>> GOOD MORNING, EVERYONE. I'M THE EXECUTIVE SECRETARY FOR THE OFFICE OF AIDS RESEARCH ADVISORY COUNCIL. THIS MORNING WE'RE GOING TO START BY HEARING SOME COMMENTS BY MR. ALPAREN, WHO IS THE OAR MANAGEMENT OFFICIAL AND WILL GO OVER SOME PROCEDURE FOR COUNCIL. >> GOOD MORNING. MY NAME IS DAVID ALPAREN, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES AND MY OFFICE HAS OVERSIGHT RESPONSIBILITY FOR 30 ADVISORY COMMITTEES HERE AT NIH, INCLUDING THE OFFICE OF AIDS RESEARCH ADVISORY COUNCIL, AND I WAS JUST ASKED TO COME AND SPEAK FOR A FEW MINUTES IN THE PROCESS. THE FIRST ITEM I WANT TO TALK ABOUT IS MEMBER APPOINTMENT. MEMBERS ARE APPOINTED TO THIS COMMITTEE IN ONE OF TWO APPOINTED CAPACITIES, FIRST FEDERAL MEMBERS ARE APPOINTED AS EXOFISH QLOAS REPRESENTING SPECIFIC AGENCIES WITHIN THE FEDERAL GOVERNMENT AS IDENTIFIED WITHIN THE COMMITTEE CHARTER AND NON-FEDERAL MEMBERS ARE APPOINTED AS SPECIAL GOVERNMENT EMPLOYEES. I KNOW THAT A NUMBER OF YOU ARE IN AN AD HOC STATUS AND I JUST WANTED TO TALK ABOUT THAT FOR ONE SECOND. BECAUSE YOU ARE CONSIDERED SPECIAL GOVERNMENT EMPLOYEES, MEMBERS WHO HAVE NOT BEEN ONBOARDED ARE CURRENTLY DELAYED DUE TO THE HIRING FREEZE. WE ARE AWAITING ADDITIONAL GUIDANCE, AND AS SOON AS WE HAVE THAT ADDITIONAL GUIDANCE, WE HOPE TO ONBOARD YOU AS QUICKLY AS POSSIBLE. THE OTHER THINGS I JUST WANTED TO TALK ABOUT ARE THAT MEMBERS, APPOINTED MEMBERS ARE THOSE THAT HAVE VOTING AUTHORITY WITHIN THE PURVIEW OF THE COMMITTEE. AD HOC MEMBERS MAY PRESENT OPINIONS, SCIENTIFIC EXPERTISE, BUT DO NOT HAVE THE AUTHORITY TO VOTE, RECOMMENDATIONS TO ACCEPT OR REJECT REPORTS PRESENTED TO THIS COMMITTEE WOULD RESIDE WITH THE APPOINTED MEMBERS. IF THIS COMMITTEE BEGINS TO FORM WORKING GROUPS OR TASK FORCES THEE THESE ARE NON-FACA COMMITTEES, AND THOSE RESULTS, REPORTS AND RECOMMENDATIONS WOULD BE ROUTED THROUGH THIS COMMITTEE IN ITS ENTIRETY FOR DISCUSSION, REVIEW AND APPROVAL. THAT'S ALL I GENERALLY WANTED TO SPEAK TO YOU ABOUT THIS MORNING. THANK YOU VERY MUCH. >> THANK YOU. AND SO I WOULD ALSO JUST LIKE TO REMIND MEMBERS OF THE OARAC OF OUR POLICY ON CONFLICT OF INTEREST. COUNCILMEMBERS MAY NOT PARTICIPATE IN THE REVIEW OR DISCUSSION OF A SPECIFIC PROGRAM OR PROJECT FOR WHICH THEY HAVE A REAL OR APPARENT CONFLICT OF INTEREST, AND IN YOUR MEETING FOLDERS, YOU WILL FIND A FORM TO SIGN ON CONFLICT OF INTEREST, SO IF YOU CAN PLEASE SIGN THAT AND THEN TURN IT IN AT THE RECEPTION DESK, WE WOULD REALLY APPRECIATE IT. I'M NOW GOING TO TURN THE MEETING OVER TO OUR NEW CHAIR, DR. MONICA GANDHI. >> SO GOOD MORNING. AND THE 44TH MEETING OF THE OFFICE OF AIDS RESEARCH ADVISORY COMMITTEE IS NOW IN SESSION. I'D LIKE TO WELCOME COMMITTEE MEMBERS, INVITED SPEAKERS, OUR NIH COLLEAGUES AND GUESTS IN THE AUDIENCE. FIRST I'D LIKE TO GO AROUND SINCE WE HAVE A LARGE NUMBER OF MEMBERS AND INVITED SPEAKERS TO GO AROUND THE TABLE AND HAVE EVERYONE JUST INTRODUCE WHO THEY ARE AND WHERE YOU'RE INTEREST YOU'RE FROM. >> JANICE CLEMENS FROM JOHNS HOPKINS UNIVERSITY. >> ALLEN GREENBERG FROM GEORGE WASHINGTON UNIVERSITY. >> SCOTT RHODES FROM WAKE FOREST SCHOOL OF MEDICINE. >> I'M TRIP GULIG, NEW YORK CITY. >> JULIE -- U.S. MILITARY HIV/AIDS RESEARCH PROGRAM. >> JOHN KAITS, KAISER FAMILY FOUNDATION. >> DAN -- BRIG HIM AND WOMEN'S HOSPITAL AND HARVARD MEDICAL SCHOOL IN BOSTON. >> PRI SIGH LA SHOE FROM UNIVERSITY OF CALIFORNIA SAN FRANCISCO. >> MICHAEL LETTERMAN, CASE WESTERN RESERVE UNIVERSITY. >> RICK BUSHMAN, UNIVERSITY OF PANCREATIC ADENOCARCINOMA. >> >> [INAUDIBLE] [INAUDIBLE] >> LYN MOFENSON, PEDIATRIC AIDS FOUNDATION. >> DICK CHASEON FROM JOHNS HOPKINS UNIVERSITY. >> PETER -- OFFICE OF AIDS RESEARCH. >> MAUREEN GOOD NOW, OFFICE OF AIDS RESEARCH. >> OKAY. >> LIZ KONIK, UNIVERSITY OF ARIZONA. >> STEPHANIE -- UNIVERSITY OF CALIFORNIA SAN DIEGO. >> CHUCK WEHR, GUY SELL SCHOOL OF MEDICINE AT DARTMOUTH. >> THANK YOU. SO OUR FIRST ORDER OF BUSINESS IS TO APPROVE THE MINUTES FROM THE NOVEMBER 17TH, 2016 MEETING. AND YOU SHOULD HAVE RECEIVED THOSE ELECTRONICALLY YESTERDAY. WERE THERE ANY ADDITIONS OR CORRECTIONS ANYONE HAS TO THE MINUTES? AND IF NOT, IS THERE A MOTION TO ACCEPT THE MINUTES AS THEY STAND STAND? ALL RIGHT. PLEASE, IS THERE ANY SECOND FOR THAT MOTION? OKAY. ALL IN FAVOR? SO THE MORNING SESSION OF TODAY'S MEETING WILL FOCUS ON ACTIVITIES OF THE OAR AND WE'LL BEGIN WITH DIRECTORS REPORT FROM DR. GOODENOW. WE'LL DISCUSS THE IMPACT OF THE MICROBIOME ON HIV PREVENTION AND PATHOGENESIS. WE ALSO WILL HAVE TIME IN THE AFTERNOON FOR FORMAL PUBLIC COMMENT, AND ANYONE WISHING TO MAKE A PUBLIC COMMENT SHOULD NOTIFY OAR STAFF FOR PROVIDING YOUR NAME AND AFFILIATION AT THE RECEPTION DESK. BECAUSE THE ALLOTTED TIME FOR PUBLIC COMMENTS IS BRIEF, I WOULD ASK MEMBERS OF THE PUBLIC TO PLEASE BE MINDFUL OF ALL INDIVIDUALS WHO WISH TO BE HEARD AND THANK YOU IN ADVANCE. O WE'LL NOW HEAR FROM GR GOODENOW. >> OKAY. I HOPE YOU CAN HEAR ME. WELCOME TO ALL AND THANK YOU FOR COMING TO OUR SECOND -- OR I GUESS IT'S THE SECOND OARAC MEETING THAT I'VE BEEN -- THAT HAS HAPPENED UNDER THE TIME THAT I'VE BEEN THE DIRECTOR HERE. SO I WOULD LIKE TO GIVE YOU ALL A VERY WARM WELCOME TO NOT ONLY THE MEMBERS OF OUR COUNCIL BUT REPRESENTATIVES FROM THE NIH, THE PARTICIPANTS FROM A NUMBER OF PROFESSIONAL AND LAY ORGANIZATIONS WHOSE INTERESTS AND ACTIVITIES ALONG WITH THE MISSION OF THE OAR AND EVEN THOUGH PEOPLE WENT AROUND AND INTRODUCED THEMSELVES, I WOULD LIKE TO WELCOME IN PARTICULAR FIVE NEW AD HOC MEMBERS AND THESE INCLUDE DR. JOHN CHINN, WHO'S AN ASSOCIATE PROFESSOR IN URBAN POLICY AND PLANNING AT THE CITY UNIVERSITY OF NEW YORK, DR. JENNIFER CATES, VICE PRESIDENT AND DIRECTOR OF GLOBAL HEALTH AND HIV POLICY AT THE KAISER FAMILY FOUNDATION, DR. RICHARD CHASEN, PROFESSOR OF MEDICINE, EPIDEMIOLOGY AND INTERNATIONAL HEALTH AT THE JOHNS HOPKINS UNIVERSITY IN BALTIMORE, AND DR. CHASEN JOINS US TODAY AS A REPRESENTATIVE FROM THE NIAID ADVISORY COUNCIL. DR. ALAN GREENBERG, PROFESSOR AND CHAIR OF THE DEPARTMENT OF EPIDEMIOLOGY AND BIOSTATISTICS AT THE MILL KIN INSTITUTE AT GEORGE WASHINGTON UNIVERSITY, AND DR. GREENBERG JOINS US TODAY AS A REPRESENTATIVE OF THE NIMH ADVISORY COUNCIL. FINALLY, DR. STEPHANIE STRAFTE, WHO IS THE ASSOCIATE DEAN OF GLOBAL HEALTH SCIENCES AND THE HAROLD SIMON PROFESSOR AFTER CHIEF OF GLOBAL HEALTH IN THE DEPARTMENT OF MEDICINE AT THE UNIVERSITY OF CALIFORNIA SAN DIEGO, AND DR. STRAFTE JOINS US AS THE REPRESENTATIVE FROM THE NIDA ADVISORY COUNCIL. AND I'LL TALK A LITTLE BIT MORE ABOUT SOME OF THIS ORGANIZATION THAT WE JUST ALLUDED TO. ONE OF OUR COUNCILMEMBERS, DR. MITSIASU, IS UNABLE TO ATTEND TODAY'S MEETING. SO GOING FORWARD, IF I CAN MAKE MY SLIDES GO FORWARD, TODAY I'M GOING TO GO OVER SOME NEW MEMBERS AND DISCUSS OARAC ORGANIZATION AND PLANS AND SOME OF OUR ACTIVITIES. SOME OF THE KEY APPOINTMENTS SINCE OUR LAST MEETING IN NOVEMBER INCLUDE, AS YOU KNOW, THE INAUGURATION OF DONALD J. TRUMP AS THE 45TH PRESIDENT OF THE UNITED STATES JANUARY 20TH, 2017. WHEN PRESIDENT TRUMP WAS PRESIDENT-ELECT, HE NOMINATED REPRESENTATIVE TOM PRICE, A REPUBLICAN CONGRESSMAN FROM GEORGIA, FOR THE SECRETARY OF HEALTH AND HUMAN SERVICES, REPRESENTATIVE PRICE WAS SWORN IN AS SECRETARY OF HEALTH AND HUMAN SERVICES FEBRUARY 10TH, 2017, AND HE IS A MEDICAL -- HAS AN M.D. LIKE ALL APPOINTEES WHO SERVE AT THE PLEASURE OF THE PRESIDENT, DR. FRANCIS COLLINS SUBMITTED HIS LETTER OF RESIGNATION AFTER THE NOVEMBER 2016 PRESIDENTIAL LEK SHUP. ELECTION. DR. COLLINS' LETTER WAS RETURNED BY THE TRUMP ADMINISTRATION AND JANUARY 19TH, IT WAS ANNOUNCED THAT DR. COLLINS WAS BEING HELD OVER AS THE NIH DIRECTOR. DR. COLLINS SPOKE ON CNBC LAST WEEK AND HAS BEEN WORKING WELL WITH THE TRUMP ADMINISTRATION AS THE DIRECTOR OF THE NIH. IN THE U.S. DEPARTMENT OF DEFENSE, DR. DAVID J. SMITH IS PERFORMING THE DUTIES OF ASSISTANT SECRETARY OF DEFENSE FOR HEALTH AFFAIRS. THE ASSISTANT SECRETARY OF DEFENSE FOR HEALTH AFFAIRS IS THE PRINCIPAL ADVISER TO THE SECRETARY DEEF FENCE FOR HEALTH ISSUES. HE ADMINISTERS THE MILITARY HEALTH SYSTEMS' BUDGET AND CO-CHAIRS THE ARMED SERVICES BIOMEDICAL RESEARCH EVALUATION AND MANAGEMENT COMMITTEE. PRIOR TO DR. SMITH'S CURRENT ROLE, HE SERVED AS THE DEPUTY ASSISTANT SECRETARY OF DEFENSE FOR HEALTH READINESS POLICY AND OVERSIGHT. IN THIS WAY, RELATED TO DOD DEPLOYMENT MEDICINE FOR HEALTH PROTECTION NATIONAL DISASTER REPORT, INTERNATIONAL HEALTH AGREEMENT SUBSUBMISSIONS AND MEDICAL READINESS FOR SERVICE MEMBERS. IN THE DEPARTMENT OF VETERANS AFFAIRS, DR. ALLY IS ACTING UNDER SECRETARY FOR HEALTH VETERANS' ADMINISTRATION AND IN THIS POSITION, SHE DIRECTS A HEALTHCARE SYSTEM WITH AN ANNUAL BUDGET OF APPROXIMATELY $61 BILLION. OVERSEEING THE DELIVERY OF CARE TO MORE THAN 9 MILLION ENROLLED VETERANS. SHE PREVIOUSLY SERVED AS THE SENIOR ADVISER TO THE UNDERSECRETARY FOR HEALTH AND THE EXECUTIVE SPONSOR OF THE MY VA INITIATIVE THAT TRANSFORMED VETERANS' ACCESS TO HEALTHCARE. AND I WILL EXPLAIN THE REASON FOR POINTING OUT SOME OF THESE APPOINTMENTS. IN ADDITION, I WOULD LIKE TO TALK ABOUT OAR UPDATES IN TERMS OF PERSONNEL. I AM DELIGHTED THAT PETER KIM AGREED TO BECOME THE DEPUTY DIRECTOR OF THE OFFICE OF AIDS RESEARCH. HE STARTED IN JANUARY. HE IS ALSO A BOARD CERTIFIED PHYSICIAN IN THE PRACTICE OF INTERNAL MEDICINE AND INFECTIOUS DISEASES, AND HE IS AN ACTIVE VOLUNTEER PROVIDING CLINICAL CARE FOR HIV AND TB-INFECTED PATIENT. DR. KIM'S VISION FOR THE OAR ALIGNS WITH MY OWN, AS HE IS INTERESTED IN RESEARCH TO INFORM STRATEGIES FOR IMPROVED HEALTH OUTCOMES FOR THOSE WITH CO-INFECTIONS AND CO-MORBIDITIES AND IS INTERESTED IN A DIVERSIFIED RESEARCH PORTFOLIO THAT IS WELL COORDINATED TO ALLOW MAXIMUM RETURN ON INVESTMENT. PRIOR TO JOINING THE OAR, DR. KIM WAS THE DEPUTY DIRECTOR FOR THE THERAPEUTICS RESEARCH PROGRAM IN THE DIVISION OF AIDS,% IN NIAID. HE HAS EXPERIENCE IN MANAGEMENT AND COMMUNITY INVOLVEMENT AND HAS OVERSEEN A BROAD AREA -- BEFORE COMPLETING HIS DOCTOR OF MEDICINE AT THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE. HE COMPLETED HIS INTERNSHIP AND RESIDENCY IN INTERNAL MEDICINE, HIS FELLOWSHIP IN INFECTIOUS DISEASE, AND WAS THE CHIEF MEDICAL RESIDENT AT THE WASHINGTON HOSPITAL CENTER. AND I CANNOT TELL YOU WHAT DELIGHTED AND RELIEVED I AM TO HAVE A DEPUTY. IN ADDITION, WE HAVE -- WE'RE VERY SUCCESSFUL IN RECRUITING A NEW HEALTH SCIENCE ADMINISTRATOR INTO THE OFFICE, AND THAT'S DR. ELIZABETH CHURCH. SHE ALSO JOINED THE OAR IN JANUARY, AND HER FOCUS IS ON HIV RESEARCH CURE AND MOLECULAR VIROLOGY. PREVIOUSLY SHE WAS A PROGRAM OFFICER IN THE BASIC SCIENCE PROGRAM IN THE DIVISION OF AIDS, NIAID, I CAN TELL YOU, CARL WAS NOT HAPPY WITH OUR RECRUITMENT FROM DAIDS. NEVERTHELESS, HIS LOSS IS OUR GAIN FOR SURE. DR. CHURCH EARNED HER BACHELOR OF ARTS IN CHEMISTRY FROM DEPAUL UNIVERSITY. BEFORE COMPLETING HER PH.D. ON RETROVIRAL ASSEMBLY AT THE UNIVERSITY OF ALABAMA IN THE LABORATORY OF ERIC HUNTER, AND SHE COMPLETED A POSTDOCTORAL FELLOWSHIP AT HARVARD MEDICAL SCHOOL IN THE LABORATORY OF DR. RON DEROGGIA, WHERE HER RESEARCH WAS FOCUSED ON HIV AND SIV. AND OUR LAST RECRUIT AS A SENIOR POLICY CONSULTANT FOR THE OFFICE OF AIDS RESEARCH IS THOMAS LASALVIA. HE JOINED OAR AS A CONTRACTOR JUST A FEW WEEKS AGO IN EARLY MARCH. HE HAS AN EXTENSIVE BACKGROUND IN GLOBAL HEALTH RELATED TO HIV/AIDS STRATEGIC PLANNING, SCIENCE ADMINISTRATION AND MANAGEMENT, AND BUILDING MULTILATERAL COLLABORATIONS. HE EARNED A BACHELOR OF ARTS IN GOVERNMENT AND INTERNATIONAL RELATIONS FROM THE UNIVERSITY OF NOTRE DAME, A MASTER'S OF LIBERAL ARTS IN AMERICAN CULTURE FROM THE UNIVERSITY OF MICHIGAN AND MASTER OF PUBLIC HEALTH SERVICES FROM BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH. HE HAS SERVED AS CHIEF U.S. GOVERNMENT REPRESENTATIVE AND NEGOTIATOR RELATED TO U.S. POLICY FOR GLOBAL HEALTH AND HIV/AIDS INITIATIVES IN DEVELOPING COUNTRIES IN THE DEPARTMENT OF STATE, OFFICE OF THE GLOBAL AIDS COORDINATOR AND HEALTH DIPLOMACY, AND HAS EXPERIENCE WITH VARIOUS AGENCIES WITHIN THE DEPARTMENT OF HEALTH AND HUMAN SERVICES. I THINK MY NOTES DID NOT INCLUDE THE FACT THAT TOM WAS PART OF NIH IN THE DIVISION OF AIDS BEFORE HE LAUNCHED OFF INTO MORE ACTIVITIES SO WE'RE VERY, VERY HAPPY ALSO TO HAVE TOM ON BOARD TO WORK WITH US WITH SOME OF THE NEW INITIATIVES AND DEVELOPING THE -- ACROSS HHS AND ACROSS GOVERNMENT INCLUDING THE STATE DEPARTMENT ACTIVITIES. A COUPLE OF OTHER UPDATES, TODAY IS THE LAST FACE TO FACE MEETING FOR DR. GANDHI, OUR CHAIR. DR. SCHU -- AND MR. ROSARIO, SO YOUR TERMS OF APPOINTMENTS WILL BE ENDING SEPTEMBER 30TH, 2017. YOU'LL BE RECEIVING CERTIFICATES OF APPRECIATION IN THE MAIL, AND I DO HOPE THAT WE CAN COUNT ON YOU TO CONTINUE TO ACTIVELY SERVE ON AD HOC COMMITTEES AND WORKING GROUPS OF THE OARAC TO THE END OF YOUR TERM AND BEYOND. I HAVE ONE SAD NUSS SAD NEWS TO RELATE TO YOU TODAY, ANDREW LOCHNER PASSED AWAY SUNDAY, APRIL 2ND. HE WAS THE DIRECTOR OF THE TULANE NATIONAL PRIMATE CENTER AND DIRECTOR OF THE NON-HUMAN PRIMATE CENTER AND IS ONE OF THE -- HIS COLLEAGUES POINTED OUT TO ME, ANDREW IS A DRIVER IN SRV RESEARCH IN THE EARLY DAYS, A STAND-UP SCIENTIST AND A GENUINELY GOOD GUY. SO I WANTED TO JUST GIVE A LITTLE BACKGROUND ON THE OARAC, WHICH WILL PROVIDE SOME EXPLANATION FOR SOME OF THE PEOPLE THAT I INTRODUCED TO YOU EARLY ON IN THE FIRST PART OF MY PRESENTATION. CHARTERED TO CONTAIN 18 VOTING MEMBERS, THOSE ARE DISTRIBUTED ACROSS 12 SCIENTIFIC MEMBERS, AT LEAST TWO OF WHOM SHOULD BE FROM PUBLIC HEALTH AND BEHAVIORAL/SOCIAL SCIENCE MEMBERS. ALL OF THIS INFORMATION IS ACTUALLY OUTLINED IN OUR CHARTER AND TO SOME EXTENT, EVEN IN THE LEGISLATION, SET UP THE OFFICE OF AIDS RESEARCH. AND THEN WE HAVE SIX GENERAL PUBLIC MEMBERS, PUBLIC POLICY, LAW, HEALTH POLICY, ECONOMICS AND MANAGEMENT. WE ALSO HAVE 10 NON-VOTING MEMBERS, SIX EX-OFFICIOS, AND THE EX-OFFICIO MEMBERS INCLUDE THE DEPARTMENT OF HEALTH AND HUMAN SERVICES SECRETARY, THE NIH DIRECTOR, THE OAR DIRECTOR, THE CHIEF MEDICAL DIRECTOR FOR THE DEPARTMENT OF VETERANS AFFAIRS, ASSISTANT SECRETARY OF DEFENSE FOR HEALTH AFFAIRS, THE CDC DIRECTOR AND THE DAIDS DIRECTOR. SO THE FACT THAT I WAS TELLING YOU ABOUT HEALTH AFFAIRS PERSON IS THE ASSISTANT SECRETARY OF DEFENSE AND THE DEPARTMENT OF VETERANS AFFAIRS AS THESE ARE ACTUALLY EX-OFFICIO MEMBERS OF THIS COMMITTEE. WE ALSO HAVE FOUR REPRESENTATIVES FROM NIH ADVISORY COMMITTEES, AND THREE OF THEM WERE INTRODUCED TODAY. THESE ALSO ARE STIPULATED IN OUR CHARTER AND IN THE LEGISLATION FOR OAR THE FOUR ADVISORY COMMITTEES THAT WE ARE SUPPOSED TO HAVE REPRESENTATION FROM ARE NIAID, NCI, AS STIPULATED, AND THEN TWO OTHER INSTITUTES THAT REPRESENT THE LARGEST HIV INVESTMENT IN THEIR PORTFOLIO, THAT IS NATIONAL INSTITUTE OF MENTAL HEALTH, THERE'S A FOURTH ONE. >> IT'S NIDA. >> THANK YOU. HOW COULD I FORGET NIDA? SORRY, STEPHANIE. OKAY. SO VERY, VERY QUICKLY, I JUST WANT TO GIVE YOU A COUPLE ACTIVITIES THAT WE'VE BEEN WORKING ON SINCE LAST NOVEMBER. SO WE'VE ACTUALLY BEEN WORKING VERY HARD TO ESTABLISH RELATIONSHIPS FOR ME AS THE NEW DIRECTOR OF OAR AND THE RELATIONSHIPS BETWEEN OAR AND OUR COMMUNITY ADD VISORS AND STAKEHOLDERS, SO WE HAD A LISTENING DAY FORT COMMUNITY AT FOR THE CO MMUNITY AT OAR EARLIER IN THE YEAR, WE'VE HAD MULTIPLE MEETINGS AT CROIX WITH ADVOCATES AND COMMUNITY GROUPS NOT REALLY CONVENIENT TO THE EAST COAST AREA BUT BEING OUT ON THE WEST COAST GAVE US A CHANCE TO MEET WITH A NUMBER OF CONSTITUENTS AND TO REALLY START TO GET -- I THINK THE FACE TO FACE MEETINGS REALLY BEING ABLE TO SIT DOWN IN A ROOM WITH PEOPLE TO HAVE A CONVERSATION FOR MY PART HAS BEEN REALLY, REALLY HELPFUL. JUST LAST WEEK, THE AIDS SOCIETY AND KAISER FAMILY FOUNDATION HOSTED AN OPPORTUNITY FOR ME TO MEET SOME OF THE PEOPLE FROM DIFFERENT ORGANIZATION AND PROFESSIONAL GROUPS WHO ALSO WORK CLOSELY WITH US OVER THE YEARS. I ALSO WAS AWARDED THE SILVER AWARD, THE 24TH AWARDEE FOR THE SILVER AWARD THIS YEAR, AN AWARD THAT COMES THROUGH CHILDREN'S HOSPITAL, AND WHEN STEVE SENT ME THE LIST, I WAS REALLY AMAZED AND VERY HONORED TO BE PART OF THE GROUP WHO HAVE RECEIVED THESE AWARDS IN THE PAST. WOULD YOU SEE A NUMBER OF NAMES FROM DIFFERENT INVESTIGATORS AND NIH STAFF, BUT THERE WERE TWO IN PARTICULAR THAT I WANTED TO POINT OUT AND THAT'S LYN MOF MOFFESON, ONE