I WANT TO WELCOME EVERYONE. THE COMMITTEE, NIH COLLEAGUES AND ALSO OUR GUESTS IN THE AUDIENCE. AND I'D LIKE TO CALL THIS MEETING, THE JUNE 5, AIDS RESEARCH ADVISORY COMMITTEE MEETING TO ORDER. THE FIRST AGENDA ITEM IS THE APPROVAL OF THE MINUTES. YOU SHOULD HAVE GOTTEN A COPY. DO WE HAVE ANY EDITS TO THE MINUTES? >> DO WE HAVE A MOTION TO APPROVE? SO MOVED. >> SECOND? AWL IN FAVOR OF APPROVAL. ANYONE OPPOSED OR ABSTAINING? THE MINUTES WILL STAND. NEXT I'LL HAND IT OVER TO KARL TO DO THE DIRECTOR'S REPORT. >> CARL DIEFFENBACH: THANK YOU, EVERYBODY IT'S A PLEASURE TO BE WITH YOU TODAY TO GO -- SO HERE IS THE SCHEDULE OF WHAT I'D LIKE TO TOUCH BASE ON BRIEFLY. A LITTLE BIT OF UPDATE ON THE BUDGET FOR THOSE WHO DIDN'T SEE TONY'S UPDATE. SLIGHTLY DIFFERENT VERSION ON THE GSI THAN YOU HEARD FROM DR. TABAK AND THEN AN UPDATE ON WHERE WE ARE WITH THE NIH CLINICAL TRIALS ENTERPRISE RENEWAL PROCESS AND THEN SCHEDULE FOR FUTURE COUNCIL METEDDINGS. SO WE STARTED THE FISCAL YEAR 2017 UNDER A CONTINUING RESOLUTION. IT WAS EXTENDED A COUPLE OF TIMES AND THEN ON MAY 5, THE BUDGET WAS SIGNED BY THE PRESIDENT AS PASSED BY THE CONGRESS. WHAT THAT LED TO WAS AN INCREASE, AT THE NIH LEVEL, OF 5.9% WITH NIAID GETTING FAIRLY SIGNIFICANT INCREASE OF 3.3%. VIRTUALLY ALL OF THAT INCREASE WAS IN THE NON-AIDS COMPONENT. VERY LITTLE OF THE MONEY, IN FACT ALMOST NONE OF IT, WENT INTO THE AIDS BUDGET. SO, KEEP IN MIND THAT MOST OF THAT WAS EARMARKED FOR OTHER PRIORITIES LIKE ANTIMICROBIAL RESISTANCE. WHAT WE WERE ABLE TO DO IS RAISE THE PAY LINE BASED - OUR BUDGET INCREASE TO THEth PERCENTILE WITH THE NEW PIs GOING TO THE 15th. AS OUR USUAL WAY, WE DO NOT -- THAT'S NOT GOING TO WORK. THERE HE IS. WE DO NOT MAKE ADJUSTMENTS TO COMPETING AWARDS. INITIATIVES MAY OR MAY NOT BE CUT BUT OVER OVERALL SUCCESS RATE WILL BE IN THE 20-22% RANGE. WE HAD A VERY SIGNIFICANT INCREASE IN THE NUMBER OF R21s THAT HAVE COME IN THIS YEAR. THE PRESIDENT'S BUDGET REQUEST WAS RELEASED ON MAY 23rd AND IT PROPOSED VERY SIGNIFICANT CUTS TO MANY OF THE DISCRETIONARY PROGRAMS. AS YOU'RE WELL AWARE THE MEMBERS OF THE HOUSE AND SENATE ON OUR COMMITTEES FEEL THAT THIS IS NOT NECESSARILY WHAT THEY ARE IN FAVOR OF. AND SO THIS WAS THE SPECIFIC LANGUAGE RELEVANT TO THE NIH. FY18 BUDGET PROPOSED DECREASE OF 7.6 BILLION OR 21% CUT. AND THERE WERE MAJOR COMPONENTS OF REORGANIZATION INCLUDING ELIMINATION OF FOGARTY, CONSOLIDATION WITH AHRQ. WHAT THAT MEANS IS AHRQ COMES IN AND BECOMES LIKE ANOTHER INSTITUTE OR CENTER WITHOUT BRINGING FUNDING WITH T SO THIS IS IN MANY WAYS JUST ANOTHER FORM OF A CUT. AND THEN THERE ARE OTHER CONSOLIDATIONS AND STRUCTURAL CHANGES ACROSS THE NIH THAT HAVE BEEN PROPOSED. YOU CAN SEE WHAT THAT WOULD LIKE LIKE TO US. IT WOULD DECIMATE US IF WE HAD 22% CUT IN AIDS RESEARCH, GIVEN THE SIZE AND SCOPES OF THE CLINICAL TRIALS THAT WE HAVE ONGOING. THE OTHER ONGOING ACTIVITIES, WE WOULD BE HARD-PRESSED NOT TO BE CLOSING THINGS AND MAKING VERY DRACONIAN CHANGES. BUT AT THE END OF THE DAY, THE PRESIDENT PROPOSES AND THE CONGRESS TERMS AND THAT IS JUST WHERE WE ARE RIGHT NOW. I THINK WE JUST HAVE TO BE PREPARED FOR MULTIPLE VENT ALTS AS WE MOVE FORWARD. TONY DID A GOOD JOHN EXPLAINING THAT THIS MORNING AND I THINK THAT WE ARE IN A WAITING MODE -- A GOOD JOB -- HE POINTED OUT THIS WAS SOMETHING LOST ON ME. I HASN'T REALIZED THIS. LIKE 19 OF THE PAST 20 YEARS, WE STARTED THE YEAR UNDER A CONTINUING RESOLUTION. SO WE'LL PROBABLY START WITH A LEVEL BUDGET AND TAKE IT FROM THERE. SO I'D LIKE TO SPEND A LITTLE BIT OF TIME GIVING A DIFFERENT A LITTLE BIT OF SPIN ON THE GSI, WHICH DR. TABAK ALSO TALKED ABOUT AT THE FIRST PART OF THE -- SECOND PART OF THE OPEN SESSION OF COUNCIL. HE SHOWS THIS CURVE THAT HE TALKED ABOUT WITH THE PEOPLE, INVESTIGATORS OVER 60, THE EARLY STAGE INVESTIGATORS, AND MID-STAGE INVESTIGATORS. SO FUNDAMENTALLY, SINCE THE DOUBLING OF THE NIH BUDGET FROM 95-2000, THERE WAS A SLIGHT INCREASE IN MID-STAGE INVESTIGATORS THAT THEN CURTAILED OFF. THE NUMBER OF EARLY-STAGE INVESTIGATORS HAS CONTINUED TO DECLINE AND LEVEL OFF AND LATE-STAGE INVESTIGATORS HAVE DONE VERY WELL. THIS IS A HYPERCOMPETITIVE ENVIRONMENT IN WHICH THE LATE-STAGE INVESTIGATOR TENDS TO DO VERY WELL. SO THEY PROPOSED TO USE SOMETHING CALLED THE GSI, WHICH USING A SCORE OF 7 POINTS FOR YOUR STANDARD RPG, WOULD SAY THAT IF YOUR SCORE WAS GREATER THAN 21, YOU WOULD THEN NOT BE ELIGIBLE FOR ADDITIONAL SUPPORT AND THE GENERAL SENSE IS THIS WOULD FREE UP MONEY FOR ABOUT 1600 NEW AWARDS OVER THE NEXT SEVERAL YEARS. WHILE THIS MAY BE TRUE, THE MONEY IS NOT EQUALLY DISTRIBUTED ACROSS THE NIH. MONEY IS APPROPRIATED TO INSTITUTES. SO WHILE ONLY 6% OF INVESTIGATORS ACROSS THE NIH FALL WITHIN THIS CATEGORY, THERE ARE SIGNIFICANT NUMBER OF INSTITUTES THAT ACTUALLY HAVE ZERO INVESTIGATORS THAT FALL WITHIN THIS, AND WITHIN NIGHED THE NUMBER IS CLOSER TO 14% -- NIAID. IN MANY WAYS YOU CAN SEE IS THIS AS A WAY OF REDISTRIBUTING POTENTIALLY TRYING TO REDISTRIBUTE FUNDS FROM THE LARGE INSTITUTES TO THE SMALL INSTITUTES. SO THIS WAS THE ORIGINAL PROPOSAL AND THIS IS WHAT REALLY GALVANIZED THE COMMUNITY, IS THAT IF YOU HAD A UM1, YOU HAD MULTIPLE PIs, EVERY PI RECEIVED 10 POINTS. SO FOR EXAMPLE, IF YOU WERE A NETWORK LEADER, YOU HAD 10 POINTS AND IF YOU WERE THEN HAD A SUB-PROJECT WITHIN THAT, YOU COULD HAVE A HUGE NUMBER OF POINTS. SO, A UM1 COULD HAVE AS MANY AS 40 POINTS. A PROGRAM PROJECT GRANT, THE P01 WOULD HAVE A SINGLE PI OF 7 BUT A SUB-PROJECT WITHIN THAT WOULD THEN BE SIX POINTS. SO IT'S A 3 PROJECT P01 IN THIS ORIGINAL ITERATION, YOU HAD 3 PROJECTS AND TWO COURSE, COULD BE AS MANY AS 37 POINTS FOR A PROGRAM PROJECT GRANT. TRAINING, YOU GOT POINTS, AND THIS TYPE OF A SCORING SYSTEM, EVEN THE P30 MECHANISM GAVE MULTIPLE POINTS. SO IT REALLY -- MANY PEOPLE VIEWED THIS AS ANTI-COLLABORATIVE, ANTI-COLLABORATIVE SCIENCE, AND HURTING THE ABILITY OF US TO WORK TOGETHER IN WAYS THAT WE THOUGHT WERE VERY IMPORTANT. THE AIDS RESEARCH COMMUNITY RESPONDED QUITE WELL. LARRY TALKED ABOUT THE IMMUNOLOGISTS. FOR EXAMPLE THE C FAR DIRECTORS GOT TOGETHER AND WROTE A VERY WELL-FRAMED LETTER ABOUT THE PROBLEMS WITH THIS KIND OF AN APPROACH. THE DELANEY COLLABORATORY PEOPLE GOT THEIR LETTER IN LAST WEEK AND ALSO MADE SIMILAR POINTS. SO THIS EINVOLVED. THIS REMAINS IN DRAFT FORM. LARRY FLASHED A SLIDE UP TODAY THAT CHANGED THIS A LITTLE BIT. IT WAS ON THE SLIDE FOR ABOUT 15 SECONDS. I SAW PAUL GET HIS CAMERA OUT AND HE WASN'T QUITE FAST ENOUGH TO CAPTURE IT. AND LARRY'S SLIDES ARE NOT AVAILABLE. SO I DON'T KNOW HOW MUCH OF THIS HAS CHANGED BUT THIS WAS AS OF 5-16 IT EVOLVED. SO FOR EXAMPLE, FOR THE CLINICAL TRIALS NETWORKS OF THE PARENT PI OF A MULTI-PI AWARD IN A UM1 WOULD RECEIVE ZERO. SO FOR CTU, THE PI WOULD BE ZERO. THE SUBPROJECTS AS THE R. THE CRS, WOULD PROBABLY BE 5. NOTICE THE P30 MECHANISM OFF THE TABLE. CENTER GRANTS ARE OFF. TRAINING IS OFF. THAT'S ALL GOOD BUT I STILL THINK THERE IS CONCERNS ABOUT THE SCORES AND WE HEARD TODAY THAT SOME OF THESE OTHER SCORES ON RO1s HAVE CHANGED. SO WE'LL JUST WAIT AND SEE WHAT FINALLY GETS PRESENTED ON THURSDAY AT THE AIDS -- AT THE DIRECTOR'S COUNCIL. SO AGAIN THIS HAS BEEN A WORK IN PROGRESS. THERE HAS BEEN MOVEMENT. THERE IS STILL CONCERN THAT THE UNDERLYING DATA THAT FORMS THIS IS NOT ACCURATE OR COMPLETE. BUT THIS WAS THE CONCLUSIONS FROM THE ORIGINAL 52 SLIDE DECK THAT NIH CAME FORWARD WITH. THIS IS AN ATTEMPT TO DO, AND IT'S NOT AN UNREASONABLE GOAL. TO TRY TO PROTECT CERTAIN POPULATIONS OF INVESTIGATORS THAT ARE QUITE VULNERABLE. THE NEW ESI, THE NEW STAGE INVESTIGATORS AS WELL AS INVESTIGATORS WERE TRANSITIONING AT THAT CRITICAL MOMENT WHERE THEY ARE UP FOR TENURE AND THEY NEED TO HAVE ONE OR TWO AWARDS UNDER THEIR BELT IN ORDER TO ACHIEVE TENURE AND THEN STAY ON AS FACULTY MEMBERS. CLEARLY, AS LARRY PRESENTED, THE COUNCIL TODAY THERE IS NOT ENOUGH MONEY IN THE SYSTEM, EVEN IF YOU IMPLEMENT THIS TO HAVE THE KIND OF EFFECT THAT WE WOULD NEED TO SEE. SO I THINK THE NUMBERS WERE SOMETHING LIKE, THE COST OVER THE NEXT FIVE YEARS, FULLY IMPLEMENTING WHAT THIS VISION IS, WOULD BE ABOUT 1.2 BILLION AND THAT -- AND THE KINDS OF THINGS THAT WE COULD ACHIEVE WITH THESE SCORING CHANGES WOULD BE ABOUT 28% OF THOSE FUNDS. SO, THE FACT THAT WE HAVE BEEN LEVEL BUDGET FOR SO MANY YEARS CONTINUES TO HAUNT US. AND THIS IS AN ATTEMPT TO GET US AT LEAST PART WAY IN THAT DIRECTION. I THINK THERE WILL CONTINUE TO BE ADDITIONAL ANALYSIS. ONE OF THE BIGGEST CONCERNS I HEARD FROM INVESTIGATORS AROUND THE COUNTRY WAS THAT THE DATASET ON WHICH ALL THIS WAS BASED WAS NOT AVAILABLE FOR INDEPENDENT ANALYSIS. THAT HAS BEEN CHANGED. THEY HAVE NOW POST TODAY AND IF YOU'RE INTERESTED, WE CAN GET YOU THAT ADDRESS. THERE HAVE BEEN A NUMBER OF PEOPLE THAT HAVE ALREADY TAKEN A WHACK AT IT AND SUFFICE IT TO SAY, IT'S NOT HOLDING UP VERY WELL. FOR THOSE OF YOU THAT SAT THROUGH LARRY'S TALK, YOU REALIZED THAT NIH SEEMS TO BE ON A MISSION, SORT OF LIKE THE BLUE'S BROTHER'S MOVIE THEY WILL GOAT DAILY CENTER COME HELL OR HIGH WATER AND WE'LL HAVE TO SEE WHERE THIS ALL GOES. I THINK THE COUNCIL WILL -- FRANCE IIS'S COUNCIL WILL HAVE A LOT TO SAY. WE'LL CONTINUE TO TRACK AND MONITOR THIS AND DO WHAT WE CAN AS THE DIVISION TO MITIGATE UNINTENDED CONSEQUENCE SYSTEM. I FEEL THAT IN MANY WAYS WE HAVE BEEN THE LEADERS IN THE AREA OF COLLABORATIVE SCIENCE BECAUSE WHERE ELSE DO YOU HAVE A DISEASE THAT IT IS FUNDAMENTAL, INFECTIOUS DISEASE OR THE IMMUNE SYSTEM, IT REALLY REQUIRES A DEGREE OF COLLABORATION TO TRULY UNDERSTAND WHAT IS HAPPENING IN HIV. SO WE'RE GOING TO DO WHAT WE CAN TO CONTINUE TO PROTECT THE COLLABORATIVE SCIENCE COMPONENTS. THERE WAS ALSO TALK TODAY THAT WAS NEW ABOUT APPEALS PROCESS OR INSTITUTE-SPECIFIC WAYS OF GETTING EXEMPTIONS FOR TRULY MERITORIOUS PEOPLE. THAT IS ALSO NEW OVER THE PAST WEEK. AND THE DEVIL WILL BE IN THOSE DETAILS. SO I THINK I JUST MESSED THIS UP SO I THOUGHT I'D PAUSE THERE AND 73 THERE ARE ANY QUESTIONS OR COMMENTS BEFORE WE GET INTO THE NEXT PART. CHRIS? >> CHRIS: MAYBE JUST CLARIFY, I THINK I UNDERSTOOD THAT THEY WERE GOING TO MOVE TO THE -- WHAT I'LL CALL DYNAMIC APPROACH VERSUS THE FIXED APPROACH IN TERMS OF THIS TO ALLOW EACH INSTITUTE, YOU SAID THEY WANTED TO MAKE AN EXEMPTION WOULD HAVE TO FORWARD A LETTER JUSTIFYING TO THE OFFICE 69 DIRECTOR BUT IT CREATED -- OFFICE OF THE DIRECTOR AND -- AND IT CREATED -- >> THAT WILL BE INTERESTING TO SEE. BECAUSE THIS IS ALL GOING TO STILL BE DRIVEN OUT OF BUILDING ONE. THE WAY WE HAVE RIGHT NOW WOULD BE WE HAVE THE OVER A MILLION DOLLAR PROCESS THAT YOU SEE IN COUNCIL, IS THAT WE, AS AN INSTITUTE, MAKE THOSE DECISIONS. THIS IS GOING TO BE TAKEN OUT OF THE HANDS OF THE INSTITUTES AND PUSHED UP TO THE HIGHER LEVEL. SO, WE'LL SEE WHAT HAPPENS WITH THAT. SO, ONE OTHER POINT. WHAT OUR ROLE HAS BEEN IS TO CONTINUE TO POINT INVESTIGATORS TO THE NIH WEBSITES TO CONTINUE TO EXPLAIN THE AREAS OF CONFUSION AND ALSO THEN TO GIVE OUR OPINIONS ON THINGS. AND ENCOURAGE THE GRANTEE COMMUNITY TOW WEIGH IN. BECAUSE THERE ARE REASONS TO THINK THAT THERE IS SOME GOOD STUFF HERE. WE REALLY DO NEED TO FIND WAYS OF IMPROVING OUR SUPPORT FOR JUNIOR INVESTIGATORS AND PEOPLE AT THIS MID-CAREER LEVEL. SO I THINK WE ALL SUPPORT THAT. THE PRINCIPLE IT'S HOW WE GET THERE THAT MATTERS. SO, I ENCOURAGE YOU STILL TO CONTINUE TO WEIGH IN AS YOU SEE FIT. AND THERE IS THE E-MAIL ADDRESS. WRITE TO LARRY DIRECTLY AS HE SAID. ALL HATE MAIL CAN GO TO LARRY. THAT WAS KIND OF FUNNY. [ LAUGHS ] >> PAUL: SO, ARE YOU AWARE OF ANY OTHER IDEAS THAT WERE FLOATED TO ACHIEVE THE SAME GOAL WITHOUT THIS DISASTER? >> SO THERE WERE A NUMBER OF IDEAS THAT WERE FLOATED, INCLUDING SOME THAT WERE BASED ON A POINT SYSTEM INCLUDING NEGATIVE POINTS FOR CERTAIN MECHANISMS AND OTHER STRATEGIES. ANOTHER IDEA WOULD BE A CAST CADING PAY LINE. SO A SENIOR INVESTIGATOR HAD TO GET A SCORE OF THIRD PERCENTILE AND AN ESI WOULD BE AT 30 OR SOMETHING LIKE THAT. SO THERE ARE LOTS OF OTHER DYNAMIC WAYS THIS COULD HAPPEN. AND I THINK THAT THERE WAS A GENERAL SENSE FOR A VARIETY OF REASONS THAT THIS WAS GOING TO BE PUSHED. >> PAUL: THIS MIGHT NOT BE THE RIGHT ENVIRONMENT TO SORT OF LET OUR OPINIONS HANG OUT. BUT WHAT WAS QUITE DISTURBING WAS THE VERY DISINGENUOUS WAY THE DATA AND SUPPORT OF THIS MOVE WAS PRESENTED. AND REALLY, IF YOU WANTED TO CUT THE LEGS OFF YOUR MOST PRODUCTIVE SENIOR INVESTIGATORS, THIS IS HOW YOU WOULD START TO DO IT. >> CARL DIEFFENBACH: I THINK WE ALL CAN MAKE OUR DECISIONS ABOUT THAT. I THINK THAT THIS IS WHERE WE HAVE TO HAVE OUR FLEXIBILITY, IS EXACTLY WITH THE MOST PRODUCTIVE SENIOR INVESTIGATORS AND THAT'S WHAT I GOT THE 70s LARRY TODAY, THAT THERE MAY BE SOME FLEXIBILITY FOR THE FIRST TIME ON THAT, WE'LL SEE. JOHN? >> JOHN: I JUST THINK THE GRADUATED OR SCALING PAY LINE SEEMS LIKE, IN A WAY, A BETTER SOLUTION BECAUSE AS WAS POINTED OUT AT THE TALK, THE TOP-END PEOPLE AREN'T ALL THE SAME AND THE TOP-END PEOPLE'S APPLICATIONS AREN'T ALL THE SAME. SO IF YOU HAVE A GRADUATED PAY LINE, YOU'RE TAKING INTO ACCOUNT THE PEER REVIEW SCORE NOT JUST LUMPING EVERYONE INTO ONE BIG CUT OFF AND IT SEEMS TO ME A MISTAKE NOT TO RECONSIDER THAT MODEL, AT LEAST AS AN ALTERNATIVE. YOU CAN STILL USE THE GSI BUT APPLY IT IN A DIFFERENT WAY. >> CARL DIEFFENBACH: THIS IS, FOR DISCUSSION -- I ENCOURAGE EVERYBODY WHO HAS OPINIONS TO WEIGH IN. I'M GOING TO MOVE ON THEN. SO WHAT I HAVE NOW IS -- SO GOING BACK BEFORE CROIX, THIS IS A AREA OF DISCUSSION THAT I HAVE BEEN ACTIVELY ENGAGED IN AS HAS MANY PEOPLE IN THE DIVISION IN TERMS OF TALKING ABOUT THE NEXT STEPS FOR OUR CLINICAL TRIALS NETWORKS, WHICH RENEW AS INITIATIVES IN FISCAL YEAR 2021. BUT BART OF THIS IS ABOUT GETTING INPUT AND FEEDBACK NOW SO THAT WE CAN CREATE THE BEST SCIENTIFIC AGENDA AS WE GO FORWARD. SO THIS IS A SUBSET OF THE SLIDES I HAVE BEEN USING AND I'VE TALKED PRETTY MUCH NETWORK MEETING SO FAR. THERE IS ONE LEFT AT THE END OF JUNE AND THEN I WILL HAVE MADE THE ROUNDS. SO, EVERY 7 YEARS AS YOU'RE AWARE, WE COMPETITIVELY RENEW OUR HIV CLINICAL TRIALS NETWORK FUNDING. AND AT THIS TIME, THAT IS THE TIME AND PLACE TO ADDRESS SIGNIFICANT CHANGES IN RESEARCH PRIORITIES THAT HAVE EVOLVED AS A RESULT OF RESEARCH PROGRESS SINCE THE LAST COMPETITION. BUT IN A WAY, THE BEST WAY TO DO THIS IS TO CREATE THE FORWARD-LOOKING RESEARCH AGENDA NOW. WE CAN THINK ABOUT WHAT WE CAN ACCOMPLISH BETWEEN NOW AND 2020 AND THEN USE THAT AS A LAUNCHING PAD FOR WHAT WILL HAPPEN BEYOND 2020 AND THINK ABOUT WHAT OUR NETWORKS WOULD LOOK LIKE WHEN WE GET TO THE YEAR 2027. THE RESEARCH PRIORITIES AT NIH OVERALL, HAVE BEEN FRAMED BY FRANCIS IN AUGUST OF 2015. INCLUDING REDUCING INCIDENTS, DEVELOPING THE NEXT GENERATION OF NOVEL THERAPIES, DEVELOPING AND IMPLEMENTING A CURE AND IMPROVING PREVENTION AND TREATMENT OF CO-INFECTIONS AND QUO MORBIDITIES, CONTINUING TO FOSTER CROSSCUTTING ACTIVITIES LIKE BASIC RESEARCH, HEALTH DISPARITIES RESEARCH AND TRAINING. SO, THERE ARE A COUPLE OF COMPONENTS OF THE EXISTING STRUCTURE THAT WE ARE QUITE SATISFIED WITH. FIRST AND FOREMOST THIS TRI-PAR TIED STRUCTURE OF THE LEADERSHIP GROUP, LEADERSHIP AND OPERATIONS CENTER, THE LABORATORY AND THE STATISTICAL AND DATA MANAGEMENT CENTER. THOSE THREE PILLARS OF LEADERSHIP SEEM TO BE WORKING EXTREMELY WELL. WE HAVE BEEN ABLE TO FORM SOME VERY SIGNIFICANT COLLABORATIONS WITHIN NIH, WITHIN HHS AND WITHIN THE FEDERAL GOVERNMENT, WITHIN THE FOUNDATIONS AND NGOs AS WELL WITH THE PRIVATE SECTOR THAT HELPED US BOLSTER OUR RESEARCH ENTERPRISE. THIS IS