>> ALL RIGHT. LET'S GET STARTED. I THINK IT'S TIME. I'D LIKE TO CALL THIS MEETING OF THE JANUARY 30, 2017, AIDS RESEARCH ADVISORY COMMITTEE TO ORDER. MY NAME IS CAROL WILSON FOR THOSE WHO DON'T ME, THE NEW CHAIR. CHIEF CAT BURGER, I THINK, HERE TODAY. AND I'D LIKED TO FIRST WELCOME ALL THE COMMITTEE MEMBERS, OUR NIH COLLEAGUES AND ALSO THE MEMBERS OF OUR GUEST AUDIENCE. OUR FIRST ORDER OF BUSINESS TODAY IS TO REVIEW AND APPROVE THE MINUTES FROM THE SEPTEMBER MEETING. YOU SHOULD HAVE RECEIVED THOSE BY E-MAIL. DO WE HAVE ANY CORRECTIONS OR ADDITIONS TO THE MINUTES? DO WE HAVE A MOTION TO APPROVE THE MINUTES? DO WE HAVE A SECOND? ALL IN FAVOR OF APPROVAL RAISE YOUR HAND. ANYONE OPPOSED, ABSTAINING? THE MINUTES ARE APPROVED AS THEY STAND. SO, OUR NEXT ORDER OF BUSINESS IS FOR THE DIRECTOR'S REPORT AND KARL WILL GO AHEAD AND GIVE US HIS UPDATE. >> KARL: GOOD AFTERNOON, EVERYONE. IT'S A PLEASURE TO BE HERE. WE DID HAVE A SNOWSTORM, WHICH IS IN KEEPING WITH WHAT WE ALWAYS HAVE AT THIS MEETING, ALTHOUGH IT WAS PRETTY TO LOOK AT. NOT QUITE THE COMPLICATION THAT WE HAD IN PREVIOUS YEARS. IT'S ALSO WONDERFUL TO HAVE A NEW CHAIR. IT'S GREAT HAVE KARIN HERE AS THE COMMITTEE CHAIR AND IT'S GREAT TO WELCOME HER. MY FIRST ORDER OF BUSINESS, OBVIOUSLY IS TO WELCOME CARA IS THE CHAIR. THE PROFESSOR OF MEDICINE IN THE DIVISION OF INFECTIOUS DISEASES AT THE UNIVERSITY OF COLORADO IN DENVER. WE HAVE ADDITIONAL NEW MEMBERS OF ARAC JOINING FOR THE FIRST TIME AT THIS MEETING. FIRST IS DR. PAUL BIENI ASZ, PROFESSOR AND HEAD OF LABORATORY AT RETROVIRALLOLOGY AT ROCKEFELLER AND ALSO A HOWARD HUGHES INVESTIGATOR. PAUL HAS SPENT HIS CAREER IDENTIFYING HOST FACTORS THAT ARE INVOLVED IN NOT JUST REPLICATION OF HIV AND RETROVIRUSES BUT ALSO THE HOST FACTORS THAT ARE INVOLVED IN TRYING TO BEAT HIV. AND SO HE HAS BEEN LOOKING AT HOST GENE PRODUCTS THAT CAN PROVIDE HOST DEFENSE AGAINST LENTIVIRUSES. OUR NEXT NEW MEMBER IS DICK CHAISSON, PROFESSOR OF MEDICINE AT THE JOHNS HOPKINS SCHOOL OF MEDICINE AND PROFESSOR OF EPIDEMIOLOGY AND INTERNATIONAL HEALTH AT BLOOMBERG. WHICH IS THE HOPKINS SCHOOL OF PUBLIC HEALTH. AND IS ALSO THE DIRECTOR OF THE JOHNS HOPKINS CENTER FOR TUBERCULOSIS RESEARCH AND ALSO PART OF THE LEADERSHIP TEAM OF THE CFAR. SO MANY HATS. CLEARLY DICK'S WORK FOCUSES ON TB AND HIV, A VERY IMPORTANT INFECTIOUS CO-MORBIDITY. SO WE WELCOME TO THE COMMITTEE. AND THE LAST NEW MEMBER IS DR. ELIZABETH MCFARLAND. BETSY IS A PROFESSOR OF PEDIATRICS AND THE HEAD OF THE DIVISION OF PEDIATRIC INFECTIOUS DISEASES IN THE DEPARTMENT OF PEDIATRICS AT THE UNIVERSITY OF COLORADO. SO, WE HAVE OUR CHAIR FROM DENVER, AND WE HAVE A NEW MEMBER FROM COLORADO. SO I THINK WE HAVE SATURATED THE MIDWEST FOR NOW. BETSY IS CURRENTLY STUDYING MATURATION OF CELL MEDIATED IMMUNE RESPONSES AND BOTH NORMAL AND HIV INFECTED INFANTS. IMMUNE RESPONSES TO HIV VACCINES IN EXPOSED INFANTS AND THE ROLE OF CYTOTOXIC LYMPHOCYTES AND THE PATHOGENESIS OF CONGENTALE-ACQUIRED HIV INFECTION AND INVOLVED IN CLINICAL TRIALS. PLEASE JOIN ME IN WELCOMING OUR NEW MEMBERS OF ARAC. [ APPLAUSE ] SO, THOSE OF YOU WHO SAW DR. FAUCI'S PRESENTATION, I'M GOING TO GIVE MY VERSION OF THE BUDGET UPDATE. AS YOU KNOW, THIS ADMINISTRATION IS DUE TO RELEASE FY18 BUDGET ON FEBRUARY 6 WITHOUT ANY INFORMATION, THERE IS NOTHING TO TALK ABOUT ON FY18. WE CAN TALK ABOUT WHERE WE CURRENTLY ARE WITH FY17 BUDGET AS ALL OF YOU ARE AWARE, WE ARE UNDER A CONTINUING RESOLUTION UNTIL THE END OF APRIL. AND AS SUCH, WE ARE FUNDED AT THE -- I GUESS PEOPLE COULDN'T HEAR ME. CAN YOU HEAR ME BETTER NOW? SORRY ABOUT THAT. AS YOU CAN SEE IN THE BUDGET REQUEST THAT PRESIDENT OBAMA SUBMITTED A YEAR AGO, WE WERE ESSENTIALLY LEVFUNDED. AS THE YEAR, FISCAL YEAR 16 YOU THINK FOLDED AND WE GOT TO 17 -- YOU THINK FOLDED -- WE ARE UNDER A CONTINUING RESOLUTION. AT THE END OF FISCAL YEAR 16, WE DID END UP GETTING AN ADDITIONAL ALLOCATION FOR ZIKA TO THE TUNE OF 152 MILLION TO SUPPORT THE VACCINE'S DIAGNOSTICS AND THEY'RE PEWSICS IN ZIKA. WE HAVE, BECAUSE IT IS -- THERAPEUTICS -- WE HAVE INTERIM PAY LINE ESTABLISHED TO THE 10th PERCENTILE WITH NEW PIs AT THE 14th. AS AN INSTITUTE POLICY, WE DON'T DOWNWARDLY NEGOTIATE OR TAKE JUDGMENTS ON COMPETING OR NONCOMPETING GRANTS BUT IN FISCAL YEAR 17, NEW RESEARCH INITIATIVES THAT ARE CURRENTLY BEING WRITTEN FOR RFAs WE SET ASIDE WILL BE CUT BY APPROXIMATELY 10% WITH A GOAL OF HAVING AN ESTIMATED SUCCESS RATE FOR THE YOU THINK SOLICITED AND SOLICITED GRANT POOLS BETWEEN 20-22%. THIS IS THE HISTORY OF NIAID FUNDING. WE HAVE BEEN ESSENTIALLY FLAT FUNDED SINCE 2005 AND THE PRESIDENT'S BUDGET IN 2017 DOESN'T REALLY CHANGE THAT. BEFORE I GO ON TO THE REPORT CARD, ARE THERE ANY QUESTIONS ABOUT THE BUDGET? SO EACH JANUARY, WE TAKE THE TIME TO ENGAGE YOU, THE COMMITTEE, WITH AN UPDATE ABOUT WHERE WE ARE AND WHERE WE THINK WE'RE GOING OVER THE NEXT YEAR. SO AS PART OF THAT, I'D LIKE TO TAKE A LOOK BACK AND SEE WHAT WE WERE ABLE TO ACCOMPLISH ON A FAIRLY MACRO SCALE WITH REGARD TO GRANT FUNDING IN FISCAL YEAR 16. SO WHAT WE -- ONE WAY TO LOOK THAT THE IS WHAT WAS THE PAY LINE? WHAT WAS THE PAY LINE AND HOW DID IT EVOLVE OVER TIME? SO YOU CAN SEE THE HISTORY GOING BACK TO 2005 OF HOW THE PERCENTILE THAT WE HAVE BEEN PAYING TO HAS CHANGED. AND WE HIT IN 2013, DURING THE SEQUESTRATION, AND WE BOUNCED BACK UP IN FY16 TO THE 13th PERCENTILE. WE FOR A SITUATION RIGHT NOW BECAUSE WE ARE UNDER CR THAT WE ARE HELD TO THE 10th PERCENTILE AND IN THE ABSENCE OF GETTING A FORMAL BUDGET FOR THE YEAR, WE WILL PROBABLY STAY NEAR THE 10, THERE MAY BE SOME UPWARD MOW BUILTO THAT BUT THAT REMAINS TO BE SEEN. SO THAT IS WHERE WE WERE IN FISCAL YEAR '16. THIS IS A COMPLICATED TABLE BECAUSE IT LAYS OUT ALL THE RESEARCH PROJECT GRANTS AND AIDS-RELATED RESEARCH GRANTS BY NUMBER OVER ALL THE YEARS AND IF YOU JUST FOCUS ON THE END, YOU CAN SEE WHAT HAPPENED IN FISCAL YEAR 16. SO INTERESTINGLY ENOUGH, IN 2016, WE HAD A DROP IN THE NUMBER OF SUBMISSIONS FROM ABOUT 1300 TO APPROXIMATELY 1000. BUT THAT LEDS TO A HIGHER SUCCESS RATE OVERALL. YOU CAN SEE FOR THE INSTITUTE, IT WAS ESSENTIALLY LEVEL WITH SLIGHT INCREASE IN THE NUMBER OF FUNDED AND ALSO INCREASE IN THE SUCCESS RATE. SO IF WE BREAK THAT OUT, THEN, IN THE DIFFERENT MAJOR CATEGORIES OF RESEARCH PROJECT GRANTS RO1s, THE SMALLER R21S, AND THEN THE BIGGER PROGRAM PROJECT GRANTS, YOU CAN SEE THAT THE NUMBERS CHANGE A LITTLE BIT MORE. SO, IN TERMS OF RO1s, WE HAD ABOUT 500. WE FUNDED ABOUT 112. FOR R21s, WE HAD ESSENTIALLY THREE-QUARTERS OR 80%. THE NUMBER WAS QUITE SIMILAR. SO I'M TRYING TO SAY THAT WE HAD 500 HERE AND APPROXIMATELY 400 HERE. THE NUMBERS ARE FAIRLY BALANCED BETWEEN RB1s AND R21s AND INTERESTINGLY ENOUGH, WE ONLY HAD 11 PROJECT GRANTS, FUNDED 5. BUT THIS INCLUDED SOLICITED PROGRAM PROJECT GRANTS MAINLY OTHER GRANTS WITH SET ASIDE PROGRAMS. THAT'S WHY THIS NUMBER IS SO LARGE. IT'S NOT THAT WE ARE FAVORING PROGRAM PROJECT GRANTS, PER SE. SO, HERE IS THE SUMMARY, THAT IS WHY I WANTED TO MAKE THIS POINT THAT THIS IS A VERY INSENT SIEVE NUMBER AT A SUCCESS RATE OF 45. -- INSENTATIVE. OVERALL, THE SUCCESS RATES WERE IN THE 22-44% RANGE FOR THE RO1s AND L21s. HOW DO WE COMPARE TO THE NIH? OVERALL THE INSTITUTE DID BETTER FOR AIDS AND NON-NADES THIS CATEGORY OVERALL. NIH'S SUCCESS RATE WAS BELOW 20. SO THE INSTITUTE MADE QUITE A COMMITMENT TO TRY TO KEEP OUR SUCCESS RATES ABOVE 20 AND WE KNOW THAT IS AN IMPORTANT AREA FOR US TO CONTINUE TO EMPHASIZE. NOW, ON THE RECENT CONFERENCE CALL WE HAD WITH YOU AS THE COMMITTEE, THERE WAS A REQUEST THAT YOU GET AS PART OF THIS UPDATE. THIS REPORT CARD. AN UPDATE ON WHERE WE WERE, WHAT WE DID IN FISCAL YEAR '16 WITH THE OAR STRATEGIC FUND OR THE HIGHER RELEVANCE AIDS RESEARCH. AS PART OF A TALK TODAY, SHE TALKED ABOUT THE NEW PRIORITIES THAT CAME INTO BEING IN 2015 THAT FRANCIS PUT OUT. AND SHE HAD THAT VERY NICE GRAPHIC OF THE AREAS OF EMPHASIS. SO WORKING WITH THE OAR TO ADDRESS THE HIGHEST PRIORITY RESEARCH, THE -- YOU POSED THIS QUESTION ON THE SLIDE, MAUREEN, WHICH I WAS GLAD TO SEE. IS BASED ON THESE STRATEGIC PRIORITIES, WHERE ARE THE GAPS AND HOW CAN WE TOGETHER, WORK TO FILL THE GAPS SO THAT THESE GAPS THAT WE ARE ADDRESSING IS THE GREATEST NEED AND THESE CAN BE ADDRESSED? SO GOING THROUGH THIS PROCESS, AGAIN HERE ARE THE PRIORITY AREAS IN WORD FORM, NOT IN THAT NICE GRAPHIC FORM OF REDUCING INCIDENCE THROUGH DEVELOPMENT OF PREP AND A SAFE AND EFFECTIVE HIV VACCINES. WORKING TOWARDS THE NEXT GENERATION OF THERAPIES AND DISCOVERING AND DEVELOPMENT OF A CURE, AND THEN IMPROVING PREVENTION AND TREATMENT OF HIV-INFECTED CO-MORBIDITIES AND CO-INFECTIONS AND DEALING WITH THE CROSS-CUTTING AREAS OF BASIC RESEARCH DISPARITIES AND TRAINING. SO THOSE ARE THE -- WHAT WE WERE DOING. SO WHAT WE DID, IS WE LOOKED AT IT FROM THE STANDPOINT OF WHERE IS THE INNOVATION? SO WHAT WE THOUGHT ABOUT WAS, IF YOU TAKE THE BROAD NEUTRALIZING ANTIBODIES AND VIEW THEM AS DRUGS, YOU GOT A SITUATION WHERE WE HAVE ALL THESE WONDERFUL DRUGS THAT EITHER INHIBIT ENTRY OR TRANSCRIPTASE INHIBITORS, PROTEASE INHIBITORS, BUT ALL OF THE BROAD NEUTRALIZING ANTIBODIES TARGET A STRUCTURE, THE ENVELOPE AND IN PACT FUNCTION. COMBINATION AGENTS HERE ARE QUITE EFFECTIVE AT CONTROLLING ANTIVIRAL REPLICATION SO A COMBINATION OF AGENCY HERE ALSO DO THE SAME. AND WE HAVE THE ABILITY AND NOT ONLY TO COMBINE DRUGS, TRADITIONAL DRUGS, BUT ALSO BROAD NEUTRALIZING ANTIBODIES, PARTICULARLY IF WE CAN GET LONG-ACTING AGENTS, WHETHER A RV'S OR BROAD NEUTRALIZING ANTIBODIES WITH PROLONGED HALF LIVES TO BE USED FOR THE PURPOSES OF PREVENTION AND TREATMENT AND POSSIBLY FOR CURE. SO THE ANTIBODIES THEMSELVES COULD BE USED AS THERAPY, COULD BE USED IN NON-VACCINE PREVENTION, BUT ALSO AS MODELS FOR WHAT WE ARE TRYING TO TARGET BY DEVELOPMENT OF IMMUNE RESPONSES THAT COULD TRIGGER THE PRODUCTION OF THESE CLASSES OF ANTIBODIES. SO, WHAT IS THE GAP HERE? WELL, THERE IS A CRITICAL BOTTLENECK AND THERE REMAINS A CRITICAL BOTTLENECK TODAY. THE ABILITY TO -- WE DO NOT HAVE OR DID NOT HAVE THE CURRENT CAPACITY TO PRODUCE THE IMMUNOGENS AND ANTIBODIES WE NEED TO AGGRESSIVELY PUSH FORWARD IN THESE AREAS OF VACCINE PREVENTION, NON-VACCINE PREVENTION, AND THE USE OF THE BROAD NEUTRALIZING ANTIBODIES AND TREATMENT. SO, THE OAR, LAST NOVEMBER, CONVENED THE ORAC MEETING AND FOCUSED ON THE CHALLENGES OF HIV VACCINE RESEARCH. OUT OF THAT CAME THE FOLLOWING FOUR BULLETS. THAT FUNDAMENTALLY THERE ARE LIMITED RESOURCES THAT WE REALLY NEED TO BEEF UP IN PRODUCT DEVELOPMENT. PRODUCT MANUFACTURING ISSUES DO SLOW CLINICAL DEVELOPMENT. ENVELOPE PROTEINS ARE HARDER TO PRODUCE THAN ANTICIPATED AND THESE PROBLEMS THAT WE UNCOVERED AS WE WOULD GO THROUGH THIS PROCESS OF STABILITY AND CLIPPING AND AGREGATION, NEED TO BE OVERCOME BY A FOCUS GROUP OF PEOPLE INVOLVED IN PRODUCTION. FURTHERMORE, SCALE-UP REMAINS A CHALLENGE. SO WE DECIDED TO GO FORWARD WITH A REQUEST THAT REALLY FOCUSED ON BUILDING THIS PRODUCTION CAPACITY. SO, THROUGH THE ALIGNMENT AND THE PROCESS THAT OAR IS GOING THROUGH AS THEY LOOK AT THE FUNDING THAT THE INSTITUTE HAS THAT IS TURNING OVER, IN '16, APPROXIMATELY 36 MILLION DOLLARS OUT OF OUR BUDGET FELL INTO LOW PRIORITY AREAS. SO THIS MONEY WAS SUBSEQUENTLY REMOVED FROM THE NIAD BUDGET AND PUT INTO THE OAR STRATEGIC POOL SO THIS MONEY WAS AVAILABLE FOR REPURPOSING. AND SO, THE BULK OF THAT MONEY CAME OUT OF BASIC IMMUNOLOGY RESEARCH AND RESEARCH ON CO-INFECTIONS AND OPPORTUNISTIC PATHOGENS APPROXIMATELY 10 MILLION OF IT WAS TUBERCULOSIS RESEARCH. THAT WAS THE MONEY WE CONTRIBUTED TO THE POOL. OUT OF THE POOL OF 65 MILLION, OAR AWARDED THE INSTITUTE 58.8 MILLION DOLLARS. AND THE BULK OF IT WAS IN THE AREA OF MANUFACTURING. WE WERE ABLE TO GET APPROXIMATELY 32 MILLION FOR THE BRC TO ESSENTIALLY DOUBLE THE SIZE OF THEIR PRODUCTION FACILITY AND WE WERE ABLE TO GET SUPPORT TO THE TUNE OF ABOUT 16 MILLION TO PUT IN THE TWO BIG CHAFEES TO BUILD OUT THEIR PRODUCTION CAPACITY. WE ADDITIONALLY RECEIVED ABOUT 7 MILLION FOR A VERY IMPORTANT GRANT TO LOOK AT THE B&T-CELL BIOLOGY FOR VACCINES FOR BOTH PREVENTION OF INFECTION AS WELL AS FOR CURE RESEARCH AND A GRANT TO LOOK AT ANTIBODY STRUCTURE FUNCTION, ANTIVIRAL FUNCTION THAT WE COULD THEN INFORM VACCINE DESIGN. NOW, SO THAT WAS LAST YEAR. ARE THERE ANY QUESTIONS ABOUT WHAT HAPPENED LAST YEAR? IN THIS SPACE? PAUL? >> PAUL: SO THE DROP IN THE NUMBER OF RO1 APPLICATIONS IS NOTABLE AND I THINK A BIT CONCERNING. CAN YOU SAY ANYTHING A BIT MORE ABOUT THAT? >> KARL: I THINK THAT PART OF IT IS A CODING ISSUE THAT IN THE PAST WE CODED A FAIR AMOUNT OF TB, AND SOME OF THE BASIC IMMUNOLOGY AS BEING AIDS RELATED, AND WE GOT CREDIT FOR THOSE. GIVEN THE LIST OF RULES, THOSE ARE NO LONGER -- WE ARE OBVIOUSLY NOT PUTTING ANYTHING THAT FALL INTUSE A LOW-PRIORITY CATEGORY INTO OUR BUCKET BECAUSE WE DON'T WANT TO HAVE THAT MONEY REMOVED FROM THAT BUDGET IN FIVE YEARS. SO THERE IS A LEARNING EXERCISE WE HAVE UNDERGONE. SO I THINK THAT REPRESENTS THE STUFF THAT IS IN THE HIGHEST PRIORITY AREAS AS WE GO FORWARD. SO I'M NOT SURE THAT THERE IS A TRUE DROP IN THE NUMBER OF APPLICATIONS. THE CONTRIBUTION TO THE LOW ALIGNMENT OR LOW-PRIORITY ALIGNMENT INTO THE HIGH-PRIORITY STRATEGIC POOL IS MORE IN 2017 THAN WE HAD IN 2016. IT'S TO 40.2 MILLION. THE OAR PROCESS IS ONGOING WITH SUBMISSIONS DUE WITHIN THE MONTH OF FEBRUARY. SO IN A YEAR, I'LL COME BACK TO YOU AND REPORT ABOUT HOW WE DID IN 2017 AND WHAT OUR CONTRIBUTION WILL BE TO THE FY18 POOL. ARE THERE QUESTIONS AT THIS POINT? WHAT WE HAVE DECIDED TO DO KEEPING WITH THE STEAL OF LOOKING AT PRODUCTION -- KEEPING WITH THE THEME OF LOOKING AT PRODUCTION, WE'D LIKE TO SOLICIT FOR A SBIR CONTRACT TO LOOK AT WAYS OF IMPROVING THE CELL SUBSTRATE. CAN WE IMPROVE THE PRODUCTION OF HIV VACCINE ANTIGENS BY GOING IN AND CHANGING THE BIOLOGY OF THE CELL THAT WE ARE USING TO PRODUCE THE VACCINE? SO CAN YOU TAKE GMP ESTABLISHED CELL SUBSTRATES, IMPROVE THEM IN SOME WAY SO YOU DON'T HAVE THE CLIPPING, SO YOU CAN GET HIGHER YIELDS FOR MANUFACTURING AND BASICALLY DEAL WITH THE CHALLENGES OF HAVING TO USE A MAMMALIAN CELL CULTURE SYSTEM SO IT BECOMES MORE RELIABLE, MORE ROBUST, SO YOU CAN GET BETTER PROTEINS THAT HAVE ALL THE PROPER GLYCOSYLATION, THE PROPER FOLDING, ALL OF THOSE ISSUES THAT WE HAVE RUN UP AGAINST OVER TIME. SO THE OBJECTIVE IS TO UTILIZE MOLECULARITY'S, SUCH AS CRISPR CAS9 TO MODULATE MOLECULAR PATHWAYS WITHIN THESE CELLS SO WE ENHANCE ENVELOPE PRODUCTION IN THESE MAMMALIAN CELL LINES AS A WAY OF ACCELERATING THE DEVELOPMENT AND ULTIMATELY THE PURIFICATION AND DOWNSTREAM PROCESSES USED IN MANUFACTURING. THIS TIMER DOESN'T LIKE IT WHEN I RUN TOO LONG. [ LAUGHS ] TRYING TO SPEED ME UP. WE THINK GIVEN THE SBIR MONEY IS APPROXIMATELY 2 1/2% OF THE NIH BUDGET BY STATUTE, IS DEDICATED TO SBIRs. WE FEEL THAT TARGETING SOME OF THE USE OF THAT MONEY TO SPECIFIC CONTRACTS LIKE THIS, IS A VERY USEFUL THING, SO THIS IS WHAT WE CAME UP WITH THIS YEAR IN TERMS OF KEEPING WITH OUR THEME OF DOING WHAT WE CAN WITH THE RESOURCES AVAILABLE TO IMPROVE MANUFACTURING. SO, IN TERMS OF THE TYPES OF PROJECTS THAT MAY COME IN UNDER THIS CONTRACT ARE METHODOLOGIES TO IMPROVE ENVELOPE PRODUCTION AS WELL AS IMPROVE THE EXISTING OF GENES THAT REDUCE SECRETION, YIELD OR STABILITY. THIS CLIPPING, THE NATURAL PROTEASE THAT IS EXIST IN THE MAMMALIAN CELLS ARE PRETTY PROFOUND. FURE IN IS THE PRIMARY ONE THAT DOES A GOOD THING. IT CLIPS THE ENVELOPE IN THE RIGHT WAY. THERE ARE LOTS OF OTHER PROTEASES NOT SO MUCH. THEY GO IN AND CLIP GP120 ONCE IT IS ALREADY CLEAVED FROM GP41, MAKING THAT PROTEIN UNUSABLE. SO THIS IS THE BATTLE WE ARE CONSTANTLY FIGHTING. ADDITIONALLY, THE IDEA OF BEING ABLE TO REMOVE ENDOGENOUS RETROVIRUSES WITHIN THE CELL MAY IMPROVE PRODUCTION. AND THEN WHAT WE ARE ALSO INTERESTED IN CONTINUING TO DEVELOP DIFFERENT STRATEGIES THAT ARE PHASE-APPROPRIATE. MEANING, ARE THERE STRATEGIES WE CAN ACCELERATE THE PRODUCTION OF ENVELOPES FOR PHASE I THAT MAY BE SCALABLE WHEN WE NEAT TO GED TO A PHASE II OR PHASE III. THIS GEDS CONFUSING BECAUSE WE TALK ABOUT NASES OF CLINICAL DEVELOPMENT -- PHASES -- BECAUSE SBIRs ALSO HAVE PHASES. SO IN PHASE I, WHAT WE WANT WHICH IS THE STARTER GRANT THAT THEY -- STARTER CONTRACT THEY WOULD RECEIVE, WILL EXPLORE BASIC -- IT BASICALLY SAYS KARL, SHUT UP. [ LAUGHS ] WE HAVE THE PHASE I ACTIVITY BUT THEN PHASE II COULD ACTUALLY INCLUDE DEVELOPMENT OF TRUE SUBSTRATES AND REALLY MOVE US INTO MORE OF A PRODUCTION. SO WHAT I NEED YOU TO DO, AS COUNCIL MEMBERS NOW, IS IF YOU HAVE ANY QUESTIONS, ASK ME NOW. CHRIS WILSON. >> CHRIS: SO MAYBE FOR YOU AND MIKE. HAVE YOU CONSIDERED SETTING SOME GOALPOSTS? IN OTHER WORDS, WE KNOW WHAT WE HAVE GOTTEN FROM KBI. WE KNOW WHAT WE HAVE GOTTEN WITH GT8. AND THAT GIVES US A BENCHMARK OF GMP PRODUCTION AT A SCALE THAT IS SUITABLE FOR ENTRY INTO CLINICAL TRIALS. IF THEY CAN'T BEAT THAT, WELL WE HAVEN'T GOTTEN IT. SO THE QUESTION TO ME, AT LEAST IN THE TRANSITION FROM PHASE I TO PHASE II OF THESE GRANTS, THERE SHOULD BE A VERY CLEAR GOALPOST SETTING BECAUSE WE NEED -- WE ARE LOOKING FOR IF NOT A LOG, A VERY SUBSTANTIAL IMPROVEMENT. >> WE AGREE COMPLETELY AND THAT IS THE ADVANTAGE OF HAVING THIS BE A CONTRACT BECAUSE YOU CAN PUT THESE IN AS MILESTONES AND THEY WILL BE COMPLETELY ENFORCEABLE SO NOTHING WILL MOVE TO PHASE II THAT DOESN'T HIT THOSE KINDS OF GOALS. WE AGREE. >> HOW ABOUT ANALYTICS? ARE YOU GOING TO PUT THAT IN THERE? >> KARL: ANALYTICS, THIS IS ABOUT IMPROVING THE CELL SUBSTRATE. THERE WILL HAVE TO BE ANALYTICS DEVELOPED TO GO IN PARALLEL WITH THIS SO THIS IS HOW THE GROUP SETS UP THE