OF OUR BOARD MEMBERS, AND DR. FAUCI. [APPLAUSE] SO I'M NOT GOING TO TALK ABOUT DETAIL, BUT JUST SO YOU KNOW, OUR PORTFOLIO REVIEW WHICH IS AT AN INTERIM EVALUATION OF THE PROCESS, WE'VE JUST BEEN THROUGH OUR THIRD CYCLE AND WE'RE ANALYZING THOSE DATA, THE STRATEGIC FUND WHICH EMANATES AS A RESULT AND THE REALIGNMENT OF RESEARCH PROJECTS WITH THE HIGHEST PRIORITIES IS ALSO IN THE FINAL PHASES OF MAKING DECISIONS BASED ON THE RECOMMENDATIONS OF THE VARIOUS PEOPLE WHO HAVE BEEN INVOLVED IN THAT, AND THE SAME FOR THE INNOVATION FUND. WE ARE IN THE PROCESS NOW OF WORKING ON THE TRANS-NIH STRATEGIC PLAN, ANOTHER ONE OF OUR MANDATED ACTIVITIES. THE 218 PLAN HAS BEEN POSTED ON THE OAR WEBSITE, AND THE 2019 PLAN HAS BEEN LAUNCHED WITH A REQUEST FOR INFORMATION AND THERE WILL BE MORE INFORMATION ABOUT THAT. THE TIME TO POST INFORMATION FROM EVERYONE EXTENDS FROM APRIL 3RD THROU GH MAY 15TH. AS WE GO FORWARD, AS YOU KNOW, IN 2015, THERE WAS A PIVOT OF THE NIH PRIORITIES AND A RESTATEMENT OF THE PRIORITIES FOR HIV/AIDS RESEARCH. IN OAR VERSION 3.0, WHICH IS THE PERIOD WE'RE NOW EMBARKING ON AFTER 30 YEARS OF OAR, AND SOME OF THIS I'VE PRESENTED THE LAST TIME, SOME OF THE OBJECTIVES THAT WE HAVE ARE TO PROVIDE IN CENTERS FOR COLLABORATIONS ALONG RESEARCH OBJECTIVES WITH THE DEMOGRAPHICS OF THE EPIDEMIC, THINK GLOBALLY, COLLABORATE AND PLAN FOR SUCCESS. I JUST WANT TO GO THROUGH A LITTLE BIT ABOUT HOW WE'RE THINKING IN TERMS OF THE EPIDEMIC, PARTICULARLY IN THE UNITED STATES, AND WHAT WE HAVE TO THINK ABOUT IN TERMS OF ALIGNMENTS. HIV IS REALLY NOW A CONDITION, DISEASE AND INFECTION THAT GOES ACROSS THE LIFESPAN AND VIRTUALLY EVERY PART OF YOUR LIFE, WHERE ANYONE'S LIFE, THERE IS A RISK AND THERE ARE SPECIFIC PREVENTIONS AND TREATMENTS THAT NEED TO BE APPROPRIATE FOR THE PARTICULAR -- WHERE PEOPLE ARE IN THEIR LIFESPAN. IN 2014, THERE WERE ABOUT 1.2 MILLION PEOPLE WITH HIV ACROSS THE AGE GROUPS, BUT THE YOUNGER GROUPS, SAY 13 TO 24, THERE WERE ABOUT 6% OF THESE CASES IN THAT AGE GROUP. WHEREAS MORE THAN 25% OF THE CASES ARE IN THE OVER 55 AGE RANGE. HOWEVER F WE LOOK AT THE DIAGNOSES IN 2015, OVER 40% OF THE NEW DIAGNOSES IN THAT YEAR OCCUR IN THE 15 TO 29-YEAR-OLD GROUP, WITH ONLY ABOUT 5% OF THE INFECTIONS OCCURRING IN PEOPLE OVER THE AGE OF 55. SO THIS IS TELLING US THAT OVER THE NEXT 10 YEARS, THERE'S GOING TO BE QUITE A SHIFT IN THE DEMOGRAPHICS OF THE EPIDEMIC IN THE UNITED STATES. THIS IS REALLY NOT JUST LOCALIZED TO THE UNITED STATES BECAUSE THIS IS A GLOBAL PHENOMENON AND THOSE OF YOU HAVE HEARD TALKS FROM PEPFAR AND FROM OTHER INTERNATIONAL GROUPS KNOW THAT THE INCREASED INCIDENTS OF HIV IN THIS YOUTH GROUP IS INCREDIBLY CONCERNING AND A SERIES ISSUE. NOT ONLY DO WE HAVE THE YOUTH ISSUE IN THE UNITED STATES BUT ON 2015, WHILE THE NUMBER OF NEW DIAGNOSES DROPPED BELOW 40,000, 30% OF THE POPULATION WHO LIVE IN THE SOUTH, THERE WERE MORE THAN 50% OF THESE NEW DIAGNOSES. SO WHAT WE'RE PLANNING TO DO, THERE'S SORT AFTER PIVOT TO THAT EVEN TODAY IN OUR OARAC AGENDA, THOSE OF YOU THAT ARE FOLLOWED OARAC, AD HOC WORKING GROUPS OR TASK FORCES CAN REALLY HELP US FOCUS IN ON THESE -- SOME OF THESE DIFFERENT ISSUES, AND TO HELP OARAC UNDERSTAND AND DEVELOP POLICIES THAT ARE APPROPRIATE FOR OUR CHANGING LANDSCAPE. SO THIS IS SOMEWHAT NEW FOR OARAC, ALTHOUGH IT'S DEFINITELY A MECHANISM THAT'S PROVIDED FOR UNDER OUR CHARTER AND THE FACA CHARTERS IN GENERAL. THE ADVICE AND RECOMMENDATIONS DELIVERED BY THE OARAC. OARAC CAN IDENTIFY THE PARTICIPANTS AND WE CAN INCLUDE RELEVANT NON-HIV EXPERTS IN THE GROUP. AND THE GROUP DOESN'T HAVE TO BE RESTRICTED TO THE OFFICIAL OARAC ITSELF. SO GOING FORWARD, SOME OF THE TASK FORCES THAT WE ARE DEVELOPING ARE A BEING FORCE ON IMPLEMENTATION RESEARCH, THAT WILL LOOK AT ECONOMIC ISSUES INCLUDES TRANS-NIH COST SHARING AND PRORATING, RETURN ON HIV/AIDS INVESTMENT FOR BIOMEDICAL ENTERPRISE AND A FRAMEWORK FOR FUTURE INVESTMENTS, AND THEN THE LAST -- OR THE THIRD ONE IN THIS FIRST ROUND WILL BE FOCUSED ON HIV COMORBIDITIES, COINFECTIONS AND COMPLICATIONS. SO STAY TUNED AND YOU'LL BE HEARING MORE ABOUT THIS AND I'M SURE MOST OF YOU WILL BE TAPPED TO BE PART OF THESE NEW WORKING GROUPS. SO THANK YOU VERY MUCH, I'M AGAIN VERY HAPPEN TO HAVE YOU ALL HERE, APPRECIATE GREATLY THE WORK THAT YOU'RE DOING AND LOOK FORWARD TO HAVING A CHANCE TO INTERACT WITH YOU ALL TODAY. THANK YOU. >> THANK YOU SO MUCH, DR. GOODENOW. NOW YOU TOLD US ABOUT THE NEW WORKING GROUPS, BUT ONE WORKING GROUP THAT WE HAD CREATED, ALREADY CREATED, THE TREATMENT AND PREVENTION GUIDELINES COMMITTEE. SO WE WILL NOW HEAR FROM TWO MEMBERS OR CHIEFS OF THE COMMITTEE, WHO IS DR. TRIP GULICH AND DR. -- HE'S ALSO THE P.I. OF THE CORNEL CLINICAL TRIALS UNIT OF ACTG AND HE'S THE CO-CHAIR WITH DRS. MARTIN HIRSCH AND CLIFF LANE OF THE PANEL THAT DEVELOPS THE DHHS TREATMENT GUIDELINES FOR ADULTS AND ADOLESCENTS,. PLEASE. >> THANK YOU, MONICA. AS MOST PEOPLE ARE AWARE, OARAC HAS FIVE WORKING GROUPS WHICH CORRESPOND TO THE FIVE GUIDELINES THAT CURRENTLY EXIST. TWO ARE ADULTS AND I'LL BE REVIEWING THOSE, THREE FALL UNDER PEDIATRICS AND ROHAN WILL BE REVIEWING THAT. WE'D LIKE TO GIVE YOU AN UPDATE OF WHAT'S HAPPENED OVER THE LAST YEAR. SO THE ADULT AND ADOLESCENTS ART GUIDELINES WERE LAST UPDATED ALMOST A YEAR AGO, IN JULY OF 2016. UPDATES IN TERMS OF WHAT THE WORKING GROUP IS UP TO, WE HAVE AN ANNUAL RETREAT AND THAT'S SCHEDULED THIS YEAR FOR MAY 9TH SO IT'S COMING UP. OUR KEY DISCUSSION TOPICS YOU SEE LISTED HERE, FOUR MAJOR THINGS WE'RE GOING TO TALK ABOUT IS WHICH FORMULATION OF SHOULD BE FIRST LINE IN RTI NUCLEOSIDE. AS YOU KNOW, BOTH OF THEM ARE CURRENTLY LISTED. WE'RE GOING TO DISCUSS BOOSTED DARUNAVIR AND CARDIOVASCULAR DISEASES, WE'RE GOING TO TALK ABOUT DOLUTEGRAVIR AND CNS EFFECTS, NEW DRUGS IN THE PIPELINE. WE ALSO ARE GOING TO REVISE MULTIPLE SECTIONS OF THE GUIDELINES CURRENTLY THESE ARE UNDERWAY, AND WE EXPCT A NEW ADDITION OF THE GUIDELINES TO BE RELEASED IN THE FALL OF THIS YEAR. WE DO HAVE ROTATIONS OF THE SCIENTIFIC MEMBERS OF THE ADULT AND ADOLESCENT ART GROUP AND HAVE RECENTLY INTRODUCED NEW SCIENTIFIC MEMBERS. SO WE HAD 27 APPLICANTS, AS YOU MAY KNOW, WE BROADLY REQUEST PEOPLE TO APPLY FOR THESE POSITIONS. THERE WERE THREE OPEN SLOTS, AND I'M PLEASED TO ANNOUNCE TO YOU TODAY WHO THOSE NEW MEMBERS WILL BE. SUSAN CU-UVIN IS AN OB-GYN FROM BROWN UNIVERSITY WHO WILL JOIN THE PANEL, ED GARDNER, DENVER PUBLIC HEALTH AND UNIVERSITY OF COLORADO, AND SERENA SPUDICH FROM YALE IS A NEUROLOGIST WITH AN INTEREST IN HIV. WE ALSO HAVE IMPORTANTLY COMMUNITY MEMBERS OF THE GUIDELINES PANEL. WE HAD SEVEN APPLICANTS THIS YEAR FOR TWO OPEN COMMUNITY SLOTS, AND THOSE WILL BE FILLED BY DANIELLE CAMPBELL, WHO IS FROM -- WORKS AT UCLA BUT IS A MEMBER OF THE COMMUNITY, AND STEVEN VARGAS, WITH THE ASSOCIATION FOR THE ADVANCEMENT OF MEXICAN-AMERICANS FROM HOUSTON. OR HOUSE-TON, AS WE SAY IN NEW YORK. I'M ALSO PLEASE TODAY RECOGNIZE PLEASED TO RECOGNIZE THE OUTGOING MEMO BRS OF THE PANEL WHO HAVE REALLY BEEN DEDICATED AND WORKED VERY HARD OVER THE LAST SEVERAL YEARS, SO I DID WANT TO MENTIO THEM BY NAME. VICKIE CARGILL, DEBRA COHAN, DANIELLE HOUSTON, MICHAEL HUGHES, BILL KAPOGIANNIS, DANIEL KURITZKES, AND MARK SULKOWSKI. THE OTHER GUIDELINES, OPPORTUNISTIC INFECTION GUIDELINES HAVE BEEN UPDATED MULTIPLE TIMES OVER THE PAST YEAR. ONE THING TO KNOW ABOUT OPPORTUNISTIC INFECTION GUIDELINES IS THAT THEY CONTINUE TO BE ACCESSED BY THE COMMUNITY REGULARLY. WE DO UPDATE THEM AS NEW INFORMATION BECOMES AVAILABLE. THAT MAY SURPRISE YOU AS TO WHAT YOU SEE HERE ARE THE PAGE VIEWS BETWEEN FEBRUARY OF '16 AND JANUARY OF '17, AND YOU CAN SEE SOMEWHERE BETWEEN ABOUT 20 AND 25,000 PAGE VIEWS PER MONTH FORTUNISTIC INFECTION GUIDELINES. AGAIN THAT MAY SURPRISE YOU BECAUSE WHILE OIs ARE DECREASING, WHY ARE WE SEEING THIS? OUR HYPOTHESIS HERE IS THAT MANY CLINICIANS ARE LESS FAMILIAR WITH THE TRADITIONAL HIV ASSOCIATED OPPORTUNISTIC INFECTIONS, AND ARE REQUIRING THE GUIDELINES OR TURNING TO THE GUIDELINES AS AN UPDATED SOURCE OF INFORMATION. SO WE'RE ACTUALLY PLEASED WITH THAT. WHAT YOU SEE HERE, THIS IS SPECIFICALLY FOR THE OI GUIDELINES, GOING FROM 2014 TO 15 OVER ON THE LEFT, INCREASING ABOUT 24% TO 15/16 AND THEN INCREASING AGAIN FROM 16 TO 17. SO AGAIN, AS THEY BECOME LESS COMMON, THEY'RE LESS LIKELY TO HAVE EXPERIENCE WITH MANY OF THE AIDS-RELATED OIs. SUCCESS FOR OUR FIELD. BUT MAKING THE GUIDELINES CONTINUE TO BE IMPORTANT. AS MENTIONED, IN THE PAST SIX MONTHS WE'VE UPDATED SECTIONS ON -- THERE ARE FUTURE UPDATES THAT ARE PENDING. THESE ARE BEING DONE RIGHT NOW. IN THE AREAS OF PCP, TOXO, TEU BERKLOW SIEVE, HBV, HCV, PAPILLOMA VIRUS, HHV-8, MALARIA AND CANDIDA. IN THE 80s AND 90s, RAN DONLIZED CLINICAL TRIALS, THE GOLD STANDARD, WERE USED TO DEVELOP THE GUIDELINES AND ADVANCE THE FIELD. MORE RECENTLY, US A MIGHT GUESS WITH DECLINING INCIDENCE OF OIs, THERE ARE VERY FEW RANDOMIZED CONTROLLED TRIALS OF OPPORTUNISTIC INFECTION MANAGEMENT AND TREATMENT. WE ARE INCREASINGLY RELYING IN THIS GUIDELINE GROUP ON OBSERVATIONAL AND COHORT DATA, AND REALLY TURNING TO RANDOMIZED CLINICAL TRIAL AND OBSERVATIONAL STUDIES FOR MORE RESOURCE LIMITED SETTINGS AND SEVERAL EXAMPLES ARE TUBERCULOSIS AND CRYPTOCOCCAL MENINGITIS, JUST NOT SEEN FREQUENTLY IN THE U.S. THESE DAYS. SO OPPORTUNISTIC INFECTIONS CONTINUE TO OCCUR, WE'RE ALL SEEING THEM, BUT THEY ARE SPORADIC OR EVEN RARE, BOTH IN URBAN AND RURAL AREAS. AGAIN, RANDOMIZED CLINICAL TRIALS FROM THE U.S. IN OPPORTUNISTIC INFECTIONS ARE RARE, SO OBSERVATIONAL OR EX--U.S. TRIALS CONTINUE TO BE IMPORTANT. WE'RE PLEASED TO SEE THE PROVIDER USE OF THE GUIDELINES REMAINS HIGH. WE WILL CONTINUE TO REVISE AS NEW DATA BECOMES AVAILABLE AND BECAUSE OF THE BREATH OF THESE GUIDELINES, THAT CAN HAPPEN SEVERAL TIMES A YEAR TO MAINTAIN THE DOCUMENT BEING UP TO DATE, AND VOLUNTEER CONTRIBUTORS AND PARTNER ORGANIZATIONS DO REMAIN ENTHUSIASTIC ABOUT THE VALUE OF THE GUIDELINE PROCESS AND THE REALTIME UPDATES. I'M GOING TO TURN TO ROHAN FOR THE PEDIATRICS. >> JUST TO INTRODUCE ROHAN, ROHAN IS THE CHIEF OF THE MATERNAL AND PEDIATRIC INFECTIOUS DISEASE BRANCH IN THE EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT, AND HE OVERSEES PEDIATRIC HIV CLINICAL TRIALS AND OBSERVATIONAL STUDY, AND SERVES ON THE DHHS PANEL FOR THE -- RETROVIRAL THERAPY AND MANAGEMENT OF HIV INFECTED CHILDREN. >> THANK YOU. THE PEDIATRIC GUIDELINES WERE LAST UPDATED JUST OVER A YEAR AGO, WE'RE IN THE PROCESS EXPECTING THE NEXT VERSION TO BE RELEASED IN THE NEXT FEW WEEKS. HOPEFULLY BEFORE THE END OF THE MONTH. THE CHANGES THAT WE'RE ANTICIPATING IN THESE NEW VERSION, WE'RE ACTUALLY MOVING TO PEOPLE FIRST LANGUAGE SO ACTUALLY WE'RE GOING TO HAVE A NEW NAME FOR THE PANEL. IT WOULD BE THE HHS PANEL ON ANTIRETROVIRAL THERAPY AND MEDICAL MANAGEMENT OF CHILDREN LIVING WITH HIV. VERY ENGAGED COMMUNITY MEMBER, WE HAD A LOT OF DISCUSSION ABOUT IT OVER THE COURSE OF THE YEAR, AND ARE MAKING THESE CHANGES THROUGHOUT THE DOCUMENT, INCLUDING IN THE PANEL NAME. WE'RE GOING TO CLARIFY THE TESTING SCHEDULE FOR INFANTS BASED ON TRANSMISSION RISK. A LOT OF CHANGES GOING ON WITH MANAGEMENT OF NEONATES EXPOSED TO HIV, GIVEN ISSUES AROUND THE EARLY TREATMENT WITH THE MISSISSIPPI BABY CASE SO ISSUES ABOUT EXPANDED PROPHYLAXIS VERSUS PRESUMPTIVE THERAPY AND ALSO HOW OFTEN TO TEST SO WE'RE CLARIFYING SOME OF THOSE ISSUES. WE'LL CONTINUE MOVING TO WEIGHT BAND DOSING RATHER THAN AGE BANS BANDS WHEN APPROPRIATE. MANY OF THE MEMBERS SERVE ON WHO WORKING GROUPS AS WELL, BUT IT ALSO MATCHES WHAT'S GOING ON WITH THE FDA AS WELL. WE DO HAVE FDA MEMBERS ON THE PANEL, AND REALLY LOOKING TO GETTING AWAY FROM THE MORE TRADITIONAL AGE BAND DOSING, AND THAT'S, IN FACT, LED TO HOW WE'RE DESIGNING OUR TRIALS GOING FORWARD AS WELL AND MOVING MORE TO WEIGHT BAND DOSING. WE'LL UPDATE THE PREFERRED ANTIRETROVIRALS FOR CHILDREN 3 TO LESS THAN 12 YEARS OF AGE. IT SOMEWHAT REMINDS ME WHAT TRIPP WAS SAYING ABOUT THE ADULT OI GUY LINES IS OF COURSE THE SITUATION WE FACE IN PEDIATRICS WITH TREATMENT ITSELF. REALLY VERY FEW RANDOMIZED CONTROL TRIALS, WE HAVE TO RELY ON SMALL PHASE 1 SAFETY AND PK STUDIES AND REALLY OBSERVATIONAL EXPERIENCE WITH RESPECT TO PANEL MEMBERS THEN DETERMINING WHAT WOULD BE PREFERRED VERSUS ALTERNATIVE. RAVAROC IS APPROVED DOWN TO 2 YEARS OF AGE, THEY ACTUALLY HAVE INVESTIGATION TALL DOSING OF RAL DOWN TO NEONATE. WE WILL NOW BE LISTING AN INVESTIGATIONAL DOSE FOR NEONATES. WE ALSO HAVE NEW MEMBERS BUT WE ACTUALLY DON'T DO THIS VERY OFTEN. THIS WAS I THINK THE FIRST TIME SINCE 2012 THAT WE HAD INVITED NEW MEMBERS. SO LISA ABUOGI FROM DENVER. LINDA LEWIS USED TO BE THE FDA REPRESENTATIVE BUT THEN POB RETIREMENT IS NOW WORKING FOR THE CLIN TOLL HEALTH CLINTON HEALTH ACCESS INITIATIVE SO WITH A LOT OF EXPERTISE, REALLY PLEASED SHE VOLUNTEERED TO RE-JOIN THE PANEL NOW AS A REGULAR MEMBER. STEVE NESHEIM FROM THE CDC, FORMERLY OF EMORY UNIVERSITY IS YOU NEW CDC REPRESENTATIVE. MURLI PURSWANI, CHIEF OF PEDIATRIC ID, LONG-STANDING CLINICAL AND PEDIATRIC HIV RESEARCHER HAS JOINED THE PANEL, THEN OUR NEW COMMUNITY MEMBER IS LESLIE RANERI FROM COLORADO. SO IN THE PEDIATRIC OI PANEL, I SHOULD SAY THAT FOR ALL OF THESE GUIDELINES, WE'RE REALLY TRYING TO ALIGN ACROSS ALL FIVE GUIDELINES AS MUCH AS POSSIBLE. I THINK THE OI IMREUP GROUPS REALLY SORT OF LED THIS EFFORT WITH NOW HAVING CHAPTERS ACTUAL LU REVIEWED BY BOTH GROUPS. THE MAJOR CHANGES HERE ARE -- I TALKED ABOUT THIS BEFORE, THIS PARTICULAR GROUP HAS MOVE TODAY A MODIFIED GRADE APPROACH AND THEY'RE STARTING OFF SORT OF THE NEXT ROUND OF THEIR CHAPTER REVIEWS JUST A FEW MONTHS AGO. THEY'VE ALREADY PUBLISHED TWO NEW CHAPTERS IN DECEMBER, THEN UPCOMING THIS SPRING, YOU CAN SEE THE ONES THAT ARE DUE. PERINATAL GUIDELINES WERE FULLY UPDATED AND RELEASED IN OCTOBER. AND I SHOULD MENTION, THIS -- IT SAYS IT HERE FOR THIS BUT I THINK IT'S THE CASE FOR ALL THE GUIDELINES THAT WE DO HAVE THE ABILITY WITH AIDS INFO'S HELP TO ACTUALLY PUBLISH UPDATES IN BETWEEN THE TIMES WE DO THE MAJOR ANNUAL UPDATES, SO HERE ESPECIALLY AS RELATED TO THE DRUG SECTIONS, THAT THOSE WILL BE UPDATED AS THEY GET REVIEWED AND VOTED UPON, BUT THE FULL UPDATE WILL ONLY HAPPEN LATER IN THE YEAR. WITH THIS UPDATE THAT WAS DONE IN OCTOBER, I WOULD HAVE REVIEWED THE MAJOR CHANGES FROM THAT AT OUR LAST MEETING BUT SINCE THEN, THERE HAVE BEEN SOME MEMBERSHIP UPDATES. DENISE JAMIESON IS STEPPING DOWN AND THERE WILL BE A NEW MEMBER, ATHENA KOURTIS FROM CDC, AND WE'RE ALSO SOLICITING A NEW OB-GYN CHAIR AS WELL. THEN WITH RESPECT TO THE UPDATES THAT ARE PLANNED FOR THE UPCOMING YEAR, AGAIN, THIS PANEL TOO IS LOOKING AT PEOPLE FIRST, LESS STIGMA ADVERTISING LANGUAGE BEING INCORPORATED INTO ALL THE SECTIONS, THE INDIVIDUAL DRUG SECTIONS WILL BE REVIEWED AND ACTUALLY WILL BE PUBLISHED OVER THE COURSE OF THE YEAR, AND THEN AGAIN BACK TO THE SORT OF ONE -- THIS ISSUE I MENTIONED ABOUT HOW MUCH EMPHASIS THERE IS NOW AROUND ISSUES RELATED TO EXPANDED PROPHYLAXIS, WE REALIZED THERE'S A LOT OF OVERLAPPING CON AT THE PRESENT TIME, SO LEADERSHIP FROM BOTH GROUPS HAVE ACTUALLY MET AND HAVE DECIDED THAT THESE THREE SECTIONS THAT ARE LISTED THERE WILL ACTUALLY BE DEVELOPED JOINTLY BY BOTH PANELS, SO THEY'LL STILL GO THROUGH THE RIGOROUS REVIEW AND VOTING PROCESS BY BOTH PANELS, BUT WILL ACTUALLY HAVE AUTHORSHIP FROM BOTH. WHAT WE'RE AIMING FOR IS ACTUALLY TO HAVE IDENTICAL VERSIONS OF THESE SECTIONS IN BOTH PANELS. BECAUSE WE'RE DEALING WITH THE FACT THAT THERE ARE CERTAINLY -- OB-GYNs ARE USED TO GOING TO THE PAIR TEE NATAL GUIDELINES, PEDIATRICIANS ARE MORE USED TO GOING TO THE PEDIATRIC GUIDELINES SO WE WANT TO MAKE SURE THE CONTENT IS THERE FOR THE FOLKS THAT USE THESE BUT REALLY TO MAKE SURE THAT RECOMMENDATIONS ARE ALIGNED, OR IN THE RARE INSTANCE THAT THEY'RE NOT ALIGNED, THAT WE REALLY ARE VERY CLEAR ABOUT WHAT THE NUANCES ARE ABOUT WHY THE RECOMMENDATIONS ARE DIFFERENT. SO WITH THAT, JOINING TRIPP TO REALLY ACKNOWLEDGE AND THANK NOT JUST THE LEADERSHIP OF THESE GROUPS BUT THE AIDS INFO SPHAF THAT WE REALLY WOULD NOT BE ABLE TO DO THESE WITHOUT, AND THEN A LOT OF VOLUNTEERS, SO WE'VE LISTED -- THERE'S OVER 200 VOLUNTEER MEMBERS OF THE VARIOUS WORKING GROUPS. THESE ARE PASSIONATE