SOMETHING WE'LL SEEK TO MAINTAIN AND CONTINUE TO FOSTER NEW COLLABORATIONS. ADDITIONALLY, WE HAVE ESTABLISHED WITHIN OUR CLINICAL TRIALS UNITS AND SITES, A BASELINE LEVEL OF FUNDINGS, WHICH ALLOWS THEM TO STAY WARM TO A POINT WHERE THEY CAN BE READY TO GO REASONABLY QUICKLY. SO, AS WE BUILD TOWARDS THE FUTURE, WHAT WE ARE SEEKING AND THE REASON I'M SPENDING TIME TALKING TO YOU ABOUT THIS TODAY, IS A WAY TO GET YOUR INPUT TOO, AS THE COMMITTEE. STAKEHOLDER INPUT INTO THE SCIENTIFIC DIRECTIONS OF THE NETWORK ENTERPRISE. AND I HAVE ALSO BEEN SPEAKING TO COMMUNITY AND ADVOCATES AS WELL. BUT WHAT WE ARE REALLY SEEKING INPUT INTO ARE THE HIGHEST PRIORITY RESEARCH QUESTIONS THAT WILL HELP US LEAD TO THE ESTABLISHMENT, CREATION AND VALIDATION OF IMPACTFUL INTERVENTIONS. ANOTHER AREA THAT THE INSTITUTE REMAINS COMMITTED TO IS A CHANGE, IS THIS BULLET. AND AFTER GOING THROUGH THE ZIKA PROCESS AND GOING THROUGH THE EBOLA PROCESS, THE IDEA THAT WE CAN HAVE NIAID CLINICAL SITE MODEL WHERE IF THERE WAS ANOTHER OUTBREAK AND WE DO NOT KNOW WHAT THE NEXT ONE WILL BE, DADE SITES ARE NO LONGER DADE SITES. THEY ARE NIAID SITES. IF THERE WAS AN OUT BREAK AND THEY NEEDED TO USE THE SITES, THEY COULD DO SO AND DO SO EFFICIENTLY AND EFFECTIVELY. AT THE SAME TIME, IF AND WHEN WE HAVE A SYPHILIS VACCINE, WHO BETTER TO TEST IT THAN OUR PREVENTION NETWORKS GOING FORWARD? SO THERE IS SOME OPPORTUNITIES HERE. SO WE'RE GOING TO WORK ON THIS INTERNALLY IN TERMS OF MAKING SURE THE DIVISIONS CAN SPEAK TO EACH OTHER AND REALLY IN THE FUTURE, WHEN WE COMPETE, THIS WILL BE THE GOAL TO MAKE SURE WE HAVE THE RIGHT POPULATIONS. THIS IS ABOUT MAKING OUR ENTERPRISE AS EFFICIENT AND EFFECTIVE AS POSSIBLE FOR ALL THEFERS DISEASE RESEARCH THAT WE SUPPORT. -- ALL THE INFECTIOUS DISEASE RESEARCH -- SO THE AREAS I'D LIKE TO FOCUS ON ARE THREE. NON-VACCINE PREVENTION, HIV VACCINES AND THERAPEUTICS. AND WHAT WE ARE SEEKING IN TERMS OF THESE AREAS OF EMPHASIS ARE ALSO QUESTIONS THAT ARE UNIQUE TO SPECIFIC GROUPS OF PEOPLE THAT WILL HELP DRIVE THESE RESEARCH EMPHASIS. FOR EXAMPLE, CAN WE INTEGRATE INTO THEY WERE PEWSICS AND PREVENTION THE POPULATIONS OF PEDIATRICS ADD LESSENT AND PREGNANT WOMEN INTO EACH OF THE THREE ABOVE? IDEALLY, WE WANT THE LEADERSHIP OF THE LOC THEN TO BE STRUCTURED SO YOU HAVE THE RIGHT LEADERS TO PERFORM THE RESEARCH AND OVERSEE THE RESEARCH IN THE SPECIFIC POPULATION. WE ARE GOING TO CONTINUE TO FOSTER AND IMPLEMENT DATA INTO OUR OPERABILITY, 23069ER DATA SHARING AND EXCHANGE AND CONTINUE TO MANDATE AND PUSH FOR PRIORITIZING, AND SHARING OF LABORATORY EXPERTISE ACROSS THE NETWORKS. SO, AGAIN, AT THE END I'LL SHOW YOU A SET OF E-MAIL ADDRESSES. WE CAN HAVE A CALL WITH ARAC DURING THE SUMMER THAT IS SEPARATE THAN OUR USUAL MID COURSE CALL TO SEEK YOUR INPUT IN THESE AREAS OF EMPHASIS, NON-VACCINE PREVENTION, VACCINES AND THERAPEUTICS. SO, WE ARE GOING TO -- THESE ARE A SERIES OF QUESTIONS THAT I WOULD LIKE TO YOU CONSIDER. HOW SHOULD THE RESEARCH EVENT -- ADVANCES LEAD TO CHANGES IN STRUCTURE? BECAUSE FORM NEEDS TO FOLLOW FUNCTION. WHAT IS THE UNIQUE RESEARCH TEAM, STATISTICAL AND LABORATORY REQUIREMENTS NEEDED IN EACH? AND DO YOU SEE GAPS THAT WE ARE NOT CURRENTLY COVERING THAT WE NEED TO CONSIDER AS WE MOVE FORWARD WITH OUR NETWORK STRUCTURES? SO, MANAGE WIN ME A MOMENT, BECAUSE I THINK THIS IS USEFUL -- IMAGINE WITH ME -- TO THINK ABOUT WHERE WE COULD BE IN 2027. AND HOW CAN WE THEN SHAPE OUR NETWORKS SO THAT THEY CAN PERFORM THE RESEARCH TO GET US THERE. SO, IF WE HAD SUCCESS COULD BE LONG-ACTING PREVENTION AND TREATMENT STRATEGIES EFFECTIVE FOR 6 MONTHS OR A YEAR. WE COULD HAVE HIV VACCINE CONCEPTS THAT HAVE PROVEN EFFICACY TO GREATER THAN 60%. WE COULD HAVE A FUNCTIONAL CURE THAT IS REPRODUCIBLE IN A LARGE SUBSET OF ANTI-RETROVIRAL-TREATED PATIENTS AND THE QUESTION IS NOT WHETHER THE FUNCTIONAL CURE CAN BE ACHIEVED, BUT WHAT IS ESSENTIALLY THE LONG-TERM DURABILITY. WE'LL ASSESS THAT. OVERALL, THE RESEARCH THAT WE ALL SUPPORTED WILL HAVE LED TO A 50% OVERALL REDUCTION GLOBAL NEHIV INCIDENCE. NOW THIS IS ACTUALLY A LOWER BAR THAN THE 909090. I DIDN'T REALIZE THAT. SO BE IT. BUT THIS IS WHAT I THINK IS REALISTIC. WE CAN DEBATE THAT AND THERE PROBABLY WILL BE PEOPLE ON BOTH SIDES OF THE FENCE ON THIS ONE. BUT ALSO I THINK WE WILL NORMALIZED EXPECTANCY FOR HIV INFECTED PEOPLE THAT BEGIN AND ADHERE TO ART. AND IT'S NOT A QUESTION OF WHETHER WE CAN ELIMINATE HIV, BUT WILL WE FULLY IMPLEMENT THE SCIENTIFIC FINDINGS? WILL THE GOVERNMENTS OF THE WORLD HAVE THE WHEREWITHAL AND DESIRE TO IMPLEMENT METHODS WE DEVELOPED? THAT'S THE CHALLENGE WE FACE. AND I WOULD LIKE TO WORK WITH YOU AND WORK WITH ALL OF US TO HELP OUR FORM FOLLOWER FUNCTION AND GUIDE OUR SCIENTIFIC OPPORTUNITY, GUIDE OUR NETWORK STRUCTURE. SO, WHERE WE ARE IN THE PROCESS IS, WE HAD A KICKOFF THAT WE CALL THIS REFINEMENT KICKOFF. IN THE PROCESS OF CONTINUING TO REQUEST FEEDBACK. I THOUGHT I'D GIVE YOU A HEADS BACK UP WHAT IS GOING ON THAT THE METING WITH LIMITED DISCUSSION AT THE FALL ARAC WITH FULL DISCUSSION AT THE ADVISORY COMMITTEE MEETING IN THE WINTER OF 2017 OR EARLY 18. BUT WHAT I WOULD PROPOSE IS THAT DEPENDING ON YOUR LEVEL OF INTEREST, WE COULD HAVE A SERIES OF CALLS BETWEEN EACH OF THEACEAE RACs SPECIFICALLY ON THE NETWORK -- ARACs. SO WE CAN SPEND THE TIME TALKING ABOUT IT. AFTER THE WINTER MEETING WHERE THE FORMAL ARAC PRESENTATIONS WILL OCCUR, WE WILL HAVE TO THEN CUT OFF THE FEEDBACK BECAUSE WE'LL HAVE TO MOVE INTO WRITING MODE, PUBLISHING WITH THE AWARDS TO BE MADE IN NOVEMBER OR DECEMBER OF 2020, FISCAL YEAR 21. SO, AGAIN, WHAT I'M INTERESTED IN IS FEEDBACK IT'S INTERESTING TO TALK TO PEOPLE. THERE HAS BEEN A LOT OF PEOPLE WHO DIDN'T WANT TO RESPOND BECAUSE THEY VIEWED IS THIS AS A QUIZ. IT'S NOT A QUIZ. TELL US WHAT YOU THINK. WE DON'T REALLY -- WE ARE INTERESTED IN WHETHER YOU HAVE A BIG VISION OR SPECIFIC NOTE AND THERE ARE NO WRONG ANSWERS. WE ARE INTERESTED IN FEEDBACK. WE'D LIKE TO HEAR FROM EVERYONE AND THE QUESTION I ALWAYS GET IS, WHEN IS THE BEST TIME TO RESPOND? THE BEST TIME TO RESPOND WAS LAST WEEK BECAUSE YOU CAN THINK OF SOMETHING NEW AND RESPOND NEXT WEEK. SO PLEASE, TAKE YOUR TIME IF YOU HAVE OPINIONS TO SHARE THEM. HERE ARE THE ADDRESSES AND YOU HAVE THEM IN THE SLIDE DECKS. SO, THIS IS OUR FUTURE MEETING SCHEDULE. TOMORROW WE HAVE THE SWG, WHERE HVTN70 FIVE WILL BE PRESENTED. WE HAVE AN ARAC ON SEPTEMBER 11. SO JANUARY 29 IS THE ARAC WHERE WE WILL BE COMPLETING THE FULL NETWORK CYCLE. THE FOLLOW-UP ARAC IS JUNE 18. PLEASE MAKE SURE THESE ARE ON YOUR CALENDAR. COMING BACK TO THIS, I'LL PAUSE AND ANSWER ANY QUESTIONS ON ANY PART OF MY PRESENTATION AND TAKE IT FROM THERE. CHRIS? >> CHRIS: SO, KARL, YOU MENTIONED THIS NOTION OF HAVING THE SITES BE NIAID SITES AT LARGE SO TO SPEAK, OBVIOUSLY ANCHORED IN ONE THING LIKE HIV. I WONDER IF IN THAT CONTEXT, YOU ALSO ARE THINKING ABOUT WHAT DIFFERENTIATE AN HBTN FROM HPTN SITE? BOTH ARE TRYING TO GO INTO UNINFECTED POPULATIONS AND PREVENT ACQUISITION OF INFECTION. THEY HAVE A DIFFERENT ARM MEMITARIUM APPROACH. IT STRIKES ME THERE MAY BE AT LEAST MUCH SIMILARITY BETWEEN THOSE TWO AND HOW THEY WOULD GO ABOUT DOING THINGS BETWEEN DIFFERENT DISEASES. >> CARL DIEFFENBACH: SO I WROTE A BLOG POST THAT WENT UP ABOUT THREE WEEKS AGO ABOUT HAVING A SINGLE PREVENTION NETWORK. AND I HAD THE PLEASURE OF WALKING INTO THE VTN MEETING AND SHARING THAT PUBLICLY. [ LAUGHS ] IT WAS A VERY INTERESTING REACTION BOTH -- THERE WAS A FAIR AMOUNT OF, WE ARE DIFFERENT. WE ARE SPECIAL. AND THEN ONE OF OUR COLLEAGUES WENT TO THE SITE MEETING WHERE THE INVESTIGATORS WERE THERE. AND THEY THOUGHT IT WAS A GREAT IDEA. IF NOTHING LESS THAN STANDARDIZING ACROSS THE NETWORKS. SO I THINK THERE IS SOMETHING TO BE SAID FOR A HYBRID MODEL WHERE WHEN IT COMES TO SITE ACTIVITIES THAT WE MOVE TO A SET OF STANDARDS, THAT ALL THE NETWORKS WOULD USE SO THEY BECAME A LITTLE BIT MORE INNER OPERABLE. SO I WOULD SAY THAT THE PHRASE I LIKE TO USE IS, WHEN YOU ASK OR TELL SOMEBODY YOU'RE GOING TO MOVE THEIR Ts, THEY TEND TO REACT AND NOT NECESSARILY IN ANYTHING OTHER THAN ENLIGHTENED SELF INTEREST. AND I THINK THAT WE WILL HAVE TO CONTINUE TO HAVE THIS DISCUSSION ON WHETHER THERE SHOULD BE ONE OR TWO PREVENTION NETWORKS. BECAUSE I THINK -- >> THE ENLIGHTENED MIGHT BE IN PARENTHESES. >> CARL DIEFFENBACH: WELL, I WAS TRYING TO BE A LITTLE BIT FACETIOUS, BUT YES. IT'S INTERESTING THAT -- GRAY, I ENCOURAGE TO YOU LOOK AT THE BLOG POST AS WELL. I WAS TRYING TO BE PROVOCATIVE AND I THINK I TRULY WAS. YES? >> BETSY MCFARLAND. SO, SORT OF IN THE SIMILAR VAIN AND ONE OF THE THINGS YOU'RE PROPOSING IS TO RESTRUCTURE PEDIATRIC EFFORT AND REDISTRIBUTE ACROSS THE MECHANISMS, WHAT ARE YOU THINKING ABOUT IN TERMS OF MAKING SURE THE PEDIATRIC VOICE GETS HEARD? >> CARL DIEFFENBACH: I THINK THAT WHAT HAPPENED OVER PEDIATRICS IS WE HAD SOME PRETTY PROFOUND SUCCESSES. WHAT I REALLY AM HOPING IS THAT THE GROUPS CAN FOCUS IN ON THE CRITICAL QUESTIONS, IN CURE, AND TUBERCULOSIS, BUT THEN THERE IS ONGOING ACTIVITIES IN ADOLESCENT PREVENTION, WHICH FRANKLY, HAS NOT RECEIVED THE KIND OF ATTENTION IT NEEDED TO RECEIVE THE CURRENT NETWORK STRUCTURE. SO I'M HOPING THAT GETS CALLED OUT IN BIGGER AND BETTER WAYS. SO I THINK THAT THERE ARE OPPORTUNITIES. THERE COULD BE A MATRIX APPROACH. AT THE SAME TIME WHY NEED FOCUSED EXPERTISE IN AREAS OF VACCINES AND MAINLY ADOLESCENT PREVENTION AND IN CURE AND TB SO WE ARE LOOKING FOR LEADERSHIP IN THE AREAS WHETHER IT'S THREE PEOPLE WITH DIFFERENT HATS OR VICE VERSA. WE HAD GOOD CONVERSATIONS WITH OUR DOCTORS COLLABORATORS AT THE CHILD HEALTH INSTITUTE. THE INSTITUTE IS SUPPORTIVE OF THIS MODEL. THEY TALKED ABOUT THIS AND IT WAS FACILITATED BY MAUREEN AND THE FOLKS AT OAR. AND THERE IS SAY STRONG COMMITMENT FOR THIS CONTINUED COLLABORATION BETWEEN THE TWO INSTITUTES TO OCCUR. THANK YOU ALL. WE'LL MOVE ON TO - I THINK DICK IS UP NEXT, RIGHT? >> CARA WILSON: SO WE'LL HAVE AN UPDATE FROM DICK ABOUT THE OFFICE OF OFFICE OF AIDS RESEARCH ADVISORY COMMITTEE. >> RICHARD CHAISSON: FIRST LET ME THANK KARL FOR NOMINATING ME TO SERVE ON THE OAR ADVISORY COMMITTEE. AS A TEMPORARY ADVISOR BECAUSE OF THE HIRING FREEZE. AND MAUREEN, THANK YOU FOR ACCEPTING ME. I'M GOING TO REPORT ON THE MEETING FROM APRIL 6. THIS IS A DESCRIPTION OF THE AGENDA. I'M GOING TO TOUCH ON MOST OF THESE TOPICS BRIEFLY BUT I REGRET THAT I WON'T BE ABLE TO REALLY TALK MUCH ABOUT THE NHLBI'S PORTFOLIO BECAUSE THEIR SLIDES WERE NOT MADE AVAILABLE AND MY NOTES WERE TERRIBLE. BUT I WILL GIVE THEM SOME CREDIT IN ANOTHER SECTION. SO, THE DIRECTOR'S REPORT WAS GIVEN AND SOME OF THE HIGHLIGHTS WERE THAT THEY ARE IN THE PROCESS OF PORTFOLIO REVIEW. SHE SPOKE ABOUT THE IMPORTANCE OF THE STRATEGIC FUND AND THE INNOVATION FUNDS AND HOW THEY HAVE BEEN USED. WE HEARD ABOUT THAT LAST TIME FROM YOU, KARL. AND THE TRANS-NIH STRATEGIC PLAN. 2018 PLAN ALREADY POSTED AND A REQUEST FOR INFORMATION WAS GOING OUT THAT THE TIME FOR INPUT ON THE 2019 PLAN. I'M SURE WE ALL RECEIVED MULTIPLE REQUESTS TO GIVE INPUT AND THAT PROCESS CLOSED A COUPLE OF WEEKS AGO. THE OVERARCHING PRIORITIES AS KARL JUST MENTIONED ARE SHOWN HERE. THE REDUCTION OF HIV INCIDENTS, THE NEXT GENERATION OF THERAPIES, CURE RESEARCH, AND ADDRESSING CO-MORBIDITIES AND CO-INFECTIONS, WITH CROSSCUTTING ATTENTION PAID TO BASIC AND CLINICAL RESEARCH, HEALTH DISPARITIES, BEHAVIORAL AND SOCIAL SCIENCES, INTERNATIONAL AND DOMESTIC EPIDEMICS AND IMPORTANTLY, TRAINING. VIRGIN 3 .0 OF OAR EMPHASIZES COLLABORATIONS AND PARTNERSHIPS ACROSS INSTITUTES AND ACROSS INSTITUTIONS AND FUNDING AGENCIES, NATIONALLY AND GLOBALLY. ALIGNING THE RESEARCH WITH THE DEMOGRAPHICS OF THE EPIDEMIC, NATIONALLY AND GLOBALLY AND THINKING GLOBALLY AND COLLABORATING. ONE OF THE THINGS THAT DR. GOOD EN OW POINTED OUT IN HER TALK IS THAT THE PREVALENCE OF HIV IN THE UNITED STATES IS OVER REPRESENTED IN OLDER INDIVIDUALS, 25% OF CASES IN PEOPLE OVER THE AGE OF 55, BUT THE INCIDENTS OF HIV IS CONCENTRATED IN YOUNGER INDIVIDUALS WITH 40% OF INCIDENT CASES BEING IN PEOPLE UNDER THE AGE OF 25. AND SO ADDRESSING BOTH ENDS OF THE SPECTRUM AND THE ENTIRE SPECTRUM OF THE LIFESPAN IS CRIT ICALLY IMPORTANT. TO HELP ADDRESS SOME OF THE CHALLENGES AND PRIORITIES IN HIV RESEARCH, THE OAR IS FORMING SOME WORKING GROUP OR TASK FORCES AND THESE ARE THE TOPICS THAT WILL BE ADDRESSED BY THESE WORKING GROUPS, IMPLEMENTATION RESEARCH, ECONOMIC ISSUES RELATED TO THE ECONOMICS OF FUNDING. AND THE RETURN ON INVESTMENT AND HOW TO MAKE THOSE INVESTMENTS. AND THEN TASK FORCE LOOKING AT CO-MORBIDITIES, CO-INFECTIONS AND COMPLICATIONS. OTHERS GAVE AN UPDATE ON THE TREATMENT GUIDELINES AND WITH HENRY SITTING STARING ME IN THE FACE, I WON'T GO INTO TOO MUCH DETAIL, BUT THE DHHS PANEL WAS PLANNING A RETREAT, WHICH I ASSUME HAS HAPPENED, IN MAY, AND THESE ARE THE KEY ISSUES THAT WE ARE GOING TO BE REVIEWED, SUBSTITUTION OF TDF AND THE IMPACT OF BOOSTED CARDIOVASCULAR DISEASE AND TO TEGRA VEER AND SIDE EFFECTS NEW DRUGS AND UPDATED GUIDELINES ARE ANTICIPATED IN THE FALL. THE OI GUIDELINES INTERESTINGLY, HAVE HAD MULTIPLE UPDATES. YOU CAN SEE JUST IN THE PAST SIX MONTHS ALL OF THE SECTIONS THAT HAVE BEEN UPDATED AND THOSE THAT ARE PENDING. SO A HUGE AMOUNT OF UPDATING HAS GONE ON. TRIP EMPHASIZE THAT IN THE 1980S AND 90s UNDER HENRY'S STRICT EYE, THE QUALITY OF EVIDENCE REQUIRED FOR GUIDELINE WAS RANDOMIZED CONTROL TRIAL BUT MORE RECENTLY THERE HAS BEEN A DIRTH OF RANDOMIZED CONTROL TRIALS FOR OIs PARTICULARLY IN THE U.S. SO INCREASING RELIANCE ON OBSERVATIONAL AND COHORT DATA AND USE OF RCTs OUTSIDE OF THE UNITED STATES, PARTICULARLY TB AND MENINGTIS. THE USE OF THESE GUIDELINES HAS BEEN INCREASING DRAMATICALLY OVER TIME BECAUSE AS THESE INFECTIONS BECOME LESS AND LESS COMMON, CLINICIANS FORGET TO HOW TO TREAT THEM AND HAVE TO LOOK UP. SO THE NUMBER OF DOWNLOADS OF GUIDELINES HAS BEEN INCREASING STEADILY AND I THINK THAT'S A VERY GOOD THING. THE PEDIATRIC GUIDELINES HAVE BEEN UPDATED AND WE EMPHASIZED THAT THEY HAVE CHANGED THEIR APPROACH TO THE LANGUAGE TRYING TO SPEAK LIKE HUMANS INSTEAD OF DOCTORS. SO THAT THE PANEL IS NOW WITH THE PANEL ON ANTI-RETROVIRAL THERAPY AND MEDICAL MANAGEMENT OF CHILDREN LIVING WITH HIV. AND THERE ARE A NUMBER OF CHANGES BEING INTRODUCED INTO THESE GUIDELINES OVER THE NEXT SEVERAL MONTHS, INCLUDING WEIGHT BANDED DOSING INSTEAD OF AGE BANDING CHANGES IN RECOMMENDED USE OF SPECIFIC A RV'S. THE PEDIATRIC OI PANEL IS ALSO GOING THROUGH A SERIES OF UPDATES AND REVISIONS AND THEY HAVE CHANGED THEIR PROCESS TO A MODIFIED GRADE APPROACH. HOW THIS WORKS OUT, I THINK WE'LL ALL WAIT TO SEE. BUT A NUMBER OF UPDATES HAVE BEEN COMPLETED AND OTHERS ARE CURRENTLY UNDER REVIEW AND WILL PROBABLY BE FORTHCOMINGS SHORTLY NEXT GINA BROWN SPOKE ABOUT THE OAR'S COMMUNITY LISTENING DAY AND YOU CAN SEE IN THE UPPER RIGHT PANEL OF OAR REPRESENTATIVES INTENTLY LISTENING TO MEMBERS OF THE COMMUNITY WHO WERE INVITED THROUGH MULTIPLE PLATFORMS TO ATTEND THIS MEETING. MULTIPLE GROUPS OF ADVOCATES AND COMMUNITY ORGANIZATIONS PARTICIPATED. AND THESE WERE THE MAJOR THEMES THAT EMERGED. THEY TALKED ABOUT THE RESEARCH GAPS THAT WERE IMPORTANT TO THE COMMUNITY AND INCLUDING AGING AND INCLUSION OF ALL POPULATIONS, CO-INFECTIONS, CO-MORBIDITIES, INCLUDING MENTAL HEALTH, PREVENTION AND THERE WAS INTEREST IN ALTERNATIVE THERAPIES AND QUALITY OF LIFE AS WELL AS CULTURAL COMPETENCY. OVERARCHING ISSUES THAT AFFECTED ALL OF THESE WERE COLLABORATION ACROSS ORGANIZATIONS, FUNDING AGENCIES, AND