EVALUATION OF THE SUBSTRAIGHT AND PRODUCTION CAPACITY. SO I THINK IT'S ALL INTEGRATED. OTHER QUESTIONS? PAUL. >> PAUL: SO THERE IS ALREADY AN SBIR GRANT MECHANISM COVERING BASICALLY THE SAME GROUND. IS THIS INTENDED TO REPLACE THAT OR RUN ALONGSIDE AND WHY DO WE NEED BOTH? KARL: SLIGHTLY BIGGER INDUSTRY THAN MORE RESOURCES THAT WE CAN PUT IN THROUGH THE GRANT. WE THINK THIS IS SO IMPORTANT THAT WE NEED FULL COURT PRESS ON THIS. >> PAUL: SO WHAT IS THE TOTAL AMOUNT OF RESOURCES -- [ MULTIPLE SPEAKERS ] >> KARL: SO HERE IS WHERE I'M KIND OF STUCK IS I'M NOT ALLOWED TO ANSWER DOLLAR AMOUNT QUESTIONS ON CONTRACTS. BUT IT'S NOT AS BIG AS SOME OF THE OTHER INITIATIVES WE HAVE SEEN. THIS IS WHERE IT'S KIND OF RIDICULOUS BUT THOSE ARE THE RULES. THAT'S WHY YOU SEE NO DOLLARS ON THESE SLIDES. BUT WHEN WE TALK ABOUT GRANTS AND GRANT PROGRAMS, WILL YOU SEE DOLLARS. AGAIN, ALL OF THIS IS MONEY THAT IS ALREADY SET ASIDE FOR SBIRs. WE ARE NOT TAKING ADDITIONAL MONEY OUT OF THE DIVISION TO DO THIS. WE THINK IT IS A REPURPOSING AND GOOD USE OF THE MONEY THAT IS ALREADY SET ASIDE FOR THE SBIR PROGRAM. TIM? >> TIM: KARL, SO THE MONEY WILL BE SPENT ON PURELY DEVELOPING THE TECHNOLOGY? OR IS IT GOING TO INCLUDE SELECTION OF THE ENVELOPES? AND THE REASON I SAY THAT IS BECAUSE THAT IS VERY CRITICAL SO IT HAS TO DOVETAIL, THE SCHIFFS YOU HAVE TO DEVELOP TO GO WITH THAT FOR VACCINE TRIAL. SO I'M A LITTLE CONFUSED. IS THIS JUST FOR TECHNOLOGY PART? >> KARL: I THINK YOU CAN'T DO TECHNOLOGY IN THE ABSENCE OF WORKING ON SPECIFIC HIGH PRIORITY IMMUNOGENS AND THAT IS PART OF THE SELECTION CRITERIA THAT WE WOULD SET ASIDE IN AN SBIR REVIEW. WHAT ARE THE ENVELOPES YOU'RE PUTTING FORWARD? ADDITIONALLY WHEN WE PUT THIS OUT THERE, WE WILL GIVE THEM EXAMPLES OF WHAT WE THINK ARE THE BEST ENVELOPES TO BE WORKING ON GIVEN WHERE THE FIELD IS RIGHT NOW. SO, WE ARE NOT GOING TO WANT THEM TO COME IN WITH MN ON OR 3B, THAT'S FOR SURE. THAT WILL GET THEM KILLED. WE AGREE. [ LAUGHS ] A GOOD MIXTURE OF TRANSMITTER FOUNDERS WOULD BE IDEAL. PAUL? >> PAUL: APOLOGIES IF IS THIS NAIVE QUESTION. BUT ARE CONTRACTS REVIEWED IN THE SAME WAY AS GRANTS? IS THERE A STUDY SECTION? >> KARL: THAT'S A FAIR QUESTION. CONTRACTS ARE REVIEWED IN A SIMILAR WAY IN THAT THERE IS AN EVALUATION PANEL THAT COMES IN AND SCORES THEM BUT THEN THERE IS A PROCESS THAT GRANTS DON'T HAVE WHERE QUESTIONS CAN BE ASKED AND ANSWERED TO IMPROVE OR REDUCE THE SCORE, DEPENDING ON HOW THE APPLICANT ANSWERS THE QUESTIONS. IT'S SIMILAR BUT DIFFERENT. >> AND THE EXISTING SBIR, HOW MANY APPLICATIONS AND AWARDS HAVE BEEN MADE IN THAT? >> KARL: WE EXPECT WE MAY GET 3-4 APPLICATIONS IN THIS BOAT GIVEN THE STRIPIGENCEY WITH WHICH IS REQUIRED -- STRINGENT SEE -- IN TERMS OF A SMALL COMPANY WITH THE CHOPS TO DO THIS KIND OF WORK, IT'S NOT -- THERE AREN'T ACADEMICS THAT CAN DO THIS KIND OF THING, PER SE. THIS IS AGAIN FOCUSED ON SMALL BUSINESS. OTHER QUESTIONS? CAN I ASK THE COMMITTEE TO MARK THEIR BALLOTS AND PASS THEM TO MARK, PLEASE. THAT DAMN ELECTRONIC SYSTEM. THOSE WHO YOUR COMPUTERS OPEN, PLEASE MARK YOUR BALLOTS. THIS IS THE ONLY TIME YOU'LL HAVE TO DO THIS TODAY. WHILE YOU'RE MARKING THE BALLOTS, I'LL MOVE ON TO PROBLEMATIC UPDATES. SO DR. FAUCI TALKED ABOUT THIS BRIEFLY WHEN HE GAVE HIS AIDES UPDATE DURING HIS ADDRESS. WE ARE IN A PRETTY AMAZING TIME IN TERMS OF WHERE WE ARE WITH PREVENTION RESEARCH. THIS YEAR ALONE, WE HAVE PUT FORWARD FIVE FAIRLY SIGNIFICANT CLINICAL TRIALS LOOKING AT DIFFERENT PREVENTION MODALITIES. STARTING WITH THE HOPE TRIAL, WHICH IS AN OPEN-LABEL EXTENSION FROM THE ASPIRE TRIAL. WE HAVE TWO ANTIBODY MEDIATED PREVENTION TRIALS, AMP TRIALS. ONE IN MSM IN TRANSGENDERS IN AMERICAS AND THE WOMEN'S STUDY IN SOUTHERN AFRICA. WE HAVE OPENED 702, THE FOLLOW ON TRIAL TO RV144 AND THE MEN'S VERSION OF LONG ACTING INJECTABLE IS OPEN IN THE AMERICAS, HPTN0A3, WITH A GOAL TOWARDS OPENING PARALLEL WOMEN'S STUDY SIMILAR TO WHAT YOU SEE FOR ANTIBODIES WITHIN THE NEXT COUPLE OF MONTHS IN SUB-SAHARAN AFRICA. SO, WE ARE IN A PRETTY INCREDIBLE TIME IN PREVENTION RESEARCH. AND AS THEY SAY, EITHER GO BIG OR GO HOME AND THAT'S WHERE WE ARE. WE ALSO REALLY WANT THESE STUDIES TO HAVE -- ROLL QUICKLY TO ANSWER THE QUESTIONS QUICKLY. SO WE PUT A FAIR AMOUNT OF ENERGY AROUND THE LAUNCH OF 702 WITH GETTING A GOOD START IN SOUTH AFRICA. SO I HAD THE ABILITY TO GO TALK WITH LINDA-GAIL BECKER ON RADIO AND TELEVISION IN SOUTH AFRICA ON WORLD AIDS DAY. ADDITIONALLY, WE HAD A 3 PART LAUNCH. I WAS IN CAPETOWN WITH LINDA GAIL. WE HAD LARRY AND GLENDA IN THE OUTSKIRTED OF JOE HANNESSBURG AND -- JOHANNESBURG AND OUR COLLEAGUES DURBAN DEALING WITH THE LAUNCH. SO WE SATURATED THE MEDIA FOR A COUPLE OF DAYS WITH THE LAUNCH OF THIS STUDY. THE INTERESTING THING FOR ME, AS GOING FORWARD, IS THIS MESSAGE WAS NOT LOST ON OTHER PEOPLE. SO WHEN I GOT BACK TO THE UNITED STATES, MANY OF THE EUROPEAN DRUG COMPANIES SAID, HOW DID YOU DO THAT? WE WERE SO IMPRESSED BY THE LEVEL OF UPTAKE YOU HAD ON YOUR MESSAGING AND THEY WERE ALSO VERY AWARE OF HOW QUICKLY ENROLLMENT BEGAN FOR 702. OF COURSE EVERYTHING SHUT DOWN FOR THE HOLIDAYS AND 702 IS NOW REOPENED AND WE HOPE WE CAN MAINTAIN THAT MOMENTUM. LAST TOPIC I WOULD LIKE TO TOUCH ON IS THAT TIME OF THE CYCLE AGAIN TO START TALKING ABOUT THE RENEWAL OF THE HIV CLINICAL TRIALS NETWORKS. AND WHILE I DON'T HAVE A LOT TO SAY ABOUT THIS TODAY, WE WILL BE SPENDING A FAIRLY SIGNIFICANT AMOUNT OF TIME ON THIS ISSUE OVER THE NEXT 4 OR 5 ARAC MEETINGS. SO THIS WILL BECOME A VERY IMPORTANT TOPIC. SO, THE GOALS ARE WE ARE SETTING FORWARD ARE FIRST AND FOREMOST, STARTING NEXT WEEK, WE ARE GOING TO START WITH WEBINARS FOCUSED FIRST ON THE KEY GRANTEE STAKEHOLDERS AND THE COMMUNITY AS WELL, TO START ILLICITTING INPUT INTO A PLAN. WE'LL FORM A PLAN TO SEEK STAKEHOLDER INPUT INTO MAINLY THE SCIENTIFIC QUESTIONS THAT NEED TO BE ADDRESSED IN A VERY FORWARD-LOOKING WAY. REMEMBER, THAT THESE NETWORKS DO NOT FORMERLY RENEW UNTIL 2020. SO REALLY WE ARE GOING TO TAKE SOME TIME, SET THE QUESTIONS SO WHEN WE GET TO 2020, AND BEYOND, WE'LL HAVE THE RIGHT QUESTIONS TO REALLY HELP US TO GET THROUGH THE NEXT DECADE WHERE WE CAN REALLY HAVE A PROFOUND IMPACT ON THE EPIDEMIC. SO, THIS IS GOING TO BE THE FIRST PART OF THE EXERCISE IS GOING TO BE ABOUT SETTING THE QUESTIONS. ADDITIONALLY, PROCESSES AND PROCEDURES ARE UNDERWAY TO EVALUATE LEADERSHIP AND INTERACTIONS AND REFINE THE PROCESSES AND PROCEDURES TO MAINTAIN APPROPRIATE LEVEL OF OVERSIGHT OF FEDERAL FUNDS BUT ALSO TO TRY TO MINIMIZE THE BURDEN AT SITE NETWORK LEADERSHIP AND NAID STAFF WHILE PROMOTING THIS GOOD STEWARDSHIP AND ULTIMATELY INVOLVE PRACTICES AND PROCEDURES TO FACILITATE CLINICAL TRIALS, IMPROVE THE ABILITY TO MONITOR FOR OPERATIONAL SUCCESS AND FEW UTILITY. ONE OVERARCHING ITEM IS WE ARE PRETTY COMFORTABLE WITH THE CURRENT TRI-APARTHEID INSTRUCTOR OF A LEADERSHIP IN OPERATION CENTER, LABORATORY CENTER AND STATISTICAL AND DATA CENTER AS A MANAGEMENT STRUCTURE NA LEADS CLINICAL TRIALS APPARATUS. WE ARE ALSO REASONABLY SATISFIED WITH HOW THE CLINICAL TRIALS UNITS AND SITES ARE FUNDED AT THIS POINT IN TIME. SO, THE KEY DATES AS WE LOOK FORWARD IS IN MAY OF 2018, SO THAT IS A WAYS AWAY. WE'LL BE COMING BACK TO A CONCEPT APPROVAL. BUT IN THE MEANTIME WE WILL BE HAVING EXTENSIVE CONSULTATIONS AS WE APPROACH ARAC. NOT RELEASED UNTIL 19 AND ULTIMATELY AWARDS BEING MADE IN DECEMBER OF 2020. SO, I REALIZE THIS IS STARTING WAY IN ADVANCE BUT THIS DATE WILL BE HERE BEFORE YOU KNOW IT AND SO WE REALLY WANT TO MAKE SURE THAT WE TAKE THE TIME TO SET A ROBUST SCIENTIFIC AGENDA THAT ADDRESSES THE HIGHEST PRIORITY RESEARCH QUESTIONS THAT NEED TO BE SOLVED IN AIDS CLINICAL RESEARCH SO THAT WE CAN REALLY BEGIN TO DEVELOP THE NEXT SET OF TOOLS THAT WILL HELP US IN THE EPIDEMIC. SO, FOR TODAY, WE ARE GOING TO HEAR FROM THE PROGRAMS ABOUT THEIR SCIENTIFIC ACCOMPLISHMENTS AND FUTURE DIRECTIONS AND HERE ARE THE DATES FOR FUTURE MEETINGS. SO, TOMORROW IS AN AVRS MEETING N DECEMBER WE HAVE -- IN JUNE WE WILL HAVE ARAC MEETING. THERE WILL BE A STRATEGIC WORKING GROUP MEETING AT THE JUNE MEETING AND HERE ARE THE DATES FOR SEPTEMBER AND THE JANUARY 18 ARAC. YOU SHOULD HAVE ALL OF THOSE ON YOUR CALENDAR ALREADY. I'LL PAUSE THERE AND ANSWER QUESTIONS. THANK YOU FOR YOUR ATTENTION. NO QUESTIONS? WE'LL KEY UP THE FIRST -- >> THANK YOU, KARL. SO, OUR NEXT SPEAKER WILL BE TRIP, GIVING US AN OVERVIEW AND UPDATE OF THE OARAC ACTIVITIES. >> THANK YOU, CARA. SO I SERVE AS YOUR LIASON MEMBER FROM OARAC. I STARTED OFF AS A MEMBER AND THEN BECAME THE ACTING CHAIR. I'M CURRENTLY THE CHAIR. I'D LIKE TO REASSURE YOU YOU'RE IN GOOD HANDS. I'D LIKE TO POINT OUT THAT MOST RECENT MEETING OF THE GROUP WAS IN NOVEMBER. IT WAS MAUREEN'S FIRST MEETING AS DIRECTOR OF THE OAR AND SHE OF COURSE IS WITH US TODAY. I'D LIKE TO START BY RECOGNIZING THE WORKING GROUPS. THERE ARE FIVE WORKING GROUPS OF OARAC WHO REPRESENT THE GUIDELINES PANELS AND UPDATE YOU ON EACH OF THE FIVE GUIDELINES. SO THE ADULT AND ADOLESCENT TREATMENT GUIDELINES, THE LAST FULL DOCUMENT UPDATE WAS THIS PAST SUMMER IN JULY. THE MAIN THING THAT WAS ADDED WAS THE ADDITION OF TAF/FTC AS A PREFERRED COMBINATION REGIMENS. WE ALSO UPDATED SWITCHING AND DRUG INTERACTIONS AND THE EVER CHANGING HEP TITIS C THERAPY SECTIONS. THE ADULT AND ADOLESCENT OPPORTUNISTIC INFECTIONS GUIDELINES HAVE BEEN UPDATED MULTIPLE TIMES. SOME OF THE SPECIFIC UPDATED DISEASES ARE WHAT YOU SEE THERE. ONE THING TO NOTE FROM THIS GROUP IS THAT OPPORTUNISTIC GUIDELINES HAVE ROBUST DOWNLOADS. THAT SURPRISED PEOPLE AT FIRST GLANCE. BUT 20 YEARS INTO HIGHLY-EFFECTIVE ANTI-RETROVIRAL THERAPY, THE EXPERTISE OF OPPORTUNISTIC INFECTIONS AND TREATING THEM HAS CHANGED. SO PEOPLE ARE CONTINUING TO CONSULT THE GUIDELINES FOR UPDATED INFORMATION. THE PEDIATRIC TREATMENT GUIDELINES WERE LAST UPDATED IN MARCH OF LAST YEAR. THESE INCLUDED NEW FIX-DOSE COMBINATION FOR CHILDREN INCLUDING FTC, AND BOTH TAF AND THE TDF FORMULATIONS OF DA NOF VEER AND IMPROVED DOSING FOR DTG. THE PEDIATRIC OPPORTUNISTIC INFECTION GUIDELINES HAD MAGE REVISION IN DECEMBER OF LAST YEAR INCLUDING UPDATES ON HHV8 AND MICROSPORDOSEIS. THE PERINATAL GUIDELINES WERE UPDATED IN 2016. OCTOBER 26 TO BE EXACT. ONE OF THE BIG RECOMMENDATIONS FROM THAT UPDATE WAS THAT IT IS NO LONGER RECOMMENDED AGAINST THE USE OF EFV IN THE FIRST EIGHT WEEKS OF GESTATION. THERE WERE ALSO SWITCHES IN ANTI-RETROVIRAL THERAPY REGIMENS IN PREGNANT WOMEN. AZT/3TC, WHICH WAS A PREFERRED COMBINATION FOR MANY YEARS, NOW ALTERNATIVES. THIS WAS BECAUSE OF TOXICITY ISSUES. THE GUIDELINES CONTINUE TO BE CONSULTED BY PEOPLE ALL OVER THE WORLD. THIS IS AN INDICATION OF PAGE VIEWS OR DOWNLOADS BETWEEN OCTOBER OF '15 AND SEPTEMBER OF '16 AND YOU CAN SEE PAGE VIEWS ARE IN ORANGE AND DOWNLOADS IN BLUE BUT YOU CAN SEE REALLY ROBUST INTEREST IN THE CHANGING GUIDELINES. THESE INCLUDE BOTH U.S. AND AROUND THE WORLD. NOW MOVING -- I SHOULD ACKNOWLEDGE THE LEADERSHIP OF THE GUIDELINES AS YOU SEE HERE IN THE EXECUTIVE SECRETARY. AND AT THE BOTTOM WE NOTE OVER 200 VOLUNTEER MEMBERS WHO SERVE ON THESE FIVE WORKING GROUPS REALLY SPANNING EXPERTISE ACROSS THE COUNTRY. AND THEY WORK A LOT IN THESE WORKING GROUPS. SO THE PROCEEDING THE NOVEMBER OARAC MEETING WAS A WORKSHOP CALLED STRATEGIES FOR HIV CURE HELD HERE AT THE NIH NOVEMBER 14-16. THIS WAS A 3-DAY MEETING. THIS WAS REALLY SET THE STAGE FOR WHAT THE OARAC CONSIDERED ON THE NOVEMBER 17th MEETING. SO IMMEDIATELY FOLLOWING THE WORKSHOP. MANY MEMBERS OF THE WORKSHOP WERE ALSO IN ATTENDANCE AT THE OARAC MEETING. SO SESSIONS ONE AND TWO OF THIS WORKSHOP WERE AN OVERVIEW OF THE MARTIN DELANEY COLLAB TOURS FOR HIV CURE RESEARCH AND YOU CAN SEE SIX OF THEM LISTED FOR YOU THERE. EACH ONE PRESENTED IN TURN WITH THEIR SCIENTIFIC PRIORITIES WERE. THERE WERE SESSIONS 3, CLINICAL STUDIES, PEDIATRICS AND EARLY TREATMENT CONSIDERATIONS FOR CURE. SESSION 4, COMMUNITY ENGAGEMENT, SOCIAL SCIENCE AND ETHICAL CONSIDERATIONS FOR HIV CURE RESEARCH. SESSION 5, CONSIDERED HIV CURE BASIC RESEARCH. SESSION 6, PRE-CLINICAL CURE RESEARCH. AND SESSION 7, BEYOND HAART INNOVATIVE APPROACHES TO CURE HIV-1. AGAIN, THIS SET THE STAGE, THIS VERY SUCCESSFUL WORKSHOP, WHICH WAS ATTENDED BY SEVERAL HUNDRED PEOPLE. REPRESENTING PEOPLE FROM ACROSS THE COUNTRY. THE LAST OARAC MEETING WAS THE DAY AFTER ON NOVEMBER 17. WE FIRST HEARD FROM MAUREEN AS THE NEW OAR DIRECTOR AND HER VISION FOR WHAT THE OAR WOULD DO. PAUL INTRODUCED THE SCIENTIFIC SESSION, FOR THIS PARTICULAR MEETING WAS THE SUBJECT OF HIV CURE. DAN FROM BOSTON PRESENTED AN OVERVIEW OF THE WORKSHOP THAT I JUST OUTLINED FOR YOU. AND THEN TONY FAUCI PRESENTED A NOVEL APPROACH FOR HIV PERSISTENCE INVOLVING ALPHA 4 BETA 7 INTEGRIN. THIS WAS FOLLOWED BY JANICE WHO TALKED ABOUT THE BASIC RESEARCH HIGHLIGHTS OF THE CURE WORKSHOP. AND THEN WE HEARD FRIDAY SIX MARTIN DELANEY COLABORATORIES. THE THREE FUNDED AND REFUNDED STEVE SPOKE FROM DARE FROM UCSF. DAVID FROM UNC AND CARE COLABORATORY AND KEITH FROM THE UNIVERSITY OF WASHINGTON IN SEATTLE DEFEAT HIV. IN ADDITION, THE THREE NEW COLLABORATORIES HAD THE OPPORTUNITY TO SPEAK WHAT THEY WERE GOING TO DO. FROM HARVARD DAN, AND 49 PENN, JAMES RILEY, BEAT HIV, AND FROM GEORGE WASHINGTON, DOUG AD THE BELIEVE COLLABORATORY. THIS GAVE US AN OPPORTUNITY TO HEAR ALL SIX AND WHAT THE FUTTHURE PLANS WERE. WE HAD A PRESENTATION ON THE ETHICAL CONSIDERATION AND THE USE OF AN LISSIC TREATMENT INTERRUPTION IN HIV CURE RESEARCH WHICH IS A HOT TOPIC. LIZA DAWSON REALLY TOOK THE LEAD ON CONSIDERING THAT. AND THEN AN INTERACTIVE DISCUSSION INVOLVING PEOPLE WHO WERE IN ATTENDANCE TALKING ABOUT MILESTONES AND PATHS FOR MOVING FORWARD RESEARCH TOWARDS A CURE AND HOW THAT COULD BE ACCOMPLISHED. THERE WAS A PUBLIC COMMENT AND THEN A CLOSING COMMENT SECTION. JUST TO SUMMARIZE, THE CONSENSUS AT THE MEETING, THE GOAL OF HIV CURE COULD BE SUSTAINED REMISSION OR TRUE ERADICATION. AND THERE WAS SOME DISCUSSION ABOUT WHETHER THOSE GOALS ARE IN OPPOSITION EACH OTHER OR ACTUALLY TWO SIDES OF THE SAME COIN AND PERHAPS REINFORCE EACH OTHER. PEOPLE, THE CONSENSUS WAS IT'S A FALSE DICHOTOMY TO TALK ABOUT ERADICATION, WHICH WE DO HAVE INFECTIOUS DISEASES VERSUS REMISSION, WHICH WE THINK OF CANCERS. AND THAT SUFFICE IT TO SAY BOTH APPROACHES ARE IMPORTANT AND BOTH WOULD BE ASPIRATIONS. THERE WILL BE BENEFITS ALONG THE WAY PURSUING EITHER GOAL FOR HIV CURE. WE REVIEWED DISTRIBUTION OF RESOURCES AND CURRENTLY, ABOUT 35% IS ALLOCATED TO BASIC, 50% TO TRANSLATIONAL, 13% TO CLINICAL AND 2% TO BEHAVIORAL AND SOCIAL RESEARCH ON HIV CURE. AGAIN, SOME CONSENSUS ABOUT THAT. PEOPLE THOUGHT THAT FELT ABOUT THE RIGHT DISTRIBUTION GIVEN WHERE WE ARE WITH THE SCIENCE IN LATE 2016. THE PATH FORWARD AND MILESTONES TO EVALUATE THE PROGRESS. GENERAL FEELING THAT WE DO NEED TO PRIORITIZE AMONG THE MANY DIFFERENT AVENUES THAT PEOPLE ARE PURSUING. MAUREEN SUGGESTED ESTABLISHING A WORK GROUP TO HELP DO THAT. FOLLOW SUCCESS AND STOP INVESTIGATIONS OR UNITS THAT ARE NOT SUCCESSFUL AND ESTABLISH METICS AND HOW TO MOVE FORWARD. THESE SHOULD BE VIABLE AND TESTABLE. AGAIN, ILLUSTRATING THE ID VERSUS CANCER MODELS. ONE POSSIBLE METRIC THAT COULD BE USED FOR CURE RESEARCH WOULD BE SIGNIFICANT CLEARANCE OF THE RESERVOIR AND HOW THAT MIGHT BE MEASURED. THERE WAS COMMENT THAT PRE-CLINICAL TO CLINICAL RESEARCH COULD TAKE 5-10 YEARS. MIGHT BE A GOAL FROMIOD PROOF-OF-CONCEPT. SO, CLEARLY MORE WORK NEEDS TO BE DONE TO WORK THROUGH THIS BUT THIS WAS HELPFUL IN THINKING ABOUT MILESTONES AND HOW TO MOVE FORWARD. AND FINALLY, AS WE RECOGNIZE ITS GREAT SET MILESTONES BUT SCIENCE IS UNPREDICTABLE. OTHER TOPICS AND CHALLENGES THAT WERE REVIEWED AT THE MEETING, PEOPLE FELT THAT LANGUAGE AND TERMINOLOGY ARE IMPORTANT AND THAT THE WORD, "CURE" COULD BE DECEPTIVE NOT ONLY TO OUR COLLEAGUES IN THE FIELD BUT TO THE COMMUNITY AND THE PUBLIC AT LARGE. AND WE HAVE TO BE CAREFUL WHEN WE USE THAT WORD ABOUT WHAT WE ARE TALKING ABOUT. AGAIN, LOTS OF ANALOGIES TO THE% INFECTIOUS DISEASE HEP C MODEL OF TRUE CURE OR ERADICATION AND THE ONCOLOGY MODEL OF CONTROL OR REMISSION. THE GOALS FOR INTERVENTIONS FOR CURE, SAFE, SIMPLE AND SCALABLE. AND ONE NEEDS TO CONSIDER THAT THE CURRENT STANDARD OF CARE WITH ANTI-RETROVIRALS IS ONE PILL ONCE A DAY AND THAT FURTHER PROGRESS IS BEING MADE THERE AS WELL. SO ANYTHIG PROPOSED FOR A CURE REALLY HAS TO BE DIRECTLY COMPARED TO WHAT THE STANDARD OF CARE FOR ANTI-RETROVIRAL THERAPY IS. I NEED TO CONSIDER RESERVOIRS BEYOND THE CD4, INCLUDING MACROPHAGES, INCLUDING SITES SUCH AS THE CNS AND GENITAL TRACT. WE CONSIDERED ANIMAL MODELS. WE CONSIDERED CLINICAL TRIAL DESIGN FOR CURE, TALKING ABOUT SAFETY, WHAT THE OPTIMAL DURATION OF SUCH CLINICAL TRIALS WOULD BE AND WHO ARE SUITABLE CONTROLS ONCE CURE RESEARCH PROGRESSES FURTHER INTO CLINICAL TRIALS. LOTS OF DISCUSSION ON WHO SHOULD BE ENROLLED IN CLINICAL TRIALS OF CURE AND DIVERSITY WAS EMPHASIZED. NOTING THAT STUDIES TO DATE REALLY HAVE NOT DONE AS WELL AS THEY COULD HAVE REPRESENTING WOMEN, PEDIATRICS, NEONATES BEING A SPECIAL GROUP, ADOLESCENTS, AND SEEKING DIVERSITY FROM A RACIAL AND ETHNIC POINT OF VIEW AS WELL. THERE WAS GENERAL CONSENSUS THAT CURE RESEARCH AT LEAST THAT THE POINT SHOULD NOT INCLUDE PREGNANT WOMEN. AND THEN COMMUNITY WAS A BIG TOPIC OF DISCUSSION AT THE OARAC MEETING. COMMUNITY ENGAGEMENT BEYOND THE COMMUNITY ADVISORY BOARDS OR CABs, PARTICULARLY MESSAGING. AGAIN, WHAT DOES CURE MEAN FOR THE COMMUNITY AND HOW WILL WE GET THERE? AND FINALLY, IMPLEMENTATION ISSUES. SO WE COVERED A LOT IN THAT PARTICULAR DAY. AND I WILL STOP THERE AND SEE IF THERE ARE