INDIVIDUALS WHO ON THEIR OWN TIME, WEEKENDS AND NIGHTS, ARE DOING THAT WORK, SO REALLY WANT TO ACKNOWLEDGE ALL OF THEM. THANKS. [APPLAUSE] >> SO IF YOU STAY UP THERE, ANY QUESTIONS FOR TRIPP OROHAN ABOUT THESE TWO SETS OF GUIDELINES IN THE PROCESS? >> I HAD A QUESTION WHILE I'M STARTING OFF. I THOUGHT IT WAS A REALLY IMPORTANT POINT YOU MADE THAT WITH THE OI GUIDELINES, THAT THE CURRENT RECOMMENDATIONS HAVE TO BE MADE AND EXTRAPOLATED FROM EITHER OBSERVATIONAL STUDIES OR INCREASINGLY RCTs PERFORMED IN SETTINGS THAT DON'T NECESSARILY REFLECT THE U.S.' PROCESSES OR DRUGS OR DRUG AVAILABILITY, AND, FOR EXAMPLE, WITH CRYPT TOE COCCAL MENINGITIS, THAT REALLY COMES TO MIND WITH THE TRIAL WHERE IT DOESN'T NECESSARILY REFLECT PRESSURE MANAGEMENT OR THINGS THAT CAN HAPPEN IN DIFFERENT SETTINGS IN THE U.S. AND I WONDERED EVEN TALK ABOUT THE GUIDELINES COMMITTEE MEMBERS OF THE OI COMMITTEE, BUT IT RELIES ON PEOPLE'S EXPERIENCE AND EXPERT OPINION AND PEOPLE REMEMBERING AND SEEING CASES, AND I WONDERED HOW THE OI GUIDELINES COMMITTEE IS BEING UPDATED OR NOT UPDATED OR LIKE IF PEOPLE HAVE BEEN ON THERE FOR A LONG TIME, BECAUSE I THINK THAT WOULD BE REALLY IMPORTANT, I THINK IT'S A HISTORICAL VIEW. >> I THINK THERE'S -- DID YOU WANT TO ADD SOMETHING ELSE? THE SECRETARY OF THE OI GUIDELINES, SHE COULD SPEAK TO THE MEMO PER SHIP PROCESS. >> I'M NOT SECRETARY BUT I'M JUST ONE OF THE LEADERSHIP OF THE OI GUIDELINES. MOBMONICA, ONE OTHER THING WE'RE ACTUALLY DOING NOW IS TO CONTINUE TO TRY TO LOOK FOR NEW MEMBERS. IN FACT, THERE'S GOING TO BE A NOMINATION FOR NEW MEMBERS COMING UP WITH THE UNDERSTANDING THAT YOU'RE RIGHT, SOME OF THE MEMBERS HAVE BEEN ON THE PANEL FOR A WHILE, AND PARTLY IT'S BECAUSE OF THE HISTORICAL EXPERTISE IN THAT PARTICULAR -- >> EXACTLY, I THINK THAT'S REALLY IMPORTANT. >> WE HAVE FOUND, FOR INSTANCE, CMV IS ONE GOOD EXAMPLE, WE COULD NOT FIND NEW CMV EXPERTS RELATED TO HIV. IT'S BECOMING VERY DIFFICULT FOR THE OI GUIDELINES TO FIND NEW MEMBERS, SO WE'RE ACTUALLY IN THE PROCESS OF DRAFTING A LETTER TO MULTIPLE ORGANIZATIONS AND ALSO PROBABLY LOOKING FOR OPEN NOMINATION, WITH THE UNDERSTANDING THAT THERE ARE SEVERAL DISEASES SUCH AS TB, OTHER DISEASES THAT ARE VERY COMMON IN RESOURCE LIMITED SETTING THAT THERE ARE EXPERTISE THAT WE CAN TAP ON TO DO THAT, BUT THERE ARE CERTAIN OIs THAT REALLY WE ARE HAVING A HARD TIME PARTLY IS BECAUSE ON ONE HAND, YOU CAN SAY WE DON'T NEED NEW EXPERTS BECAUSE THERE'S NO NEW FINDINGS, THERE'S NO NEW INFORMATION ABOUT HOW TO MANAGE CMV, FOR INSTANCE, RETINITIS AND HIV INFECTED PATIENT BUT SOMETHING THAT IS ONGOING, EVEN WHEN TO STOP PCB PROPHYLAXIS, THOSE NEW INFORMATION BECOMES AVAILABLE WITH OBSERVATIONAL COHORT DATA. >> I WOULD JUST LIKE TO ADD, THIS IS THE SAME ISSUE THAT WE'RE DEALING WITH ON PEDIATRIC GUIDELINES. ONE OF THE REASONS WE'VE NOT SOLICITED FOR NEW MEMBERS FOR ABOUT FIVE YEARS IS BECAUSE THE EXPERTISE HERE IN THE UNITED STATES IS PRIMARILY SENIOR LEVEL PEOPLE, THERE ARE NOT A LOT OF JUNIOR LEVEL PEOPLE GOING INTO PEDIATRIC HIV HERE BUT THERE'S CERTAINLY PLENTY THAT WE DRAW UPON THAT HAVE INTERNATIONAL EXPERIENCE. SO IT'S A SIMILAR PROCESS OF MAINTAINING THAT EXPERTISE THAT WE NEED FOR THESE. I THINK ON THE PEDIATRIC SIDE, IT'S PROBABLY SIMILAR AS WELL, AS THERE'S LESS AND LESS EXPERIENCE WITH THE DISEASE HERE, THERE'S MORE AND MORROW LINES ON THESE GUIDELINES. SO THEIR IMPORTANCE, THE ADULT OI GUIDELINES, IS PROBABLY SIMILAR FOR PEDIATRIC GUIDELINES AS WELL. >> AND EXPERTS, OKAY. THANK YOU. >> TRIPP, I'D LIKE TO ASK ABOUT TWO THINGS. THE GLOBAL MARCH TO DALUTEGROVIR AND THE LACK OF REALLY GOOD DATA ON DRUG-DRUG INTERACTIONS, I KNOW ELLIS IS VERY FAMILIAR WITH THAT TOPIC, BUT WITH THE WHO AND MANY COUNTRIES NOW RUSHING TO DALUTEGROVIR, THERE DOESN'T SEEM TO BE ANY PLANS IN PLACE TO DEAL WITH THE MILLION OR MORE PEOPLE PER YEAR WHO HAVE TB COINFECTION AND NEED TREATMENT. I THINK THE DHHS GUIDELINES ARE A REALLY IMPORTANT SOURCE OF INFORMATION AND GUIDANCE, AND I GET THE IMPRESSION THAT GLOBALLY GLOBALLY, COUNTRIES AND THE WHO ARE RUSHING TO FOLLOW YOU BUT NOT REALLY DEALING WITH THE DRUG-DRUG INTERACTION ISSUE. I JUST WANT TO KNOW HOW YOUR PANEL IS ADDRESSING THAT. >> THE FIRST THING TO SAY IS THAT OUR FIVE GUIDELINES PANELS, OUR MANDATE IS FOR U.S. TREATERS. HAVING SAID THAT, WE DO HAVE AN EYE THAT THE REST OF THE WORLD DOES READ OUR DWIED LINES AND THAT DEVELOPING COUNTRIES ARE PARTICULARLY LOOKING TO THE U.S. GUIDELINES TO SEE HOW THEY MIGHT MANAGE THINGS. SO ALTHOUGH STRICTLY SPEAKING WE'RE ADVISING U.S. DOCS, WE DO CONSIDER ISSUES LIKE THIS THAT ARE IMPORTANT TO THE DEVELOPING WORLD. DO YOU WANT TO SPEAK TO THE DRUG-DRUG INTERACTION? >> AS YOU KNOW, WE ARE VERY KEEN ON WANTING TO KNOW WHAT'S GOING ON WITH THE USE OF -- WITH DOLUTEGRAVIR UNDERSTAND THEY'RE OUT THERE BEING USED IN MANY PARTS OF THE WORLD. WE ARE FORCED TO -- IN A WAY TO SAY TAF CANNOT BE USED WITH ANY -- WHATSOEVER BECAUSE THAT IS THE WAY THE DRUG LABEL IS. ON THE OTHER HAND, I UNDERSTAND THERE ARE DIFFERENT RECOMMENDATIONS IN THE WHO GUIDELINES WITH REGARDS TO WHETHER DOLUTEGRAVIR CAN BE USED WITH EVERYTHING AND WHETHER TAF CAN BE USED SO DEFINITELY THERE NEEDS TO BE DRUG-DRUG INTERACTION STUDIES DONE TO RESOLVE THOSE ISSUES, AND WE'RE VERY INTERESTED IN TRYING TO GET SOME OF THOSE STUDIES GOING, TO TRY TO ADDRESS THE VERY IMPORTANT QUESTION. BUT AS I SAID, OUR HANDS ARE TIED BECAUSE THE PRODUCT LABEL DEFINITELY SAY YOU CANNOT USE TAF WITH ANY RIFF MY SIN WHATSOEVER. >> I THINK, DAN, YOU HAD A COMMENT ABOUT THIS. >> JUST THAT THE ISSUE AROUND DOLUTEGRAVIR, ALTHOUGH CLEARLY DATA ARE NEEDED IN TERMS OF EFFICACY, THE COUNTER VEILING ISSUE IS THAT IT IS FAR EASIER TO SWITCH TO PRIMARY TREATMENT OR INITIAL TREATMENT WITH DOLUTEGRAVIR THAN TO IMPLEMENT PRE-TREATMENT DRUG RESISTANCE TESTING. AND WITH THE DRAMATIC SPREAD OF NNRTI RESISTANCE AND THE INCREASING PREVALENCE OF TRANSMITTED NNRTI RESISTANCE, THE ISSUE FOR ALL THE OTHER PEOPLE WHO DON'T HAVE TB IS, DO YOU TREAT FIRST WITH AN EE VAB RINES BASED -- AND THEN GO TO DOLUTEGRAVIR, OR DO YOU START WITH DOLUTEGRAVIR. THAT'S THE ISSUE THE WHO IS GRAPPLING WITH. I MEAN, THERE IS A RECOMMENDATION TO DOUBLE THE DOSE OF DOLUTEGRAVIR WITH RIFAMPIN, BUT TAF IS CLEARLY MUCH MORE COMMON. >> FOR PEOPLE'S INFORMATION, DICK IS RIGHT TO SAY THAT DOLUTEGRAVIR WORLDWIDE IS BECOMING INCREASINGLY PROMINENT. WE LEARNED AT CROIX THAT IT IS NOW THE PREFERRED FIRST LINE DRUG FOR SEVERAL DEVELOPING COUNTRIES, INCLUDING SOUTH AFRICA, BOTSWANA AND BRAZIL. SO THIS WILL CONTINUE TO BE AN ISSUE WORLDWIDE. COST APPARENTLY FACTORS INTO THAT DECISION WHEN COMPARED WITH EE VAF RINSE, GENERIC DOLUTEGRAVIR WAS ACTUALLY LESS EXPENSIVE IN SOUTH AFRICA. >> BUT DICK, YOUR POINT I THINK IS A REALLY GOOD ONE BECAUSE IT EXPANDS OUR GUIDELINES, IT'S JUST AS SIMPLE AS DOUBLE THE DOSE, WHICH WE'RE NOT SURE IF THAT'S GOING TO BE COMPLETELY EFFECTIVE, ESPECIALLY WITH TAF, AND WE ALSO DON'T KNOW IF PEOPLE CAN DO THAT. -- WAS NOT HELPFUL IN TERMS OF DRUG-DRUG INTERACTIONS DOWN THE LINE. ANY OTHER QUESTIONS OR THOUGHTS ABOUT THESE TWO PRESENTATIONS? OKAY. SO ACTUALLY WE -- BECAUSE THESE ARE WORKING GROUPS OF THE OAR, WE ARE GOING TO VOTE, AND THE VOTE HERE AND THE QUESTION IS, DO YOU ACCEPT THE PRESENTATION. [LAUGHTER] SO NOT YOU AS PEOPLE BUT JUST ACCEPT THE PRESENTATION OF THE DHS TREATMENT AND PREVENTION GUIDELINES, ARE THERE ANY ADDITIONS OR SUGGESTED CORRECTIONS? WE TALKED ABOUT SOME THINGS WE WERE INTERESTED IN BUT ANY CORRECTIONS TO WHAT WAS PRESENTED, AND IF THERE ARE NO ADDITIONS OR CORRECTIONS, IS THERE A MOTION TO ACCEPT THE CHANGES AND PLANS FOR THE GUIDELINES THAT WERE PRESENTED BY ROHAN AND TRIPP? OKAY. THANK YOU. AND SECOND OVER HERE. THANK YOU SO MUCH. SO ALL IN FAVOR? OKAY. THANK YOU. SO NEXT WE'RE GOING TO GO TO A READOUT AND FROM THE 2017 WORKSHOP ON MACROPHAGE INFECTION BY HIV. SO AS WE TALKED ABOUT IN THE AFTERNOON, WE'RE GOING TO TALK ABOUT THE IMPACT OF MICROBIOME ON HIV PREVENTION AND PATHOGENESIS, BUT THIS FIRST PART IS REALLY TO TALK ABOUT MAYBE AN OFTEN NEGLECTED CELL, THE MACROPHAGE, AND ITS IMPLICATIONS FOR PATHOGENESIS AND CURE. AND THERE WAS A WORKSHOP HELD IN JANUARY THAT DR. CLEMENT IS GOING TO PRESENT ON THE WORKSHOP FOR THE FIRST 30 MINUTES, AND THEN FOLLOWING THAT, DR. CLEMENT AND DR. FAR SEE A GARCIA WILL ACTUALLY REPOND TO QUESTIONS. JUST TO INTRODUCE JANICE, VICE DEAN FOR FACULTY AT THE JOHNS HOPKINS SCHOOL OF MEDICINE. THE FIRST TO -- LENTIVIRUSES AND THEIR ROLE IN CHRONIC NEUROLOGIC DISEASES. DR. CLEMENT HAS DEVELOPED AN SIV MODEL FOR HIV PATHOGENESIS, TREATMENT AND ERADICATION, AND HAS EXTENSIVE KNOWLEDGE OF THE CURRENT STATE OF RESEARCH FOR MACROPHAGES AS A REAS VOYEUR FOR HIV/SIV, SO SHE CEASE GOING TO TALK ABOUT THIS ENTIRE MEETING DEVOTED TO THE MACROPHAGE, AND I'LL JUST QUICKLY INTRODUCE DR. GARCIA, WHO IS GOING TO HAVE TIME AFTER YOUR PRESENTATION WITH YOU TO HELP RESPOND TO QUESTIONS, PROFESSOR OF MEDICINE MICROBIOLOGY AND IMMUNOLOGY AT THE UNIVERSITY OF NORTH CAROLINA CHAPEL HILL. AND THROUGHOUT HIS CAREER, DR. GARCIA HAS MADE SEVERAL CONTRIBUTIONS TO OUR UNDERSTANDING OF HIV PATHOGENESIS. RECENTLY DEVELOPED INNOVATIVE HUMANIZED MICE MODEL SO TO ADDRESS KEY QUESTIONS IN HIV CURE RESEARCH. SO THE CELL THAT WE DON'T TALK ABOUT ENOUGH, THE MACROPHAGE, SO PLEASE, DR. CLEMENTS. >> I WANT TO THANK YOU FOR THE OPPORTUNITY TO TALK ABOUT THIS MEETING. IT WAS REALLY SPURRED BY A CONVERSATION BETWEEN VICTOR GARCIA AND BRUCE WALKER, WHO NOTED AT A PROMINENT MEETING, HIV MEETING, THAT THERE WAS REALLY A RELATIVELY POOR REPRESENTATION OF THE ROLE OF THE MACROPHAGE IN PATHOGENESIS AND CURE, BUT THAT THE FOCUS IS LARGELY ON CD4 CELLS, WHICH DOES REPRESENT THE MAJOR RESERVOIR IN BOTH HIV AND SIV. SO BRUCE DECIDED TO SPONSOR THIS MEETING AT THE RAYGON INSTITUTE AND REALLY WAS OUR HOST, AND WE HAVE TO THANK BRUCE FOR HIS GENEROSITY. FOR BROAD INVITATIONS, THAT WAS THE GOAL OF THE MEETING, TO INCLUDE ANYBODY WHO REALLY WANTED TO SPEAK ON THIS ISSUE. SO WE EXTENDED INVITATIONS TO MANY PEOPLE, SOME COULD NOT COME, MANY CAME ON VERY SHORT NOTICE, AND THE GOAL OF THE MEETING WAS TO HAVE A LOT OF DISCUSSION. SO EVEN THE FORMAL TALKS WERE QUITE SHORT, EACH SESSION ALSO HA A PANEL OF FOUR DISCUSSANTS SO THAT ONCE THE SHORT TALKS WERE OVER, THE DISCUSSANTS COULD GIVE WHAT THEIR BASIC RESEARCH WAS ABOUT AND SORT OF AN OVERVIEW, AND TO ENCOURAGE DISCUSSION. SO IT WAS A VERY OPEN-ENDED MEETING. WE HAD LOTS MORE DISCUSSION THAN FORMAL TALKS. IT WAS IN EARLY JANUARY. WE STARTED PLANNING IN LATE NOVEMBER. SO AS I SAID, IT WAS VERY RAPIDLY PUT TOGETHER. I'M GOING TO GIVE YOU AN OVERVIEW OF EACH SESSION AND WHO SPOKE, JUST TO GIVE YOU AN IDEA OF HOW WIDELY REPRESENTATIVE -- REPRESENTATION WE HAD, THEN I'M GOING TO GIVE YOU SOME CONCLUSIONS FROM EACH SESSION RATHER THAN -- THERE'S NO TIME TO GO INTO EACH TALK BUT YOU CAN SEE BY THE TITLES OF EACH TALK, THERE WERE A RANGE OF TOPICS. SESSION 1 WAS FOCUSED ON THE ESTABLISHMENT OF INFECTION IN MACROPHAGES, AND KEN WILLIAMS FROM BOSTON COLLEGE WAS THE MODERATOR. RON SWANSTROM TALKED ABOUT HIV R5 VIRUSES, WHICH ARE BOTH T-CELL AND MACROPHAGE TROPIC. QUENTIN SATTENTAU TALKED ABOUT SPREAD OF HIV-1 AND FROM MACROPHAGES, IT CAN ENGULF T-CELLS BUT ALSO RESULTS IN REAL INFECTION. RON COLLMAN TALKED ABOUT SHAPING THE MACROPHAGE RESERVOIR IN VIVO, PARTICULARLY IN CD4-DEPLETED AN MILLIMETERS, AND THEN LONG-LIVED MACROPHAGES THAT LIVE IN MANY, MANY TISSUES WAS TALKED ABOUT BY DR. KURODA. AS YOU CAN SEE, WE HAD A VERY VARIED PANEL FROM MANY SCHOOLS AND FROM DIFFERENT POINTS OF VIEW FROM THE CNS TO THE PERIPHERY. SESSION 2 WAS MACROPHAGES AND HIV PERSISTENCE, LATENCY AND ACTIVATION. TRISHA BURDO MODERATED AND WE HAD REPRESENTATION FROM EMORY, FROM KRISTINA GAVEGNANO AND THE ROLE OF JAK/STAT SIGNALING IN MYELOID REDIVED HIV RESERVOIRS. NOBODY HAD TALKED ABOUT ANYTHING OF THIS SORT AND IT WAS VERY INTERESTING. MARIO STEVENSON, THE ROLE OF MACROPHAGES IN HIV-1 PERSISTENCE UNDER ART, JASON BRENCHLEY, CAPACITY OF MYELOID CELLS TO SUPPORT SIV REPLICATION IN VIVO, AND POLARIZATION OF THE MACROPHAGES, THE STATE OF THE KNACK PHAGE IS MACROPHAGE IS CHANGED BY HIV INFECTION AND BY THE INFLAMMATORY OR NON-INFLAMMATORY ENVIRONMENT IN TISSUES, AND AGAIN, THE PANEL. SESSION 3 FOCUSED ON SIV/HIV INFECTION OF MACK FAMGS AND HOW IT AFFECTED THE IMMUNE SYSTEM. WE SOMETIMES OVERLOOK THE FACT THAT MACROPHAGES ARE AN IMPORTANT ARM OF THE INNATE IMMUNE RESPONSE, AND CATHY COLLINS ACTUALLY MODERATED THAT AND HER INTEREST IS IN THE ROLE OF BONE MARROW PRECURSORS IN HIV INFECTION. D IONNA WILLIAMS FROM MY LAB TALKED ABOUT VERY NOVEL STUDIES SHE'S DOING TO LOOK AT HOW INTERFERON BETA IS MODULATED IN HIV INFECTED RESERVOIRS AND HAS SOME NOVEL MECHANISMS ON THAT. KIERA CLAYTON FROM BRUCE'S LAB TALKED ABOUT HER VERY IMPORTANT STUDIES THAT SHOW THAT CD8 CELLS ARE NOT GOOD AT MEDIATING CLEARANCE OF INFECTED MACROPHAGES AND, IN FACT, ACTIVATE THEM AND CAUSE A LOT OF INFLAMMATORY RESPONSES. KEN WILLIAMS TALKED ABOUT TARGETING MONOCYTE AND MACROPHAGE ACTIVATION IN SIV PATHOGENESIS, AND AGAIN, WE HAD THE BROAD PANELISTS TO DRIVE THE DISCUSSION AND TO KEEP IT EVEN-HANDED SO THAT PEOPLE HAD BOTH POINTS OF VIEW. ON ALL THESE TOPICS. SESSION 4 WAS EMERGING TECHNOLOGIES. HOW ARE WE GOING TO LOOK AIN'T FECTED MONOCYTES, MACROPHAGES, THE PATHOLOGY FOR THOSE CELLS, T-CELLS EXPAND EXPONENTIALLY WHEN YOU STUDY THEM AND PUT THEM IN CULTURE, WHILE MONO SITES AND MACROPHAGES ARE NOT EXPONENTIALLY DIVIDING CELLS. MATHIAS WAS THE MODERATOR. JANET HONEYCUTT, FACULTY MEMBER WITH DR. VICTOR GARCIA TALKED ABOUT THEIR VERY NOVEL MOUSE MODEL, WHICH THE HUMANIZED MOUSE IS ONLY POPULATED WITH HUMAN MYELOID CELLS. DR. MONTANES WHO COMES FROM HARVARD AND MIT IS APPLYING SINGLE CELL GENOMICS TO STUDY TISSUE MACROPHAGES. WHEN WE THINK ABOUT IT, WE'RE GOING TO HAVE TO FOCUS ON MORE SINGLE CELL ANALYSIS ON SOME OF THESE GENOMES, AND TO UNDERSTAND WHAT'S GOING ON NOT ONLY IN THE MACROPHAGE RESERVOIR BUT THE T-CELL RESERVOIR, AND SINGLE CELL TECHNOLOGY IN OTHER FIELDS IS VERY, VERY POPULAR AND VERY ACTIVE, AND IT'S SOMETHING THAT I THINK THE HIV FIELD WILL HAVE TO ADOPT. I SPOKE ABOUT THE QUANTITATION OF LATENT MACROPHAGE RESERVOIRS WITH THE NEW QUANTITATIVE VIRAL OUTGROWTH ASSAY, AND ABBY SHIFT TALKED ABOUT ALVEOLAR MACROPHAGES AS A POTENTIAL RESERVOIR AND AGAIN OUR PANELISTS. THE CONCLUDING SESSION WAS VERY IMPORTANT. THE CONCLUDING SESSION WAS EXPERTS WHO ESSENTIALLY TOOK EVERYTHING THAT WAS SAID AND LOOKED FOR THE RESEARCH OPPORTUNITIES TO SUGGEST, AND I THINK THAT MAY BE OF THE MOST INTEREST TO THIS GROUP. THE INTRODUCTORY SESSION, WE INVITED SOMEONE WHO DIDN'T WORK ON HIV AT ALL BUT RATHER WORKED ON THE BASIC ONTOGENIC AND TISSUE SPECIFIC CONTROL OF MACROPHAGE FUNCTION. THIS IS AN EVOLVING FIELD, OVER THE LAST FIVE YEARS, THERE'S BEEN A NEW UNDERSTANDING OF THE EMBRYONICALLY DERIVED MACROPHAGES IN TISSUES. IT WAS THOUGHT FOR A LONG TIME THAT ONLY CERTAIN TISSUES LIKE BRAIN HAD THESE EMBRYONIC CELLS, THE MICROGLIA, BUT IT'S NOW KNOWN THAT ALMOST ALL THE TISSUES, THE RES NANT MACROPHAGES IN ALL TISSUES ARE DERIVED FROM AN EMBRYONIC PRECURSOR. THEY'RE NOT SHORT LIVED, BUT RATHER THEY CAN SELF-RENEW.