUDY THIS
WAS LED BY VICTOR WITH THE
POSTDOC CHRIS NIXON AT THE TIME.
AND THE STUDY WAS
STRAIGHTFORWARD.
IT WAS AN ABSOLUTE RESULT IN
HUMANIZED MICE AND INFECTED
MACAQUES AND GIVE MULTIPLE DOSES
AND GET A ROBUST REVERSAL OF
LATENCY.
THIS REVERSAL HAS NO IMPACT ON
THE SIZE OF THE RESERVOIR AND
THEY WENT BACK TO LATENCY AND
THE NUMBER DIDN'T CHANGE OVER
TIME.
ONE THING WE DID IN OUR GROUP IS
TO DEMONSTRATE THIS TREATMENT
WAS ACTUALLY SYNERGISTIC WITH CD
8 DEPLETION.
WHEN YOU PULL OUT THE CLOGGING
OF LATENCY OF VIRAL EXPRESSION
AND DONE BY THE CD 8 YOU HAVE
LYMPH NODE THE ACTIVITY OF THE
LATENCY REVERSING AGENT TO BE
BECOME MORE POWERFUL AND SAME WE
SAW IN THE STUDY A FEW YEARS
AGO.
AND THAT'S PART OF THE WORK I
WAS REFERRING THAT JUSTIFIED THE
REASON WHY THIS IS A PRO LATENCY
ACTIVITY OF THE CD 8 T CELLS.
THE NEXT STUDY WAS LED WITH MOD
AND OTHERS AND THIS WAS TRYING
TO SEE IF THE REVERSAL OF
LATENCY INDUCED BY AZD5582 COULD
BE HELPED BY ADMINISTERING
MONOCLONAL ANTIBODIES TO REDUCE
THE RESERVOIR SIZE.
THIS STUDY WAS I GUESS THE
CLASSICAL STUDY YOU CAN SEE AS
THE GLASS HALF FULL OR HALF
EMPTY.
BUT THE REALITY IS THAT WE SAW
FOR THE FIRST TIME A SIGNAL OF
AZD5582 IN REDUCING THE
RESERVOIR SIDES WHEN USED
TOGETHER WITH THOSE NEUTRALIZING
ANTIBODY.
THIS WORK WAS PUBLISHED A WHILE
AGO AND AGAIN OPENED UP THE IDEA
THAT AZD5582 NOT WITHSTANDING
THE COMPLICATION IN PEOPLE WE
ALL RECOGNIZE BUT AS A PROOF OF
PRINCIPLE OF A MOLECULAR
MECHANISM MAY END UP
METABOLIZING THE PERSISTENT
RESERVOIR.
THE NEXT STUDY WAS SEEING
SYNERGY BETWEEN AZD5582 AND
REVERSAL EFFECT BY THE SUPER
AGONIST.
BECAUSE OF THE PROBLEMS WE HAD
TO REDIRECT OUR EFFORTS BY USING
ANOTHER IL-15 SUPER AGONIST THAT
WAS GENERATED AND DEVELOPED IN A
SERIES OF STUDIES AND AGAIN WE
CAN TALK DURING THE DISCUSSION
WHAT IS SIMILAR OR DIFFERENT
BETWEEN THE MOLECULE BUT IT'S
THE BEST WE GET IN TERMS OF
REPLICATING THE EFFECT.
THE STUDY NOW IS A STUDY OF
AZD5582 WITHOUT THE SUPER
AGONIST AND TO SEE THE IMPACT ON
THE ESTABLISHMENT OF THE
RESERVOIR STUDY WAS LED IN THE
FIRST ROUND.
AND THIS IS WHAT SHARON LEWIN
WAS ALLUDING TO.
THESE ARE STUDIES WHERE THE
READOUTS ARE THE SLOPE OF
DECLINE OF VIREMIA.
THE CLASSICAL MODEL SAID IF
CELLS DIE FASTER THE VIREMIA
WILL BECOME MORE STEEP AND IN
CONTRAST OF CELLS IF THE SLOPE
IS MORE GENTLE IT'S LESS DEEP
THERE'LL BE A PROLONGED LIFE
SPAN OF INFECTED CELLS OR
INCREASED PRODUCTION OF RNA FOR
THE PER CELL BASIS.
AGAIN, THESE ARE MODELS WE
CAN -- AND I DON'T WANT TO SPEND
TOO MUCH TIME DISCUSSING THIS
BUT THESE ARE MODELS THAT CAN BE
VERY PRONE DO DISCUSSION BECAUSE
OF THE DISCUSSIONS MADE FROM THE
MATHEMATICAL POINT OF VIEW.
AND WE SHOWED THE DEPLETION OF
CD 8 T CELLS HAVE AN IMPACT ON
THE CURVE OF VIREMIA DECLINE.
AND THERE WERE 35 ANIMALS
DIVIDED IN THREE EXPERIMENTAL
GROUPS RECEIVING HETERODIMERIC
GROUP IN THE CONTROL ANIMALS.
THE MAIN RESULT YOU SEE WE'RE
DOING INITIAL ANALYSIS AND
AZD5582 IN COMBINATION DOES
EFFECT THE PRODUCTIVE INFECTED
CELLS AND IN FACT MAKES THE LIFE
SPAN LONGER.
THIS IS JUST FOCUSSING ON THE
INTERVENTION TIME FRAME.
ALSO IN THE STUDY WHEN YOU START
LOOKING AT THE RESERVOIR SIDE IN
BLOT AND LYMPH NODES
SEQUENTIALLY OVER TIME YOU SEE
THE ANIMALS RECEIVING AZD5582
AND A FASTER DECLINE OF THE
RESERVOIR COMPARED TO THE
CONTROL ANIMALS.
SO THERE IS -- THIS IS AN AFFECT
TRANSIENT BECAUSE AFTER 300 DAYS
IT'S NO LONGER SIGNIFICANT AND
AN ABILITY TO PERTURB THE
RESERVOIR.
THIS IS BY FOCUSSING ON THE
INITIAL PHASE OF THE STUDY.
THE STUDY IS BASICALLY ALMOST
FINISHED.
WE'RE STILL DOING SOME ANALYSIS
BUT THE KEY POINTS OF THIS
PARTICULAR COMBINATION OF
APPROACH IS AZD5582 ALONE OR
WITH HETERODIMERIC IL-15 INDUCES
A SLOWER DECLINE OF VIREMIA
WHICH MEANS INFECTED CELLS OR
VIRUS PRODUCTION AND THE
INTERVENTION PERTURBS THE
ESTABLISHMENT OF THE VIRUS
RESERVOIR FOR SEVERAL WEEKS.
IT DOES THAT IN LAB AND LYMPH
NODE AND HAS RATIONALE FOR
FURTHER EXPLORING THE MECHANISM
OF REVERSAL OF LATENCY WITH
ADDITIONAL INTERVENTIONS.
IT DOESN'T HAVE TO BE AZD5582
AND RECOGNIZE THE PROBLEMS GOING
WITH HUMANS IN THE COMPOUND AND
THE PANEL WAY TARGET REMAINS
VIABLE.
THIS IS THE STUDY WE'RE DOING
NOW IN WHICH BASICALLY WE'RE
TRYING TO ADD A COCKTAIL THE
SAME COCKTAIL OF NEUTRALIZING
SIV ENVELOPE SPECIFIC ANTIBODIES
AT THE TIME OF ART INITIATION.
THE IDEA IS TO INDUCE EITHER
MORE DRAMATIC PERTURBATION OF
THE ESTABLISHMENT OF THE
RESERVOIR BY A CLEARING
COMPOUND WITH THE LATENCY
REVERSAL.
WITH THIS I ACKNOWLEDGE IT'S
BEEN GREAT WORKING ONE OUR
WONDERFUL LEADER AND THE FORCE
BEHIND THE STUDY AND I WANT TO
EMPHASIZE VICTOR BECAUSE THIS
WHOLE THING TO ME IS SOMETHING I
STILL REMEMBER AS IT WAS
YESTERDAY.
THANK YOU VERY MUCH.
>> WE'RE DEFINING THE STRATEGIES
AS EFFICACIOUS AND WHETHER OR
NOT THEY MAKE CELLS ABLE TO BE
CLEARED.
AND FURTHER STUDIES HAVE
PERSISTENCE IN TISSUES.
THE HLE TARGETING APPROACH IS
BEING FURTHER TESTED IN BOTH THE
IN VIVO MODELS AND SO WE HAVE
SOME PRELIMINARY EVIDENCE THAT
WE'RE SEEKING OFF FURTHER WAYS
TO EXPAND.
WE HOPE THIS WILL BE AN
IMPORTANT WAY TO CLEAR CELLS.
ONE OF THE ASPECTS THAT GUIDO
JUST MENTIONED IS THE HOPE WE'LL
BE ABLE TO ADD AN EVALUATION OF
THIS HLAEVL9 ANTIBODY TO AUGMENT
CLEARANCE IN THE PRIMATE MODEL
LATER THIS YEAR.
AND THEN FINALLY OR CONTINUOUSLY
TO ASSESS THE SYSTEMS AND ASSESS
THE ADVANCES IN VIVO SYSTEMS AND
PREPARE THEM TO MOVE TO HUMAN
TESTING.
SO IN THAT REGARD CONTINUE AND
OUR CARE COLLABORATORY MOVED
FORWARD UNDER THE CLINIC AND THE
HOPE TO TEST MEMETIC IN THE LRA
PHASE 1 STUDY.
I THINK THESE ARE CHALLENGING
THING AND THINK THEY'LL COME UP
IN THE PANELS TOWARD THE END.
IT SHOULD BE RECOGNIZED THE IAP
MOLECULE WOULDN'T HAVE BEEN
DEVELOPED WITHOUT OUR
COLLABORATION.
AND FINALLY ANOTHER
COLLABORATION WITH MICROGENETICS
A COMPANY WORKING IN HIV AND HAS
SINCE LEFT THE FIELD BUT THE
MOLECULES THAT WERE DEVELOPED
THERE WERE TRYING TO HAVE A
PROOF OF CONCEPT STUDY WITH THEM
IN HUMANS AS WELL.
SO, AGAIN, AND OPEN FOR
QUESTIONS.
>> I GUESS IT COULD BE MORE
BROADLY ADDRESSED.
AND REGULATE LATENCY
HISTORICALLY HAVE USED
PROVIRUSES IN CELLS THAT HAVE
BEEN SELECTED TO BE EASED WITH
WHICH LATENCY IS REVERSED AND
THEN DO COMPLIMENTARY STUDIES
GOING TO PRIMARY CELLS WITH A
POPULATION OF PROVIRUSES AND
REPRESENT THE IN THE LATTER
EXPERIMENT IS A FOLD INCREASE IN
RNA.
BUT MY QUESTION IS IN THOSE
COMPLEMENTARY EXPERIMENTS WHAT
FRACTION OF THE PROVIRUSES ARE
BEING ACTIVATED.
THAT'S KEY IF IT'S 2% BUT IF
IT'S 99% WE ARE GETTING CLOSE.
DO YOU HAVE A SENSE OF WHAT
FRACTION OF PROVIRUSES ARE BEING
ACTIVATED BY THE GENES THAT
COMPLEMENT.
>> THE SHORT ANSWER IS NO, WE
DON'T.
I THINK IT'S A REASONABLE GUEST
THE RESERVOIR IS HETEROGENEOUS
HAVE GOT DIFFERENT STATES AND
DIFFERENT CELLS AND SOME CELLS
WILL BE LIMITING OTHERS NOT.
SO I THINK IT'S UNLIKELY ANY ONE
THING WILL BE IN ALL THE
RESERVOIR BROADLY.
I THINK THAT'S WHY WE HAVE TO GO
FOR A KITCHEN SINK MULTI-PRONGED
APPROACH.
IN TERMS OF FINDING WAYS TO LOOK
AT THAT THERE'S A SINGLE CELL
PROBE A WAY TO MEASURE THE SEQ.
THOSE ARE EXPENSIVE EXPERIMENTS
AS I'M SURE YOU KNOW.
THE ANSWER AT THIS POINT NO WE
DON'T BUT WOULD BE REALLY
IMPORTANT.
>> JUST A COMMENT.
IN JAY LEV CELLS WE LOOKED AT
REVERSE TRANSCRIPTASE ACTIVITY
ASSAY AND GFP WITHIN THE CELL
ALONE WE DO SEE THAT THERE ARE
HIGHER PERCENTAGE OF CELLS
ACTIVATED AND THEN ALMOST SEEMS
THE CELLS PRODUCING VIRUS MAY BE
PRODUCING MORE VIRUS.
SO I ASSUME THAT'S HAPPENING IN
THE PRIMARY CELLS AS WELL.
>> TO QUESTION YOUR QUESTION, I
GUESS I AGREE.
I THINK THIS IS A CHALLENGE FOR
THE FIELD AND I THINK WE MISSED
OPPORTUNITIES IN THE PAST BY
EXPECTING TOO MUCH FROM A SINGLE
DRUG OR GENE KNOCK DOWN OR
PATHWAY.
I THINK EVERYTHING WE TALKED
ABOUT THIS WEEK SHOWS THERE'S
MULTIPLE FACTORS THAT LEAD TO
PERSISTENT PROVIRAL INFECTION IN
DIFFERENT CELL POPULATIONS.
AND SO THE KITCHEN SINK IS PRO
ETCH IS HELPFUL SOMETIMES
BECAUSE YOU SEE A SIGNAL AND
THEN HAVE TO UNRAVEL IT.
AND I THINK WE'VE OFTEN IGNORED
PROMISING EFFECTS THAT ARE ONLY
TWO OR THREEFOLD INDUCTION AND
AS WE MOVE THEM FORWARD AND TEST
THEM IN OTHER MODELS OR COMBINE
THEM WITH OTHER THINGS WE
RECOGNIZE THEY MAY ACTUALLY BE
USEFUL.
I THINK IT'S A VERY DIFFICULT
AREA THAT CAN REALLY ONLY BE
MOVED FORWARD BY DIFFERENT
APPROACHES IN DIFFERENT MODELS
AND LOOKED AT HOLISTICALLY.
>> MY QUESTION IS FOR HUNGBING
AND I THINK OF CD 8 POSITIVE K
CELLS AND EXPANDED THE CELLS IN
THE PRESENCE OF PEPTIDES AND
THEY SEEM GET POOR RESPONSES.
I'M WONDERING ARE YOU USING THEM
WITHIN THE CD 8 T CELLS IS THAT
A MARKER YOU'RE FAMILIAR WITH ON
THE OTHER SIDE?
>> FOR ALL T CELL WORK WE ARE
VERY FOCUSSED ON THE CD 8 T
CELLS.
SO WHEN WE DO THE PRIMING OR
CLOTH WE DID DELIVERY TO EXCLUDE
NK CELLS.
AS THE NOT THE PATH WE HAVE
ADVOCATED AND SO BY CHALLENGE WE
HAVE THAT ONE OF THE NK GA
POSITIVE CLONES TO PASS
ANTIBODY.
BUT THE PRIMARY FUNCTION IS TOO
REGULATE NK CELLS.
THAT'S ALWAYS THE MAIN.