ANY QUESTIONS. >> THANK YOU, TRIP. ALL RIGHT. SO WE'LL MOVE TO A SERIES OF PROGRAMMATIC UPDATES NOW. THE FIRST WILL BE DEANNA FROM DIRECTOR OF THE BASIC SCIENCES PROGRAM. >> SO GOOD AFTERNOON, EVERYONE. SO THIS AFTERNOON MY EXPLAIN TO GIVE YOU AN OVERVIEW OF THE BASIC SCIENCES PROGRAM. OUR KEY ACCOMPLISHMENTS AND FUTURE DIRECTIONS. I UNDERLINE THE S HERE ON THE FIRST SLIDE IN MY TITLE BECAUSE OUR PROGRAM ACTUALLY ENCOMPASSES VERY DIFFERENT AREAS. SO I'LL GIVE YOU AN OVERVIEW OF WHERE WE FIT WITHIN THE DIVISION OF AIDS THE, OUR STRUCTURE AND ORGANIZATION AND TOUCH ON A FEW KEY PROGMMATIC SCIENTIFIC HIGHLIGHTS AND THEN WE'LL SAY A FEW WORDS ABOUT WHERE WE ARE HEADED FOR EACH OF OUR DIFFERENT AREAS. OUR SPECIFIC FY19 INITIATIVE PROPOSALS WILL BE PRESENTED AT THE NEXT MEETING. SO, AS THE BASIC SCIENCES BRANCH, MUCH OF WHAT WE SUPPORT IS REALLY EARLY EARLY STAGE BASIC SCIENCE. OUR FOUNDATIONS ARE IN FOR THE MOST PART, BOTH UNSOLICITED AND SOLICITED GRANTS. THE COHORTS IN SOME CONTRACTS. WE WORK WITH OTHER PROGRAMS WITH THERAPEUTICS, PREVENTION AND VACCINES AND WE OFTEN SEE THAT OUR INITIAL PROJECTS GROW IN THEIR DIRECTIONS AND AREAS THAT FALL IN BETWEEN PROGRAMS HAVE BECOME INCREASINGLY IMPORTANT. AND OVER THE PAST FEW YEARS, WE HAVE CONTINUED TO WORK HARD TO TRY TO LEVERAGE TOGETHER IN AREAS WHERE IT MAKES SENSE FOR US TO WORK BETWEEN PROGRAMS. AND IT HAS BEEN FOR EXAMPLE, VERY EXCITING AND INTERESTING TO SEE THAT INVESTIGATORS WHO HAVE DEDICATED THEIR LIVES TO WORKING ON HIV CURE NOW HAVE SWITCHED OVER AND DEDICATED SIGNIFICANT EFFORTS TO CURE. SO, REGARDLESS, OUR MAIN FOCUS IN THE BASIC SCIENCES PROGRAM IS TO SUPPORT A WIDE-BASE OF PROJECTS WITH DEPTH AND DIVERSITY. SO THIS SLIDE IS ACTUALLY A BUDGET SLIDE AND IT IS INTENDED TO GIVE YOU A BROAD SENSE OF HOW FUNDING IS ALLOCATED WITHIN OUR PROGRAM. THE ANNUAL BUDGET IS AROUND 340 MILLION. HALF OF THE GRANTS COME FROM THE UNSOLICITED POOL AND THE OTHER HALF ARE SOLICITED THROUGH RFAs, PROGRAM ANNOUNCEMENTS AND CONTRACTS. THESE ARE IN THE MIDDLE YOU CAN SEE THE THREE BRANCHES THAT I'LL DISCUSS IN A MINUTE AND ON THE RIGHT ARE SORT OF THE BIG PICTURE MAIN TOPICS THAT WE COVER. SO, AGAIN, WE ARE COMPOSED OF THREE BRANCHES AND ONE TEAM AND THIS IS THE ORGANIZATIONAL CHART LISTING THE PEOPLE WHO WORK IN BSP. THE EPIDEMIOLOGY BRANCH LED BY CARLIE WILLIAMS HAS BEEN FOCUSED ON OUTCOMES OF HIV DISEASE AS WELL AS THE EPIDEMIOLOGY OF HIV TRANSMISSION, BETWEEN INDIVIDUALS. THE PATHOGENIS AND BASIC RESEARCH BRANCH LED BY KARL, FOCUSES ON BASIC SCIENCE AND ON MECHANISTIC WORK. AND BUT THEIR FOCUS HAS REALLY SHIFTED OVER THE PAST FIVE YEARS FROM A HEAVY FOCUS ON PATHOGENESIS IN THE ABSENCE OF ANTI-RETROVIRALS TO A FOCUS ON TRYING TO UNDERSTAND WHERE AND HOW THE VIRUS PERSISTS IN PEOPLE WHO ARE TREATED AND IN THE FACE OF AN IMMUNE RESPONSE. THE TARGETED INTERVENTIONS BRANCH LED BY SANDRA BRIDGES, CONTINUES TO FOCUS ON SPECIFIC INTERVENTIONS. THE TARGET HIV WITH INCREASED FOCUS ON DRUGS OR BIOLOGICAL AGENTS AIMED AT ELIMINATING THE PERSISTENT RESERVOIR IN PEOPLE WHO ARE ON THERAPY. SO ADMINISTRATIVELY, ALL THREE BRANCHES OVERSEE A LARGE PORTFOLIO OF GRANTS. THE EPIDEMIOLOGY BRANCH HAS FOR MANY YEARS, AS I SAID, FOCUSED ON THE OUTCOMES SO OF DISEASE WITH THE MAX AND THE Ys AND THESE ARE TWO DOMESTIC COHORTS YOU'RE FAMILIAR WITH. THE MACS STUDIED THE EPIDEMIC IN MEN WHO HAVE SEX WITH MEN FOR 30 YEARS. AND THE YIHS HAS BEEN FOLLOWING INFECTED WOMEN FOR OVER 20 YEARS. AND AN IDEA I'LL COME BACK TO A LITTLE BIT LATER. IN ADDITION TO A LARGE NUMBER OF GRANTS, THE PATHOGENESIS AND BASIC RESEARCH BRANCH OVERSEES THE CFARs, THEIR 18 RIGHT NOW. AND THE CFARs ARE INTENDED TO FOCUS ON THEIR INDIVIDUAL PRIORITIES AND THEIR SPECIFIC AREAS. ALSO THE MARTIN DELANEY COLLABORATORIES JUST RE-AWARDED AS JUST MENTIONEDS AND THE REAGENTED PROGRAM. THE TARGETED INTERVENTIONS BRANCH OVERSEES THE BEYOND HAART GRANTS AND THESE ARE BASICALLY CELL AND GENE THERAPY GRANTS THEY ARE CO-FUNDED AND CO-MANAGED BY NHLBI. AND THEN SEVERAL CONTRACTS THAT ARE LISTED HERE. WE HAVE A CONTRACT TO DEVELOP MOUSE MODELS AND TEST DRUGS IN-VIVO. WE HAVE A CONTRACT INVOLVED IN DEVELOPING SCREENS AND DESTING OF NEW COMPOUNDS FOR THERAPEUTICS AND MICROBICIDES AND WE HAVE A CONTRACT TO DEVELOP A DUAL-AFFINITY RETARGETING MOLECULE AND I'LL TALK ABOUT THAT LATER TOO. AND THEN WE HAVE A QVOA CONTRACT MEANT TO BE ABLE TO TEST RESIDUAL VIRAL RESERVOIRS IN INFECTED PEOPLE THAT ARE TREATED. AND ESSENTIALLY, WITH THE EXCEPTION OF THE DART CONTRACT, ALL THE CONTRACTS SHADED A LITTLE BIT DARKER ARE INTENDED TO PROVIDE SERVICES TO OUR SCIENTIFIC COMMUNITY. SO, MOVING ALONG TO HIGHLIGHTS AND CHALLENGES, I'LL START WITH THE EPIDEMIOLOGY BRANCH. SO AS I MENTIONED BEFORE, THE EPIBRANCH HAS BEEN FOCUSED ON OUTCOMES AND RIGHT NOW WE ARE REALLY, REALLY IN THE THICK OF MAKING SIGNIFICANT CHANGES IN HOW WE SUPPORT AND MOVE FORWARD IN SUPPORTING THE WORK THAT NEEDS TO BE DONE IN TWO MAJOR AREAS. SO WE ARE WORKING HARD TO PARTNER WITH OTHER INSTITUTES TO CONTINUE TO STUDY THE OUTCOMES OF DISEASE AND AT THE SAME TIME, WE WANT TO LEAD EFFORTS TO GET A BETTER UNDERSTANDING OF HOW, WHEN AND WHERE TRANSMISSIONS OF HIV OCCUR. SO, ADVANCES HAVE BEEN MADE AS EVERYBODY KNOWS. LIFE EXPECTIES OF TREATED HIV INFECTED PEOPLE ARE SIMILAR TO THOSE WHO ARE UNINFECTED. BUT TREATMENT DOES NOT FULLY RESTORE HEALTH. TREATED PATIENTS REMAIN AT HIGHER -- SIGNIFICANTLY HIGHER RISK OF COMPLICATIONS THAT ARE GENERALLY ASSOCIATED WITH AGING. THEY ARE AT HIGHER RISK OF CARDIOVASCULAR DISEASE, LUNG, LIVER, KIDNEY DISEASE, THE END ORGAN DISEASES. CERTAIN TYPES OF CANCERS, NEUROCOGNITIVE DISORDERS, FRAILTY AND AGING. BUT PERHAPS ONE OF THE BIGGEST HEALTH CHALLENGES TO HIV INFECTED PEOPLE ARE BEHAVIORAL IN NATURE. THE MOST IMPORTANT BEING OF COURSE ADHERING TO MEDICATIONS, BUT ALSO THINGS LIKE STOPPING SMOKING. SO, THIS PAPER BY THE WALIN SKI AND FRIEDMAN GROUP, REPORTS THAT OVER 40% OF HIV-INFECTED PEOPLE IN THE UNITED STATES SMOKE. AND IT CONCLUDES THAT HIV SMOKERS IN THE U.S. LOSE OVER SIX YEARS OF LIFE EXPECTSY FROM SMOKING, POSSIBLY OUTWEIGHING THE LOSS FROM HIV INFECTION ITSELF. AND SO HERE THEY STATE THAT SMOKING CESSATION SHOULD BECOME A PRIORITY IN HIV TREATMENT PROGRAMS. AND SO, AS THESE COMPLICATIONS ARE MANY, THEY ARE DIVERSE AND COMPLEX. AND THEY ARE PERVASIVE IN THE GENERAL POPULATION AND ARE ALSO STUDIED IN OTHER INSTITUTES. THE EPIBRANCH IS WORKING REALLY HARD TO PARTNER MORE CLOSELY WITH THE OTHER INSTITUTES THAT SPECIALIZE IN STUDYING THE PATHGENIC MECHANISMS OF THESE TYPES OF DISEASES. SO, WE PLAN TO STAY VERY INVOLVED IN CONTINUING TO TRACK AND TO UNDERSTAND THE OUTCOMES OF HIV DISEASE. AND WHILE WE KEEP ONE FOOT FIRMLY AND FOLLOWING OUTCOMES, WE ALSO WANT TO INCREASE OUR EFFORTS IN UNDERSTANDING TRANSMISSIONS. TO THIS END, WE ARE FOCUSED ON UNDERSTANDING WHERE VIRAL LOADS ARE STILL NOT BEING FULLY SUPPRESSED BOTH ON A VERY HIGH INTERNATIONAL LEVEL BUT ALSO ON A MORE LOCAL INDIVIDUAL LEVEL. SO ONE OF THE MANY DATA POINTS CAPTURED IN IDEA ARE CD4 COUNTS -- ARE INITIATION THROUGHOUT THE WORLD. IDEA IS THE INTERNATIONAL EPIDEMIOLOGIC DATABASE EVALUATE AIDS. AND IT IS BASICALLY AN INTERNATIONAL CONSORTIUM WITH SITES IN OVER 130Y COUNTRIES AND IT COLLECTS DATA, CLINICAL DATA, ON OVER 1.7 MILLION ADULTS AND CHILDREN THROUGHOUT THE WORLD. THIS FIGURE SHOWS THAT THE MEDIAN CD4 COUNTS AT OUR INITIATION INCREASED IN ALL REGIONS OF THE WORLD SINCE 2007. BUT IT ALSO SHOWS THAT THERE IS GREAT ROOM FOR IMPROVEMENT EVERYWHERE. SO NOW I'M FOCUSING ON THE DYNAMICS OF SPREAD BETWEEN INDIVIDUALS. MODELING STUDIES ARE GIVING US VERY IMPORTANT INSIGHTS DEMONSTRATING THAT CONCENTRATING EFFORTS MAY BE MORE SPECIFICALLY, MIGHT HAVE A GREATER IMPACT. SO, WHILE OF COURSE EVERYBODY SHOULD BE TREATED, THIS STUDY BY SUSAN LITTLE INDICATES THAT FOCUSED EFFORTS KEY INDIVIDUALS -- SO THOSE WITH THE HIGHEST TRANSMISSION NETWORKS SCORES ARE THOSE THAT MIGHT BE AT HIGHEST RISK OF TRANSMITTING TO OTHERS, SLIGHT A GREATER IMPACT IN PREVENTING SPREAD OF HIV THAN RANDOM OR UNFOCUSED EFFORTS. SO IN MAY YOU'LL HEAR ABOUT OUR PLANS TO USE BIG DATA AND M HEALTH, CELL PHONES, ALL SORTS OF DATA TO BETTER UNDERSTAND CLUSTERS OF INFECTION AND TRANSMISSION PATTERNS. SO NOW MOVING TO BASIC RESEARCH. WE CONTINUE TO MAINTAIN A HEALTHY AND WIDE BASE OF BASIC SCIENCE PROJECTS. ON VERY DIVERSE AREAS, INCLUDING BASIC IMMUNOLOGY, CELLULAR, BIOLOGY, IMAGING, STRUCTURAL STUDIES, RESTRICTION FACTORS, BUT AGAIN AS I MENTIONED BEFORE, BIG FOCUS OVER THE PAST 5-10 YEARS HAVE BEEN TO STUDY HIV IN THE PRESENCE OF ANTIVIRAL DRUGS AND FOCUSING ON RESIDUAL VIRALS. SO THIS YEAR, AS JUST MENTIONED, WE RECOMPUTED AND RE-AWARDED THE MARTIN DELANEY COLLABORATORIES AND THESE GRANTS ARE FUNDED TO SUPPORT COORDINATED BASIC TRANSLATIONAL AND CLINICAL RESEARCH FOCUSED ON DEVELOPING STRATEGIES TO ACHIEVE AN HIV CURE, DEFINED AS EITHER SUSTAINED HIV REMISSION OR ERADICATION. EACH OF THESE COLLAB TOURS INCLUDES A PROVIDE SECTOR PARTNER IN ORDER TO FACILITATE RAPID FRANCEALATION AND EXPECTED TO CARRY OUT PRECLINAL AND CLINICAL STUDIES TO TEST EITHER THE NEW SINGLE OR COMBINATION STRATEGIES FOR HIV CURE. AS MENTIONED BEFORE, WE FUNDED SIX AND HERE I LIST THE NAMES OF THE INVESTIGATORS OF THE COLLABORATORIES NOT TO GO THROUGH EACH NAME ONE BY ONE, BUT TO GIVE YOU A FEEL FOR THE NUMBER OF DIFFERENT LAB THAT IS ARE INVOLVED. AND THE HOPE WITH THESE AWARDS IS THAT COLLABORATIVE SCIENCE WILL LEAD US TO SOME NEW INSIGHTS. AND RELATED TO OUR EFFORTS CURE, WE ALSO HAD THE CURE MEETING THAT TRIP MENTIONED EARLIER, THE STRATEGIES TOWARDS CURE MEETING LAST NOVEMBER; AND I'LL SAY WE HAD 800 REGISTRANTS AND 1,400 VIDEO VIEWS. SO I THINK OUR PUSH TOWARDS CURE HAS CERTAINLY BEEN QUITE FRUITFUL. NOW SCIENTIFICALLY, A PERSISTENT PROBLEM IN MEASURING PERSISTENT VIRUS INVOLVED GETTING AN ACCURATE MEASUREMENT OF HOW MUCH VIRUS THERE IS LEFT IN PEOPLE WHO ARE TREATED. THERE ARE MANY, MANY ASSAYS. I THINK THERE MAY BE 10-15 DIFFERENT ASSAY. AND EACH ONE TELLS US SOMETHING SLIGHTLY DIFFERENT ABOUT WHAT THAT RESIDUAL VIRUS LOOKS LIKE. HERE ON THIS GRAPH ON THE LEFT, EACH OF THE DOTS REPRESENTS AN INDIVIDUAL. THE IUPM ASSAY GIVES THE FREQUENCIES OF INFECTIOUS VIRUS, THE NEXT ONE OVER, THE INTACT PROVIRUS, BASICALLY GIVES THE NUMBER OF PROVIRUSES THAT THEORETICALLY COULD BE TURNED ON IN A PERSON. AND THEN THE GAG AND TOTAL, THE OTHER TWO, BASICALLY CORRESPOND TO ANY A LITTLE BIT OF HIV THAT COULD BE IN A CELL OF AN INFECTED PERSON WHO IS ON TREATMENT. NOW, IF YOU LOOK ON THE LEFT, YOU'LL NOTE THAT THIS IS THE SCALE IS A LOG SCALE. AND THERE IS SIGNIFICANT VARIATION BOTH WITHIN ASSAYS BUT ALSO BETWEEN ASSAYS. SO FOR EXAMPLE, IF YOU LOOK AT THE IUPM ASSAY, TYPICALLY YOU CAN FIND BETWEEN 1-10 INFECTIOUS VIRUSES PER MILLION CELLS. AND THEN IF YOU LOOK OVER FURTHER TO THE RIGHT FOR THE TOTAL NUMBER OF INFECTED CELLS, IT'S FROM 1000 -100,000. BUT PERHAPS THE BIGGEST FRUSTRATION IN THE FIELD IS THAT THERE IS NO CLEAR CORRELATION BETWEEN THESE DIFFERENT WAYS OF MEASURING RESIDUAL VIRUS. SO, IF YOU LOOK AT THE BOWLS ON THE RIGHT, EACH BOWL BASICALLY CAN REPRESENT ONE PERSON. AND ONE INDIVIDUAL MIGHT HAVE A VERY SMALL FREQUENCY OF REPLICATION COMPETENT VIRUS AND HIGH LEVELS OF TOTAL VIRUS. ANOTHER MIGHT HAVE MORE REPLICATION COMPETENT VIRUS BUT RELATIVELY LITTLE TOTAL HIV DNA. SO, IN OTHER WORDS, THERE IS NO GOOD RATIO, NO CLEAR RATIO BETWEEN THE DIFFERENT WAYS OF MEASURING VIRUS. AND THIS REMAINS A FAIRLY CONTENTIOUS TOPIC OF DISCUSSION IN THE FIELD. BUT WHAT WE REALLY KNOW WELL IS, AND HAVE KNOWN FOR QUITE A LONG TIME, IS THAT TAKING PEOPLE OFF OF THERAPY RESULTS IN VERY, VERY RAPID REBOUND OF VIREMIA USUALLY IN JUST 2-3 WEEKS. AND ALTHOUGH THERE HAVE BEEN A FEW FAIRLY RARE AND VERY NOTABLE CASES OF PROTRACTED PERIODS WITH ABSENCE OF REBOUND, VIRTUALLY ALL PATIENTS REBOUND. AND WE KNOW NOW THAT EVEN THOSE TREATED SUPER SUPER EARLY, EVEN BEFORE SERA CONVERTING, EVERYBODY APPEARS TO REBOUND. ANOTHER THING THAT IS WELL-KNOWN IS THE STABILITY OF THE FREQUENCY OF REPLICATION COMPETENT VIRUS AND HOW THIS STABILITY -- BUT HOW THIS STABILITY IS MAINTAINED. SO IN OTHER WORDS, THERE IS THIS STRIKING LACK OF VARIATION AND FREQUENCY OVER LONG, LONG PERIODS OF TIME AND HOW THIS OCCURS, HOW IT IS MAINTAINED THIS WAY IS UNKNOWN. BUT RECENT STUDIES BY SEVERAL LABS AND THIS IS A SLIDE THAT I GOT FROM SHARON LEWIN, WHICH I THINK SHOWS WELL THE IDEA, RECENT STUDIES BY OTHERS HAVE SHOWN THE OCCURRENCE OF CLONAL EXPANSION OF LATENTLY INFECTED CELLS. ON THE LEFT IS WHAT HAS BEEN OBSERVED IN VIREMIC PEOPLE. SO BASICALLY, IF YOU SAMPLE PEOPLE WHO HAVE HIGH LEVELS OF VIRUS REPLICATING, YOU SEE RANDOM INTEGRATION. BUT ON THE RIGHT-HAND SIDE WHERE NEW ROUNDS OF INFECTION COMPLETELY SUPPRESS VIRAL REPLICATION, A DIFFERENT REALITY EMERGES. WHAT YOU SEE IS THAT THERE IS CLONAL EXPANSION. AND WHAT IS DRIVING THIS CLONAL EXPANSION IS UNKNOWN. IT'S UNCLEAR. IT MAY BE DRIVEN BY THE INTEGRATION SITE. IT MIGHT BE DRIVEN BY HIV-SPECIFIC T-CELL RESPONSES OR THERE MIGHT BE SOME HOMEOSTATIC MECHANISM RELATED. AND I THINK THIS IS ACTUALLY REALLY INTERESTING, RELATED TO HOMEOSTATIC -- TO IMLONGIC MEMORY. SO IN OTHER WORDS, IT MIGHT BE SOME MECHANISM THAT IS RELATED TO THE BIOLOGICAL ROLE OF THESE CELLS TO MAINTAIN T-CELL MEMORY. IN A RECENT STUDY FROM ANOTHER GROUP, IT WAS SHOWN THAT THERE IS A NEGATIVE CORRELATION BETWEEN THE SIZE OF THE EXPANDED CLONE AND THE PROBABILITY OF REACTIVATION SUCH THAT THE LARGER SORT OF MORE NUMEROUS THE CLONE, THE CLONAL POPULATION, THE LOWER THE LIKELIHOOD OF REACTIVATION. AND ESSENTIALLY ALL I'M TRYING TO SAY HERE, THE TAKEHOME MESSAGE, IS THESE CLONAL POPULATIONS BEHAVE VERY DIFFERENTLY. AND SOME MAY BE MUCH HARDER TO REACTIVATE THAN OTHERS. SO, WE CLEARLY HAVE A LOT OF WORK TO DO IN THIS AREA. NOW MOVING TO OUR TARGETED INTERVENTIONS GROUP. WITH THE SUCCESS OF A RV'S, WE CONTINUE TO SUPPORT STUDIES ON NEW TARGETS BUT THE MAIN SHIFT HAS ACTUALLY BEEN TOWARDS THE STUDY OF BIOLOGICAL MOLECULES FOR CURE ERADICATION OR CONTROL. AND YOU'RE ALL QUITE FAMILIAR WITH THE BROADLY NEUTRALIZING ANTIBODIES. AND THIS FIGURE SHOWS YOU THE EFFECTS OF THE RCL1 AND VERY SIMILAR RESULTS HAVE BEEN SHOWN WITH THE OTHER BROADLY NEUTRALIZING ANTIBODIES BUT THE MAIN POINT WITH THESE STUDIES IS THAT WE WANT TO FIND WAYS TO MANIPULATE OR TO MODIFY THE IMMUNE SYSTEM IN ORDER TO FIND LONGER LASTING WAYS TO PROTECT% OR CONTROL, TO MANIPULATE THE IMMUNE SYSTEM AGAINST HIV. SO BIOLOGICALS OR MEDICINAL PREPARATIONS MADE FROM LIVING ORGANISMS AND THEIR PRODUCTS. AND THE EXAMPLES INCLUDE THE MONOCLONAL ANTIBODIES, ANTIGEN RECEPTORS, DUAL AFFINITY RETARGETING MOLECULES, CHECK POINT INHIBITORS OR COMBINATIONS OF THESE. AND THIS NEXT SLIDE IS INTENDED TO SHOW THAT THERE ARE MANY, MANY CELL SURFACE SIGNALING MOLECULES INVOLVED IN THE NETWORK OF RECEPTOR LIGAND INTERACTIONS WITH BOTH STIMULATORY AND INHIBITORY CAPACITY. AND THESE -- OR IMAGINE TAKING PIECES OF THESE COULD BE COPIED OR OTHERWISE ADAPTED OR MANIPULATED TO EFFECT IMMUNE LOGIC INTERACTIONS. AND AN EXAMPLE OF WORK BEING DONE THROUGH TARGETED INTERVENTIONS BRANCH IS THIS DARTS CONTRACT WE AWARDED TO MACROGENICS. MACROGENICS HAS ALREADY PUT NUMEROUS DARTS INTO THE CLINIC FOR ONCOLOGY STUDY WITH NO MAJOR BOUT OF EFFECTS IN PEOPLE. THE DARTS THAT WERE CHOSEN HERE BY MACROGENICS WERE CHOSEN BY VIRTUE OF THEIR AMOUNT TOW RECOGNIZE ENVELOPE ON THE SURFACE OF INFECTED CELLS. AND TO RECOGNIZE GP120 AND GP41. BUT BECAUSE RECOGNITION REQUIRES VIRAL GENE EXPRESSION, WE WILL NEED TO INCLUDE LATENCY REACTIVATING AGENTS WITH THESE TYPES OF STRATEGIES. SO FINALLY, I WANT TO SPEND A FEW MINUTES TALKING ABOUT THE RECENT AND VERY EXCITING RESULTS OF THE ASTA 4 BETA 7 STUDIES -- ALPHA 4 BETA 7 STUDIES CARRIED OUT BY DR. FAUCI'S LAB. SO ALPHA 4 BETA 7 IS AN INTERGRIN PROTEIN THAT IS EXPRESSED ON THE SURFACE OF LYMPHOCYTES AND IT PROMOTES HOMING OF LYMPHOCYTES TO INFLAMED TISSUES. NAIVE AND EFFECTOR LYMPHOCYTES USE THIS ALPHA 4 BETA 7 INLET GRIN AND FOLLOW SEQUENCE OF EVENTS WHICH INCLUDES CHEMOKINE MEDIATED ACTIVATION ROLLING AND SUBSEQUENT ADHESION, AND THEN TRANSENDOTHELIAL MIGRATION FROM BLOOD TO GUT MUCOSAL TISSUES VIA V CAM FIBERI IN EFFECT IN AND MAD CAM. SO MOLECULES OF THE SURFACE OF THE ENDOTHELIAL MUCOSA. BLOCKING ALPHA 4 BETA 7 INHIBITS THE TRANSMIGRATION AND ANTIBODIES TO ALPHA 4 BETA 7 HAVE BEEN USED IN INFLAMMATORY DISEASES SUCH AS CROHN'S DISEASE OR INFLAMMATORY BOWEL DISEASE. AND THE MANIFESTATIONS OF THESE GUT DISEASES RESULTS FROM THE DYSREGULATED RECRUITMENT OF LYMPHOCYTES TO SITES OF INFLAMMATION WHERE THEY INFLICT CYTOKINE MEDIATE THE DAMAGE. AND THE ANTIBODIES USED CLINICALLY ARE BASICALLY THOUGHT TO BLOCK THE TRANSMIGRATION AND THEREFORE TO REDUCE INFLAMMATION. SO, AS I MENTIONED A FEW MONTHS AGO, DR.S AN SARY AND DR. FAUCI PUBLISHED A PAPER WHERE TREATED AND INFECTED RHESUS MONKEYS WERE TREATED WITH ANTI-ALPHA 4 BETA 7. AND THIS IS THE KEY FIGURE SHOWING THE RESULTS. AND TO ORIENT YOU, PLEASE FOCUS ON THE TOP LEFT HAND PANEL AND NOTICE THE EXPERIMENT TOOK PLACE OVER THE COURSE OF FIVE SEPARATE PHASES. MARKS BY SHADING OVER TIME. IN PHASE I, THE ANIMALS WERE INFECTED AND YOU CAN ALL SEE THE RISE AND THE PEAK IN VIREMIA AT WEEK FIVE THAT CORRESPONDS TO PHASE II, ALL THE ANIMALS WERE SUPPRESSED WITH ANTI-RETROVIRAL DRUGS. IN PHASE III, ALL THE ANIMALS CONTINUED ON DRUGS BUT ALPHA 4 BETA 7 INFUSIONS WERE BEGUN IN THE TEST ANIMALS, WHICH ARE IN THE TOP LEFT PANEL. IN PHASE 4, THE INFUSIONS WERE CONTINUED. IN TEST ANIMALS AND ALL THE ANIMALS WERE TAKEN OFF OF