INVESTIGATORS, ADDRESSING STIGMA AND PARTICIPANT EDUCATION AND THEY GAVE A STRONG VOTE OF SUPPORT FOR BASIC SCIENCE RESEARCH. AND THEN COMMUNITY ENGAGEMENT MESSAGE WAS ENGAGE OFTEN AND EARLY AND FOLLOW GOOD PARTICIPATORY PRACTICES. SO THE REST OF THE MEETING WAS SPENT TALKING ABOUT TWO SCIENTIFIC ISSUES, A WORKSHOP ON MACROPHAGE INFECTION AND HIV THAT WAS HELD AT THE RAGON INSTITUTE IN JANUARY. THROWN TOGETHER IN A HURRY, ATTENDED BY A LARGE NUMBER OF BEAM A GREAT INTEREST, AND THE QUESTIONS THAT WERE ADDRESSED THERE WERE THE ROLE OF MACROPHAGES IN CHRONIC INFECTION AND LATENCY AND THE QUESTION OF WHETHER HIV PERSISTS IN MACROPHAGES AND DOES THIS DRIVE INFLAMMATION AND VIRAL REBOUND? AND YOU CAN SEE SOME OF THE TOPICS DISCUSSED, HOW VIRAL TRANSCRIPTION OCCURS AND MONOCYTE VERSUS EMBRYONIC CELL DERIVED MACROPHAGES AND ARE MACROPHAGES RECEDING B-CELL AND SHOULD THEY BE TARGETED IN CURE TRIALS OR SHOULD WE LET SLEEPING DOGS LIE? NO ANSWER TO THAT LAST QUESTION. JUST A LOT OF INTEREST IN PURSUING THESE ISSUES WITH ONGOING RESEARCH. AND THEN THE REST OF THE DAY WAS DEDICATED TO THE MIC ROW BIOME WITH A DESCRIPTION OF THE NATIONAL MICROBIOME INITIATIVE WHICH THE NIH IS SAY PARTNER IN AND MANY OTHER AGENCIES INVOLVED IN THIS AS WELL. THE NIH HAS INVESTED A SUBSTANTIAL AMOUNT OF MONEY IN THE FIRST PHASE OF THIS INITIATIVE OF THE MICROBIOME AND WILL CONTINUE TO IN THE SECOND PHASE. FIRST PHASE WAS MORE OR LESS A FINDING OUT WHERE WE ARE PHASE AND THEN LOOKING MORE MECHANISTICALLY IN THE SECOND PHASE. JUST A COUPLE OF EXAMPLES THAT CAME UP AND THIS IS MY NOD TO THE NHLBI. THEY FUNDED THE LOAN. MICROBIOME PROJECT IN HIV, MULTI-CENTER PROJECT THAT LOOKED AT THE LUNG MICROBIOME, ENCOUNTERING SERIOUS TECHNICAL CHALLENGES, HOW TO GO THROUGH A HIGHLY CONTAMINATED SPACE TO GET INTO A LESS MICROBIALY DIVERSE SETTING IN THE LUNG? THEY OVERCAME THAT AND THIS WAS ONE REPORT FROM THAT GROUP ON THEIR PRELIMINARY FINDINGS WHERE TWHIPPLEI STOOD OUT. AND NO BIG DIFFERENCES BETWEEN PEOPLE WITH AND WITHOUT HIV. JACK FROM THE UNIVERSITY OF MARYLAND TALKED ABOUT GENDER DIFFERENCES IN THE MICROBIOME TALKED ABOUT THE MICROGENDER OHM AND THE ESTROPPA LOAM. THE ROLE OF ESTROGENS AND DRIVING BACTERIAL DIVERSITY IN THE GUT IN PARTICULAR, AND THE ROLE THAT THIS MIGHT HAVE ON DISEASE MANIFESTATIONS LATER IN LIFE FASCINATING TALK. FLOTTO LEAVE MEN OUT, HE ALSO TALKED ABOUT THE PENEILE MICROBIOME AND SHOWED THESE DATA FROM THE STUDY OF CIRCUMCISION WHERE THE MICROBIOME WAS STUDIED IN A SUBPOPULATION OF MEN IN THE CONTROL AND INTERVENTION ARM OF THE UPPER GRAPH SHOWING THE CONTROL GROUP, PRE AND POST CIRCUMCISION. THERE WAS NO CIRCUMCISION. THEY WERE CONTROLLED. JUST PRE AND POST FOLLOW-UP AT ONE YEAR. YOU SEE REALLY NO CHANGE IN THE DISTINCTY OR QUANTITY OF THE MICROBIOME BUT IN THE CIRCUMSIDES GROUP, THE MICROBIOME GROUPED CHANGED WITH THE REDUCTION IN THE NUMBER OF ORGANISMS AND QUANTITY OF EACH AND WILL FURTHER STUDY HAS LOOKED AT THE EFFECTIVENESS ON HIV TRANSMISSION. THERE WAS A LOT OF INTEREST IN THE VAGINAL MICROBIOME AND ITS EFFECT ON HIV INFECTION AND HIV PREVENTION. THESE ARE DATA FROM THE CAPRICA STUDY SHOWING THE ASSOCIATION OF PREFFA TELLA DOMINANCE IN THE VAGINAL MICROBIOME WITH BOTH VAGINAL INFLAMMATION AND INCIDENT HIV INFECTION WHERE HAVING A PREFFA TELLA PREDOMINANCE WAS ASSOCIATED WITH 20-FOLD RISK OF HAVING INFLAMMATION AND A 13-FOLD RISK OF SEROCONVERSION IN THE CAPRICA STUDY. AND THEN, REALLY FASCINATING DATA PRESENTED LAST YEAR IN DURBAN SHOWING THAT AMONG WOMEN WHO WERE ADHERENT OVER 50% ADHERENT IN THE CAPRICE STUDY TO THE TA NOF VEER GEL, THE OVERALL EFFICACY WAS 56% BUT AMONG THOSE WOMEN WHO HAD ELECTO BACILLUS DOMINANT FLORA, IT WAS 78% VERSUS 26% FOR THOSE WHO WERE NOT LACTOBACILLUS DOMINANT. AND ONE OF THE VERY PROVOCATIVE FINDINGS PRESENTED AT DURBAN LAST YEAR AND REPRESENTED AT OAR MEETING WAS THIS WORK ON IN-VITRO WORK ON GARDENER RELLA EATING AT THE NOF VEER. AND IN-VITRO, ON THE LEFT, WHEN TA NOFFA VEER IS ADDED TO THESE CULTURES, THE GARDNA RELLA GOB ELSE IT UP AND IT'S NO LONGER IN THE SUPERINATE ENT OVER A PERIOD OF HOURS WHERE IT'S MOSTLY INTRACELLULAR. LACKO BACILLUS DOESN'T GOBBLE IT UP AND THIS WAS ONE OF THE INTERESTING FINDINGS. BUT THE PARTNERS PREP STUDY FOUND THAT WITH ORAL PREP, THERE WAS NO ASSOCIATION OF THE VAGINAL MICROBIOME AS MEASURED BY BACTERIAL ADVANTAGE NOSEIS AND EFFICACY OF PREP. SO THE CONCLUSIONS FROM THIS WHOLE SERIES OF PRESENTATIONS. WHAT THE ROLE OF THE VAGINAL MICROBIOME IS WITH ART, TOPICAL OR OTHERWISE, AND CONCLUDING THAT MORE STUDIES ARE NEEDED. IT WAS A REALLY FASCINATING SERIES OF PRESENTATIONS. SO I'LL GIVE YOU MY CLOSING THOUGHTS AND KARL, I'M NOT PILING IT ON HERE BUT I THOUGHT I'D ADD CLOSING THOUGHTS. THE OAR3.0 EMPHASIZES COLLABORATION AND PARTNERSHIPS AND GLOBAL LEVERAGING OF RESOURCES AND CROSSCUTTING PROGRAMS AND THE HIGHLIGHTS OF THE MEETING THAT I'M DESCRIBING WERE REALLY BIG SCIENCE, BIG DATA, THE MACROPHAGE WORKSHOP, MULTIPLE INVESTIGATORS COLLABORATING, MICROBIOME RESEARCH REQUIRING HUGE TEAMS RANGING FROM MICROBIOLOGY TO BIO INFORMATICS. AND SO, WHAT WOULD THE IMPACT OF THE GRANT SUPPORT INDEX BE ON THIS TYPE OF SCIENCE? AND WE ALREADY HAD A DISCUSSION ABOUT IT SO I JUST ADD MY THOUGHTS THAT IS IT A REAL DISINCENTIVE AS ORIGINALLY PROPOSED TO INTERDISCIPLINARY COLLABORATION AND PARTNERSHIP AND IT'S A PARTICULAR DISADVANTAGE TO LEADING PROGRAMS LIKE CFARs AND TRAINING GRANTS AND I'M DELATED TO HEAR THAT I NO LONGER NEED TO BE AS CONCERNED AS I WAS A COUPLE OF WEEKS AGO. SO THAT IS THE REPORT. HAPPY TO TRY TO ANSWER QUESTIONS OR DEFLECT THEM TO MAUREEN WHO MIGHT BE BETTER ABLE TO ANSWER THEM. [ LAUGHS ] >> HOW MUCH OF THE EMPHASIS ON MICROBIOME IS ON BACTERIA VERSUS VIRUS, FUNKY AND ET CETERA. >> RICHARD CHAISSON: THERE ARE PROBABLY OTHERS WHO COULD ANSWER THAT BETTER BUT I THINK A LOT OF THE INITIAL FOCUS WAS ON BACTERIA BECAUSE IT WAS EASIER AND THE VIRAL MICROBIOME IS MORE CHALLENGING BUT THERE WAS SEVERAL PRESENTATION THAT IS LOOKED AT THE VIRAL MICROBIOME. THE WHOLE INITIATIVE REALLY STARTED WITH WHAT WAS EASIEST AND MOST DESCRIPTIVE AND AS NOW EVOLVING INTO A MORE RIGOROUS AND TECHNOLOGICALLY SOPHISTICATED APPROACH. >> CARA WILSON: THANK YOU. SO NOW AS WELL HAVE AN UPDATE ON AVRS ACTIVITIES. >> AFTAB ANSARI: SO, THE AVRS MEETING TOOK PLACE IN JANUARY OF 2017 AND I GUESS YOU COULD ADVANCE THE SLIDE. WHO WILL ADVANCE THE SLIDE? I GOT TO GO TO THE PODIUM? [ LAUGHS ] SO, THERE WAS BASICALLY THREE PRESENTATIONS. THERE WERE PART OF THAT MEETING THE FIRST PART WAS THE TWO LARGE REPORTS PRESENTED BY MARTIN HAINES FROM DUKE AND DENNIS BURTON FROM SCRIPPS. THE SECOND PRESENTATION IS FROM THE VACCINE RESEARCH PROGRAM UPDATE AND THE THIRD WAS THE SPECIAL PRESENTATION BY DR. MARTIN WHICH I'M NOT SURE WE HAVE TIME TO GET INTO. SO, THE FIRST WAS AWARDED TO DR. MARTIN HAINES IN 2005. IT WAS A 7 YEAR CHAVI AWARD. IN 2012, THERE WERE TWO CHAVI-IDs AWARDED ONE TO MARTIN HAINES AT DUKE AND OTHER WAS TO DENNIS BURTON. CURRENTLY THE DISCUSSIONS ARE UNDERWAY DETERMINE THE PROGRAM COMPETITIVELY RENEWED IN FY19 AND IF SO, IN WHAT FORM.& SO I'M GOING TO TRY TO SUMMARIZE. IT WAS NOT AN EASY JOB TO SUMMARIZE ALL THE PRESENTATIONS THAT WAS THERE WITH BOTH BART CHAINS DENNIS BURTON. THERE WERE 70-80 SLIDES WITH DETAILED INFORMATION. AND HARD TO SYNTHESIZE ALL THAT IN A VERY FEW MINUTES BUT I'LL GIVE YOU THE OVERALL AND THEN GIVE YOU SOME HIGHLIGHTS FROM MY PREJUDICE MIND THAT GOT MY INTEREST AND GIVE YOU SOME OF MY THOUGHTS AND WHAT THEY ARE THINKING ABOUT GOING FORWARD IN THE TWO CHAFEE PRESENTATIONS. AND AFTER THAT, I THINK JIM BRADOCK WILL TAKE OVER FROM THERE. SEWED FOR THE DUKE CHAVI, TWO OVERALL MAJOR GOALS, KNOW WAS TO DEVISE STRATEGIES TO OVERCOME ROAD BLOCKS AND I REMEMBER THIS OCCURRED QUITE A WHILE AGO AND THEY WENT THROUGH AND IDENTIFIED A WHOLE SERIES OF ROAD BLOCKS THEY THOUGHT WERE IMPORTANT TO ADDRESS FOR MAKING AN EFFECTIVE HIV VACCINE. THE SECOND WAS TO DESIGN IMMUNOGENS AND TEST THEM IN VARIOUS ANIMAL MODELS AND OBVIOUSLY ULTIMATELY IN HUMANS AND COORDINATION WITH HVTNs. SO THE EIGHT ROAD BLOCKS IN SHORT. STUDY IMMUNE RESPONSES TO GET SAMPLES FROM THESE PATIENTS AND SO ON AND SO FORTH AND TO UNDERSTAND PATHOGENIC MECHANISMS. SECOND WAS TO IDENTIFY CORRELATES OF TRANSMISSION RISK IN THE RV144 CLINICAL TRIAL THAT WAS DONE BY THE MHRP. THIRD, HOW TO OVERCOME THE DIVERSITY OF HIV FOR INDUCING HIV SPECIFIC T-CELL RESPONSES. THE NEXT ONE WAS, WHY IS IT SO HARD TO PRODUCE BROADLY NEUTRALIZING ANTIBODIES? AND THERE WAS A ROAD BLOCK THEY HAD IDENTIFIED. AND THEN IMPORTANTLY, WHY ARE THESE BROADLY NEUTRALIZING ANTIBODIES MADE DURING SELECT NATURAL HIV INFECTION BUT RARELY OCCUR DURING VACCINATION? AND THERE WAS AN INTERESTING AND IMPORTANT QUESTION THEY WERE TRYING TO ADDRESS. WHAT IS THE OPTIMAL IMMUNOGEN DESIGN. HOW TO MONITOR IF YOU HAVE A VACCINE, HOW TO MONITOR THAT IN AN OBJECTIVE AND PRODUCTIVE FASHION AND FINALLY, THE NEED FOR ITERATIVE HUMAN PHASE 1 CLINICAL TRIALS AND HOW TO GET THESE CLINICAL TRIAL MATERIALS. SO, AGAIN, AS I SAID, THERE WAS A LONG, LONG LIST OF ACCOMPLISHMENTS BY THIS CHAVI. THERE WERE THERAPIES SCIENCE AND NATURE AND ALL KINDS OF - AUDIO PAPERS IN SCIENCE AND NATURE AND CELL ARTICLES AND EDITORIALS AND SO ON. ENORMOUS AMOUNT OF PRODUCTIVITY AS EXPECT FROM A CHAVI. BUT I'LL GIVE YOU MY PREJUDICE VIEW, HIGHLIGHT THE ACCOMPLISHMENTS I THOUGHT WERE APPEALING TO ME. THE FIRST ONE I LIKE TO HIGHLIGHT IS THIS CONCEPT OF IN SILL COHOMOLOGUES COMBINATION TO GENERATE MOSAICKIC T-CELL IMMUNOGENS FOR OPTIMIZED CD4 AND 8. AND THIS CONCEPT WAS HIGHLIGHTS IN THE NATURE MEDICINE PAPER THAT PUBLISHED. SO MOSAIC GENES ARE SELECTED AND WHAT IS IMPORTANT WAS WHEN THEY WERE SELECTING THOSE TO KEEP IN MIND, TO AVOID THOSE NON-NATIVE EPITOPES, SO THEY HAD TO CHOOSE AUTHENTIC IMMUNOACIDS IN BETWEEN THOSE SO WE DON'T GET A PROBLEM WITH NON-NATIVE EPITOPE ISSUES. SO THAT WAS PUBLISHED IN NATURE MEDICINE. THE NEXT ONE THAT FIELD ME WAS THE STUDY THE DETAILED CHARACTERISTICS AND THE BIOLOGY OF WHAT BECAME A BUZZWORD, THE HIV TRANSLATED VIRUSES AND THEY CHARACTERIZED SNOWS DID A LOT OF WORK IN TERMS OF TRYING TO IDENTIFY WHAT THE DIFFERENCES ARE BETWEEN THOSE TRANSMITTED FOUNDER VIRUSES THAT WERE FIT AS OPPOSED TO THE HIGH FITNESS VERSUS LOW FITNESSES AND HIGHLIGHTED THAT IN A COUPLE OF PAPERS, ONE OF THEM IS LISTED THERE, AND HIGHLIGHTS BY THE FACT THEY HAVE HIGH FITNESS HAS HIGH REPLICATING CAPACITY, AND HIGH ENVELOPE CONTENT AND INFECTIVITY AND EFFICIENT DENDRITIC CELL INTERACTION AND INTERESTINGLY THEY WERE RESIST TONIGHT TYPE I INTERFERONS AND IT WAS THE OPPOSITE FOR THE LOW TRANSMISSION FITNESS VIRUSES. THE NEXT ITEM, AND AGAIN IT WAS INCREDIBLE FINDINGS THAT THERE WAS AID CO-EVOLUTION ASPECT OF THESE BNABs WITH THE TRANSMITTER FOUNDER VIRUSES AND THEY MAPPED THE CO-EVOLUTION OF THESE TRANSMITTED FOUNDER VIRUSES AND THE CD4 BINDING SAID BNAB AND DEMONSTRATED THAT THIS B NAB ACTIVITY THAT THEY SAW DID NOT OCCUR UNTIL THE VIRUS RESEARCHED EXTRA OARED NARY AMOUNT OF DIVERSITY. YOU THINK IT WOULD COME UP RIGHT AWAY BUT THEY FOUND JUST THE OPPOSITE T REALLY HAD TO DIVERSIFY QUITE A BIT FOR THE B NAB TO BE SHOWN. AND AGAIN, THE B NAB GERMLINE BINDING WAS SHOWN TO BE SPECIFIC FOR THE FOUNDER VIRUS I THINK IT WAS A A FASCINATING FINDING, COUNTERINTUITIVE ABOUT WAS TRUE. THE NEXT ONE IS THE ONATOLOGYNY AND HERE THEY HAVE ENORMOUSLY INCREDIBLE JOB OF GOING FROM TRANSMISSION TO BNAB DEVELOPMENT FOR A CD4 MIMICKING BINDING SITE BNAB. THEY MAPPED OUT THE WHOLE FROM THE BEGINNING TO THE END. I THINK IT WAS INCREDIBLE AMOUNT OF WORK AND BEAUTIFULLY DONE. AND NAY BUILT A GM FACILITY TO MOVE THESE THINGS ALONG AS THEY COME UP IN TERMS OF INSTRUMENTS. THIS FACILITY WAS FUNDED BY DUKE SCHOOL OF MEDICINE. PREPRODUCTION IN GMP TEAM IN PLACE. THE PREPRODUCTION WORK BEGUN ON GP120s AND SOLUBLE STABLE TRIMERS AND THEN THEY HAVE DEVELOPED DIFFERENT PARTNERSHIPS WITH DAIDS, THE ECONOMIC GMP PRODUCTION PART THE. SO I'M NOT GOING INTO EACH OF THIEVES IN DETAIL. SUFFICE TO SAY THEY HAVE SIX VACCINES CURRENTLY IN MANUFACTURE AND THEY ARE LISTED ON THIS SLIDE. AND THEY ARE ALSO LISTED AND DESCRIBED THE INVESTIGATORS WHO ARE IN CHARGE OF EACH OF THOSE VACCINES AND THE FUNDING SOURCE FOR THOSE IT INCLUDES THE CHIMP OX ONE MVA CONSERVED MOSAIC INSERT STRATEGY THAT IS IN RESPONSE TO OTHER WORK SO WHAT DO THEY WANT TO DO GOING FORWARD? THEY WANT TO ENTER THE TRANSLATION PHASE OF HIV DEVELOPMENT AND DOITERATIVE PRE-CLINICAL STUDIES USING BNAB K1 MICE ANDITS AND MACAQUES AND THEY WANT TO UTILIZE A GMP FACILITY TO MAKE CANDIDATE VACCINES AND CONSTRUCTS. AND THEY WANT TO DO CLINICAL 1 TRIALS IN INCREDIBLE AMOUNT OF DIFFERENT IMMUNE RESPONSES THEY ARE MEASURING AT THE SAME TIME. AND I'LL TELL YOU, THAT IS LIKE A FACTORY. THEY HAVE GOT EVERYTHING FROM SOUP TO NUTS IN TERMS OF MEASURING IMMUNORESPONSES FROM INNATE IMMUNITY TO ACQUIRED IMMUNITY. AND ALSO AT THE MOLECULAR LEVEL, I SHOULD SAY, THEY ARE POISED WITH NEW MOMENTUM TO MAKE ACCELERATED PROGRESS UNTIL PARTNERSHIP WITH SCRAPS, CHAVI AND VRC AND THE REST OF THE FIELD. SO THE SCRIPPS CHAVI-ID WAS PRESENTED TO DENNIS BURTON. AND THEIR APPROACH WAS TO MAKE A NEUTRALIZING ANTIBODY BASED HIV VACCINE WITH THE MAJOR FOCUS OF THE CHAVI ON DESIGNING VACCINES WITH SPECIFICITY FOR CD4 BINDING SITE, AND GLYCAN EPITOPE AND V2 APEX EPITOPE AND SMOTHERS I WILL MENTION IN A MINUTE. AND THE IMMUNOGENS ARE CHOICE AND SHOULD BE DESIGNED RATIONALLY, DESIGNED GERMLINE TARGETING IMMUNOGENS, RATIONALLY DESIGNED BOOSTING IMMUNOGENS, AND NATIVE TRIMERS. SO THEY HAVE BASICALLY OUTLINED THREE STRATEGIES ACCOMPLISH THAT. THE FIRST ONE WAS TO TRIMER APPROACH WHERE THEY WERE GOING TO USE A COCKTAIL OF THESE AND SEQUENTIAL IMMUNIZATION WITH THESE TRIMERS. THE SECOND STRATEGY WAS LINEAGE PRESENTATION ON TRIMERS AND THE THIRD STRATEGY WAS TO FIRST USE GERMLINE TARGETING AND THEN RATIONAL BOOSTING AND FINALLY TRIMER FINISHING. SO THERE WAS A STRATEGY OUTLINED FOR THEIR CHAVI. THIS IS A CARTOON THAT SUMMARIZES THE ORIENTATION OF THE VARIOUS EPITOPES THEY WERE TARGETING STARTING ON THE MIDDLE ON TOP. THE APEX WAS BEING TARGETED AS ONE OF THEM WITH PG9 BEING THE PROTOTYPE BNAB IDENTIFIED. AND THEN THERE WAS A TOP RIGHT IS THE HIGH MANOSE PATCH, THE GLYCAN MANOSE THAT A TYPICAL ANTIBODY THEY IDENTIFIED WAS PG50128. NEXT A CD4 BINDING SITE. AND ANTIBODY IS WHAT THEY HIGHLIGHTED. AND THE GP120,. THE ONE THING THAT ABOUT CHAVI I LIKED A LOT WAS 24 CONCEPT OF REVERSE ACTION ALGAE. SO TAKE AN INFECTED INDIVIDUAL WHO IS MAKING A BNAB AND ISOLATED UPON THE HIV SPECIFIC BNAB FROM THE PERSON AND SEQUENCE THE B REGION OF THE ANTIBODY AND DEFINED SPECIFICALLY THE EPITOPE OF THE ENVELOPE THAT IS TARGETED AND BY THAT, YOU WILL KNOW WHAT THE DESIGN IS THAT IS TARGETED BY THE BNAB AND THEN YOU CAN TAKE THAT IMMUNOGEN AND ESSENTIALLY USE IT IN NATIVE FORM OR MODIFY IT AND THEN TRY TO GO AND MAKE A VACCINE MAYBE POTENTIALLY BY COMBINATION OF SEVERAL OF THESE YOU WILL ACHIEVE A COCKTAIL OF BNAB THAT IS WILL BE VERY, VERY EFFECTIVE AND USEFUL BECAUSE THEY ARE COMING FROM INITIALLY FROM THE HUMANS AND THEIR RATIONAL APPROACH WAS TO USE THE TWO SIDES AND THE ENVELOPE STRUCTURE AND VARIATION AND THE B NABS ARE GENERATED IN THESE PATIENTS AND AT THE SAME TIME, LOOK AT NATURAL INFECTIONS AND PULL OUT THE ANTIBODIES IN THOSE AND LOOK AT WHAT GAVE RISE TO NOSE AND THE IMMUNOLOGY BY LOOKING AT THE B-CELLS AND 26789 HELPER CELLS BIOLOGY. -- T HELPER CELLS AND THEN COMBINE THE TWO