SO TO YOUR QUESTION, WE HAVEN'T
LOOKED AT THAT PART.
>> UNIVERSITY OF NEBRASKA.
QUESTION ABOUT THE PEPTIDE IS
CONSERVED CROSS DIFFERENT CLAY
OF HIV AND BETA SHOW THE IMPACT
PRESSURE ON THE VIRUS.
HAVE YOU OBSERVED THE ESCAPE
MUTATION.
>> SO FAR WE ONLY IDENTIFIED
THOSE THREE PEPTIDES.
THERE'S A B57 PEPTIDE AND THE
RAF IL-82 AND THE IL-9 IS HIGHLY
CONSERVE ED AND IT'S RELATIVELY
CONSERVED.
SO IN TERMS OF IMMUNE PRESSURE
FOR MUTATION WE DON'T KNOW YET.
THAT'S SOMETHING WE WANT TO
INVESTIGATE.
AND WHEN WE DO EXPRESSION ASSAY.
IN VITRO FIVE DAYS, SIX DAYS
MAYBE NOT LONG ENOUGH TO DRIVE
MUTATION BUT SAY IN THE FUTURE
THE IN VIVO MODEL THEN WE CAN
LOOK AT THOSE.
IF THEY GIVE PRESSURE ENOUGH.
THANKS.
>> GUIDO, SHAURN SHED COMPELLING
DATA YESTERDAY AND STARTING AND
CORRELATED EFFECTS.
>> IT'S POSSIBLE AND DEPLETION
SEEMS LIKE THE STRAIGHTFORWARD
INTERVENTION AND IT'S
MULTI-FACTORIAL AND IT'S
POSSIBLE THERE IS APE EFFECT
LIKE THAT THAT JUSTIFIES THE
KINETIC OF VIRAL DECLINE.
ONE THING TO KEEP IN MIND IS
THAT REALLY THE ULTIMATE READ
OUT OF THE STUDY IS THE
RESERVOIR THE NUMBER OF YELLS
THAT ARE ENTERING THE PERSISTENT
RESERVOIR WITH REPLICATION
PRESUMABLY PROVIDERS.
MY REASONING IS IF IS JUST A
SIMPLE LOOK OF KILLING BY THE CD
8 CELLS BECAUSE THEIR NATURE AND
MICROBIOLOGY STUDY SHOULD NOT
HAVE IMPACT ON THE RESERVOIR
SIZE.
THERE'S AN IMPACT ON THE
RESERVOIR SIZE IT'S AN EFFECT
DISTINCT FROM THE CD 8
IMPAIRMENT.
OTHERWISE YOU HAVE TO PREDICATE
ACTIVITY ON THE CD IS MORE
POWERFUL THAN CD 8 DEPLETION
ITSELF.
>> YOU HAVE INFECTION OF THE
TARGET AND IMMUNO RERECTORY --
IMMUNOREGULATORY EFFECTS AND
THERE'S MULTIPLE COMPONENTS TO
THEIR ACTIVITY.
WE SAW WITH THE mRNA VACCINE
CONTROL YOU MIGHT ENHANCE YOUR
INCREASE SET POINT.
I THINK IN MOST OF YOUR STUDIES
TODAY YOU HAVEN'T DONE ANY
TREATMENT INTERRUPTIONS IS THAT
RIGHT?
THAT PLAY BE AN IMPORTANT
FACTOR.
>> I DISAGREE AND WE CAN ARGUE
ABOUT THIS ALL THE TIME.
THE PRIMARY POINT OF THIS STUDY
IS TO LOOK AT THE EFFECT ON REZ
RESERVOIR SIZE AFTER THE
INTERVENTION AND YOU LOSE THE
ABILITY TO MEASURE THAT.
IF WE THINK WE'RE CLOSE TO A
CURE THEN TREATMENT INTERRUPTION
STUDIES ARE GREAT BUT IT'S
SIMILAR TO THE LOVELY STUDY WITH
THE VACCINE I'M INTERESTED TO
SEE WHAT THE FREQUENCY OF
PERSISTENT INFECTION IS AT THE
END OF ALL THESE INTERVENTIONS.
THEN CAN WE MEASURE IMMUNE
RESPONSES SUFFICIENT ENOUGH
THEY'LL BE GOOD ENOUGH TO ALTER
AN ATI.
IF YOU CONVINCE GUIDO NOW TO DO
A TREATMENT INTERRUPTION WE'LL
LOSE ALL THE DATA FROM THE STUDY
WE HAVE.
>> IS IT SUFFICIENT TO CHANGE
THE REBOUND AND THINGS LIKE
THAT.
IL COMES DOWN TO PRODUCT
DEVELOPMENT AND ANSWERING
SCIENTIFIC QUESTIONS.
I'M MORE IN THE SECOND CAMP BUT
MAYBE I'M WRONG.
>> I TOTALLY UNDERSTAND WHAT
YOU'RE SAYING, DAVID.
THE POINT IS IF THERE IS AN
ADVERSE EFFECT ON THE CD 8
CONTROL YOU MIGHT NOT SEE IT
WITHOUT YUPT RUMPS AND DO THESE
INNING MONKEYS.
THEY'RE A GREAT AVENUE.
>> IT DEPENDS ON HOW DURABLE AND
REVERSIBLE IT IS LIKE MANY DRUGS
WE USE IN MEDICINE ALL THE TIME.
WE USE DRUGS FOR DEFINED PERIOD
OF TIME AND WITHDRAW IT AND WE
HAVE TO WORRY ABOUT ALL THOSE
THINGS AN TEST AND SEE THEM.
>> WE'RE IN OUR COFFEE BREAK.
THANK YOU VERY MUCH FOR A GREAT
DISCUSSION.
IT'S A GOOD SEGUE TO CLEAR THE
PANEL DISCUSSION AFTER THE BREAK
PLEASE COME BACK PROMPTLY AT
11:00.
THERE SHOULD BE A COFFEE BREAK
SET UP AND IF YOU HAVE A POSTER
PLEASE REMOVE IT DURING THE
BREAK. THANK YOU.
OKAY.
LET'S GET STARTED WITH THIS
DISCUSSION.
WE HAVE TWO PAMS.
THE FIRST PANEL WILL BE TALKING
ABOUT TRANSLATING HIV CURES
STRATEGIES TO THE CLINIC AND
IT'S GOOD HAVE A PANEL
DISCUSSION AND THE TOPIC LIKE I
SAID IS TRANSLATING HIV CURE
STRATEGIES TO THE CLINIC.
DISCOVERIES ARE MADE IN CURES
STRATEGY BOUGHT BECAUSE THE
CULTURE AND COMMITMENT NEEDED TO
TRANSLATE TO CLINICAL TRIALS IS
LOOKING.
WE TASK THE PEOPLE ON THE PANEL
TO TELL US HOW TO PROPEL
INNOVATIVE RESEARCH OUT OF THE
LAB AND INTO THE CLINIC TO
IMPROVE THE LIVES OF PEOPLE
LIVING WITH HIV.
DR. STEVE DEEKS HAS AGREED TO BE
THE CHAIR OF THE SESSION.
I'LL HAND IT OVER TO HIM.
>> GREAT.
THANK YOU.
THIS IS A TOPIC I FEEL A LOT OF
PASSION ABOUT.
HOPEFULLY WE'LL GET A GOOD
DISCUSSION GOING AND STEVEN
DEEKS DOING CLINICAL TRIALS IN
THIS RELATED AREA FOR SOME TIME
AND CO-CHAIRING THIS WITH SANDY.
WE'LL INTRODUCE OURSELVES AN
SECOND AND THE LET ME GIVE
BEFORE PERSPECTIVE HERE.
I THINK THE HIV ESTABLISHMENT
AND COLLABORATORIES DO AN
OUTSTANDING JOB OF IDENTIFYING
UNIQUE AND INNOVATIVE STRATEGIES
FROM THE PETRI DISH THROUGH THE
PRE-WHEN I CAL MODELS INCLUDING
MOUSE AND MACAQUE MODELS.
WE HAVE DONE A GREAT JOB IN
IDENTIFYING POTENTIAL
INTERVENTIONS THAT CAN LEAD TO
DURABLE CONTROL OR CURE ON THE
OTHER HAND I THINK WE'RE OKAY OF
REPURPOSING ESTABLISHED DRUGS IN
PROOF OF CONCEPT OF STUDIES AND
GATES AND MHRP.
WHAT WE'RE NOT GOOD AT IS THE
PART IN THE MIDDLE OF TAKING
NOVEL DRUGS AND MOLECULES AND
ASSETS WHERE THAT THERE'S NO
EXISTING DRUGS BECAUSE IN THAT
PARTICULAR VALLEY THE WORK IS
NOT ACADEMICS CAN DO AND
RESOURCE INTENSIVE AND GO SOUP
TO NUTS HOW TO GET THINGS FROM
THE IDEAS INTO THE CLINIC.
WHAT THE NEEDS ARE IN TERMS OF
DEVELOPING NEW PRODUCTS AND HOW
THE NETWORKS WILL WORK TO
DEVELOP THE STUFF AND COME UP
WITH SOLUTIONS FOR THE ISSUES.
>> ANY THOUGHTS?
>> THANKS, STEVE.
I'M SANDY VASAN I CONDUCT THE
MILITARY HIV RESEARCH PROGRAM.
WE DO SPEND TIME WHERE STEVE
REFERENCED THE VALLEY OF DEATH
WHERE WE TAKE IDEAS FROM THE
PRECLINICAL SPACE AND MOVE THEM
FORWARD TO POPULATIONS NEEDED
MOST.
THE MDCs HAVE BEEN GREAT IN THE
LATEST ROUND WITH SO MANY
COLLABORATORIES LETTING A
THOUSAND FLOWERS BLOOM AND CAN
SEE THE SYNERGY ACROSS
COLLABORATORIES BUT HOW DO WE
GET TO THE PAINFUL PARTS OF DOWN
SELECTING THOSE THAT NEED THE
INVESTMENT IN MOVING FORWARD
THROUGH THE VALLEY OF DEATH AND
UNGLAMOROUS THINGS SUCH AS
TOXICITY TESTING AND STABILITY
AND RELEASE AND THINGS THAT ARE
LESS FUN OF LOOKING AT GRAPHS OF
VIRAL DECAY.
THOSE ARE THINGS WE'VE CALLED
OUR PANELISTS IN TO ANSWER.
ONE MORE NOTE.
WHEN WE THINK OF THE INFANTS,
CHILDREN AND ADOLESCENTS WHEN WE
THINK OF TRANSLATING STRATEGIES
TO BE TESTED IN THOSE VERY
SPECIAL POPULATIONS IT ADDS
REGULATORY HURDLES AND NOT JUST
DEVELOPMENT HURDLES BUT SPECIFIC
CONSIDERATIONS AND WE WERE
REMINISCING OF HOW
ANTIRETROVIRAL THERAPY HOW
DIFFICULT IT WAS FOR CHILDREN TO
TAKE THEIR ART MEDS BECAUSE SO
FEW WERE AVAILABLE FOR
SPECIFICALLY FOR CHILDREN AND
THOSE THAT HAD AWFUL TASTES,
POOR FORMULATIONS.
IT WAS DIFFICULT.
OVER TO YOU.
>> WHAT ARE THE INTERVENTION
STRATEGIES IN THE CLINIC AND GO
DOWN THE LINE AND ASK KATIE TO
PONTIFICATE FROM ZOOM LAND.
>> I'M MARINA CASKEY AT
ROCKEFELLER AND KATIE IS GOING
TO BE THE NEXT AND I HAVE
EXPERIENCED BRINGING STUDIES
INTO THE CLINIC FROM THEA CT
PERSPECTIVE AND STUDIES
INDEPENDENTLY AT ROCKEFELLER.
I HAVE SOME OPINIONS ABOUT
THOSE.
MOST MY WORK HAS BEEN WITH BNAB
AND A KEY HURDLE IS ACCESS TO
THE STUDY PRODUCTS.
I THINK NOT ONLY THE NOVEL STUDY
PRODUCTS THAT HAVE TO BE
MANUFACTURED THE FIRST LOT TO
TOXICITY TESTING AND REGULATORY,
ETCETERA BUT EVEN REPURPOSED
DRUGS.
IT'S NOT SO STRAIGHTFORWARD
BECAUSE THEY HAVE HIGH COST.
SOMETIMES THE FUNDING MECHANISMS
DO NOT ALLOW.
EITHER YOU DON'T HAVE THE
PARTNERSHIP WITH INDUSTRY YOU
HOPE TO HAVE IF THEY'RE NOT
ALREADY INVOLVED IN THE HIV
FIELD AND EVEN IF THE DRUGS THE
PURCHASE CAN BE HIGH AND FUNDING
MECHANISMS CAN BE LIMITING.
YOU ASKED ME HOW WERE YOU ARE
ABLE TO DO THEY WILL AU -- ALL
THE STUDIES AND THEY'VE BEEN
THROUGH DIFFERENT TYPES OF
PHILANTHROPY AND GAVE US THE
OPPORTUNITY TO DO STUDIES WE DID
AND PARTNER AND PROVIDE OR HAVE
ACCESS FOR INVESTIGATION
UNDERSTANDING THE TWO TO ENABLE
NEW LOTS TO BE PRODUCED WITH YOU
KEYS THE STUDIES ARE NOT SIMPLE.
IT'S REALLY DIFFICULT TO RECRUIT
PARTICIPANTS.
WE'RE ASKING A LOT FROM AND
STEPPING FORWARD IN THE RESEARCH
AND THE INVESTIGATORS AND GROUPS
AND SITES THAT REALLY HAVE THE
APPETITE TO EMBARK IN THESE
CHALLENGING STUDIES TO NOT ONLY
LAUNCH BUT CARRY OUT.
AND ALL THE SAMPLE COLLECTIONS
IN PARTNERSHIPS WITH VARIOUS
COLLEAGUES AND LOOK AT THIS FROM
VARIOUS ANGLES AND WE HAVE TO
COME TOGETHER AND UNDERSTAND WE
HAVE TO HAVE A WHOLESOME
UNDERSTANDING OF WHAT THE
INTERVENTIONS MAY BE DOING.
NOT RELYING ON ONLY STANDARD
ASSAYS AND LOOKING AT
INTERESTING SIGNALS IN GENT
STUDIES.
I'M THE CO-P.I. FOR THE
COLLABORATORY AND CHAIR FOR THE
SCIENTIFIC COMMITTEE.
I WANT TO THANK THE NIH FOR
FUNDING A PEDIATRIC PURE AGENDA.
THE BAR IS HIGH FOR PEDIATRICS
WHEN WE TALK ABOUT INTERVENTIONS
IT'S IMPORTANT TO REMIND THE
AUDIENCE A BABY WITH HIV DOES
BECOME AN ADULT AND CAN LIVE TO
THE FOURTH DECADE OF LIFE AND
IT'S IMPORTANT TO THINK HOW THE
STRATEGIES CAN BE APPLIED ACROSS
THE AIDS SPECTRUM AND WITH
UNIQUE CONSIDERATIONS FOR
DEVELOPING THE IMMUNE SYSTEM IN
WHICH THE RESERVOIR IS
ESTABLISHED.