DRUGS. AND YOU CAN SEE THAT OF THE EXPERIMENTAL ANIMALS, TWO REMAIN SUPPRESSED THE ENTIRE TIME. SORRY, I DON'T KNOW HOW TO USE THE POINTER. TWO REMAINED COMPLETELY SUPPRESSED. AND THE OTHERS HAD SOME UPS AND DOWN AND BLIPS. THESE ARE THE EXPERIMENTAL ANIMALS. THE CONTROL ANIMALS ALL REBOUNDED AND ALL STAYED HIGH. THIS PANEL HERE SHOWS THE AVERAGE OF THE TWO WHERE THE ALPHA 4 BETA 7 ANTI-ALPHA 4 BETA 7 ANIMALS TREATED WERE SUPPRESSED AND THE CONTROLS REBOUNDED AND STAYED HIGH. ON THE RIGHT-HAND SIDE, THIS BASICALLY IS SHOWING DNA LEVELS AND GASTROINTESTINAL TISSUES AND HERE AGAIN THE EXPERIMENTAL ANIMALS, THERE IS A RISE DURING THE PEAK VIREMIA DROP WITH DRUGS AND THEN THESE BLITZ OF BLIPS AND THEN COMPLETELY SURPRESSED WHEREAS THE CONTROL ANIMALS SHOWED SIGNS OF HIV DNA AND THESE ARE THE AVERAGES. SO THE REMARKABLE THING IS THESE RESULTS ARE IN THE ABSENCE AND NOW THE ANIMALS HAVE BEEN OFF OF DRUGS FOR LONG PERIODS OF TIME. I THINK OVER TWO YEARS. AND I'M ALMOST DONE WITH MY TALK AND IF THERE ARE ANY QUESTIONS ON THIS WE WILL DIRECT THEM TO DR. AN SARY WHO IS RIGHT HERE WITH US. SO MECHANISTICALLY IT REMAINS UNCLEAR HOW THIS OCCURS BUT COMES ON THE HEELS OF MANY, MANY YEARS OF WORK ON ALPHA 4 BETA 7 IN BOTH OF THE LABS AND IT ALSO COMES AFTER DR. ANN SARY SHOWN IN PREVIOUS WORK THAT ANTI-ALPHA 4 BETA 7 IS ALSO PROTECTIVE FROM ACQUISITION OF INFECTION. SO, IN THE COMING YEARS IT'S GOING TO BE REALLY, REALLY CRITICAL TO GET A BETTER UNDERSTANDING OF THE EXPERIMENTAL CONDITIONS THAT MEDIATE THESE EXCITING RESULTS SO THAT WE CAN SEE WHAT CAN BE MOST IMPORTANTLY IN PEOPLE WHO ARE CHRONICALLY INFECTED. AND AS MENTIONED BEFORE, THERE IS ALREADY A CLINICAL TRIAL UNDERWAY AND WE ARE PUTTING A LOT OF EFFORT INTO UNDERSTANDING THIS WORK. SO, TO SUMMARIZE, I HOPE I HAVE SHOWN YOU TODAY IN TERMS OF VERY BIG PICTURE DIRECTION, THAT IN EPI, WE ARE WORKING HARD TO PARTNER WITH THE OTHER INSTITUTES, TO UNDERSTAND THE OUTCOMES OF HIV DISEASE. WE ARE ALSO WORKING TOWARDS A BETTER UNDERSTANDING OF WHAT DRIVES HIV TRANSMISSION BETWEEN INDIVIDUALS. IN THE PATHOGENESIS AND BASIC RESEARCH BRANCHES AND THE TARGETED INTERVENTIONS BRANCH, WE ARE WORKING TO UNDERSTAND THE MECHANISMS OF HIV PERSISTENCE AND IN FINDING NEW WAYS TO GET RID OF THAT LAST BIT OF VIRUS. I WANT TO END BY THANKING MY COLLEAGUES, ESPECIALLY ALAN FOR HELPING ME WITH GETTING THIS ALL TOGETHER. BUT MORE IMPORTANTLY, I WANT TO THANK MY PROGRAM FOR ALL THE WORK THEY DO EVERY DAY FOR BASIC SCIENCES PROGRAM. THANK YOU. [ APPLAUSE ] PAUL? >> PAUL: SO I'D LIKE TO CHALLENGE YOU ON A COUPLE OF POINTS. SO I WAS STRUCK. I DIDN'T KNOW THIS BEFORE. THAT ABOUT HALF OF THE BASIC SCIENCE BUDGET IS FOR SOLICITING RATHER THAN UNSOLICITED WORK. I WOULD ARGUE THE MAJORITY OF THE REALLY PARADIGM SHIFTING ADVANCES THAT HAVE BEEN MADE COME FROM COMPLETELY UNEXPECTED OUT OF LEFT FIELD, SOURCES. HOW DO YOU JUSTIFY THAT DIVISION? >> SO, I COMPLETELY AGREE WITH YOU. I THINK THAT PART OF WHEN WE SAY SOLICITED, THE CATEGORIES ARE PRETTY BROAD. I MEAN, IF IT'S SOLICITED TRYING TO UNDERSTAND OR QUANTIFY RESIDUAL PROGRESS. IT'S FAIRLY OPEN. IT'S THE CATEGORIES CAN BE QUITE BROAD. SO, I WOULD SAY THAT IT'S NOT AS BAD AS IT SEEMS. SOME OF IT IS TARGETING PEOPLE TOWARDS BIGGER SUBJECTS. BUT I HEAR YOU. >> PAUL: OKAY. I'D LIKE TOW JUST MAKE THAT POINTED. SOLICITED AREAS OF RESEARCH NEED TO BE PROTECTED. THE OTHER THING I WOULD RAISE IS THE -- WHILE OBVIOUSLY PURSUING A CURE IS CLEARLY A WORTHWHILE THING TO DO, I THINK IT WOULD BE TRUE TO SAY THAT MOST OF WHAT WE HAVE LEARNED SO FAR FROM CURE RESEARCH IS HOW DIFFICULT AND MAYBE EVEN IMPOSSIBLE IT IS GOING TO BE. SO, ALSO FROM YOUR LITTLE CHART HERE, IT LOOKS LIKE ABOUT A THIRD OF THE RESOURCES ARE GOING TO CURE RESEARCH. SO, FOR HOW LONG IS THAT SUSTAINABLEAT? WHAT POINT -- ESTIMATE POINT IN THE FUTURE WHERE THERE ISN'T MUCH PROGRESS -- NOW WE DON'T EVEN KNOW WHAT WE ARE MEASURING. HOW DO YOU JUSTIFY THAT DIVISION OF RESOURCES? >> SO, THE WAY I SEE IT IS WHAT WE KNOW -- WE KNOW OUR ENEMY. IT'S BEING DEFINED PRETTY CLEARLY AND WE HAVE A TARGET. AND SO, WE ARE FOCUSED ON GETTING RID OF THAT. I COMPLETELY AGREE IT'S AN EXTREMELY DIFFICULT PROBLEM TO OVERCOME AND THAT -- FOR EXAMPLE, I WOULD AGREE WITH YOU THAT THE REACTIVATION STRATEGIES IS PROBABLY A TOUGH ROAD TO TAKE. BUT STILL, I MEAN, WE HAVE THE TARGET. WE ARE NOT COMPLETELY WORKING IN THE ABSENCE OF AN IDEA OF WHAT TO DO. >> I FULLY UNDERSTAND AND APPRECIATE THAT. BUT I WOULD CONVEY THAT THERE IS A SENTIMENT IN THE FIELD THAT THE CURE RESEARCH DOES NOT HAVE TO BE OF THE SAME QUALITY TO GET GOOD CHANCE OF RECEIVING FUNDING COMPARED TO OTHER AREAS OF BASIC RESEARCH IN HIV. >> THANK YOU. AND I AGREE AND I THINK WE ARE ALSO INTERESTED IN STIMULATING, FOR EXAMPLE, THE RESTRICTION FACTORS AND OTHER AREAS BUT WE DO ALSO HAVE A BROAD BASE. BUT THANK YOU AND I AGREE. >> COULD YOU COMMENT ON THE FUTURE OF THE MACS AND YIHS? >> LET'S SEE HOW MUCH I CAN COMMENT. I THINK I BASICALLY TOLD YOU -- GAVE YOU AN IDEA AND THERE IS A LOT OF WORK AND DISCUSSION GOING ON. AND I THINK YOU GET THE IDEA THAT WE WANT TO STAY VERY INVOLVED BUT WE NEED TO PARTNER WITH THE OTHER INSTITUTES BECAUSE OF THEIR EXPERTISE. SO THAT PROBABLY DOESN'T SATISFY YOU AND I THINK THAT IT'S SOMETHING THAT IS IN THE WORKS. [ OFF MIC ] >> BOTH. THEY GO HAND-IN-HAND. [ OFF MIC ] >> THANK YOU. I THINK WE'LL MOVE ON NOW, THANKS. OUR NEXT SPEAKER IS SARAH REID WHO IS GOING TO GIVE US UPDATE ON THE THERAPEUTICS RESEARCH PROGRAM. >> SARAH: GOOD AFTERNOON. CAN YOU HEAR ME? MY NAME IS SARAH REID, DIRECTORS OF THE THERAPEUTICS RESEARCH PROGRAM. IT'S MY PLEASURE TO GIVE YOU SOME UPDATES ON RECENT ACTIVITIES OF THE PROGRAM AS WELL AS TO GIVE YOU AN IDEA OF OUR FUTURE DIRECTIONS. OUR OVERALL OBJECTIVE OF THE THERAPEUTICS PROGRAM IS TO PLAN, IMPLEMENT AND EVALUATE A SCIENTIFIC AGENDA FOR PRE-CLINICAL DEVELOPMENT AS WELL AS CLINICAL TESTING OF DIAGNOSTICS AND THERAPIES TO TREAT AND CURE -- >> SARAH, COULD YOU GET CLOSER TO THE MICROPHONE? >> SARAH: SORRY. OR CURE HIV INFECTION, ITS CO-INFECTIONS, AS WELL AS CO-MORBIDITIES. WE ARE ORGANIZED IN FOUR BRANCHES. THE HIV RESEARCH BRANCH IS HEADED BY CARLA, AND THE COMPLICATIONS AND CO-INFECTIONS BRANCH BY BEVERLY SMITH. >> DRUG DEVELOPMENT IS HEADED BY JOE AND TB BRANCH BY RICHARD. WE HAVE A SMALLER GRANT PORTFOLIO RELATIVE TO BSP BUT THE LARGEST GRANTS WITHIN IT FUND OUR ADULT THERAPEUTIC CLINICAL TRIALS NETWORKS, ACTG AS WELL AS INSIGHT. WE ALSO HAVE A NUMBER OF RESEARCH SUPPORT CONTRACTS AND A NUMBER OF THESE ARE DESIGNED TO SUPPORT THE WORK THAT GOES ON WITHIN THE CLINICAL TRIALS NETWORKS, BOTH THERAPEUTICS AS WELL AS SOME OF THE PREVENTION TRIALS NETWORKS WITHIN OTHER PROGRAMS. THOSE ARE QUALITY ASSURANCE PROGRAMS THAT ARE FOCUSED ON IMMUNOLOGY, VIROLOGY AND CLINICAL PHARMACOLOGY. WE ALSO HAVE A PATIENT SAFETY MONITORING SUPPORT CONTRACT FOR INTERNATIONAL LABS AND THEN WE HAVE SOME RESEARCH CONTRACTS THAT ARE FOR SUPPORTING MORE PRE-CLINICAL DEVELOPMENT WORK. THE MOST RECENT ADDITION TO OUR RESEARCH SUPPORT CONTRACTS IS THE TBQA OR THE MICROBACTERIUM TUBERCULOSIS QUALITY ASSESSMENT PROGRAM AND THIS WE VERY RECENTLY AWARDED IN THE LAST MONTH, BECAUSE OF THE INCREASING WORK IN TUBERCULOSIS OUR CLINICAL TRIALS NETWORKS ARE DOING. IN ADDITION TO THOSE RESEARCH SUPPORT CONTRACTS WE ALSO HAVE A NUMBER OF SBIR CONTRACTS THAT WE HAVE BEEN ABLE TO SOLICIT OVER THE LAST SEVERAL YEARS. AND WE SOLICIT BY PUBLISHING TOPICS OF INTEREST AND THE ONES YOU SAW FROM KARL THIS MORNING AND THEY KIND OF RUN THE GAMUT DEPENDING ON WHAT IT IS WE SOLICITED IN ANY GIVEN YEAR. BUT THESE ACTIVE CONTRACTS WE HAVE YOU CAN SEE ARE FOCUSED ON A VARIETY OF TOPICS OF INTEREST TO OUR PROGRAM INCLUDING ALTERNATIVE DELIVERIES FOR ANTI-TB DRUGS, A COUPLE OF CONTRACTS FOCUSED ON SAMPLE PREPARATION BLOOD AND SPUTUM AND MEASUREMENTS OF RESISTANCE IN HIV AND TB. BUT I'D SAY THE BULK OF THE WORK THAT THE PROGRAMS INVOLVED WITH IN TERMS OF THE NUMBER OF GRANTS THAT WE SUPPORT AS WELL AS THE HUMAN RESOURCES WITHIN OUR PROGRAM ARE REALLY FOCUSED ON OVERSEEING CLINICAL TRIALS. CURRENTLY WE HAVE 58 INTERVENTIONAL CLINICAL TRIALS WE ARE OVERSEEING AND THAT MEANS THOSE ARE INACTIVE STAGES EITHER IN DEVELOPMENT THROUGH -- IN FOLLOW-UP. AND IF THOSE TRIALS WERE TO MEET THEIR TARGET SAMPLE SIZES IT WOULD MEAN A TOTAL ENROLLMENT OF OVER INITIATEY,000 PARTICIPANTS. AND -- 30,000 -- AND CURRENTLY WE HAVE OVER 13,000 ENROLLED ACROSS THE TRIALS. THEY RANGE WIDELY IN SIZE FROM UNDER A DOZEN PARTICIPANTS FOR THE VERY HIGH-RISK PROOF-OF-CONCEPT STUDIES TO OVER 6000 FOR SOME OF OUR CLINICAL END POINTED STUDIES AND THEY ALSO COVER A BROAD RANGE OF SCIENCE AND I'LL GET INTO MORE OF THAT TO GET A FLAVOR FOR WHEN I TALK ABOUT OUR RESEARCH PRIORITIES. IN ADDITION TO INTERVENTIONAL CLINICAL TRIALS WE ALSO SUPPORT SMALL NUMBER OF OBSERVATIONAL STUDIES. A COUPLE OF THOSE ARE DESIGNED PURELY FOR COLLECTING SAMPLES FOR GENETIC ANALYSIS BUT SOME OF THEM ARE ALSO LOOKING AT SPECKS OF TIMING OF AREN'T RETROVIRAL THERAPY, FOR EXAMPLE EARLY THERAPY IN LOOKING AT EFFECTS ON RESERVOIRS AS WELL AS IMMUNE RESPONSES AND TAKE ADVANTAGE OF THE HISTORY WITHIN THE ACTG OF FOLLOWING PARTICIPANTS FROM THE TIME THEY ARE NAIVE AND START THERAPY AND LOOK AT EFFECTS OVER TIME ON THINGS SUCH AS RESERVOIR ON DIFFERENT ASPECTS OF AGING AND SO ON. BUT TO GET INTO SOME OF OUR MORE SPECIFIC FOCUS AREAS OF RESEARCH, AGAIN IT COVERS A BROAD RANGE OF TOPICS INCLUDING NOVEL TREATMENT STRATEGIES AND I'LL GET INTO A LITTLE BIT MORE OF WHAT THAT MEANS EXACTLY. WE ALSO ARE INTERESTED IN HIV CURE SUSTAINED REMISSION FROM A CLINICAL ASPECT. WE ARE ALSO INTERESTED IN CO-MORBIDITIES IN THE SETTING OF SUPPRESSIVE ART AS WELL AS IMPORTANT CO-INFECTIONS AND ALL OF THESE RESEARCH FOCUS AREAS SHARE THE MAIN GOAL OF IMPROVING OUTCOMES FOR PEOPLE LIVING WITH HIV. SO FIRST TO GET INTO NOVEL TREATMENT STRATEGIES. PREVIOUSLY AS A PROGRAM, AND OUR CLINICAL TRIALS NETWORKS REFLECTED THIS, WE WERE INTERESTED IN ANSWERING QUESTIONS ABOUT WHEN TO START ART AND WHAT TO START. I THINK WE REALLY MOVED BEYOND THAT WITH SOME RECENT TRIALS WRAPPING UP OR COMING TO MAJOR RESULTS, INCLUDING THE START TRIAL, WHICH IN MIDDLE OF 2015, THE DSMB REACHED A DECISION TO END THE RANDOMIZED PORTION OF THAT TRIAL BECAUSE OF A VERY CLEAR BENEFIT OF ART THERAPY REGARDLESS OF CD4 COUNT YOU START. AND THERE WAS A CLEAR BENEFIT IN TERMS OF AIDS EVENTS AND DEATH AS WELL AS SERIOUS NON-AIDS EVENTS. SO REALLY IT PUT TO REST THE QUESTION OF WHEN TO START ART. ADDITIONALLY WE ENDED SOME OF OUR LARGER PHASE III STUDIES THAT WERE BEING DONE IN NAIVE. ART NAIVE PARTICIPATS INCLUDING THE ACTG57 STUDY. AND SHOWED THAT ARDENT WAS INFERIOR TO REGIMENS INCLUDING TOLERABILITY AND GUIDELINES. IN ADDITION, WE HAD OR CONCLUDED STUDIES IN EXPERIENCED PATIENTS OR SECOND LINE THERAPY, AND LAST YEAR A5273, THE SELECT TRIAL PRESENTED RESULTS AT COO I AND THIS WAS A STUDY IN EXPERIENCED PATIENTS ON SECOND LINE THERAPY AND THIS THIS WAS LOOKING AT THE ROLE OF NRTIs IN TREATMENT REGIMENS FOR PEOPLE WHO ACTUALLY HAD KNOWN RESISTANCE MUTATIONS AND INTERESTINGLY, THE TRIAL SHOWED A BENEFIT OF CONTINUING DESPITE HAVING RESISTANCE MUTATIONS AND THEN FINALLY WE HAVE THE ACTG AND THE THIRD-LINE STUDY CALLED MULTIOC TAF OR 5288 LOOKING AT PUTTING TOGETHER OPTIMAL THERAPY AFTER VIROLOGIC FAILURE IN SETTINGS THAT COMPLETED ENROLLMENT AND WE'LL LOOK FOR RESULTS FROM THAT TRIAL SOON. SO WHAT IS NEXT AFTER ANSWERING THESE QUESTIONS ABOUT WHEN TO PART AND WHAT TO START? WE REALLY HAVE BEEN FOCUSED IN THE LAST SEVERAL YEARS ON TRYING TO COME UP WITH A PIPELINE OF FORMULATIONS FOR BOTH PREVENTION AND THERAPY AND WE HAVE BEEN WORKING CLOSELY WITH THE PREVENTION SCIENCES PROGRAM FOR FORMULATIONS THAT WOULD HOPEFULLY IMPROVE ACCESS AS WELL AS ADHERENCE TO THERAPY. AND IS THIS MAINLY THROUGH SUSTAINED RELEASE AND LONG ACTING FORMULATIONS. SO WE HAD A NUMBER OF INITIATIVES OVER THE YEARS THAT WE THINK HAVE HELPED TO STIMULATE THIS FIELD AND WE THINK COMPLIMENT THAT WHICH IS GOING ON IN THE PHARMACEUTICAL INDUSTRY. IN THIS PAST YEAR WE HAD A COUPLE OF FUNDING ANNOUNCEMENTS TO SOLICIT APPLICATIONS TO DISCOVER SMALL MOLECULES OR SUSTAINED RELEASE FORMULATIONS AND ALSO A FUNDING ANNOUNCEMENT TO SUPPORT THE FORMULATIONS IN SUSTAINED RELEASE FORM FOR ART. WE ALSO FUNDED AN R24, WHICH IS A RESEARCH RESOURCE GRANT. AND THAT AWARD WENT TO CHARLIE AT HOPKINS FOR THE LEAP PROGRAM WHICH IS LONG ACTING EXTENDED RELEASE FOR ANTI-RETROVIRALS PROGRAM. AND THAT SERVES AS A HUB FOR COMMUNICATION AND DATA SHARING AMONG INVESTIGATORS WHO ARE INTERESTED IN THIS FIELD. AND THE LEAP PROGRAM HAS TAKEN OVER WHAT USED TO BE A ORGANIZED WORKSHOP, ANNUAL WORKSHOP TO DISCUSS WHAT ARE SOME OF THE RESEARCH GAPS IN THE DEVELOPMENT OF LONG ACTING FORMULATIONS. AND THIS YEAR IS THE FOURTH WORKSHOP WHICH WILL PRECEDE CROI THIS YEAR. IN ADDITION TO THESE GRANT MECHANISMS WE HAVE BEEN SOLICITING, WE ALSO HAVE CLINICAL TRIALS THAT ARE IN VARIOUS STAGES OF DEVELOPMENT CURRENTLY BUT WE ARE REALLY LOOKING FORWARD TO TESTING SOME OF THE THESE CONCEPTS. A5357 IS LOOKING AT A COMBINATION OF CABO TEGRA VEER IN CONJUNCTION WITH A LONG ACTING BROADLY NEUTRALIZING ANTIBODY, BRCA1. AND 5359 IS LOOKING AT A COMBINATION OF RETRO VIRALS IN A POPULATION WHO HAVE BEEN KNOWN TO HAVE CHALLENGE SYSTEM WITH ADD MEANERS. WE ARE ALSO KEEPING AN EYE ON ISSUES WITH DRUG RESISTANCE. THIS HASN'T BEEN SOMETHING WE HAVE PUSHED AS A RESEARCH AREA IN THE RECEIPT YEARS BUT REALIZE WE NEED TO CERTAINLY -- RECENT YEARS -- PAY ATTENTION AS ART IS ROLLING OUT WIDER AND WIDER SETTINGS IN VARYING DEGREES OF MONITORING. SO WE HOSTED EARLIER THIS YEAR A CONSULTATION TO LOOK AT WHAT ARE THE NEEDS IN TERMS OF DRUG RESISTANCE. WE RECOGNIZE THAT SURVEILLANCE NEEDS ARE SIGNIFICANT. THAT WE REALLY NEED TO GET A BETTER HAND ON WHAT IS GOING ON WITH DRUG RESISTANCE AND WE ALSO DIME A CONCLUSION THAT IT IS UNDERSTOOD DRUG RESISTANCE WITHIN DIVERSE. LIMITED UNDERSTANDING OF MUTATIONS PRESENT AT LOW LEVELS OR OTHERWISE KNOWN AS MINORITY VARIANTS. AND CONTRIBUTIONS TO TREATMENT FAILURES IN DIFFERENT SUBTYPES. WE ALSO HAVE A QUESTION THAT AROSE FROM 5273 WHICH I MENTIONED, WHICH IS THE RESIDUAL ACTIVITY OF NRTIs WHEN STANDARD RESISTANT MUTATIONS ARE PRESENT AND WHAT IS THE MECHANISM? WE WANT TO LOOK AT HIV DRUG RESISTANCE TESTING NEEDS FOR SPECIFIC POPULATIONS AND IN PARTICULAR IN RESOURCE LIMITED SETTINGS, AND WHAT MIGHT BE SOME WAYS TO AID IN TESTING FOR EXAMPLE AT POINT OF CARE TESTING IN USES OF DIVERSE SPECIMENS? WHICH THEN WE'LL NEED TO LOOK AT HOW WILL THE NEW TESTS BE IMPLEMENTED? SO MOVING ON TO A CURE AND SUSTAINED REMISSION, WHICH ALONG WITH THE BASIC SCIENCES PROGRAM HAS BEEN AN AREA OF INTEREST OF OURS FOR SEVERAL YEARS. AND WE THINK THAT WE HAVE LEARNED SOME THINGS, FOR EXAMPLE, THAT LATENCY REVERSAL ALONE SEEMS TO BE INSUFFICIENT FOR A SUSTAINED REMISSION. WE ALSO KNOW NOW THAT LOW RESERVOIR SIZE ALONE IS ALSO INSUFFICIENT. AND WE THINK THAT AN ENHANCED IMMUNE RESPONSE WILL BE NEEDED FOR SUCCESSFUL CURE STRATEGY. SO SOME OF THE APPROACH THAT IS WE HAVE BEEN FOLLOWING IN THE RECENT PAST AND CURRENTLY REALLY CENTERED AROUND QUANTIFICATION OF RESERVOIRS AND AS WELL AS DESCRIBING RESERVOIRS AND WE HAVE WORK GOING ON WITHIN THE ACTG AS WELL AS WITH INDIVIDUAL INVESTIGATORS LOOKING AT SOME OF THESE QUESTIONS INCLUDING WHAT IS THE EFFECTIVE VERY EARLY TREATMENT ON RESERVOIRS? AND WE ARE LOOKING AT THIS IN DIVERSE POPULATIONS INCLUDING IN HIV INFECTED INFANTS ALONG WITH OUR COLLEAGUES IN THE PREVENTION SCIENCES PROGRAM IN THE MATERNAL ADOLESCENT PEDIATRIC BRANCH. WE STUDIED A NUMBER OF LATENCY REVERSING AGENTS AND CONTINUE TO DO SO AND HAVE LOOKED AT VARIOUS IMMUNE-BASED THERAPIES TO DEPLETE OR CONTROL RESERVOIRS INCLUDING ANTI-PD-L1 AND OTHERS. IN THE PAST YEAR, WE HAD SOME INITIATIVE ACTIVITIES IN THESE AREAS TO TRY TO MOVE BEYOND THOSE APPROACHES. WE SOLICITED PILOT CLINICAL TRIALS THAT HAVE BEEN TRYING TO AIM SPECIFICALLY NOT JUST AT REVERSING LATENCY BUT ELIMINATING LATENTLY INFECTED CELLS. WE HAVE ALSO BEEN MORE RECENTLY TRYING TO ADVANCE HIV THERAPEUTIC VACCINE SCIENCE AND TO SOLICIT APPLICATIONS TO ADVANCE UNDERSTANDING OF VACCINATION STRATEGIES WHAT IMMUNE RESPONSERS WILL BE NECESSARY FOR CONTROLLING HIV INFECTIONS AND THEN FINALLY WITH OUR PEDIATRIC COLLEAGUES TO BETTER UNDERSTAND HIV PERSISTINENCE INANTS AND WE THINK THIS IS A UNIQUE POPULATION GIVING REVOLVING IMMUNE SYSTEM AND THE SETTING IN WHICH THEY ARE INFECTED AND WE REALLY NEED A BETTER UNDERSTANDING THERE. SO THERE HAS BEEN SOME INTERESTING TAINTED LIESING RESULTS RECENTLY IN NON-HUMAN PRIMATES WHEN IT COMES TO THERAPEUTIC VACCINES. DAN AND HIS LAB RECENTLY PUBLISHED IN NATURE A STUDY LOOKING AT ADD 26MVA VACCINATION IN COMBINATION WITH TLR STIMULATION AND SHOWED REALLY INTRIGUING EFFECTS ON VIRAL CELT POINT. YOU CAN SEE ON THE RED LINE THE COMBINATION OF THERAPEUTIC VACCINE PLUS THE TLR7 STIMULATION SHOWED A SIGNIFICANT EFFECT ON VIRAL SET POINT AND ONE INTERESTINGLY IN WHICH THE SET POINT WAS CORE LATERRED WITH T-CELL BREATH AND VACCINATION. AND IN FACT, OF THOSE ANIMALS THAT RECEIVED BOTH VACCINATION AS WELL AS TLR7 STIMULATION, THREE OF THOSE NINE ANIMALS BECAME POST-TREATMENT CONTROLLERS. THIS IS A REALLY INTRIGUING RESULT AND I THINK GIVES OR SHOWS PROMISE THERAPEUTIC VACCINES MIGHT BE A USEFUL PART OF CURE STRATEGIES GOING FORWARD. BUT DESPITE THESE ADVANCES IN NON-HUMAN PRIMATES, WE HAVE NOT SEEN A ROBUST DEMONSTRATION OF EFFICACY IN ANY HUMAN TRIALS INVOLVING THERAPEUTIC VACCINES. AND WE REALIZE THERE ARE MANY