FOR IMMUNOGEN DESIGN AND FOR THE IMMUNIZATION STRATEGIES TO FINALLY END UP AT THE IMMUNOGEN EVALUATION AND THEN VACCINE. AND THEN HAVE AN ITERATION OF THAT. SO FOR THE SCRIPPS CHAVI, THEY HAVE TWO VACCINES THAT THEY ARE FOCUSING ON. ONE IS A BG506 TRIMER PROTEIN AND THE OTHER ONE IS THE EODGT8 PEPTIDE NANOPARTICLE. THE INVESTIGATORS ARE LISTED AND THOSE ARE BEING FUNDED BY THE GATES FOUNDATION. SO, I'LL STOP THERE AND SO I SHOULD SAY, AFTER THE PRESENTATION THERE WAS A LOT OF DISCUSSION AMONG PANEL MEMBERS OF THE ABRS. THERE WAS LOTS OF COMPLIMENTS PASSED BECAUSE THE QUALITY OF SCIENCE WAS UNBELIEVABLE AND BEAUTIFUL SCIENCE BEING DONE. BUT ONE OF THE THOUGHTS THAT WAS EMPHASIZED WAS THAT THESE CHAVIs SHOULD TRY TO PRIORITIZE STUDIES IN THE FINAL TWO YEARS OF THE CURRENT AWARDS BECAUSE THERE IS SO MANY DIFFERENT APPROACHES THAT WERE BEING IDENTIFIED, SO MANY VACCINE CANDIDATES, SO MANY DESIGNS, THEY WERE ASKED TO MAYBE TRY TO PRIORITIZE THEM TO BE ABLE TO COME TO THE END OF AT LEAST SOME OF THEM. ED AND IT WILL BE GOOD TO KNOW HOW WELL -- SO THIS IS ONE THING THEY DIDN'T PRESENT VERY WELL AND THE COMMITTEE FELT THAT THEY SHOULD HAVE SOME DATA TO SHOW HOW YOUNG INVESTIGATORS ARE BEING RECRUITED INTO THE AIDS VACCINE PRE-CLINICAL FIELD TO ALLOW TO SHOW HOW THE TRAINING PROGRAMS ARE FUNCTIONING. THERE WAS ALSO DISCUSSION ABOUT HOW EXPENSIVE THIS WAS. VERY, VERY EXPENSIVE TO MOVE THIS TO THE FACILITY. AND THEY SHOULD TRY TO REDUCE COSTS AND INCREASE EFFICIENCY FOR MANUFACTURE AND PROTEIN IMMUNOGENS AND PERHAPS THE MRNA BASIC IMMUNOGENS SHOW PROMISE AND MAY REDUCE RELIANCE ON PROTEINS. THE NEXT THING WAS, THE ADVICE FROM THE COMMIT THEY IMMUNOGENS BEING PRODUCED FOR CLINICAL TRIALS SHOULD BE TESTING HYPOTHESIS RATHER THAN TRYING TO PLAY WITH THEM. THEY SHOULD BE VERY CLEAR-CUT HYPOTHESIS SOME OF THESE. AND LASTLY, WITH CHAVI ENGAGED IN CLINICAL PRODUCT MANUFACTURE, THE COMMITTEE GENERALLY FELT THAT THE PIPELINE APPEARS EXTREMELY PROMISING. SO JIM, I'LL LET YOU TAKE IT FROM THERE. >> JIM: THE SECOND HALF OF THE MEETING WAS DEDICATED TO A PROGRAMMATIC UPDATE. THERE WERE THREESENTATIONS FROM THE VAC TEEN PROGRAM, ONE FOR PRE-CLINICAL AND ONE FOR TRANSLATIONAL AND ONE FOR CLINICAL TRIALS. MY PRESENTATION REALLY IN THE PAST I HAD GIVEN IN-DEPTH PORTFOLIO REVIEWS FOR THIS PRESENTATION I JUST SHOWED WHAT WAS -- WHAT AWARDS WERE MADE IN FY16 AND THEN THAT YOU COULD ABOUT THE PROGRAM ANNOUNCEMENTS THAT ARE ON THE STREET FOR 17 AND 18, HIGHLIGHTING WHICH PROGRAM ANNOUNCEMENTS HAD SET ASIDE FUNDS, AND THE ONLY PROGRAM SET ASIDES FUNDS IN 18 WAS FOR IHBD. THE TRANSLATIONAL PRESENTATION HIGHLIGHTED OTHER VEHICLE SCENES OUTSIDE OF THE CHAVI-IDs IN PRODUCTION. INCLUDING SOME THAT ARE FUNDED BY BILL AND MELINDA GATES FOUNDATION AND DALE GAVE A VERY NICE CLINICAL PRESENTATION, 2016 WAS A VERY BIG YEAR FOR THE CLINICAL SCIENCE. ONE OF THE STUDIES THAT WAS INITIATED IN 2016 WAS THE ANTIBODY MEDIATED PROTECTION STUDY KNOWN ASASM, TWO HBTN PROTOCOL, ONE IN HIGH-RISK WOMEN AND ONE IN MSMs IN NEITHER AND SOUTH AMERICA AND THIS WAS ONE OF THE A LITTLES FOR 200016 -- HIGHLIGHTS. HBT100 WAS COMPLETED AND THIS IS A TRIAL TRYING TO DUPLICATE RV144 WITH PRODUCTS DESIGNED FOR SOUTH AFRICA. HVTN PHASE I00 TO SEE IF THEY WERE UM NOGENIC IN SOUTH AFRICA. THEY MOVED ON TO A PHASE II B3 STUDY. HPTN702 AND THAT WAS INITIATED 2342016. -- IN 2016. THERE WAS A PRESENTATION OR IT WAS TALKED ABOUT THE AD26 TRIAL THAT IS PLANNED FOR LATTER PART OF 2017. THIS IS THE TRIAL TO BE DISCUSSED TOMORROW AT THE STRATEGIC WORKING GROUP MEETING BASED ON ADD 26 VACCINE AND GP120 BOOST AND HERE ARE THE RATIONAL FOR MOVING THIS VACCINE FORWARD. HERE IS WHAT THE PROTOCOL LOOKS LIKE. HBTN705. AND ADD 26 FOLLOWED BY GP140 PROTEIN BOOST SO THIS WILL BE DISCUSSED AT THE STRATEGIC WORKING GROUP OF WHICH THE AIDS VACCINE RESEARCH SUBCOMMITTEE IS THE VACCINE ARM WITHIN THE STRATEGIC WORKING GROUP AND THEY WILL BE HERE TOMORROW. SO, THESE ARE THE FUTURE MEETINGS. KARL SHOWED THIS VERY BRIEFLY BUT LET ME HIGHLIGHT OUR NEXT MEETING SEPTEMBER 12 AND 13 AND ONE OF THE THINGS WE WILL DO IS HAVE A WORKSHOP IN PEDIATRIC HIV VACCINES TO TALK ABOUT THE CURRENT STATUSES AND CHALLENGES AND OPPORTUNITIES. >> CARA WILSON: IF THERE ARE NO QUESTIONS, WE'LL MOVE ON. THANK YOU. WE'L MOVE ON TO THE CONCEPT PROPOSALS. THE FIRST THREE ARE FROM THE BASIC SCIENCES PROGRAM. AND THE FIRST ONE IS CALLED TARGETED IN-VIVO DELIVERY OF GENE THERAPEUTICS FOR HIV CURE. AND BETTY POON WILL BE PRESENTING THAT. >> BETTY POON: GOOD AFTERNOON. I'M A PROGRAM OFFICER IN THE BASIC SCIENCES PROGRAM IN THE DIVISION OF AIDS AND I'M PRESENTING THE INITIATIVE TARGETED IN-VIVO DELIVERY OF GENE THERAPEUTICS FOR HIV CURE FOR ARAC CONSIDERATION AND APPROVAL. SO THE OBJECTIVE OF THIS INITIATIVE IS TO ADVANCE STRATEGIES TO EFFICIENTLY DELIVER ANTI-HIV GENE THERAPIES TO SPECIFIC TARGET CELLS IN-VIVO. THIS WILL BE AN RFA USING THE RO1 MECHANISM IT'S A NEW INITIATIVE WITH A DURATION OF AWARDS BECAUSE OF THE RO1 OF UPWARDS OF 5 YEARS AND WE ESTIMATE THAT WE WOULD BE ABLE TO SUPPORT BETWEEN 5-6 AWARDS. SO WHY THIS INITIATIVE AT THIS TIME. SO TODAY, MANY STRATEGIES HAVE BEEN DEVELOPED FOR EX-VIVO DELIVERY OF GENE THERAPIES AGAINST HIV. IN OTHER WORDS TAKING THE CELLS OUT OF THE BODY AND TRANSDUCING THEM IN CULTURE AND PUTTING THEM BACK. HOWEVER, WHAT WE SEE AS THE PRIMARY HURDLE THAT THE TIME IS TO BE ABLE TO DELIVER THESE THERAPIES TO KEY CELL SUBSETS IN-VIVO. FOR EXAMPLE, IF WE WANTED TO TARGET HIV-INFECTED CELLS IN TISSUE SANCTUARIES THAT ARE NOT AMENABLE FEDERAL EX-VIVO MANIPULATION OR T-CELLS SUCH AS THE STEM CELL MEMORY THAT ARE IN VERY RARE SUPPLY. SO TARGETED TECHNOLOGIES ARE NEEDED IN ORDER TO DELIVER THESE GENE THERAPY PAYLOADS TO SPECIFIC TARGET CELLS AND SITES IN-VIVO TO ALLOW MORE AFFECTIVE EXTREME ERADICATION OF HIV. THIS INITIATIVE WILL ALSO LEVERAGE OUT GOING KNOWLEDGE OF FEATURES THAT ARE SPECIFIC TO LATENTLY INFECTED CELLS TO TARGET THE RESERVOIRS IN TISSUE SANCTUARIES. THE SCHEMATIC ON THE LEVEL IS FROM A RECENT REVIEW OF THERAPEUTIC GENE EDITING AND IT HIGHLIGHTS SOME OF THE KEY DIFFERENCES BETWEEN IN-VIVO GENE EDITING STRATEGY ON THE LEFT-HAND SIDE AND SOME OF THE STEPS THAT ARE INVOLVED IN EX-VIVO GENE EDITING ON THE RIGHT-HAND SIDE. SO AS I SAID, TO DATE, THE MAJORITY OF GENE THERAPIES AGAINST HIV HAS INVOLVED EX-VIVO DELIVER THEY INVOLVES GENETIC MODIFICATION OF T LYMPHOCYTES OR STEMS CELLS TAKEN OUT OF THE BODY AND MODIFIED IN CULTURE AND REINFUSED BACK INTO THE PATIENT. THERE IS MULTIPLE STEPS INVOLVED CHOOSING THE ISOLATION OR HARVESTING OF CELLS THAT WOULD USUALLY INVOLVE A VERY LARGE BLOOD DRAW OR A DRUG THAT WILL ALLOW MOBILIZATION OF STEM CELLS OUTSIDE OF THE BODY INTO THE -- OUT OF THE BONE MARROW INTO THE BLOOD FOR HARVESTING. EX-VIVO EDITING IN CULTURE THAT WILL INVOLVE A VARIETY OF DELIVERY MECHANISMS, CULTURING OF THE CELLS AND EXPANDING THEM AND THEN REIN FUSING THEM BACK INTO THE PATIENT AND AGAIN, A LOT OF TIMES THAT INVOLVES A CONDITIONING REGIMEN IN ORDER TO MAKE ROOM FOR THESE CELLS TO BE ENGRAFTED. ON CONTRAST, IF YOU LOOK ON THE FAR LEFT, IN-VIVO GENE APPROACHES IS ACTUALLY MINIMALLY INVASIVE, POTENTIALLY MORE SELECTIVE AND LESS TOXIC BECAUSE IT INVOLVES MUCH LESS MANIPULATION BOTH OF THE PATIENTS AND OF THE CELLS THEMSELVES. AND WOULD AVOID THE CURRENT POOR SURVIVAL AND ENGRAFTMENT OF EX-VIVO MODIFIED CELLS WHEN INTRODUCED BACK INTO IN-VIVO. THIS IS AN EXAMPLE PUBLISHED IN MOLECULAR THERAPY ABOUT A MONTH OR SO GO WHERE THE LABORATORIES OF DR. CALEVEL FROM TEMPLE UNIVERSITY USED CHRIS PER CAS9 TO SPECIFICALLY TARGET THE HIV PROVIRUS. THEY USED THE GUIDE RNAs, TARGETED HIV GENOME AND IN A VARIETY OF MOUSE MODELS, WHEN THE AAV EXPRESSING CAS9 AND GUIDE RNAs ARE INTRODUCED BY INTRAVENOUS OR INTRAVAGINAL DELIVERY, THEY SHOWED IN THIS PAPER THAT THEY COULD EXCISE HIV IN MULTIPLE TISSUES AND ORGANS IN THESE MICE MODELS. HOWEVER, AAV HAS VERY BROAD TROPISM SO YOU CAN SEE THIS EFFECT IN MULTIPLE TISSUES AND ORGANS AND ONE OF THE MODELS THEY USED WAS TRANSGENIC MICE WHERE THEY HAD AAV IN ALL THEIR CELLS. SO WHAT IS NEEDED IN RESEARCH IN ORDER TO BASICALLY FOCUS AND TARGET THE DELIVERY AND EXPRESSION OF THIS THERAPY. IT SHOULD BE NOTED THIS IS JUST ONE EXAMPLE I HIGHLIGHTED. THERE ARE OTHER GENE THERAPIES THAT WOULD BENEFIT FROM IN-VIVO TARGETED DELIVERY APPROACH INCLUDING SHRINK FINGERS BEING DONE EX-VIVO AND SH RNA FOR TRANSCRIPTION, APTAMERS AS WELL AS DELIVERY OF IMMUNOTHERAPY -- IMMUNOTHERAPEUTICS SUCH AS CHIMERIC RECEPTORS OR T-CELLS OR SOME OF THOSE RARE STEM CELL MEMORY T-CELLS THAT I MENTIONED EARLIER. SO THE SCOPE OF THE RESEARCH OF THE INITIATIVE WOULD BE TO SUPPORT DIRECT IN-VIVO DELIVERY APPROACHES TO IMPROVE DELIVER TOW SPECIFIC TARGET CELLS AND SITES. AND THE TARGET CELLS AND SITES WOULD DEPEND UPON THE GENE THERAPEUTIC APPROACH. THIS IS TO MAXIMIZE TARGET EXPRESSION AND MINIMIZE OFF TARGET EFFECTS AND BECAUSE THIS IS GOING IN-VIVO, IT'S TO MINIMIZE THE POTENTIAL IMMUNOGENICITY OF THE DELIVERY VECTORS VIRAL OR NON VIRAL. WE WOULD EXPECT APPLICANTS HAVE A SUCCESSFUL THERAPEUTIC APPROACH WITH PRELIMINARY DATA AT THE TIME OF SUBMISSION IN ORDER TO CONTRAIT ON THE CAGERETTING ASPECT OF THEIR APPROACH AND DELIVERY IN THE ANIMAL MODEL. WE WOULD REQUEST IN-VIVO ANALYTICAL STUDIES TO INFORM THE BIOLOGICAL FEASIBILITY OF THE APPROACH AND THAT INCLUDES STUDIES OF THE BIOAVAILABILITY, TISSUE DISTRIBUTION, EXPRESSION AND STABILITY AS APPROPRIATE TO THE THERAPY. SOME EXCLUSIONS WOULD BE PURELY EX-VIVO STUDIES THAT DO NOT INCLUDE AN IN-VIVO TARGETING DELIVERY COMPONENT AS WELL AS THE DISCOVERY OR DEVELOPMENT OF NEW GENE THERAPY PAYLOADS BECAUSE AGAIN THE FOCUS OF THIS RFA WOULD BE ON THE IN-VIVO DELIVERY OF THE GENE THERAPEUT THERAPEUTIC. WHAT THIS INITIATIVE WILL ACCOMPLISH WOULD BE INCREASED THERAPEUTIC EFFICIENCY BY ALLOWING TARGETING OF SPECIFIC SITES AND CELLS AGAIN SUCH AS IF THE GOAL IS TO TRY TO EXCISE HIV OR TO PROTECT T-CELLS, THIS WOULD RESULT IN ENHANCED EASE OF USE FOR CLINICAL APPLICATIONS BECAUSE YOU WOULDN'T HAVE ALL THE EX-VIVO MANIPULATIONS THAT ARE INVOLVED CURRENTLY. AND WE ALSO ENVISION THIS FOSTERING COLLABORATION WITH INVESTIGATORS FROM OTHER FIELDS SUCH AS BIOENGINEERING USING NANOTECHNOLOGY, OR NEW VIRAL VECTORS, AND THEY WOULD BE COLLABORATING WITH GENE THERAPIESED AND VIROLOGISTS TO APPLY TECHNOLOGIES TO HIV. SO WHERE DOES THIS FIT IN AND WITH WHAT THE CURRENT AIDS CURE STUDIES PORTFOLIO IS? WE RUN THE GAMUT BETWEEN BASIC, TRANSLATIONAL AND CLINICAL TRIALS AND WE SEE THIS INITIATIVE AS BASICALLY STRADDLING THE BASIC AND PRE-CLINICAL TRANSLATIONAL RESEARCH. WE ARE NOT SUPPORTING CLINICAL TRIALS USING THIS RFA. THERE IS CURRENTLY A COUPLE OF PROGRAMS IN OUR PORTFOLIO THAT DO ANTI-HIV THERAPIES. WE HAVE THE HEART PROGRAM WHICH ARE U19s WHICH WE MANAGE IN COLLABORATION WITH OUR COLLEAGUES FROM NHLBI AS WELL AS MARTIN DELANEY LABORATORIES BUT THESE INVOLVE EVIVO MANIPULATION AND MODIFICATION OF CELLS. SO WE CAN SEE THESE STRATEGIES BEING BENEFITING FROM AN IN-VIVO TARGETING APPROACH. THERE ARE A FEW INVESTIGATOR INITIATED GRANTS PROPOSING IN VIVO TARGETING BUT THESE GRANTS HAVE THE PROOF-OF-CONCEPT STUDIES CURRENTLY LATE IN THE GRANT PERIOD, BECAUSE THE PRIMARY FOCUS OF THESE GRANTS HAVE BEEN ON THE GENE PAYLOAD ITSELF. THEY HAVE RELATIVELY FEW ANIMALS BECAUSE THEY COME IN SO LATE. THEY LACK SOME OF THESE CRITICAL BIOANALYTICAL STUDIES. WE CAN THANK YOU FOR THEIR TIME AND HELPFUL COMMENTS. THEY BOTH RECOMMENDED APPROVAL FINDING THIS CONCEPT TO BE IMPORTANT TO PURSUE AND ENCOURAGE AND THIS IS A VERY IMPORTANT INITIATIVE AND WELL PUT TOGETHER. THANK YOU. SOME OF THE COMMENTS THEY PROVIDED WAS TO RECOMMEND THAT THE RESEARCH SCOPE MAKES CLEAR THE MULTIPLE APPROACHES ARE ENCOURAGED. I GAVE THE EXAMPLE OF DIRECT TARGETING OF THE LATENTLY IN EFFECTED CELLS FOR EXCISION BUT OTHER APPROACHINGS COULD BE INCLUDING ACTIVATION BY CHRIS PER AND BY OTHER GENE THERAPEUTICS, TARGETING OF IMMUNE CELLS TO RENDER NON INEFFECTIVE. WE AGREE AND EXAMPLES WILL BE PROVIDED IN THE RFA HIGHLIGHTING THE BREATH OF RESPONSIVE GENE THERAPY APPROACH THAT IS INCLUDE BUT ARE NOT RESTRICTED TO THE ONCE ABOVE. THEY ALSO COMMENTED THAT IT WOULD BE IMPORTANT TO ELABORATE WHAT WOULD BE CONSIDERED A SUCCESSFUL THERAPEUTIC APPROACH WITH PRELIMINARY DATA IN HAND. WE WOULD BE DEFINING A SUCCESSFUL THERAPEUTIC APPROACH AS GENE THERAPY STRATEGY THAT HAS SHOWN SOME ANTI--HIV EFFICACY BUT NOT NECESSARILY SPECIFIC TARGETING IN AN IN-VITRO OR EX-VIVO SYSTEM. WE MENTIONED BEFORE HOW WE WANTED TO FOSTER COLLABORATION AND THE REVIEWERS COMMENTED THAT A COLLABORATION BETWEEN A GROUP WITH A NOVEL TARGETING OR DELIVERY METH WITH A GROUP HAS THE WORKING PAYLOAD. WHAT IS THE GENE THERAPY APPROACH? SHOULD BE EN SCOURGED WE AGREE. WE ENVISION A TEAM SCIENCE APPROACH BRINGING TOGETHER VIROLOGISTS AND GENE THEY WERIST AND BIOENGINE EARS AND CHEMISTS FOR THE STUDIES. THIS COMMENT WAS ALSO BROUGHT UP BECAUSE ONE OF THE SCENARIOS THAT COULD HAPPEN IS THAT SOMEONE COULD READ A PAPER ABOUT GENE THERAPY AND KNOCKING OUT CCR5 AND ANOTHER GROUP THAT WOULD HAVE NO EXPERIENCE IN EITHER HIV OR GENE THERAPY WOULD SIMPLY TAKE THAT INFORMATION AND JUST WRITE A GRANT TO SAY WE HAVE A NEW VECTOR. IT WAS NOTED THE RFA DOESN'T SEEM TO REQUIRE ASSAYS OR PROTOCOL THAT IS SHOW THERAPEUTIC EFFECTIVENESS OF THE APPROACH BUT SEEMS TO EMPHASIZE THE NEED FOR ASSAYS AND PROTOCOL THAT IS PROVIDE PROOF OF PRINCIPAL THE APPROACH DOES INDEED TARGET THE VIRUS INFECTED CELLS FOR EXAMPLE OR ANY OF YOUR TARGET CELLS IN-VIVO. THE RFA FOCUS WILL BE ON THE SPECIFICITY OF THE DELIVERY AND TARGETING OF THE THERAPEUTIC PAYLOAD IN THE ANIMAL MODEL. HOWEVER, WE ALSO SEE THAT EXPRESSION AND ACTIVITY, IN OTHER WORDS THE EFFECTIVENESS OF THE THERAPEUTICS WILL BE STUDIED AS PART OF THE ITERATIVE PROCESS AND IMPROVING THE TAR TARGETING OVER TIME T WILL BE A ITERATIVE PROGRESS. WE DON'T ANTICIPATE IT TO BE 100% EFFECTIVE IN THE FIRST ROUND SO THERE WILL BE TIME DURING THE R01, DURING THE 5 YEARS TO GO BACK AND REFINE AND IMPROVE THE STRATEGIES. SO I'D LIKE TO CONCLUDE THAT WE ARE ASKING YOUR APPROVAL FOR THE INITIATIVE FOR TARGETED INCH VIVO DELIVERY OF -- IN-VIVO -- FOR HIV CURE. AND I WOULD BE HAPPY TO TAKE ANY QUESTIONS. >> CARA WILSON: LET'S OPEN THE FLOOR FOR DISCUSSION OF THIS PROPOSAL. >> SO IS YOUR SENSE THAT THERE ARE A LOT OF IDEAS HOW TO ACHIEVE THIS GOAL THAT ARE NOT CURRENTLY BEING FUNDED? OR IS THE GOAL OF THIS TO GET PEOPLE TO THINK ABOUT THIS? BECAUSE IT REALLY SOUNDS LIKE SCIENCE FICTION. >> I JUST CAME BACK FROM THE AMERICAN SOCIETY OF GENE AND CELL THERAPY AND THERE WAS A WHOLE SESSION ON IN-VIVO DELIVERY OF GENE THERAPEUTICS AT THIS STAGE, MOSTLY FOR GENETIC DISEASES OR CANCER. SO, LIKE ANYTHING LIKE WHAT HAPPENED IN STAR TREK, IT SOUNDS& LIKE SCIENCE FICTION BUT THE TECHNOLOGY IS OUT THERE AND IS BEING BROUGHT IN. I'D LIKE TO TAKE THAT AND TRY TO BRING THAT INTO THE HIV FIELD AND THAT IS JUST ONE EXAMPLE WHERE I DON'T SEE THAT AS SCIENCE FICTION. DO I BELIEVE THE FIELD HAS THE TECHNOLOGY AND IT IS JUST GOING TO BE A QUESTION OF HOW TO SUPPORT THAT TO MOVE FORWARD. >> CAN YOU GIVE ME AN EXAMPLE OF AN ADVANCE THAT HAS BEEN MADE? >> I CAN GIVE YOU TWO MAYBE. SO, AS I MENTIONED, ANO ASSOCIATED VIRUS SEEMS TO BE VERY BROAD AND AV TENDS TO BASICALLY GO TO THE LIVER. THERE HAS BEEN IDENTIFICATION OF AAV SEROTYPES THAT ARE NOT LIVER-SPECIFIC AND TEND TO TARGET OTHER CELLS INCLUDING HEMATOPOIETIC STEM CELLS. IN TERMS OF A NO ONE-VIRAL