I HOPE YESTERDAY YOU GOT A
FLAVOR FOR DISTINCT FEATURES OF
INFECTION TO A PLACE OF
REMISSION AND CURE.
I'LL START WITH A RETROSPECTIVE
LOOK AND WE DIDN'T KNOW HOW TO
DOSE IN NEWBORNS ONLY FOR
PROPHYLAXIS AND IT'S HOW MANY
REGIMENTS LAG BEHIND ADULTS.
IT'S ONLY TWO AND THE STAYED ON
IT FIVE YEARS BEFORE WE STOPPED
DRUG TREATMENT.
ONE MAIN HURDLE IS INVESTMENT IN
BASIC EFFECTIVE DRUGS FOR
CHILDREN IF WE HAVEN'T CURED WE
ED ACCESS FOR TREATMENT AND
YOUNG ADOLESCENT TREATMENT.
THE MAJOR HURDLE IS INDUSTRY
INVESTMENT IN OUR AGENDA AND
DELIVERY OF PRODUCTS WE BELIEVE
COULD HAVE DIFFERENT OUTCOMES IN
THE PEDIATRIC SETTING WHERE THE
RESERVOIR IS LOW.
IT'S LOW DIVERSITY AND WHERE THE
IMMUNE SYSTEM IS A CLEAN SLATE
BECAUSE MANY HAVE POSITIVE HIV
SPECIFIC CELLS THE SECOND IS THE
REGULATORY ASPECT OF PEDIATRIC
CARE AND WE HAVE TO RESPECT THAT
AND DO WHAT WE FEEL IS GOING TO
BE SAFE WITH EFFECTS AND HAVING
AN APPROACH TO PEDIATRIC STUDIES
WITH A FOCUS ON DIFFERENT
CONSIDERATIONS THE AIDS SPECTRUM
IS GOING TO BE CRITICAL
EFFICIENT.
AND THERE'S RESTRICTED FUNDING
SO THERE'S PRIORITIZATION AND
PROOF OF CONCEPT STUDIES MAY NOT
BE THE TOP PRIORITY.
AND THE ETHICAL CONSIDERATIONS
FOR CONSENT AND ASCENT.
MANY HURDLES BUT I THINK WE'RE
IN A UNIQUE POSITION BASED ON
THE DIFFERENCES IN PEDIATRIC
RESERVOIRS TO ACHIEVE REMISSION
AND CURE FOR THIS POPULATION.
I'LL TOUCH ON THE FINDING
MAURICIO PRESENTED YESTERDAY AND
WE'RE LEARNING A LOT ON THE
PROFESSION I THINK WILL HELP.
HOW DO YOU MOVE THE INFANT STUDY
IN A MACAQUE MODEL TO CHILDREN
AND AT WHAT AGE SHOULD WE START
AND HOW DO WE TRANSLATE STUDIES
FROM A TWO-WEEK-OLD INFANT TO A
2-YEAR-OLD CHILD.
THERE'S INVESTMENT IN THE AGENDA
AND THEY MOVED THIS PRECLINICAL
STUDY TO CLINICAL TRIALS.
THE SAME PEOPLE DOING THE TRIALS
ARE DEVELOPING THE PROTOCOL AND
CONCEPT AND IT'S TIME CONSUMING
AND GET WITH THE FDA TO BEGIN TO
SEE HOW TO MOVE THE JUNE
DELIVERY SYSTEM OF BIOLOGICS IS
PROMISING AND PROCUREMENT OF
PRODUCT.
THEY'VE BEEN ABLE TO HELP US
CONNECT AND CONTACT VARIOUS
ORGANIZATIONS THINKING ABOUT
PRODUCT DEVELOPMENT.
LASTLY AND WHATEVER WE FIND HAS
TO BE ABLE TO IMPLEMENT THIS.
IT'S NOT JUST CLINICAL TRIALS
AND ENGAGING IN COMMUNITY THEY
WANT TO KNOW IF WE FIND
SOMETHING WE HAVE A PLAN TO MOVE
THIS OUT ON A LARGER SCALE.
WITH THAT I'LL STOP AND TURN IT
OVER TO DAVE.
WE'RE ALL THINKING OF THE SAME
THING AND I'LL TRY TO ADD
SOMETHING DIFFERENT.
IT MY BE WORTHWHILE TO REFLECT
BACK ON AN OPINION PIECE WRITTEN
IN SCIENCE AT THE BEGINNING OF
THE COLLABORATORY.
AND EFFORT HAS BEEN USEFUL AND
SUCCESSFUL OVER NOW ALMOST 20
YEARS.
THERE'S DIFFERENT NEEDS AND THE
QUESTION IS WHETHER THE CURRENT
FUNDING IN IMPLEMENTING SYSTEMS
ARE THERE'S SEVERAL ONES TO PUSH
DIFFERENT THINGS FORWARD OR
WHETHER WE NEED SOME A NEW NOVEL
DIFFERENT OR SPECIAL STRUCTURE
TO DO THAT RECOGNIZING THE
INFRASTRUCTURE HAS MULTIPLE
OTHER DEMANDS AND DEMANDS ON
SCIENCE AND MEDICINE WE'LL BE
FINDING ABOUT SOON.
ON WHAT KINDS OF IDEAS CAN BE
MORE RAPIDLY BROUGHT OUT OF STFB
AREA OF WHICH THIS GROUP IS --
SCIENTIFIC GROUP WHERE THIS
GROUP IS A FERTILE FIELD AND HOW
THAT CAN BE BROUGHT FORWARD FOR
DIFFERENT APPROACHES AND TRIALS.
I AGREE THE STICKING POINT IS
FROM ANIMAL MODEL TO PEOPLE AND
HAVING RESOURCE OR FUNDS OR
SUPPORT TO PRODUCE IT'S PROBABLY
NOT A PRODUCT.
I THINK IT'S A TOOL OR CANDIDATE
MOLECULE OR SOME EXPERIMENTAL
COMPOUND THAT WOULD BE CAN BE A
MOLECULE AND ALREADY BEING MADE
IN THE VACCINE AND PREVENTION
SPHERE WHETHER THERE NEEDS TO BE
MORE USE OF THOSE RESOURCE OR
CONSTRUCTION OF A NEW
INFRASTRUCTURE TO PRODUCE
SMALLER NOVEL PNEUMOTHERAPIES
BUT IT'S SOMETHING TO THINK
ABOUT.
AS I RECALL THERE WAS A DEEP
INVESTMENT WE WERE HOPING THAT
WOULD DO THE WORK TRANSFERRING
FROM LAB TO CLINIC.
ON ZOOM WE HAVE ANDY CATES TO
GIVE US THE -- ANDY KAYTES AND
I'LL LET KATIE GO NEXT AND THEN
ANDY.
KATIE.
YOU'RE STILL ON MUTE.
SIGN LANGUAGE?
>> I WAS TRYING TO UNMUTE.
SORRY.
CAN YOU HEAR ME NOW?
I'M A TRANSLATIONAL RESEARCHER
AT THE UNIVERSITY OF
PENNSYLVANIA.
I'VE BEEN HER VICE CHAIR IN THE
ACTG CURE TSG THE PAST THREE
YEARS.
THOUGH I'VE BEEN GRABBING HER
WITH MY NAILS AND NOT LETTING
HER GO SHE'S ALLOWED TO MOVE ON
AND IN 10 DAYS MYSELF AND
JONATHAN LEE WILL BE LEADING THE
GROUP.
THREES A SMALL MECHANISM THROUGH
THE ATCG SEVERAL CONCEPTS MOVED
FORWARD THROUGH.
THAT'S ONE PATHWAY FOR IDEAS
GENERATED THROUGH THE A STRONG
PATHWAY IN THAT REGARD.
I'LL ECHO THE CONCERNS ABOUT THE
NEED FOR STRONG INDUSTRY
PARTNERSHIPS WHETHER WITH AN NIH
BODY OR INDUSTRY PARTNER.
THAT'S HOW WE ME OF FORWARD
AROUND RECOGNIZING WE'RE AN
EXPERIMENTAL MEDICINE STUDIES
AND ASKING THE RIGHT SCIENTIFIC
QUESTIONS WITH AMPLE SAMPLES AND
TIMING AND REGIMENTS AND WHAT
NOT WITH FEASIBILITY IS A HUGE
CHALLENGE FOR THESE STUDIES AT
THIS POINT.
IT BECOMES A LOGISTICAL OR
PRACTICAL ISSUE THINKING OF THE
PEDIATRIC PARALLELS TO ADULT AND
PEDIATRIC STUDIES.
WE'RE FAR BEHIND IN
UNDERSTANDING THESE IN WOMEN
COMPARED TO MEN AND IT MAY BE
BECAUSE OF HOW INFEASIBLE OUR
STUDY ARE.
THE MORE REASONABLE WE MAKE THE
STUDIES FOR PARTICIPANTS, THE
MORE ABLE WE ARE TO TRULY ENROLL
FOR THOSE W.H.O. CRAN KNOT PRART
OPERATE FOR A LONG PERIOD OF
TIME IN THE STUDIES.
WITH THAT I DON'T THINK I'VE
RAISED PARTICULARLY NEW CONCEPTS
BUT I DO THINK THIS WILL HELP US
MOVE THE FIELD FORWARD.
THANK YOU.
>> ANDY.
>> THANK YOU VERY MUCH.
I AGREE WITH EVERYTHING THAT'S
BEEN SAID I'M FROM THE
UNIVERSITY OF CALIFORNIA SUNDAY
AND I'M PRART OF THE HIV
COLLABORATORY.
I'VE BEEN FORTUNATE ENOUGH TO BE
INVOLVED IN THE MDC SINCE THE
FIRST ITERATION.
I'M FORTUNATE TO BE PART OF THE
CURE TSG WITH WONDERFUL
LEADERSHIP WITH MA MARINA AND
KATIE.
IT'S BEEN WONDERFUL.
FROM A COMMUNITY STANDPOINT I
THINK WE'RE STARING INTO A
CRYSTAL BALL AND HOPING FOR AN
IMAGE WHAT HIV WILL BE LIKE IN
THE COMMUNITY.
WE HAVE CONCERN ABOUT
SCALABILITY AND WILL IT BE
AVAILABLE FOR ALL AND IS A CURE
GOING TO BE AS AVAILABLE IN THE
DEEPEST PART OF AFRICA AS WELL
AS NEW YORK CITY?
IMPORTANT TO THE COMMUNITY IS WE
ARE UNABLE TO TRANSMIT TO A
PARTNER THAT IS WE AND PEOPLE
WOULD LIKE TO BE ABLE TO HAVE AN
HIV NEGATIVE TEST ON AN EXAMPLE
BUT THAT SAID THERE'S THE ISSUE
OF BECOMING HIV NEGATIVE AFTER
LIVING WITH HIV AFTER HOWEVER,
LONG, NOW YOUR ALL OF A SUDDEN
OF THE RYAN WHITE SYSTEMS BUILT
FOR HIV.
THOSE ARE THINGS THAT KIND OF
COME INTO PLAY AND WHEN YOU TALK
ABOUT GETTING INTO THE CLINIC A
THOUGHT COMES TO MIND OF A CAR T
CELL TRIAL AT CITY OF HOPE AND
YOU NEED TO STAY AT THE CITY OF
HOPE FOR TO WEEKS STRAIGHT AS A
PARTICIPANT.
SO IS THAT THE KIND OF THING
THAT IS GOING TO BE NECESSARY
FOR SOMEONE TO RECEIVE A CURE OR
AS SIMPLE AS TAKING AN ASPIRIN?
I THINK HOPEFULLY THE TRUTH IS
IN THE MIDDLE.
CLOSER TO THE ASPIRIN WOULD BE
NICE.
WE TALK ABOUT DIFFERENT GENETICS
FOR PERSON OR BIO TYPE AND HOW
IS THAT GOING TO WORK?
CAN THAT BE DONE IN A SIMPLE WAY
OR BE A LARGER TWEAK TO GET
SOMETHING TO FIT INTO A CERTAIN
PERSON'S BODY?
WE HAVE THE DAMAGE OF THE
MEDICATIONS OVER THE YEARS
PEOPLE HAVE TAKEN.
CERTAINLY IT'S NOT GOING TO BE
AS MUCH OF AN ISSUE OF THOSE
TREATED WITH ART.
FOR A NUMBER OF PEOPLE MAJORITY
OF PEOPLE OVER 50 RIGHT NOW
THAT'S A REAL SITUATION.
SO WILL THINGS LIKE NEUROPATHY,
COGNITION, OTHER INFLAMMATORY
ISSUES BE ABLE TO BE REVERSED
AND PUT BACK TO WHAT THEY ARE
WERE PRIOR TO US TAKING ART?
DON'T KNOW THAT'S REALLY GOING
TO BE SOMETHING WE'RE ABLE TO
ACCOMPLISH FOR NOT.
IT'S REALLY DIFFICULT TO
FORECAST WHAT A CURE WILL LOOK
LIKE INSIDE THE CLINIC BUT IT'S
GOING TO TAKE PHARMACEUTICAL
COMPANIES PLAYING WELL WITH ONE
ANOTHER.
I ASSUME WE WON'T BE WORKING
WITH ONE COMPOUND.
IT WILL IB ACOMBINATION THERAPY
OF SORTS.
WILL THE BE REPEATED THERAPIES
OVER THE COURSE OF WEEKS,
MONTHS, YEARS.
WHAT HAPPENS AS FAR AS THE
TESTING TO FIND OUT IF SOMEBODY
ACTUALLY IS HIV NEGATIVE AND
CURED AND DOESN'T NEED TO BE ON
ART ANYMORE?
HOW WOULD THIS PLAY IN THE
INCARCERATED POPULATIONS.
LOTS OF QUESTIONS TO ANSWER.
AND I THE COMMUNITY IS FULL OF
QUESTIONS MORE THAN ANSWERS.
>> WHY DON'T WE TRY TO COME UP
WITH SOLUTIONS.
WE OUTLINED THE PROBLEMS AND
BARRIERS AND THEY'RE CONSISTENT.
LET'S FOR EXAMPLE, THINK ABOUT
AND THERE'S BEEN WORK ON USING
SOME CUTTING EDGE GENE EDITING
TOOL TO DIRECTLY ACTIVATING THE
HIV PROVIRUS.
AND INFECT WITH HIV RATHER THAN
DEPENDING ON THE PROD ACTIVATING
APPROACHES.
THESE ARE PRODUCTS THAT ARE
GOING TO HAVE TO GO THROUGH THE
PRECLINICAL DEVELOPMENT.
SOMEONE WILL HAVE TO DO ALL THE
TALK STUFF.
MAKE A PRODUCT.
ALL THE RELEASE CRITERIA.
THAT'S USUALLY A TWO, FOUR,
MILLION DOLLAR KIND OF THING AND
SMAC MIMETICS.
WE NEED ALL THIS STUFF TO BE
PRODUCED.
WHAT MODELS DO WE NEED TO FUND
THAT AND INVESTMENT FOR THE
PRODUCTS.