VARIABLES THAT STAND TO BE OPTIMIZED FOR EACH CANDIDATE AND REGIMEN AND THEREFORE WE PUT FORWARD OUR INITIATIVE FOR ADVANCING HIV THERAPEUTIC VACCINES SCIENCE TO ALLOW FOR IMPROVEMENTS IN THESE VACCINATION STRATEGIES. AND WE ARE HAPPY TO RECEIVE A ROBUST RESPONSE TO THAT AND ARE HOPING TO MAKE AWARDS IN THE SECOND-QUARTER OF 2017. ANOTHER BIG AREA OF FOCUS FOR US HAS BEEN AND CONTINUES TO BE MONOCLONAL ANTIBODIES. AND THEIR ROLE IN CURE SUSTAINED REMUAGES. SEVERAL CLASSES THAT MIGHT BE USEFUL IN CURE INCLUDING BADLY NEUTRALIZING ANTIBODIES AND DERIVATIVES. HIV SPECIFIC ANTI-THOUSANDS MIGHT BE OMIZED TO KILL CELLS EXPRESSING ANTIGENS -- MIGHT BE OPTIMIZED -- SUSTAINED REMISSION WITH ALPHA 4 BETA 7 STUDIES IN PARTICULAR. NOTE ONLY DO WE THINK THE MABs MIGHT HAVE DIRECT EFFECT THEMSELVES BUT THERE IS POTENTIAL TO LEARN FROM THOSE STUDIES TO IDENTIFY MECHANISMS IN CELLS THAT MIGHT BE ESSENTIAL FOR CLEARING THE RESERVOIR THAT MIGHT THEN INFORM OUR THERAPEUTIC VACCINE DEVELOPMENT. SO WHERE ARE WE WITH BROADLY NEUTRALIZING ANTI-NOBODY'S WE HAD A COUPLE OF TRIALS THAT WE HAVE SUPPORTED IN THE LAST YEAR THAT HAVE PUBLISHED RESULTS WITH USING SINGLE BNAB. THESE ARE WERE STUDIES DONE THROUGH THE ACTG AS WELL AS THROUGH THE INTRAMURAL PROGRAM AND THEY SHOWED A PRETTY MODEST DELAY IN TIME TO VIRAL REBOUND COMPARED TO NO TREATMENT AT ALL. AND ON THE RIGHT IS THE SIMILAR EXAMPLE WITH SHOWING A MODEST DELAY IN TIME TO VIRAL REBOUND BUT NOTHING THAT WE THINK WOULD LEAD TO A SUSTAINED REMISSION ON ITS OWN. WE SAW THERE WERE VIRUSES THAT WERE RESISTANT BEFORE THERAPY WAS STARTED AND THEY EMERGED VERY QUICKLY WITH MONOTHERAPY. AND SO NOW, WE ARE TURNING TOWARDS NEXT STEPS WHICH WOULD BE COMBINATIONS OF B NABS AND SOME ARE IN THE WORKS NOW INCLUDING COMBINATIONS WITH ANTIBODIES SUCH AS 101074. AND I WON'T GO INTO DETAIL ON THE STUDY THAT DEANNA JUST DESCRIBED WITH ALPHA 4 BETA 7 BUT NEED TOES SAY WE ARE VERY INTRIGUED BY THOSE RESULTS AS WELL. WE REALIZE THERE IS AN INTRAMURAL STUDY GOING ON AND HOPING TO WORK VERY CLOSELY WITH OUR COLLEAGUES TO HOPE TO ADVANCE THE NEXT STEPS IN THE CLINICAL DEVELOPMENT PROCESS. WE HAD DISCUSSIONS WITH THE ACTG INVESTIGATORS AND MHRP INVESTIGATORS ABOUT WHAT THOSE NEXT TRIALS MIGHT LOOK LIKE. AND THEN FINALLY, WE ARE VERY INTERESTED IN HOW CAN THE BROADLY NEUTRALIZING ANTIBODIES PERHAPS BE FURTHER MANIPULATED OR OPTIMIZED TO HAVE MORE OF AN EFFECT ON RESERVOIR? ARE THERE MODIFICATIONS THAT COULD BE MADE TO ENHANCE FCR BINDING FOR EXAMPLE, TO INCREASE POTENCY, PROLONG HALF-LIFE, GET BETTER TISSUE PENETRANTS, ET CETERA. CAN WE ALSO CREATE BI-SPECIFIC ANTIBODIES THAT MIGHT BE EFFECTIVE IN ELIMINATING LATENTLY INFECTED CELLS COUPLING WITH IMMUNOTOXIN? AND SO WE ALSO HAD A FUNDING INITIATIVE OUT THIS PAST YEAR THAT WAS TARGETING OPTIMIZATION OF BROADLY NEUTRALIZING ANTIBODIES. MOVING ON TO CO-MORBIDITIES AS DEANNA DISCUSSED. WE KNOWN FOR QUITE SOMETIME THAT EVEN IN THE SETTING OF THERAPY, HIV INFECTED PEOPLE HAVE CHRONIC RESIDUAL IMMUNE INFLAMMATION AND ACTIVATION. DESPITE WHEN YOU START ART, IS ALWAYS GREATER THAN HIV UNINFECTED COMPARATORS. THIS SAY RECENT EXAMPLE OF A STUDY THAT WAS PUT OUT BY THE INSIGHT INVESTIGATORS LAST YEAR LOOKING AT THE CONTROL GROUPS FROM THE SMART TRIALS AND SHOWING THAT BOTH ILS. SINGS AND D DIMEER ABLE TO PREDICT AIDS AS WELL AS NON-AIDS, VENTS AND HAD THE WORST OUTCOMES. SO WE R. WHERE WE HAVE BEEN FOCUSED ON THE IMMEDIATE PAST HAVE BEEN AND CONTINUE TO BE ON WHERE ARE THESE DEFECTS THAT LEAD TO IMMUNE ACTIVATION INFLAMMATION? CAN WE USE KNOWN INTERVENTIONS WHERE WE KNOW WHICH IMMUNE ACTIVATION PATHWAYS THEY ARE EFFECTING TO GET AT SOME OF THESE QUESTIONS? SO WE HAD A NUMBER OF STUDIES BOTH THROUGH THE ACTG AS WELL AS THROUGH INVESTIGATOR INITIATED CLINICAL TRIALS THAT ALL AIMED AT TRYING TO TEASE OUT EXACTLY WHAT ARE THE PATHWAY THAT IS ARE CONTRIBUTING TO IMMUNE ACTIVATION AND INFLAMMATION. AND THEN ON THE DOWNSTREAM SIDE WE ARE FOCUSED ON WHAT INTERVENTIONS CAN WE USE TO REVERSE THE EFFECTS ON END ORGAN DISEASE INCLUDING CARDIOVASCULAR, NEURO, BONE, LIVER AND EFFECTS ON AGING AND ONE OF THE BIGGER TRIALS AND MORE SUCCESSFUL COLLABORATION WE HAVE BEEN ABLE TO FOSTER HAS BEEN IN THE AREA OF CARDIOVASCULAR DISEASE FOLLOWING UP ON EARLIER STUDIES SHOWING THAT STATENS HAVE A EFFECT ON DECREASING IMMUNE ACTIVATION INFLAMMATION THAT IS INDEPENDENT OF EFFECT ON LIPIDS. WE HAVE BEEN ABLE TO COLLABORATE WITH NHLBI ON FUNDING THE REPRIEVE TRIAL, WHICH IS A LARGE STUDY LOOKING AT THE EFFECT OF STAT IN SYSTEM ON MAJOR ADVERSE CARDIOVASCULAR EVENTS IN HIV INFECTED PATIENTS. THIS IS FUNDED THROUGH RL1 WITH NHLBI BUT REALLY LEVERAGES A LOT OF THE RESOURCES FROM NIAID, INCLUDING ACTG CLINICAL TRIALS NETWORK. A LOT OF OUR SUPPORT CONTRACTS ARE OFFICE OF CLINICAL OVERSIGHT HAS BEEN VERY INVOLVED. OUR REGULATORY STAFF IS VERY INVOLVED. AND THEN WE HAVE ALSO GOTTEN FUNDING FROM OUR PHARMACEUTICAL PARTNERS AND I SHOULD ALSO ADD THE OFFICE OF AIDS RESEARC CONTRIBUTED FUNDING AS WELL. SO THIS IS AN EXAMPLE OF A REALLY SUCCESSFUL COLLABORATION AND I THINK A DIRECTION THAT WE WANT TO CONTINUE IN WHERE THERE ARE OVERLAPPING AREAS OF INTEREST IN TERMS OF PRIORITIES WITH OUR PARTNER ICs. WE'D LIKE TO BE ABLE TO LEVERAGE SOME OF THE INFRASTRUCTURE WE ALREADY PUT INTO PLACE TO ANSWER SOME OF THOSE QUESTIONS. WITH REPRIEVE, MORE SAY LARGE STUDY. TARGET SAMPLE SIDE IS 5500. WE ENROLLED 2600 AS OF LAST WEEK. WE HAVE OVER 100 SITES ALREADY ENROLLING AND WE ARE LOOKING TO ADD PROBABLY 10-20 MORE IN THE U.S. AS WELL AS ACROSS THE WORLD. AND IMPORTANTLY, AGAIN THIS IS ABOUT LEVERAGING. WE HAVE BEEN ABLE TO FUND NOT ONLY US BUT OUR PARTNER ICs FUNDING REALLY IMPORTANT SUB-STUDIES AS A RESULT OF THEORIES PREV TRIAL. SO NHLBI FUNDED A STUDY LOOKING AT THE EFFECTS OF STAT INS ON ARTHEROSCLEROTIC PLAQUES. NIAID FUNDED A STUDY LOOKING AT THE INFLUENCE OF SEX AND REPRODUCTIVE AGING. AND NIDDS LOOKING AT THE EFFECTS OF KIDNEY FUNCTION AND NIAMS VERY RECENTLY FUND AID STUDY TO LOOK AT THE EFFECTS OF REDUCED PHYSICAL FUNCTION AND FRAILTY. AND THEN MOVING ON TO IMPORTANT COFINNECTIONS. WE REALLY HAVE BEEN -- CO-INFECTIONS. WE HAVE BEEN FOCUSED IN THE LAST 5-7 YEARS ON TRYING TO MAKE SOME DENSE ON THE TB EPIDEMIC, WHICH IS I THINK CRITICALLY IMPORTANT FOR PEOPLE WHO ARE LIVING WITH HIV. IN THE PAST, IN 2015, THERE ARE 10.4 MILLION INCIDENT TB CASES. ONE PENALTY 2 MILLION WERE IN PEOPLE WHO ARE LIVING WITH HIV -- 1.2. -- THERE WERE 1.4 MILLION UNINFECTED WITH 400,000 DEATHS IN PEOPLE LIVING WITH HIV MAKING TB ACTUALLY THE NUMBER 1 INFECTIOUS CAUSE OF DEATH IN THE WORLD. AND YOU CAN SEE ON THE BAR GRAPH, THESE ARE THE TB-RELATED DEATHS EXCLUSIVE OF HIV AND THIS GRAY BAR, THE ADDITIONAL DEATHS FROM TB AMONG PEOPLE LIVING WITH HIV. SO YOU CAN SEE THAT THIS IS A SIGNIFICANT NUMBER OF DEATHS OVERALL AND MAKES UP ABOUT 1/3 OF DEATHS IN HIV INFECTED PEOPLE. THIS GRAPHIC ON THE RIGHT SHOWS YOU OVER TIME REALLY HOW TB COMPARES AS AN EPIDEMIC ON THE WHOLE WITH A NUMBER OF OTHER INFECTIOUS DISEASES THAT WE KNOW HAD SIGNIFICANT IMPACTS AND I THINK IT IS JUST REALLY VERY STUN DEPICTION OF THE RELATIVE IMPORTANCE OF TB COMPARED TO OTHER DISEASES LIKE SMALLPOX AND MALARIA AND PLAGUE, INFLUENZA AND CHOLERA AND EVEN AIDS. SO WHAT ABOUT THE CONNECTION BETWEEN T. AND HIV? PEOPLE LIVING WITH HIV ARE 21-34 TIMES MORE LIKELY TO DEVELOP ACTIVE TB. IT'S THE MOST COMMON PRESENTING ILLNESS AND IT IS THE LEADING CAUSE OF DEATH AMONG PEOPLE LIVING WITH HIV. THEY ARE MORE LIKELY TO DEVELOP MDR AND XDRT. AND REQUIRE PROLONED TREATMENT AND THE OUTCOMES ARE MUCH POORER. SOME REALLY STUNNING STATISTICS ARE THAT IN PEOPLE LIVING WITH HIV, MORE THAN TWO NEW TB CASES ARE DIAGNOSED PER MINUTE AND MORE THAN -- THERE ARE MORE THAN TWO NEW TB CASES PER MINUTE. THERE ARE A LOTS OF CRITICAL GAPS IN TB RESEARCH PARTICULARLY IN TB HIV CO-INFECTION. TB IS MORE DIFFICULT TO DIAGNOSIS THAN HIV INFECTED SO WE NEED NEW DIAGNOSTICS AND BIOMARKERS. IT'S MORE DIFFICULT TO TREAT. MORE TREATMENT FAILURE, DRUG RESISTANCE AND DRUG DRUG INTERACTIONS SO WE NEED TO DO DRUGS AND TREATMENT STRATEGIES IT'S MORE DIFFICULT PREVENT AND WE NEED A MORE EFFECTIVE VACCINE PARTICULARLY IN PEOPLE WITH HIV. AND WE THAN PEOPLE LIVING WITH HIV ARE AN IMPORTANT DRIVER OF THE EPIDEMIC. THEY PLAY AN IMPORTANT ROLE IN TB TRANSMISSION PATTERNS AS WELL AS IN THE EMERGENCE OF DRUG RESISTANCE SO WE NEED NEW STRATEGIES TO INTERRUPT THAT TRANSMISSION IN HIV INFECTED POPULATIONS. THIS SLIDE IS FROM THE W.H.O.'S NTB STRATEGY. JUST ILLUSTRATES THE NEED FOR NEW TOOLS IN ORDER TO ACHIEVE THE NTB STRATEGY GOALS WHICH ARE TO REDUCE THE INCIDENTS OF TB BY 90% BY THE YEAR 2035 RELATIVE TO 2015. YOU CAN SEE WITH THIS MODELING THAT EVEN IF WE WERE TO COMPLETELY OPTIMIZE THE TOOLS THAT WE HAVE AT HAND, INCLUDING UNIVERSAL HEALTH COVERAGE, WE WOULD REDUCE THE INCIDENCE BY 10% PER YEAR. WHAT WE'LL WE NEED ARE NEW TOOLS TO REALLY PUT AN EFFECT OF THAT TRAJECTORY TO BRING US DOWN TO DECREASE OF 90% BY THE YEAR 2035. THIS WOULD INCLUDE NEW EFFECTIVE VACCINE, NEW DRUGS AND TREATMENT REGIMENS AS WELL AS NEW DIAGNOSTICS. SO FOR US, OUR RESEARCH PRIORITIES REALLY REFLECT THESE GAPS. WE KNOW THAT SHORTER MORE EFFECTIVE REGIMENS ARE NEEDED AND TO THIS END, THE ACTG HAS A NUMBER OF TRIALS THAT ARE LOOKING AT TREATMENT OF TB INCLUDING THE ROLE OF -- IN SHORTENING DRUG TREATMENT REGIMENS AND TRYING TO OPTIMIZE NEW DRUGS. WE HAVE HAD A FOCUS ON HOST DIRECTED THERAPIES OVER RECENT YEARS AND HAD SUCCESS IN FUNDING A NUMBER OF APPLICATIONS THROUGH OUR UH2 AND 3 PROGRAM WHICH WILL HOPEFULLY LEAD TO SOME CLINICAL TRIALS OF THOSE THERAPIES. AND WE ARE ALSO SIMILAR TO OUR ANTI-RETROVIRAL PROGRAM, WE ARE INTERESTED IN LONG-ACTING FORMULATIONS TO HELP SIMPLIFY TREATMENT OF TB. WE ALSO ARE IN NEED OF IMPROVED DIAGNOSIS PARTICULARLY IN PEDIATRIC TB AS WELL AS IN DRUG-RESISTANCE. WE NEED BETTER BIOMARKERS AND MOLECULAR DIAGNOSTICS. TO THIS END, WE ARE INVOLVED IN A NUMBER OF PROJECTS INCLUDING THE TB RESEEK PROJECT WHICH IS A GLOBAL DATABASE TO HELP AID MOLECULAR DIAGNOSIS OF DRUG RESISTANT TB AND ALSO HAD -- I'D LIKE TO HIGHLIGHT WE ALSO PUT A LOT OF SPORT ESTABLISHING TB COHORTS TO HELP GET AT SOME OF THESE PROBLEMS INCLUDING DIAGNOSIS. SO THE REPORT COHORTS ARE A NETWORK OF COHORTS THAT HAVE BEEN ESTABLISHED IN VARIOUS COUNTRIES WITH HIGH PREVALENCE OF TB AS WELL AS HIV. AND THEY HAVE BEEN COLLABORATIVE PROJECTS WITH THE GOVERNMENTS OF THOSE CRIES WHERE THERE HAS BEEN JOINT -- COUNTRIES -- BILATERAL FUNDING FOR A NUMBER OF THEM AND THESE ARE CONSORTIA THAT ARE ESTABLISHED IN EACH DIFFERENT REGIONS BUT THAT ARE LINK THE VIA INTERNATIONAL COORDINATING CENTER AND THE GOAL IS THAT ALL OF THEM WILL BE USING COMMON PROTOCOLS AND MANUALS OF OPERATIONS AND DATA STANDARDS AS WELL AS LAB STANDARDS IN ORDER TO ENSURE HIGH-QUALITY DATA AND LAB PROCESSES ACROSS THE CONSORTIA TO BE ABLE TO LEVERAGE ALL OF THE SAMPLES COLLECTED UNDER THESE COHORTS. AND THIS IS JUST SHOWING YOU WHERE SOME OF THESE REPORT CONSORTIA HAVE BEEN ESTABLISHED. THE INITIAL COHORTS WERE ESTABLISHED IN INDIA FOLLOWED BY BRAZIL AND SOUTH AFRICA. INDONESIA HAS BEEN FUNDED THROUGH DCR AND WE ALSO HAVE CHINA WHO HAS VERY RECENTLY EXPRESSED INTEREST AS WELL AS THE PHILIPPINES AND A NUMBER OF OTHER COUNTRIES THAT EXPRESSED INTEREST AS WELL BECAUSE IT IS REALLY BEEN A VERY UNIQUE EFFORT TO ESTABLISH COMMON PROTOCOLS ACROSS COUNTRIES. TO FINISH OUT OUR TB RESEARCH PRIORITIES, WE ARE ALSO VERY INTERESTED IN VACCINE STRATEGIES. THIS IS A NEW AREA FOR US AND WE PARTNERED WITH OUR SISTER DIVISIONS OVER THE LAST TWO YEARS TO REALLY TRY TO STIMULATE THIS FIELD. WE HAD OUT SOME VERY BROAD PARs SOLICITING R21 AND RO1 APPLICATIONS, REALLY FOCUSED ON IMMUNOLOGY AND VACCINOLOGY AND WE HAD A REALLY GREAT RESPONSE TO THOSE PARs. WE ARE HOPING TO START FOCUSING ON TRYING TO ESTABLISH BETTER ANIMAL MODELS INCLUDING WITH COINFECTION MODEL WITH SIV AND ALSO TO POTENTIALLY DO MECHANISTIC STUDIES OF VACCINE CANDIDATES IN HUMAN INTRODUCE. SO THOSE ARE DIRECTIONS FOR THE FUTURE. AND THEN FINALLY NON-VACCINE PREVENTION, WE HAVE A NUMBER OF EFFORTS THERE AGAIN WITH THE ACTG AND PARTNERSHIP WITH IMPACT. WE HAVE A LARGE EFFORT UNDERWAY TO TRY TO LOOK AT THE USE OF -- TO PREVENT TRANSMISSION TO HOUSES HOLD CONTACTS OF PEOPLE WITH MDRTB. AND MORE RECENTLY, WE FOCUSED ON STRATEGIES TO TRY TO INTERRUPT THE TRANSMISSION CHAIN AND HOSTED A WORKSHOP EARLIER IN 2016 TO TRY TO FOCUS ON WHAT SOME OF THE GAPS ARE THERE. FINALLY JUST A FEW WORDS ABOUT VIRAL HEPATITIS. WE HAVE BEEN REALLY MOST ACTIVE LOOKING AT HEPATITIS C AND HIV CO-INFECTION THAT HAD SOME REALLY GREAT SUCCESS SYSTEM THERE. MOSTLY -- SUCCESSES THERE. THE PHARMACEUTICAL COMPANIES HAVE DONE A GREAT JOB COMING UP WITH VERY EFFECTIVE TREATMENTS AND NOTABLY ARE INCLUDED HIV INFECTED PEOPLE IN THEIR TRIALS. SO WE THINK THAT WE PROBABLY CAN FOCUS A BIT LESS ON HEPATITIS C BUT DO THINK THAT FOCUS NEEDS TO REMAIN ON HEPATITIS B WHICH IS ALSO A SIGNIFICANT ISSUE IN PEOPLE WITH HIV INFECTION. SO AFTER 10% OF MIFF INFECTION ARE COINFECTED WITH HEPATITIS B. IT ALSO CAN BE A CHRONIC INFECTION SIMILAR TO HIV BECAUSE OF THE PERSISTENCE OF VIRAL DNA AS WELL AS INADEQUATE IMMUNE REONS AND WE KNOW THAT MORTALITY FROM LIVER-RELATED CONDITIONS IS INCREASED IN HIV I THINK EFFECTED PEOPLE. HIV-INFECTED PEOPLE. SO WE PUT A COUPLE OF PRETTY BROAD PAs TO SEE IF WE CAN SOLICIT SOME MORE INTEREST IN THE AREA OF HEPATITIS B AND HIV CO-INFECTION. THESE RESEARCH PRIORITIES THAT WERE LAID OUT IN THE PAs SPAN FROM BASIC AND PRE-CLINICAL THROUGH CLINICAL AND WE ARE TRYING TO ANSWER A LOT OF QUESTIONS AND RELATED TO THE PATHOGEN SIS OF CO-INFECTION. WE NEED IN-VITRO TEST SYSTEM TO ENHANCE DRUG DISCOVERY AND DEVELOPMENT. SMALL ANIMAL MODELS THAT MIMIC CO-INFECTION. WE ARE INTERESTED IN EVALUATION OF SAFETY AND EFFICACY OF NEW THERAPEUTIC INTERVENTIONS AND SPECIFICALLY IMMUNE-BASED THERAPIES AND OF COURSE WE LIKE TO IDENTIFY TARGETS OF EFFECTIVE HBV CURE STAT DEGREES IN HIV-INFECTED INDIVIDUALS. SO THIS SLIDE SLIDE THAT I WANT TO TAKE A MOMENT TO THANK THE STAFF OF THE THERAPEUTICS RESEARCH PROGRAM WHO ARE LISTED HERE. THEY HELPED ME GREATLY OVER THE LAST FOUR MONTHS, SOME OF YOU MIGHT KNOW I HAVE BEEN OUT ON MATERNITY LEAVE AND ONLY RECENTLY RETURNED. SO NOT ONLY DID THEY HELP TO SUPPORT ME WHILE I WAS OUT AND CARRY ON THE WORK OF THE PROGRAM, THEY ALSO HELPED TO PUT TOGETHER THE SLIDES FOR THIS PRESENTATION AND I'M VERY THANKFUL FOR THAT. SPECIAL THANKS TO PETER KIM WHO WAS ACTING PROGRAM DIRECTOR FOR ME FOR THE LAST FOUR MONTHS IN MY PLACE. MAYBE IT WAS A MONTH TOO MANY FOR HIM BECAUSE NEXT THING I KNOW HE'S BECOME THE DEPUTY DIRECTOR OF THE AUSS OF AIDS RESEARCH. BUT IN THE MEANTIME, I REALLY WANT TO THANK HIM FOR THE SUPPORT HE GAVE ME AND FOR HISS LEADERSHIP OF THE PROGRAM WHAT I WAS OUT. AND WITH THAT, I WILL TAKE QUESTIONS. [ APPLAUSE ] >> SO I HAVE TWO QUESTIONS. ONE IS SPECIFIC AND SON MORE GENERAL. THE FIRST IS REPRIEVE. IT'S BEEN OPEN FOR TWO YEARS AND YOU'RE LESS THAN 40% ENROLLED. WHAT IS THE DAZED VIEW ON IT AND WHETHER IT IS ON TARGET -- DAIDS VIEW ON THAT? >> SO, IT'S TECHNICAL AN NHLBI-FUNDED GRANT. SO THEY ARE ALL OVER THE MILESTONES FOR THAT ONE AND YOU'RE RIGHT, IT'S BEHIND ON THE MILESTONES BUT I THINK IT'S FALLEN -- HAD A NUMBER OF ISSUES RELATED TO SITE START UP AND SO - THAT ARE PRETTY TYPICAL FOR TRIALS OF THAT SIZE, INCLUDING GETTING OUR INTERNATION SITES UP AND RUNNING. VERY RECENTLY WE WERE ABLE TO BRING ON BRAZIL SOUTH AFRICA. SO THOSE NUMBERS DON'T REALLIRIES FLECT THE ENROLLMENTS WE WILL SEE IN THOSE COUNTRIES AND WE ARE LOOKING TO BRING ON SITES IN ADDITIONAL INTERNATIONAL SITES THAT WILL BE HIGH ENROLLERS. THAILAND IS ENROLLING LIKE GANGBUSTERS AND IT IS JUST TAKING A LONGER TIME TO GET THE INTERNATIONAL SITES UP AND RUNNING BUT WE ARE VERY KEENLY AWARE OF THINGS. I LOOK AT THE NUMBERS ON A WEEKLY BASIS AS DOES THE ENTIRE TEAM AND WE CAN, FOR -- WE CONSULT REGULARLY WITH NHLBI TO SEE WHAT IT IS WE CAN DO TO STIMULATE ENROLLMENT FURTHER. WE HAD ACTUALLY NYE ADDS OFFICE OF THE DIRECTOR, COMMUNICATION TEAM RECENTLY REALLY PUT ON A AMAZING PR CAMPAIGN FOR US TO TRY TO BOOST ENROLLMENT AND SO WE ARE HOPING TO SEE THE FRUITS OF THOSE EFFORTS SOON. AND FOR THOSE WHO HEARD DR. FAUCI'S COMMENTS THIS MORNING, HE MENTIONED AN OP-ED PIECE HE WROTE WITH BARBARA STREISAND. JUST ONE PIECE OF THE PR CAMPAIGN THAT HIS TEAM PUT TOGETHER. SO WE ARE HOPING THAT WILL ALSO HAVE INFLUENCE. >> MY SECOND COMES MORE GENERAL. I'M STRUCK BY THE ABSENCE OF ANY DISCUSSION IN THE AREA AROUND IMPLEMENTATION SCIENCE. IT SEEMS TO ME IF WE ARE TALKING ABOUT IMPROVING OUTCOMES FOR PEOPLE LIVING WITH HIV, I MEAN, WE HAVE A PUBLIC ISSUE WHERE THE NUMBER OF PEOPLE SUPPRESSED IN THE UNITED STATES DOESN'T APPROACH THAT OF ANY OTHER INDUSTRIALIZED COUNTRY AND THAT IF WE ARE GOING TO ACTUALLY GET THE BENEFITS OF ALL OF THE INVESTMENTS YOU'RE DOING FOR TRIALS, INCLUDING START, WE HAVE TO FIGURE OUT HOW TO MOVE THAT NEEDLESS. AN IMPORTANT AREA TO FOCUS ON.IS FROM THE NIH'S PERSPECTIVE. I KNOW IMPLEMENTATION SCIENCE HAS BEEN EMPHASIZED ON THE PREVENTION SIDE OF THINGS AND ALSO IMPORTANT ON THE THERAPEUTIC SIDE. >> I AGREE. AND I THINK THAT HAS BEEN A MOVING TARGET FOR US. SO IT HAS NOT TRADITIONALLY BEEN SOMETHING WE FOCUSED ON AND IT IS AN AREA THAT I THINK WE WOULD LOOK TO PARTNER WITH OTHER FUNDERS AND STAKEHOLDERS AND IS NOT TAKE ON OUR OWN. THE PREVENTION SCIENCES PROGRAM HAS TAKEN ON TREATMENT AS PREVENTION AND I THINK A LOT OF THE IMPLEMENTATION ISSUES THAT KIND OF FALLEN UNDER THAT RESEARCH FOCUS IN