% SO THAT PROVIDES A MECHANISM, A POTENTIAL MECHANISM IF THOSE CELLS GET INFECTED BY HIV, IT COULD POTENTIALLY BE A LONG LIVED RESERVOIR. SO THESE NEW CONCEPTS OF MACROPHAGE ONTOGENY HAVE NOT YET BEEN INCORPORATED IN HIV RESEARCH, AND THERE'S -- AND THIS IS ANOTHER OPPORTUNITY, POTENTIAL ROLE OF MACROPHAGE AS LONG LIVED LATENT RESERVOIRS IS RAISED BY THESE STUDIES. CAN KURITZKES GAVE A VERY EXHAUSTIVE OVERVIEW OF THE CLINICAL TRIALS OF HIV CURE AND REALLY SET THE STAGE FOR WHERE WE WERE IN NOT ONLY CURE RESEARCH, BUT IN THINKING ABOUT STRATEGIES THAT HAVE BEEN SPECIFICALLY ADDRESSED AND HOW MACROPHAGES HAVE NOT BEEN REALLY INCLUDED IN THOSE STRATEGIES, AND THAT WE HAVE TO REALLY INCLUDE THEM IN THE THINGS THAT WE TALK ABOUT AND THINK ABOUT. LASTLY STEVE DIEKS PROVIDED THE BASE BEING SCIENCE OVERVIEW. SO WE TRIED TO GET THE MEETING STAGE BY THESE THREE TALKS. HE TALKED ABOUT THE CD4 RESERVOIR, THE SIZE AND STABILITY OF THE RESERVOIR, T-CELL SUBSETS THAT COMPRISE THE RESERVOIR, AND THE SOURCE OF VIRUS PRODUCTION. AND THE SOURCE OF PERSISTENCE AND THE TIMING OF RESERVOIR ESTABLISHMENT, AND CURRENT THOUGHTS ABOUT MACROPHAGES AS A RESERVOIR AND PREVENTION OF INFECTION AND LATENCY. SO IT WAS A VERY GOOD TALK, IT SET THE STAGE FOR WHERE WE ARE PARTICULARLY WITH UNDERSTANDING THE T-CELL RESERVOIR, AND DR. DE EKS EMPHASIZED THAT WHILE THE HUMAN MACROPHAGE CONTRIBUTES TO THE HIV RESERVOIR IN THAT THEY ARE INFECTED EARLY ON DURING INFECTION, AND THAT THEY ARE PRESENT AFTER ART, THAT MONOCYTES AND MACROPHAGES, DESPITE WHETHER THEIR A RESERVOIR OR NOT, CONTRIBUTE TO INFLAMMATION ESPECIALLY IN THE BRAIN, AND THAT THAT ALONE REQUIRES MORE INVESTIGATION. SO SESSION 1, AS I SAID, WAS THE ESTABLISHMENT OF HIV INFECTION IN MACROPHAGES. THE SESSION PROVIDED EVIDENCE THAT MACROPHAGES ARE INFECTED IN VIVO. I THINK WE SOMETIMES FOR GET BECAUSE WE ARE IN THE ERA OF ART WHERE WE ONLY SEAT LATENT RESERVOIRS, BUT EARLY ON, HIV INFECTS MACROPHAGES AND IN THE PRESENCE OF LOW CD4 T-CELL COUNTS AND HIGH MONOCYTE TURNOVER, THESE FACTORS THAT WE KNOW ABOUT MAY POTENTIATE HIGHER LEVELS OF MACROPHAGE INFECTION. THAT'S PARTICULARLY TRUE IN SIV MODELS. WE'RE NOT CLEAR ON HOW THAT PLAYS A ROLE IN HUMANS AS YET. MOREOVER AT LEAST IN MEE TROA, IN VITRO -- CAN BE RESISTANT TO ANTIRETROVIRAL THERAPY. -- CAN FORM THESE SYNAPSES WITH THE T-CELLS AND THE MACROPHAGES GET INFECTED WITHOUT EXPOSURE TO ANTIRETROVIRAL THERAPY AND BNABS, SUGGESTING THAT CURRENT THERAPIES MAY BE INSUFFICIENT OR IN INADEQUATE TO STOP CELL-TO-CELL SPREAD OF THE VIRUS. THIS MAY BE PARTICULARLY IMPORTANT IN CURE OR N1 VIRUS REBOUNDS, BECAUSE WHILE THE MACROPHAGE MAY NOT HAVE VERY HIGH LEVELS OF VIRUS, IT COULD POTENTIALLY SPREAD THAT VIRUS TO T-CELLS, WHICH WOULD THEN EXPONENTIAL REPLICATE THE VIRUS. OVERALL, THE PHYSIOLOGICAL RELEVANCE OF MACROPHAGES AND INFECTIONS IN VIVO IN M-TROPIC VIRUS WAS OPEN TO DISCUSSION AND IT WAS A REALLY GREAT DISCUSSION. I THINK THAT WAS THE BEST PART OF THE MEETING. EVERYBODY HAD A VOICE. THE SECOND SECTION WAS MACROPHAGES AND HIV PERSISTENCE, LATENCY AND ACTIVATION. RESEARCH WAS PRESENTED DESCRIBING POTENTIAL MACROPHAGE RESERVOIRS IN VIVO AND -- THE METHODS THAT INHIBIT HIV REPLICATION IN MACROPHAGES ARE RELATIVELY UNKNOWN -- FOLLOWING SUCCESSFUL INFECTION AND MAXIMALLY STIMULATE THAT VIRUS IN MACROPHAGES TO PRODUCE VIRUS IS STILL UNDERINVESTIGATED. WE REALLY DON'T KNOW, AND MY LAB WORKS ON THIS AND I KNOW OTHERS DO, WE DON'T KNOW HOW TO MAXIMALLY ACTIVATE THE MACROPHAGE BECAUSE ACTIVATION CAN SET THAT MACROPHAGE ON A PATHWAY TO THE M2 PATHWAY, WHICH ACTUALLY SUPPRESSES THAT INFLAMMATORY RESPONSE, SUPPRESSES THE VIRUS. SO THESE MACROPHAGES AND POTENTIALLY LATENCY IN MACROPHAGES IS GOING TO BE VERY DIFFERENT FROM T-CELLS. SESSION 3 DISCUSSES IMMUNE RESPONSES TO HIV AND SIV INFECTED MACROPHAGES WHICH IS AN INNATE IMMUNE CELL. STUDIES REPORTED INEFFICIENT TYPE 1 RESPONSES IN BRAIN AND OTHER TISSUES THAT PRODUCE HIGH LEVELS OF THE CHEMOKINE -- YOU DON'T GET INTERFERON ALFAMATE, VIA A VERY NOVEL MECHANISM SUPPRESSES THE PRODUCTION OF A ALPHA WHICH COULD LIMIT THE INFECTION. ADAPTIVE IMMUNE PERSPECTIVE, THE DEMONSTRATION OF IMPAIRED CD8 CELL KILLING OF MACROPHAGES, BY CURE, LATENT, SHE SHOWED THAT IT REALLY DRIVES A PERSISTENT PRO INFLAMMATORY CYTOKINE AND CHEMOKINE RESPONSE THAT RECRUITS T-CELLS AND SO THIS WAS A MECHANISM THAT YOU CAN SEE AS THE CD8 CELL TRIES TO KILL THE MACROPHAGES THAT MIGHT BE INFECTED T ACTUALLY RESPONDS TO BE RECRUIT T-CELLS WHICH IS A NORMAL RESPONSE OF A MACROPHAGE, TO RECRUIT CELLS TO THE SITE TO GET INFLAMMATION AND KILLING BUT THEN IT CAUSED THE T-CELL TO BE INFECTED AND INFLAMMATION. SO INFLAMMATORY MONOCYTES ARE LIKELY TO CONTRIBUTE TO NIH NEUROLOGICAL DISEASES AS WELL AS CARDIOVASCULAR DISEASES BASED ON INFLAMMATION. UNDERSTANDING THESE SIGNATURES IN INFLAMMATION AND USING INHIBITORS TO CONTROL HIV ASSOCIATED INFLAMMATION WILL PROBABLY BE IMPORTANT FOR COMORBIDITIES AND POTENTIALLY FOR ERADICATION TOO, BECAUSE WE DON'T WANT THAT MACROPHAGE, WHETHER IT'S LATENTLY INFECTED OR NOT, TO BE PRO INFLAMMATORY, AND TO BE A SITE FOR EXPANSION OF VIRUS. SESSION 4 STUDIED -- REALLY PRESENTED A NEW TECHNIQUES TO LOOK AT MONOCYTES AND MACROPHAGES. TWO TECHNIQUES WERE PARTICULARLY DISCUSSED. ONE WAS THE SINGLE CELL ASSAY, AND THE OTHER WAS LIKE THE T-CELL QVOA USED FOR TELL CELLS. LAST CONCLUDING REMARKS, THE PANEL INCLUDE DAN, JAY, DIANE, AND JIM FROM VIIV HEALTHCARE. MACROPHAGE BIOLOGY, HIV PATHOGENESIS, HIV/SIV RESERVOIR, HIV ERADICATION AND MODEL SYSTEMS FOR STUDYING MACROPHAGES WERE DISCUSSED. I THINK THE QUESTIONS, THE MOST IMPORTANT, IS HIV LATENCY IN MACROPHAGES -- INFECTION IN LATENCY DIFFERENT IN DIFFERENT TISSUES. BECAUSE EACH TISSUE, WE HEARD, HAS DIFFERENT POPULATIONS AND DIFFERENT PHENOTYPES OF MACROPHAGES. SO IT MAY BE THAT WE'RE NOT DEALING WITH ONE KIND OF LATENCY OR INFECTION BUT MULTIPLE. HIV INFECTION AND LATENCY IS VERY DIFFERENT -- IS IT DIRN IN MDM VERSUS THE EMBRYONIC DERIVED MACROPHAGES? BECAUSE THEY ARE VERY DIFFERENT CELLS AND THE EMBRYONIC ONES CAN SELF-RENEW. HOW IS VIRAL TRANSCRIPTION REGULATED IN INFECTED MACROPHAGES? THAT IS A VERY UNDERSTUDIED AREA OF RESEARCH. CAN THE MACROPHAGE RESERVOIR RE-SEED THE T-CELL RESERVOIR? IN TERMS OF HIV PATHOGENESIS, WHAT IS THE EFFECT OF CART ON PERSISTENT INFLAMMATION IN HIV INDIVIDUALS? WE KNOW THE BRAIN, THERE IS ONGOING INFLAMMATION AND AS WELL AS THE HEART. HOW DOES RESIDUAL VIREMIA CONTRIBUTE TO THIS INFLAMMATION? AND IF MONOCYTE/MACROPHAGES ARE AT THE CENTER OF INFLAMMATION PATHWAYS, WHAT THERAPIES CAN BE USED IN COMBINATION WITH CART TO ADDRESS THIS? THE RESERVOIR QUESTION, WHICH I THINK IS MOST RELEVANT TO ERADICATION, THE MACROPHAGES DIRECTLY CONTRIBUTE TO LATENCY AND PERSISTENCE IN THE RESERVOIR. I THINK THIS IS A COMPLETELY UNKNOWN AREA, AND REALLY UNDERSTUDIED. VERY DIFFICULT TO STUDY IN PEOPLE BECAUSE IT'S TISSUE, BUT IT IS APPROPRIATE IN ANIMAL MODELS. WHAT'S THE HALF-LIFE OF INFECTED MACROPHAGES DURING INFECTION WITH ART? THAT'S UNCLEAR. ESPECIALLY IN THIS -- NOW IN THIS NEW ERA WHERE WE KNOW THERE'S AT LEAST TWO KINDS OF MACROPHAGES. HOW DO SEQUENCES IN MACROPHAGE POPULATIONS DIFFER IN DIFFERENT TISSUES? AND HOW ARE THEY DIFFERENT FROM WHAT WE SEE IN THE PLASMA VIRUS? WHAT ARE THE ME METHODS TO IDENTIFY DIFFERENT SUBPOPULATIONS OF HIV INFECTED MACROPHAGES AND THEIR INFECTION PROFILE, AND WHEN HIV INFECTED ART TREATED -- WITHIN HIV INFECTED ART TREATED INDIVIDUALS, DO SHORT LIVED MTMs OR LONG LIVED EMBRYONIC MACROPHAGES CONTRIBUTE TO THE RESERVOIR OR PERSISTENT INFECTION? IN TERMS OF ERADICATION, HOW CAN INFECTED MACROPHAGES BE TARGETED BY IMMUNE SYSTEMS, WE'RE THINKING ABOUT T-CELLS BUT NOT MACROPHAGES, HOW WILL THE IMPACT OF -- STUDIES BE LONGITUDINALLY ASSESSED, QUANTIFIED, AND IN WHAT TISSUES? AND FINALLY A QUESTION WAS RAISED, AND I THINK THIS WAS RAISED BY STEVE DEEKS, SHOULD WE LET SLEEPING DOGS LIE? IN RESPONSE NOT ONLY TO THE MACROPHAGE BUT PERHAPS TO ALL RESERVOIRS, DO WE HAVE TO ERADICATE ALL RESERVOIRS OR WOULD A FUNCTIONAL CURE IN COMBINATION WITH THERAPIES TO COMBAT INFLAMMATION BE SUFFICIENT FOR HIV INDIVIDUALS AND CAN HIV TRANSCRIPTION BE BLOCKED IN MACROPHAGES, THAT IS THE ISSUE HE RAISED. THERE WAS A REAL OPPORTUNITY FOR THE MODEL SYSTEMS, BOTH THE MACAQUE AND HUMANIZED MOUSE MODEL, TO EXPLORE THE ROLE OF TISSUE MACROPHAGES BRAIN AND OTHER TISSUES AND THEIR ROLE IN LATENCY. AND CULTURES ARE NOW VERY POPULAR, AND HAVE NOT REALLY BEEN APPLIED TO -- ORGANOID CULTURES -- HIV AS MUCH AS APPLIED TO NEW ZIKA STUDIES. SO -- DERIVING PERSISTENT INFLAMMATION AND MAY CONTRIBUTE TO THE VIRAL RESERVOIR, AND IT'S PROBABLY IMPORTANT TO ADDRESS MACROPHAGES AS WELL AS T-CELLS IN STUDIES OF HIV LATENCY AND REACTIVATION AS WELL AS THERAPEUTIC STUDIES FOR ERADICATION. SO I'M GOING TO INVITE -- VICTOR, WOULD YOU LIKE TO COME UP HERE AND ADDRESS SOME OF THE QUESTIONS? >> SO WE HAVE QUITE A BIT OF TIME FOR DISCUSSION BUT BEFORE WE DO, I ALSO WANTED TO RECOGNIZE DR. DIANE ROUSH. R., WHO IS THE DIRECTOR OF THE DIVISION OF AIDS RESEARCH FOR THE NATIONAL INSTITUTE OF MENTAL HEALTH, AND THERE WAS -- IN YOUR PACKET, YOU'LL SEE AN EXPLANATION AND A SUMMARY OF THE NIMH RESEARCH PORTFOLIO. THAT'S RELATED TO THIS YOU A GENERAL DA OF HIV CNS MACROPHAGES, AND SO ARE YOU GOING TO GO OVER IT? YES. >> OKAY, IT'S GREEN. SO DR. GOODENOW JUST ASKED ME TO SUMMARIZE SOME OF THE EFFORTS THAT NIMH AND OTHER ICs WITH AN INTEREST IN THE CNS EFFECTS OF HIV INFECTION ARE DOING TO ADDRESS SOME OF THESE QUESTIONS. AS YOU PROBABLY KNOW, THE WHOLE AREA OF HIV IN THE CNS RESEARCH IS A HIGH PRIORITY, ONE OF THE MAJOR GOALS OF THE NIMH MISSION, SO WE TEND TO TAKE THE LEAD ON A LOT OF THESE THINGS, BUT A LOT OF OUR EFFORTS ARE CO-SPONSORED BY OTHER INSTITUTES, PARTICULARLY NINDS. RM NIDANIDA DOES SOME CHILD HEALTH, AND CERTAINLY NIAID, DIVISION OF AIDS. SO I PUT TOGETHER THAT SUMMARY, A LOT OF THE WORK YOU SEE THERE IS DONE UNDER THE -- JAIMHON JOSEPH IN OUR OFFICE HAS TAKEN THE LEAD IN BUILDING THIS PORTFOLIO OF RESEARCH AROUND HIV IN THE CNS, MACROPHAGE, HOW IT AFFECTS MONOCYTES AND MACROPHAGES, ET CETERA. SO WE'VE DONE A NUMBER OF OUR FOAs, WE'VE DONE A NUMBER OF MEETINGS, WE HAVE A PRETTY SUBSTANTIAL PORTFOLIO. WE ALSO PARTICIPATE WITH THE DAIDS OF AIDS CLINICAL TRIALS GROUP WHEN THEY DO THERAPEUTIC INTERVENTIONS LOOKING AT CURES AND RESERVOIRS, WHENEVER IT'S REASONABLE, WE HAVE A NEUROAIDS COMPONENT TO IT OR WE DO CSF ASSESSMENTS AND NEURAL COGNITIVE ASSESSMENTS TO TRY TO UNDERSTAND THE COGNITIVE IMPACT WITHIN THE CNS. LOOKING AT KIDS WHO HAVE BEEN INFECTED LONG TERM, DOING CSF, LOOKING FOR VIRAL ESCAPE IN THE CSF, ET CETERA. AND ALSO WE WORK WITH THE IMPACT STUDY WHEN THEY'RE DOING CURE STUDIES ON INFANTS TO TRY TO LOOK AND SEE WHETHER THESE THERAPEUTIC REGIMENS CAN PENETRATE THE CNS AND CAN HAVE A PROTECTIVE EFFECT ON THE IMPACT OF HIV IN THE CNS. ONE OTHER STUDY WE'RE ALSO COFUNDING IS THE U.S. MILITARY HIV/AIDS STUDY IN THAILAND, WHERE THEY'RE RECRUITING PEOPLE VERY EARLY IN INFECTION AND ASSESSING THEM PRIOR TO INFECTION AND THEN TREATING THEM RIGHT AWAY AND LOOKING AT LONG-TERM EFFECTS OF EARLY TREATMENT, AND WE DO NEUROCOGNITIVE ASSESSMENTS, CSF, VIRAL BRAIN IMAGING, ET CETERA, TO TRY TO LOOK AT THE ESTABLISHMENT OF THE RESERVOIR AND HOW LONG THE EARLY TREATMENT HAS AN IMPACT ON THE CNS. SO THERE'S A VERY ROBUST AGENDA ADDRESSING THIS. ONE OF THE THINGS THAT DR. GOODENOW AND I TALKED ABOUT THAT REALLY WE NEED TO THINK ABOUT MORE IS A MAJOR CONSEQUENCE OF THIS MEETING THAT WAS HELD, IS THAT PERHAPS WE NEED TO BRING IN SOME MONOCYTE MACROPHAGE EXPERTS, NOT NECESSARILY TARGETING HIV, BUT WHO REALLY UNDERSTAND THE BIOLOGY OF MONOCYTES AND MACROPHAGES AND THEIR IMPACT ON THE IMMUNE SYSTEM AND HOW THAT BIOLOGY MAY IMPACT WHAT'S HAPPENING IN THE HIV WORLD. SO THAT'S CERTAINLY ON OUR RADAR AND WE'RE OPEN TO -- ALWAYS OPEN TO NEW IDEAS AND DISCUSSIONS, SO JUST TO KNOW THAT THIS IS -- THERE'S A VERY ROBUST CNS EFFORT GOING ON IN THE RESEARCH ARENA. THANK YOU. >> QUESTIONS. >> I WANT TO THANK YOU FOR YOUR SUMMARY. I WASN'T ABLE TO BE AT THE CONFERENCE BUT IT SOUNDS LIKE SOME VERY IMPORTANT ISSUES WERE DISCUSSED. I HAVE TWO SPECIFIC QUESTIONS. YOU MENTIONED THERAPY, IN A VERY SHORT SENTENCE AND I WONDERED, WAS THERE DISCUSSION ABOUT NOVEL FORMS OF THERAPY, FOR EXAMPLE, INTRANASAL INSULIN, WHERE WE HAVE AN ONGOING TRIAL, LOOKING AT -- AND OTHERS HAVE NEW IDEAS FOR MACKO PHAGE FOR MACROPHAGE FOCUSED THERAPIES. WE CAN NOW IMAGE MACROPHAGES IN VIVO, IT WAS THAT PART OF THE DISCUSSION, BOTH FOR THE BRAIN AND THE SYSTEMIC -- >> WE TRIED TO INCLUDE EVERYONE BUT WE DID NOT GET PEOPLE LIKE YOU TALKING ABOUT THE INSULIN AND WE DID NOT HAVE ANYONE TALKING ABOUT THE HUMAN IMAGING, BUT THAT IS SOMETHING, IT'S NONINVASIVE, BUT YOU COULD GET A LOT OF INFORMATION ABOUT IT, BUT THAT WAS NOT DISCUSSED, UNFORTUNATELY. >> IT WASN'T A CRITICISM. >> I KNOW. BUT IT'S A REALLY POSH POINT. >> IF I COULD JUST ASK A CLARIFYING QUESTION, WHAT WOULD INTRANASAL -- DO WITH MACROPHAGES? >> THAT'S SORT OF THE DRUG OF THE MOMENT, BEING TESTED AND TRIALED IN MANY DIFFERENT NEURODEGENERATIVE DISEASES FROM ALZHEIMER'S DISEASE TO MCI. WE HAVE A TRIAL IN AS I MENTIONED HIV-ASSOCIATED NEUROCOGNITIVE DISORDER THAT NIMH FUNDS. IT'S BEING TESTED IN MS AND THE CONCEPT IS THAT DELIVERY OF VERY SMALL DOSES OF INSULIN, NOT ENOUGH TO AFFECT GLYCEMIC CONTROL, CAN ENTER THE BRAIN THROUGH INTRANASAL DELIVERY. AND AFFECT CHANGES IN INFLAMMATION AND POTENTIALLY ACT AS A NEUROPROTECTIVE STRATEGY. LOTS OF IFS IN THAT SENTENCE. >> SPECIFICALLY MACROPHAGES COULD HAVE AN IMPACT ON INFLAMMATION FROM MACROPHAGES. >> CORRECT. >> THERE'S SOME IDEA ON THAT. >> SO THIS IS A PRETTY EXCITING TOPIC THAT YOU MET ABOUT AND I WANTED TO ASK YOU ONE QUESTION AND JUST MAKE A POINT ABOUT SOME ASPECTS OF MONOCYTE MACROPHAGE DERIVED INFLAMMATION. I DON'T KNOW THIS LITERATURE WELL, BUT ARE THERE SOME GOOD SYSTEMS FOR IN VITRO INDUCTION OF LATENCY AND PRIMARY DERIVED MACROPHAGES THAT CAN BE STUDIED AND USED AS MODELS FOR EVALUATING WHAT'S GOING ON IN VIVO, BECAUSE THE IN VIVO WORK IS REALLY, REALLY HARD. >> THERE ARE PEOPLE DEVELOPING THEM. MY LAB IS DEVELOPING THEM, YOU KNOW, SO -- AND I THINK OTHER LABS AS WELL. WE CAN INFECT MONOCYTE-DERIVED MACROPHAGES FROM HUMANS WITH HIV, AND WE SEE THEM NATURALLY CONTROL VIRUS AND BECOME LATENT, AND SO WE'RE STUDYING HOW THAT HAPPENS AND HOW WE CAN REACTIVATE THEM. TNF WILL REACTIVATE THEM, THOSE CELLS, TO ABOUT THE SAME LEVEL AS THE -- AS INFECTION BEFORE, BUT THESE ARE ALL SHORT TERM EXPERIMENTS, WITHIN A MONTH, SO WE DON'T KNOW WHETHER THAT IMPACTS ON -- THAT DOESN'T SAY ANYTHING ABOUT HOW LONG THAT CELL COULD REMAIN LATENT. SO WE'RE ONLY IN THE INFANCY OF DOING THOSE STUDIES, AND I THINK WE NEED MORE PEOPLE, JUST A FEW LABS DOING IT IS NOT SUFFICIENT BECAUSE WE ALL HAVE DIFFERENT POINTS OF VIEW. >> THAT'S GREAT. THE OTHER THING I WANTED TO POINT OUT THE INFLAMMATION IN TREATED HIV INFECTION, THAT'S BEEN ATTRIBUTED IN PART FOR THE ACTIVITY OF MONOCYTES, CAN HAVE MULTIPLE, MULTIPLE SOURCES, NOT JUST LOW LEVEL HIV REPLICATION, BUT ALSO ISSUES SUCH AS RELATED TO MICROBIAL TRANSLOCATION, THE PRESENCE OF OXIDIZED LIPIDS, AND EVEN A POSITIVE FEEDBACK LOOP WHEREBY THESE MONOCYTES THAT ARE PRO COAGO LANT ACTIVATING THE EXTRINSIC COAGULATION CASCADE CAN THEN BE ACTIVATED THEREAFTER BY THE DOWNSTREAM PRODUCTS OF COAGULATION AND THE PROAT YAL CYST OF COAGULATION FACTORS. FINALLY, T-CELLS THEMSELVES CAN IRRITATE MONO SITES AND INDUCE THEM TO BE MORE ANGRY. >> THANK YOU FOR ADDING THAT. THOSE ARE THINGS THAT WE ACTUALLY DIDN'T TOUCH ON, BUT I MEAN, OBVIOUSLY THE MONOCYTES, WHETHER IT'S INFECTED -- AND MACROPHAGE WHETHER IT'S INFECTED OR NOT PLAYS A VERY IMPORTANT POTENTIALLY WHAT HAPPENS DURING LATENCY. >> I THINK A POINT THAT FOLLOW ON WHAT YOU SAID IS THE FACT THAT THERE'S A VERY GOOD REASON WHY PEOPLE FOCUSED ON T-CELLS. THEY'RE EASY TO GET. THEY'RE THERE, AND THEY'RE THERE IN VERY LARGE NUMBERS. WORKING WITH MONOCYTES IN MACROPHAGES IS SIGNIFICANTLY MORE DIFFICULT, AND THE ACTION IS NOT IN THE PERIPHERY. THE ACTION IS IN THE TISSUES. SOME OF THESE TISSUES LIKE THE BRAIN ARE IMPOSSIBLE TO ACCESS IN ANY FORMERLY ON, OTHER THAN JUST -- INDIVIDUALS. THAT GIVES YOU A VERY, PERHAPS, LIMITED IDEA WHAT IS HAPPENING TO THE ORGAN, SO THIS IS GOING TO TAKE, LIKE -- SAID, NOT ONLY THE DEVELOPMENT OF NEW TECHNOLOGY, BUT A FOCUS ON THE TISSUES, WHAT IS HAPPENING SYSTEMICALLY YOU A WAY FROM THE PERIPHERY BECAUSE THAT'S WHERE THE INFECTED MACROPHAGES ARE. >> YOU KNOW, ONE OF THE THINGS THAT I THINK -- THIS IS FROM MY POINT OF VIEW, THERE ARE MANY -- THERE ARE THOUSANDS OF MONKEYS IN STUDIES IN THE U.S. UNDER STUDY WITH SIV FOR VACCINES AND PATHOGENESIS, PROBABLY MORE FOR VACCINES NOW, NONE OF THEM USE CSF TAPS TO SEE WHAT'S GOING ON IN THE CNS. NOW, IN PEOPLE, THERE'S A REASON NOT TO DO IT. BUT IN MONKEYS, YOU COULD EASILY DO IT. WE OBTAINED SIX MONKEYS FROM A STUDY JUST TO SEE IF THE CNS WAS INFECTED. AND ALL SIX MONKEYS HAD VIRUS IN THE CNS. SO WE'RE MISSING AN OPPORTUNITY TO UNDERSTAND THE ROLE OF VACCINES NOT ONLY IN THE PERIPHERY, BUT DO THEY PLAY AN IMPACT ON THE BRAIN, AND FOR THE MONKEY STUDIES, YOU