WE SHOULD LOOK TO THE VACCINE
EFFORTS IN WHICH THE
COLLABORATORIES THEY ARE HAVE
THE THEY ARE HAVE THE CAPACITY
TO DO BASIC DISCOVERY AND HAVE
CAPACITY WORKING WITH GNP
FACILITIES TO MAKE THE PRODUCTS.
THEY'RE MUCH BIGGER.
THEY HAVE THIS CAPACITY TO MAKE
THE PRODUCTS AND THEN THERE'S
IDEAS FORMED IN THE LABS THE
GERM LINE STUFF AND TRANSITION
TO THE NETWORK.
SAMPLES COME BACK AND SO FORTH.
WE DON'T HAVE THE CAPACITY.
SHOULD BE?
SHOULD THE COLLABORATORIES TO
HAVE THE CAPACITY AND WHO WILL
DO THE WORK?
JUST THROWING THAT OUT THERE.
IF OTHER PEOPLE HAVE POTENTIAL
SOLUTIONS FEEL FREE.
SANDY AND THEN DAVID.
>> I APPRECIATE THE
SOLUTION-BASED APPROACH AND
REFLECTING ON ANDY'S ELOQUENT
COMMENTS WE'RE TRYING TO
OVERCOME TWO SETS OF HURDLES
WHEN WE TALK ABOUT TRANSLATING
STRATEGIES.
THE FIRST IS THAT EARLY
TRANSLATION GETTING SOME OF
THESE IDEAS COMING OUT OF THE
MDCs INTO PEOPLE.
AND GETTING THEM TO A SMALL SET
OF PEOPLE AND PROOF OF CONCEPT
IS ONE BIG HURDLE AND TAKING
THAT FURTHER, I MEAN WE HAVE
CURED PEOPLE AS A FIELD BUT
THROUGH STEM CELL
TRANSPLANTATION.
OR BONE MARROW TRANSPLANTATION
IT'S CREATED HOPE IT'S POSSIBLE.
WE HAVE TO THINK OF THOSE
OVERLAPPING AND DIFFERENT
BUCKETS OF EARLY TRANSLATION AND
SCALABILITY.
AND FOR SOLUTION I APPRECIATE
YOUR ANALOGY THE VACCINE REALM
WE WORK UNBOTH -- IN BOTH
PLACES AND THERE'S GRANTS FOR
ADDRESSING THESE ISSUES.
THEY COULD BE A SUPPLEMENT TO
THE MDCs IF YOU MEET CERTAIN
CRITERIA YOU CAN APPLY FOR A
SUPPLEMENT TO GET INTO THE MORE
RESOURCE INTENSIVE CLINICAL
DEVELOPMENT PHASE.
>> STIMULATED BY WHAT YOU SAID.
PHARMA COMPANIES ARE EN BUSINESS
TO STAY IN BUSINESS MAKING
MEDICINES FOR PEOPLE.
THEY HAVE TO SELL THEM AND STAY
IN BUSINESS.
THEY'RE UNDER VARIOUS PRESSURES
DIFFERENT THAN SOME OTHER PEOPLE
IN THE ROOM.
WE COULD ASK THE NIH TO MAKE A
MOLECULE.
AND MAYBE NOT TO BE DISCUSSED
ONLINE WITH A ZILLION PEOPLE BUT
FURTHER CONVERSATIONS TO
APPROACH THE RELEVANT FAR PLA
INTEREST AND SEE IF THERE'S
SOMETHING IN THE MIDDLE.
COULD WE CONTRACTOR AGREE WITH
SOME OF THEM TO COLLABORATE TO
PROVIDE SOME OF THE SERVICES AT
SOME TIME WITH SOME SORT OF SKIN
IN THE GAME ON BOTH SIDES AND
BENEFIT ON BOTH SIDES.
IT WOULD BE A NOVEL WAY TO
APPROACH IT.
MAY BE THE NEXT PANEL CAN
DISCUSS THEIR OBSTACLES AND WHAT
THEY THINK ABOUT THAT AND IF
THEY HAVE SOME OTHER PARALLEL
SORTS OF IDEAS.
THE OTHER TRIGGER POINT IS THE
DECISION ABOUT WHO OR WHEN IT
GETS TO BE DECIDED SOME APPROACH
OR SOME MOLECULE IS WORTH THIS
INVESTMENT TO GO FORWARD INTO
HUMAN STUDIES.
THE DECISION MADE BY A PROGRAM
OR FEDERAL ENTITY.
OR PEOPLE LIKE THE GATES AND A
PARALLEL PRAC.
THERE'S BEEN A PROCESS AND THOSE
ARE OTHER PLAYERS OUT THERE THAT
MIGHT BE WILLING TO JOIN TO MAKE
THAT INVESTMENTS TO MOVE
FORWARD.
>> HAVING ONGOING CONVERSATIONS
WITH THE PROGRAM OFFICERS AND
THE CLINICAL TRIALS NETWORK WAS
HELPFUL BECAUSE THERE'S SO MANY
CONVERSATIONS AND ISSUES BEHIND
THE SCENES WE DON'T HAVE ACCESS
TO THE INFORMATION THAT'S VERY
HELPFUL.
I THINK IF THERE'S PROMISING
FINDING WE COULD THINK AHEAD OF
TIME IN TERMS OF HOW TO
ACCELERATE THE PROCESS THROUGH
EARLY CONVERSATION AND THERE'S
LEGAL ISSUES AROUND THE SEQUENCE
FOR 101074 OR OTHER BNABS OR
OTHER SYSTEMS TAKING A LONG TIME
TO GET A CLEAR CUT ANSWER.
STANDARDIZING THE PROCESS AND
REALLY TAKING ADVANTAGE OF WHAT
ALL RIGHT EXISTS IN OTHER RARE
DISEASE SPACES, ETCETERA WOULD
BE MORE TIME EFFICIENT FOR US.
WE'RE LEARNING THROUGH THE
PROCESS AND COMING UP WITH A
PROCESS TO DO THIS.
HAVING EARLY ACCESS TO FUND TO
ACCELERATE THE PROCESS AS
SUGGESTED WHERE IF THERE'S HOPE
FOR CLINICAL TRIALS INSTEAD OF
HAVING TO APPLY FOR A GRANT AND
IT WOULD BE HELPFUL TO MOVE
THINGS FORWARD EXPEDITIOUSLY.
>> I WANT TO CALL ON PEOPLE IN
THE AUDIENCE TO HELP.
WE NEED HELP IN THE ROLE OF THE
ACTG AND THE WHOLE PROCESS.
>> I WANT TO COMMEND THE PANEL
AND TOPIC BECAUSE IT'S
IMPORTANT.
I WANT IT SHARE SINCE THERE'S
ATTENTION ON THE COMMENTS AND
WE'RE DRAFTING PART OF A LARGER
GROUP DRAFTING THE AIDS
PRIORITIES AND THAT TOPIC WAS
HIGHLIGHTED TO BE SINGULARLY
PLACED ON THE PRIORITIES MOVING
FORWARD TRYING TO INCENTIVIZE
INSTITUTES TO EXPAND ONGOING
EFFORTS.
NIAID ALREADY HAS SOME EFFORTS
IN THE AREA AND CARL CAN PERHAPS
COMMENT BUT TO EXPAND BUT THE
PIPELINE IS ALREADY NOTED LAS
BEEN SUCCESSFUL IN IDENTIFYING
MULTIPLE POTENTIAL AVENUES.
AND THE NCI HAS DONE IT
EFFICIENTLY WITH SEVERAL
PROGRAMS TO SUPPORT THE
PRODUCTION AND REGULATORY
INFRASTRUCTURE AND SUPPORT FOR
FDA MASTER FILINGS.
I THINK WE NEED THAT AS WE GROW
THE MDC EFFORT GOING FORWARD.
MIRE FROM THE PRIORITY OR
INVESTIGATOR SIDE WE CAN THEN
INCENTIVE SIZE MORE INSTITUTES
TO FOLLOW THAT EXAMPLE.
THE OTHER IS INDUSTRY
PARTNERSHIPS.
I THINK WE NEED TO BE MORE
DIALOGUE TO MAKE IT MORE
INCENTIVE I'D INDUSTRY
INVESTMENT IN THE ACADEMIC
EFFORT BECAUSE THEY HAVE
DIFFERENT PRESSURES AS NOTED.
THEY HAVE DIFFERENT PRIORITIES
REGARDING INTELLECTUAL PROPERTY
AND PROPERTY DEVELOPMENT
AND SOMETIMES WE THINK WOULDN'T
IT BE GREAT TO HAVE A AND B BUT
THERE'S NO WAY THEIR LAWYERS
WOULD AGREE AND COME UP WITH A
MODEL AND DIALOGUE TO WHAT WOULD
BE A MIDDLE GROUND.
WE AS ACADEMICS DON'T HAVE THE
PULL FOR THE FOLKS THAT MAKE THE
DECISIONS.
WE TALK TO INVESTIGATORS AND
THEY SAY IT'S A WONDERFUL IDEA
AND THEN WE HIT A BRICK WALL.
>> THE GATES FOUNDATION IS GOOD
AT ENCOURAGING THE INDUSTRY TO
DO THAT.
JOE.
>> THE PROCESS AND GETTING
SOMETHING UNIQUE FOR HIV OR
SPECIFIC THERE'S DISCUSSION
ABOUT SPECIFICITY.
THE PROBLEM WITH REPURPOSED
MOLECULES IS THE LACK OF
SPECIFICITY.
THE ACTG WON'T REALLY HELP
GETTING A MOLECULE FROM
SOMEONE'S LAB TO TOXICITY
INVOLVED AND THAT SORT OF THING.
MY REACTION IS IT'S SUCH AN
ENTREPRENEURIAL PROCESS.
THIS RISK THING.
PEOPLE ARE WILLING TO TAKE A
RISKING -- PEOPLE WITH MONEY,
MEANING, ARE WILLING TO TAKE A
RISK IF THEY CAN SEE A REWARD.
THE ALTRUISTIC REWARD IS NOT THE
SAME AS MON -- MONETARY REWARD.
MAYBE BNAB OR SIMPLER LIKE THIS
CD4 MEMETIC 3408 CULE WHICH
MAYBE TURNS PEOPLE'S OWN
ANTIBODY TO BNABS.
THE PRESENTATION WAS TREMENDOUS
FROM THE COLLABORATORY.
HOW CAN WE GET THOSE TO MOVE
FASTER?
WHAT THE ACTG DOES WELL IS WE'RE
GOOD AT THE COMPONENT PARTS AND
THE DATA PART.
WE HAVE OUTSTANDING DATA PART
AND EXCELLENT STATISTICAL
SUPPORT.
WE HAVE ENGAGED SITES AND WHERE
WE FALL DOWN IS WE DON'T REALLY
AND WE DON'T REALLY WOULD CAN'T
DO COMPLICATED TRIALS IN HUMANS
LIKE WE DO IN ANIMALS AND MICE.
WHAT'S THE PRIMARY GOAL AND WE
LOOK AT THIS AND THAT TERTIARY
OBJECTIVE AND THE WHOLE PROCESS
GETS CONFLATED AND WE DO THIS
ALL THE TIME.
TO SAY WHAT ASSAY YOU'LL DO ON
WHAT SPECIMEN AND HAVE THE
LABORATORY CENTER FIGURE THAT
OUT AND DEVELOP MTAs HOW YOU'LL
TRANSFER TO THE LAB IS ALL NUTS.
INSTEAD WE SHOULD DECIDE WHAT
THE PRIMARY OBJECTIVE IS.
WE CAN'T DEVELOP PROTOCOLS WE
COMMITTEE.
WE HAVE TO HAVE SOME CONSENSUS
FOR PROPOSALS.
WE HAVE TO HAVE PEER REVIEW
BECAUSE THAT'S WHAT THEY ARE
INSIST ON IS IMPORTANT AND HAVE
COMMUNITY INPUT.
ONCE THE IDEA IS FORMULATED AND
THERE'S AGREEMENT I MIGHT DO A
CONTROL TRIAL.
SO WE'RE NOT GOING TO GET 100%
AGREEMENT AND PMARINA HAS BEEN
FANTASTIC WITH THIS AND THEY
MOVED THE PROTOCOLS FASTER SO
WE'RE ALREADY GOING TO DO THAT.
THE FINAL THING IS WE PROBABLY
NEED TO BE MORE SPECIALIZED.
WE NEED RESOURCES AND COST THEM
APPROPRIATELY AND WE
DISINCENTIVIZE SITES.
AND WE'LL GIVE A STATIN OR
PLACEBO AND SEE IF IT WORKS.
THERE'S SO MUCH WORK CONSENTING
A PERSON AND THAT'S TIME THAT
HAS TO BE COMBPENSATED FOR AND
THE FINAL THING AND THE FINAL
THING IS WHAT KATIE SAID THE
COMPLEXITY AND ABILITY FOR
PEOPLE TO DO WHAT WE ASK THEM TO
DO IS INCREDIBLY HARD.
I HAD NOED A YA BUT WE TALKED
ABOUT IT AND SHE LIKED IT AND
JOHN LEE DIDN'T LIKE IT.
WE DO THE ATI PROTOCOLS AND TAKE
PEOPLE PERFECTLY HEALTHY WE'VE
NEVER MET AND CONVINCE THEM
MAYBE YOU WANT TO DO AN ATI
TRIAL AND DECIDE UP FRONT.
WHAT IF WE DIDN'T DECIDE UP
FRONT.
WHAT IF WE MADE THE ATI
OPTIONAL?
PEOPLE W.H.O. JOIN A STUDY LEARN
SO MUCH BEING PART OF A STUDY.
WHAT SANDY SAID ABOUT THE STUDY
WAS SO INFORMATIVE.
THEY WEREN'T GOING TO HAVE AN
ATI AND WHEN IT BECAME CLEAR
MAYBE WE SHOULD I THINK YOU SAID
EVERY SINGLE PERSON AGREED TO
HAVE AN ATI.
THEY ALREADY CONTRIBUTED AND
KNOW SOMETHING'S LAND AND
THEY'RE WILLING.
I THINK WE NEED TO BE A LITTLE
BIT MORE FLEXIBLE ON HOW WE
DESIGN OUR STUDIES AND THOSE ARE
SOME OF MY POSITIVE THOUGHTS
THAT ARE HOPEFULLY SOLUTION
ORIENTED.
THEN WE HAVE TO GO THROUGH THE
PROCESS.
FOR THE RECORD I DO LIKE
CONTROLLED STUDIES.
I ALWAYS TALK ABOUT THIS AND
PEOPLE GET ANNOYED AND I DON'T
KNOW WHY.
I LOOK AT THE VACCINE WORLD AND
I'M JEALOUS AND ENVIOUS AND
MAYBE IT'S NOT THE WAY IT WORK,
THEY DISCOVER THE IDEA AND CROSS
THE HALL AND KNOCKS ON THE DOOR
AND TOM KENNY MAKE A PRODUCT AND
THE BOTH CALL LARRY CORY AND THE
VTM LEADERSHIP AND WITHIN MONTHS
THEY HAVE SOMETHING IN THE
FIELD.
WE DON'T DO ANY OF THAT.
AND WE COULD.
I DON'T KNOW WHY.