TERMS OF TREATMENT AS PREVENTION SO IS FALLS MORE UNDER THE PREVENTION PROGRAM BAILIWICK. BUT I THINK IT IS SOMETHING THAT THE NEEDLE IS MOVING IN TERMS OF OUR APPETITE FOR GETTING INVOLVED IN IMPLEMENTATION RESEARCH. AND I THINK WE WILL BE SEEING MORE EFFORTS IN THAT REGARD BUT WE WON'T BE DOING IT ON OUR OWN. WE ARE LOOKING TO PARTNER WITH OTHERS. CHRIS? >> CHRIS: YES, SO, YOU DID PUT OUT THE NOTION OF TRYING TO COME UP WITH IMPROVED ANIMAL MODELS FOR TB. THIS IS A CAUSE CELEB IN SOME WAYS. THE HIV COMMUNITY PLAYED A VERY VALUABLE ROLE IN CREATING MORE STANDARDIZED MODELS SUCH AS THE REPEATED LOW DOW'S DOSE, CHALLENGES. TB ALL OVER THE MAP AS YOU KNOW. AND THERE HASN'T BEEN ANY KIND OF ORGANIZING PRINCIPLE, MEANING MONEY, THAT HAS ALLOWED AND SORT OF FORCED PEOPLE TO COALES ON SOME MORE -- AT LEAST MORE RATIONAL -- SO WHAT IS IT YOU ACTUALLY INTEND TO DO? HOW WELL COORDINATED WILL YOU BE WITH OTHER FUNDERS LIKE THE AIDS FOUNDATION? AND HOW RIGOROUS ARE YOU GOING TO BE IN TRYING TO FORCE PEOPLE TO NOT JUST HAVE THEIR MODEL OF CHOICE? >> WELL, WE WILL GET INTO HOPEFULLY, ONE OF THE UPCOMING MEETINGS, WHAT OUR PLAN INITIATIVE IS IN THIS AREA. BUT I'LL JUST SAY I AGREE THAT FUNDING HAS BEEN AN INITIATIVE THIS AREA AND IT MIGHT WIND UP BEING FOR US AS WELL BECAUSE IT TAKES A SIGNIFICANT AMOUNT OF RESOURCES TO REALLY HAVE CONCERTED EFFORT IN THAT AREA. I'M NOT SURE WE'LL GET THERE BUT WE REALLY WANT TO TRY. SO WE HAVE THIS TEAM THAT IS A COMBINATION OF DAIDS AND DATE AND NOW OUR CLOSED FROM DIR AS WELL WHO ARE FOCUSED SPECIFICALLY ON TB VACCINE-RELATED WORK AND THIS IS WHERE THESE CONVERSATIONS HAVE COME UP. >> THE DRUG STUFF IS MAYBE NOT SO HANDICAPPED -- THERE ARE ISSUES BUT NOT ADDS PROFOUND -- >> SO WE SEE THE GLARING NEED BUT AGAIN THE RESOURCES ARE THE PROBLEM BECAUSE WE WANT TO HAVE -- WE ARE INSPIRED BY OUR VACCINE COLLEAGUES IN DAIDS AND SEE HOW POWERFUL THOSE ANIMAL MODELS CAN BE IF DONE IN A RUGEROUS WAY BUT WE NEED TO BE ABLE TO PUT THE RESOURCES BEHIND IT. IN THE DIVISION OF AIDS, WE ARE SPECIFICALLY INTERESTED IN TB AND HIV CO-INFECTION. SO WE HAVE TO FIGURE OUT DOES THAT MAKE SENSE AT THIS STAGE TO HAVE ANIMAL MODEL THAT IS TB-SIV, FOR EXAMPLE, CO-INFECTION AND WHAT WOULD OUR ROLE BE IN THAT EFFORT? IT'S REAL I -- >> I'M PLEASED TO HEAR THAT. THIS STRIKES ME AS A PLACE WHERE -- IT'S A LMOST LIKE A GO BIG OR GO HOME. DABBLING WILL NOT HELP. >> AGREE. >> I THINK THE TWO DIVISIONS NEED TO GET-TOGETHER AND WITH, AND TRY TO COME UP WITH A CONCERTED APPROACH. OTHERWISE YOU PROBABLY ARE JUST WASTING MONEY. I THINK IT REALLY IS IMPORTANT TO THINK THIS THROUGH BEFORE JUST TRICKLING MONEY INTO IT. TRICKLE DOWN HERE WILL NOT WORK, I DON'T BELIEVE. >> IT SOUNDS VERY FAMILIAR TO A CONVERSATION OUR TEAM HAS BEEN HAVING AND I'M HOPEFUL WE ARE STILL WORKING ON IT. >> SARAH, WITH SUCH A BROAD RESEARCH AGENDA, CAN YOU GIVE US A FEELING FOR EFFORT DOMESTIC VERSUS INTERNATIONAL FOR ALL OF THERAPEUTICS? >> THAT'S HARD. BECAUSE EACH OF THE FOCUS AREAS IS VERY DIFFERENT. SO, FOR EXAMPLE, WITH CURE IT'S BEEN VERY DOMESTIC UNTIL RECENTLY WHEN WE HAVE BEEN PARTNERING WITH LOOKING AT STUDIES IN THAILAND FOR EXAMPLE. OTHERWISE IN TERMS OF OUR INTERVENTIONAL STUDIES, THEY ARE HIGH-RISK AND VERY SMALL SINGLE-SITE TRIALS WHERE WE SPECIFICALLY DID THEM IN DOMESTIC SITES ONLY. WHEREAS TB IS INTERNATIONAL. SO I THINK IT IS EASIER TO LOOK AT THEM SORT OF ON A FOCUS AREA BY FOCUS AREA. INTERESTINGLY, REPRIEVE, WE THOUGHT WE NEEDED TO FOCUS THAT DOMESTICALLY AND THEN REALIZED THAT A LOT OF CARDIOVASCULAR CARE IS PRETTY SIMILAR IN SOME OF OUR PARTNER COUNTRIES LIKE SOUTH AFRICA AND BRAZIL FOR EXAMPLE. SO WE HAVE BEEN ABLE TO EXPAND THAT TRIAL. BUT IT DEPENDS ON -- IT REALLY DEPENDS ON WHAT IS THE CO-INFECTION? WHERE IS IT PREVALENT? WHAT IS THE CO-MORBIDITY? WHERE IS THAT PRELL INNOCENT WHAT IS THE STANDARD OF CARE FOR TREATING IT? SO IT REALLY KIND OF IS ALL OVER THE PLACE IN TERMS OF INTERNATIONAL VERSUS DOMESTIC. DOES THAT ANSWER YOUR QUESTION? IS THERE SOMETHING MORE SPECIFIC? [ OFF MIC ] >> I THINK PROBABLY MAYBE 50/50 BECAUSE OF THE -- I DON'T KNOW. DOLLARS WISE IT WOULD CORRESPOND BECAUSE WE HAVE MUCH LESS MONEY GOING TO THESE TINY PILOT TRIALS FOR CURE, FOR EXAMPLE. AND YET A LOT OF THE SORT OF HUMAN RESOURCES ARE GOING IN THAT DIRECTION. SO I THINK IT KIND OF BALANCES OUT BETWEEN INTERNATIONAL AND DOMESTIC. >> THANK YOU, SIR A THAT WAS GREAT. WE ARE GOING TO TAKE A 10 MINUTE BREAK AND START RIGHT UP AT ABOUT 3:15. THANK YOU. >> OUR NEXT SPEAKER IS THE DIRECTOR OF THE RESEARCH PROGRAM WHO WILL GIVE US AN OVERVIEW. >> THANK YOU FOR YOUR ENDURANCE THIS AFTERNOON. I JUST WANTED TO LET YOU KNOW WE ARE GETTING CLOSE. THIS IS THE PANEL PRESENTATION, IF I'M CORRECT. AND I'D LIKE TO JUST GIVE A SPECIAL WELCOME TO OUR COLLEAGUE, MY COLLEAGUES FROM THE UNIVERSITY OF COLORADO. IT'S NICE TO SEE YOU GUYS BOTH JOINING THE ARAC. I WANTED TO GIVE A PROGRAMMATIC UPDATE. FIRST I WANTED TO REMIND EVERYONE. YOU SEEN THIS SLIDE BEFORE ABOUT THE PRIORITIES IN HIV VACCINE RESEARCH AND DEVELOPMENT. THEY ARE TWO-FOLD OF THE WE FUND RESEARCH TO INFORM VACCINE DESIGN THROUGH DISCOVERY OF IMMUNOGENS THAT WOULD PROTECT ANIMALS IN THE CHALLENGE MODELS. AND THEN, PARTICULARLY IN THE CASE OF PROTECTION, WE NEED TO UNDERSTAND THOSE PROTECTIVE RESPONSES TO IDENTIFY CORRELATES OF PROTECTION. AND THEN DEVELOP HYPOTHESES TO TEST THOSE IN THE CLINICAL SETTING, WHICH BRINGS US DOWN TO THE VACCINE DEVELOPMENT RESEARCH WHERE WE NEED TO TRANSLATE THOSE PROMISING IMMUNOGENS INTO CLINICAL TRIALS MATERIAL. WE HEARD A LOT ABOUT THE CHALLENGES THAT PRESENT US IN THAT AREA REGARDING PRODUCTION OF VACCINES AND I'LL TALK ABOUT THAT A BUILT TODAY AND THEN FINALLY I'LL CLOSE ON EVALUATING SAFETY AND IN PARTICULAR EFFICACY TRIALS FOR VACCINES. SO, THIS IS THE SLIDE WHERE I'M GOING TO TELL YOU WHAT I'M GOING TO TALK ABOUT TODAY. SO, IF YOU WANTED TO PAY ATTENTION TO ONE SLIDE, THIS WOULD BE IT. AND I'D LIKE EVERYBODY TO MAKE NOTE OF THE COMMENT THAT KARL HAD. YOU'LL REMEMBER HE SAID THIS IS A PRETTY AMAZING TIME AND I THINK THAT WAS IN REFERENCE TO VACCINES AND BROADLY NEUTRALIZING ANTIBODIES. AND I CAN'T AGREE ANY MORE. THERE HAS BEEN A LOT OF HIGHLIGHTS FROM THE VACCINE PROGRAM IN THE LAST YEAR. BUT I'M REALLY GOING TO BREAK IT DOWN INTO TWO AREAS TODAY. I'M GOING HIGHLIGHT ON THE DISCOVERY AND DESIGN ADVANCES THAT FOCUS REALLY IN THE AREA OF BROADLY NEUTRALIZING ANTICIPATE BODIES BECAUSE THIS IS REALLY A TRANSFORMATIVE YEAR LAST YEAR AND I'LL TALK ABOUT SOME OF THE STUDIES THAT IDENTIFIED SORT OF A UNIQUE IMMUNE PROFILE THAT IS ASSOCIATED WITH THE ABILITY TO PRODUCE BROADLY NEUTRALIZING ANTIBODIES. I'LL TALK ABOUT NEW APPROACHES FOR MAPPING USING ASPIRATION AND I'LL FOCUS QUITE A FEW SLIDES ON THE PROOF OF PRINCIPLE THAT WE NOW HAVE IDENTIFIED IMMUNOGENS THAT CAN IN FACT PRIME AND DRIVE BROAD NEUTRALIZING ANTIBODIES INTO SMALL ANIMAL MODEL WHICH IS A HUGE MILESTONE FOR VACCINE RESEARCH. I WILL ALSO TOUCH ON THE DEFINITION OR DETERMINATION OF THE FREQUENCIES OF THESE PRECURSORS THAT WOULD BE NEEDED TO ENGAGE THESE GERMLINES FOR BNABs AND HOW FEASIBLE IS THAT? ARE THEY AT HIGH NEVE LEVELS TO MAKE THAT A IMPORTANT VACCINE STRATEGY? AND THEN I'LL REVIEW A LITTLE BIT ON NATIVE PROTEIN BEING TESTED AND THEN I'LL TALK AGAIN ABOUT TRANSFORMATIVE WORK FROM GEORGE SHAW DESCRIBING HIS NEW SCHIFF MODELS AS TOOLS FOR STUDY OF BNAB INDUCTION AND FOR VACCINE DESIGN AS A MOLECULAR GUIDE IN THAT AREA. THE SECOND PART OF MY TALK WILL BE AGAIN DIRECTIONS FOR VACCINE AS WE TRANSLATE THESE PROTECTIVE VACCINES FROM NON-HUMAN PRIMATES TO HUMANS AND FOCUS ON ACCELERATING GETTING THESE INTO TESTING AND I'LL REVIEW THREE HIGH PROFILE CLINICALLY EFFICACY TESTING. I WANT TO MAKE ONE COMMENT HERE REGARDING CLINICAL TRIALS. MANY TIMES WHEN I COME UP HERE, IT'S BEEN ASKED OF ME, MARY WHAT ARE YOU TESTING DOMESTICALLY AS FAR AS HIV VACCINES? I WANT TO ADDRESS THIS NOW. WE DO HAVE SEVERAL STUDIES THAT ARE ONGOING IN THE UNITED STATES FOR HIV VACCINE DEVELOPMENT. THESE ARE USUALLY PHASE I OR/2A VACCINES STUDIES THAT INVOLVE SOME OF THE PRODUCTS THAT I'LL SHOW LATER. ALSO THERE IS A P5 PROGRAM, A SMALL P5 PROGRAM VACCINE TRIAL ONGOING IN THE UNITED STATES. AND WE JUST RECENTLY PRODUCED A NEW CLAVE BGP120 ENVELOPE. 16 GRAMS THAT WILL BE VEALED AND TESTED AGAIN. SO WE HAVEN'T FORGOTTEN ABOUT THIS IMPORTANT EPIDEMIC IN THE UNITED STATES. FIRST, LOOKING AT THE ABILITY TO TALK ABOUT THE IMMUNE TRAITS THAT ARE LINKED WITH BROADLY NEUTRALIZING ANTIBODY PRODUCTION. SO EVERYBODY KNOWS THAT THEY ARE UNUSUAL. THEY TAKE YEARS TO DEVELOP. THEY ARE OFTEN HIGHLIGHTY SOMATICALLY MUTATED. -- HIGHLY SOMATICALLY MUTATED AND THEY ONLY OCCUR IN A CERTAIN PORTION OF INDIVIDUALS. AND SO, THE QUESTION IS, CAN WE LEARN FROM THOSE INDIVIDUALS WHO DO IN FACT MAKE THEM? SO WE HAVE PROOF-OF-CONCEPT THE HUMAN REPERTOIRE CAN MAKE THESE BNABs BUT WHAT ARE SOME OF THE SPECIAL FEATURES ABOUT THOSE FOLKS WHO DO MAKE THEM? THIS BUILDS ON WORK THAT CAME FROM THE LAB IN 2013, BUT A RECENT PAPER LAST SUMMER FROM TONY MOODY SHOWN ON THE LOWER LEFT, THEY LOOKED AT A COUPLE OF DIFFERENT COHORTS OF HIV-INFECTED INDIVIDUALS AND COMPARED THOSE WHO DID MAKE BNABs WITH THOSE TWO DIDN'T AND THEY FOUND THE FOLLOWING. THEY HAD A -- THE IMMUNE PROFILE WAS DIFFERENT IN THOSE WHO MADE BROADLY NEUTRALIZING ANTIBODIES. HIGHER FREQUENCY OF AUTO ANTIBODIES AND HIGHER CIRCULATING MEMORY T-CELLS AND LOWER FREQUENCY OF CD4T REALM CELLS AND THEY HAD A HIGHER EXPRESSION OF PD-1. SO HOPEFULLY, IDENTIFYING THESE IMMUNE PARAMETERS IN FOLKS WHO COULD MAKE BROADLY NEUTRALIZING ANTIBODIES MAY HELP US UNDERSTAND THE REIMPORTANCES FAVOR DEVELOPMENT. THE NEXT POINT I WANTED TO MAKE IS SHOWN OFF IN THE LOWER RIGHT. THIS IS A PAPER THAT CAME OUT OF THE LAB THIS SUMMER AS WELL. AND I JUST WANT TO MAKE A TONIGHT THAT WE THINK THAT THE INFANTS MAY ALSO HELP US AND BE REV LA TORY AS FAR AS COULDING HOW BROADLY NEUTRALIZING ANTIBODIES DEVELOP. THEY MAY NOT FOLLOW THE SAME RULES AS ADULTS. JULIE HAS SHOWN NOW IN TWO PAPERS THAT THESE INFANTS CAN DEVELOP BOTH BROAD AND POTENT NEUTRALIZING ANTIBODIES IN A SHORT PERIOD OF TIME, IN LESS THAN A YEAR, AND THEY ARE MUCH LESS HYPERMUTATED. SO THEY MAY IN FACT FOLLOW A DIFFERENT PATH WAY. AND IT PROBABLY HAS SOMETHING TO DO WITH THE FACT THAT THEIR IMMUNE SYSTEMS ARE IMMATURE AND MAY NOT HAVE ALL THE TO REPS CHECKPOINTS. BUT FROM THAT STANDPOINT IT MAY BE VERY INFORMATIVE WAY FOR US TO BE ABLE TO ACCELERATOR THE INDUCTION OF BROADLY NEUTRALIZING ANTIBODIES. SO WHAT ABOUT THESE NEW APPROACHES FOR MAPPING OF THE IMMUNE RESPONSE? THEY HAVE TAKEN AN OLD TECHNIQUE, MANY ARE FAMILIAR WITH THE AS OPERATION TECHNIQUES. BUT NOW THEY ARE USING IT IN THE SETTING OF FIRST PRE-CLINICAL IN PRIMATES WHO RECEIVED OR INFECTED OR RECEIVD VACCINES AND NOW IN HUMANS. AND THEY ARE ABLE TO DIRECTLY SAMPLE THE DRAINING LYMPH NODES OBVIOUSLY BEFORE AND AFTER VACCINATION AND DO THIS LONGITUDINALLY AND IMPORTANTLY, THEY HAVE CONFIRMED THAT THERE IS A -- NO SAMPLING BIAS, PER SE. THAT WAS A CONCERN THAT YOU WOULD JUST GET LIMITED CELLS. BUT THEY SHOWN THAT THESE CELLS ARE REPRESENTATIVE OF THE ENTIRE LYMPH NODES BY COMPARING WITH EXCISIONAL BIOPSIES OF LYMPH NODES. IT PERMITS ASSESSMENT OF THE T FOLLICULAR AND GERMINAL CENTER AND ALLOWS COMPARISON OF CIRCULATING LYMPHOCYTES IN THE PERIPHERY TO ENGAGE HOW DO THOSE TWO COMPARTMENTS RELATE TO EACH OTHER AND THEN THE FINDINGS THEY HAD WAS THAT THE QUANTITATIVELY GERMINAL CENTER ACTIVITY AND FOUND THAT THE NEUTRALIZING ANTIBODIES CORE LATED WITH GERMAL CENTER B-CELL MAGNITUDE AND NOT THE ELIASA ANTIBODY TITER AND THE T FOLLICULAR CELLULAR CELL WAS ASSOCIATED WITH THE VACCINE-ELICITED HIV NEUTRALIZING ANTIBODIES. THIS IS AN ULTRASOUND OF A NEEDLE TAPPING INTO A LYMPH NODE. AND WE THINK THAT LYMPH NODE BINDING ASPIRATION AND ANALYSIS COULD POTENTIALLY HELP US IDENTIFY CORRELATES IN HUMAN CLINICAL TRIALS. SORE SO HERE I WILL SPEND MORE% TIME GOING OVER THE SCIENCE AND SOME OF THE REALLY KEY PUBLICATIONS FROM LAST YEAR ON THE PROOF OF PRINCIPLE THAT IMMUNOGENS CAN PRIME AND DRIVE NEUTRALIZING ANTIBODIES. SO, THE BACKGROUND HERE IS THAT MOST IN THE FIELD NOW REALIZE THAT THERE IS PROBABLY NOT JUST GOING TO BE ONE HIV IMMUNOGEN. IT'S VERY LIKELY THAT THERE WILL NEED TO BE SEQUENTIAL IMMUNIZATIONS. THERE WILL BE A PRIMING IMMUNOGEN AND A BOOSTING IMMUNOGEN. MUCH LIKE WHAT WE HAVE DONE IN 44. SO IT'S GOING TO BE COMPLICATED. IT PROBABLY WON'T BE JUST ONE MAGIC BULLET. THE IDEA IS THE BACKDROP IS THAT TO INDUCE BROADLY NEUTRALIZING ANTIBODIES THROUGH IMMUNIZATIONS BY DEFINED SERIES OF ENVELOPES MAY GUIDE AFFINITY MATURATION. THE BACKGROUND INFORMATION IS THAT AS WE ALL KNOW, THESE NATURALLY DEVELOPING BROADLY NEUTRALIZING ANTIBODIES REQUIRE EXTENSIVE HYPERMUTATION AND INVOLVES CO-EVOLUTION PROCESS WITH VIRAL ESCAPE OVER YEARS AND CAN BE DIRECTED TOWARDS A VARIETY OF DIFFERENT VIRAL TARGETS AND OF COURSE THOSE WOULD DEFINE VARIOUS LINEAGE FAMILIES. SO THE REAL QUESTION HERE IS IN ORDER TO ANSWER THIS, FIRST WE NEED TO DESIGN IMMUNOGENS THAT CAN ENGAGE GERMLINE AND THAT IS TESTABLE. AND THEN SCENTLY IMMUNOGENS THAT CAN IMPROVE ON THE IMMUNE RESPONSE AND BOOST THOSE TO DRIVE FURTHER AFFINILITY MALTERATION AND POTENTIALLY ACCELERATE THE IMMUNE RESPONSE. SO HERE IS AGAIN SOME OLDER STUDIES THAT WERE PUBLISHED IN 2013 THROUGH 2015 WHERE IT WAS A PROOF-OF-CONCEPT THAT YOU COULD ENGAGE AND ACTIVATE GERMLINE WITH IMMUNOGENS DIRECTED TOWARDS CD4 BINDING SITE. AND THESE ARE STUDIES FROM BILL AND LEO'S LAB. SO BUILDING ON THOSE RESULTS, WE HAVE HAVE EVIDENCE THAT SEQUENTIAL IMMUNIZATION IN MOUSE MODELS. THE IDEA HERE IS THAT THE ANIMAL MODELS ARE AN IMPORTANT BRIDGE BETWEEN VEG AND CLINIC AND THEY ARE REALLY GETTING THEIR MONEY'S WORTH OUT OF THE MOUSE MODELS. THEY ARE MUCH MORE ECONOMICAL. IT'S ALMOST SURGICAL IN PRECISION ABOUT THE IMMUNOLOGIC QUESTION THANK YOU CAN ASK. AND WHAT THEY HAVE REALLY PROVED IS THAT THE RIGHT HUMAN GERMLINE ANTIBODY GENE CAN BE ENGAGED AND I'M SHOW YOU AN EXAMPLE ON MY NEXT SLIDE. BUT BASICALLY, THIS WORKS IN DIFFERENT TYPES OF MICE. IS THERE A LOW BAR, A MEDIUM BAR AND A HIGHER BAR IN MICE WITH INTERGREATED ANTIBODY GENES AND THOSE WITH FULLY NAIVE ANTIBODY REPERTOIRES AND THOSE ARE SOME OF THE PAPERS THAT CAME OUT LAST YEAR REGARDING THE TYPES OF GENETICS MODIFICATION IN THESE VARIOUS MOUSE MODELS. BUT IF YOU GO -- THIS IS THE SLIDE I'D LIKE TO SPEND A LITTLE BIT OF TIME ON. AS AN EXAMPLE OF HOW THESE SOPHISTICATED MOUSE MODELS CAN BE USED TO TEST THE CONCEPTS OF INDUCTION OF BADLY NEUTRALIZING ANTIBODIES. SO A SERIES OF TAILORED IMMUNOGENS THAT DIRECT AFFINITY MATURATION TOWARDS HIV NEUTRALIZING ANTIBODIES. THEY USE THE VRCO1. THIS IS THE SCHIFF PAPER FROM LAST SUMMER. THEY USED A HEAVY CHAIN KNOCKIN MOUSE AND USED THREE DIFFERENT IMMUNOGENS, FIRST WAS THE MINIMAL ENGINEERED OUTER DOMAIN GERMLINE TARGETING 8 PRIME AND YOU CAN SEE THIS GERMLINE IMMUNOGEN DID ENGAGE THE PRECURSORS BUT THERE WAS NO NEUTRALIZATION HERE SHOWN ON THE RIGHT. AFTER BOOSTING WITH THE GERMLINE TARGETING 3 BOOST, HERE YOU CAN SEE THAT THERE IS DRIVING MORE OF THE VRC01 CLASS MUTATIONS BUT NO NEUTRALIZATIONS. NO NEWTIZING ACTIVITY UNTIL THEY WERE FINALLY BOOSTED WITH A NATIVE TRIMER-TYPE MOLECULE WHICH THEN YOU CAN SEE TAKES OFF THE VRC01 DURATION AND WE YIELD ANTIBODY ACTIVITY WITH NEUTRALIZATION EFFECTS. SO WE ARE OPTIMISTIC THAT IF THE PRECURSORS EXIST, WE THINK WE CAN ENGAGE THESE PRECURSORS AND BY MAKING THE RIGHT DECISIONS USING THE RIGHT IMMUNOGENS, WE CAN POTENTIALLY DRIVE THOSE ANTIBODIES. IS IT A PRACTICAL STRATEGY THOUGH TO TARGET THESE PRECURSORS? HOW FREAK ARE THEY? ARE THEY RARE? -- HOW FREQUENT ARE THEY? SO THIS WORK WAS PUBLISHED AND IT'S REASSURING TO KNOW THAT THE VRC01 CLASS GERMLINE PRECURSORS EXISTED A SUFFICIENT ENOUGH FREQUENCY IN MOST HUMANS -- SO NOT JUST A SUB SET IT'S MOST PEOPLE. YOU HAVE THOSE FOR IT TO BE A REALISTIC TARGET FOR IMMUNIZATION. SO ABOUT 1 IN TWO MILLION B-CELLS OR APPROXIMATELY 15-90 TARGETS PER LYMPH NODE. CURRENTLY THEY ARE IDENTIFYING PRECURSOR FREQUENCIES FOR OTHER BNABS AND PLIM LARRY I CAN REPORT THAT UNFORTUNATELY, SOME OF THOSE PRECURSORS ARE LESS COMMON FOR OTHER FAMILIES. BUT WE ARE OPTIMISTIC THAT OTHER BROADLY NEUTRALIZING FAMILIES WILL BE FEASIBLE. SO WHAT ABOUT USING NATIVE TRIMER PROTEINS AS VACCINE IMMUNOGENS? SHALL THE RATIONAL FOR NATIVE IMMUNOGENS ARE THEY PREFERENTIALLY BIND BROADLY NEUTRALIZING ANTIBODIES OVER NON. AND THEY EXPRESS MULTIPLE NEUTRALIZING EPITOPES SO THEREFORE THEY COULD PRIME OR BOOST MULTIPLE LINEAGES IN THEORY AND IT MAY BE IMPORTANT TO USE THESE AS BOOSTS TOWARDS THE END OF THE IMMUNIZING SEQUENCE BECAUSE THEY COULD HELP TO DIRECT THIS SPECIFIC ANGLE OF THE APPROACH WHICH SOME OF THESE ANTIBODIES ARE SO PARTICULAR. THEY NEED TO DO THAT. SO WE CONTINUE TO FUND TRIMER ENGINEERING AND HOPEFULLY BROADEN THE AUTOLOGOUS ANTI-RESPONSES OBSERVED IN ANG MALL MODELS. THESE TRIMERS WILL BE TESTED IN HUMANS WHEN AVAILABLE FOR STUDY. THE LAST PART ABOUT THE WHOLE EXPLOSION IN BROADLY NEUTRALIZE ING ANTIBODY RESEARCH IS THESE NEW MODELS YOU MAY HAVE SEEN GEORGE'S PAPER, WHERE HE WORKED WITH THE -- SHIV MODELS, WORKED WITH THE DESIGNER APPROACH TO SHIVS WHERE HE TOOK PRIMARY TIER TWO OR TRANSMITTER FOUNDERS AND DESIGNED 14 NOVEL SHIVs AND TESTED THOSE IN 98 RHESUS MACAQUES, ALL OF WHOM BECAME PRODUCTIVELY INFECTED. ALL OF THESE 14 SHIVs REPLICATED EFFICIENT LEES IN HUMANS AND RHESUS, CD4 T-CELLS IN THE LAB. AND ALSO 14 SHIVs TRANSMITTED EFFICIENCIES BY ALL THE TYPICAL ROUTES