KNOW, I'M SORT OF ON MY -- I'M WAVING MY FLAG, BUT THERE'S NO REASON NOT TO DO THAT. YOU DON'T HAVE TO DO IT WITH ALL OF THEM, BUT TO DO SOME, A THOUSAND MONKEYS, WE HAVE A SMALL PERCENTAGE, BUT IT SHOULD BE SOMETHING THAT PEOPLE GET SUPPLEMENTS FOR. OKAY, I'LL JUST LOOK AT THE CSF AND THEY COULD SEND IT TO SOMEONE WHO WOULD ANALYZE IT. SO I THINK WE HAVE A LOT OF OPPORTUNITIES THAT WOULD COST US NO MORE, WE'RE DOING THE RESEARCH ON THESE THINGS. BUT WE'RE NOT FOLLOWING THROUGH ON ALL THE THINGS WE COULD DO. >> THANK YOU VERY MUCH. I REALLY WANT TO COMPLIMENT YOU ON WHAT I SEE AS A REALLY EXCELLENT AND LONG OVERDUE MEETING. TO REALLY FOCUS ON SOMETHING THAT HAS BEEN UNDERAPPRECIATED. I'D LIKE TO ADD ONE THING TO EX-TEND WHAT VICTOR, MY COLLEAGUE OF MANY YEARS HAVE SAID, T-CELLS ARE THERE IN LARGE NUMBERS, EASIER TO WORK AT. I'D LIKE TO CALL ATTENTION TO SOME OF THE EARLIER PUBLICATIONS THAT LOOKED AT THE FIRST CELLS THAT WERE INFECTED IN THE NON-HUMAN PRIMATE. THE MESSAGE THAT CAME OUT OF THOSE STUDIES WAS THAT IT WAS A T-CELL. AND THAT EFFECTIVELY PUT THE MACROPHAGE ON THE BACK SHELF, AND AS RECENTLY AS THIS LAST YEAR, WE'VE PUBLISHED SOME OF OUR WORK ON MACROPHAGES, REVIEWERS HAVE ASKED ABOUT THE RELEVANCE OF IT, AND I THINK THAT AS IMPORTANT AS NON-HUMAN PRIMATE STUDIES ARE, THAT THEY HAVE TO BE KEPT IN PERSPECTIVE AS BEING MODEL SYSTEMS FOR THE HUMAN. THEY WILL GIVE US A LOT OF INFORMATION, BUT I WOULD SUBMIT THAT IN THIS PARTICULAR CASE IN WHICH WE BOUGHT IN TO THE IDEA THAT THE ONLY CELL INFECTED WAS A CD4 T-CELL, THAT IT SENT US DOWN THE WRONG PATH AND DELAYED THE TIME WHEN A VERY IMPORTANT MEETING LIKE THIS HAD TO -- REALLY HAD TO BE DONE. JUST ONE ADDITIONAL POINT, YOU SPOKE ABOUT COMPARTMENTIZATION, I THINK THAT IS REALLY CRITICAL. STUDIES OF COLLEAGUES IN MY LABORATORY HAVE BEEN ISOLATING MACROPHAGES FROM THROUGHOUT THE FEMALE REPRODUCTIVE TRACT, AND UPON WHETHER YOU'RE IN THE END MEE TREE UM, CERVIX OR ECTOCERVIX, WITH THE PHENOTYPE AND FUNCTION OF RESIDENT MACROPHAGES ARE DIFFERENT, SO AS ONE FOCUSES ON THE BRAIN, AND OTHER VASCULAR SYSTEM, I THINK IT'S GOING TO BE EQUALLY IMPORTANT TO LOOK AT INDIVIDUAL MUCOSAL SITES, THE TYPE OF STUDIES YOU'RE DOING, VICTOR, WHERE THEY'RE AVAILABLE FROM THE HUMAN TO REALLY SEE THE SUBTLE DIFFERENCES THAT ARE THERE, BECAUSE I THINK YOU, THROUGH THIS MEETING, HAVE TAPPED INTO SOMETHING SO IMPORTANT THAT IT IS GOING TO HAVE IMPORTANT RAMIFICATIONS IN THE YEARS TO COME. >> I DID HAVE ONE QUESTION, IS THERE ANY REASON TO THINK THAT -- REVERSAL AGENTS THAT WORK ON CD4 CELLS ARE NOT GOING TO WORK ON MACROPHAGES BECAUSE OF THE SYNAPSIS OR ANY OTHER REASON? >> WELL, SO ANTIRETROVIRAL DRUGS HAVE DIFFERENT EFFICACIES IN MACK MACROPHAGES IN VITRO, AT LEAST -- >> THERE ARE OTHER DRUGS PEE SIDES -- >> IF YOU GO TO THE ERADICATION DRUGS, A LOT OF STUDIES HAVE BEEN DONE ON THE T-CELLS, BUT WE'VE DONE SOME OF THEM IN MACROPHAGES AS WELL, AND WE'VE PUBLISHED ON IT. MACROPHAGES DO REACTIVATE DIFFERENTLY, AND THE TRANSCRIPTIONAL PATHWAYS ARE DIFFERENT. SO IT WILL BE DIFFERENT. BUT IT'S THE SAME KIND OF EPIGENETIC REGULATION IN MACROPHAGES, SO WE IMAGINE THAT THE H STACK TYPE ACTIVATORS WILL WORK THE SAME, BUT THE PATHWAYS THAT ACTIVATE MACROPHAGES FOR HIV IN MACROPHAGES IS DIFFERENT THAN THE -- >> [INAUDIBLE] >> THE POINT MADE, IF YOU USE SOME OF THESE, THERE MIGHT BE SOME SIGNIFICANT SEQUELAE IN THE BRAIN THAT MIGHT NOT BE SOMETHING YOU WANT TO SEE HAPPEN. SO EVEN THOUGH IT MIGHT BE ACTIVATED, WOULD THAT BE PRODUCTIVE OR COUNTERPRODUCTIVE IN A PATIENT THAT IS YET TO BE DETERMINED. THE OTHER THING TO KEEP IN MIND IS THAT EVEN IN TISSUES, THE FREQUENCY OF T-CELLS IS SIGNIFICANTLY HIGHER THAN OF MYELOID CELLS IN GENERAL. SO WHEN YOU'RE LOOKING TO STUDY MACROPHAGE INFECTION IN A CO T-CELLS, THINGS CAN GET REALLY CONFUSING AND IT'S VERY DIFFICULT TO ASSESS WHAT IS HAPPENING TO A MACROPHAGE WHEN YOU HAVE 50 T-CELLS AROUND IT. SO THAT IS A MAJOR PROBLEM AND WILL NEED TO BE ADDRESSED SO THAT WE DON'T GET CONFUSING RESULTS ABOUT WHAT MIGHT BE HAPPENING IN TISSUES IN VIVO. >> THANK YOU ALL. >> THANKS. [APPLAUSE] >> ANY QUESTIONS FROM ANY OF THE OTHER SESSIONS? OTHERWISE WE'RE A LITTLE BIT EARLY, WHICH IS TOTALLY FINE, AND WE'LL HAVE A LITTLE BIT LONGER OF A BREAK, BUT ANYTHING ELSE THAT PEOPLE WANT TO BRING UP FROM THAT SESSION OR ANYTHING ELSE? SO WE'RE DUE TO COME BACK AT 10:25, MAYBE WE CAN COME BACK UNTIL 10:20 AND THAT WAY WE CAN STAY A LITTLE BIT AHEAD. SO NOW OUR NEXT TALK IS GOING TO BE A REPORT ON CONTINUED STAKEHOLDER ENGAGEMENT IN THE OAR, AND THIS IS GOING TO BE DELIVERED BY DR. GINA BROWN, WHO SERVES AS MEDICAL OFFICER IN THE OAR AS COORDINATOR OF MICROBICIDES AND WOMEN AND GIRLS HIV RESEARCH. REALLY IMPORTANT PERSON FOR ME HERE. PRIOR TO JOINING THE OAR IN 2008, DR. BROWN SERVED AS A MATERNAL/FETAL MEDICINE SPECIALIST IN THE NEW YORK CITY DEPARTMENT OF HEALTH, AND MENTAL HYGIENE. SHE WAS THEN A CONSULTANT TO THE NEW YORK STATE DEPARTMENT OF HEALTH AIDS INSTITUTE ON POLICIES, RESEARCH AND CARE ISSUES SPECIFICALLY AFFECTING WOMEN, AND THE WOMEN'S HEALTH DIRECTOR OF THE WOMEN AND CHILDREN'S CARE CENTER AT COLUMBIA PRESBYTERIAN MEDICAL CENTER RESPECTIVELY. SHE THEN CAME TO THE OAR AND NOW SHE'S GOING TO TALK ABOUT THE OAR CONTINUED STAKEHOLDER ENGAGEMENT. >> GREAT, THANKS, MONICA, AND THANKS, EVERYBODY, FOR COMING TODAY. IT'S GREAT TO SEE SOME WONDERFUL FAMILIAR FACES. SO THE OFFICE OF AIDS RESEARCH UNDER THE DIRECTORSHIP OF DR. GOODENOW HAS TALK YOUD A LOT ABOUT BEING ABLE TO BRING IN AND UNDERSTAND THE INPUT FROM THE COMMUNITY, AND AS PART OF THIS, WE PUT TOGETHER A COMMUNITY LISTENING DAY. THE IDEA WAS TO INVITE MEMBERS OF THE COMMUNITY TO THE OFFICE OF AIDS RESEARCH AND TO GET A CHANCE TO ACTUALLY HEAR WHAT THEY'RE THINKING ABOUT WHAT'S HAPPENING IN RESEARCH, WHAT'S HAPPENING WITH COMMUNITY ENGAGEMENT, AND SO WE SET UP A COMMUNITY LISTENING DAY ON FEBRUARY 1ST, 2017. IT WAS REALLY A MULTI-STAFF EVENT. I THINK THERE'S PROBABLY NOT AN AREA WITHIN OAR WHERE THERE WASN'T A STAFF MEMBER WHO WAS INVOLVED, SO IT'S THE FOLKS SITTING OUTSIDE WHO ORGANIZED THE ROOM AND GOT US HERE, PIPER, MANY OF YOU KNOW RENE, I THINK THAT'S -- IN THE CORNER OVER THERE. THE BUDGET FOLKS REALLY HELPED IN TERMS OF TAKING NOTES, YOU SEE OUR STAFF AND THEN OTHER SCIENCE FOLKS, SO IT REALLY TOOK A VILLAGE TO PULL THIS TOGETHER, AND ALSO TO GET INPUT FROM ALL OF YOU ABOUT WHO NEEDED TO BE AT THE TABLE. SO THE GOALS WERE REALLY SIMPLY TO HEAR FROM THE COMMUNITY, AND WE GAVE THEM A FRAMEWORK AROUND WHAT THEY THOUGHT WERE THE RESEARCH GAPS AND ALSO THE RESEARCH OPPORTUNITIES THAT NEEDED TO BE ADDRESSED WITHIN NIH. WHAT WERE SOME OF THEIR ACTUAL CONCERNS AROUND HIV, AND THEN ALSO REALLY GETTING A SENSE FROM THEM, WHAT ARE THE BEST PRACTICES THAT NEED TO BE PUT FORTH SO THAT WE REALLY HAVE CONTINUED COMMUNITY ENGAGEMENT. HOW DO WE LEARN FROM WHAT WE'VE DONE IN THE PAST, HOW DO WE KEEP THEM ENGAGED AND HOW DO WE GET INFORMATION OUT IF N., HAVE A BETTER SENSE OF WHAT'S GOING ON IN THE RESEARCH COMMUNITY AS A WHOLE, BUT ALSO IN NIH RESEARCH IN GENERAL. SO IT WAS A STRUCTURED CONVERSATION. THEY WERE HERE FOR TWO HOURS, THEY WERE IN THIS VERY ROOM FOR TWO HOURS, AND IT WAS A FACILITATED DISCUSSION. THE ONLY FACILITATION WAS REALLY TO ROLL OUT HERE ARE THE RESEARCH GAPS AND OPPORTUNITIES, WHAT WE WANT TO HEAR FROM YOU NOW INT HOW WE CAN BETTER ENGAGE YOU, HOW WE CAN PROVIDE INFORMATION DISSEMINATION. WE SENT OUT ABOUT 60 INVITATIONS TO COMMUNITY ORGANIZATIONS KIND OF ACROSS THE COUNTRY, WE TALKED TO A LOT OF FOLKS ABOUT WHO WERE THE MAJOR COMMUNITY ORGANIZATIONS THAT NEEDED TO BE HERE, AND PART OF BECAUSE OF SORT OF THE TRANSPORTATION ISSUES OF GETTING PEOPLE IN, WE ENDED UP WITH A REAL EAST COAST FROM NEW YORK ON DOWN REPRESENTATION. WE ALSO PROVIDED AN OPPORTNITY FOR A HANDFUL OF FOLKS WHO SAID THEY COULDN'T ATTEND TO PARTICIPATE ONLINE AND SUBMIT COMES. AND THEN AT THE END OF EACH KIND OF SESSION OR SECTION OF A LOT OF PEOPLE TALKING, AND THEN GETTING THE QUESTIONS ONLINE, OR DISCUSSION POINTS FROM ONLINE, WE WOULD DO A BRIEF SUMMARY SO THAT EVERYBODY KIND OF AGREED THAT THESE WERE THE POINTS. I THINK THE MOST IMPORTANT PART OF THIS IS WE DID VERY LITTLE SPEAKING AND WE REALLY DID LISTEN TO PEOPLE COMING UP TO TALK WITH US AND TRIED TO GEAR IT AWAY FROM A QUESTION AND ANSWER SESSION BUT REALLY ABOUT WHAT THEIR OPINIONS WERE. SO FOR REGISTERED ATTENDANT, WE HAD 28 PARTICIPANTS WHO CAME IN PERSON AND THREE WHO TOLD US THEY WOULD JOIN US ONLINE AND THEY REPRESENTED A PANOPLY OF ORGANIZATIONS, TYPES AND COMMUNITY ORGANIZATIONS THAT WOULD -- THAT REALLY ARE BENEFITING FROM THE HIV RESEARCH THAT HAPPENS BOTH FUNDED BY NIH AND IN GENERAL. SO THEY WERE GLOBAL, NATIONAL, ON THE GROUND COMMUNITY AGENCY, PLACES LIKE GMAC, IRIS HOUSE IN NEW YORK, THE LATINO COMMISSION ON AIDS, WHITMAN WALKER, HIV, THE MEDICAL ASSOCIATION FOR THE COMMUNITY OF CLINICIANS WERE ALSO REPRESENTED, SOME WOMEN'S SPECIFIC HEALTH AGENCIES, INDIVIDUALS LIVING WITH HIV WHO EITHER REPRESENTED AN AGENCY OR THEY THEMSELVES WERE PART OF THIS DISCUSSION AS INDIVIDUALS. SO THE OTHER THING WE FOUND OUT AFTER THE SESSION, 28 PEOPLE IN THE ROOM WHO WERE FROM THE AGENCIES, WE HAD THE THREE PEOPLE WE KNEW ABOUT ONLINE AND THEN THE ORGANIZATION WITHIN NIH THAT DOES THE COUNT ALSO TOLD US ABOUT ALL THE OTHER PEOPLE THAT ENDED UP ONLINE. THESE WERE NOT SOLICITATIONS, WE DIDN'T SEND THE INFORMATION OUT, BUT IT'S A SMALL COMMUNITY AND INFORMATION PASSES. SO WE HAD 63 PEOPLE WHO JOINED US LIVE ONLINE, 7, THEY WEREN'T ABLE TO DETERMINE WHERE THE LOCATION WAS, ONE FROM CANADA, TWO FROM SOUTH AFRICA. 20 PEOPLE WERE NIH FOLKS WORKING FROM NIH COMPUTERS, SIX WERE FROM DHHS IN GENERAL, AND THEN WE HAD 37 OTHERS, AGAIN, WE COULDN'T TELL, THEY USED A VARIETY OF WAYS TO BE A PART OF THIS USING ANYTHING FROM COMCAST TO ANY OTHER LEVEL OF PRIVATE PROVIDERS. BUT IN ADDITION, WITH THE WEEK OR SO AFTER, PEOPLE LOOKED AT THIS ONLINE, SO THOSE WERE THE ARCHIVED SET OF -- FILMING OF THIS DISCUSSION WITH 24 FROM THE U.S., NINE AGAIN UNKNOWN AND ONE KA NAID CANADIAN. 16 WERE FROM NIH, 17 FROM OA WE DON'T HAVE A SENSE OF WHETHER THEY WERE IN COUNTRY, OUT COUNTRY AR WHERE ELSE THEY GOT THE INFORMATION, BUT IT WAS TOTALLY UNEXPECTED THAT THIS MANY PEOPLE WERE ACTUALLY PART OF LISTENING IN. WE HEARD A LOT FROM FOLKS ONLINE AFTERWARD ABOUT UNABLE TO ATTEND, INTERESTED IN CONTINUING THE CONVERSATION. SO THE FIRST DISCUSSION POINT AROUND WHAT WERE THE RESEARCH GAPS AND TEUPTS, AND FROM THAT GROUP OF PEOPLE AND THE FOANTS FOAX ONLINE, THERE WAS REALLY TREMENDOUS AGREEMENT THAT IN THESE PARTICULAR AREAS, WE NEED TO PUT IN ADDITIONAL FOCUS. AGING IN PARTICULAR WAS BROUGHT UP BY MANY OF THE FOLKS WHO GOT UP TO SPEAK. NOW IT MAY HAVE BEEN A VIRTUE OF THE AGE RANGE OF THE PEOPLE HE HAD IN THE ROOM, BUT I THINK WE'RE ALSO RECOGNIZING WHERE THE SCIENCE HAS GONE, WHAT WE'VE LEARNED ABOUT INFLAMMATION AND WHAT WE NEED -- WHAT THEY THINK SOME OF THE MAJOR ISSUES ARE THAT NEED TO BE ADDRESSED. THEY TALKED ABOUT THE NEED FOR BROADER IC INVOLVEMENT AS WE ADDRESS THIS AGING ISSUE TO LOOK AT MANY OF THE CO-MORBID ITS AND COINFECTIONS THAT PEOPLE AGING WITH HIV ARE FACED WITH, AND THEY ALSO TALKED ABOUT THEY NEED TO BETTER UNDERSTAND FRAILTY, THE ACCELERATED MORBIDITY AND MORTALITY, AND THEN THE ISSUES OF POLYPHARMACY, WHICH I THINK WE PROBABLY DON'T DISCUSS ENOUGH, AND WHAT THAT MAY MEAN FOR BOTH FRAILTY, MORBIDITY AND MORTALITY FOR THE AGING GROUP OF FOLKS LIVING WITH HIV INFECTION, ALSO WHAT THE ETHNIC GENDER AND SEX DIFFERENCES WITH THIS GROUP OF PEOPLE, THAT IT'S NOT A MONOLITHIC GROUP OF FOLKS OVER THE AGE OF 50. SOMETHING I THINK WE'VE FOCUSED A LOT ON AND THAT I THINK IS ABSOLUTELY IMPORTANT, BEING ABLE TO SORT OUT WHAT'S HIV, WHAT'S HIV TREATMENT AND WHAT'S JUST GENERAL AGING TO DETERMINE WHAT THE KINDS OF INTERVENTIONS. VIRTUALLY ANYBODY WHO GOT UP TO SPEAK TALKED ABOUT THE NEED TO INCLUDE WOMEN IN THESE ANALYSES. AND NOT TO JUST PRESENT DATA ON MEN. AND THEN ALSO THAT WE NEED TO MAKE SURE THAT WE DO THIS RESEARCH IN THE POPULATIONS MOST AT RISK. YOUNG INDIVIDUALS, YOUNG BLACK MSM, YOUNG AFRICAN-AMRICAN WOMEN, MAKING SURE WE INCLUDE BOTH RACIAL AND DIFFERENT ETHNIC POPULATIONS TO BETTER UNDERSTAND WHAT THE EPIDEMIC LOOKS LIKE IN THE UNITED STATES AND OUTSIDE. AROUND MORBIDITY AND MORTALITY ISSUES, PEOPLE BROUGHT UP THE ISSUES OF HEPATITIS C AND HIV IN THE INTERSECION AND NOW WE'RE SEEING THIS IN PLACES WHERE WE TRADITIONALLY DIDN'T SEE AN HIV EPIDEMIC: INDIANA, WEST VIRGINIA, THEY TALKED ABOUT SOME OF THE WORK THAT'S BEEN DONE THERE BOTH CLIPICALLY BUT CLINICALLY BUT A LSO THE IMPORTANCE OF UNDERSTANDING THIS EPIDEMIC AND THE RESEARCH THAT NEEDS TO BE DONE. EVERYBODY TALKED ABOUT THE NEED TO BETTER UNDERSTAND THE MENTAL HEALTH ISSUES AND HOW THAT IMPACTS BOTH ENROLLMENT IN HIV RESEARCH TRIALS OR RESEARCH INTERVENTIONS OR FOLLOW-UP STUDIES, BEING ABLE TO MAINTAIN PEOPLE IN STUDIES, BUT ALSO% BEING ABLE TO BETTER UNDERSTAND WHAT THIS MEANS FOR THE OUTCOMES FOR TREATMENT, ET CETERA. AROUND HIV PREVENTION, THE WIDE RANGE OF INTERVENTIONS THAT ARE NEEDED, NOT JUST SINGULAR APPROACHES TO HIV PREVENTION, BUT WE NEED A WIDE RANGE FOR LOTS OF DIFFERENT WAYS THAT PEOPLE WILL BE ABLE TO TAKE THEIR INTERVENTION, THE ISSUES OF HOW YOU APPROACH IT BOTH ABOUT LOCAL INTERVENTION, SYSTEMIC, ET CETERA, WERE BROUGHT UP. AND THEN ALSO THAT WE NEED TO BETTER UNDERSTAND, IT'S NOT JUST PROVIDING PREVENTION BUT WE NEED TO THINK WHAT THE PREVENTION CASCADE IS LIKE, PARTICULARLY AROUND THE ISSUES OF ADHERENCE AS PEOPLE FALL IN AND OUT OF WHAT METHOD THEY WOULD USE TO PREVENT HIV INFECTION. AROUND TREATMENT ISSUES -- THEY ALSO BROUGHT UP THE ISSUE OF LONG ACTING PREVENTION INTERVENTIONS. AROUND TREATMENT ISSUES, IT'S THE THINGS WE'D EXPECT. WE NEED TO THINK ABOUT LONG TERM THERAPY TO ADDRESS THIS ADHERENCE ISSUE, BUT ALSO THINK ABOUT SOME OF THE ALTERNATIVE THERAPIES, PARTICULARLY THOSE USEFUL IN ADDRESSING MENTAL HEALTH ISSUES AND ALSO ALTERNATIVE APPROACHES TO HOW YOU DELIVER CARE. THAT KEEP INDIVIDUALS LIVING WITH HIV FROM RUNNING BACK AND FORTH TO THE CLINICIAN EVERY WEEK, EVERY COUPLE OF WEEKS, BECAUSE AS THEY PUT IT, THEY HAVE OTHER THINGS TO DO WITH THEIR LIVES AND COME IN AND OUT OF HOSPITAL OR CLINIC SETTINGS. THE ISSUES OF QUALITY OF LIFE AND HEALTH WERE ALSO BROUGHT UP, BEING ABLE TO LOOK AT TREATMENT FROM THE POINT OF VIEW OF HOW YOU IMPROVE QUALITY OF LIFE AND WHAT THAT MAY MEAN FOR ULTIMATE HEALTH OUTCOMES AND BEING ABLE TO UNDERSTAND THIS INTERSECTION, AND THEN THE REAL NEED TO FIGURE OUT HOW WE CAN ENHANCE PROVIDER COMMUNICATION TO THEIR CLINICIANS AND THEY SAW THIS ACTUALLY AS A RESEARCH ISSUE, NOT JUST AN IMPLEMENTATION OR TREATMENT AND MANAGEMENT ISSUE, BUT ALSO THE ISSUES OF CULTURAL COMPETENCY, HOW DO WE BETTER EDUCATE PROVIDERS TO BETTER UNDERSTAND THE PEOPLE THAT THEY'RE WORKING WITH AND BEING ABLE TO DELIVER INFORMATION TO THEM. AND PROVIDE APPROPRIATE TREATMENT AND MANAGEMENT ULTIMATELY, AGAIN, THEY SAW THIS AS A RESEARCH ISSUE, NOT SIMPLY A CARE AND TREATMENT ISSUE. THERE WERE SOME OVERARCHING ISSUES. WE WERE CALLED ON BETTER NIH COLLABORATION, SO INTRAAGENCY COLLABORATION, BUT ALSO FOR THE U.S. GOVERNMENT IN GENERAL TO HAVE BETTER INTERAGENCY COLLABORATION, BRINGING UP THE WORK THAT'S DONE WITH CDC, HRSA AND OTHERS, ALONG WITH WHAT NIH DOES, TO MAKE SURE WE'RE NOT OVERLAPPING AND DOING THE SAME THINGS, BUT ALSO MAKE SURE THAT WE'RE FEEDING EACH OTHER IN TERMS OF THE KIND OF WORK THAT NEEDS TO BE DONE. AND THEY ALSO CALLED TO TASK ACADEMIA. DON'T BRING IN THE COMMUNITY AFTER YOU'VE DETERMINED WHAT THE STUDY IS, AFTER YOU'VE GOTTEN THE FUNDING AND YOU'VE DETERMINED WHAT YOUR STUDY STRUCTURE WILL BE LIKE, BUT BRING THEM IN AHEAD OF TIME AND THEY CAN BE INKRED PLI HELPFUL IN TERMS OF YOUR ABILITY TO CONDUCT YOUR STUDY IN A MUCH MORE SUCCESSFUL FASHION IF THEY ARE PROVIDING YOU WITH INPUT. THERE WAS DISTINCT NEED FOR STIGMA AND SOCIAL SCIENCE RESEARCH, UNDERSTANDING THE COMMUNITIES YOU'RE WORKING IN AND WHAT IT MEANS FOR YOUR ABILITY TO CARRY OUT RESEARCH SUCCESSFULLY, KEEP PEOPLE IN RESEARCH AND ALSO GET ADHERENCE TO THE INTERVENTIONS. I WAS A TINY BIT SURPRISED BECAUSE I THOUGHT