>> THEY DECIDED WE NEEDED T CELL
IMMUNITY AND THEY LAD AN OUTCOME
T CELL IMMUNITY AND COULD DO
STUDIES THAT TOOK SIX MONTHS OR
LESS THIS SHOWED YOU CREATE T
CELL IMMUNITY AND OFF YOU GO.
YOU CAN DO STUDIES IN KIN DE
DERREN -- KINDERGARTEN AND WE
DON'T KNOW WHAT WE WANT TO DO.
DO WE WANT TO LOWER IPDA?
WE DON'T KNOW YET.
IT MAKES IT HARDER TO CRYSTALIZE
STUFF AND SAY THIS IS HOW WE
SHOULD DO IT.
I'M JEALOUS OF THEM TOO FOR LOTS
OF REASONS.
IF WE HAD A CONSENSUS FOR LRAs
IN HUMANS, DO WE NEED AN INT
INTERRUPTION.
>> WE KNOW WITH WHAT WE'RE
AFTER BUT DON'T KNOW THE
APPROACH AND IT SHOULD BE BASED
ON THE INTERESTING OPTION AND
WHICH ARE THE SPECIFIC
APPROACHES THAT SHOULD BE NOT
NECESSARILY TWO GROUPS BUT THE
APPROACH.
AND WORK WITH THE ACTG OR NOT TO
BRING IT TO LIFE.
BUT TO ME IT SHOULD BE APPROACH
FOCUSSED.
>> I'M A CARD CARRYING VACCINER
AN I BELIEVE IN EARLY STAGE
CANDIDATE FOR PHASE I STUDIES
BUT WE'RE LOOKING AT IMPACT ON
HUMAN LEATH AND THROUGH GET IT
THROUGH THE LARGER SCALE TRIALS
TO LICENSURE IS EXCEEDINGLY
COMPLEX ESPECIALLY IN THE
PREVENTION VACCINE SPACE.
YOU CANNOT DO THAT WITHOUT
INDUSTRY AND LARGE SCALE
INVESTMENT AND THAT'S BEEN
DIFFICULT TO GARNER FOR A
VARIETY OF REASONS.
THAT'S WHERE THE THERAPEUTIC
CURE FIELD HAS BETTER
OPPORTUNITY TO PARTNER WITH
INDUSTRY OR BETTER CHANCES OF
GETTING THOSE PARTNERSHIPS WHICH
IS PROBABLY AN ABOUT AS WELL TO
THE NEXT PANEL BECAUSE THERE'S A
MARKET OF DEFINED PEOPLE WHO
WOULD IMMEDIATELY EMBRACE AND
MANY PEOPLE IN THE ROOM SAID SO
THEMSELVES WE CAN LEVERAGE THAT
IN THE THERAPEUTIC SPACE TO WORK
TOWARDS THOSE INDUSTRY PARTNERS
FOR THE LARGER SCALE TRIALS.
>> THERE'S THE RELATIONSHIP OF
THE PARTICIPANTS IN THE STAFF
AND TAUGHT US COVID HOW
IMPORTANT THAT IS AT THE TOWN
HALL LAST NIGHT THERE WAS A
ROBUST DISCUSSION ABOUT TUSKEGEE
AND IT'S INTERESTING THERE'S
BEEN GROUP THREE ARE FROM
DESCENDANT OF THE TUSKEGEE
SURVIVE PUT TOGETHER AN AMAZING
PRESENTATION WHAT THE STUDY AND
CONS
CONSENT PROCESS AND HOW IT CAN
NEVER BE DONE AGAIN AND I'VE
BEEN DOING THIS WORK FOR A LONG
TIME IN TERMS OF THE SOCIAL
SCIENCES OF THE RESEARCH NEEDED
TO BRING PEOPLE UP TO SPEED TO
DESIGN TO HELP DESIGN TRIALS.
THERE'S LEGALESE NO ONE CAN USER
LIKE THE MICROSOFT END USER
ABREEMENT
IT AGREEMENT
AGREEMENT.
WE NEED TO REVISE THIS AND
THREES WE NEED TO RETHINK HOW WE
DO THIS AND WE HAVE SOME SOCIAL
BEHAVIOR RESEARCH HAPPENS IN A
HAPHAZARD MANNER.
AND I WOULD ARGUE WHAT WE NEED
IS AN EXTERNAL CORE WHERE WE
LEVERAGE ALL THE EXPERIENCE AND
ACROSS THE MULTIPLE
COLLABORATORIES OR NETWORKS.
THE MOST EFFICIENT WAY IS TO
HAVE AN EXTERNAL CORE TO TAP
INTO AS WE PROGRESS IN DESIGNING
THE TRIALS AND TURNING THIS FROM
BENCH TO BODIES.
>> I'LL SPEAK MORE ABOUT PRODUCT
ACCESS.
THAT'S NUMBER ONE HURDLE AND THE
VACCINE ENVY THEME.
WARE IN A BETTER POSITION
BECAUSE OUR CLINICAL TRIAL
TRIALS DON'T HAVE TO BE
GINORMOUS AND THAT'S EARN
AMAZING POSITION FOR US AS
CLINICAL TRIALISTS TO ESTABLISH
THE TRIALS WHICH ARE FAR HARDER
IN THE VACCINE WORLD.
LET'S REMEMBER THAT BEFORE WE
GET JEALOUS OF THE VACCINE
FIELD.
PARTNERSHIPS WE'RE BEING MAYBE A
LITTLE BIT NAIVE ABOUT THE
INDUSTRY PARTNERSHIP.
ACCESSING THROUGH AN INDUSTRY
PARTNERSHIP IS INCREDIBLY HARD.
MOST THE PRODUCTS WE WANT HAVE
NOT BEEN DEVELOPED FOR HIV AND
THEREFORE THOSE INDUSTRIES ARE
NOT REALLY INTERESTED IN FIRST
OF ALL HAVING ACCESS LET ALONE
FUNDING OF OTHER PRODUCTS.
AND I'VE HAD EXPERIENCES WITH
ABBVIE AND BOTH HAVE BEEN
DIFFICULT PROCESSES BECAUSE
NEITHER COMPANY CARES TOO MUCH
ABOUT HIV BUT HAVE A LICENSED
PRODUCT AND EASIEST THING HAS
BEEN PURCHASE THE ENVOLMAB.
AND EVEN IF LICENSED YOU CAN
ACCESS IT BUT NEED MONEY WITHOUT
HAVING TO WORK WITH AN INDUSTRY
PARTNER WOULD BE ADVANTAGEOUS
BECAUSE THE INDUSTRY PARTNER IN
THE END WON'T HAVE AN ACTIVE
ROLE BECAUSE THEY'RE NOT TRYING
TO DEVELOP A PRODUCT FOR HIV.
THE SECOND PART IS ANTIBODIES
AND I THINK CONTRACTS FOR
MANUFACTURERS COULD BE A GOOD
WAY TO GO.
AND THEY MADE ANTIBODIES UNDER
CONTRACT.
AND SOME HAVE BEEN ABLE TO
DEVELOP ANTIBODIES VERY FAST AND
CAN WE DO MORE WITH THE VRC.
>> JULIAN YOU HAVE THE LAST WORD
SO MAKE IT GOOD.
>> GREAT COMMENT.
I WOULD SHARE AN OBSERVATION AND
MAYBE A SUGGESTION.
BEFORE HIV ARPA-H WE TALKED
ABOUT GETTING MORE PROSECUTES
GMP MANUFACTURER AVAILABLE FOR
CLINICAL TESTING.
THIS A COMBHON KWHLG AND OUR
COLLEAGUES ARE TAPPING INTO A
NUMBER OF WAYS THERE'S A
GENERATION AND AS EITHER FIELD
BRINGS PRODUCTS INTO IND
ENABLING STUDIES AND GMP, THAT
COMMON SITUATIONAL AWARENESS
EARLY I THINK COULD BE VERY
HELPFUL BECAUSE SUBSEQUENT
ACCESS TO PRODUCTS AND
COORDINATED PLANNING FOR ACCESS
IN THE CURE AND VACCINE SPACES
AS PRODUCTS MOVE TO MANUFACTURE
CAN BE HELPFUL.
THERE ARE ALREADY SOME COMBINED
CURE VACCINE CURE PRE
PRESENTATION GRANTS ALL RIGHT.
THAT COLLABORATIVE SPIRIT
BETWEEN BOTH FIELDS COULD BE
HELPFUL DOWN THE ROAD.
HOPEFULLY THAT WAS HELPFUL.
>> THANK YOU.
SO WE'LL GO AHEAD AND END NOW.
WE'VE BEEN BASHING INDUSTRY THE
LAST HOUR FOR NOT DOING THEIR
PART.
SO THEY'LL HAVE A CHANCE NOW TO
GET BACK AT US.
I THINK THEY HAVE THE NEXT
PANEL.
SANDY, ANY FINAL WORDS?
OKAY.
THANKS A LOT, EVERYONE.
>> DEPRIVING THE ROLES OF
RESPONSIBILITIES AND
UNDERSTANDING PRIORITIES.
THIS IS WHAT I TALKED ABOUT BUT
I'LL LEAVE IT TO THE PANELISTS
TO TELL US AND WE HAVE SOME
QUESTIONS UP HERE TO GUIDE YOU
AND WE HAVE PEOPLE JOINING US
ONLINE IF YOU CAN SPOTLIGHT
THEM.
THANK YOU.
>> THANK YOU, UUDAJ AND THE
OPPORTUNITY TO SPEAK ABOUT THE
COLLABORATORIES AND THE CURRENT
PRIZE AS A WHOLE.
I'M RICK DUNHAM WITH VIIV AND
LEAD THE IMMUNIOLOGY PROGRAM
AND STARTED AS A POSTDOC IN THE
ORIGINAL DARE AND COMING THROUGH
THE CARE COLLABORATORY AS AN
INDUSTRY PARTNER EMBEDDED IN THE
LABS AT UNC AND THEN NOW WORKING
AS PART OF THE EXECUTIVE
COMMITTEE ON PAVE.
I HAVE PERHAPS A UNIQUE
PERSPECTIVE SITTING IN ALL THE
POSSIBLE ROLES EXCEPT FOR AT THE
NIH I GUESS AT THIS POINT.
THE ROLE MUCH INDUSTRY IN THE
DELANEY COLLABORATORY WAS
ENVISIONED IN THE ORIGINAL
SCIENCE PAPER I BELIEVE 2009
WHERE THIS ROLE -- THIS
THREE-WAY COLLABORATION BETWEEN
INDUSTRY, GOVERNMENT AND
ACADEMIA WAS ENVISIONED WHERE
EACH WAS BRINGING THEIR
EXPERTISE TO THE TABLE AND EACH
GAINING FROM THE WORK TOGETHER
TO BETTER THE SCIENCE OF HIV
YOU'RE AND BRINGING MEDICINES
FORWARD.
AND THIS IS REALLY I THINK BEEN
REASONABLY WELL EXECUTED DESPITE
THE OBVIOUS SHORT COMINGS THAT
ARE ALWAYS GOING TO BE PRESENT
IN THIS TYPE OF PORK --
PORCUPINE SETTING AND THERE'S
COLLABORATORIES OVER YEARS IN
TARGET SCREENS AND VALIDATION
EXERCISES AND REPURPOSED DRUGS,
ETCETERA.
I THINK IT'S BEEN PRETTY
SUCCESSFUL.
I THINK STEVE YOU UNDERESTIMATE
THE INVESTMENT IN THE
COLLABORATORY SPACE.
IT'S IMPORTANT TO RECOGNIZE
THAT.
THE INVESTMENT IT'S REQUIRED TO
BRING THESE INTO THE SPACE.
JENNIFER IS THE CO CHAIR SO
INTRODUCING YOURSELF AND
EXAMPLES OF HOW THE
COLLABORATORIES HAVE WORKED AND
COME BACK TO TRY TO BRAIN STORM
ON THE BARRIERS AND HOW TO COME
ACROSS THE BARRIERS.
JENNIFER.
>> THANKS, RICK.
CAN YOU HEAR ME?
>> YES.
>> I'M JEN GORDON CHIEF OFFICER
AT EXCISION THERAPEUTIC FOUNDED
AT TEM -- TEMPLE AND SPENT MY
CAREER IN ACADEMIA.
I CAN SPEAK TO BOTH SIDES OF THE
FENCE SO TO SPEAK.
I THINK WE HEARD A LOT EXAMPLES
IN THE EARLY STAGES OF HOW
INDUSTRY AND ACADEMIC
PARTNERSHIPS ARE WORKING I THINK
THE CHALLENGE AND I HOPE WE'LL
TALK ABOUT THAT TODAY IS AND
HAVE PLATFORMS LIKE NDC AND
INDUSTRY IS WORKING TOGETHER AND
WE OFTEN HAVE DIFFERENT GOALS
AND VISIONS AND THERE'S A LACK
OF RESOURCES ESPECIALLY IN THE
VALLEY OF DEATH.
THE CHALLENGES ARE VERY
DIFFERENT FOR BIG PHARMA VERSUS
THE SMALL BIO TECH.
I HOPE WE CAN FOCUS ON THAT
DURING OUR DISCUSSION TODAY AS
WELL.
>> I'LL CALL ON CARL NEXT.
>> CAN YOU HEAR ME?
>> YES.
>> I'M CARL BALIBAR AND BEEN
ACROSS NOVARTIS AND MERCK.
RECENTLY WORKING IN THE HIV
CURES SPACE.
I REPRESENT A BROADER TEAM IN
OUR DISCOVERY GROUP THAT IS
COLLABORATING WITH THE NBC AN
CARE, ERASE, GRID AND I THINK WE
HAVE A LOT OF EXCITING
CONTRIBUT
CONTRIBUTIONS AND INTERACTIONS
AROUND TECHNOLOGY DEVELOPMENT
AND VALIDATION.
WE HAVE DEVELOPED ULTRA
SENSITIVE ASSAYS SUCH AS P24,
SAMOA AND APPLIED THOSE THROUGH
OUR RESEARCH.
WE'VE WORKED ON THE AT HOME
BLOOD COLLECTIVE DEVICE WHICH
CAN BE USEFUL IN ENABLING
RESEARCH WHERE PEOPLE DON'T HAVE
TO GO TO THE CLINIC REGULARLY
AND STE IF THEY'RE CURED.
ARE AND IT'S TESTED HYPOTHESES
AND CONTRIBUTE TO THE FIELD AT
LARGE.
>> CAN YOU HEAR ME?
>> PERFECT.
I'M ELENA VENDRAME AT GILEAD AND
I'VE BEEN THERE ABOUT FIVE YEARS
AND MOSTLY WORKING ON HIV CURE
CLINICAL TRIALS.
I GUESS TO HIGHLIGHT A LITTLE
BIT WHAT OUR COLLABORATION HAS
BEEN WOVE HAD SEVERAL OVER THE
YEARS AND HAVE MANY
COLLABORATIONS OUTSIDE OF THE
NETWORKS THAT EITHER OUTGOING OR
CLEATED OVER TIME.
THE MAIN CONTRIBUTE HAS BEEN
SCIENTIFIC ADVICE AS WELL
PROVIDING DRUG PRODUCT FOR
DIFFERENT STUDIES ON THE NPH
SIDE FOR MODELS OR IMP AGONISTS
FOR DISH STUDIES.