TRANSMITTED BY ALL THE ROUTES. THE REALLY IMPORTANT BOTTOM LINE THAT IS SPECTAC SPLASH IF YOU GET A CHANCE TO SEE GEORGE PRESENT THIS -- SPECTACULAR, HIS ENTHUSE AM LEVEL IS ABOUT 5 LOGS HIGHER THAN - MINE BUT I'M VERY EXCITEDDED ABOUT IT. THE IMPORTANT POINT OF THIS IS THAT WHEN HE COMPARES THE MUTATION PATH WAY IN THE NON-HUMAN PRIMATES COMPARED TO HUMANS WHO EVENTUALLY DEVELOPED THESE, THEY ARE VERY SIMILAR THESE MUTATIONS, OR IDENTICAL. IT'S UNBELIEVABLE. SO THE IDEA IS THAT THIS IS PROBABLY NOT A RANDOM EVENT. AND IT'S PROBABLY DETERMINATIVE AND THAT WE THINK COULD BE VERY HELPFUL IN FORMING A VACCINE DESIGN. AND GENERAL REFERS TO IT AS SORT OF A MOLECULAR GUIDE FOR VACCINE DESIGN. SO STAY TUNED. THESE ANIMALS ARE BEING INFECTED WITH THESE VARIOUS SHIVs AND THEY ARE LOOKING TO SEE HOW THEIR NEUTRALIZATION PATTERNS ARE DEVELOPING OVER TIME. IT SEEMS TO BE THAT THEY ARE DEVELOPING NEUTRALIZING ACTIVITY SOONER THAN WE SEE IN HUMANS AND WE FIND THIS TO BE A VERY EXCITING PART OF VACCINE RESEARCH. SO, MOVING INTO THE SECOND PART OF MY TALK, I'D LIKE TO JUST REVIEW A LITTLE BIT ON THE TRANSLATION ASPECTS. THIS IS ALWAYS A CHALLENGING AREA FOR US BECAUSE WE HAVE TO MAKE THE VACCINES THAT WE TEST. IF IT WASN'T FOR THE U.S. GOVERNMENT, WE WOULD BE IN TROUBLE FROM HIV VACCINE RESEARCH. SO WE REALLY RELY ON THE FUNDING OF NIH AND OBVIOUSLY THE GATES FOUNDATION, TO MOVE THIS WORK ALONG. IN ADDITION TO THE TRANSLATION, WE ACCELERATE VACCINES INTO TESTING. BUT HERE IS THE BOTTOM LINE FOR THE ACCELERATION EFFORTS. THE NUMBER 1 SOURCE OF DELAY AS KARL ALLUDED TO EARLIER TODAY, IS THESE GMP MANUFACTURING BOTTLENECKS. AND WE HAVE TAKEN A LOT OF STEPS AND WORKED AS AN INSTITUTE, OAR WAS HELPFUL AS KARL DESCRIBED, IN SHUTTLING A LOT OF FUNDING TO HELP IMPROVE MANUFACTURING. WE ALSO HAVE WORKED ON FINDING ALTERNATIVES TO THIS PAINSTAKING PROCESS OF DEVELOPING STABLE CELL LINES. SO, WORKING WITH TRANSIENT TRANSFECTIONS. WE HAVE SOME RESULTS WITH THAT. COMPARING THE STABLE CELL LINE VERSUS TRANSIENT TRANSFECTION. AND THEN ALSO USING mRNA WHICH COULD REALLY JUST BE TRANSFORMATIVE AND CIRCUMVENT THE NEED TO PRODUCE THESE PROTEINS AND THE FACT THAT THEY ARE STABILIZED mRNA NOW WILL REALLY POTENTIALLY ADVANCE THE HIV VACCINE FIELD. WE KNOW IT IS BEING USED IN ZIKA AND WE ARE HOPING TO USE THAT IN HIV IMMUNOGENS SOON. THERE IS ALSO EFFORTS HIGHLY FOCUSED ON PLATFORM PURIFICATION PROCESSES TO ACCELERATE TESTING OF IN PARTICULAR, THE TRIMERS BY USING BROADLY NEUTRALIZING ANTIBODIES TO PURIFY AND THEN PHASE APPROPRIATE MANUFACTURINGS AS KARL TALKED ABOUT IN HISS SBIR PRESENTATION. OTHER DELAY AREAS WE FEEL WE MADE A LOT OF PROGRESS IN THOSE AREAS WORKING WITH THE REGULATORS TO INCREASE CONSISTENCY IN STREAMLINING AND APPROPRIATE MINIMIZE THE USE OF TOXICOLOGY STUDIES THAT AREN'T THAT I THINK FORMATIVE AND LEVERAGE OUR EXEXTENSIVE EXPERIENCE WITH THESE PRODUCTS. SO, THIS IS JUST AN EXAMPLE OF THE TRANSIENT TRANSFECTION PROCESS THAT I WANTED TO TALK ABOUT. IF THIS WAS IN WORKING WITH BART HAINES, HE WAS ABLE TO PROVIDE DNA FOR ONE OF HIS GP120 WHICH WAS THEN TRANSFECTED INTO A -- CELL AND CULL TERS WERE GROWN AND WITHIN 3 1/2 MONTHS, WE OBTAINED A HALF A GRAM OF PROTEIN, WHICH WAS A VERY ACCELERATED PROCESS BY PASSING THE NEED TO DO THE STABLE CELL LINE. THE CAVEAT HERE IS THAT ONE OF THE REASONS WHY THIS WAS SO QUICK IS ALL THE DOWNSTREAM PURIFICATION HAD BEEN ALREADY DEVELOPED. BUT THIS WAS THE MAIN QUESTION HERE WAS THIS TRANSIENT TRANSFECTION PROCESS AND THE DEVELOPMENT OF THE CELL LINE. THIS PROTEIN HAS BEEN CHARACTERIZED PRETTY EXTENSIVELY AND IT COMPARES VERY FAVORABLY TO THE PROTEIN GENERATED FROM THE STABLE CELL LINE. WE WILL TEST THIS IN A SMALL PHASE I STUDY BECAUSE THE IMPORTANT PART IS WHAT DOES THE IMMUNOGENICITY LOOK LIKE? THERE ARE DIFFERENCES IN THE LIE CANNED PATTERNS BUT HOPING -- GLYCAN PATTERNS BUT HOPING WE WILL BE INFORMED BY THE IMMUNE RESPONSES. AND THEN FINALLY -- SORRY ABOUT THE ANIMATION. I MENTIONED THE OTHER WAY TO ACCELERATE WILL BE TO MAKE AVAILABLE TO RESEARCHERS WHO ARE TRYING TO PURIFY TRIMERS ET CETERA, TO MAKE AVAILABLE RELEVANT NEUTRALIZING ANTIBODIES THAT COULD HELP WITH TRY MAKER CAPTURE AND OTHER DOWNSTREAM PROCESS, FOR EXAMPLE, IN IMMUNOAFFINNITY COLUMNS. SO WE ARE LOOKING AT DIFFERENT SOURCES OF THESE ANTIBODIES, FOR EXAMPLE THE PLANT-DERIVED VERSUS CELL LINE. THERE IS ADVANTAGES THERE WITH SHORTER TIME LINES AND GENERATING LARGER AMOUNTS. WE HOPE THAT WILL ENABLE FOLKS TO GET THEIR PRODUCTS INTO TESTING QUICKER IF IT IS STANDARDIZED SOMEWHAT. FINALLY, I WANTED TO GET INTO THE VACCINE CONCEPTS AND HIGHLIGHT A FEW HIGH PROFILE EFFICACY TRIALS THAT ARE CURRENTLY IN TESTING OR WILL START LATER THIS YEAR. SO FIRST IS THE POX PROTEIN. YOU HEARD ME TALK ABOUT THIS BEFORE WHERE WE ARE TRYING TO EXTEND AND SUBSTANTIATE THE RESULTS. THIS HVTN100 IS A SMALL TYPO HERE. THIS STUDY ACTUALLY THE ACCRUAL WAS BETWEEN FEBRUARY AND MAY OF 2015. THE PRIMARY IMMUNOGENICITY WAS TWO WEEKS AFTER THE FOURTH VACCINATION WHICH WAS DECEMBER 2015. AND THEN AS A RESULT OF THE IMMUNE ANALYSIS OF THOSE PARTICIPANTS SAMS, THERE WAS A GO DECISION -- SAMPLES -- FOR THAT MEANING THAT WE FELT THE CORRELATES COULD BE TESTED IN THE HVTNZ02 PIVOTAL PHASE II B3 STUDY. SO YOU HEARD TONY TALK ABOUT THIS TODAY AND KARL. IT'S THE ONLY ONGOING HIV VACCINE EFFICACY WORLDWIDE. IT'S OCCURRING IN SOUTH AFRICA. THERE ARE 15 SITES THAT WILL BE INVOLVED IN 8 OF THE 15 SITES HAVE BEEN ACTIVATED. THE VACCINATION STARTED IN LATE OCTOBER. THEY TOOK OFF TREMENDOUSLY BUT THEN WERE SLOWED DOWN BY THE HOLIDAYS AND WERE RAMPING UP AGAIN TO MOVE THAT TRIAL ALONG. THE SECOND EFFICACY STUDY THAT IS A HUGE EFFORT THAT I WANT TO REMIND YOU ABOUT IS THASM STUDY OR THE ANTIBODY MEDIATED PROTECTION STUDY WHICH IS THE INFUSION OR PASSIVE INFUSION OF THE BRCL1 AND ESSENTIALLY TWO STUDIES THAT ARE GEOGRAPHICALLY LOCATED. THE AMERICAS TRIAL AND THE AFRICA STUDY IN WOMEN. AND IT'S A PHASE II B STUDY TO EVALUATE THE STUDY OF THE EFFICACY IN REDUCING HIV-1 INFECTION. I WANT TO MAKE A SPECIAL POINT HERE FROM A VACCINE STANDPOINT. WE HAVE KNOWN FOR A LONG TIME THAT BROADLY NEUTRALIZING ANTIBODIES CAN PROTECT THE ANIMALS FROM CHALLENGE. SHIV CHALLENGE. WE DON'T KNOW WHETHER BROADLY NEUTRALIZING ANTIBODIES CAN PREVENT HUMAN INFECTION AND IS THERE A MAJOR INVESTMENT IN THE ATTEMPTS TO DEVELOP BROADLY NEUTRALIZING IMMUNOGENS AND WE THINK IT IS REALLY IMPORTANT TO TEST THAT CONCEPT TO MAKE SURE THAT WE ARE ON THE RIGHT TRACK WITH THE RESEARCH EFFORTS IN THIS AREA. SO,ASM WAS STARTED IN MARCH AND MAY OF 2016. THIS IS A 2B STUDY WHERE ZRC01 IS INFUSED. THE VOLUNTEERS RECEIVE THIS EVERY 8 WEEKS FOR 10 DOSES. IT'S BEEN REMARKABLE. THE RETENTION RATE IS SOMETHING LIKE 98%. THAT WAS ONE OF THE MAJOR CONCERNS THAT PEOPLE SAID LIKE THEY NEVER WILL COME BACK. ALL THESE INFUSIONS. BUT THEY ARE DOING FINE. IT'S ABOUT 25% ENROLLED. ABOUT 1000 PEOPLE INVOLVED SO FAR AND WE ARE HOPING TO HAVE RESULTS IN 2019 TO 2020 TIMEFRAME. THIS IS THE LAST EFFICACY STUDY I'LL BRING UP AND SARAH HAD REFERRED TO THIS A LITTLE BIT. THIS IS A RESEARCH ACTIVITY THAT NIAID HAS BEEN FUNDING FOR YEARS THROUGH THE DANBA UKE LABORATORY USING THE ADD 26 VECTOR WITH EN VE LOAVE PRIMING. THERE IS ALSO A FUNDED RESEARCH ON AD26 PRIMING WITH MDA BOOSTING THAT SARAH HAD TALKED ABOUT AS FAR AS THERAPEUTIC VACCINE. IN THE PREVENTION AREA, JANSEN JUST REALLY FOCUSING ON SIMPLIFYING THE REGIMEN AND USING THE 26 MOSAIC WITH SO-CALLED TRIMERIC PROTEINS TO BOOST HUMORAL IMMUNITY. THIS VACCINE IS SORT OF BILLED AS A GLOBAL VACCINE BECAUSE OF THE MOSAIC NATURE. IT SHOULD CONFER, THE HOPE IS TO CONFER PROTECTION TO A BROAD ARRAY OF VIRAL CHALLENGES. SO, THE PHASE I AND PHASE II A STUDIES HAVE BEEN CONDUCTED. MANY OF THEM IN THE UNITED STATES AND IN OTHER PARTS OF THE WORMED. HVTN705 IS A STUDY PLANNED TO START LATER THIS YEAR. IT'S TO EVALUATE THE VACCINE EFFICACY OF AD26 MOSAIC 4 HIV PLUS CLAYED CGP ONE HIN 40 REGIMEN AND PRIMED WITH THE 26 MOW SAYIC AND BOOSTED WITH BOTH AS SHOWN HERE. IT'S A RANDOMIZED CONTROLLED 1-1 RANDOMIZATION PLACEBO-CONTROLLED STUDY OF 2600 WOMEN WHO ARE AT MODERATELY HIGH-RISK IN SOUTHERN AFRICA; AND YOU CAN SEE THE OVERALL DESIGN HERE. THE FIRST EFFICACY SIGNAL IS GOING TO BE CHECKED AT MONTH 24, TWO YEARS ITO THE STUDY. IF THERE IS EFFICACY, THE STUDY WILL CONTINUE LOOKING FOR DURABILITY AT MONTH 36. FINALLY, I'D LIKE TO JUST HIGHLIGHT SOME OF THE VRP SUPPORTED WORKSHOPS IN 2016. THEY WERE VERY POPULAR. THESE ARE JUST SOME OF THE ONES THAT I LIKE TO TELL YOU ABOUT. THE FIRST ONE IS THE NANOTECHNOLOGY FOR HIV RNA AND VACCINE DELIVERY WORKSHOP IN SEPTEMBER. THAT WAS A DIVERSE GROUP OF RESEARCHERS, ACADEMICS AND BIOTECH FOLKS WHO PARTICIPATED ALL ACROSS-THE-BOARD FROM ADJUVANTS, NANOTECHNOLOGY, NUCLEIC ACID DELIVERY, mRNA AND SOME VERY STIMULATING DISCUSSIONS AND HOPEFULLY COLLABORATIONS AND LOOKING FORWARD TO ANOTHER REPEAT OF THAT WORKSHOP. WE HAD THE SECOND HIV ENVELOPE MANUFACTURING WORKSHOP AND AGAIN THAT IS WELL ATTENDED AND VERY POPULAR BECAUSE THERE IS SO MUCH EFFORT ON TRYING TO ACCELERATE THE PRODUCTION OF THOSE IMMUNOGENS AND THEN LAST JUNE, WE HAD A GREAT AVRS MEETING. WE INVITED BACK SOME OF THE AWARDEES, THE 2012 AWARDEES, TO SHOWCASE SOME OF THEIR INNOVATIVE RESEARCH. WE ALSO HAD PRESENTATIONS FROM THE TWO NEW PIs FOR CONSORTIA FOR INNOVATIVE AIDS RESEARCH AND NON-HUMAN PRIMATE GRANTS AND THEN WE ALSO HAD THE LABORATORIANS PRESENT AND TEACH US ABOUT THE TECHNOLOGY THAT THEY ARE GOING TO USE WHEN THEY DO THE CLINICAL ANALYSIS OF THESE GERMLINE TARGET THE IMMUNOGENS. HOW ARE WE GOING TO FINISH WE ARE ENGAGING GERMLINE -- TO KNOW -- AND AR E WE ON THE ROAD TO DEVELOPING THIS ANTIBODIES. THAT WILL TAKE A CLOSE COORDINATING EFFORT FOR THE LABORATORIANS AND THEN FINALLY BONNIE WAS KIND ENOUGH TO GIVE US A PRESENTATION ON THE NIH, HIV/AIDS RESEARCH PRIORITIES AND GUIDELINES FOR DETERMINING AIDS FUNDING AND A SUMMARY OF THE NOVEMBER 2015 OARAC MEETING. AND THEN LASTLY, WE HAD A WORKSHOP ON THE CONTRIBUTION OF SEXUAL BEHAVIOR IN THE GLOBAL HETEROSEXUAL HIV EPIDEMIC IN SEPTEMBER. SO, WITH THAT, I'D LIKE TO ACKNOWLEDGE THE VACCINE RESEARCH PROGRAM LISTED HERE ARE THE INDIVIDUALS WHO ARE PART OF THE VACCINE RESEARCH PROGRAM. THE VACCINE CLINICAL RESEARCH BRANCH IS HEADED BY DALE HEW AND: [ READING ] THESE INDIVIDUALS WORK HARD EVERY DAY ON HELPING US GET TOWARDS AN HIV VACCINE. I'D LIKE TO ACKNOWLEDGE THE NIAID FUNDED NETWORKS AND PARTNERS, INCLUDING THOSE FOLKS WHO ARE LISTED ON THE RIGHT AND OUR CRITICAL PARTNER IN THE POX PUBLIC PRIVATE PARTNERSHIP, THE BILL AND MELINDA GATES FOUNDATION. SO WITH THAT, I'LL TAKE QUESTIONS IF THERE ARE ANY. [ APPLAUSE ] >> A COUPLE OF QUESTIONS. SO, THE REPEAT OF THE RV144 TRIAL THAT IS BEING -- I GUESS GOING ON, RIGHT? >> YES. >> DID THEY TAKE INTO OR CHANGE THE STRATEGY FOR THE ADJUVANT OR THEY DID NOT? >> I'M SORRY. I DIDN'T GO INTO THAT. I APOLOGIZE. THEY DID. BECAUSE OBVIOUSLY ONE OF THE PROBLEMS WITH RV144 IS THE DURABILITY OF THE EFFECT. AND SO, THEY CHANGED THE ADJUVANT FROM ALUM TO MF59 WITH THE IDEA THAT THE MF59 COULD INDUCE A MORE DURABLE ANTIBODY RESPONSE. THEY ALSO MODIFIED THE IMMUNOGENS SO THE PRIMING WITH THEEL VEHICLE WOULD CONTAIN SEQUENCES THAT WERE RELEVANT FOR THE AREA BEING STUDIED IN SOUTHERN AFRICA, SO THERE WERE SEQUENTING IN THEAL VAC PRIMING VECTOR AND IN THE BOOSTING PROTEINS. [ INDISCERNIBLE ] SO, I GUESS THAT IS -- [ INDISCERNIBLE ] >> NO. IT'S NOT. >> THAT'S VERY COMPLICATED. AT LEAST TWO STUDIES, ONE SHOWING THAT AN ADJUVANT WORKS, SO FUNDAMENTALLY WE ARE VERY AWARE AND WE HAVE INTEGRATED THE THINKING INTO OUR DESIGN AND ARE COMFORTABLE. I THINK THIS IS A GOOD 20-MINUTE CONVERSATION WE SHOULD HAVE WITH YOU ABOUT WHAT WE KNOW. >> THERE IS MULTIPLE STUDIES AND WHEN MF59 WAS COMPARED TO ALUM ADJUVANTED VACCINES IN THE RELEVANT MODEL WITH THE SHIV CHALLENGE, THOSE ANIMALS WERE PROTECTED WITHIN THE 59. SO THERE IS DATA THAT YOU MAY NOT HAVE SEEN BUT IS VERY SUPPORTIVE OF MF59. >> THE SECOND QUESTION, I REALLY HAVE FOLLOWED THE VRC1 TRIAL I THINK I MENTIONED TO YOU BEFORE. THE POINT TO ME IS IS THAT I THOUGHT WE HAD DATA ALREADY IN THE CLINICAL CENTER THAT DIDN'T WORK. >> VRC01 -- [ MULTIPLE SPEAKERS ] WE TALKED ABOUT THIS AND I'LL JUST REITERATE HERE IS THAT FUNDAMENTALLY, WE THINK THAT PREVENTION OF HIV INFECTION AND TREATING CHRONICALLY-INFECTED INDIVIDUALS IS WORLDS APART. HIV TRANSMISSION AS YOU KNOW, IS VERY INEFFICIENT AND IF WE CAN HAVE AN INDIVIDUAL WITH ANTIBODY LOADED ONBOARD IN THE RIGHT PLACES AT THE RIGHT TIME, WE MAY VERY WELL BE ABLE TO PREVENT INFECTION PRESUMABLY BASED ON THE NON-HUMAN PRIMATE MODELS THAT SHOW THAT. BUT I DON'T THINK VRCL1 WAS EVER BUILT TO TREAT CHRONIC INFECTION TO TREAT HIV, EVER. [ OFF MIC ] >> GOING TO TALK TO US ABOUT PREVENTION SCIENCES PROGRAM. >> OKAY. CAN YOU HEAR ME? AS MARY SAID, ONE STEP CLOSER. WE ARE ALMOST THERE. I AM VERY PLEASED TO BE ABLE TO TALK TO YOU THIS AFTERNOON ABOUT THE STATE OF THE PREVENTION SCIENCES PROGRAM AT DAIDS. I'M GOING TO TALK TO YOU A LITTLE BIT ABOUT WHAT ARE OUR BASIC AT LEAST HIGH-LEVEL PROGRAM OBJECTIVES. WHAT ARE THE PROGRAMS AND NETWORKS THAT WE ARE WORKING WITH TO ACCOMPLISH THOSE OBJECTIVES? LOOKING BACK AT 2016 AND REALLY JUST A FEW OF THE HIGH-LEVEL PROGRAM HIGHLIGHTS AND ACCOMPLISHMENTS. AND THEN WE'LL TALK ABOUT THE FUTURE DIRECTIONS. WE'LL TALK ABOUT WHERE ARE WE IN 2017 AND WHERE WILL WE BE GOING BEYOND THAT? SO, FIRST OFF, I WANTED TO KIND OF REORIENT YOU. MANY OF YOU HAVE SEEN THIS A NUMBER OF TIMES BUT WE ARE ORGANIZED INTO FOUR BRANCHES. WE HAVE THE CLINICAL MICROBICIDE RESEARCH BRANCH WITH ROBERTA BLACK AS THE CHIEF. WE HAVE THE CLINICAL PREVENTION RESEARCH BRANCH, DAVID BURNS IS THE BRANCH CHIEF THERE. THE MATERNAL ADD LESSENT AND PEDIATRIC RESEARCH BRANCH AND DEB ANDIANA IS THE BRANCH CHIEF THERE AND THEN THE PRE-CLINICAL MICROBICIDE AND PREVENTION RESEARCH BRANCH WITH JIM TURPIN AS THE BRANCH CHIEF. SO WHAT ARE OUR OBJECTIVES? AS YOU HAVE SEEN WITH THE OTHER PROGRAMS, WE HAVE A NUMBER OF OBJECTIVES AND THEY ARE QUITE DIVERSE. NOT GOING INTO ALL OF THE SPECIFICS, THE SUBOBJECTIVES HERE, BUT OUR HIGH-LEVEL OBJECTIVES IS TO DELIVER NEW PREVENTION TOOLS THAT CAN REDUCE HIV INCIDENCE IN POPULATIONS AT RISK -- [ READING ] WE ARE WORKING VERY CLOSELY IN COLLABORATION WITH THE BILL AND MELINDA GATES FOUNDATION AS WELL AS OTHERS TO ACHIEVE THAT OBJECTIVE. AND THEN IN PARTNERSHIP WITH NICH. AND NIMH WE ARE LEADING EFFORTS TO IMPROVE HIV TREATMENT FOR PREGNANT WOMEN, INFANTS, CHILDREN AND ADD LESSENTS AND WE NEED TO DO THAT MUCH MORE EFFICIENTLY THAN WE HAVE DONE IN THE PAST. [ READING ] SO HOW ARE WE TRYING TO ACHIEVE THESE OBJECTIVES? I'LL RUN THROUGH NOT EVERY SINGLE DETAIL, BUT I'LL RUN THROUGH OUR MAJOR PROGRAMS AND THEN THE NETWORKS THAT WERE RESPONSIBLE FOR WORKING WITH. WE HAVE A CONTRACT, WHICH IS OUR CONTRACT RESOURCES FOR MICROBICIDES AND PREVENTION. THIS IS THE SECOND ITERATION THAT WAS AWARDED IN 2016. AND THIS REALLY IS A FOUNDATION, PARTICULARLY IN OUR PRE-CLINICAL AREA. THIS IS A GAP-FILLING RESOURCE TO HELP GET PRODUCTS FROM THE EARLY PRECLINICAL STAGES THROUGH HOPEFULLY TRANSLATION AND INTO CLINICAL TESTING. IF THEY MAKE THE GO-NO-GO, THEY MAKE THE GO SORT OF CRITERIA IN OUR ESTABLISHED ALGORITHMS, WE ALSO WANT TO MAKE THE CUTS AS EARLY AS POSSIBLE IN PRODUCTS THAT ARE NOT MERITORIOUS TO MOVE FORWARD OR HAVE VARIOUS ISSUES. SO WE WANT TO DO THAT EARLY. WE HAVE OUR PROGRAM, SOLICITED PROGRAM IN THE MUCOSAL ENVIRONMENT IN HIV PREVENTION, OTHERWISE KNOWN AS THE MEHP. AND THAT PROGRAM HAS BEEN OR THE FIRST TO REALLY HELP US ENHANCE OUR UNDERSTANDING OF THE MUCOSAL ENVIRONMENT AND HOW THE PREVENTION INTERVENTIONS THAT WE ARE TESTING INTERACT WITH THE GENITAL AND GI MUCOSA AND HOPEFULLY OPTIMIZING THAT INTERACTION TO BETTER PROMOTE INHIBITION OF HIV TRANSMISSION AND ACQUISITION. THEN WE HAD OUR PRE-CLINICAL INNOVATION PROGRAM, WHICH IS REALLY OUR TRANSLATIONAL MAKING THE GAP FROM THE EARLY DISCOVERY AND DEVELOPMENT STAGES FURTHERING PRODUCT DEVELOPMENT AND MOVING INTO WHAT WE CALL THE PRE-PHASE I OR PHASE 0, THE TRANSLATIONAL VERY EARLY CLINICAL TESTING. AND THEN, I'M SORRY -- I SWITCHED THOSE AROUND AS I'M SURE YOU NOTICED. THAT WAS THE INTEGRATED CLINICAL PRE-CLINICAL PROGRAM. THE IPCP THAT I JUST DESCRIBED. THE PRE-CLINICAL INNOVATION PROGRAM IS THAT EARLIER STAGE OF INNOVATION LOOKING AT TESTING OF SINGLE AND COMBINATION DRUG STRATEGIES AND WE ARE ALSO IN THAT VERY EARLY STAGE OF INNOVATION TRYING TO PROMOTE THE INTEGRATION OF A NEW ADHERENCE TECHNOLOGIES INTO THE PREVENTION PIPELINE. THEN WE HAVE OUR SUSTAINED RELEASE OF ANTIVIRALS FOR TREATMENT AND PREVENTION AS SARAH DESCRIBED IN MUCH MORE DETAIL. THIS IS A LONGSTANDING COLLABORATION WITH A AND THAT REALLY THE MAJOR OVERARCHING OBJECTIVE IS TO BUILD A PIPELINE OF LONG-ACTING RELEASE FORMULATIONS FOR AT LEAST IN OUR PROGRAM, FOR NON-VACCINE BIOMEDICAL PREVENTION AND OF COURSE IN THE THERAPEUTICS PROGRAM, FOR TREATMENT. THEN WE HAD SEVERAL ITERATIONS OF THE METHODS FOR PREVENTION PACKAGES, OTHERWISE KNOWN AS THE MP3 PROGRAM. AND THAT WAS TO BRING TOGETHER ENTER DISCIPLINARY, MULTIDISCIPLINARY TEAMS TO FACILITATE THE DESIGN AND TESTING OF COMBINATION PREVENTION PACKAGE SYSTEM. SO THIS REALLY BROUGHT TOGETHER THE CLINICAL TRIALS, CLINICIANS, STATISTICIANS AND TRIAL METHODOLOGISTS MODELERS, BASIC SCIENCE FOLKS, TO REALLY AS NEEDED TO REALLY DEVELOP THESE COMBINATION PREVENTION PACKAGES AND THEN DUKE THE VERY EARLY WORK TO DETERMINE WHETHER OR NOT THESE PACKAGES SHOULD MOVE INTO MAYBE INTO THE FIELD, INTO