WE'RE TALKING WITH COMMUNITY, BUT MANY OF THEM TALKED ABOUT THE NEED TO MAINTAIN THE BASIC SCIENCES RESEARCH THAT HAS TO BE DONE THAT GETS US TO THE POINT WHERE WE HAVE AN INTERVENTION OR WE HAVE A TREATMENT, WE HAVE A MANAGEMENT PROCESS THAT WE REALLY NEED TO CONTINUE TO FUND BASIC SCIENCES RESEARCH. ALWAYS INCLUDING THE MOST AFFECTED COMMUNITIES BY RACE, BY LOCATION, RECOGNIZING WHERE THE EPIDEMIC IS, BY SEX AND GENDER, AND THEN ALL OF THEM SAID THAT NIH NEEDS TO STEP UP AROUND THE ISSUES OF IMPLEMENTATION SCIENCE. WE NEED TO KNOW BETTER HOW THESE THINGS THAT WE BUILD, THESE IND VENGSES THAT WE INTERVENTIONS WE HAVE, HOW TO BEST ROLL THEM OUT AND GET THEM DONE EFFECTIVELY SO WE CLOSE THAT LINK BETWEEN WHAT WE LEARN AND BEING ABLE TO APPLY IT. AROUND COMMUNITY ENGAGEMENT AND INFORMATION DISSEMINATION, THEY REALLY TALKED ABOUT, AGAIN, TARGETING THE COMMUNITY EARLY IN THE DESIGN PROCESS OF STUDIES, AND THEN MAKING SURE THAT THE WAY WE PROVIDE INFORMATION IS CONSISTENT ACROSS THE GOVERNMENT AGENCYIES AND THAT IT'S IN A LANGUAGE THAT CAN BE USED BY THE COMMUNITY TO EDUCATE THEIR CONSTITUENTS SO THAT IT'S NOT TOO HIGH LEVEL, BUT IT IS INFORMATIVE. THEY ALSO TALKED ABOUT THERE ARE MANY SUCCESSFUL MODELS FOR INVOLVING THE COMMUNITY AND THAT WE DON'T NEED TO GO ABOUT TRYING TO REINVENT THE WHEEL BUT TO MAKE USE OF THESE SUCCESSFUL MODELS THAT MANY STUDIES HAVE DONE IN THE PAST ARE DOING CURRENTLY, AND TO KIND OF ROLL IT OUT IN THAT WAY. AND THEN ALSO UNDERSTANDING THE SOCIAL AND STRUCTURAL FACTORS THAT APPLY TO RESEARCH ENGAGEMENT. IT'S VERY HARD TO GET SOMEONE TO COME BACK AND FORTH FOR THEIR STUDY VISITS IF THEY DON'T HAVE THE MONEY TO GET THERE, OR IF YOU'VE GOT THEM BOUNCING AROUND TO EIGHT OR NINE DIFFERENT PLACES TO GET THEIR KIND OF INTERVEPTIONS OR LABORATORY AND THINGS LIKE THAT DONE, SO WE NEED TO UNDERSTAND HOW THESE FOLKS WORK. THEY TALKED A LOT ABOUT LOOKING AT THE GOOD PARTICIPATORY PRACTICE FRAMEWORK FOR COMMUNITY ENGAGEMENT. WE HAVE A FRAMEWORK THAT EXIST, WE NEED TO PROBABLY MAKE BETTER USE OF IT, HOW THAT BECOMES AN INSISTENT PART ABOUT WHEN YOU APPLY FOR FUNDING AND YOU'RE DOING RESEARCH IN THE COMMUNITY, HOW YOU MAKE USE OF THIS. AND AS I SAID, CONSISTENT MESSAGING, AND THE OTHER THING THEY REALLY HAMMERED OUT THROUGHOUT THE DISCUSSION WAS, YOU NEED TO DOCUMENT THE NIH RESEARCH SUCCESSES. WE NEED TO OWN WHEN WE DO SOMETHING WELL AND BE ABLE TO TALK ABOUT IT, AGAIN, IN A LANGUAGE THAT THE GENERAL COMMUNITY UNDERSTANDS. EVERYTHING FROM GOVERNMENTAL COMMUNITY TO PEOPLE WORKING ON THE GROUND TO KNOW WHAT'S OUT THERE AND WHAT'S WORKING AND WHAT WE'VE DONE WELL. THE OTHER THING THEY'VE ALL TALKED ABOUT IS WE NEED TO START TO DOCUMENT WHAT THE CROSSOVER BENEFITS ARE TO HIV RESEARCH. THEY RAISE THE ISSUES OF OUR UNDERSTANDING THE ROLE OF INFLAMMATION AND CARDIOVASCULAR DISEASE AND HOW A LOT OF THAT HAS COME FROM THE CONSISTENT WORK THAT'S BEING DONE IN HIV. LOCKING AT THE FEMALE GENITAL TRACT INFLAMMATION, THE MICROBIOME, AND HOW THAT ISSUE HAS REALLY BEEN PUSHED AROUND HIV BUT IT ACTUALLY INFLUENCES THINGS LIKE PREMATURITY AND PREGNANCY OUTCOME, SO TO OBSERVE THAT WE'VE DONE A LOT OF THINGS IN HIV ROW SECH THAT REALLY BENEFIT THE GREATER MEDICAL AND BIOMEDICAL COMMUNITY AND BEHAVIORAL COMMUNITY AT LARGE. SO THE NEXT STEPS WITH THIS IS, THEY RECOMMENDED THAT WE REALLY TAKE ADVANTAGE OF OTHER PLACES WHERE PEOPLE GATHER FROM THE COMMUNITY. THERE ARE OTHER LISTENING DAY SESSIONS, PERHAPS, THAT WILL BRING FOLKS TO NIH PERIODICALLY BUT ALSO FOR THE MANY CONFERENCES THAT ARE OUT THERE WHERE WE'RE REPRESENTED AND COMMUNITY MEMBERS ARE REPRESENTED SORT OF ACROSS THE BOARD IN TERMS OF SCIENCE AND NON-SCIENCE BUT HIV-RELATED CONFERENCES TO BE THERE AND SET UP SESSIONS WHERE THEY CAN COME AND TALK WITH US, EXPRESS THEIR CONCERNS ABOUT AND THOUGHTS ABOUT RESEARCH, PROVIDE US WITH INFORMATION ABOUT WHAT THEY THINK NEEDS TO BE DONE, AND THERE'S A BETTER SENSE OF US HEARING THEM AND THEM HEARING US. THERE HAVE BEEN A NUMBER OF THOSE INSTANCES THAT HAVE HAPPENED SINCE THIS FEBRUARY 1ST, THAT HAVE BROUGHT DR. GOODENOW IN CONTACT WITH MANY COMMUNITY MEMBERS AT DIFFERENT CONFERENCES AND MEETINGS BOTH ON AN INDIVIDUAL LEVEL BUT ALSO ON A SMALL GROUP LEVEL. WE NEED TO CONTINUE TO HAVE PEOPLE LIVING WITH HIV REPRESENTATION ON THE WORK WE ALL DO ACROSS NIH, THE ADVISORY COUNCILS, THE COMMUNITY ADVISORY BOARDS FOR THE STUDIES, AND THEN ALSO WHEN WE'RE DOING CONFERENCE PLANNING AND CONFERENCE GROUPS, TO MAKE SURE WE'RE REALLY ADDRESSING THIS FROM AN ISSUE OF RESEARCH THAT BENEFITS -- ANSWERS THE QUESTIONS BUT RESEARCH THAT ULTIMATELY HELPS US BE BETTSER AT WHAT WE DOOR FOR HIV-INVECTEDINFECTED INDIVIDUALS. THANK YOU. [APPLAUSE] >> ANY QUESTIONS FOR DR. BROWN? >> THANK YOU FOR YOUR SUMMARY. I'M HEARING QUITE A BIT FROM COMMUNITY ADVISORY BOARDS THAT I WORK WITH ABOUT REPRODUCIBILITY OF RESEARCH RESULTS. OBVIOUSLY THIS IS A BIG TOPIC WRITTEN LARGE, AND I WONDERED IF IT CAME UP AND IF IT DID, HOW WOULD OAR RESPOND TO THAT? >> HOW THEY -- I THINK THE WAY THAT MIGHT HAVE COME UP IN TERMS OF DISCUSSION IS IN A BROADER WAY, ABOUT -- AS WE'RE PLANNING RESEARCH, MAKING SURE THAT WHEN WE REPEAT THINGS, MAKING SURE THAT IT'S FOR A USEFUL EFFICIENT WAY AND NOT SORT OF UNNECESSARY OR NOT PARTICULARLY USEFUL DUPLICATION, BUT THEY ALL RECOGNIZE THERE NEEDS TO BE SOME DUPLICATION OF THE EFFORTS AND SOME DUPLICATION OF THE FUNDING AROUND THAT. BUT THEY DIDN'T SPECIFICALLY SAY REPRODUCIBILITY. THEY TALKED ABOUT MAKING SURE IT'S AN EFFICIENT AND USEFUL DUPLICATION OF EFFORT AS OPPOSED TO IT'S AN INTERESTING TOPIC, LET'S DO A LOT OF THAT. >> I HAD A QUESTION WHICH ADDRESSES -- WHICH GOES TO WHAT YOU TALKED ABOUT, ABOUT THE NEW WORKING GROUPS THAT ARE GOING TO BE FORMED, AND YOU HAD MENTIONED THE RETURN ON HIV/AIDS INVESTMENT FOR BIOMEDICAL RESEARCH. IT SEEMS BASED ON WHAT YOU TALKED ABOUT WITH THE CROSS CUTTING INITIATIVES THAT THE ECONOMIC ANALYSIS HAS TO INCLUDE EFFECTS ON CARDIOVASCULAR HEALTH AND IMMUNITY IN THE FEMALE GENITAL TRACT AND ALL THESE OTHER AREAS, IT'S GOING TO BE COMPLEX BUT IT SHOULD ALL BE IN THE ECONOMIC ANALYSIS. >> WE'RE JUST AT THE EARLY PHASE OF CONSTRUCTING THESE, AND I THINK AS YOU POINT OUT, THERE ARE SO MANY FACTORS BOTH FROM THE COMORBIDITIES THEMSELVES AND IN THE MULTI-FACTORIAL ASPECTS OF THE ECONOMICS, SO I THINK WE'RE ACTUALLY GOING TO HAVE TO PROBABLY BREAK THEM DOWN INTO SMALLER PIECES BECAUSE WHAT I DON'T WANT IS FOR WORKING GROUPS TO TURN IN TO STANDING SUBCOMMITTEES TO GO ON IN PERPETUITY. I'D LIKE THESE TO BE NIMBLE, VERY FOCUSED, GET THE JOB DONE QUICKLY, THEN WE MOVE ON TO THE NEXT ONE, HAVE OUTCOMES TO QUICKLY NOT NECESSARILY -- TO REALLY JUST KEEP THINGS MOVING ALONG RATHER THAN HAVING A HUGE AGENDA THAT COULD TAKE YEARS. WE NEED TO GET SOME OF THESE THINGS WORKED OUT AND THOUGHT ABOUT FASTER THAN THAT. I JUST WANT TO MAKE ONE COMMENT ABOUT THIS EVENT, BECAUSE THIS WAS THE FIRST TIME THAT I HAD REALLY ENGAGED LIKE THAT WITH A LARGE GROUP OF INDIVIDUALS WHO ARE NOT SCIENTISTS BASICALLY, BECAUSE AS A BASIC SCIENTIST THIS, IS NOT SOMETHING WE USUALLY DO. I HAVE TO SAY THE PEOPLE WHO WERE THERE THAT SHOWED UP WERE JUST FANTASTIC, THEY WERE SO WELCOMING, THEY WERE JUST REALLY THERE AND KEPT SAYING WHAT CAN THEY DO TO HELP US. I THINK WHAT STRUCK ME THE MOST IS THAT WHEN IT CAME TIME FOR THE BREAK, NOBODY GOT UP AND THEY SAID, NO, NO, LET'S JUST KEEP GOING. WE JUST WENT THROUGH THE WHOLE AFTERNOON WITHOUT TAKING A FORMAL BREAK OR ANYTHING. IT WAS REALLY AMAZING. >> THANK YOU FOR A GREAT PRESENTATION AND YOUR IMPORTANT WORK. A QUICK COMMENT AND A QUICK QUESTION. THE COMMENT IS, WE HAVE A VERY ACTIVE COMMUNITY ADVISORY PORD FOR OUR -- I JUST FOUND IT VALIDATING THAT SOME OF THE SAME THEMES THAT YOU'RE HEARING NATIONALLY, WE'RE HEARING LOCALLY: AGING, WOMEN, YOUTH, SO THAT WAS VERY REFRESHING TO SEE. MY QUICK QUESTION IS, WERE THERE ANY SURPRISES TO THE PROGRAMMATIC STAFF AT NIH AT OAR TO WHAT YOU HEARD? WERE THERE THINGS THAT YOU LEARNED THAT YOU WOULDN'T HAVE EXPECTED? >> FOR ME, THE CONCEPT THAT THEY REALLY PUSH THE IMPORTANCE OF BASIC SCIENCES RESEARCH SURPRISED ME A BIT, BUT IT'S A WELL EDUCATED COMMUNITY OF FOLKS WHO HAVE BEEN DOING THIS WORK FOR MANY YEARS, SO I THINK HOW THEY GET ALL THESE THINGS ALL TIE TOGETHER, BUT MORE THAN A COUPLE PEOPLE BROUGHT IT UP AND CORRECTED ME WHEN I DID A SUMMARY AND DIDN'T MENTION IT, THAT IT NEEDED TO BE AB IMPORTANT PART OF THE RESEARCH THAT WE DO HERE. THAT WAS A SURPRISE. I DON'T KNOW ABOUT OTHER FOLKS WHO WERE THERE, WHO WERE PART OF OUR STAFF WHO WERE LISTENING, BUT -- AND THEN THE REALLY SOMEWHAT -- I GUESS I'D CALL IT A SOPHISTICATED UNDER STANDING OF HOW THE AGENCIES REALLY CAN INTERACT WITH EACH OTHER TO PUSH A UNIFIED AGENDA, AND THE REAL NUDGE TO MAKE SURE THAT THAT ACTUALLY HAPPENS IN A VERY CLEARLY DEFINED MORE STRUCTURED WAY, I THOUGHT NOT SO MUCH A SURPRISE BUT THAT MANY FOLKS TALKED ABOUT IT AND IDEAS ABOUT HOW THAT NEEDED TO HAPPEN. >> OKAY. SORRY, CHUCK. PLEASE. >> I THINK IT'S EXCELLENT THAT YOU'RE ABLE TO DO THIS. JUST LOOKING AT THE PICTURES, SOME OF THE COMMUNITY ACTIVISTS THAT ARE THERE, THAT CARE VERY DEEPLY, IT'S EXCITING TO SEE THEY'RE PRESENT. THE QUESTION IS, DID ANY DISCUSSION COME U AND IF YOU SPOKE ABOUT IT, I APOLOGIZE, ABOUT HIV AND THE ELDERLY? BOTH FROM THE STAND POINT OF CARE OF THE ACQUISITION, WHICH IS A REAL FACTOR TOO, WHICH WE HEARD EARLIER TOO FROM DR. GOODENOW, BECAUSE IT SEEMS TO ME THAT THERE IS THIS POPULATION TREND WITH HIV IN THE ELDERLY, WHICH IS MUST MORE THAN JUST PEOPLE LIVING LONGER. >> ABSOLUTELY. I THINK THAT WAS PART OF THE BROADER -- I SUMMARIZED IT BUT IT WAS PART OF THE BROADER DISCUSSION, REALLY UNDERSTANDING -- 50 IS NOT 80. RISK EXISTS ALL ALONG THE LIFE CYCLE, AND THAT WE REALLY NEED TO THINK ABOUT IT AS NOT ONE BIG MONOLITHIC GROUP OF PEOPLE BUT TO UNDERSTAND THE ISSUES OF FRAILTY, MORBIDITY, AS IT AFFECTS DIFFERENT AGE GROUPS ALONG THE CONTINUUM. >> JUST WANTED TO COMMENT, LOOKING AT THE SLIDES, THERE WERE A LOT OF FAMILIAR FACES. I SAW LINDA D. THERE, AND LINDA D. IS AT EVERY COMMUNITY ADVISORY BOARD, SHE'S ON ABOUT EIGHT AT HOPKINS. IT RAISES THE QUESTION OF, YOU KNOW, A, HOW MUCH OF A BURDEN DO ALL THESE ADVISORY COMMITTEES PLACE ON THE COMMUNITY IN THAT -- AT A PLACE LIKE HOPKINS WHERE THERE ARE PROBABLY 50 OR 60 COMMUNITY ADVISORY BOARDS RELATED TO HIV, AND HOW MUCH OF A BURDEN DO WE PLACE ON THE SAME PEOPLE OVER AND OVER AGAIN WHO AREN'T PAID TO DO THIS FOR A LIVING, AND EITHER CAN WE BE MORE EFFICIENT WITH COMMUNITY ENGAGEMENT ACROSS RESEARCH PROGRAMS OR HOW DO WE GET NEW BLOOD TO REPRESENT THE COMMUNITY, BECAUSE THERE ARE PEOPLE WHO HAVE BEEN STALWARTS FOR 30 YEARS WHO CONTINUE TO SHOW BACK AND ADVOCATE BUT WE HAVE TO EITHER MAKE IT EASIER FOR THEM OR GET MORE OF THEM. >> SO THERE'S SORT OF A BALANCE THAT WE HAVE, FOR THIS EVENT, THESE ARE -- WHAT'S THE WORD? IT'S NOT A STRUCTURED GROUP OF PEOPLE, IT'S WHO COULD COME OR WHO WAS WILLING TO COME, AND THEY ALL RECOGNIZE THE IMPORTANCE OF BRINGING OTHERS INTO THIS CONVERSATION AS WELL. THERE ARE NEW FACES IN THE ROOM, SO THERE ARE PEOPLE THAT YOU PROBABLY DIDN'T KNOW OR RECOGNIZE WHO CAME AS PART OF THESE DISCUSSIONS, AND I THINK THE OTHER WAY THAT THIS WILL HAPPEN IS, AS WE DO THESE IN THE ENVIRONMENT THAT FOLKS ARE AT AS OPPOSED TO ASKING THEM TO DO SOMETHING SEPARATE AND DIFFERENT IN TRAVEL, WE'LL GET A LOT MORE OF THE MORE GENERAL COMMUNITY REPRESENTATION AND COMMUNITY DISCUSSION. I THINK IF WE STYLE IT IN A VERY -- SOME OF THESE CAN BE KIND OF OPEN FORUMS OR SORT OF LIKE A TOWN HALL TYPE OF THING, IN THESE SITUATIONS, WHAT DO YOU THINK WOULD WORK BEST, WE'LL GET THAT KIND OF INPUT GOING ALONG THE WAY. MAUREEN? >> WHEN WE ARE WERE OUT AT CROIX, WE HAD AT LEAST THREE DIFFERENT GROUPS THAT WE MET WITH, AND I WAS SURPRISE THERE PEOPLE. VERY VOCAL, VERY EDUCATED. IT WAS LIKE A WHOLE NEW GENERATION, AND THEN ALSO I NEGLECTED TO SAY WE ALSO WERE INVITED TO GIVE AN ORIENTATION TO A GROUP OF NEW NGO REPRESENTATIVES FOR UN AIDS, AND THAT ALSO WAS A WHOLE NEW GENERATION OF INTERNATIONAL INDIVIDUALS, AND WE HEAR YOU AND I THINK THE IDEA OF GOING OUT AND MAKING SURE WHEN WE'RE AT MEETINGS -- USUALLY NOW WHEN I TRAVEL, I'M TRYING TO MAKE SURE THAT IF I'M GOING TO NASHVILLE FOR THE CFAR THAT I GET TO SEE SOME OF THE LOCAL PEOPLE AS WELL. SO WE'RE WORKING ON THAT. >> I THINK THERE WAS SOMETHING TO SAY ABOUT WHAT DR. CHASEIN SAID ABOUT OUR COMMUNITY ENGAGEMENT. I THINK WE HAVE AN OPPORTUNITY THAT WE HAVE A NEW GENERATION OF PEOPLE COMING, AND ALSO THAT THE PARADIGM IN TERMS OF HIV HAS CHANGED, THAT WE HAVE ALL THESE BIOMEDICAL INTERVENTIONS NOW, WE NEED TO HAVE BEHAVIORAL RESEARCH BUT WE ALSO NEED TO LOOK AT HOW% THAT APPLIES TO BIOMEDICAL AND PREVENTION OR CARE, AND WE WANT PEOPLE TO BE RETAINED OR ALL OF THAT IS IMPORTANT, SO I THINK THERE IS SOMETHING TO SAY ABOUT BEING MORE INTENTIONAL ABOUT COMMUNITY ENGAGEMENT. THAT IT'S NOT ONLY SOMETHING IN WHICH YOU WOULD CALL A BUNCH OF PEOPLE TO TALK ABOUT IT OR IT'S NOT JUST TO BRING PEOPLE WITH HIV WITHOUT HAVING KIND OF A SPECIFIC PROFILE ABOUT WHAT YOU NEED IN YOUR SITE IS NECESSARY THAT WILL BE USEFUL AS A MEMBER OF A -- SOMETIMES -- WHICH MEMBERS THEY HAVE NOT BEEN PREPPED TO THE POINT IN WHICH THEY CAN BE -- THEY CAN FEEL THEY'RE USEFUL, AND THEY KIND OF SET OUT TO JUST SIT IN THERE AND FEELING FRUSTRATED ABOUT THE PROCESS. SO IF THEY SHOULD BE A MORE INTENTIONAL THOUGHT PROCESS ABOUT HOW COMMUNITY ENGAGEMENT SHOULD WORK AND HOW COULD BENEFIT THE ACTUAL SCIENTIFIC PROCESS, I THINK THAT WILL BENEFIT MORE AND WILL ADD EVEN MORE TO WHAT HAS BEEN ACCOMPLISHED TO COMMUNITY INVOLVEMENT ENGAGEMENT AND PARTICIPATION. I WANT TO THANK YOU BECAUSE THE COMMUNITY TELLS ALL THE TIME THAT WE NEED TO MAKE INFORMATION WHEN WE TRANSLATE IT TO THE COMMUNITY, THE SCIENTIFIC INFORMATION, SO YOU DID A GREAT JOB TO TRANSLATE COMMUNITY LANGUAGE TO SCIENCES, SO I REALLY APPRECIATE THAT. THAT WAS GREAT. SO THAT'S IT. >> THANK YOU. WE'RE GOING TO HAVE A LITTLE MORE TIME FOR DISCUSSION SO YOU THINK WE SHOULD MOVE ON. DR. GREENBERG. >> JUST A QUICK IDEA. AS OAR IS AWARE, THE DCC FAR WILL BE HOSTING THE NATIONAL CFAR MEETING IN NOVEMBER. AS PART OF THAT, IT'S PRACTICALLY A WEEK LONG, THERE'S A TWO-DAY MEETING FOR THE NATIONAL C FAR COMMUNITY COALITION. WONDER IF IT'S IN WASHINGTON, D.C., IT WOULD BE UP TO THEM, OF COURSE, BUT FOR AN OPPORTUNITY TO HAVE NIH SCIENTISTS INTERACT WITH THE COMMUNITY REPRESENTED ACROSS THE COUNTRY. >> THANK YOU SO MUCH. SO NEXT WE'RE GOING TO NOW HEAR AN UPDATE ON THE NIH AIDS EXECUTIVE COMMITTEE AND THE TRANS-NIH PLAN FOR HIV-RELATED RESEARCH. DR. PETER KIM'S BIOWAS ALREADY COVERED BY DR. GOODENOW AT THE BEGINNING OF THIS SO I WON'T GO OVER EVERYTHING, BUT WE'RE THRILLED TO HEAR FROM HIM ABOUT THE NEXT STEPS IN THE PLAN. >> THANK YOU. SO ONE OF THE THINGS WE'VE BEEN WORKING ON UNDER THE LEADERSHIP OF DR. GOODENOW IS TO INCREASE COMMUNICATION, COORDINATION AND COLLABORATION ONLY AMONG THE VARIOUS NIH INSTITUTES, BUT ALSO WITH OTHER U.S. AGENCIES AND OTHER NON-USG COLLABORATORS. AND ACTUALLY BEYOND THAT, WHAT WE'RE ALSO HOPE DOG ISING TO DO IS TO FACILITATE WITHIN OAR A STRONGER CONNECTION BETWEEN THE OARAC AS EXEMPLIFIED BY THIS MEETING TODAY, AND OTHER EXTERNAL FACING OAR-SPONSORED WORKING GROUPS SUCH AS THE HHS GUIDELINES COMMITTEE, AND OUR INTERNAL WORKING GROUPS. ONE OF THOSE REALLY IMPORTANT WORKING GROUPS IS THE NAEC, AND I'M NOT SURE IF THIS HAS EVER BEEN PRESENTED BEFORE, BUT WE WANTED TO MAKE THE OAR COMMITTEE AND OTHERS AWARE OF WHAT THIS IS AND WHAT WE'RE HOPING TO DO, SO THE NAAC STANDS FOR THE NIH AIDS EXECUTIVE COMMITTEE, AND WHAT IT IS IS A COMMITTEE COMPOSED OF REPRESENTATIVES FROM EVERY NIH INSTITUTE, CENTER AND OFFICE THAT IS INVOLVED IN AIDS RESEARCH. IT ACTUALLY IS WITHIN THE CONGRESSIONAL MANIFEST OF THE OAR, AND FOR A WHILE ACTUALLY HAD A HIATUS IN TERMS OF MEETING BUT WAS RE-ESTABLISHED BY DR. EYE SIN DPER BECAUSE OF THE CHANGES THAT WERE OCCURRING THROUGH OAR AND THERE WAS A CRITICAL NEED FOR INFORMATION DISSEMINATION FROM THE OAR TO OUR NIH COLLEAGUES. NOW UNDER THE LEADERSHIP OF DR. GOODENOW, WHAT WE'RE HOPING TO DO IS TAKE THE NAEC INTO A SECOND PHASE WHERE IN