>> I'M AT IMMUNITY BIO WHICH HAS
CHALLENGES AS DIFFERENCES WITH
BIO TECH AND BIG PHARMA WITH
RESPECT TO PARTICIPATING IN
ACADEMIC RESEARCH, ETCETERA.
I WOULD SAY I WOULDN'T BE HERE
IF IT WASN'T FOR OUR ABILITY TO
HAVE WORKED IN THE PAST WITH OUR
ACADEMIC COLLEAGUES AND THE NDC
BECAUSE HAVE BEEN VERY
SUCCESSFUL AT BEING ABLE TO GET
THE PRODUCT TO THE MDCs FOR
PRECLINICAL MODELS AND IN THE
CLINIC FOR HIV STUDIES.
IT'S A TESTAMENT TO THE
DILIGENCE OF OUR PARTNERS.
IMMUNITY BIO DOESN'T HAVE AN
INFECTIOUS DISEASE LABORATORY SO
EVERYTHING WE DO IS BY NATURE IS
A COLLABORATION.
IT HAS IT'S OWN CHALLENGES.
IF WE CAN MOVE OUR SUPER AGONIST
CLINICALLY AND PRE CLINICALLY IN
THE HIV SPACE AND VACCINE SPACE
AS AN ADJUVANT, FOR EXAMPLE.
I'LL STOP THERE AND THEN I THINK
WE'LL TALK ABOUT OTHER ISSUES AS
WE MOVE FORWARD.
>> I'M ONE OF THE FOUNDERS OF
ACCELAVIR.
WE'RE KIND OF DIFFERENT.
WE'RE A SMALL COMPANY AND
MORPHED INTO RAY CRO FOCUSSED ON
MOLECULAR ASSAY DEVELOPMENT
GENOMICS AN ASSAY DEVELOPMENT
BROADLY ACROSS GENE THERAPY AND
HAVE BEEN FOCUSSED ON HIV
RESEARCH AND YOU'RE FOR A WHILE.
MY BACKGROUND AS A STUDENT 14
YEARS AGO IN BOB'S LAB AND THE
WORK HAS BEEN FOCUSSED ON HIV.
I THINK OUR ROLE HAS BEEN AS A
RESEARCH FACILITATOR AND PARTNER
THOSE THAT DON'T HAVE IPDA OR
THE VIRAL SEQUENCING APPROACHES
GROUPS ARE APPLYING NOW.
WE HAVE INTERVENTIONAL AND
OBSERVATIONAL CLINICAL STUDIES.
I FEEL LIKE WE'RE BECOMING A
WEALTH OF KNOWLEDGE HOW TO
IMPLEMENT THESE ASSAYS AT SCALE
YOU NEED FOR A CLINICAL STUDY
AND HOW TO INTERPRET DATA OR
WHAT TIME POINTS AND BLOOD
VOLUME REQUIREMENTS YOU NEED TO
CONSIDER WHEN YOU SCOPE AN
ASSAY.
I THINK ONE THERE'S AREAS WHERE
WE SEE OPPORTUNITY FOR THE
DELANEY COLLABORATORIES TO WORK
MORE EFFICIENTLY.
THERE'S RESOURCE GAPS LABS
STRUGGLE WITH WELL CHARACTERIZED
MATERIALS OR ACCESS TO SAMPLES
OR ANIMAL MODELS I THINK WE
COULD HELP FACILITATE AND
CERTAINLY WE'VE SEEN EFFORTS
ACROSS COLLABORATORIES THAT ARE
DUPLICATIVE.
TO A DISCUSSION IN THE PREVIOUS
PANEL IF WE CAN HELP FACILITATE
OPPORTUNITIES FOR DIVERSE GROUPS
AS AN ASSAY PARTNER TO HELP AC
SEGREGATE TOWARDS CLINICAL TRIAL
I THINK THAT WOULD BE AN
EXCITING PLACE FOR US TO BE MORE
IMPACTFUL.
>> SO VII V IS WORKING ON A
COMPREHENSIVE PORTFOLIO TO
PROVIDE LONG LIVED IMMUNITY TO
THE VIRUS TO ENABLE ART-FREE VIR
OWE LOGIC -- VIROLOGIC AND
THERE'S GOOD WORK TO DO
TOGETHER.
WE HAVE SOME GOOD EXAMPLES OF
DOING THAT.
I'LL HIGHLIGHT WHAT SEEMS
MUNDANE TO EVERYBODY BUT THE
PROVISION OF ANTIRETROVIRAL
DRUGS FOR MONKEY STUDIES IS NOT
TRIVIAL TO PROVIDE JUST THE
INFRASTRUCTURE FOR ALL THESE
STUDIES AND HIGHLIGHT THE WORK
WE DID IN COLLABORATION WITH UNC
AND MEMORY TO BRING FORWARD TO
DO THE TARGET VALIDATION.
AND HAVE OBJECTIVES OF PHARMA
AND ACADEMIA THAT CAME TOGETHER
IN A UNIQUE WAY.
TO MAKE REAL PROGRESS IN NOVEL
LATENCY REVERSING AGENT.
THAT WAS UNIQUE.
WE MADE A LOT OF PROGRESS THERE
AND THOSE ALSO HIGHLIGHT THE
BARRIERS FOR OTHER PAR GETS AN
MODALITIES TO LINE THE TIMING
HAS TO ALIGN IN PARTICULAR IT'S
VERY DIFFICULT TO ALIGN THE
TIMING OF AN INDUSTRY WITH THE
TIMING OF COLLABORATORY GRANTS
WRITTEN FOR NEXT FIVE YEAR
PERIOD, FOR INSTANCE.
AND THE INCENTIVES HAVE TO WORK
AT THE RIGHT TIME AND THAT DRUG
DISCOVERY PROGRAM WITH RESPECT
TO THE COLLABORATORY.
ARE THERE KEY BARRIERS THAT
PREVENT THEM OR THEIR GROUPS OR
OTHER GROUPS FROM GOING DEEPER
INTO COLLABORATIONS HERE.
DOES ANYONE WANT TO TAKE A FIRST
STEP THERE.
>> AND THERE'S A STIMULATOR AND
EVERYONE KNOWS IL-15 ALONE WILL
CURE HIV.
SO HOW DO WE PICK AND CHOOSE
BENEFITS TO BE THE BEST.
IT'S NOT EASY.
I'M CHARGED EVERY DAY BY OUR
CEO -- HE WANTS TO SEE THE NEXT
TRIAL THAT HAS A COMBINATION AND
I NEED IT NAME IT TOMORROW AND I
CAN'T BECAUSE THE COMBINATIONS
WE WOULD LIKE TO DO ARE STILL
BEING INVESTIGATED IN AND OF
THEMSELVES TO AALLOW THEM TO GET
TO THE STAGE WHERE IT MAKES
SENSE TO COMBINE THEM WITH OUR
SUPER AGONIST AND CREATES
PROBLEMS WHEN A TRIAL NEEDS
MULTI-FACTORIAL COMBINATIONS OF
DIFFERENT AGENT MANY OF WHICH
ARE OWNED BY DIFFERENT ENTITIES
THE INTELLECTUAL PROPERTY ISSUES
COME TO THE FRONT BEFORE IT
COMES TO THE FRONT.
AND WHO ACCESS OF WHO IS COMING
TO THE TRIAL AND THEY'RE IN THE
SIMPLE QUESTIONS AND IN SOME
TRIALS THE COMBINATIONS ARE NOT
FOR EXAMPLE TRIAL WITH ACTG AND
USING ANTIBODIES LICENSED BY
GILEAD PLUS OR MOLECULE.
THERE NEEDED TO BE AN AGREEMENT
TO DO BOTH STUDIES.
AND IF YOU ADD THREE OR FOUR
OTHER MOLECULES OR ENTITIES INTO
THAT MIX AND I'D LOVE A SOLUTION
COMING TO THE TABLE FOR
INTELLECTUAL PROPERTY CONCERNS
THAT MAKES IT DIFFICULT TO AGREE
HOW TO MOVE FORWARD BECAUSE IT'S
NOT ALWAYS THAT CLEAR.
>> EACH ENTITY HAS TO BE PUT
TOGETHER AND THE DEVELOPMENT
PARADIGMS REQUIRE A LOT OF
INVESTMENT SO UNLESS YOU HAVE
LINE OF SIGHT IT'S HARD TO MAKE
THE INVESTMENTS TO MULTIPLE
TARGETS WITH THE THOUGHT LATER
ON THEY CAN ALL BE COMBINED.
IS THERE STILL A PRODUCT WITH
REMAINING ONES IF THERE'S A
SAFETY SIGNAL THAT COMES UP WHEN
YOU START COMBINING THINGS
TOGETHER THAT CAN PREVENT
PROGRESSION AND CLINICAL
DEVELOPMENT.
IT'S UNLIKELY THE OCCUR'S GOING
TO COME FROM A SINGLE AGENT AND
IT REQUIRES A LOT OF INVESTMENT.
I THINK THAT'S WHERE DIFFERENT
COMPANIES COMBINE BUT AS JUST
POINTED OUT THOSE COMBINATIONS
OR PRIOR AGREEMENTS CAN BE
DIFFICULT TO PUT TOGETHER.
WHEREIN A.
IT WAN BE HARD TO TAKE AN ASSET
FROM ONE THERAPY AREA TO ANOTHER
AND THERE'S BEEN STUDIES WITH PD
1 AND MERCK HAS A MOLE MOL KWUL
AND PEOPLE WANT TO RE --
MOLECULE AND PEOPLE WANT TO
REPURPOSE IT FOR HIV AND IT'S
OWNED BY THE ONCOLOGY PART OF
MERCK.
THEY HAVE ULTIMATE RIGHTS TO
WHETHER IT CAN BE USED IN
DIFFERENT TRIALS AND PURPOSES.
IT'S NOT AS IS SIMPLE AS SAYING
SOMEBODY OWNS THE ASSETS.
IT'S MORE COMPLICATED AND THAT
COULD BE A BARRIER AS WELL.
AND WE TRY TO ENABLE AS BEST WE
CAN WITH PD 1 WHAT WE'VE DONE IN
COLLABORATION WITH MDC IS TAKING
TOOLS FROM EARLIER STAGES OF THE
PROGRAM AND ARE ABLE TO DO BASIC
RESEARCH IN ANIMAL MODELS AND WE
PUBLISHED ON THOSE RESULTS
LOOKING AT PD 1 AND IL-10 FOR
RESERVOIR CONTROL AFTER
INTERRUPTION.
THAT'S WHERE WE TRY TO
CONTRIBUTE EVEN WHEN WE MIGHT BE
ABLE TO PROVIDE A CLINICAL
ASSET.
>> THERE'S DEVELOPING THE
COMPONENTS OF COMBINATIONS IN
ADDITION TO BEING TIME CONSUMING
IT'S NOT VERY SEXY.
THAT WON'T BE INCLUDED IN THE
GRANT PROPOSAL TO TAKE THE
SINGLE AGENT THROUGH ITS DOSE
FINDING TOXICOLOGY STUDIES.
AND THAT FALLS SOLELY IN THE
PHARMA DOMAIN TO BRING INTO THE
PROOF OF CONCEPT EFFICACY BASED
STUDIES.
THAT'S A BARRIER TO GET TO THE
EFFICACY STUDIES.
>> TO BUILD ON WHAT WAS SAID SO
FAR I COMPLEEPTLY AGREE ON THE
CHALLENGE -- COMPLETELY AGREE ON
PUTTING TOGETHER MULTI-PARTY
AGREEMENT AND HOW DO WE
PRIORITIZE FOR REQUESTS FOR THE
SAME DRUG FOR CLINICAL STUDY AND
WOULD LIKE TO PROVIDE A DRUG TO
EVERYONE WHO ASKS FOR IT BUT
HAVE TO BE MINDFUL OF WHAT WE
HAVE COMMITTED TO AND HAVE TO
PRIORITIZE THE BIGGEST DATA GAP
OR UNMET NEEDS AND FACED WITH
CHALLENGES.
>> RELATED TO THAT WE HEARD HOW
TO ENCOURAGE INDUSTRY IT TAKE
MORE RISK BUT MAY BE IT'S REALLY
THE OPPOSITE.
HOW TO HELP INDUSTRY DERISK AND
PROVIDE SUPPORT FOR THESE TYPES
OF ACTIVITIES.
AND WHAT KIND OF ROLE COULD NIH
PLAY IN PROVIDING THAT.
WE HEARD ABOUT THE CHALLENGES
WITH CMC.
I THINK THIS WOULD FIT IN THE
SAME CATEGORY.
AND PROVIDE FOR THE BIG GAP IN
BETWEEN.
>> AND MAYBE WE LOOK AT KILLING
EFFICACY STUDIES AND SOMETHING
AT LEAST WAS NEW TO ME AS
SOMEONE TRANSITIONING FROM
ACADEMIC SIDES TO MORE INDUSTRY
ORIENTED SIDES.
THAT'S A LESSON THE FIELD COULD
MAYBE TAKE SETTING A MORE
STRUCTURED MILESTONE DRIVEN
MECHANISM FOR ESSENTIALLY
KILLING IDEAS THAT ARE EXCITING
IN PAPERS BUT MAYBE DON'T HAVE
THE CAPACITY TO PROGRESS TO
CLINICAL STUDIES.
I'VE HEARD A LOT OF DISCUSSION
TODAY ABOUT WHEN WE NEED AND
HAVE CANDIDATES THAT PROGRESS
MIGHT BE MORE EFFICIENT.
AND WOULD MIRROR THE DE RISKING
JEN AND OTHERS COMMENTED ON THE
PRECLINICAL THINGS ADVANCE TO
PHASE 1 STUDIES.
>> IN THE PAST SOME APPLICATIONS
HAD A JOINT IP AGREEMENT ACROSS
INDUSTRY PARTNERS.
I DON'T KNOW HOW MANY
COLLABORATORIES NOW HAVE SUCH
AGREEMENTS OR HAVE DONE THOSE
THINGS.
IS THAT SOMETHING THAT CHANGED
AND THINGS HAVE MOVED.
IS THAT SOMETHING THAT'S STILL
CONCEIVABLY POSSIBLE?
WOULD IT BE POSSIBLE TO SET UP
SUCH A JOINT AGREEMENT FOR A
COLLABORATORY OR TROOPS EVEN OH,
MY GOD ACROSS THE ENTIRE
COLLABORATORY PROGRAM.
I'M JUST REMEMBERING THE WORK
THAT THE GROUPS DID FOR THE DRUG
REQUEST AND NOT SURE HOW MUCH
THAT GOT USED THOUGH IT TOOK
YEARS TO DEVELOP.
IS THERE ANOTHER WAY TO THINK
ABOUT WAYS TO THINK ABOUT THE
HURDLES OR KEEP DOING OUR BEST
AS WE HAVE BEEN?
>> ANYBODY WANT TO JUMP IN AND
COMMENT ON DAVE'S QUESTION?
>> IT'S EASY TO DO THAT IN THE
BEGINNING OF AN MDC IF YOU
IDENTIFY THE COMPOUNDS YOU WANT
TO USE IN YOUR TRIAL.