PROGRAMS IF WE HAVE ENOUGH INFORMATION ALREADY OR INTO LARGER TESTING IN THE CLINICAL TRIALS NETWORKS AND OTHERWISE. WE ALSO HAD THE I KNOW PROGRAM, TO INCREASE THE KNOWLEDGE TO REDUCE HIV INCIDENCE AND THAT WAS REALLY FOCUSED ON PROMOTING INNOVATIVE RESEARCH TO INCREASES ACCESS AND TESTING UPTAKE IN POPULATIONS, IN KEY POPULATIONS, WHERE WE HAVE NOT BEEN ABLE TO HISTORICALLY REACH AS WELL. AND THEN WE HAVE THREE NETWORKS THAT WE WORK WITH WITHIN OUR PROGRAM, AND I'LL GO OVER AGAIN THE BASIC OBJECTIVES OF EACH OF THE NETWORKS. WE HAVE THE HIV PREVENTION TRIALS NETWORK AND THEY REALLY ARE OVERARCHING OBJECTIVE IS TO DISCOVER AND DEVELOP INNOVATIVE RESEARCH STRATEGIES TO REDUCE HIV ACQUISITION AND TRANSMISSION AND SO THEY ARE TASKED WITH TWO MAJOR AREAS OF TESTING THESE PREVENTION COMBINATION PREVENTION PACKAGES OR INTEGRATED STRATEGIES. AND THEN THEY HAVE ALSO BEEN FOCUSING ON DEVELOPING SYSTEMIC PREP AND SPECIFICALLY MOST RECENTLY, LONG-ACTING AGENTS. THEN WE ALSO WORK WHAT THE IMPACT NETWORK, INTERNATIONAL MATERNAL AND PEDIATRIC AND ADOLESCENT CLINICAL TRIALS NETWORK. AND THAT NETWORK HAS A VERY BROAD MANDATE FOCUSING ON THE POPULATION OF PREGNANT WOMEN, INFANTS, AND CHILDREN. AND THEY REALLY HAVE BEEN TASKED WITH HIV TREATMENT, PREVENTION, CURE EFFORTS IN THESIS POPULATIONS AS WELL AS LOOKING IN THE PAST AT CO-MORBIDITIES AND COMPLICATIONS WHICH THEY ARE STILL DOING BUT PROBABLY CHANGING SOME AS FAR AS IN INTRODUCED THAT WORK AS WE ARE IN THE PRESENT MOVING INTO THE FUTURE. AND THEN, ALSO LOOKING AT HOW TO IMPROVE TB DIAGNOSIS TREATMENT AND PREVENTION IN THESE POPULATION. MICROBICIDE TRIALS NETWORK. THERE ARE A LOT OF WORDS THERE. AND BUT BASICALLY, THE OBJECTEDDIVES ARE FOCUS ON TOPICAL HIV PREVENTION PRODUCT DEVELOPMENT, INTEGRATING APPROPRIATE BEHAVIORAL AND SOCIAL SCIENCE AND FOCUSING ON KEY POPULATIONS AT RISK. TO HAVE YOU SEE HOW IT ALL -- ALL THESE THINGS I MENTIONED, HOW THEY FIT TOGETHER ALONG THE DEVELOPMENT PIPELINE FROM DISCOVERY ALL THE WAY TO THE EFFICACY TESTING AND THE PHASE III CLINICAL STUDIES, AND AS YOU CAN SEE, OUR CONTRACT, IS THE PLATFORM FOR ALL OF IT AND THEN WE HAVE THE VARIOUS PRE-CLINICAL AND TRANSLATIONAL PROGRAMS THAT FEED INTO THE 3 CLINICAL TRIAL NETWORKS. SO FOR SOME PROGRAM HIGHLIGHTS. SO FOR 2016, MANY OF YOU PROBABLY ALREADY ARE FAMILIAR WITH A LOT OF THESE. AND SOME OF THESE THAT DR. FAUCI AND KARL HAVE ALREADY HIGHLIGHTED IN THEIR PRESENTATIONS EARLIER TODAY. BUT, I TRIED TO TAKE A COUPLE OR THREE OF THE HIGH-LEVEL ACCOMPLISHMENTS IN EACH OF THE PROGRAM AREAS THAT WERE RESPONSIBLE FOR. SO AS MANY OF YOU KNOW, THE PROMISE STUDY ACTUALLY CAME TO AN END THIS SEPTEMBER AND THAT WAS LOOKING AT HOW TO PREVENT MOTHER TO CHILD TRANSMISSION AS WELL AS LOOKING AT MATERNAL HEALTH WITH HIV TREATMENT AND THE RATES OF INFECTION AS EVERYONE WILL REMEMBER WERE QUITE LOW. WE HAD THE 12-MONTH RESULTS THUS FAR AND THE TRANSMISSION RATES WERE.3% AT 6 MONTHS AND .6% AT 12 MONTHS. SO THE PROTECTION DOES SEEM TO BE QUITE DURABLE. THE INFANT SURVIVAL RATE WAS AT 98.9% WHICH IS VERY, AS EVERYONE KNOWS, VERY HIGH, AND THERE WEREN'T REALLY SIGNIFICANT DIFFERENCES BETWEEN THE ARMS. P1093 IS A STUDY LOOKING AT THE PK AND WILL SAFETY OF DELL RETEG VEER AND ALL THE WAY FROM INFECTS TO ADOLESCENCE AND IT'S MOVING IN A STEP-WISE AGE STEP-DOWN MANNER. WE HAVE GOTTEN THE FDA AND EMAITUDES DATA TO GET APPROVAL OF DTG DOWN TO 6 YEARS OF AGE AND WE ARE, WHOING NOW DOT YOUNGEST TO WORK ON THE YOUNGEST COHORTS. AND AS EVERYONE IS AWARE AND HAS BEEN DISCUSSED, THE ASPIRE RESULTS WERE REPORTED THE INITIAL RESULTS WERE REPORTED AT CROI, THE INTERVAGINAL RING. AND AFTER CROI, WE HELD A CONSULTATION AT THE DIVISION OF AIDS TO REALLY LOOK IN DEPTH AT THOSE RESULTS AND DETERMINE THE WAY FORWARD. THE HOPE AS A RESULT OF THAT UTHE HOPE STUDY, WAS INITIATED, THE OPEN-LABEL FOLLOW ON TRIAL OF THE RING AND AT THIS POINTED, THERE ARE ABOUT 300 WOMEN ENROLED. I THINK THE BEAUTY OF THIS STUDY IS THAT WOMEN CAN DECLINE USE OF THE INTERVAGINAL RING EITHER UPFRONT OR AS THEY GO ALONG IN THE STUDY AND THEY CAN STILL BE IN THE STUDY. SO WE REALLY WANTED TO LOOK AT WHO DECLINES, WHO ACCEPTS, DO THEY CONTINUE TO ADHERE OVER TIME? AND THAT REALLY PIONEERING A DIFFERENT WAY OF LOOKING AT ADHERENCE COUNSELING THAN WE HAVE IN THE PAST. AND THEN THE MTN017 STUDY WHICH IS RECTAL TA NOF VEER GEL STUDY COMPLETED. THE FIRST PHASE II RECTAL GEL STUDY AND RESULTS WERE REPORTED AT CROI. ALSO REPORTED AT CROI AND AIS, WAS THE HPTN073 STUDY, PREP DEMONSTRATION PROJECTS IN THE U.S. IN BLACK MSM AND ALSO AS MARY HAS ALREADY DISCUSSED, THE ASM STUDY -- STUDIES, STARTED EARLIER THIS YEAR. SHE TALKED ABOUT THEM AND THEN AS KARL AND DR. FAUCI MENTIONED, 083, IN MSM IN THE AMERICAS HAS BEEN INITIATED AND AS MENTIONED WE ARE HOPING THAT TO START THE STUDY IN WOMEN THIS YEAR AND HOPEFULLY WITHIN THE NEXT COUPLE OF MOSS. AND THEN IN OUR PRE-CLINICAL AREAS, OUR CONTRACT WAS AWARDED. OUR RAIS APPLICATIONS WERE RECEIVED AND REVIEWED, WHICH HAS TO DO WITH MUCOSAL INJURY IN ADOLESCENCE AND THIS IS THE NEXT STEP, THE FOLLOW ON FROM OUR MUCOSAL ENVIRONMENT PROGRAM THAT I TALKED ABOUT EARLIER. AND THEN THREE OF OUR STAFF IN THE PRE-CLINICAL GROUP HAD POSTERS PRESENTED AT R4P. SO, 2017 AND BEYOND. WHAT ARE WE FOCUSING ON? WHAT DO WE THINK WE ARE GOING TO NEED TO FOCUS ON OVER THE NEXT SEVERAL YEARS? SUSTAINED RELEASE. THAT IS DEFINITELY GOING TO BE -- IT IS AND I THINK WILL CONTINUE TO BE ONE OF OUR MAJOR AREAS OF FOCUS. WE ARE CONTINUING THOSE EFFORTS WITH THE THERAPEUTIC RESEARCH PROGRAM AS I JUST CEMENTED THE% HOPE STUDY IS CONTINUING. AND THEY WILL CONTINUE TO AYOO AND SO FAR THE RETENTION RATES ARE QUITE HIGH. BEGIN THE PHASE III STUDY OF CABO TEGRA VEER IN WOMEN. WE NEED TO INCREASE EFFORTS IN THE MULTIPURPOSE PREVENTION TECHNOLOGIES SPACE. AND YOU'LL BE SEEING MORE ABOUT THAT AS WE GO THROUGH THE YEAR AND DISCUSS UP COMING INITIATIVES. AND THEN, I THINK OUR, ONE OF OUR SIGNIFICANT CHANGES IS GOING TO BE THAT WE ARE GOING TOO HEAVILY ENCOURAGE OR REQUIRE THAT FUTURE PRODUCTS REALLY PROVIDE SIMULTANEOUS COVERAGE AGAINST ACQUISITION IN BOTH THE VAGINAL AND RECTAL COMPARTMENTS AND THAT IS IN RESPONSE TO EMERGING INFORMATION THAT BASICALLY, AS MANY OF YOU MAY HAVE BEEN AT THE MEETING THAT WAS HELD THAT MARY'S GROUP AND OUR GROUP WORKED TOGETHER ON TO DISCUSS THE INCIDENCE OF PREVALENCE OF ANAL INTERCOURSE AND HOW THAT IS CONTRIBUTING TO HIV TRANSMISSION BOTH IN THE U.S. AND AROUND THE WORLD. AND I THINK THAT WE HAVE HAD TO ACKNOWLEDGE THAT THERE IS MORE ANAL INTERCOURSE IN THE HETEROSEXUAL POPULATION THAT HAS BEEN PREVIOUSLY APPRECIATED. THEN WE NEED TO BETTER UNDERSTAND CONTEXT BOTH MUCOSAL CONTEXT AS WELL AS INDIVIDUAL AND COMMUNITY CONTEXT. WE HAVE TO INCREASE OUR UNDERSTANDING OF THE MICROBIOME AND AS I HAVE SAID MANY TIMES BUT I THINK IT HAS BECOME MORE IMPORTANT THAN EVER, THE INTEGRATION OF BEHAVIORAL SCIENCE AND TO ALL PHASES, INCLUDING STARTING AT THE VERY EARLY PRE-CLINICAL STAGES, AND WE COLLABORATE WITH PARTNERS OF COURSE TO DO THAT. OUR COLLEAGUES IN THE INSTITUTES OF MENTAL HEALTH, DRUG ABUSE, AS WELL AS CHILD HEALTH AND DEVELOPMENT. AND THEN AS I BELIEVE MANY OF YOU MAY REMEMBER, THERE WAS AN INITIATIVE ON SIMULATION SCIENCE BOUGHT FORWARD IN THIS PAST YEAR TO COUNCIL AND WE ARE HOPING TO BE ABLE TO USE SIMULATION SCIENCE TO REALLY HAVE AS MUCH INFORMATION, CERTAINLY MORE INFORMATION THAN WE CURRENTLY DO, TO BE ABLE TO CONSIDER WHAT, WHICH PRODUCTS AND STRATEGIES AND PARTICULARLY COMBINATION PREVENTION STRATEGIES TO TAKE FORWARD IN THESE LARGE TRIALS AS EVERYONE KNOWS THEY ARE HUGE INVESTMENTS. SO WE ARE TRYING TO USE AS MUCH INNOVATIVE TECHNOLOGY OR METHODOLOGIES AS WE CAN TO MAKE THOSE DECISIONS EARLY. AND THEN WE HAVE TO INCREASE OUR FOCUS ON ADOLESCENCE. CERTAINLY IN THE U.S. OUR MAJOR FOCUS WOULD BE YOUNG BLACK MSM AND YOUNG WOMEN IN SUB-SAHARAN AFRICA. WE ARE COLLABORATING WITH THE NICHD ON THEIR ADOLESCENT TRIALS NETWORK AND OTHER FUNDING OPPORTUNITIES TO LOOK AT ADOLESCENTS IN THE DOMESTIC SETTING. AND THEN WE WILL NEED TO CONTINUE TO WORK WITH THE HPTN AND MTN ON PRODUCT DEVELOPMENT FOR ADOLESCENTS INTERNATIONALLY. THE HPTN HAS A STUDY THAT IS RECENTLY STARTED. HPTN082 LOOKING AT UPTAKE AND ADHERENCE OF TRA VADA IN YOUNG WOMEN DOWN TO THE AGE OF 16 TO REALLY BETTER UNDERSTAND THAT PARTICULARLY IN SUB-SAHARAN AFRICA. AND THEN MTN RECENTLY COM -- SUCCESSFULLY COMPLETED MTN023 STUDY, A STUDY OF THE SAFETY OF DEPIRRINE INTERVAGINAL RING IN ADOLESCENTS 15-17 YEARS OF AGE HERE IN THE UNITED STATES. AND THEN WE ARE COLLABORATING WITH NIMH TO CONTINUE TO SUPPORT MORE OF THE FORMATIVE WORK SO WE BETTER UNDERSTAND MOTIVATIONS FOR RISK BEHAVIORS AS WELL AS ADHERENCE BEHAVIORS AND FOCUSING ON YOUNG BLACK MS. AND ADOLESCENT GIRLS AND YOUNG NIM SUB-SAHARAN AFRICA. AND THEN TO ONE OF THE QUESTIONS EARLIER AND AS SARAH SAID, OUR GROUP HAS BEEN WORKING ON IMPROVING THE TREATMENT AND PREVENTION CASCADES. AND TO REALLY ACCOMPLISH THIS WORK, THIS INCLUDES PARTNERING WITHIN THE DIVISION OF AIDS. WE PARTNERED QUITE A BIT WITH OUR BASIC SCIENCE PROGRAM COLLEAGUES, EPIDEMIOLOGY GROUPS SPECIFICALLY, AND THEN OUR COLLEAGUES IN MENTAL HEALTH, DRUG ABUSE, OAR COLLEAGUES, PEPFAR, CDC, USAID, GATES FOUNDATION, THIS REALLY IS HUGE EFFORTS AND IT REALLY IS BIG TEAM SCIENCE THAT IS REQUIRED TO MOVE THESE EFFORTS FORWARD. AND THESE ARE SEVERAL EXAMPLES OF STUDIES THAT WE ARE DOING LOOKING AT COMBINATION PREVENTION STRATEGIES THAT ARE LARGELY FOCUSING ON THE TREATMENT, TESTING AND TREATMENT CASCADE. MANY MAY KNOW THAT HPTN071, OTHERWISE KNOWN AS THE POP ART STUDY, IS A VERY LARGE COMMUNITY RANDOMIZED TRIAL IN ZAMBIA. 21 COMMUNITIES IN ZAMBIA AND SOUTH AFRICA LOOKING AT UNIVERSAL TESTING AND TREATMENT USING COMMUNITY HEALTH WORKERS TO GET FOLKS TESTED AS WELL AS TO SUPPORT ADHERENCE LONG TERM. THEN HPTN074 IS INJECTING DRUG USERS AND THEIR PARTNERS. 075 LOOKING AT MSM AND CAN WE ENROLL AND RETAIN MEN WHO HAVE SEX WITH MEN IN SUB-SAHARAN AFRICA GIVEN THE RISK ENVIRONMENT IN WHICH THE STUDIES ARE BEING CONDUCTED? AND THEN AS I MENTIONED, MP3s WE HAVE WORK IN ADOLESCENTS, YOUNG WOMEN, YOUNG MEN AND MEN WHO HAVE SEX WITH MEN IN VARIOUS SETTINGS. AND THEN, REALLY TRYING TO MORE EFFICIENTLY MOVE TREATMENT FORWARD FOR WOMEN, PREGNANT WOMEN, CHILDREN AND ADOLESCENTS USING ALL OF OUR AVAILABLE RESOURCES, THAT INCLUDES THE CLINICAL TRIAL NETWORKS AS WELL AS CONTRACT RESOURCES. AT THIS POINT, IT'S ABOUT AN 8-10 YEAR LAG TIME FROM AN ART APPROVAL IN ADULTS TO THE APPROVAL IN CHILDREN. WE REALLY HAVE TO SHORTEN THAT TIME. WE HAVE BEEN WORKING WITH W.H.O. AND THE FDA ON DEFINING THE REQUIREMENTS TO BE ABLE TO MOVE FORWARD MORE QUICKLY AND TO ANTICIPATE FROM THE ADULT INFORMATION, BOTH THE RESEARCH INFORMATION AND THE GUIDELINES, WHERE WE NEED TO GO NEXT. WHAT IS THE NEXT BEST THING IN INFANTS AND CHILDREN, PREGNANT WOMEN? AND THEN PARTNERING, THAT IS A BIG THEME AS YOU CAN HEAR TO DO EVERYTHING THAT WE DO. BUT, TO WORK IN THE SPACE OF TB DIAGNOSIS AND PREVENTION AND TREATMENT OF PREGNANT WOMEN AND CHILDREN. SO, HIGH LEVELS SUMMARY. FOCUS ON ADOLESCENTS AND YOUNG ADULTS. WE MUST DO BETTER WITH THAT IN THE FUTURE. FOCUS ON SUSTAINED RELEASE AND WE REALLY NEED TO SIMULTANEOUSLY COVER BOTH COMPARTMENTS. THEN WE NEED TO CUT DOWN THE LAG TIME IN PEDIATRIC ART. THEN WE ARE WORKING WITH TRP TO CONTINUE TO BUILD COHORTS AT THE REALLY EARLY WELL-TREATED CHILDREN SO THAT CURE CAN BE STUDIED IN THIS POPULATION AS INTERVENTIONS COME ALONG THAT ARE APPROPRIATE. TB A HUGE PROBLEM AS SARAH TALKED TO US ABOUT IN DEPTH. AND WE NEED TO MAKE PROGRESS IN ALL AREAS. AND THEN AS I HAVE SAID MULTIPLE TIMES, PARTNERSHIPS ARE ABSOLUTELY CRITICAL. THESE ARE OUR CURRENT REACH PARTNERS WHICH YOU CAN SEE WITHIN DAIDS, WITHIN NIAID AND OTHER INSTITUTES AND CENTERS, OAR, OTHERS GOVERNMENT AGENCIES, AND I WILL MELANED GATES FOUNDATION, OTHER -- BILL AND MELINDA GATES FOUNDATION AND AS WELL AS PHARMA PARTNERS. AND AGAIN, THAT IS HOW IT ALL FITS TOGETHER. AND I WANTED TO TAKE A FINAL MOMENT HERE TO REALLY THANK ALL OF THE MEMBERS OF THE PREVENTION SCIENCES PROGRAM WHO WORK VERY HARD ON ALL OF THIS WORK EVERY DAY AND TRYING TO MOVE US TOWARDS BETTER PREVENTION INTERVENTIONS. SO I THANK YOU AND I'M GLAD TO TAKE QUESTIONS. [ APPLAUSE ] >> THANK YOU FOR THAT PRESENTATION. TWO THINGS COME TO MIND WHEN YOU HAVE ANG EMPHASIS OF WORKING ON PREVENTION WITH CHILDREN AND YOU MENTIONED LOOKING AT CURE IN CHILDREN WHO ARE WELL TREATED, IS THE WORD YOU USED. AND I'M JUST WONDERING WHAT DO YOU FORESEE AS BEING SOME OF THE CONSENT OR ETHICAL ISSUES? I KNOW THAT ATN SITES IN THE PAST HAVE HAD ISSUES EVEN GETTING APPROVAL TO TRY PREP IN TRA VADA IN MINORS. THAT'S MY FIRST QUESTION FOR YOU. >> YES. ABSOLUTELY. AND VERY GOOD QUESTION. THERE HAVE BEEN A COUPLE OF -- IT IS A QUITE DIFFICULT PROBLEM. THE REGULATORY AND LEGAL ISSUES SURSURROUNDING RESEARCH IN THOSE UNDER 18 YEARS OF AGE OR WHATEVER IS DEFINED IN VARIOUS COUNTRIES AS ADULT AGE OR ABLE TO CONSENT FOR THEMSELVES. THAT IS A HUGE CHALLENGE. IT'S GOING TO REMAIN A CHALLENGE. THERE ARE A COUPLE OF EXAMPLES WHERE THAT HAS BEEN ABLE TO BE DONE THOUGH, CERTAINLY IN THE UNITED STATES SO THAT GIVES US HOPE. THE ADOLESCENT TRIALS NETWORK WAS ABLE TO DO THAT WITH THE TRUVADA PREP STUDY AT SEVERAL SITES HERE IN THE U.S. AND AS I THE RING STUDY, WAS ABLE TO DO THAT IN 15-17-YEAR-OLD YOUNG WOMEN. BUT IT WAS -- REQUIRED A LOT OF NEGOTIATION. WE SUBSEQUENTLY HAVE HELD A COUPLE WORKSHOPS ON THIS ISSUE AND HAD BOTH IRB MEMBERS AS WELL AS FOLKS FROM FDA AND VARIOUS EMPHASIS. AND AS YOU'RE SAYING, IT'S A COMPLICATED ISSUE AND I THINK THAT WE ARE GOING TO HAVE TO TRY TO CONTINUE TO HAVE THE CONVERSATION WITH IRBs WITH ETHICS COMMITTEES AND MAYBE MINISTRIES OF HEALTH AND OTHERS TO TRY AND EMPHASIZE THAT THE THIRD OF ALL NEW INFECTIONS IN 2015 WERE IN ADOLESCENTS, 15-24 YEARS OF AGE. SO THIS IS A HUGE PROBLEM AND WE HAVE GOT TO BE ABLE TO MOVE FORWARD IN SOME WAY WITH RESEARCH, PREVENTION RESEARCH IN THIS POPULATION. SO, STAY TUNED. >> WHAT DO YOU THINK THE BARRIERS HAVE BEEN FOR GETTING NEW DRUGS MOVED INTO PEDIATRIC POPULATIONS? >> THAT IS AN ABSOLUTELY GREAT QUESTION. I THINK TO SOME DEGREE, THERE IS SOME -- THE SYSTEM HAS BEEN BUILT SUCH THAT I THINK IT LEANS TOWARDS INERTIA RATHER THAN MOVEMENT, AND THAT IS NOT TO SAY THAT PEOPLE DON'T HAVE THE BEST OF INTENTIONS. THEY DO. BUT THIS PARADIGM OF HAVING TO HAVE LOTS OF INFORMATION IN ADULTS TO BEGIN WITH AND THEN AGE DE-ESCALATING -- NOT THAT THIS IS NOT IMPORTANT HAVE THAT THAT SAFETY INFORMATION, AND THEN SLOWLY MOVING TOWARDS THE YOUNGEST AGES. IF YOU LOOK AT OUR PHARMACEUTICAL PARTNERS, IN FAIRNESS, THERE IS PROFIT WISE, THERE ISN'T A WHOLE LOT IN IT AS YOU'RE WELL AWARE, FOR THEM IN THAT REGARD. AND I DO BELIEVE THEY ARE MAKING BEST EFFORTS, BUT IT'S BEEN DIFFICULT AND WE ARE TALKING ABOUT YEARS STRETCH IF WE ARE WAITING FROM ADULTS TO AND ALL OF THE EFFICACY INFORMATION, WHICH WE HAD TO DO IN THE PAST. SO BASICALLY, WE HAVE BEEN TALKING TO THE FDA AND THE W.H.O. AND SAYING, OKAY, SO, IS ALL OF THAT ACTUALLY REQUIRED BEFORE WE CAN MOVE INTO YOUNGER CHILDREN? IF SO, IF NOT, WHAT ARE THE MINIMAL REQUIREMENTS? AND I HAVE BEEN HEART END THAT AT LEAST THE FDA AND W.H.O. HAVE SAID THAT IF THERE IS EFFICACY IN ADULTS IF WE SEE ANY EVIDENCE OF THAT, THEN WE CAN ASSUME THAT THERE WILL BE EFFICACY IN CHILDREN. SO WE DON'T NEED THESE LARGE ETCH KEYS STUDIES IN CHILDREN AS WELL EVERY SINGLE TIME. AND WE DON'T HAVE TO HAVE A COMPARISON. AND THIS HAS BEEN RECENTLY DISCUSSED. WE DON'T HAVE TO COMPARE WHAT WE HAVE TO THE NEW REGIMEN IN A LARGE STRATEGY TRIAL AS WE HAVE DONE IN THE PAST. WE CAN GET THAT EFFICACY INFORMATION, THE SAFETY INFORMATION IN ADULTS AND THEN GET AT LEAST THE BASIC SAFETY AND THEN PK INFORMATION TO DETERMINE DOSING IN CHILDREN AND WE SHOULD MOVE AHEAD. SO I THINK THAT THERE WERE GOOD INTENTIONS AND THE IDEA THAT WE WERE PROTECTING CHILDREN BY GOING MORE SLOWLY -- I CERTAINLY UNDERSTAND AND APPRECIATE, BUT I THINK A DIFFERENT WAY OF THINKING ABOUT THAT IS CHILDREN NEED THESIS BETTER DRUGS, THESE OPTIMAL DRUGS AS MUCH AS ADULTS. SO MOVING FORWARD QUICKER IS ALSO HELP DOLPH CHILDREN. >> THANK YOU, SHERRILL. -- HELPFUL TO WHICH WERE. THIS IS AN OPEN MEETING AND WE'D LIKE TO PROVIDE AN OPPORTUNITY FOR THE PUBLIC TO COMMENT. IF WE HAVE ANYONE IN THE AUDIENCE WHO WOULD LIKE TO ASK A QUESTION, MAKE A COMMENT ABOUT ANYTHING THEY HAVE SEEN OR HEARD TODAY. KARL DID YOU HAVE ANY FINAL COMMENTS? >> I WANT TO THANK ALL OF YOU FOR ATTENDING TODAY. AGAIN THIS MEETING IS AN ANNUAL EVENT WHERE WE TALK ABOUT WHERE WE ARE IN THE FUTURE. IT'S KIND OF A WIERD TIME GIVEN WE DON'T HAVE A BUDGET AND A LOT IS GOING TO UNFOLD. I LOOK FORWARD TO, AS THINGS UNFOLD, WE WILL HAVE CALLS WITH THE ARAC, COUNCIL MEMBERS, AS WE HAVE MIDPOINT SO WE CAN KEEP YOU UP-TO-DATE. ONE OTHER COMMENT THAT WE HAVE STARTED -- COMING BACK TO THE CLINICAL TRIALS. WE WILL BE HOLDING MORE SIGNIFICANT AMOUNTS OF COMMUNICATION OVER THE NEXT SIX MONTHS OR SO FIRST SET OF WEBINARS IN EARLY FEBRUARY AND WE'LL DO FACEBOOK LIVE BUT WE WILL HAVE A MORE ENGAGED PROCESS. AT SOME POINT I THINK MAYBE A CALL WITH ALL OF YOU WHERE WE GET TO THAT CALL MIDPOINT AND TALK TO YOU ABOUT WHERE WE ARE IN THAT PROCESS. BAUDS YOU'RE ENGAGEMENT IN OUR CLINICAL TRIALS, RESTRICTIONING IS GOING TO BE AN ESSENTIAL COMPONENT. SO WITH THAT, I'LL TURN IT BACK TO YOU. >> ALL RIGHT. IF THERE IS NO FURTHER BUSINESS, WE'LL GO AHEAD AND ADJOURN THIS MEETING. JUST A REMINDER OUR NEXT MEETING IS JUNE 5. SAFE TRAVELS. THANK YOU.