ADDITION TO THE INFORMATION DISSEMINATION ASPECT OF THE NAEC, WE WOULD LIKE TO ACTUALLY ALSO FACILITATE INFORMATION FLOW IN THE OTHER DIRECTION, MEANING INFORMATION FROM THE IACs AND OFFICES TO THE OAR, AND ALSO FROM ONE IC TO THE OTHER. SO THIS IS ACTUALLY A DELIBERATE MOVE THAT WE'RE MAKING TO HELP ACTUALLY BRO DEP THE BROADEN THE CONVERSATION AMONG THE NIH AND THOSE ACTUALLY ACTIVELY INVOLVED IN FUNDING HIV RESEARCH. SO SOME OF THE THINGS WE HOPE TO DO IS DISSEMINATION OF INFORMATION, ABOUT FUNDING OPPORTUNITIES AND REPORTING PROCESSES. WE'RE ASKING EACH OF THE ICs THAT WHEN THEY HAVE PHASE OR RFAs, INITIATIVES OR OTHER OPPORTUNITIES THEY'RE PLANNING TO PRESENT AT THE MEETING SO THAT IT CAN BE DISCUSSED AMONG THE VARIOUS REPRESENTATIVES OF THE NIH, SO JUST SIMPLY NOT AS A PERMISSION GRANTING FUNCTION BUT JUST SIMPLY TO INCREASE DISCUSSION AND SEE IF OTHER ICs OR OTHER ENTITIES MIGHT BE INTERESTED IN JOINING IN THAT OPPORTUNITY. THE OTHER THING WE HOPE TO DO, AND WE WILL DO, IS TO HAVE INCREASED DELIBERATION ABOUT THE TRANS-NIH PRIORITIES, WHICH WILL WE'LL TALK ABOUT, AND ALSO TO REALLY FACILITATE GREATER DISCUSSION ON NEW APPROACHES AND PARTICULARLY NEW AREAS OF SCIENCE AND SCIENTIFIC ADVANCES THAT MAY ACTUALLY HAVE IMPLICATIONS ACROSS THE BOARD FOR NIH OR AT LEAST MULTIPLE ICs. ONE OF THE WAYS THAT THESE KIND OF DELIBERATIONS CLEARLY GET MANIFESTED IS THE TRANS-NIH PLAN, AS DR. GOOD NOW DISCUSSED THIS MORNING, IT WAS RECENTLY RELEASED, AND WHAT IT REPRESENTS IS AN OVERARCHING DELINEATION OF THE HIGH PRIORITY RESEARCH AREAS ACROSS NIH, AND IF YOU WERE TO LOOK INTO IT, YOU'D SEE THE HIGH PRIORITY AREAS AS REDUCING THE INCIDENCE OF HIV/AIDS, NEXT GENERATION THERAPIES, RESEARCH TOWARD A CURE, OTHER COMPLICATIONS, AND THEN CROSS CUTTING AREAS SUCH AS BASIC SCIENCE, WHICH CLEARLY CROSS CUTS BEHAVIORAL/SOCIAL SCIENCES, INFORMATION DISSEMINATION AND SUCH. THE FY18 PLAN ACTUALLY REPRESENTS A BIT OF A CHANGE FROM THE TRADITIONAL MODEL OF THE TRANS-NIH PLAN WHICH WAS A MUCH THICKER DOCUMENT THAT WENT INTO MUCH DEEPER DETAIL ABOUT WHAT THE PRIORITIES ARE, AND THE FY18 PLAN ACTUALLY REPRESENTS AN EVOLUTION OF THAT PLAN TO MAKE A MORE SUMMARIZED VERSION REALLY FOCUSING ON THE HIGH PRIORITY AREAS, AND FOR THE FY19, WE ACTUALLY PLAN TO CONTINUE IN THAT EVOLUTIONARY PROCESS WHERE WE WILL CONTINUE TO JUST FOCUS ON THE HIGH PRIORITY AREAS, BUT ALSO MAYBE PERHAPS DELINEATE A LITTLE BIT MORE ABOUT WHAT THE THINKING IS IN TERMS OF THESE AREAS. ALSO THE NIH PLAN ACTUALLY WILL REFLECT A DISCUSSION ON MULTIPLE LEVELS ACROSS THE BOARD TO OUR CUSTOMERS AND THE COMMITTEES THAT WE'RE ENGAGED WITH, FIRST AND FOREMOST, STARTING WITH THE REQUEST FOR INFORMATION THAT WAS JUST RECENTLY RELEASED, AND WE REALLY BELIEVE THAT THE COMMUNITY HAS TO HAVE A VOICE AND PERHAPS IS THE MOST IMPORTANT VOICE AS WAS DISCUSSED BY GINA IN DEVELOPING OUR PLANS, AND SO WE ACTUALLY ARE ENCOURAGING EVERYONE AND ANYONE TO REALLY RESPOND TO OUR RFI AS WAS STATED THIS MORNING, THE DEADLINE IS MAY 15TH, BUT WE'D REALLY LIKE TO HEAR FROM ALL SECTORS OF THE COMMUNITY THAT ARE AFFECTED BY THE HIV EPIDEMIC AND NOT JUST INVESTIGATORS CLEARLY, THAT'S AN IMPORTANT VOICE BY OUR COMMUNITY PARTNES, AND OTHERS THAT ARE WORKING ON THIS AREA. AND THEN OF COURSE WE HAVE OAR-COORDINATING COMMITTEES WHICH ARE ACTUALLY INTERNAL COMMITTEES TO THE NIH COMPOSED OF IC REPRESENTATIVES, AND WE HAVE MULTIPLE COMMITTEES FOCUSED ON THE DIFFERENT SPECIFIC AREAS OF EMPHASIS, AND THERE'S SOMETHING LIKE 11 OR 12 DIFFERENT COMMITTEES, AND THIS YEAR WHAT I'M HOPING TO DO IS THEN ALSO INCORPORATE SOME OF THOSE DISCUSSIONS AND SUMMARIES INTO DISCUSSION AT THE NAEC SO THAT THE NAEC HAS A GREATER ROLE IN ALSO DISCUSSING AND DELIBERATING ON WHAT THE TRANS-NIH PLAN SHOULD BE. AND THEN, OF COURSE, AS DR. GOODENOW DISCUSSED, WE ALSO BELIEVE THAT THE OARAC AND THE DELIBERATIONS AND DISCUSSIONS AND THE RECOMMENDATIONS OF THE OARAC WILL PLAY HEAVILY ALSO INTO THE FINAL PRODUCT OF THE FY19 TRANS-NIH PLAN. SO I THINK THAT'S ALL I HAD. I KNOW THIS IS AN AREA THAT THE OARAC COUNCIL, I'M NOT SURE IF IT EVER HAS, BUT IT'S SOMETHING WE WANTED TO LET THE OARAC KNOW IN THIS NEW MODEL OF THE OARAC WHERE WE HAVE A GREATER DISCUSSION AND COMMITMENT WITH THE OARAC AND MOVING THE RESEARCH FORWARD. SO I THINK IF THERE'S -- >> ASSUMING THERE'S OPPORTUNITY FOR COMMENT? >> YES, WE HAVE TIME. >> PETER, THANK YOU VERY MUCH FOR THAT PRESENTATION. AS YOU KNOW, AN AREA OF GREAT INTEREST TO US IN THE AIDS CLINICAL TRIALS GROUP HAS BEEN THE OPPORTUNITY TO COLLABORATE WITH DIFFERENT ICs, AND WE'VE HAD A SUCCESSFUL AND FRUITFUL COLLABORATION WITH SEVERAL ICs, INCLUDING NIMH, NINDS, NIA, TO SOME EXTENT NIDA, A LITTLE BIT WITH NINR, NCI, AND I HOPE I'M NOT LEAVING ANYONE OUT AT THE MOMENT, BUT -- OH, AND NHLBI, WHICH HAS FUNDED INDEPENDENT GRANT APPLICATION LINKED TO OUR TRIALS, BUT THE LONG LIST OF OTHER ICs THAT I DIDN'T REFER TO HAVE BEEN PRETTY RECALCITRANT IN TERMS OF WANTING TO COLLABORATE WITH THE NETWORKS AND PARTICULARLY NOW THAT THE NETWORK RE-COMPETITION IS BEING -- OR THE CONTINUATION OF THE NETWORKS IS BEING REIMAGINED AND DISCUSSED, I THINK IT WOULD BE CRITICALLY IMPORTANT TO BRING AS MANY OF THE OTHER ICs TO THE TABLE AS POSSIBLE, AS NIAID NARROWS ITS FOCUS OR SHARPENS ITS FOCUS ON WHAT IS THE VIRUS DOING, HOW ARE WE GETTING RID OF THE VIRUS AND HOW ARE WE TREATING THE VIRUS, THERE ARE ALL THE OTHER ASPECTS OF HIV DISEASE, WHICH FALL PROPERLY INTO THE REMIT OF SEVERAL OTHER ICs. AND SINCE YOU MENTIONED THE ISSUE AROUND RFAs, OCCASIONALLY WITH ALL THE BEST INTENTIONS, ALL THE OTHER INSTITUTES MAY TIE THEMSELVES UP IN KNOTS THAT ARE NOT HELPFUL, FOR EXAMPLE, NHLBI WITH WHICH WE USED TO HAVE A TERRIFIC WORKING RELATIONSHIP NOW REQUIRES THAT YOU REQUIRE TWO LENGTHY UL1 APPLICATIONS IF YOU WANT TO DO A CLINICAL TRIAL, SO WE DON'T NEED A COORDINATING CENTER TO DO A TRIAL, WE HAVE ONE, WE DON'T NEED A DATA MANAGEMENT CENTER TO DO A TRIAL, WE HAVE ONE, WE NEED THE ADDITIONAL FUNDING TO DO THE HEART OR LUNG OR BLOOD PARTS OF THE TRIAL. AND SO THE MECHANISMS HAVE BEEN CHANGED IN A WAY THAT MAY BE GREAT FOR DOING PURE CARDIOVASCULAR RESEARCH BUT NOT SO HELPFUL FOR DOING COLLABORATIVE WORK ACROSS INSTITUTES. I KNOW WE'RE GOING TO BE TALK ABOUT THIS IN ANOTHER MEETING, BUT JUST TAKE THE OPPORTUNITY NOW TO BRING THAT UP TO THE COMMITTEE. >> THANKS. I'LL JUST RESPOND REALLY BRIEFLY TO SAY ACTUALLY WHAT YOU'RE SAYING IS VERY TIMELY, AND WE AGREE THAT LARGE INVESTMENTS OF AIDS FUNDING SUCH AS THE CLINICAL TRIAL NETWORKS REALLY DESERVE TO BE DISCUSSED AND ICs -- WE CAN'T FORCE ICs TO DO SOMETHING, BUT I THINK THEY NEED TO BE GIVEN OPPORTUNITY TO WEIGH IN, SO ACTUALLY THE VISION OF AIDS WILL BE PRESENTING ON SOME OF THEIR PLANS FOR THE CLINICAL TRIAL NETWORKS TO THE NEXT UPCOMING NAEC MEETING ON APRIL 18TH, AND ANY IC REPRESENTATIVES THAT ARE LISTENING TO THIS OR HERE IN THE ROOM, WE REALLY ENCOURAGE YOU TO COME HEAR WHAT THEY HAVE TO SAY AND ACTUALLY ACTIVELY PARTICIPATE IN THAT DISCUSSION, BECAUSE I THINK IT'S REALLY AN IMPORTANT ASPECT OF WHAT WE DO AND HOW WE WANT TO MOVE FORWARD. >> THAT WAS NOT ONLY A GOOD PITCH FOR THE NETWORKS, BUT VERY GOOD SEGUE ACTUALLY TO THE NEXT TALKS, BECAUSE WE ARE GOING TO HAVE NOW AN UPDATE ON THE RESEARCH ACTIVITIES FROM THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. SO TWO SPEAKERS HERE, FIRST IS DR. DAVID GOFF, AND HE RECENTLY JOINED THE NIH JUST IN SEPTEMBER, AS THE DIRECTOR OF THE DIVISION OF CARDIOVASCULAR SCIENCES AT THE NATIONAL HEART LUNG AND BLOOD INSTITUTE. AND IN HIS CURRENT POSITION, HE FOSTERS A CARDIOVASCULAR RESEARCH PROGRAM WITH COLLECTIVE EFFORTS IN BASIC TRANSLATIONAL CLINICAL AND POPULATION RESEARCH. DR. GOFF IS A DISTINGUISHED CARDIOVASCULAR EPIDEMIOLOGIST AND PHYSICIAN. AND PRIOR TO JOINING THE NIH IN SEPTEMBER, DR. GOFF WAS DEAN OF THE COLORADO SCHOOL OF PUBLIC HEALTH AND HAS ALSO SERVED AS THE CHAIR OF THE DEPARTMENT OF EPIDEMIOLOGY AND PREVENTION IN THE DIVISION OF PUBLIC HEALTH SCIENCES AT THE WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE. SO I WILL INTRODUCE DR. COOK LATER, BUT PLEASE, DR. GOFF, MITIGATING COMORBIDITIES AND ACCELERATING CARES. >> THANKS VERY MUCH. AND YES, I'M ONE OF THE NEW GUYS HERE, I ACTUALLY STARTED THE MONDAY AFTER THANKSGIVING. SO EVEN MORE RECENTLY THAN SEPTEMBER. AND DELIGHTED TO BE HERE. TRAINED AS A GENERAL INTERNIST AND HAVE -- BACK IN THE DAY DID SOME CLINICAL CARE THAT INVOLVED PEOPLE WITH HIV AND AIDS, AND DELIGHTED TO BE PART OF THE LEADERSHIP TEAM AT NHLBI THAT'S BEEN ASKED TO HELP IMPLEMENT OUR STRATEGIC VISION WITH RESPECT TO HIV-RELATED RESEARCH. I'M JOINED TODAY BY DR. MICAELA COOK, CHIEF OF STAFF FOR THE INSTITUTE. SO WE'LL BE DOING A LITTLE BIT OF A TAG TEAM PRESENTATION BECAUSE AS THE NEW GUY ON THE XENO, SHE KNOWS A THESCENE, SHE KNOWS A LOT OF THE HISTORY OF HOW WE GOT TO WHERE WE ARE AND SHE'S GOING TO BE COVERING SOME OF THAT MATERIAL. SO LET'S PROCEED. WE'RE GOING TO ORGANIZE OUR PRESENTATION ADDRESSING TWO BIG THEMES. THE THEME OF MITIGATING COMORBIDITIES AND THE THEME OF ACCELERATING CURES FOR PEOPLE LIVING WITH HIV AS THOSE ARE THE TWO PRIMARY GOALS OF OUR WORK AT NHLBI. FIRST WE'LL TALK A LITTLE OF OR UNDERSTANDING OF THE EVOLVING EPIDEMIC, YOU'VE ALREADY HEARD A LITTLE ABOUT THAT TODAY SO THIS WON'T BE REALLY NEW TO YOU BUT IT WILL BE FROM THE CONTEXT OF HEART, LUNG, BLOOD AND SLEEP DISORDERS, AND THEN DR. COOK WILL TAKE OVER AND TALK ABOUT SEIZING OPPORTUNITIES FOR OUR FUTURE RESEARCH IN NHLBI. SO THIS IS A FIGURE FROM A PAPER BY LEGARTH THAT SHOWS HOW THE SURVIVAL AND LONGEVITY OF PEOPLE LIVING WITH HIV HAS IMPROVED OVER THE DECADES SUCH THAT NOW IN THE MORE RECENT ERA, THE SURVIVAL HAS INCREASED TO ABOUT 22.5 YEARS STARTING AT AGE 50, CLOSING THE SURVIVAL GAP BETWEEN PEOPLE LIVEING WITH HIV AND PEOPLE WHO ARE FREE OF THAT INFECTION TO ABOUT A DECADE. AND THEN FROM THE SAME PAPER SHOWING THAT PEOPLE WHO ARE VERY WELL CONTROLLED WITH THEIR DISEASE, HAVE AN EVEN NARROWER GAP IN LONGEVITY FROM AGE 50 TO WHERE SURVIVAL IS NOW ABOUT 25.6 YEARS VERSUS ABOUT 34 YEARS, SO LESS THAN A DECADE OF DIFFERENCE IN LIFE EXPECTANCY. WITH THAT INCREASED SURVIVAL AND LONGEVITY HAS COME THE INCREASE IN CO-MORBID CONDITIONS. SMITH HAS PROJECTED BY 2030, THE VAST MAJORITY OF INDIVIDUALS LIVING WITH HIV WILL HAVE A CHRONIC DISEASE CO-MORBID CONDITION, 84%, OVER A QUARTER WILL HAVE THREE OR MORE CO-MORBID CONDITION, AND ALMOST 80% OF THESE PATIENTS WILL BE LIVING WITH SOME FORM OF CARDIOVASCULAR DISEASE. AND THAT'S A PREVALENCE THAT'S NOT QUITE TWICE BUT 30% ABSOLUTE GREATER THAN THE POPULATION IN GENERAL LIVING WITHOUT THIS INFECTION. SO IT'S A HUGE BURDEN OF CARDIOVASCULAR DISEASE PROJECTED TO OCCUR IN PEOPLE LIVING WITH HIV AS LIFE EXPECTANCY CONTINUES TO IMPROVE, SO THIS CERTAINLY GETS THE INTENTION OF SOMEONE WHO'S LEADING A DIVISION OF CARDIOVASCULAR SCIENCES OR LEADING A NATIONAL HEART LUNG AND BLOOD INSTITUTE. SO WHAT'S GOING ON HERE, WHY DO WE THINK THIS BURDEN OF CO-MORBID IT IS OCCURRING? IN ARE A COUPLE INTERESTING HYPOTHESES OR MECHANISMS GETTING A LOT OF ATTENTION, OUR SCIENTISTS ARE EXPLORING RELATED TO CHRONIC IMMUNE INFLAMMATION, ALSO RELATED TO SOME OF THE POTENTIAL EFFECTS OF THE THERAPY FOR HIV ITSELF. UNIFYING THEME RELATED TO CHRONIC IMMUNE ACTIVATION INFLAMMATION THAT LINKS ACROSS THE DISEASES OF INTEREST TO NHLBI, SO THIS SLIDE IS FOCUSED ON DISORDERS OF THE BLOOD, PEOPLE LIVING WITH HIV HAVE ABOUT TWICE THE BURDEN OF VENOUS THROMBOEMBOLISM AS UNAFFECTED CONTROLS, AND WE BELIEVE THAT RELATES TO CHRONIC IMMUNE ACTIVATION AND INFLAMMATION THAT AFFECTS MONOCYTES AND MACROPHAGES, PLATELET ACTIVATION AND AGGREGATION, AND ABNORMAL EPITHELIAL CELL ELABORATION OF ADHESION MOLECULES AND SO FORTH THAT THEN LEADS TO ABNORMAL COAGULATION AND VENOUS THROMBOEMBOLISM. WITH RESPECT TO LUNG DISORDERS, IN THE DIVISION OF LUNG DISEASE, A LOT OF INTEREST IN THESE ISSUES AS WELL. CO-MORBID CONDITIONS SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ASTHMA, SLEEP DISORDERS, APPROACHING ABOUT TWO THIRDS OF PEOPLE LIVING WITH HIV MUCH MORE COMMON THAN IN THE UNINFECTED POPULATION. AND AGAIN, CHRONIC ACTIVATION AND INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOLOGY IN THE LUNG, ESPECIALLY RELATED TO INFLAMMATORY LUNG DISEASES AND THAT ADDITIONAL COINFECTIONS ALSO PLAY A ROLE IN PROMOTING INFLAMMATION. FINALLY WHAT'S CLOSEST TO MY HEART IS TALKING ABOUT THE MECHANISMS RELATED TO CARDIOVASCULAR DISEASE. WE ALSO HAVE STRONG EVIDENCE THAT IMMUNE ACT -- PRESERVED EJECTION FRACTION. THIS MAY BE A DISTINCTION THAT'S SOMEWHAT NEW TO SOME IN THE ROOM BUT THERE ARE TWO MAJOR GROUPS OF HEART FAILURE THAT WE STUDY, HEART FAILURE WHERE THE HEART IS WEAK IN ITS ABILITY TO PUP PUMP, HEART FAILURE WITH REDUCED EJECTION FRACTION AND HEART FAILURE WHERE THE HEART HAS DIFFICULTY RELAXING AND ACCEPTING BLOODS, AND THAT'S HEART FAILURE WITH PRESERVED EJECTION FRACTION, AND PEOPLE LIVING WITH HIV TEND SO HAVE AN ESPECIALLY HIGH BURDEN OF THE LATTER TYPE OF HEART FAILURE. SURADO HAS PUBLISHED THAT ALMOST HALF OF PEOPLE LIVING WITH HIV HAVE SOME FORM OF CARDIAC DYSFUNCTION, THE VAST MAJORITY -- THE ABILITY OF THE HEART TO RELAX, ACCEPT BLOOD AND PUMP. THAT PARTICULAR FORM OF HEART INFLAMMATION AND FIBROSIS THAT IS RELATED, WE BELIEVE, TO THE CHRONIC IMMUNE ACTIVATION AND INFLAMMATION. SO WITH THAT AS A BACKGROUND FOR SOME OF THE PATHOPHYSIOLOGY THAT LINKS HIV INFECTION AND POTENTIALLY TREATMENT WITH CHRONIC COMORBIDITIES OF INTEREST TO HEART LUNG AND BLOOD AND SLEEP DISORDERS, I'D NOW LIKE TO TURN THE PRESENTATION OVER TO DR. COOK, WHO WILL COME AND TALK A LITTLE BIT ABOUT OPPORTUNITIES THAT WE SEE FOR THE FUTURE. THANK YOU.. >> AND JUST TO GIVE MORE OF AN IDEA OF DR. COOK CURRENTLY SERVING AS THE CHIEF OF STAFF IN THE MEDIA OFFICE OF THE DIRECTOR OF THE NHLBI AND IN THIS CAPACITY, DR. COOK SERVES AS SENIOR ADVISER TO THE NHLBI DIRECTOR, LIAISON WITH SENIOR OFFICIALS WITHIN AND OUTSIDE THE INSTITUTE AND PROVIDES STRATEGIC DIRECTION AND OVERSIGHT FOR CROSS CUTTING ACTIVITIES ACROSS THE INSTITUTE. PRIOR TO THIS, DR. COOK SERVED AS MEDICAL OFFICER IN THE DIVISION OF CARDIOVASCULAR SCIENCES IN THE NHLBI AND SERVED AS THE DEPUTY AIDS COORDINATOR TORE THE INSTITUTE. SHE RECEIVED HER MEDICAL DOCTORATE FROM HARVARD MEDICAL SCHOOL AND MASTERS IN PUBLIC HEALTH FROM HARVARD AND COMPLETED HER CLINICAL TRAINING IN INTERNAL MEDICINE IN CARDIOLOGY AT MGH. >> FANTASTIC. THANK YOU SO MUCH. IT'S TRULY A PLEASURE TO BE HERE AND WE APPRECIATE THE OPPORTUNITY TO JOIN YOU AND TALK A LITTLE ABOUT THE STRATEGIC OPPORTUNITIES WE SEE RELATED TO HEART, LUNG, BLOOD AND SLEEP RESEARCH AND THE PRIORITIES AROUND MITIGATING COMORBIDITIES AND ACCELERATING CURES. SEVERAL OF YOU ARE FAMILIAR TO US THROUGH SEVERAL OF THESE EFFORTS OVER THE YEARS TO ADDRESS THE PUBLIC HEALTH NEEDS THAT WE SEE EMERGING WITH THIS EVOLVING EPIDEMIC. THE NHLBI REALLY BEGAN TO ORGANIZE IN 2012 A LITTLE BIT DIFFERENTLY THAN WE HAD BEFORE. WE ESTABLISHED A CROSS FUNCTIONAL NHLBI AIDS TEAM THAT WAS REALLY TO ENHANCE OUR COHERENCE, OUR COORDINATION, AND OUR OUTREACH TO THE INVESTIGATOR COMMUNITY IN A WAY WE THOUGHT COULD ACTUALLY GENERATE AND INVESTIGATE OUR COMMUNITY THAT WOULD INTERESTED IN THE RESEARCH INTERSECTION WE WERE SEEING AT NHLBI. SEVERAL OF YOU JOINED NUSS A WORKING GROUP IN 2012 WHICH WAS OUR FIRST EFFORT TO REALLY BRING TOGETHER INVESTIGATORS FROM THE INFECTIOUS DISEASE AND HIV RESEARCH COMMUNITY WITH THOSE OF THE CARDIOVASCULAR, PULMONARY AND HEMATOLOGIC COMMUNITY TO REALLY TALK ABOUT WHAT WE HAVE AS EVIDENCE TO PUSH FORWARD A NEW RESEARCH AGENDA AND TO HELP US IDENTIFY PRIORITIES FOR RESEARCH THAT THE INSTITUTE COULD SUPPORT. THIGHSTHESE RECOMMENDATIONS LED TO SEVERAL NICHE INITIATIVES THAT WE RELEASED LATER AFTER THE 2012 WORKSHOP THAT BASICALLY FOCUSED IN ON BASIC AND CLINICAL RESEARCH MECHANISMS THAT REALLY TRIED TO UNDERSTAND THE EPIDEMIOLOGY, THE PATHOPHYSIOLOGY, SOME OF THE MECHANISMS, TREATMENT OPPORTUNITIES, AND MANAGEMENT STRATEGIES THAT WERE IMPORTANT TO COMORBIDITIES RESEARCH AGENDA. BUT WE ALSO RECOGNIZE THAT CURING HIV FELL SQUARELY WITHIN OUR PORTFOLIO AND IN COLLABORATION WITH OTHER ICs AND WITH THE OAR, WE WERE ABLE TO WORK TOGETHER WITH NIAID