IT'S EASY.
YOU PROBABLY HAVE WRITTEN YOUR
GRANT APPLICATION WITH A
PARTICULAR COMPOUND IN MIND AND
GOTTEN A LETTER OF SUPPORT TO DO
THAT IN THE GRANT APPLICATION.
THAT'S THE EASY PART.
THE FIRST AGREEMENT THAT HAPPENS
IS A MULTI-PARTY NON-DISCLOSURE
AGREEMENT AND MAYBE AND MAYBE TO
THINK ABOUT THAT RATHER THAN
JUST RELYING ON AN NDA TO GET
THINGS STARTED.
IF YOU HAVE A SET IDEA OF WHAT
COMPOUNDS YOU'RE TRYING TO USE
YOU KNOW WHERE YOUR GOING AND IF
YOU KNOW WHERE YOU'RE GOING THE
ROAD IS EASIER.
>> I'LL ADD IN PRINCIPLE IF
POSSIBLE EACH COMPANY AND EACH
INSTITUTION APPLIES A DIFFERENT
LENS TO ESTABLISHING THOSE
AGREEMENTS SPEAKING MORE FROM
THE COMPANY LOOKING OUT
PERSPECTIVE NOW AND SOME
INSTITUTIONS ARE VERY BROAD IN
TERMS OF THE DRUGS WE'RE
PROVIDING EVEN AS JUST AN
ANTIRETROVIRAL AS THE PART OF
THE BACKBONE AND PART OF THE
INVESTIGATIVE WORK FOR THE RIGHT
TO OWN INTELLECTUAL PROPERTY ON
THE DRUGS WE'RE TRYING TO
PROVIDE FOR THE STUDIES.
IT'S ACTUALLY VERY DIFFICULT
FROM OUR PERSPECTIVE AS ACQU
ACQUIRERS OF INTELLECTUAL
PROPERTY TO DO THE STUDIES.
>> THERE'S A LEDGER ON THE OTHER
SIDE THE APPLICATION IS TO GET
FEDERAL FUNDS AND THEY ARE MAKE
CERTAIN REQUIREMENTS TO GET THE
FEDERAL FUNDS.
AGAIN, IT'S A HIGH LEVEL
DISCUSSION BUT MAYBE SOMETHING
TO THINK ABOUT.
WE WANT TO TRY TO MOVE FORWARD
AND THINK OF A COLLABORATIVE
AGREEMENT FOR A COLLABORATORY.
>> IT MAY DEPEND ON THE STAGE OF
THE ASSET AND THE MORE SPECIFIC
AGREEMENT IS THE BETTER THE
CHANCE WHEN IT'S REALLY BROAD
IT'S HARD FOR AN INDUSTRY
PARTNER TO DECIDE ON RIGHTS IN
THE DISCOVERY SPACE YEARS BEFORE
IT EVER GOES TO THE CLINIC.
IF THERE'S AN ASSET SOMEONE
WANTS TO PARTNER WITH SOMETHING
ELSE THEN THOSE AGREEMENTS
BECOME MORE TANGIBLE.
IT'S A LITTLE EASIER TO
UNDERSTAND WHAT THE ASK IS UP
FRONT OF AND THERE'S LESS RISK I
THINK.
>> AND TO ADD TO THAT I THINK
ULTIMATELY AN AGREEMENT IS EASY
TO PUT IN PLACE IF THERE'S A
COMMON MISSION BETWEEN THE PA
PARTIES THAT ENTER THE AGREEMENT
AND EVALUATE THE PROJECT ON ITS
OWN AND WHAT QUESTION IS
ANSWERING IS SOMETIMES KEY TO BE
ABLE TO OVERCOME SOME OF THE IP
ISSUES AND GENERALLY SPEAKING
WE'RE ALL I THINK IN FAVOR OF
TRYING TO COLLABORATE MORE AND
FIND NEW WAYS OF OVERCOMING THE
HURDLES BUT SOMETIMES THE
SPECIFICS ARE NEEDED TO ENTER
INTO A SPECIFIC AGREEMENT.
>> I'M SIDNEY A Ph.D. STUDENT
WIN THE ERASE COLLABORATORY.
I RUN A MONKEY STUDIO AND HAD
THE PLEASURE OF WORKING WITH
INDUSTRY PARTNERS WHETHER
ANTIRETROVIRALS OR COMPOUNDS.
WE HEARD A LOT OF DISCUSSION
ABOUT IP RIGHTS.
AS WE MOVE CLOSER TO A THERAPY
FOR A CURE AS MY STUDY HAS SHOWN
WE NEEDED SEVERAL COMPOUNDS NORD
TO SEE REDUCTION IN THE
RESERVOIR FOR INTACT DNA.
HOW DOES INDUSTRY SEE
INTELLECTUAL PROPERTY RIGHTS
BEING SOLVED INTO AN ACTUAL
THERAPY IF WE EVER GET THERE AND
IF WE'RE STRUGGLING I HEARD A
LOT IT'S DIFFICULT BUT I DON'T
HEAR ANY ACTUAL SOLUTIONS.
AND SO COULD YOU BE MORE
SPECIFIC AND I REALIZE
INTELLECTUAL PROPERTY RIGHTS ARE
DIFFICULT BUT THERE'S A LOT OF
PEOPLE THAT DEPEND ON US.
AND SO SPECIFICS I THINK ARE
IMPORTANT.
SO --
>> IF THERE WAS A CURE TODAY
THAT HAD INTELLECTUAL PROPERTY
CONTRIBUTIONS FROM EACH OF US
HERE I EXPECT OUR RESPECTIVE
INSTITUTIONS WOULD BE ABLE TO
WORK THAT OUT.
AND SO I THINK I'LL START THERE
I DON'T THINK THAT'S THE HURDLE.
THE HURDLE IS WHERE THE
QUESTIONS THAT SWIRLED FROM THE
PREVIOUS DISCUSSION AND BEING
HIT HERE WHAT IS THE PATH?
SO THEN THE SOLUTIONS ARE
OBVIOUS ONES FOR THAT PATH TO
START THE DISCUSSION.
ANYONE ELSE WANT IT WEIGH IN?
>> I THINK IF THERE'S A SPECIFIC
COMBINATION AND EVIDENCE TO
SUPPORT IT AN AGREEMENT CAN BE
MADE.
MECHE AND GILL -- GILEAD ARE
BRINGING IT THROUGH AND WHEN
IT'S DIFFUSED AND THERE'S NOT
ENOUGH EVIDENCE TO SAY IT WILL
WORK OUTRIGHT IT'S HARD IT TAKE
THAT RISK.
SO IT'S ABOUT DE RISKING AND
PART OF THAT IS DOING THE
SCIENCE.
UNDERSTAND HADDING --
UNDERSTANDING THE FUNDAMENTAL
BIOLOGY AND TAKING EACH ASSET
AND SHOWING WHAT IT CAN DO ON
ITS OWN AND THE COMBINATION A
GREATER PROBABILITY OF SUCCESS.
>> I AGREE AND MY FOLLOW-UP
QUESTION IS NDAs TAKE A LONG
TIME IS THERE A WAY TO SHORTEN
THE TIME AS A HURDLE TO GETTING
TRIALS DONE AND FOR OTHERS IT
COULD BE AN ISSUE.
I THINK IF THERE WAS AN
INTERMEDIATE ENTITY BETWEEN THE
NDCs AND PHARMA COMPANIES AND I
THINK ACTG DOES THIS WELL TO
INTERACT WITH A PARTNER FOR
DRUGS AVAILABLE IS PART OF THE
COMPLEXITY.
IT MAY IN THE JUST BE
INTERACTING WITH YOUR UNIVERSITY
BUT THOSE IN THE COLLABORATORY
IT QUAN CAN SLOW IT DOWN.
>> THEY SIT THERE AND IT'S BAND
WITH FOR THE PARTIES IN THE NTA.
SOMETIMES MERCK COMES BACK A
COUPLE DAYS AND WE'RE THERE FOR
WEEKS WE HAVE OTHER PRIORITIES
AND THE PEOPLE DOING NTAs ARE
BUSY AND TAKES WEEKS.
THE MORE COMPLEXITY THE LONGER
IT TAKES.
>> THERE'S A QUESTION FOR THE
OTHER PANELISTS.
YOU GUYS ARE READING ALL THE
GREAT WORK THESE FOLKS ARE DOING
AND YET IT SEEMS THERE'S A HUGE
AMOUNT OF PRECLINICAL ACTIVITY
THAT WOULD HAPPEN WITHIN YOUR
COMPANY THAT WOULD SORT OF TAKE
AN EXCITING FINDING AND A PAPER
AND GET IT TO A DERISK POINT
WHERE YOU MIGHT INVEST IN A
CLINICAL STUDY.
BRIDGING THAT GAP WAS A FOCUS
LAST DISCUSSION AND MIGHT BE
USEFUL IF THE INDUSTRY FOLKS CAN
TALK A LITTLE BIT WHAT THE
PROCESS LOOKS LIKE WHEN YOU READ
A PAPER WITH AN EXCITING NEW
TREATMENT MODALITY AND HAVE
ASSETS WHAT ARE STEPS BETWEEN
THE PAPER AND INITIATING THE
CLINICAL STUDIED AND IF FOLKS IN
THE ROOM CAN UNDERSTAND THAT
BETTER MAY BE ABLE TO MEET YOU
AT A LOWER RISK POINT.
>> I CAN GIVE A GOOD EXAMPLE HOW
THAT HAPPENED INSIDE THE
COLLABORATORY THINKING ABOUT THE
RESPECT OF MEMETICS.
WE SAW A GREAT PAPER THE IP
PROTEINS INVOLVED IN IP
EXPRESSION AND ANTAGONIZE THE
SMALL MOLECULES YOU CAN DRIVES
THE VIRUS OUT OF LATENCY.
IT LED TO A SERIES OF WHAT WE
CALL TARGET VALIDATION
EXPERIMENT.
THAT'S VALIDATE THE TARGET AND
AT THE SAME TIME START MAKING
SMALL MOLECULE ANALOGS TO SEE IF
THAT'S THE BEST ONE AND CAN FIND
MORE AND THE PROCESS OF
IDENTIFYING THE MOLECULE TO TAKE
THROUGH IN VITRO EXPERIMENTS, IN
VIVO EXPERIMENTS IN THE MOUSE
WITH THE PRIMATE WITH ANN AT
EMORY THAT PROCESS PROBABLY TOOK
FIVE YEARS START TO FINISH WITH
THE IN VITRO SIDE ONE WILL A
TEAM OF THAT ENDED UP IN THE
FIVE TO 10 PEOPLE RANGE.
I DON'T KNOW HOW MUCH WAS
INVESTED JUST TO GET TO THE
MOLECULE AND THEN THE
COLLABORATORY TO DO THE ANIMAL
MODEL STUDIES.
THERE'S A SUBSTANTIAL AMOUNT OF
INVESTMENT THAT LHAPPENS AND TH
TYPICAL APPROACH IS TO WAIT TO
PHASE II AND WE DESCRIBED THE
PROCESS IMMEDIATELY AFTER THE
ANIMAL STUDY SHOWED IT WORK AND
LET THE COMMUNITY SEE THE TARGET
AND DEVELOPED THE TARGET BECAUSE
IT WAS DONE AS PART OF THE
COLLABORATORY.
THAT'S A PRETTY GOOD EXAMPLE HOW
THAT CAN HAPPEN IN THIS
COLLABORATIVE SETTING.
MAYBE OTHERS WOULD DRAW
ATTENTION TO OTHER EXAMPLES.
>> THERE'S TARGET VALIDATIONS
WITHIN OUR OWN ASSAY AND MODELS
IN HOUSE IS THE FIRST STEP.
PUBLICATIONS ARE GREAT BUT WE
NEED TO BE ABLE TO RECAPITULATE
AND FOLLOW-UP WITH OUR
PARAMETERS.
THAT'S A KEY FIRST STEP AND THAT
CAN TAKE A WHILE.
AND COULD BE A BETTER TOOL
MOLECULE TO RECAPITULATE THOSE
RESULTS.
>> I WANTED TO SHIFT GEARS A
LITTLE BIT.
I'M A PROGRAM OFFICER AT DADE.
I'M INVOLVED IN BEAT HIV AND
HOPE AND IN MY ROLE I HAVE THE
PRIVILEGE OF WORKING WITH ALL
OUR COMMUNITY REPRESENTATIVES
AND GET THEIR FEEDBACK ALL THE
TIME.
I'VE HEARD A LOT WHEN THEY'RE
GOING OUT IN THE PUBLIC TRYING
TO EDUCATE THE PUBLIC ABOUT HIV
CURE.
THEY HEAR BACK A LOT BIG PHARMA
DOESN'T WANT TO CURE HIV BECAUSE
THAT MAKE SO MUCH OFF OUR DRUG
AND SO FORTH.
.
AND I KNOW IT'S MISINFORMATION
BUT IT'S DIFFICULT TO CONVINCE
SOMEBODY ELSE AND I'M SURE YOU
HEAR THIS ALL THE TIME.
ARE THERE TALKING POINTS FOR THE
COMMUNITY REPS TO HELP THEM GET
PAST THAT?
>> WE DO OUTREACH AND THE
CYNICAL POSITION IS ONE PRETTY
WELL ESTABLISHED AND HARD ONE TO
BEAT EVEN IF WE WERE OUT FULL
TIME TALKING WITH THE BEST
TALKING POINTS I THINK WE'D HAVE
A SUBSTANTIAL POPULATION THAT
BELIEVES AND THE COMMUNITY
ADVISORY BOARD AND THEN OUR OWN
COMMUNITY ENGAGEMENT PROCESSES
ARE KEY TO THAT AS WELL.
ANYONE ELSE?
>> WHEN YOU TALK TO THE
COMMUNITY IT'S IMPORTANT TO
UNDERSTAND THERE'S COMPANIES
WITH ANTIRETROVIRALS AND TO SAY
THEY DON'T WANT A CURE BECAUSE
THEY WANT TO CONTINUE TO SELL
THEIR DRUGS IS MISINFORMATION.
AND POINTING TO THE FACT THAT
GILEAD IS INVOLVED IN SEVERAL
TRIALS WITH THE TRL9 AGONIST AND
OTHER COMPOUNDS SPEAKS TO THE
FACT THAT, YES, CURE IS STILL
STRONG POINT OF PURPOSE.
>> TO ADD TO THAT I THINK
LOOKING AT HOW BIG THE PORTFOLIO
IS NOT ONLY AT SINGLE COMPANIES
BUT ACROSS THE COMPANIES I THINK
AT GILEAD WE HAVE SEVERAL SAETS
IN THE PIPELINE AND I THINK IT'S
A SIGN WE'RE COMMITTED TO IT AND
ARE DOING ACHT COMMUNITY
ENGAGEMENT TO TRY TO GET THAT
MESSAGE OUT.
WE HAVE AN HIV CURE DEDICATED
COMMUNITY ADVISORY BOARD WE'RE
HOPING WILL CONTINUE TO SPREAD
THE MESSAGE AND INVESTED NOT
ONLY IN OUR OWN INTERNAL EFFORTS
AND WE HAD A WHOLE HIV CURE
GRANT PROGRAM THAT WAS GEARED
TOWARDS FUNDING NOVEL IDEAS WITH
THE IDEA OF BRINGING NEW IDEAS
AND POTENTIAL PRODUCTS INTO THE
PIPELINE.