VECTOR DELIVERY SYSTEM, THERE HAS BEEN ADVANCES IN NANOPARTICLES THAT HAS ACTUALLY BEEN ON A MORE BROAD AREA WHERE PEOPLE ENGINEERS HAVE DESIGNED A WHOLE SERIES OF NANOPARTICLES AND LOOKED IN-VIVO USING BARCODING THEM TO SEE WHETHER YOU CAN IDENTIFY A SPECIFIC NANOPARTICLE STRUCTURE THAT WOULD GO TO A TISSUE OR CELL OTHER THAN THAT WOULD BE IMPROVED. >> THIS IS SAY HUGER AREA OF INVESTIGATION BROADLY. I MEAN HUGE, AND IT'S TOUGH AS YOU SUGGEST. I MEAN THE ONLY PLACES THAT HAVE BEEN SUCCESSFULLY TARGETED WITH NANOPARTICLES EITHER HAVE BEEN TOPICAL OR THE LIVER WITH REGARDS TO PROTEIN. SO THAT ONE SEEMS TO BE A BIG WINNER. THAT'S THE LIVER. THESE CELLS ARE GOING TO BE A LOT TOUGHER. THAT DOESN'T MEAN WE SHOULDN'T BE INVESTING IN AN AREA. THIS IS HUGE F IT HITS, IT'S GOING TO BE HUGE. THIS IS NOT FOR THE FATE OF HEART FOR THE PEOPLE WHO WANT A ROI IN THE NEXT FEW YEARS, UNLIKE OUR CURRENT ADMINISTRATION, FOR EXAMPLE. UNDERSTAND. [ LAUGHS ] >> I WON'T COMMENT ON THAT ONE. [ LAUGHS ] I'M ENJOYING IT. GOOD THING I'M FLOTVISIBLE. COULD YOU IMAGINE THAT AWARDS COULD BE MOST RESPONSIVE IF THEY BROUGHT IN AN INVESTIGATOR THAT WAS NEW TO THE HIV FIELD THAT CAME FROM THESE SEMINOLE FIELDS? BECAUSE IF YOU'RE INTENT IS TO BRING THE GROUPS TOGETHER, THAT MIGHT BE SOMETHING TO CONSIDER. >> YES. DEFINITELY. I THINK I MEAN WE -- >> THYME GLAD, PAUL YOU HAVE GOTTEN OVER YOUR SHYNESS. NICE TO SEE. >> YES. >> ANY OTHER R. CARA WILSON: ANY OTHER COMMENTS? WE'LL NEED TO -- >> WE HAD ONE MORE. >> JUST TO CLARIFY. SO THEN IN THE FALL YOU WOULD ACTUALLY SORT OF LIKE IN THE U19, YOU HAVE TO HAVE A CORPORATE PARTNER, YOU WOULD IS STIPULATE THAT THERE HAD TO BE SOMEBODY WHO WAS AN EXPERT IN THIS THAT WOULD ESSENTIALLY -- I'M TRYING TO UNDERSTAND HOW YOU'RE GOING TO MANDATE THAT THIS IS -- >> I DON'T THINK WE WOULD MANDATE. I THINK WE WOULD GIVE AREAS OF EXPERTISE THAT WE WOULD ENVISION TO BE THE MOST -- THE BEST STRATEGY FORWARD AND WE CAN IMAGINE DURING THE REVIEW PROCESS THAT THE REVIEWERS WOULD IDENTIFY THE BEST STRATEGIES THAT WOULD MOVE THAT. SO I DON'T THINK WE WOULD REQUIRE IT. I THINK WE WOULD SAY THIS IS HOW WE CAN SEE THIS APPROACH AND THIS IS THE TYPE OF AS AS WE WOULD NEED. THIS IS THE STRATEGY THAT WE WOULD WANT. >> YOU ARE REALLY TRYING TO PUSH DIVERSE FIELDS TOGETHER AND SO IT WILL TAKE SOME DIRECTION TO GET THAT TO HAPPEN. >> YES. WE WOULD AGREE. >> IT JUST WILL HAVE TO BE SOME TEETH IN IT. >> I THINK IS THERE SAY MIDDLE GROUND BECAUSE THIS IS AN R01. THIS IS THE EARLIEST AND PRELIMINARY. SO IDEALLY SOMEBODY WOULD COME IN AND MAYBE A DUAL PI SITUATION RATHER THAN MANDATING X OR Y. THAT IS THE BEST COLLABORATION. AND I THINK THAT THERE WILL BE ENOUGH INTEREST IN THIS FROM THE THERAPY COMMUNITY THAT THE CREAM WILL RISE TO THE TOP. ABOUT YOUR POINT IS WELL TAKEN. FOR FUTURE, THERE WILL BE A TIME WHEN YOU'RE A LITTLE BIT FURTHER DOWN THE TRANSLATIONAL ROAD TO BE A LITTLE BIT MORE PRESCRIPTIVE. >> CARA WILSON: SO LET'S VOTE ON THIS PROPOSAL. IF YOU GO TO VOTING MATERIALS, OPEN SESSION AND CLICK ON VOTE ON DOCUMENTS, YOU SHOULD FIND THE PROPOSAL THERE. ANYBODY HAVING PROBLEMS ACCESS ING THIS? LET'S MOVE AHEAD WITH THE VOTING. >> VAST MAJORITY HAVE VOTED. >> CARA WILSON: THE NEXT PROPOSAL IS NEXT GENERATION BIOLOGICS FOR SUSTAINED HIV REMISSION. >> HI, MY NAME IS LISA SANDERS AND I'M PRESENTING A NEWS TISHATIVE ENTITLED NEXT-GEN BIOLOGICS FOR SUSTAINED HIV REPREDICTION. THE PURPOSE OF THIS INITIATIVE IS TO DEVELOP TRULY INNOVATIVE BIOLOGICS WITH INTENT TO CONTROL HIV. GRANTS ARE TWO-YEAR R61 FORWARD BY 3-YEAR R33 MECHANISMS. WE EXPECTING TO MAKE BETWEEN 4-6 AWARDS. WE HAVE ALWAYS BEEN INTERESTED IN BIOLOGICS AND IMMUNOTHERAPY BUT OUR INTEREST RECEIVED A BOOST WHEN CANCER IMMUNOTHERAPY WAS NAMED BREAKTHROUGH OF THE YEAR BY SCIENCE MAGAZINE IN 2013. THE YEARLY PUBLICATION, ANTIBODIES TO WATCH FOR AVAILABLE IN PUBMED, DESCRIBES SEVERAL VERY INNOVATIVE ANTIBODIES. FOR EXAMPLE, A PCSK9 INHIBITOR TO TREAT HIGH CHOLESTEROL LEVELS. THIS IS UNDER INVESTIGATION TO TREAT CHRONIC HEADACHES AND FOR ENTIRE DIFFERENT INDICATION, CREPE ES MAB IS BEING DEVELOPED FOR PATIENTS WITH PRODROMAL OR MILD ALZHEIMER'S DISEASE BY TARGETING AMYLOID BETA. ON THIS AND THE NEXT SLIDE CURRENTLY LEADING BIOLOGICS FOR TREATMENT OF HIV INFECTION. DEVELOPED BY -- BIOLOGICS. THE IGG4 ANTIBODY BINDS THE CELLULAR DOMAIN OF THE T-CELL RECEPTOR AND DOESN'T INTERFERE WITH THE IMPORTANT BIOLOGICAL FUNCTIONS OF HIV. IT IS ACTIVE AGAINST MULTIDRUG RESISTANT HIV AND DOES NOT REQUIRE DAILY DOSING. THE BIOLOGICAL LICENSE APPLICATION WAS FILED IN MAY 2017 WITH PRIORITY REVIEW. 140Y IS ALSO A FULLY HUMANIZED IGG4 ISOTYPE ANTIBODY DIRECTED AGAINST CCF5T DOESN'T IN FEATURE WITH THE IMPORTANT FUNCTION OF CCR5 MEDIATING IMMUNE RESPONSES. THE PHASE II B CLINICAL TRIAL HAS BEEN COMPLETED. AS YOU VERY WELL KNOW, WE DO -- A SELECTIVE ANTI-INFLAMMATORY DEVELOPED BY MILLENNIUM PHARMACEUTICALS FOR TREATMENT OF CROHN'S DISEASE AND BINDS TO THE IN TREK RIN ALPHA 4 BETA 7. A ANTIBODY WAS FOUND TO LEAD TO LASTING VIRAL CONTROL IN HIV INFECTED MONKEYS. CURRENTLY A PHASE I TRIAL IS UNDERWAY IN HIV INFECTED PATIENTS. AND ECD4IG WITH A SMALL CCR5 PEPTIDE LEADS TO HIV ENVELOPE GLYCOPROTEIN. IT HAS BEEN SHOWN TO BE EFFECTIVE IN RHESUS MONKEY STUDIES. GMP MANUFACTURING OPTIMIZATION AND PHARMACOKINETICS AND AAV VECTOR DELIVERY AND PROGRESS FOR PREPARATION FOR THE HUMAN STUDIES. IN ADDITION, SOME THERAPEUTIC VACCINES SHOW PROMISE IN CONTROLLING HIV INFECTION. HIV ANTIVIRAL HAVE BEEN HIGHLY EFFECTIVE. THE FOLLOWING SLIDES THE DISADVANTAGES. THEY HAVE ASSOCIATE THE TOXICITIES. HIV REBOUNDS RAPIDLY WHEN THE DRUGS, EXPANDED AND NOT ACTIVE AGAINST LATENT HIV. SO IDEALLY, THE NEWLY PROPOSED BIOLOGICS EXPECTED TO DO BETTER IN ONE OR SEVERAL OF THESE POINTS. IF THEY WOULD INDUCE CONTROL OF HIV REPLICATION AFTER STOP OF TREATMENT, THEY WOULD NOT NEED TO BE GIVEN LIFELONG. AND THE BEST CASE SCENARIO, THEY WOULD SIGNIFICANTLY DECREASE THE LATENT RESERVOIR. AS I MENTIONED EARLIER, THE PURPOSE OF THIS INITIATIVE IS TO DEVELOP NEXT GENERATION TRULY INNOVATIVE BIOLOGICS THAT CAN ACHIEVE POST TREATMENT CONTROL STATUS IN HIV HIV INFECTED PERSONS AND ALTERNATIVE LIFELONG HAART. THE IDEA IS THAT THE PROPOSED DESIGNED BIOLOGICS WILL NEVER EMPLOYED IN THE HIV FIELD BEFORE. IDEALLY THEY SHOULD INCORPORATE OR TAKE INTO ACCOUNT THE NEWEST IMMUNOPHARMACOLOGICAL TECHNOLOGIES AND PLATFORMS. HIV ANTIVIRAL DEVELOPMENT HAS MAINLY BEEN FOCUSED ON SMALL MOLECULE INHIBITORS. INNOVATIVE STRATEGIES FOR BIOLOGICS TO COMPLIMENT OTHER ONGOING EFFORTS. IN ADDITION, TECHNICAL INNOVATIONS THAT BIOLOGICS CONSTANTLY NEED TO BE SURVEYEDERT AND HOW THEY CAN BE BUILT INTO AND IMPROVE HIV CURE STRATEGIES. THE NEXT SLIDE SHOWS THE OBJECT AND I WAS SCOPE. THE PROPOSED INITIATIVES SHOULD PROMOTE RESEARCH INNOVATION AND NOT PRODUCT DEVELOPMENT. THE PROPOSED NEXT GENERATION TRULY INNOVATIVE BIOLOGICS PREFERENTIALLY RATIONALLY DESIGNED TO UNDERSTAND AND EXPLOIT THE MECHANISMS INVOLVED IN HIV CONTROL. AND LISTED HERE ARE SOME EXAMPLES. SUCH AS SYNTHETIC VACCINES LIKE mRNA VACCINES, NEW ANTIBODY DRUG OR ANTIBODY BIOLOGIC CONJUGATES, NEW PEPTIDE INFORMATION SUCH AS PEPTIDES, THERAPEUTIC MANIPULATION OF INNATE IMMUNE CELLS SUCH AS NK AND NKT AND MATE CELLS. RNA THERAPEUTICS AND FINALLY XENONUCLEIC ACIDS. AND ANOTHER OBJECTIVE COULD BE TO DEVELOP ANALYTICAL ASSAYS FOR THE BIOLOGIC TO MEASURE QUANTITY IN THE PLASMA BODY FLUIDS AND TISSUES FOR PHARMACOKINETICS AND PHARMACODYNAMIC STUDIES. THE NEXT OBJECT SIEVE TO TEST NEWLY-DEVELOPED BIOLOGIC IN HIV IN VETE ROSE MODELS FEASIBLE IN ANIMAL MODELS. IN-VITRO STUDIES CAN BE -- IF THEY DO NOT MAKE SENSE FOR THE BIOLOGIC, FOR EXAMPL IF THEY ARE REQUIRED INDUCTION OF IMMUNE RESPONSE AND NOT JUST CELL KILLING. FOR THE IN-VITRO STUDIES, THE USE OF PRIMARY CELLS FROM HAART TREATED PATIENTS IS ENCOURAGED. THE ANIMAL MODELS SHOULD BE PROOF-OF-CONCEPT NOT LARGE-SCALE STUDIES. ALSO, THE INVESTIGATOR SHOULD LOOK FOR OTHER TARGET EFFECTS, ANTIDRUG ANTIBODIES, AUTOIMMUNE ANTIBODIES AND IMMUNE COMPLEX FORMATION. SINCE THIS IS PHASE AWARD, MILESTONES NEED TO BE MET AFTER TWO YEARS FOR FUNDING OF THE GRANT TO CONTINUE. TO DISCUSS THE EXAMPLES LISTED ON THE EARLIER SLIDE, ANTIBODIES MUST BE ENGINEERED TO INDUCE IMMUNE RESPONSES OR CELL KILLING. ANTIBODIES CAN BE ENGINEERED TO ENHANCE ACTIVITIES TO SEE RECEPTOR MODIFICATIONS. NEW ANTIBODY FORMATS INCLUDE HEXABODIES, MINIBODIES, FLEX I BODIES, ANTIBODY DRUG CONJUGATES. ANTIBODY MIMETTICS ACT BIOLOGICALLY BUT DON'T HAVE THE PHYSICAL STRUCTURE OF ANTIBODIES. STABLE PEPTIDES ARE PEPTIDES THAT HAVE A SYNTHETIC BRACE. STABLING IS USED TO ENHANCE FARMS CLOTHIC PERFORMANCE OF PEPTIDES AND INCREASE CELL PENETRATION. ZONEO NUCLEIC ACIDS ARE SYNTHETIC ALTERNATIVES TO THE NATURAL NIKE LICK ASS IDS AS INFORMATION STORING BIOPOLYMERS THAT DIFFER IN THE SUGAR BACKBONE. AS WITH 2011, TYPES OF SYNTHETICS HAVE BEEN SHOWN TO FORM BACKBONES TO RESTORE GENETIC INFORMATION. THE STUDY OF APPLICATION HAS CREATE A FIELD KNOWN AS XENOBIOLOGY. ON THE NEXT SLIDE, ARE AREAS THAT WE DEEM NON RESPONSIVE TO THIS INITIALATIVE. CLASSIC ANTIBODIES WITHOUT MAJOR MODIFICATIONS, ENT BODIES LINKED TO BACTERIAL TOXINS. GENE THERAPIES, A FIELD ON ITS OWN. DEAL FROM ERROR RUNS APPROVED WITHOUT A CLEAR RATIONAL, SMALL IMPROVEMENTS TO EXISTING PRODUCTS USING HIV PREVENTION PRODUCTS SUCH AS PROPHYLACTIC VACCINES WITHOUT MAJOR MODIFICATIONS, PURELY DESCRIPTIVE RESEARCH OR STRUCTURAL STUDIES AND OF COURSE CLINICAL TRIALS. THE PROPOSED INITIATIVE WILL START IN FISCAL YEAR 2019. AND OVERLAP IS THE MARTIN DELANEY COLLABORATORIES WHICH THAT AIM TO MOVE ESTABLISHED CURE STRATEGIES INTO CLINICAL TRIAL. IT ALSO OVERLAPS WITH THE COURT JA FOR INNOVATIVE AIDS RESEARCH THAT SUPPORT PROPHYLACTIC VACCINES AND HAVE A SMALL CURE FOCUS AND ALSO SOLELY SUPPORT NON-HUMAN PRIMATE STUDIES. THE TARGETING PERSISTENT HIV RESERVOIR INITIATIVE EXPIRED IN 2017. THE REVIEWERS FOR THIS INITIATIVE -- WE LIKE TO THANK YOU FOR YOUR COMMENTS. THEY ARE ACCOMMODATION WAS APPROVAL FOR THIS INITIATIVE. THEY REQUESTED REQUIREMENT FOR ASSAY THAT IS MEASURE ANTIDRUG ANTIBODIES AND ALSO IMMUNE ANTIBODIES AND FOR MINIMIZING OF TARGET EFFECTS. AND THIS REQUIREMENT WAS INCLUDED ON OBJECTIVES AND SCOPE. THEY ASK THE BIOLOGIC CAN BE PART OF A KICK AND KILL STRATEGY OR WHETHER IT NEEDS TO INDUCE VIRAL CONTROL ON ITS OWN. AND OUR ANSWER IS, THAT A KICK AND KILL STRATEGY MIGHT BE IMMEDIATE STEP BUT NOT THE ULTIMATE GOAL WHICH IS THAT THE BIOLOGIC INDUCES VIRAL CONTROL ON ITS OWN. THE THIRD QUESTION WAS WHETHER THE BIOLOGIC IS INTENDED TO REPLACE ART, INDUCE VIRAL CONTROL IN THE ABSENCE OF ART OR BE USED AS ADJUNCTIVE THEY WERE. WE SHOULD CLARIFY AS BIOLOGIC ANTIVIRAL DRUGS ARE EXCLUDED FROM THIS INITIATIVE. AND OUR ANSWER IS THAT ADJUNCTIVE THERAPIES ARE NOT THE INTENT OF THIS INITIATIVE AND THE BIOLOGIC IS INTENDED TO INDUCE VIROLOGIC CONTROL FOR HAART FOR AN EXTENDED PERIOD OF TIME. NEXT IT WAS SUGGESTED TO EMPHASIZE NOVELTY AND EXPLORATORY OF WHAT WE ARE LOOKING FOR RATHER THAN TALKING ABOUT PRODUCT DEVELOPMENT. AND PEOPLE MAKE THIS POINT CLEAR WHEN WE WRITE THE FUNDING OPPORTUNITY ANNOUNCEMENT. THE FINAL QUESTION WAS WHETHER THE APPLICANTS ARE REQUIRED TO TEAM UP WITH A COMPANY AND OUR ANSWER IS, THAT DUE TO THE BUDGET LIMITATIONS AND INDUSTRY CONSULTANT MAY BE MORE APPROPRIATE BUT AMENABLE TO SUGGESTIONS IN THIS REGARD. AND THE LAST SLIDE IS THE REPEAT FOR THE BEGINNING SLIDE AND WE ARE ASKING FOR APPROVAL FOR THIS INITIATIVE. THIS CONCLUDES MY PRESENTATION. THANK YOU VERY MUCH FOR YOUR ATTENTION AND I'M HAPPY TO ANSWER YOUR QUESTIONS AND DISCUSS YOUR COMMENTS. >> CARA WILSON: THANK YOU. THIS PROPS SAL NOW OPEN FOR DISCUSSION. >> [ OFF MICROPHONE ] >> THEY DID A GREAT JOB OF ANSWERING OUR QUESTIONS AND SO I'M VERY HAPPY WITH THE PROPOSAL >> BETTY POON: THANK YOU. >> CARA WILSON: ALL RIGHT. IF THERE ARE NO OTHER QUESTIONS -- DID YOU HAVE ANYTHING ELSE? NO? LET'S GO AHEAD AND VOTE. CARA WILSON: LET'S MOVE TO THE THIRD PROPOSAL AND THEN WE'LL TAKE A BRIEF BREAK. AND THIS IS THE NIH AIDS REAGENT PROGRAM AND A LAWRENCE LAWRENCE WILL PRESENT. >> DIANE LAWRENCE: GOOD AFTERNOON AND THANK YOU VERY MUCH. MY NAME IS A LAWRENCE LAWRENCE A PROGRAM OFFICER IN THE BASIC SCIENCES PROGRAM AND THE INITIATIVE CONCEPT THAT I'LL BE PRESENTING IS THE CONTINUATION OF THE NIH AIDS REAMOUNT PROGRAM. THE PURPOSE OF THIS INITIATIVE IS TO PROVIDE ACCESS TO HIGH-QUALITY, STANDARDIZED BIOLOGICAL AND CHEMICAL REAGENTS THAT ARE DIFFICULT TO OBTAIN AND ESSENTIAL FOR HIV/AIDS RESEARCH. THIS INITIATIVE WOULD INVOLVE A CONTRACT MECHANISM THAT IS RENEWAL OF THE CURRENT PROGRAM AND THE DURATION OF THE AWARD WOULD BE A MAXIMUM OF 7 YEARS. WE ANTICIPATE ONE AWARD. THIS PROGRAM SERVES AS A REPOSITORY FOR A BROAD RANGE OF UNIQUE QUALITY ASSURED REAGENT THAT ARE MADE AVAILABLE FREE OF CHARGE FOR THE GLOBAL HIV/AIDS RESEARCH COMMUNITY. IT PROVIDES ECONOMY OF SCALE THAT ALLOWS THE GOVERNMENT PURCHASE OR PRODUCE LARGE QUANTITIES OF REAGENTS FOR A REDUCED PRICE. AND IT FACILITATES RESOURCE SHARING BY NIH GRANT SPEC INTRAMURAL INVESTIGATORS BY ALLEVIATING THE BUSHED EN OF REAGENT DISTRIBUTION BY INDIVIDUAL LABORATORIES. THE PROGRAM IN THE THIRDYth YEAR OF PRACTICE OPERATION AND MORE THAN 9000 PUBLICATIONS ACKNOWLEDGE THE PROGRAM OF A SOURCE OF RESEARCH MATERIALS. LIKE THE CURRENT CONTRACT, THE SCOPE OF THE PROPOSED NEW CONTRACT WOULD BE TO ACQUIRE, MAINTAIN, PRODUCE, EXPAND AND DISTRIBUTE STATE-OF-THE-ART STANDARDIZED REAGENTS FOR HIV/AIDS RELATED RESEARCH TO QUALIFIED INVESTIGATORS -- [ READING ] IN THE NEXT FEW SLIDES ACCIDENT I WILL SHOW DATA FROM THE CURRENT PROGRAM THAT I HOPE WILL DEMONSTRATE CONTINUED NEED FOR THIS PROGRAM. CURRENTLY THERE ARE NEARLY 2600 UNIQUE REAGENTS AVAILABLE TO REGISTERED USERS. AND THIS GRAPH SHOWS THE DISTRIBUTION OF THE TYPES OF REAGENTS THAT ARE AVAILABLE. THE MOST PROMINENT IS IN DNA CATEGORY. AND THE WIDE VARIETY OF UNIQUE REAGENTS AND STANDARDS THAT ARE AVAILABLE IS CONSIDERED A MAJOR BENEFIT TO RESEARCHERS. THE GRAPH ON THIS SLIDE SHOWS THE ACCUMULATIVE NUMBER OF REGISTERED USERS AND YOU CAN SEE THERE HAS BEEN A STEADY INCREASE OVER THE PAST DECADE. THE MAJORITY OF REGISTRANTS ARE ACADEMIC RESEARCHERS FROM THE UNITED STATES. THIS SLIDE SHOWS SHIPMENT INFORMATION FOR THE PROJECT YEAR SPANNING JULY 2015 TO JULY 2016. THE PROGRAM MADE AROUND 2300 SHIPMENTS DURING THAT YEAR FULFILLING REQUESTS FROM MORE THAN 1000 LABORATORIES IN THE UNITED STATES AND INTERNATIONALLY. OF THE NEARLY 2000 FILES SHIPPED, THERE WERE MORE THAN 1400 UNIQUE REAGENTS ORDERED AND THE MOST POPULAR OF THESE ORDERS WERE FOR ANTIBODIES AND DNA AND THE TOP 20 REAGENTS ORDERED ARE SHOWN IN THE TABLE ON THE RIGHT. IN AN EFFORT TO STAY RESPONSIVE AND VALUABLE TO THE RESEARCH COMMUNITY, THE PROGRAM TYPICALLY ADDS BETWEEN 100 AND 200 NEW REAGENTS EACH YEAR. AND I JUST WANT TO POINT OUT THE DIP IN THE MIDDLE, 2011 YEAR, THIS WAS AN UNUSUALLY LOW NUMBER OF ACQUISITION THAT IS YEAR DUE TO THE TRANSITION. THIS WAS THE YEAR OF THE RECOMPETITION FOR THE MOST RECENT CYCLE OF THE CONTRACT. SO YOU CAN SEE WE ANTICIPATED THIS SLOW DOWN BY INCREASING THE ACQUISITIONS FOR THE PREVIOUS YEAR IN 2010. SOME EXAMPLES OF REAGENTS THAT WE RECENTLY ADDED OR ARE IN THE PROCESS OF ADDING TO THE REPOSITORY INCLUDE THE N6 AND NEUTRALIZING ANTIBODIES. SUBTYPE C INFECTIOUS CLONES AND ANTI-CD2 ANTIBODIES. SIV INFECTED 3D8 CELL LINE. THE PROGRAM HAS UNDERGONE SEVERAL IMPROVEMENTS SUCH AS RECYCLING AND