AND FOR EVERYONE IN THE FIELD.
>> I ECHO EVERYTHING SAID AND
SAY WE'VE DONE IT BEFORE.
AND WE HAD THERAPIES NOT SO
GREAT AND LOW CURE RATES.
WE MOVED ON AND DID THE FIRST
PROTEASE INHIBITORS AND
ULTIMATELY GOT A TWO-DRUG
REGIMENT OVER WEEKS.
IT'S A STEPWISE PROFESSION AND
LOOK WHAT WE DID WITH HCV.
WHERE HE STARTED WITH LARGE
SINGLE PILL REGIMENTS AND WILL
HOPEFULLY HAVE LONG ACTING AND
THE NEXT STEP IS CURE.
THIS IS THE NATURAL PATH AND
WHAT WE'VE DONE AND WHAT WE'LL
CONTINUE TO DO.
>> WE TALK ABOUT THE ADVISORY
BOARDS OF INCENTIVIZING BETTER
RELATIONSHIPS ONE THE INDUSTRY
AND REACH OUT AND SAY WOULD YOU
BE WILLING TO PARTNER WITH A
PARTICULAR PROGRAM BECAUSE YOU
HAVE A GREAT ASSET AND WE GET
THE LETTER AND GRANT AND DO THE
WORK ANDO -- OR THE MECHANISM
OF SUPPORT AND A GRANT FROM NIH
SUPPORT AND ACADEMIC EFFORTS AT
A SUBSIDIZED RATE AND THAT'S
WONDERFUL AS WELL.
MY QUESTION IS WHAT OTHER MODELS
CAN WE THINK ABOUT?
WOULD IT BE HELP SUPPORT THE
VALE OF DEATH WITH ACADEMIA AND
INDUSTRY AND WOULD YOU BE ABLE
TO TAP YOUR RESOURCES IN SUPPORT
OF ACADEMIA IF THERE WERE
INSTRUMENTS THAT WOULD JOINTLY
GIVE YOU MONEY BECAUSE NORMALLY
WE DON'T PUT MONEY IN THE GRANTS
AND WE EXPECT YOU TO FLIP THE
BILL AND GET US A LETTER.
WITH REGARDS TO THE FUTURE IS
THERE ANOTHER WAY TO THINK ABOUT
OUR PARTNERSHIPS THAT PERHAPS
FROM YOUR SIDE OR IS THIS THE
BEST WE CAN DO
>> CAN EVERYONE HEAR ME?
>> YES.
>> I'VE HAD EXPERIENCE WITH TWO
CLINICAL TRIAL AND TWO OF WHICH
I'VE BEEN ON THE PROTOCOL TEAM
FOR.
I'LL MENTION THE NAME OF THE
PHARMACEUTICAL COMPANY SINCE
IT'S ALREADY BEEN MENTIONED, BMS
WE HAD AN HIV DIVISION AND THEY
ENDED THAT AS PEOPLE ARE
PROBABLY AWARE AND NOW WHEN A
PROTOCOL REACHES OUT FOR A
COMPOUND FOR AN HIV TRIAL THEY
WANT NOTHING TO DO WITH IT.
THE CRITICISM THAT EXISTS
LARGELY IS WITH COMPANIES THAT
ARE NO LONGER IN THE HIV SPACE
OR ARE NOT IN THE HIV SPACE.
WE'RE NOT TALKING ABOUT MERCK
AND VIIV AND GILEAD.
YOU ALL DO VERY WELL FOR US.
WHEN YOU HAVE A COMPOUND
APPRESSED FOR ONE INDICATION AND
THEN WANT TO USE IT FOR HIV, AND
THERE'S A FEAR THAT THE TRIAL
COULD POTENTIALLY HAVE A
NEGATIVE OUTCOME AND POTENTIALLY
GET THAT DRUG PULLED FROM THE
MARKET WELL, IF THAT'S THE FEAR
YOU NEED TO DO SOMETHING ABOUT
THE FEAR.
THE SOLUTION WOULD BE TO NOT
TRASH ONE DRUG BECAUSE IT DIDN'T
WORK FOR A CERTAIN INDICATION
AND IT DOES FOR ANOTHER
INDICATION.
I KNOW AND CERTAIN DRUGS YOU
CAN'T GIVE TO CERTAIN PEOPLE BUT
FINE FOR WHAT THEY'RE APPROVED
FOR.
WHEN IT BECOMES UNAFFORDABLE TO
REPURPOSE OR USING A DRUG AND
THEN THEY ARE HAVE TO SCRAMBLE
AND CHANGE THE PROTOCOL AND LOOK
FOR A DIFFERENT COMPOUND, IT
JUST COST MORE MONEY AND TAKES
MORE TIME.
IF WE CAN INCENTIVIZE
PHARMACEUTICAL COMPANIES TO PLAY
NICELY AND SOME HELP WOULD BE
REALLY NICE.
IF THERE COULD BE AN INCENTIVE
FROM THE FDA OR OTHERWISE, I
THINK THAT WOULD GO A LONG WAY
TO GETTING US FURTHER DOWN THE
ROAD WHERE WE NEED TO BE FOR A
CURE AND OTHER THINGS.
>> THANK YOU FOR COMMENTING.
AND RELATE D ALL THIS COMES TO
RISK ASSET CALCULATION DONE BY
MULTIPLE PEOPLE WITHIN EACH
INSTITUTION.
AND IF WE CAN FIND WAYS TO TWEAK
THAT AND DECREASE RISK VIA
SAFETY RISK AROUND REPURPOSING
FOR INTELLECTUAL PROPERTY RISK
FOR THE NOVEL COMPOUNDING IN
COMBINATION WITH OTHER
INSTITUTIONS THAT'S HOW WE'RE
GOING TO DO THIS.
IF WE CAN DECREASE THE RISK OR
BENEFIT WE CAN MOVE FORWARD.
>> NOBODY WOULD TURN DOWN THE
NOBEL PRIZE FOR CURING HIV,
TRUST ME.
>> I DON'T HAVE A SUGGESTION FOR
HOW TO DO THAT BUT MAYBE
PANELISTS DO AND MAYBE THE
AUDIENCE DOES AND MAYBE USE THE
REST OF THE TIME AS THE LAST
GROUP DID GO TO A SOLUTION.
>> I WANTED TO SPEAK TO
SOMETHING LOUIS SAID.
OUR BIGGEST COST DON'T COME AT
THE DISCOVERY SPACE BUT THE
CLINICAL DEVELOPMENT SPACE.
IF YOUR WRITING GRANTS AND WANT
TO DEVELOP IT WITH THE INDUSTRY
PARTNER I DO THINK INCENTIVIZING
THAT WITH FUNDING WOULD BE
HELPFUL BECAUSE IF WE HAVE A
LARGE PORTFOLIO OF ASSETS AND
HAVE TO PRIORITIZE WHAT WE PULL
OUR INVESTMENT BEHIND SOMETHING
THAT IS A DON'T OF AN ALTERNATE
THERAPY IS GOING TO LOOK A
LOT -- WILL HAVE LOWER PRIORITY
OF A THERAPY IN AND OF ITSELF
AND CAN WRITE GRANTS FOR AN
INDUSTRY PARTNER AND PROVIDE
FUNDING FOR A CLINICAL
DEVELOPMENT I THINK YOU COULD
GET TRACTION AND MOVING ASSETS
THAT MAY NOT BE ON TOP OF THE
PRIORITY LIST.
>> IMMUNITY BIO IS AN ONCOLOGY
COMPANY AN 803 NOW CALL ANTIVA
WAS JUST APPROVED BACK IN APRIL
FOR USE IN BLADDER CANCER FROM
THE FDA.
IT ALSO MADE IT CHALLENGING TO
PROVIDE -- AND THIS IS ONE WITH
WHAT WAS TALKED ABOUT THIS
MORNING MENTIONING A PROBLEM
WITHIN 803.
IT WASN'T A PROBLEM BUT THE FACT
THAT AS RICK MENTIONED WAS RISK
BENEFIT DECISIONS BEING MADE IN
THE COMPANY SAYING WELL WE'RE
WAITING FOR THE FDA APPROVAL AT
THE MOMENT IF WE HAVE AN ADVERSE
EVENT IN A PRE CLINICAL STUDY
OUT COULD DERAIL THE PROGRAM AND
NO WAY THE COMPANY WILL ALLOW ME
TO PROVIDE THE DRUG IN THAT
SITUATION.
WE'RE PAST THAT SO HOPING IT
WILL BE EASIER BUT TO LUIS'
POINT IF THERE'S WAY TO GET
FUNDING FOR PROVIDING 803 OR
ANTIVA FOR ANY PART OF THE
PROCESS I WOULD WELCOME THAT AND
SO WOULD THE COMPANY.
RIGHT NOW IN EVERY SITUATION
WE'VE BEEN INVOLVED IN WITH
RESPECT TO EARLY PRE CLINICAL
WORK AND NOW IN CLINICAL
STUDIES, WE'VE GIVEN DRUG --
THERE'S A COST TO DOING THAT
OBVIOUSLY.
AND MAKE SURE THERE'S A FUNDING
MECHANISM THAT REWARDED BOTH
PARTNERS IN THAT SITUATION.
>> ONE THING I'D LIKE TO ADD IS
SOMETIMES LIKE THE DERISKING
PROCESS WE TALKED ABOUT CAN ALSO
BE PART OF THE COLLABORATION.
FOR EXAMPLE, THERE'S THE ABILITY
TO WEIGH IN SOME SCIENTIFIC
ADVISER FROM THE COMPANY OR
ENTITY THAT PROVIDE THE DRUG,
THAT MAY HELP US MAYBE DESIGN
THE STUDY IN A WAY THAT IS LESS
RISKY FROM A SAFETY PERSPECTIVE,
FOR INSTANCE, SO THAT RISK
BENEFIT SCALE MOVE TOWARDS THE
BENEFIT AND LESS TOWARDS THE
RISK.
>> I'M A CO-CHAIR FOR HOPE AND
THANK YOU FOR BRINGING UP THE
TOPIC OF HIV CURE.
I WANTED TO ADD A TALKING POINT
AND FRAMING IT IN THAT COMPANIES
ARE DRIVEN BY PROFIT.
I'LL THROW THAT BACK AND SAY
THEN IT'S IN THE INTEREST OF A
COMPANY TO PURSUE CURE AND TO BE
THE FIRST TO COME TO MARKET WITH
A CURE.
IMAGINE THE RISK OF NOT PURSUING
CURE AND SITTING ON THE
SIDELINES AND LETTING
COMPETITORS GET ALL THE MONEY.
JUST WANTED TO ADD THAT.
>> THANK YOU FOR THE PANEL AND
I'VE ENJOYED THE DISCUSSION.
>> THANKS FOR EVERYONE STAYING
TO THE END AND FOR THE
OPPORTUNITY TO DISCUSS THIS.
I THINK I SPEAK FOR ALL OF US
WE'RE EXCITED ABOUT THE END
GROUND AND MAYBE WE CAN FIND A
WAY TO SOLVE SOME OF THE
PATTERNS.
>> WE'VE COME TO THE END OF THE
THREE-DAY EVENT.
I JUST WANT TO THANK OUR
LEADERSHIP STARTING OFF THE
NIAID DIRECTOR AND CARL AND
GUIDING US THROUGH THE PROCESS
AND THE PROGRAM MANAGEMENT TEAM
AND PROGRAM OFFICERS WHO HAVE
BEEN WONDERFUL IN MAKING THIS A
SUCCESSFUL GET TOGETHER AND
BESIDES NIAID WE HAVE OTHER ICOs
THAT SUPPORT THE MARTIN DELANEY
AND SPECIAL THANKS TO THE
INVESTIGATORS.
WITHOUT YOU WE'RE NOT HERE SO WE
THANK YOU FOR ALL THIS WONDERFUL
SCIENTIFIC DELIBERATIONS THE
LAST THREE DAYS.
WE APPRECIATE WHAT YOU DO.
FINALLY GET THIS THING DONE BUT
I APPRECIATE THE P.I.s FOR
SPONSORING AND CONTRIBUTING FOR
THE COUGH YO BREAKS AND THE NIH
PROGRAM OFFICER COLLEAGUES
BRINGING THE SNACKS.
WE APPRECIATE THAT AND NIH
STAFF.
IT'S BEEN A FANTASTIC MEETING
AND EVERY ONE OF YOU FOR MAKING
A SEAMLESS TRANSITION BETWEEN
PRESENTATIONS.
I PRESENT THAT AND THE NIH
VIDEOCAST WHO ARE STREAMING THIS
ONLINE WORLDWIDE AND WE ARE
CONTRACTOR SUPPORT AND WE WANT
TO THANK EVERYONE AND THANKS A
LOT AND WISH YOU A SAFE TRAVEL
BACK HOME.
SEE YOU NEXT YEAR.
>> THERE'S ONE OTHER PIECE I'VE
BEEN TASKED WITH AND I HOPE YOU
FORGIVE ME FOR JUST JUMPING IN
HERE.
I'M DEREK MATT THE CO-CHAIR AND
I WANT TO START WITH THIS.
THIS LAST PIECE WAS POWERFUL FOR
ME.
I RARELY GET TO HEAR FROM
INDUSTRY IN SPEAKING ABOUT THE
COLLABORATION NOT ONLY WITH THE
ACADEM YOU CAN INSTITUTIONS IN
WHICH WE INTERACT BUT ALSO
EXPLORING HOW TO INTERACT WITH
US AS COMMUNITY MEMBERS AS WELL.
IT'S QUITE POWERFUL TO HEAR
THAT.
AND HOPE TO HEAR MORE AT THE
LEVEL WITH WHICH YOU GUYS
OPERATE.
I WANTED TO SAY THAT AS WELL.
THE THREE BRAINY AWARDS LET'S
GET US OUT OF HERE.
THE BRAINIES GO TO WHAT WE FELT
WAS THE MOST POWERFUL
PRESENTAT
PRESENTATIONS OVER ALL BUT IT
WAS A HARD DECISION AND THERE
WERE WONDERFUL PRESENTATIONS.
OVER ALL THEY WERE ALL GREAT OF
COURSE AND SO IN CERTAIN WAYS
THIS IS JUST OFF THE TOP OF OUR
HEADS AS WELL.
THE VERY FIRST ONE GOES TO
DRDR
DR. KULPA.
I WANT TO THANK HER FOR HER
SLIDE PRESENTATION.
WE'LL GET THAT TO HER.
AND I'LL BUTCHER THIS NAME.
I'M SORRY.
THE SECOND ONE GOES TO CATHERINE
RAGONELAGA.
YES.
AND DR. LETTI.
IS SHE HERE?
>> WE'LL MAKE CERTAIN SHE GETS
HER SLIDE.
THESE ARE SO SPECIAL TO US SO
ENJOY YOUR BRAINIES EVERYONE AND
HAVE A WONDERFUL TRIP.
THANK YOU.