REUSE OF SHIPPING CONTAINERS AND OTHER GREEN INITIATIVES. PROCESS IMPROVEMENTS TO REDUCE THE TURN AROUND TIME FOR ORDER PROCESSING AND SHIPMENT AND REDUCING BACK ORDERS BY IDENTIFYING REAGENTS THAT TAKE LONGER TO REPLENISH OR BEING DEPLETED QUICKLY. USING BARCODING AND RFID TECHNOLOGY TO IMPROVE INVENTORY TRACKING, DATA FILE MANAGEMENT OF REGISTRANTS, REAGENTS AND WILL DONATIONS AND SO DIGITAL FILE MANAGEMENT AND EXPANDING QUALITY CONTROL EFFORTS SUCH AS VERIFYING DEDNA SEQUENCES AND CONFIRMING WOULD EXPRESSION IN CELL LINES. SOME IMPROVEMENTS THAT WE ARE CONSIDERING FOR THE NEAR FUTURE AS WELL AS FOR THE NEXT FUNDING CYCLE INCLUDES ENHANCING THE WEBSITE AND CALL LOG SEARCH FUNCTIONS. -- - CATALOG -- TO DRIVE INVENTORY DECISIONS WE WOULD LIKE TO DEVELOP A NEEDS ASSESSMENT SURVEY FOR REGISTERED USERS AND WE PLAN TO EXPLORE OPTION TOES ACCORD NADE THE PROGRAM'S ACTIVITIES WITH OTHER SIMILAR PROGRAMS. I'D LIKE TO THANK THE REVIEWERS FOR COMMENTS AND DISCUSSION. BOTH REVIEWERS RECOMMENDED APPROVAL FOR THIS CONCEPT AND THEY BOTH FELT THAT THE CURRENT REAGENT PROGRAM IS A VALUABLE RESOURCE FOR BASIC HIV/AIDS RESEARCHERS IN THE U.S. AND INTERNATIONALLY. THEY RECOMMENDED THAT THE PROGRAM SHOULD MAINTAIN ITS ROLE AS A REPOSITORY OF RARELY-USED UNIQUE REAGENTS SUCH AS DNA COLLEGES AS WELL AS A LOW-COST SUPPLIER OF EXPENSIVE POPULAR REAGENTS SUCH AS ANTIBODIES. AND HERE I HAVE SHOWN SOME OF THE MAJOR POINTS THAT CAME UP IN OUR DISCUSSION. FIRST, THEY WANTED TO KNOW HOW THE NUMBERS OF REQUESTS HAVE CHANGED OVER TIME AND I DID GET THE DATA ON THIS AND OVER THE PAST 10 YEARS, THE NUMBER OF SHIPMENTS AND NUMBER OF FILES SHIPPED HAS BEEN RELATIVELY STABLE. SECOND POINT THE COST OF THE CURRENT PROGRAM SEEMS RATHER HIGH AND WITH THE RENEWAL, WE WILL BE EXPLORING WAYS TO REDUCE COSTS. BUT WHAT WE FOUND IS THE COSTS FOR THIS PROGRAM ARE CONSISTENT WITH OR LOWER THAN COMPARABLE REPOSITORIES THAN OTHER RESEARCH AREAS. CAN SOME NON-HIV REAGENTS BE TRANSFERRED TO OTHER REPOSITORIES TO SAVE COSTS? AND THE ANSWER IS YES, WE ARE LOOKING AT POTENTIAL TRANSFER OF ITEMS THAT ARE NO LONGER USEFUL TO THE HIV RESEARCHERS TO OTHER REPOSITORIES THAT MAY BE MORE APPROPRIATE SUCH AS THE BEI RESOURCES REPOSITORY. AND FINALLY, ARE THERE WAYS TO ENCOURAGE SUGGESTIONS FROM THE RESEARCH COMMUNITY TO HELP DRIVE DECISIONS ABOUT THE INVENTORY? AND THE ANSWER IS YES, THIS IS SOMETHING WE WOULD LIKE TO FACILITATE AND WILL BE A PART OF OUR PLANNED NEEDS ASSESSMENT SURVEY. SO WITH THAT, I SEEK YOUR APPROVAL FOR THE RENEWAL OF THE AIDS REAGENT PROGRAM AND I'M HAPPY TO ANSWER ANY QUESTIONS. >> CARA WILSON: THANK YOU. SO THIS PROPOSAL IS OPEN FOR DISCUSSION. ANYONE HAVE COMMENTS? NOTHING IN THE REVIEWERS? LET'S VOTE. OKAY, WE'LL TAKE A BREAK NOW. 10 MINUTE BREAK. COME BACK RIGHT AROUND 3:00. AND START BACK UP. THANK YOU CONTRIBUTIONS OF OUR LATE COLLEAGUE, DR. MARK WAYNEBURG, WHO WE TRAGICALLY LOST RECENTLY. HE SPENT A SIGNIFCANT AMOUNT OF HIS LATTER CAREER FOCUSING ON HIV DRUG RESISTANCE. HE WAS AN OUTSTANDINGS SCIENTIST AND AN HIV ACTIVIST WHO IS COMMITTED TO MAKING SURE THAT PEOPLE HAD ACCESS TO TREATMENT WHEREVER THEY WERE. SO MAY HE LEFT PEACE. SO, WHAT WE WANT TO DO IN THIS PARTICULAR STUDY, IS TO EVALUATE THE IMPACT OF HIV DRUG RESISTANCE ON TREATMENT SUCCESS. AND THAT'S A VERY BROAD AREA BUT WE BROKEN IT DOWN INTO -- I THOUGHT I HEARD SOMEBODY ELSE. WE HAVE BROKEN IT DOYNE INTO THREE MAJOR CATEGORIES THAT WE WANT TO FOCUS ON. FIRST WE WANT TO BETTER UNDERSTAND GENOTYPE-PHENOTYPE OUTCOME CORRELATIONS, PARTICULARLY IN NON B SUB TYPE AND I'LL EXPLAIN WHAT WE MEAN BY THAT. I THINK WE ARE ALL FAMILIAR WITH INNOVATIONS AND DIAGNOSTICS WHICH HELP US DETECT MUTATIONS IN MINORITY VARIANTS, OFTENTIMES LESS THAN 1% OF THE TOTAL VIRAL POPULATIONS. SO WE ARE INTERESTED IN UNDERSTANDING WHAT IS THE EFFECT OF DETECTIVESSING THESE MUTATIONS AT SUCH A LOW FREQUENCY. AND THEN WE ALSO WANT TO UNDERSTAND INTERESTING PHENOMENONS WHERE SOME DRUGS MAINTAIN ACTIVITY IN THE ABSENCE OF GENOTYPIC RESISTANCE MUTATIONS AND ON THE OPPOSITE SIDE, WHY SOME DRUGS FAIL -- I'M SORRY. SOME DRUGS MAINTAIN CLINICAL ACTIVITY IN SPITE OF HAVING RESISTANCE AND ON THE FLIP SIDE, SOME DRUGS FAIL IN THE ABSENCE OF HAVING RESISTANCE. SO WE HAVE TWO MECHANISMS. R01, R21, MECHANISM, ESTIMATED 2.4 MILLION AND WE ARE ANTICIPATING 4-5 AWARDS. SO WHAT IS THE PROBLEM? THE GOOD NEWS IS THAT WE HAVE EXPANDED ANTI-RETT ROSE VIRAL DRUG COVERAGE RATHER SIGNIFICANTLY, PARTICULARLY IN RESOURCE-LIMITED SETTINGS. BUT AS A RESULT, BOTH ACQUIRED AND TRANSMITTED RESISTANCE HAS INCREASED. AND WORLD HEALTH ORGANIZATION IS ESTIMATING THAT THIS CONTINUED TREND COULD JEOPARDIZE THE 90-90-90 INITIATIVE THEY PROPOSED. THE W.H.O. ALSO ESTIMATES IF WE REACH PRE-THERAPY DRUG RESISTANCE GREATER THAN 10% IN SIGNIFICANT POPULATIONS, THAT THERE COULD BE SOME SERIOUS CONSEQUENCES. AND SOME OF THOSE CONSEQUENCES WOULD BE INCREASED NUMBERS OF DEATHS. WE KNOW TREATMENT IS PREVENTION. SO A SIGNIFICANT NUMBER OF NEW INFECTIONS, AND ALSO THE COST OF ANTI-RETROVIRAL THERAPY WOULD INCREASE. SO HOW DO WE RESPONDS TO THIS? A LITTLE MORE THAN A YEAR AGO, WE HOSTED A CONSULTATION WHERE WE BROUGHT CLINICIANS, VIROLOGISTS AND EPIDEMIOLOGISTS TO, NIAID TO DISCUSS THIS ISSUE OF DRUG RESISTANCE AND BY THE WAY, THIS CONSULTATION HAS BEEN PUBLISHED. AND THESE ARE SOME OF THE GAP THAT IS WE IDENTIFIED. AND THESE GAPS ARE THE SAME ONES THAT WE FOCUSED THE PURPOSE ON AND WE SAW IN THE PREVIOUS SLIDE. SO AGAIN, WE WANT TO UNDERSTAND THE RELATIONSHIP BETWEEN MUTATIONS AND ALSO POLYMORPHISMS. HOW THIS EFFECTS ANTI-RETROVIRAL DRUG SENSITIVITY AND ULTIMATELY HOW THAT TRANSLATES INTO VIROLOGIC RESPONSE, IN OTHER WORDS GENOTYPE, PHENOTYPE AND OUTCOME CORRELATIONS. AND WE ARE PARTICULARLY INTERESTED IN NON B SUBTYPES BECAUSE THEY ARE THE MAJORITY OF SUBTYPES GLOBALLY. AGAIN, WE WANT TO UNDERSTAND THE RELEVANCE OF THESE MINORITY VARIANTS. DO THEY PREDICT TREATMENT FAILURE OR TREATMENT SUCCESS? AND THEN, UNDERSTANDING AS WE MENTIONED, WHY SOME DRUGS RETAIN ACTIVITY EVEN WHEN THE GENOTYPE SAYS THAT THERE SHOULDN'T BE ACTIVITY AND OF COURSE THE OPPOSITE SITUATION AS WELL. AND SO ANOTHER RESPONSE TO THIS SITUATION WITH RESISTANCE, WAS THE DEVELOPMENT OF THIS SOLICITATION. AND AGAIN, OUR GOALS ARE OPTIMIZING TREATMENT RESPONSES. WE WANT TO ENHANCE EFFICACY OF TREATMENT AS PREVENTION AND REDUCE THE INCIDENCE OF HIV INFECTIONS. SO LET'S LOOK AT SOME OF THE STUDIES THAT ARE HELPING US GUIDE THIS INITIATIVE. SO, IF YOU LOOK AT THE TIME SINCE THE ROLL OUT OF MANY OF THE ANTI-RETROVIRAL DRUG TREATMENT PROGRAMS, PARTICULARLY IN RESOURCE-LIMITED SETTINGS, NOT SURPRISINGLY, YOU SEE AN INCREASE IN RESISTANCE BOTH ACQUIRED AND PRE-TREATMENT RESISTANCE. THESE DATA ARE FROM EAST AFRICA WHERE THIS EFFECT IS MOST PROFOUND BUT YOU CAN ACTUALLY SEE IS THIS TREND PRACTICALLY IN ANY REGION THAT YOU LOOK AT EVEN IN SOME OF THE RESOURCE-RICH SETTINGS. NOW, WE HAVE SOME GOOD DATA THAT SHOWS ANTI-RETROVIRAL DRUGS BIND TO THE DIFFERENT HIV SUBTYPES WITH DIFFERENT AFFINITIES. AND THAT MAY PARTIALLY EXPLAIN WHY WE SEE THIS PHENOMENON WHERE THE DRUG RESISTANCE MUTATIONS OCCUR AT DIFFERENT FREQUENCIES ACROSS DIFFERENT SUBTYPES. SO IN THIS PARTICULAR STUDY, THEY ARE FOCUSING ON NUCLEOSIDE ANALOGUES AND THEY HAVE GROUPED ALL THE Bs TOGETHER AND ALL NON-B SUBTYPES ARE INCLUDED IN ONE GROUP. AS AN EXAMPLE, IF YOU LOOK AT THE THYMA DEAN AMIA LOG MUTATIONS, YOU CAN SEE THAT THEY ARE ALMOST DOUBLE THE PERCENTAGE OF TAMS IN B SUBTYPES AS WHAT WE SEE IS IN THE NON B SUBTYPES COLLECTIVELY. ANDYOU CAN SEE FOR MANY OF THE THESE OTHER MUTATIONS, SIMILAR DIFFERENCES, MANY OF THEM STATISTICALLY SIGNIFICANT, M ONE 84V FROM EXPOSURE AND ALSO STATISTICALLY SIGNIFICANT IN A COUPLE OF OTHERS. AND YOU CAN SEE THIS SAME TREND WHEN YOU LOOK AT OTHER CLASSES OF ANTI-RETROVIRAL DRUGS LIKE PROTEASE INHIBITORS AND NON NUKES AS WELL. NOW, ALL MUTATIONS ARE NOT CREATED EQUAL. AND SO, A PARTICULAR MUTATION OR A PATTERN OF MUTATIONS CAN HAVE A DIFFERENT IMPACT ON DRUG SUSCEPTIBILITY NEDIFFERENT SUBTYPES. AND SO THIS IS ACTUALLY SOME WORK FROM MARK WAYNEBURG'S LAB AND IN THIS PARTICULAR EXPERIMENT, THEY ARE LOOKING AT INTERGRACE INHIBITOR RESISTANCE AND THE FIRST HALF OF THE SLIDE IS LOOKING AT DATA IN SUBTYPE B, VIRUSES. AND THE LEFT OR I'M SORRY, THE RIGHT SIDE, IS LOOKING AT SUBTYPE C VIRUSES. AND WHAT YOU CAN SEE PARTICULARLY IN THIS CASE, THIS COMBINATION MUTATION AT 92 AND AT 155, PRODUCES 100-FOLD REDUCTION IN SENSITIVITY. AND SUBTYPE B VIRUS. BUT WHEN YOU LOOK AT THIS SAME COMBINATION IN SUBTYPE C, IT'S LESS THAN PROBABLY 5-FOLD REDUCTION. SO IT COULD POTENTIALLY HAVE MORE ADDITIONAL ACTIVITY OR PARTIAL ACTIVITY. AND YOU SEE THE SAME THING FOREL VI TAG VEER WITH THE SAME COMBINATION OF MUTATIONS AND FURTHERMORE, EVEN THE SINGLE MUTATIONS, THERE ARE DIFFERENCES IN THE EFFECT THAT THEY HAVE. SO THIS IS A BIG DEAL BECAUSE IN RESOURCE-LIMITED SETTINGS, WE DON'T HAVE THE LUXURY OF THROWING DRUGS THOUGHT MAY HAVE RESIDUAL ACTIVITY. -- THROWING DRUGS OUT THAT MAY HAVE RESIDUAL ACTIVITY. WE TALKED ABOUT A PHENOMENON WHERE DRUGS MAINTAIN ACTIVITY EVEN IN THE PRESENCE OF DRUG RESISTANCE MUTATIONS. SO THIS IS A STUDY. AND IT IS SHOWING A LINEAR RELATIONSHIP WHEN YOU DO A LOG LOG PLOT LOOKING AT THE CORRELATION BETWEEN GENOTYPE AND PHENOTYPE. ON THE Y AXIS, WE ARE LOOKING AT THE GENOTYPIC SENSITIVITY SCALE. USING DATA FROM THE STANFORD DATABASE. AND OF COURSE AS YOU GO FURTHER TO THE RIGHT AND GET HIGHER UP, YOU HAVE MORE RESISTANCE MUTATIONS AND MORE RESISTANCE. FOR PHENOTYPE, WE START HERE AT ONE, WHICH MEANS THE DRUG HAS FULL ACTIVITY AND AS WE INCREASE, OR GO HIGHER, THE DRUG LOSES ACTIVITY. THIS IS FOLD REDUCTION. IF WE GO LESS THAN ONE, THE DRUG IS ACTUALLY HYPERSENSITIVE. AND SO THESE ARE DATA THAT SHOWS YOU THAT THIS GROUP OF VIRUSES HERE THAT EVEN THOUGH THEY HAVE INTERMEDIATE AND HIGH-LEVEL MUTATION PATTERNS, THEY MAINTAIN FULL SUSCEPTIBILITY AND IN SOME INSTANCES, BEING FURTHER DOWN HERE, THEY ARE ACTUALLY HYPERSUSCEPTIBLE. SO, WHY DOES THIS HAPPEN? WHAT ARE THE EXPLANATIONS? THESE ARE IN SUBTYPE C VIRUSES AND THIS IS A PHENOMENON WE MAY NOT SEE IN SUBTYPE B VIRUSES. SHIFTING GEARS TO TALK ABOUT MINORITY VARIANTS. SO THESE ARE SOME DATA THAT WERE PRESENTED AT CROIX THIS YEAR. AND WORKING IN SOUTH AFRICA, THIS IS THE TASK STUDY, TREATMENT AS PREVENTION, A TRIAL GOING ON IN SOUTHERN AFRICA. SO, WE ARE LOOKING AT THE LEFT PANEL. THEY ARE COMPARING PRE-TREATMENT RESISTANCE BEING DETECTED USING NEXT GENERATION SEQUENCING, WHICH CAN DETECT MUTATIONS IN THE AS LOW AS 22% OF THE TOTAL VIRAL POPULATION COMPARED WITH THE STANDARD SANGER SEQUENCING WHICH CAN ONLY DETECT MUTATIONS ABOUT 20% OF THE POPULATION. AND WHAT CAN YOU SEE IN ALL OF THESE CASES, IN THE GREEN BARS, THE NEXT GENERATION SEQUENCING, DETECTIVES TWICE AS MANY MUTATIONS IN THESE INDIVIDUALS AS THE STARRED SANGER SEQUENCING. WHEN WE LOOK IN THE RIGHT PANEL AND LOOK AT THE RATES OF VEER LODGE IDENTICAL SUPPRESSION FOR PATIENTS POUT THEY WEREY, THE CURVES ARE TOTALLY SUPER IMPOSABLE. THERE IS NO DIFFERENCE FROM MINORITY VARIANTS OR THROUGH THE STANDARD METHOD. AND THIS IS INTERESTING. IT COULD BE A RESULT OF THE REGIMEN THAT MOST OF THESE PATIENTS WERE ON. BUT IN THIS PARTICULAR STUDY, WE SEE A DIFFERENT PATTERN. SO, THEY LOOKED AT THE PRESENCE OF MINORITY VARIANCE AT BASELINE AND IN THIS DODGITUDEINAL STUDY, LOOK AT THE TOP CURVE -- LONGITUDINAL STUDY. THESE ARE INDIVIDUALS WHO REMAIN SUPPRESSED OVER TIME. IT GRADUALLY DECLINES AS WE OFTEN SEE. WHEN THERE ARE NO MINORITY VARIANTS DETECTED AT BASELINE. HOWEVER, THE RED CURVE WHICH SHOWS THE TRAJECTORY WHEN THERE ARE MINORITY VARIANTS DETECTED, YOU SEE THAT THESE TWO CURVES DIVERGE RATHER EARLY AS WE TRACK THESE INDIVIDUALS AND THE DIFFERENCES ARE HIGHLY SIGNIFICANT. SO WHY DO WE SEE THESE TWO DIFFERENCES IN THIS PARTICULAR STUDY VERSUS THE PREVIOUS STUDY? WE NEED TO CONSIDER REGIMENT EFFECT. IS IT EFFECT OF CERTAIN TYPES OF MUTATIONS OR PARTICULAR MUTATIONS? IS IT A SUBTYPE ISSUE? AND THERE ARE A VARIETY OF OTHER QUESTIONS LISTED ON HERE WE NEED TO CONSIDER. SO THE SCOPE OF RESEARCH. WHAT ARE WE INTERESTINGED IN? STUDIES USING SPECIMENS FROM WELL CHARACTERIZED CLINICAL COHORTS BECAUSE WE CAN DO ANALYSIS IN THE SAMPLES AND CORRELATE THAT TO WHAT WE SEE CLINICALLY. STUDIES OF GENOTYPE, PHENOTYPE, VEER LOGIC OUTIMMEDIATE CORRELATIONS PARTICULARLY IN NON B SUBTYPES. STUDIES ON THE CONTRIBUTIONS OF MINORITY VARIANTS TO TREATMENT OUTCOMES. AND STUDIES TRYING TO UNDERSTAND THE BIOLOGICAL BASIS FOR TREATMENT SUCCESS AND SETTINGS WHERE THERE IS THE OCCURRENCE OF RESISTANCE AND THEN OF COURSE THE OPPOSITE SITUATION. THIS INITIATIVE WILL NOT SUPPORT CLINICAL TRIALS. HOWEVER, IF INVESTIGATORS HAVE COLLECTED ARE CAVED SAMPLES FROM AIKIN CALL TRIAL, THAT WOULD BE ACCEPTABLE -- ARCHIVED -- SURVEYS OF RESISTANCE, W.H.O. PROMOTES THAT COUNTRIES DO SURVEYS AND CLINICS AND DIFFERENT AREAS. RESISTANCE TO OTHER BIOLOGICS WILL NOT BE ADDRESSED IN THIS INITIATIVE. STUDIES PRIMARILY FOCUSED ON ADHERENCE AND ALSO COST EFFECTIVENESS STUDIES. WE WOULD LIKE TO THANK DR. SALLY HODDER AND DR. WILLIAM POWDERLY FOR THEIR TIME IN REVIEWING OUR CONCEPT AND ALSO THE INSTRUCTIVE FEEDBACK THAT THEY PROVIDED US SO THE REVIEWERS AGREED THAT THE FOCUS SHOULD BE ON SUBTYPES ON THE NON B SUBTYPES BUT THEY POINT OUT THAT IF STUDIES INCLUDE SUBTYPE B IN ADDITION TO SOME OF THESE OTHER SUBTYPES, THESE CAN BE HIGHLY INFORMATIVELY FOR MAKING GOOD COMPAREONS AND WE TOTALLY AGREE WITH THAT. REVIEWERS ACKNOWLEDGE THE LEADING CAUSE FOR FAILURE IN THE ABSENCE OF GENOTYPIC RESISTANCE IS POOR ADHERENCE. SO, IF THEY ARE GOING TO INVESTIGATE BIOLOGICAL MECHANISMS FOR THIS PARTICULAR PHENOMENON, THEY SHOULD HAVE VERY GOOD DATA TO SUPPORT ADHERENCE, FOR EXAMPLE, PLASMA DRUG CONCENTRATIONS OR OTHER PLEASURES OF ADHERENCE. IF THEY HAVE OTHER PHARMACOKINETIC DATA TO HELP US UNDERSTAND WHY SOME DRUGS MAY MAINTAIN ACTIVITY EVEN IN THE PRESENCE OF GENOTYPIC RESISTANCE AND ONE OF THE REVIEWERS FASCINATED BY THE DATE AT WE JUST SAW AND POSED A QUESTION, CAN WE IDENTIFY REGIMENS THAT ARE GOING TO HAVE ACTIVITY IRRESPECTIVE OF WHETHER THERE IS PRETREATMENT RESISTANCE OR NOT? BECAUSE USING THESE MORE RIGOROUS REGIMENS MAY ELIMINATE THE NEED FOR BASELINE RESISTANCE TESTING WHICH IS OFTEN NOT DONE IN RESOURCE-LIMITED SETTINGS. SO IN GENERAL, WE SEE A FRAMEWORK WHERE THERE ARE MULTIPLE INPUTS AND THESE INPUTS INCLUDE THE DRUG REGIMEN, THE WHOLE GENOMICS INCLUDING THE MUTATION PATTERNS, AND SUBTYPES AND PHARMACOKINETICS AND ADHERENCE COMING TOGETHER TO DETERMINE THE VEER LOGIC RESPONSE AND THE EFFICACY OF THE TREATMENT AND I THANK YOU FOR YOUR TIME AND WILL BE HAPPY TO ADDRESS ANY QUESTIONS. >> CARA WILSON: THANK YOU. THIS IS NOW OPEN FOR DISCUSSION. GO AHEAD. >> THANK YOU. I JUST HAD A QUICK POINT OF CLARIFICATION BECAUSE YOU MENTIONED THE CHANGING TECHNOLOGY FROM SANGER TO NEXT GENERATION SEQUENCING. SO IS NEXT GENERATION SEQUENCING GOING TO BE A REQUIREMENT SEEING AS HOW THE DATA YOU SHOWN US SHOW THAT IT IS MORE SENSITIVE AND DETECTIVESSING THESE MUTATIONS IN. >> THAT WILL DEPEND ON WHAT THE INVESTIGATORS WILL PROPOSE. SO IF THEY ARE GOING TO FOCUS ON THE ROLE OF MINORITY VARIANTS, THEY WILL NEED TO HAVE ONE OF THE ACCEPTED METHODS TO LOOK AT NEXT GENERATION SEQUENCING AND COMPARE THAT WITH THE STANDARD SANGER SEQUENCING. >> NELSON? I'M SORRY. YOU PICK. >> [ OFF MIC ] I MAY HAVE MISSED IT, BUT WILL YOU EMPHASIZE ISSUES ABOUT VIRAL FITNESS AND HOW TO MEASURE THAT BEST? PERHAPS IN THE CONTEXT OF THE WHOLE VIRAL GENOME WHERE THERE MAY BE COMPENSATORY MUTATIONS AND DIFFERENT GENES AND SO FORTH? >> YES, SO THAT CONCEPT OF VIRAL FITNESS BECOMES IMPORTANT WHEN YOU SEE DRUGS THAT MAY HAVE ACTIVITY EVEN IF THERE IS RESISTANCE, FOR EXAMPLE YOU PROBABLY THINK OF M184V MUTATION WHICH CRIPPLES THE VIRUS AND THERE ARE A WHOLE HOST OF OTHER TYPES OF MUTATIONS THAT HAVE BEEN IDENTIFIED. SO IF SOMEONE PROPOSED THAT AND HAD A GOOD MEASURE OF VIRAL FITNESS, THAT IS SOMETHING THAT COULD CERTAINLY BE CONSIDERED. >> JOHN AND I WERE SEPARATED AT BIRTH, STILLBIRTHS. SO THE THREE THINGS -- STILL BROTHERS. PAY ATTENTION TO THE REAL VIRALLOLOGY AND RECOGNIZE THE HOST GENOME GETS A VOST TOO. AND THE POPULATIONS WHERE THESE NON SUBTYPE B VIRUSES REPLICATE AND HAVE SIGNIFICANT DIFFERENCES WHERE THE MOST WORK WAS DONE AND LASTLY I THINK YOU'LL DIG HARD TO FIND THE RIGHT COHORTS. ESPECIALLY IF YOU'RE LOOKING AT NON SUBTYPE B COHORTS, ONLY A HANDFUL OF PEOPLE WHO HAVE ACCESS AND JUST THINKING ABOUT IT FOR A WHILE, JUST ASKING MAUREEN ABOUT WHO THE PET FAR DEPUTY PRINCIPAL FOR NIH WAS. I THINK THAT IS REALLY WHERE YOU GET POTENTIALLY RICH SOURCE OF MATERIAL. I THINK THERE IS A LOT OF WAYS TO THINK THROUGH THIS AS A VIROLOGIST BUT TO GET AHOLD OF THE SPECIMENS, WE HAVE FOLLOW-UP, CLINICAL DATA, YOU HAVE REAL INFORMATION ON THE PHENOTYPE, WHICH IS CLINICAL FAILURE, AND I THINK THAT WILL BE A HEAVY LIFTED AND I JUST I THINK THIS INITIATIVE MAKES A LOT OF SENSE BUT WE WANT TO MAKE SURE THE RIGHT KIND OF PEOPLE IN OUR TRIBE UNDERSTAND THIS MECHANISM IS SOMETHING THAT IS ON THE STREET. BECAUSE IF YOU GIVE ACCESS TO THOSE KINDS OF COHORTS, I THINK YOU COULD REALLY GO TO TOWN ON THIS. >> THANK YOU, NELSON. >> CARA WILSON: LET'S VOTE, PLEASE ON THIS PROPOSAL. LET'S MOVE ON TO THE DISCUSSION OR PRESENTATION OF THE VIROLOGY QUALITY ASSURANCE PROGRAM. >> JOE FITZGIBBON: I'M GOING TO PRESENT THE NIAID VIROLOGY QUALITY ASSURANCE PROGRAM, THE VQA. SO THE VQA SERVES A CRITICAL& FUNCTION IN PROVIDING QUALITY ASSURANCE AND STANDARDIZATION OF VIRAL ASSAYS. THAT ARE PERFORMED ACROSS OUR CLINICAL SITES. AND THAT ALLOWS THE DATA TO BE COMBINED FOR GENERALIZE INTERPRETATION AND WIDE APPLICABILITY OF THE FINDINGS. SO, THE MECHANISM FOR THIS IS A CONTRACT N01, SO NO GSI POINTS. THIS IS A RENEWAL. IS THERE A CURRENT VQA IN PLACE. THE DURATION OF THE REWARD WILL BE SEVEN YEARS AND WE WILL MAKE ONLY ONE AWARD. SO IN TERMS OF SIGNIFICANCE, THE ACCURATE DETECTION AND QUANTIFICATION OF HIV AND RELATED VIRAL PATHOGENS IN DIVERSE LYING CALL SPECIMENS IS THE FOUNDATION REALLY FOR -- BIOLOGICAL SPECIMENS -- AND NOVEL STRATEGIES. AND AS KNOW, MANY OF OUR DADE SPONSORED CLINICAL TRIALS HAVE PRIMARY OBJECTIVES RELATED TO VIRALLIC OUTCOME. SO THE VQA INSURES THAT THE CLINICAL LABORATORIES GENERATING THE DATA CAN PRODUCE ACCURATE VIRE LOGIC DATA TO BE COMBINED ACROSS ALL CLINICAL SITES FOR TRIALS. SO THIS SLIDE SHOWS SOME OF THE SCOPE OF WORK FOR THE CONTRACT AND THESE BULLETS ARE TAKEN FROM THE CURRENT CONTRACT AND THEY'LL BE VERY SIMILAR FOR THE NEXT VERSION. SO ONE OF THE FIRST THING THAT THEY WILL NEED TO DO IS IMPLEMENT STANDARDS OF PERFORMANCE FOR EXISTING AND NEWLY-DEVELOPED VIROLOGIC ASSAYS AND CO-INFECTIONS AND PROVIDE PROFICIENCY TESTING PROGRAMS TO ASSESS THE 80 OF THE LABORATORIES TO SUCCESSFULLY PERFORM THE ASSAYS. AND THEN THEY WILL ALSO CONDUCT STUDIES ON THE EVALUATION STANDARDIZATION AND APPLICATION OF NEW AND EXISTING VIRAL LOGIC AND BIOSTATISTICAL METHODS FOR HIV AND RELATED CO-INFECTIONS AND IN ORDER TO DO THIS WORK, THEY WILL NODE TO -- [ READING ] AND THIS SLIDE SHOWS THE OPTIONS THAT WILL BE ATTACHED TO THE CONTRACT NOW. OPTIONS WE ONLY ACTIVATE IF WE NEED THEM AND WHEN WE ACTIVATE OPTIONS TO A CONTRACT WE NEED TO PUT ADDITIONAL MONEY INTO THE CONTRACT TO COVER THE COST OF THE OPTIONS. SO THE FIRST TYPE OF OPTION WE HAVE IN THIS CONTRACT IS TO SUPPORT ADDITIONAL LABORATORIES. AND WE USUALLY NEED THIS IN CASE WE HAVE A LARGE CLINICAL TRIAL STARTING THAT HAS 10 OR 12 LABS WE HAVEN'T WORKED WITH BEFORE AND THAT NEED COVERAGE UNDER THE VQA. WE CAN ACTIVATE AN OPTION, PUT MORE MONEY INTO THE CONTRACT AND SUPPORT THOSE LABS. AND THE SECOND TYPE OF OPTION IS SUPPORTIVE QUALITY ASSURANCE PROGRAMS FOR ASSAYS OF VIRAL DISEASE AGENTS OTHER THAN HIV AND OTHER CORELATED INFECTIONS. THIS CAN BE ANY TYPE OF VIRUS, ZIKA, EBOLA AND IN THIS KAY F WE NEED TO, WE CAN OPEN THIS CONTRACT TO USE BY OTHER NIAID DIVISIONS. THE THIRD TYPE OF CONTRACT OPTION IS SUPPORTIVE LATE-STAGE VALIDATION OF ASSAYS AND CLINICAL TESTING IN A CERTIFIED LABORATORY. WE MAY NEED THIS 23 WE WANTED TO USE THE NEWER VIVALLIC ASSAYS IN OUR CLINICAL TRIALS WHERE THE RESULT OF THAT ASSAY IS GOING TO BE USED FOR MAKING A DECISION ON PATIENT MANAGEMENT WITHIN THE TRIAL AND THEN IT WILL NEED TO BE DONE IN A CLIA CERTIFIED LABORATORY. THIS IS NEW. WE HAVEN'T HAD THAT OPTION IN THE PAST. SO, THE CONTRACT ACCOMPLISHMENTS SOME OF THEM ARE LISTED HERE. THE QUALITY ASSURANCE PROGRAM IS CURRENTLY SERVING OVER 100 DADE-SUPORTED OR COLLABORATIVE LABS IN 22 COUNTRIES AND PROVIDING STANDARDIZED REAGENTS, PROFICIENCY TESTING PANELS FOR HIV TNA. TOTAL NEW CLAYIC ASS ID. -- NUKE LAIC ACID: FOR THE PAST, ABOUT TWO YEARS, THEY HAD AN HIV INNER GRACE INHIBITOR RESISTANCE QUALITY ASSURANCE PROGRAM ALSO AND STARTED PILOT PROJECTS FOR QUALITY ASSURANCE OF RESERVOIR AND CURE ASSAYS INCLUDING Q VIA, CADNA. AND CELL ASSOCIATED RNA AND SINGLE COPY ASSAY. [ READING ] SO THE ASSAY EVALUATION PROGRAM WORKED IN 15 METHODS IN USE OR ANTICIPATED BY THE CLINICAL TRIAL NOTE WORK DATES. SOME OF THEM ARE LISTED HERE. WORKED ON STABILITY OF VIRAL LOAD RESULTS AFTER LONG TERM STORAGE. VALIDATION OF THE LOWER LIMIT OF QUANTITATION OF HIV VIRAL LOAD ASSAYS AND. [ READING ] THOSE ARE USED BY NETWORK AND NON NETWORK LABS. AND THEY HAVE LOOKED AT THE EFFECT OF SAMPLE PREPARATION ON VIRAL LOAD PLATFORMS,. [ READING ] SO THIS SLIDE JUST SHOWS THE GROUPS THAT THE VQA SUPPORTS. WHAT IS NOT SHOWN ON THIS SLIDE ARE THE MANY NON-NETWORK STUDIES THE VQA ALSO SUPPORTS. TO SORT OF PUT IT IN CONTEXT, THIS IS ONE OF A NUMBER OF QUALITY ASSURANCE CONTRACTS WE HAVE IN THE DIVISION OF AIDS, INCLUDINGS IMMUNOLOGY, CLINICAL PHARMACOLOGY ASSURANCE CONTRACT, PATIENT SAFETY MONITORING INTERNATIONAL LABORATORIES CONTRACT, THE TB QUALITY ASSURANCE CONTRACT AND THE EXTERNAL QUALITY ASSURANCE PROGRAM OVERSIGHT LABORATORY. SO, IN TERMS OF CHANGES FROM THE LAST CONTRACT, WE DON'T EXPECT A LOT OF CHANGES MUCH OF THE WORK WILL BE SIMILAR TO WHAT THEY ARE DOING NOW. WE DO FORESEE EXPANSION OF QUALITY ASSURANCE PROGRAMS FOR RESERVOIR ASSAYS AND NEXT GENERATION SEQUENCING. ALSO EXPANDED EVALUATION OF NEW STRATEGIES FOR POINT OF CARE HIV VIRAL LOAD AND POINT OF CARE SHALLY INFANT DIAGNOSIS. AND AS I SAID BEFORE, THE OPTION TO SUPPORT LATE-STAGE VALIDATION AND TESTING AND CLIA LABORATORIY IS NEW FOR THIS VERSION OF THE CONTRACT. SO, THE REVIEWERS FOR THIS CONCEPT WERE DR. HILLIER AND DR. HAMMER AND I WANT TO THANK BOTH OF THEM FOR THEIR INPUT ON THIS. IT HELPED US OUT. BOTH REVIEWERS WERE VERY POSITIVE AND THOUGHT THE PROGRAM WAS VALUABLE. PROVIDES A NEEDED SERVICE TO ENHANCE THE QUALITY AND REPRODUCIBILITY OF CLINICAL TRIAL DATA. ONE QUESTION THAT THEY HAD WAS, HOW IS THE CONTRACT EVALUATED AND DO THEY RECEIVE USER FEEDBACK. SO THE CONTRACT DOES HAVE AN ADVISORY GROUP AND THAT INCLUDES VIRALLOLOGISTS FROM ALL OUR CLINICAL TRIAL NETWORKS. THAT GROUP MEETS BY PHONE ON A MONTHLY BASIS AND THEY GET A LOT OF FEEDBACK. THEY ARE ALSO EVALUATED ANNUALLY, THE CO R AND THAT'S ME, AND THE REVIEW IS SHARED WITH THE ONE TRACTOR AND POSTED ON THE CPARS CITIZEN THAT CAN BE USED BY OTHER GOVERNMENT AGENCIES SEEKING CONTRACTORS. CURRENTLY THEY DON'T HAVE THE USER FEEDBACK SURVEYS BUT WE AGREE THIS IS IT A GOOD IDEA AND WE WILL WORK TO INCLUDE THAT AND THE STATEMENT OF WORK FOR THIS CONTRACT. ADDITIONAL QUESTIONS ARE HERE. ONE WAS HOW THE CONTRACT WILL BE PRIORITIZED IN THE CURRENT FUNDING ENVIRONMENT AND HOW IT WILL RESPOND TO THE NEXT VERSION OF THE CLINICAL TRIAL NETWORKS. OUR QUALITY ASSURANCE CONTRACTS HAVE BEEN PRIORITIZED HIGHLY BY THE DIVISION FOR CRITICAL SUPPORT TO THE CLINICAL TRIALS WORK. AND WE HOPE THAT WILL CONTINUE. THE CONTRACT ALWAYS RESPONDS TO THE NEEDS OF THE NETWORK AND WILL DO SO IN THE NEXT VERSION AS WELL AND THAT IS WHY THEY HAVE MOVED INTO QUALITY ASSURANCE RESERVOIR ASSAYS AND POINT OF CARE TESTING AND NEXT GENERATION SEQUENCING. AND THEY'LL CONTINUE TO ADAPT TO THE NETWORK NEEDS IN THE FUTURE. THE NEXT QUESTION IS IF WE ARE REDUCED TO REDUCE DUE TO FINANCIAL CONSTRAINTS, HOW WILL THAT BE DONE? WE HOPE WE WON'T DO THAT BUT IF WE HAD TO WE WILL PROTECT THE TESTING ROLE OF THE CONTRACT AND POSSIBLY AT THE EXPENSE OF THE ASSAY EVALUATION PROGRAM. ANOTHER QUESTION IS HOW CAN COMPANIES SUPPORT THE CONTRACT? PERHAPS THROUGH OPTION FUNDED THROUGH PUBLIC/PRIVATE PARTNERSHIPS? WE ARE TALKING TO OUR CONTRACTS PEOLE ABOUT THAT AND WE ARE NOT SURE IF THIS IS GOING TO BE POSSIBLE BUT WE ARE EXPLORING THAT OPTION. ANOTHER COMMENT THAT WAS PROMPT PUBLICATION OF FINDINGS SHOULD BE ENCOURAGED. WE AGREE WITH THAT IN DISSEMINATION OF FINDINGS THROUGH PUBLICATION AND PRESENTATION IS IN THE CURRENT STATEMENT OF WORK AND ALSO IN THE FLEW STATEMENT OF WORK. SO -- IN THE NEW STATEMENT OF WORK. I'M BACK TO THIS SLIDE AND I'LL STOP AND TAKE QUESTIONS. >> CARA WILSON: THANK YOU. THIS PROPOSAL IS NOW OPEN FOR DISCUSSION. >> I HAVE A QUESTION. CURIOUS HOW THE DECISION BETWEEN EXPANDING THE NUMBER OF LABORATORIES PARTICIPATING IN THE PROFICIENCY PROGRAMS IS BALANCED WITH THE SHIPPING SAMPLES AND KEEPING THEM CENTRALIZED? THERE ARE ADVANTAGES TO THE POINT OF CARE. YOU WILL HAVE TO HAVE LOTS OF LABS BUT FOR SOME ASSAYS YOU COULD ARGUE FOR CENTRALIZING IT. >> JOE FITZGIBBON: THAT'S SOMETHING WE HAVE NO END OF DISCUSSION ON. IT'S DIFFICULT THING AND THE NETWORKS REALLY ARE HAVE TO DECIDE WHETHER THEY NEED TO ADD NEW LABS EAR WHETHER THEY CAN DO THINGS CENTRALLY. SOMETIMES CENTRALLY THEY CAN'T DO THINGS CENTRALLY BECAUSE THEY CAN'T SHIP OUT OF CERTAIN COUNTRIES TO OTHER COUNTRIES. SO, IN THOSE CASES, WE HAVE TO BRING ON A LAB WITHIN THAT COUNTRY. BUT OTHER TIMES WHEN THEY AND CAN WE ENCOURAGE THEM TO DO THAT. >> CARA WILSON: ANY ADDITIONAL COMMENTS? OKAY. PLEASE VOTE ON THIS PROPOSAL. >> CARA WILSON: HALTING TB TRANSMISSION IN HIV ENDEMIC SETTINGS IS NEXT. >> SUDHA SRINIVASAN: GOOD AFTERNOON. I'M PAWAN SINHA, A PROGRAM OFFICER IN THE TB CLINICAL RESEARCH BRANCH IN THE THERAPEUTICS PROGRAM AT DAZED. I'M SUDHA SRINIVASAN: THANK YOU FOR THIS OPPORTUNITY TO PRESENT THIS NEIGHBORRATIVE, TITLED HALTING TB TRANSMISSION IN HIV ENDEMIC SETTINGS AND I PRESENT THIS FOR YOUR CONSIDERATION AND APPROVAL. SO, THE OBJECTIVES OF THIS INITIATIVE ARE TO GAIN IMPROVED UNDERSTANDING OF THE CRITICAL DRIVERS OF TB TRANSMISSION AT THE INDIVIDUAL LEVEL AND EXPANDED TO MEMBERS OF THE TRANSMITTER RECIPIENT CLUSTER CHAINS, TRCC IN HIV INFECTED POPULATIONS. TO HELP THE DEVELOPMENT OF INTERVENTIONS TO MEASURE TB TRANSMISSION AT THE INDIVIDUAL AND COMMUNITY LEVEL AND AN INCREASED UNDERSTANDING OF ARROW BIOLOGY OF INFECTIOUS PARTICLES AND TO GAIN A BETTER UNDERSTANDING OF THE BIOMEDICAL, ENVIRONMENTAL AND POPULATION-BASED DRIVERS OF MTB TRANSMISSION IN HIV-ENDEMIC SETTINGS. THE MECHANISM R01, WITH A FIRST YEAR TOTAL COSTED FOR THE INITIATIVE 3.8 MILLION, THE DURATION OF THE AWARD IS 5 YEARS AND WE ANTICIPATE TO MAKE 3-5 AWARDS. SO I'D LIKE TO START OFF DEFINING TRCC. TRANSMISSION OCCURS BETWEEN THE INFECTIOUS INDIVIDUAL OR THE TRANSMITTER, T, AND THE SUSCEPTIBLE INDIVIDUAL, OR THE RECIPIENT R, AND THIS EXTENDS TO A CLUSTER OR CHAIN OF INDIVIDUALS CONTACTS, CC, AND THIS WE COLLECTIVELY DEFINE AS TRCC. THE PROBLEM. DESPITE BEING PREVENTIBLE AND TREATABLE, TB REMAINS THE MOST COMMON LIFE-THREATENING OPPORTUNISTIC INFECTION AND LEADING CAUSE OF DEATH AMONG PEOPLE WITH HIV AND IN HIV ENDEMIC SETTINGS. THE GLOBAL TB RESEARCH COMMUNITY HAS IDENTIFIED ONGOING TB TRANSMISSION AS THE DRIVING FORCE OF TB INCIDENTS IN HIGHBRED SETTINGS WHICH IS FURTHER COMPOUNDED BY HIV CO-INFECTION AND WILL RISING RATES OF DRUG RESISTANT TB. AS THE FIGURE ON THE RIGHT SHOWS, THE TB EPIDEMIC IS HIGHLIGHTY CORRELATED WITH HIV PREVALENCE. TB DISEASE INCIDENCE IS DRIVEN BY RECENT TRANSMISSION RATHER THAN REACTIVATION OF LATENT INFECTION, PARTICULARLY IN HIV POSITIVE INDIVIDUALS. THE IMPACT OF HIV AND TREATMENT ON TB TRANSMISSION DYNAMICS ARE NOT REALLY WELL UNDERSTOOD. THIS IS TO QUICKLY REMIND YOU OF THE TRANSMISSION CYCLE AND THE COMPLEX INTERPLAY OF FACTORS THAT COULD IMPACT TB TRANSMISSION. WE START OFF WITH THE -- THERE IS THE INFECTIOUSNESS OF THE PERSON WITH THE ACTIVE TB DISEASE OR THE TRANSMITTER, WHICH YOU SEE ON THE RIGHT AND THE PINK BUBBLE. THERE IS THE INFECTIOUSNESS OF THE AEROSOL CONTAINING THE MICROBE AND THE METABOLIC AND PHYSIOLOGIC STATE OF THE BUGS. THERE IS THE EXSUPPOSURE OF THE INFECTIOUS AEROSOL BY THE SUSCEPTIBLE RECIPIENT AND THE PROXIMITY AND FREQUENCY AND DURATION OF THE EXPOSURE ALL IMPACT TRANSMISSION. AND THEN THERE ARE ENVIRONMENTAL FACTORS SUCH AS VENTILATION, HUMIDITY AND UV LIGHT ET CETERA THAT ALSO IMPACT TRANSMISSION. AND LAST BUT NOT LEAST, THERE IS THE SUSCEPTIBILITY OF THE EXPOSED INDIVIDUAL AND RISK FACTORS SUCH AS HIV AND DIABETES CERTAINLY IMPACT TRANSMISSION. THE EXTENT OF CONTRIBUTION OF THESE FACTORS AND THE MANNER HOW THEY IMPACT TB TRANSMISSION PARTICULARLY IN HYBRID AND HIV ENDEMIC SETTINGS IS QUITE COMPLEX AND NOT REALLY WELL UNDERSTOOD AT THE MOMENT. SO, IN ORDER TO TEASE OUT THESE ISSUES AND TO IDENTIFY THE RESEARCH GAPS AND RESEARCH QUESTIONS THAT WILL INFORM NOVEL INTERVENTIONS AND STRATEGIES TO EFFECT TB TRANSMISSION, WE HAD TWO WORKSHOPS, THE FIRST OF WHICH WAS IN MARCH OF 2016 AND THEN TO SPECIFICALLY IDENTIFY INTERVENTIONS AND STRATEGIES APPLICABLE IN HIV ENDEMIC SETTINGS, WE JUST HAD ONE LAST WEEK IN SOUTH AFRICA. SO RATHER THAN GIVE YOU A LONG LIST AND BULLET FORM, I THOUGHT I WOULD GIVE YOU SOME OF THE OUTCOMES OF THE WORKSHOPS IN THE GRADE CATEGORIES AND THESE WERE RESEARCH GAPS AND QUESTIONS IDENTIFIED BY THE EXPERTS THAT CAME TOGETHER AT THESE WORKSHOP WORKSHOPS. STARTING AT THE LEFT HERE IS THE SOURCE CASE. OR THE TRANSMITTER OF THE INFECTIOUS TRANSMITTER AND THERE WERE VARIOUS DETERMINANTS WITHIN THIS BOX THAT WERE IDENTIFIED AS BEING IMPORTANT FOR TRANSMISSION SUCH AS THE BEST LOAD, THE INFECTION STATUS OF THE TRANSMITTER, PREVIOUS HISTORY OF DISEASE, DRUG TREATMENT, DRUG RESISTANCE, THE ABILITY TO AEROSOLIZE THE INFECTIOUS AEROSOL AND LONG CAPACITY AND BEHAVIORS SUCH AS COUGH, WHICH IS STILL DETERMINED TO BE ONE OF THE MOST IMPORTANT DETERMINANTS OF TRANSMISSION AND ONE OF THE MOST IMPORTANT FACTORS THAT IMPACTED TRANSMISSION WAS IDENTIFIED TO BE IMPROVED METHODS TO IDENTIFY THE SOURCE CASES, ESPECIALLY IN THESE SETTINGS. AND THE SECOND BOX IS PATHOLOGY OF DISEASE AND AGAIN, THIS IS A HOST FACTOR OR THE TRANSMITTER FACTOR THAT IMPACTS TRANSMISSION WHERE THE EXTENT OF LUNG DAMAGE AND CAVITIES HAS BEEN SHOWN TO IMPACT TRANSMISSION. IN THE MIDDLE OF THE FIGURE, YOU SEE IN THE GREEN BOX IS BIOAEROSOLS AND THE STUDY OF ARROW BIOLOGY AGAIN WHICH HAS BEEN DETERMINED TO BE ONE OF THE MOST IMPORTANT FACTORS IN IMPACTING TRANSMISSION DYNAMICS OR DETERMINED IN DROP LET SIZE, TRA JECTION AND VELOCITY OF THE INFECTIOUS AEROSOL BY PHYSICAL PROPERTIES OF MUCUS, AND THE ABILITY OF THE BACTERIA TO SURVIVE IN THE AIR HAVE BEEN DEEMED TO BE VERY IMPORTANT AND AGAIN, THESE BULLET POINTS AT THE END SORT OF IDENTIFY THE MOST IMPORTANT QUESTION OR RESEARCH GAP THAT THE WORKSHOP PARTICIPANTS IDENTIFIED DEFINING THE ROLE OF MTB STRAIN DIVERSITY IN THE INFECTIOUS PROCESS. MOVING FURTHER TO THE RIGHT, THE ENVIRONMENT IS VERY IMPORTANT IN TRANSMISSION DYNAMICS WHERE THE PATIENT - THEN LAST BUT NOT LEAST, THE SUSCEPTIBILITY TO INFECTION WHERE RISK FACTORS SUCH AS HIV INFECTION, THE AGE OF THE SUSCEPTIBLE RECIPIENT, MACROPHAGE FUNCTION AND OTHERS WERE THOUGHT TO BE IMPORTANT. AND ONE IMPORTANT RESEARCH GAP OR QUESTION IDENTIFIED WAS THE FACT THAT WE STILL DON'T HAVE GOOD MARKERS FOR IDENTIFYING RECENT EXPOSURE AND INFECTION. SO BASED ON THESE RECOMMENDATIONS, AND RESEARCH IN THE FIELD, THE SCOPE OF THE RESEARCH FOR THIS INITIATIVE IS AS FOLLOWS. WE SEEK MULTIDISCIPLINARY STUDIES THAT CHARACTERIZE THE HOST, THE PATHOGEN, THE MICRO-ENVIRONMENT INTERACTIONS WHICH IMPACT TRANSMISSION IN HIV ENDEMIC SETTINGS. SPECIFICALLY STUDIES OF ARROW BIOLOGY, CHARACTERIZING INFECTIOUS AEROSOL MICRO-ENVIRONMENT AND ENVIRONMENTAL ASPECTS, DEVELOPMENT AND STUDIES OF NEW METHODS, TO MEASURE TRANSMISSION IN VARIOUS CONGREGATE SETTINGS. HOST FACTORS INCLUDING IDENTIFICATION OF BIOMARKERS AND RECENT TB EXPOSURE AND INFECTION. UNDERLYING GENETIC EPIGENETIC FACT EXPOSE RELATED REGULATORY GENES AND SIGNALING PATHWAY THAT IS PLAY A ROLE IN DIFFERENCES IN HOST RESPONSES. IMPORTANTLY THE ROLE OF HIV IN INFLUENCING TRANSMISSION IN THE EFFECTS OF TREATMENT. ELUCIDATION OF CHARACTERISTICS OR SUBPOPULATIONS OF MTB STRAINS INCLUDING DRUG RESISTANT STRAINS, STUDIES OF NOSEO COMMIAL TRANSMISSION AND HIGH-RISK GROUPS SUCH AS HEALTH CARE WORKERS. [ READING ] THE REVIEWERS FOR THIS INITIATIVE WE THANK THEM FOR TAKING TIME REVIEW THIS INITIATIVE AND PROVIDE FEEDBACK WHICH WAS VERY IMPORTANT AND USEFUL FOR US. THEY WERE VERY POSITIVE ABOUT THIS INITIATIVE AND THOUGHT IT WAS CRITICALLY IMPORTANT AREA OF RESEARCH AS TB REMAINS TO BE THE GREATEST KILLER OF PEOPLE WITH HIV. TRANSMISSION IN THE COMMUNITY, HOME, HEALTH CARE SETTINGS, DRIVES A LARGE PORTION OF CASES PARTICULARLY DRUG RESISTANT TB. UNDERSTANDING THE MECHANISM LOCATIONS AND CONTROL OF TRANSMISSION IS ESSENTIAL FOR REDUCING THE TB HIV BURDEN AND NOVEL APPROACHES WILL BE VERY INFORMATIVE FOR THE FIELD. THE FORCE OF INFECTION IS HIGH IMPACTING DISEASE INCIDENCE. WHEN WE HAD PRESENTED THIS CONCEPT INITIALLY TO THE REVIEWERS, THEY DID NOT HAVE SPECIFIC QUESTIONS RATHER THEY SUGGESTED WE FOCUS AND STREAMLINE OUR INITIATIVE AS WE WERE VERY AMBITIOUS AND BROAD AND SO, THIS IS WHAT I PRESENT TO YOU TODAY IS THE INITIATIVE THAT HAS BEEN MODIFIED BASED ON REVIEWER RECOMMENDATIONS. SO I WILL STOP THERE AND I'M HAPPY TO ANSWER ANY QUESTIONS. >> CARA WILSON: THANK YOU. DO WE HAVE ANY COMMENTS OR DISCUSSION? >> I WOULD JUST ASK THE REVIEWERS SINCE THEY KNOW A LOT MORE ABOUT THIS PARTICULAR TOPIC THAN I DO, BUT IN THE U.S. GOVERNMENT HAS SPENT A TON OF MONEY SINCE 2001 ON AEROSOLIDES INFECTIOUS DISEASES AND INTENTIONAL EXPOSURES AND I KNOW FROM LITTLER THAT THE ACADEMIA WAS LARGELY THE ENGINE FOR THAT DISCOVERY SINCE IS THAT TIME. HOW MUCH DO YOU THINK THAT BODY OF INFORMATION COULD CONVEY TO ASKING THESE KINDS OF QUESTIONS? I'M THINKING ABOUT ESPECIALLY IN THE TERMS OF ARROW BIOLOGY, THE CERTAIN INFRASTRUCTURE TO STUDY THOSE KINDS OF QUESTIONS WHICH WOULD THEN LEAD TO POTENTIALLY BRINGING IN PARTNERS THAT HAVE THAT KIND OF CAPABILITY. >> WELL, THE ARROW BIOLOGY OF TB TRANSMISSION HAS BEEN EXHAUSTIVELY STUDIED. E HEARD A WONDERFUL REVIEW LAS T WEEK AT THE MEETING IN CAPETOWN BEGINNING IN 1856 BEFORE THE DISCOVERY OF THED TUBERICAL BACILLUS AND GOING ON THROUGH THE GUINEA PIG EXPERIMENTS AND NOW IN SOUTH AFRICA MDR WITH GUINEA PIGS. FRANKLY, I DON'T SEE THAT AS THE HIGHEST PRIORITY AND I DON'T SEE THE BIODEFENSE TYPES OF RESEARCH AS CONTRIBUTING SO MUCH. AND THAT WOULD LARGELY BE NON RESPONSIVE IN THAT TB RELIES ON ANIMAL MODEL. BUT IF YOU LOOK AT POINT 3 ON THIS SLIDE, UNDERSTANDING WHAT IS DRIVING TRANSMISSION, THAT SEEMS TO ME THE KEY AND TWO PRESENTATIONS AT THE WORKSHOP IN SOUTH AFRICA REALLY DRIVE THIS HOME, THE STUDY FROM SERITA FROM THE CDC OF XDRTB PUB ENGLISH IN THE NEW ENGLAND JOURNAL AND UPDATED AT CROIX. BUT, THAT IS AN 80% HIV INFECTED POPULATION WITH 80% MORTALITY AND A PERCENT OF THE CASES THE TRANSMISSION IS UNKNOWN. THERE IS NO REASON THAT COULD BE FIGURED OUT WHY THIS PERSON HAS TB. WE KNOW IT IS IN A CLUSTERED STRAIN BEING TRANSMITTED BUT THERE ARE NO EPIDEMIOLOGICAL LINKS AND NO WAY TO KNOW HOW THIS PERSON GOT TB. AND THAT'S IMPORTANT. AND A STUDY WITH 600 CHILDREN WITH TB, OVER HALF OF WHOM HAD HIV INFECTION, OVER 80% HAD NO SOURCE CASE DESPITE AN EXHAUSTIVE EVALUATION OF THEIR HOUSEHOLDS. SO, HOW DOES AN 11-MONTH OLD CHILD GET TB WHEN THERE IS NOBODY IN THEIR ENVIRONMENT THAT YOU KNOW OF WHO HAS TB! SO I THINK THESE ARE EXTRAORDINARILY IMPORTANT QUESTIONS BECAUSE PEOPLE COME IN AND DIE OF TB AND NOBODY CAN FIGURE OUT WHERE THEY ARE GETTING IT. WHAT HAPPENS WHEN SOMEONE COUGHS OUT THE ORGANISM, I THINK IS FAIRLY WELL UNDERSTOOD, BUT WHERE IT OCCURS AND WHO IT IS AND WHAT THE CHAINS OF TRANSMISSION ARE LARGELY ARE UNKNOWN IN THIS STETTING, WHICH IS KIND OF -- >> HOST FACTORS WOULD BE CRITICAL TO BE RESPONSIVE TO THIS MECANISM. YOU WOULD NEED REALLY, REALLY LARGE NUMBERS TO GET AT SOME OF THE AREAS. >> AND I ALSO THINK IT'S MOST IMPORTANT. I THINK LOOKING FOR GENETIC SUSCEPTIBILITY, THERE IS IT SAY LOT OF WORK GOING ON IN GENETIC SUSCEPTIBILITY BOTH TO INFECTION AND PROGRESSION. BUT HIV JUST TRUMPS IT ALL. IF YOU LOOK AT THESE BIOLOGICS -- BIZEO SIGNATURES PREDICTING TB PROGRESSION, IT WASHES OUTS ALL OF THE BIOMARKERS. >> CARA WILSON: IF THERE ARE NO OTHER COMMENTS. LET'S GO AHEAD AND VOTE. OUR LAST PROPOSAL, UNDERSTANDING IMMUNOPATHOGENESIS OF TB AND HIV INFECTED AND EXPOSED CHILDREN. >> PATRICK JEAN-PHILIPPE: GOOD AFTERNOON, EVERYONE. LAST TALK OF THE DAY. SO THANK YOU FOR STAYING TO SEE THIS PRESENTATION. MY NAME IS PATRICK JEAN-PHILIPPE AND I'M HERE TO AND FOR YOUR APPROVAL FOR YOUR CONCEPT IN UNDERSTANDING IMMUNOPATHOGENESIS OF TB IN HIV AND INFECTED AND EXPOSED CHILDREN. THE EFFECTIVE OF THIS INITIATIVE IS TO SUPPORT RESEARCH TO IDENTIFY CHANGES AND MECHANISMS IN MARKERS IN THE CONTEXT OF MICROBACTERIUM EXPOSURE, INFECTION OR DISEASE IN PEDIATRIC POPULATION THAT HAS BEEN EXPOSED TO INFECTION WITH HIV. SO WE ANTICIPATE THAT FOR THIS WILL BE WE ANTICIPATE 3-5 APPLICATIONS. I DON'T THINK I NEED TO TELL THIS AUDIENCE ABOUT TB. THE STAGGERING NUMBER OF NEW INFECTIONS FOR SIGNIFICANT PORTION OF WHICH WERE PEOPLE LIVING WITH HIV. WITH CHILDREN, LESS THAN 15 YEARS BEING 10% OF THE TOTAL BURDEN WITH SIGMORETALITY. AND WE ARE ALSO KNOWING THAT CHILDHOOD TB IS A DIFFERENT DISEASE THAN ADULT TB WITH HIGH-RISK OF THE SAME FORM OF THE DISEASE BUT PARTICULARLY TB MENINGITIS, INFECTION AND NON-SPECIFIC MANIFESTATION AND CLINICAL COURSE, WHICH CREATE DIAGNOSTIC CHALLENGES AND ALSO WITH UNDER-NOTIFICATION AT THE PROGRAM LEVEL AND RESULTS IN OTHER TREATMENT. WE ALSO KNOW THAT THE YOUNG AGE IS SIGNIFICANT RISK FACTOR FOR TB-INDUCED MORBIDITY AND MORTALITY. HIGH RATE OF PROGRESSION TO ACTIVATE DISEASE UPON EXPOSURE. UP TO 30-50% OF CHILDREN IN FIRST YEAR OF LIFE EXPOSED TO TB MAY GO ON TO DEVELOP ACTIVE TB DISEASE AND WITH YOUNG AGE, FURTHER INCREASING DIAGNOSTIC CHALLENGES AND WE KNOW FROM APPLICATIONS FROM THE CHEMOTHERAPY ERA, THAT THE RATE IN CHILDREN 0-4 YEARS OLD WAS 44% INFECTION RATE. THERE IS SOME OF THESE MORTALITY DESPITE TB TREATMENT. AND ON TOP OF ALL THIS HIV FURTHER HAS HYBRID ABILITY WITH SIGNIFICANT INCREASE IN DISEASE ACTIVE TB COMPARED TO THIS INFECTED. SOME OF THIS STILL PERSISTING DECIDE DESPITE ANTI-RETROVIRAL TREATMENT AND EVEN IN TB-EXPOSED -- HIV EXPOSED CHILDREN THE INCIDENCE IS INCREASED SO ALL THIS SEEMS TO POINT TO EVIDENCE NOT THE HOST PATHOGEN SIS INTERACTION IN THIS POPULATION WHICH ARE REALLY FULLY UNDERSTOOD AND CLEARLY MAKING IT A AREA OF RESEARCH IN NEED OF SITUATION, OF STIMULATION. SO, THIS SLIDE JUST GIVES YOU A HIGH LEVEL OVERVIEW OF SOME OF THE KEY MECHANISMS THAT PLAY IN THESE POPULATIONS. WE KNOW THAT THERE IS IMPAIRMENT IN INNATE IMMUNE CELLS IN EARLY DEFENSE AGAINST MTB, IMPAIRMENT IN NUMBERS, AND CHEMOTAXIS AND IMPAIRED TISSUE AND PRIMING AND OBVIOUSLY CYTOKINE SKEWING. THERE IS SIGNALING OR SOME ALTERED SIGNALING AND CYTOKINE AND IMPAIRED INFLAMMATORY CYTOKINE SECRETIONS AND RESPONSES. WE KNOW THAT THE ADAPTIVE RESPONSE WHICH IS ALREADY DELAYED IN ADULT IS EVEN FURTHER DELAYED IN THESE CHILDREN WITH THIS SKEWING AND CD4 T-CELLS WITHIN THE MACROPHAGES AND CTLs. SO, SO FOR SCOPE OF RESEARCH, WE ANTICIPATE THAT THE SUPPORTED PROJECTS WILL TAP INTO ONGOING CHEMICAL TRIALS, PROSPECTIVE COHORTS AND OTHER RESEARCH SETTINGS, WHAT TARGET POPULATION IS FOLLOWED, OR WE'LL USE LYING CALL SAMPLES FROM THE TARGET POPULATION FROM WELL CHARACTERIZED AND ENVIRONMENTAL REPOSITORIES AND OUR TARGET POPULATION AS I ALLUDED TO BEFORE, THE CHILDREN WILL DEFINE AS 14 YEARS OR YOUNGER, WHICH ARE EXPOSED TO MTB AND INFECTED WITH HIV. OBVIOUSLY OTHER POPULATIONS AS COMPARATORS ALSO CAN BE JUSTIFIED. AND WE ANTICIPATES ALSO ESTABLISHMENT OF OR USE OF NON-HUMAN PRIMATE PEDIATRIC ANIMAL MODEL THAT CAN RECAPITULATE MTBI INFECTION. WHAT IS NOT REPORTED IS NON RESPONSIVE, NON TARGET POPULATIONS IF THEIR PRIMARY FOCUS OF RESEARCH CLEARLY IS NEW CHEMICAL TRIALS OR PROSPECTIVE COHORT, GIVEN ISSUE WITH TIME AND COST AND RESEARCHERS IN NON-INDUSTRY ANIMAL MODEL. SO, THIS IS SOME OF AREA OF INTEREST FOR THIS RFA AND THEY INCLUDE THE ROLE OF I'M SORRY MUNE MECHANISMS IN MTB AND HIV IMMUNITY. SUCH INNATE MECHANISMS MACROPHAGE AND CELLS IN THE ALTERNATION IN PATTERN RECOGNITION RECEPTORS AND CELL SIGNALING PATHWAYS. ADAPTIVE IMMUNE RESPONSE INCLUDING CD4, CD8 T-CELL RESPONSE. THE ROLE OF REGULATORY T-CELLS AND THE TH SPECIFICATION REGULATIONS AND THE DESCRIPTION FACTORS AND EPIGENETIC PROGRAMMING AND INNATE AND ADAPTIVES INTERFACE INTERACTIONS AND NEUTROPHILS AND OTHER RELEVANT CELLS. WE ALSO INTERESTED IN IMMUNE CORRELATES AND PROGRESS NASTIC HOST MARKERS, PROTECTION FROM TB INFECTION OR ACTIVE TB IN CHILDREN, IN THOSE CHILDREN. ALSO A KEY AREA OF INTEREST IS NEONATES AND THE COURSE OF SIGH SUSCEPTIBILITY TO TB INCLUDING INNATE AND TB IMMUNE RESPONSES AND WE WOULD BE ALSO INTERESTED IN EVALUATING DIFFERENCE IN PEDIATRIC IMMUNITY FOLLOWING NATURAL INFECTION WITH VACCINATION AND THE INFERENCE OF AGE OPTIMIZATION AND THOSE RESPONSES OF THOSE AGAINST TB AND OBVIOUSLY IMMUNOPATHOGENESIS OF TB IS OF INTEREST TO US AS WELL. SO IT'S JUST ANOTHER VIEW OF SOME OF AREA OF INTEREST AND THIS IS QUITE BROAD. WE HAVE EXISTING PROGRAMS THAT ADDRESS SOME ASPECT OF THIS RESEARCH AND THEY EITHER DO NOT INCLUDE THE TARGET POPULATIONS OR NOT FOCUS ON TB IMMUNOPATHOGEN SIS OR NON SUPPORTED ANIMAL MODELS AND THEREFORE ARE NOT OVERLAPPING WITH THE CURRENT PROPOSAL. SO, THIS HAS BEEN REVIEWED BY OUR REVIEWERS, DR. CHRIS WILSON AND BETSY MCFARLAND. WHICH WE THANK YOU FOR TAKING THE TIME TO REVIEW THIS INITIATIVE AND FOR THEIR HELPFUL COMMENTS AND THEY WERE VERY SUPPORTIVE OF THESE INITIATIVES. THEY FEEL THAT IN THE NON-HUMAN PRIMATE, WHEN A NON-HUMAN PRIMATE SHOULD BE IN SCOPE FOR ANIMAL STUDIES AS THE INITIATIVE MODEL OF HIV TO STUDY EARLY IMMUNITY, WHICH WE AGREED IN THIS PROPOSAL REFLECT THIS CHANGE, THEY FELT THAT THE COMPARATIVE STUDIES IN CHILDREN THAT ARE NOT INFECTED WITH TB AND HIV INFECTED IN EXPOSED MAYBE ALSO OF VALUE. WE AGREE TO THIS AND HAVE MADE THIS CHANGE. AND SIMILARLY, PREFERRED THAT ONGOING COHORTS FOLLOWING MTB INFECTED CHILDREN, BUT WITH KNOWN TIMING OF MTB EXPOSURE WILL BE ESSENTIAL FOR THE CONCEPTS PROPOSING TO LOOK AT CORRELATES OF IMMUNE PROTECTIONS AND WE ARE SO REWARDING, REWARD ED DESCRIPTIONS OF THE COHORTS AND POPULATION WHICH IS SUPPORTED. THEY ALSO FEAR THAT THERE SHOULD BE LANGUAGE THAT SHOULD ALLOW FOR A BROADER SCOPE OF INVESTIGATION AND SHOULD MAKE IT CLEAR THAT THE RFA IS INTERESTED IN BOTH MECHANISMS OCCURRING AS A RESOURCE OF MTB INFECTION IN THOSE THAT MIGHT EXIST MTB EXPOSURE AND PATHOGENESIS. AND SO, WE HAVE INTEREST IN THAT AREA AS I JUST MENTIONED BEFORE. MECHANISM OF IMMUNOLOGIC MATURITY IN NEONATES AND INFANTS AS A CAUSE OF HIGH SUSCEPTIBILITY TO TB AND ALSO WANT TO POINT THOUGHT WE SUPPORT RESEARCH FOR BEING DISCRETION IN HIV INFECTED AND NEONATES OR IN NANTS A SEPARATE RFA JUST THE FOCUS IS NOT ON TB IMMUNOPATHOGENESIS. AND FINALLY, THE FURTHER DEFINITION OF COHORTS SHOULD BE BROAD, AND THAT A PROPOSAL THAT WORK FROM SUCH A POPULATION COULD BE RESPONSIVE EVEN THOUGH THEY ARE NOT DEFINED. SO WE AVOIDED CONCEPT TO MAKE SURE THAT SETTINGS IN THE POPULATIONS CAN BE FOLLOWED WOULD BE ALLOWED AND NOT JUST COHORTS OR CHEMICAL TRIALS. AND SO THIS CONCLUDES MY PRESENTATION AND I'M AVAILABLE TO ANSWER ANY QUESTIONS AND THANK YOU FOR YOUR ATTENTION. >> CARA WILSON: THANK YOU. THIS IS OPEN FOR DISCUSSION COMMENTS? GO AHEAD. >> THINKING BACK TO A LITTLE EARLIER WHEN I WAS TALKING ABOUT THE MY CROW GENDER OHM, IT STRIKES ME THAT ONE FASCINATING THING ABOUT TB IS THAT YOUNG CHILDREN HAVE THE SAME RISK OF DEVELOPING TB REGARDLESS OF SEX BUT ONCE YOU GET TO ADOLESCENCE, MALES HAVE A MUCH HIGHER RISK, AND THAT PERSISTS THROUGHOUT LIFE AND IT PERSISTS EVEN IN THE PRESENCE OF HIV. BUT WONDER IF LOOKING AT THE ROLE OF SEX HORMONES IN ADD LES AND COMPARING THAT TO YOUNGER CHILDREN MIGHT SOMEBODY THAT WOULD BE FITTING FOR THIS RFA, BECAUSE IT'S REALLY AN AREA THAT HASN'T BEEN ADDRESSED VERY WELL IN THE PAST. >> SO I HAVE TO SAY IS THAT SOME OF THIS FOCUS WAS IN YOUNGER CHILDREN, AND THERE IS ALSO AN AGE GAP ON THE POPULATION THAT HAS BEEN INFECTED AND AS WRITTEN, WE MIGHT NOT BE ABLE TO SORT OF FULLY EVALUATE SOME OF THE RULE OF SEX HORMONES SINCE WE ARE RECRUITING UP TO 14. BUT, WE CAN GO BACK TO PROGRAM AND HAVE DISCUSSIONS AND SEE IF THESE ARE AVAILABLE. THAT WOULD BE INTERESTING. BUT SO FAR FOR YOUNGER CHILDREN AND WHAT COMES WITH THAT AGE. -- [ INAUDIBLE ] >> CARA WILSON: ARE THERE ANY ADDITIONAL QUESTIONS, COMMENTS? NO? ALL RIGHT. PLEASE VOTE ON THIS PROPOSAL. NOW, SINCE THIS IS AN OPEN MEETING, I'D LIKE TO OFFER THE PUBLIC A CHANCE TO COMMENT. DOES ANYONE IN OUR AUDIENCE HAVE ANY COMMENTS, QUESTIONS, ABOUT ANYTHING THEY HEARD TODAY? ANYONE? NO. OKAY. I'D LIKE TO THANK ALL THE MEMBERS OF THE COMMITTEE, OUR NIH COLLEAGUES FOR THE WORK THEY HAVE PUT INTO THESE PROPOSALS TOGETHER AND REVIEWING THEM. OUR NEXT MEETING IS SEPTEMBER 11. AS A REMINDER. DO YOU HAVE ANY ADDITIONAL COMMENTS? >> THANK YOU, CARA. I THINK WHAT KIM AND I WILL DO IS POLL ALL OF YOU FOR MAYBE AN ADDITIONAL PHONE CALL OVER THE SUMMER IN ADDITION TO THE ONE WE USUALLY HAVE AS THE MID-COURSE DISCUSSION ABOUT THE AGENDA FOR THE SEPTEMBER MEETING. SO, WE CAN TALK IF PEOPLE WANT TO TALK SPECIFICALLY ABOUT NETWORK ACTIVITIES. IF PEOPLE FEEL THEY NEED MORE THAN ONE ADDITIONAL CALL BETWEEN NOW AND THEN, PLEASE CONTACT ME AND KIM AND WE'LL SEE WHAT WE CAN SET UP FOR CALLS. AGAIN, IDEALLY, YOU PUT YOUR COMMENTS WRITING BUT IF YOU'RE MORE COMFORTABLE SPEAKING OVER THE PHONE, YOU WILL BE UNIQUE BECAUSE MOST PEOPLE DON'T WANT TO SHARE THEIR OPINIONS BY VOICE. THEY MUCH MORE PREFER TO BE ON THE WEB. BUT YOU'RE ALL NOT A BUNCH OF SHY AND RETIRING WALL FLOWERS, SO I APPRECIATE THE OPPORTUNITY TO ENGAGE WITH YOU ON THIS TOPIC IN ANY WAY POSSIBLE. >> CARA WILSON: OKAY. IF THERE ARE NO FURTHER COMMENTS, THIS MEETING IS ADJOURNED.