ON AN INITIATIVE THAT WE'LL TALK ABOUT A LITTLE BIT LATER. WE THEN CONVENED ANOTHER WORKING GROUP IN 2015 AND THE REAL PURPOSE AT THAT TIME WAS TO REVIEW OUR PROGRESS AND IDENTIFY ADDITIONAL GAPS THAT WE NEEDED TO PURSUE. AND WE RECOGNIZED AT THAT POINT IN TIME THAT WHILE WE HAD BEEN VERY BROADLY FOCUSED ON BASIC AND CLINICAL RESEARCH NEEDS, THAT THERE WAS AN OPPORTUNITY TO START TO HONE IN ON SOME SPECIFIC AREAS OF HIV-RELATED HEART LUNG BLOOD AND SLEEP RESEARCH THAT WE COPPER SUE, AND SOME OF THOSE AREAS INCLUDED LOOKING AT THE ROLE OF DYSBIOSIS IN CARDIOVASCULAR AND HEMATOLOGIC COMPLICATIONS, APPROACHES TO HIV RELATED HEART LUNG BLOOD AND SLEEP COMORBIDITIES AMONGST THOSE LIVING WITH HIV AND WE HONED IN ON IMPLEMENTATION RESEARCH TO DEVELOP IMPLEMENTATIONS THAT MAY HELP WITH THE UPTAKE OF EVIDENCE-BASED INTERVENTIONS AND STRATD GEES AMONGST MANAGEMENT AND TREATMENT DILEMMAS AMONGST PEOPLE LIVING WITH HIV. WE SAW THIS AS THE OPPORTUNITY TO REALLY SEIZE NEW OPPORTUNITIES AND TO START TO EXPAND THE PORTFOLIO THAT WE INVEST IN AT NHLBI. THERE WERE SEVERAL FOCUS AREAS THAT EMERGED FROM THE WORKING GROUP, THE WORKING GROUP ACTIVITIES IN 2012 AND 2015. THIS IS JUST A SNAPSHOT ACROSS THE PAROLE PORTFOLIO BUT ALSO IMPLEMENTATION SCIENCE WHICH AS AN INSTITUTE WE WERE ALSO VERY HEAVILY FOCUSED ON. AND YOU'LL SEE THROUGHOUT SEVERAL OF THESE FOCUS AREAS AND RECOMMENDATIONS, THAT EPIDEMIOLOGY AND POPULATION SCIENCE EMERGED, PATHOPHYSIOLOGY AND MECHANISMS REALLY COME TO THE FORE, AS WELL AS TREATMENT, PREVENTION, CLINICAL TRIALS THAT CAN ROW MOTOR THAT AND GIEP AND CELL THERAPIES THAT MAY BE RIPE FOR CURE. AS WE STARTED TO APPROACH SOME OF THESE OPPORTUNITIES, WE RECOGNIZED THAT THERE WAS IDEAL ALIGNMENT WITH THE STRATEGIC VISION AT THE NHLBI AND, IN FACT, IT WAS PURPOSEFUL IN THE CONSORT AND THE WAY IN WHICH WE APPROACHED THE NHLBI RECENTLY RELEASED STRATEGIC VISION THAT FOCUSES ON FOUR MAJOR PRIORITIES. UNDERSTANDING HUMAN BIOLOGY, AND THIS IS REALLY ABOUT UNDERSTANDING THE MECHANISMS THAT GOVERN NORMAL FUNCTION, AND THEN UNDERSTANDING THANK YOU HUMAN DISEASE IN TERMS OF WHAT PERTURBS THAT NORMAL FUNCTION AND PAT THOUGH BIOLOGY THAT ADVANCES DISEASE AND HOW WE LEVERAGE THAT TO UNDERSTAND PREVENTION AND MANAGEMENT. ANOTHER FOCUS AREA OF THE NHLBI STRATEGIC VISION IS ON FACILITATING INNOVATION AND ACCELERATINGRESEARCH TRANSLATION AND DEVELOP AGO WORKFORCE WITH THE RESOURCES THAT CAN IMPLEMENT EVIDENCE INTO PRACTICE. WE BEGAN TO SEAT SEE THE OVERLAP BETWEEN SEVERAL OF THE WORKING GROUP RECOMMENDATIONS AS WELL AS THE NIH PRIORIIES AROUND MITIGATING CO-MORBIDITY AND ACCELERATING -- AND THROUGH THE EFFORT OF REALLY LOOKING AT OUR STRATEGIC OPPORTUNITIES, WE BEGAN TO REALLY FOCUS ON HOW OUR PAROLE AND PORTFOLIO AND SEVERAL KEY ELEMENTS COULD START TO ADVANCE THESE STRATEGIC OPPORTUNITIES. FROM SEVERAL OF THE RFAs THAT TARGETED BASE UK RESEARCH IN CLINICAL SCIENCE, WE HAD SEVERAL PUBLICATIONS AND PROGRAMS THAT FOCUSED ON THE PATHOGENESIS OF HIV RELATED HEART LUNG BLOOD AND SLEEP DISORDERS. THERE WERE MANY INVESTIGATIONS THAT SHED LIGHT ON UNDERLYING MECHANISMS FOR THE INCREASE IN COMORBIDITIES AMONGST PEOPLE LIVEING WITH HIV. FOR EXAMPLE, ONE GRANT THAT'S HIGHLIGHTED AT THE BOTTOM OF THE SLIDE HEERY HERE RELATES TO SOMETHING FUNDED THROUGH ONE OF THE RFAs RFAs -- WHICH WAS A PREVIOUSLY UNRECOGNIZED MECHANISM FOR CELLULAR CONTROL THAT COULD INCREASE THE FREQUENCY OF THROMBOSIS IN HIV PATIENTS. THESE SORTS OF OPPORTUNITIES HAVE LED US DOWN THE PATH OF UNDERSTANDING WHERE WE CAN GO NEXT. WE ALSO HAD THE OPPORTUNITY TO IP VEST IN TO INVEST IN A CLINICAL TRIAL. WE'VE TALKED ABOUT OPPORTUNITIES TO WORK WITH THE AIDS CLINICAL TRIALS GROUP SO WE'D BE HAPPY TO ANSWER QUESTIONS RELATED TO CLINICAL TRIAL FUNDING MECHANISMS. AND THIS WAS ONE OF THE LARGEST CLINICAL TRIALS THAT HAS FOCUSED ON AN INTERVENTION TO TRY TO PREVENT CARDIOVASCULAR DISEASE AMONGST INDIVIDUALS LIVING WITH HIV, AND WE FOUND A VERY COLLABORATIVE WORKING RELATIONSHIP WITH OUR COLLEAGUES AT NIAID AND ACROSS THE INVESTIGATOR COMMUNITY TO REALLY UNDERSTAND HOW WE CAN OPERATIONALLY EXECUTE STUDIES LIKE THIS WITHIN EXISTING INFRASTRUCTURE. THIS STUDY SPECIFICALLY TESTS THE EFFICACY OF -- STATIN TO REDUCE MAJOR CARDIOVASCULAR ADVERSE EVENTS AMONGST PATIENTS THAT WOULDN'T HAVE NORMALLY QUALIFIED FOR A STATIN BASED ON NORMAL CLINICAL GUIDELINES, AND IT WAS REALLY ABOUT UNDERSTANDING THE PLEA OWE TROPIC EFFECTS AND THE INFLAMMATORY CONDITION THAT COULD PROMOTE ACCELERATED CARDIOVASCULAR DISEASE AMONGST PEOPLE WITH HIV. WE ARE TARGETING 6500 PARTICIPANTS TO BE ENROLLED IN OVER 100 SITES. AND AGAIN, APPRECIATE THE COLLABORATIVE OPPORTUNITY THAT THE STUDY HAS ALLOWED US TO BOTH LEARN FROM AND GROW. WE ALSO HAVE STARTED TO LOOK AT HOW WE LEVERAGE OTHER EXTANT COHORTS TO BE ABLE TO FACILITATE COMORBIDITIES RESEARCH. AND HERE I JUST GIVE THE EXAMPLE OF THE MULTICENTER AIDS COHORT STUDY AND THE WOMEN'S INTERAGENCY HIV STUDY WHERE WE'VE BEGUN TO START TO LOOK AT HOW WE CAN ADD CERTAIN PROTOCOLS OR HEART LUNG BLOOD AND SLEEP RESEARCH RELATED ACTIVITIES THAT WOULD ALLOW US TO UNDERSTAND THINGS SUCH AS CARDIOPATHOBIOLOGY, DYSRHYTHMIA, BIOMARKERS OF DISEASE AND VENOUS THROMBOEMBOLISM. HERE ARE EXAMPLES OF THE TYPES OF THINGS THAT WE ARE BEGINNING TO PURSUE, INCLUDING THE CONDUCT OF AN ECHOCARDIOGRAM EXAMINATION AND PERHAPS FOLLOW UP WITH CARDIAC MRI THAT MAY ALLOW US TO ASSESS CLINICAL AND SUBCLINICAL CARDIOVASCULAR DISEASE, OR EVEN PROVIDING THE OPPORTUNITY FOR ELECTROCARDIOGRAPHIC EXAMINATIONS, WHERE WE CAN ASSESS DIFFERENCES AND PROGRESSION IN ECGs, AND UNDERSTAND THE HEIGHTENED RISK OF DYSRHYTHMIAS, ESPECIALLY AMONGST WOMEN. WE'VE ALSO STARTED TO LOOK AT POTENTIALLY BIOMARKERS, BOTH TRADITIONAL AND NOVEL BIOMARKERS THAT MAY ALLOW US TO UNDERSTAND THAT CONDITION OF HEART FAILURE WITH PRESERVED EJECTION FRACTION THAT DR. GOFF SPOKE ABOUT WITH A LITTLE MORE UNDERSTANDING AND KNOWLEDGE. AND AGAIN, VENOUS THROMBOEMBOLISM, ANOTHER OPPORTUNITY FOR US TO UNDERSTAND THE INTERPLAY BETWEEN PLATELET ACTIVATION AND ENDOTHELIAL INJURY AND HYPERCOAGOABILITY THAT CAN PRODUCE BOTH VENOUS THROMBOEMBOLISM AS WELL AS REDUCED CARDIOVASCULAR OUTCOMES AND EVENTS. FROM A PULMONARY SLEEP PORTFOLIO PERSPECTIVE, WE SEE THE OPPORTUNITY TO UNDERSTAND FROM PULMONARY FUNCTION TESTING TRADITIONAL CHEST CTs, THE ASSESSMENT OF LUNG FIBROSIS AND RESPIRATORY HEALTH AMONGST INDIVIDUALS LIVING WITH HIV, AND WE KNOW THAT THE INFLUENCE OF SLEEP APNEA AND QUALITY ON METABOLIC SUBCLINICAL CARDIOVASCULAR AUTONOMIC AND NEURAL BEHAVIORAL FUNCTION IS NOT WELL UNDERSTOOD IN THIS POPULATION, BUT YET AN OPPORTUNITY FOR US TO LEVERAGE EXTANT RESOURCES IN ORDER TO DO SO. AND LASTLY, FOCUSING IN ON THE MANAGEMENT OF COMORBIDITIES IS THE OPPORTUNITY FOR US TO UNDERSTAND THE IMPLEMENTATION RESEARCH THAT CAN HELP US WITH GUIDELINE-DRIVEN STRATEGIES. I TALKED A LITTLE ABOUT THE FACT THAT NHLBI HAS ESTABLISHED WITHIN THE INSTITUTE A CENTER FOR TRANSLATIONAL RESEARCH AND IMPLEMENTATION SCIENCE, AND THAT CENTER HAS BEEN INTEGRAL IN THIS CROSS FUNCTIONAL TEAM AT NHLBI THAT LOOKS AT THE NEEDS OF HOW WE CAN FACILITATE AN NIH-RELATED RESEARCH AGENDA, AND AS PART OF THAT TEAM, THEY'VE RECENTLY PUBLISHED IN RESPONSE TO SOME OF THE WORKING GROUP ACTIVITIES AN INTENT TO PUBLISH AN RFA THAT WILL BE RELEASED IN THE SPRING THT WILL FOCUS ON RESEARCH THAT WILL DELIVER THE OPPORTUNITY FOR PROVEN EFFECTIVE INTERVENTIONS ONCOMORBID HEART, LUNG AND SLEEP DISEASES, AND THE GOAL HERE IS REALLY TO UNDERSTAND THOSE LAY TRANSLATION RESEARCH METHODS THAT COULD ACTUALLY INCREASE THE UPTAKE OF KNOWN STRATEGIES THAT ARE EFFECTIVE IN THE POPULATION. IN ADDITION TO RESEARCH THAT FOCUS ONCOMORBIDITIES, WE'VE ALSO BEEN HEAVILY FOCUSED WITH OUR SISTER AGENCY, NIAID, ON RESEARCH THAT REALLY IS RELATED TO A CURE. SO WE'VE BEEN WORKING WITH NIAID ON THIS INITIATIVE CALLED "BEYOND HAART," A COLLABORATION THROUGH A U19 GRANT MECHANISM THAT BASICALLY HAS BEEN FOCUSED ON KEY ELEMENTS OF HEMATOPOIETIC STEM CELLS AND CURE, AND SPECIFICALLY INCLUDING THE GENERATION OF HIV PROTECTED BLOOD CELLS, EXPANSION OF THOSE CELLS, CONDITIONING OF THE RECIPIENT, AND ULTIMATELY INFUSION AND INGRAFTMENT. AND WE UNDERSTAND THE COMPLEXITY AND THE CHALLENGES IN SUCH APPROACHES, BUT FEEL LIKE THE GRANTS THAT HAVE BEEN FUNDED UNDER THIS PROGRAM REALLY WILL PROVIDE US THE KNOWLEDGE TO LEARN AND UNDERSTAND IF THERE REALLY IS THE POTENTIAL FOR CELL THERAPY CURES IN HIV. SO IN SUMMARY, WE'RE TRYING TO CHART A FUTURE FOR HIV-RELATED HEART LUNG BLOOD AND SLEEP RESEARCH THAT IS REALLY AN INTEGRATED PORTFOLIO OF DURCH RESEARCH STRATEGIES AS WELL AS ACROSS A BROAD SPECTRUM OF DISEASES THAT WE THINK HAVE AN INCREASING BURDEN AMONGST INDIVIDUAL LIVING WITH HIV. WE ALSO KNOW THAT CHRONIC IMMUNE INFLAMMATION ARE INCREDIBLE TARGETS FOR US TO UNDERSTAND BETTER BUT ALSO CAN BE MECHANISMS THAT MAY BE AFFILIATED AND AASSOCIATED WITH ACCELERATED AGING AND MAY HAVE APPLICABILITY EVEN OUTSIDE THE POPULATION OF INDIVIDUALS LIVING WITH HIV AND AN OPPORTUNITY FOR US TO LEARN ABOUT UNDERLYING NORMAL BIOLOGY AND PATHOBIOLOGY. WE DO INTEND TO CONTINUE SUPPORTING RESEARCH ACROSS A BROAD SPECTRUM, AND ALSO INCLUDE WE'D LIKE TO LEVERAGE OUR OPPORTUNITIES TO REALLY ADVANCE THIS WORK. AND GIVEN THAT, THE PRIORITIES ARE SO CONSISTENT WITH THE NHLBI STRATEGIC VISION, WE FEEL THIS IS JUST PART OF OUR MISSION. BUT WE CAN'T DO IT ALONE AND WE'VE BEEN FORTUNATE TO HAVE NE NOMINAL PARTNERS ACROSS THE NIH, INCLUDING AT SISTER INSTITUTES AND CENTERS, AS WELL AS WITHIN OAR. WE ALSO REALIZE WE COULDN'T DO IT WITHOUT THE COMMUNITY OF THE HELP OF OTHERS, SO WE'RE VERY HAPPY TO HAVE HAD THIS COLLABORATIVE OPPORTUNITY TO PRESENT HERE TODAY, AND HOPE THAT IT CAN HELP ACCELERATE BOTH MITIGATING OUR COMORBIDITIES AND CURES. THANK YOU FOR THE OPPORTUNITY. [APPLAUSE] >> WE'LL OPEN UP SPECIFICALLY FOR THIS SESSION FOR RIGHT NOW. SORRY, TRIP. >> THANKS FOR YOUR PRESENTATION. THERE'S SOME RECENT DATA SUGGESTING THAT UNDERLYING RISK FACTORS, TRADITIONAL ONES, MAY PLAY A MORE IMPORTANT ROLE ACTUALLY THAN INFLAMMATION AND IMMUNE ACTIVATION. COULD YOU JUST -- NHB AND END ORGAN DISEASE, SPECIFICALLY HEART AND LUNG.% COULD YOU JUST SPEAK TO THE RESEARCH AGENDA FOR THE TRADITIONAL RISK FACTORS? >> AS YOU HEARD A MOMENT AGO, THE REPRIEVE STUDY IS DOING EXACTLY THAT WITH RESPECT TO STATINS AS A MAJOR INTERVENTION FOR REDUCING RISK OF CARDIOVASCULAR DISEASE. I WAS INVOLVED IN THE EFFORT TO EVALUATE THE RISK SCORE TO IDENTIFY ELIGIBILITY FOR STATINS, AND WE RECOGNIZED THAT THERE WAS SOME POPULATIONS AT HIGHER RISK WHOSE RISK ESTIMATE WOULD BE UNDERESTIMATED BY THAT RISK SCORE AND PATIENTS WITH HIV ARE ONE OF THOSE POPULATIONS, PATIENTS WITH OTHER FORMS OF INFLAMMATORY CONDITIONS, PERHAPS LUPUS, RHEUMATOID ARTHRITIS ARE OTHER EXAMPLES OF PATIENT POPULATIONS THAT MAY BE AT HIGHER RISK THAN THAT RISK SCORE WOULD TYPICALLY IDENTIFY, AND SO THE REPRIEVE TRIAL IS AN EXAMPLE OF A STUDY IN WHICH WE'RE TRYING TO MOVE BEYOND THE RISK SCORE THAT'S BEEN DEVELOPED IN THE GENERAL POPULATION TO UNDERSTAND BETTER THE HEIGHTENED RISK OF PEOPLE WITH HIV. AND SO IT MAY BE THAT EVEN WHEN WE THINK THAT RISK IS NOT VERY HIGH, THE ADDITIONAL INFLAMMATION WOULD MEAN THAT THESE INDIVIDUALS MIGHT BENEFIT FROM A STATIN, SO THAT'S AN EXAMPLE OF THAT SORT OF RESEARCH, AND I THINK IT WOULD SERVE AS A MODEL FOR OTHER TYPES OF RISK FACTORS, WHETHER IT BE BLOOD PRESSURE, USE OF ASPIRIN AS AN EXAMPLE WHICH MIGHT RELATE TO THE CARDIOVASCULAR HEALTH, OR OTHER TREATMENTS THAT MIGHT BE INVOLVEED OR VENOUS THROMBOEMBOLISM OR CHRONIC LUNG CONDITIONS. >> TRIP, YOU WERE REALLY REFERRING TO THE -- ACCORD STUDY AND HOW MUCH SMOKING AND DIABETES AND HYPERTENSION CONTRIBUTE ABOVE AND BEYOND THIS QUESTION OF INFLAMMATION AND HIV, AND SO ALSO WONDERING ABOUT EFFORTS TO REDUCE SMOKING IN HIV INFECTED POPULATIONINGS AND DIABETES AND, YOU KNOW, THE STUFF YOU GUYS THINK ABOUT ALL THE TIME, BUT I THINK WE NEED TO HEIGHTEN OUR RESEARCH AND OUR CLINICAL FOCUS ON. >> I WOULD AGREE, AND THAT'S ALSO A WONDERFUL OPPORTNITY FOR IMPLEMENTATION SCIENCE. I THINK WE KNOW PEOPLE WHO SMOKE SHOULD STOP, SO THERE'S PROBABLY NOT POPULATIONS THAT WE WOULD RECOMMEND ARE PROTECTED FROM THE ADVERSE EFFECTS OF SMOKING, SO IT MAY BE MORE AN IMPLEMENTATION SCIENCE AGENDA IN THAT PARTICULAR INSTANCE WHERE WE% NEED TO LEARN MORE ABOUT HOW TO BEST HELP PEOPLE WHO ARE AT ESPECIALLY HIGH RISK, INCLUDING PEOPLE WITH HIV STOP SMOKING IF THEY DO SMOKE. SIM LARLLY, THOUGH, WITH RESPECT TO BLOOD PRESSURE OR DIABETES, WITH BLOOD PRESSURE, WE KNOW FROM THE SPRINT TRIAL AND OTHER STUDIES THAT TREATING BLOOD PRESSURE DOWN TO LOWER LEVELS IS VERY EFFECTIVE, ESPECIALLY IN HIGHER RISK POPULATIONS. WE DON'T HAVE SUBSTANTIAL KNOWLEDGE OF EXACTLY THE RIGHT THRESHOLD IN PEOPLE LIVING WITH HIV, AND THAT WOULD BE AN INTERESTING IDEA TO TAKE BACK TO THE INSTITUTE AND MULL OVER. WITH RESPECT TO DIABETES, IT'S QUITE COMPLICATED BECAUSE THE EVIDENCE IS CONFLICTING ABOUT THE ROLE OF DIABETES CONTROL, PER SE, IN PREVENTING CARDIOVASCULAR DISEASE. WHAT WE DO KNOW IS PREVENTING DIABETES IS REALLY IMPORTANT. SO THAT'S AN AREA I THINK REALLY FRUITFUL FOR CONSIDERING ADDITIONAL RESEARCH. >> SO THAT WAS A VERY IMPRESSIVE LISTING OF RESEARCH FOR ADULTS, AND AS A PEDIATRICIAN, I'D LIKE TO ASK YOU WHAT IS YOUR RESEARCH AGENDA FOR CHILDREN. JUST THE TWO PIECES HERE, THE HIV-INFECTED CHILD, BUT THE SECOND IS THE HIV UNEXPOSED INFECTED CHILD, WHICH IS GOING TO BE THE BULK OF, HOPEFULLY, THE CHILDREN OF THE FUTURE. AND IN HIV INFECTED CHILDREN, PARTICULARLY PERINATALLY ADOLESCENTS, SIGNIFICANT LUNG DISEASE HAS BEEN OBSERVED IN AFRICAN ADOLESCENTS THAT I DON'T KNOW HAS BEEN LOOKED AT VERY MUCH, AND THEN FOR THE HIV EXPOSED UNINFECTED CHILD, THERE ARE TWO ISSUES. ONE IS THE ISSUE OF CARDIAC MALFORMATIONS WITH IN UTERO ANTIRETROVIRAL EXPOSURE, AND THE OTHER IS THE POTENTIAL FOR LONG-TERM EFFECTS OF BOTH HIV AND ANTIRETROVIRAL EXPOSURE IN THESE EXPOSED UNINFECTED CHILDREN WHO AT LEAST IN AFRICAN STUDIES HAVE HIGHER RATES OF MORTALITY THAN GENERAL POPULATION INCREASED IP FEKTIOUS MORBIDITY. SO THERE'S A WHOLE SERIES OF RESEARCH ISSUES IN CHILDREN THAT I DIDN'T HEAR ANY OF THEM DISCUSSED. AND THEN THE LAST PIECE IS PREVENTION. IF YOU REALLY WANT TO PREVENT CARDIAC DISEASE IN HIV-INFECTED INDIVIDUALS, THEN YOU NEED TO START IN CHILDREN WHERE INFLAMMATION IS ALSO AN ISSUE. >> SURE. >> I THINK THIS IS ACTUALLY A REALLY IMPORTANT POINT THAT YOU BRING TO THE FORE AND I WOULD AGREE WITH YOU, IN SOME OF OUR EFFORTS, WE HAVE FOCUSED VERY HEAVILY ON THINKING ABOUT THE ADULT POPULATION AS WELL AS OUR DOMESTIC POPULATION AS WE STARTED TO KIND OF FORMULATE OUR EARLY DIRECTIONS AND BUILDING OUR PORTFOLIO. WE HAVE BEEN A PARTNER AND WORKED WITH NICHD WITH THE STUDY IN THE PAST, AN THIS GIVES OPPORTUNITY FOR US TO THINK ABOUT A LITTLE BIT FURTHER WHERE THE TYPES OF INTERSECTION OF QUESTIONS THAT MAY BE IMPORTANT TO THE NHLBI RESEARCH AGENDA MAY BE ABLE TO LEVERAGE OTHER TYPES OF COHORTS OR EFFORTS THAT ARE ONGOING THAT WOULD ALLOW US TO THINK ABOUT HOW WE CAN SPECIFICALLY STIMULATE RESEARCH IN THESE AREAS. THE OTHER THING I JUST WANTED TO COMMENT ON IS THAT I DO THINK SOME OF THE BREADTH OF OUR PORTFOLIO THAT MAY NOT NECESSARILY BE SPECIFIC TO HIV COULD STILL BE RELEVANT IN THIS POPULATION, AND WE DO HAVE A HEART DISEASES AND STRUCTURAL DEVELOPMENT BRANCH WITHIN OUR DIVISION OF CARDIOVASCULAR SCIENCES THAT FOCUSES ON LOOKING AT DRIVERS OF CARDIAC MALFORMATIONS, ET CETERA, WHERE THERE CAN BE NATURAL OPPORTUNITIES FOR SYNERGY AND PERHAPS THIS IS AN AREA THAT WE NEED TO WORK TO I WOULD SAY MAKE A MORE PUBLIC PUSH AROUND WHERE THE OPPORTUNITIES FOR SYNERGY COULD ARISE FOR OUR INVESTIGATOR COMMUNITY. >> [INAUDIBLE] >> SAY THAT ONE MORE TIME? >> I SAID HAPPY TO HELP. >> FANTASTIC. >> WE APPRECIATE THAT. >> SO PRISCILLA. >> GREAT. FANTASTIC PRESENTATION. BUT I JUST WANT TO FOLLOW UP ON TRIP'S POINT THAT IT'S PROBABLY NOT JUST ALL TRADITIONAL RISK FACTORS, THERE WAS A STUDY IN% JAMA CARDIOLOGY, SHOWING EVEN IF YOU TAKE AWAY ALCOHOL, PRE-EXISTING CORONARY DISEASE, RACE, HIV INFECTED -- I THINK IT'S VERY COMPLICATED AND IT'S NOT JUST THE TRADITIONAL RISK FACTORS, THE INCREASED RISK. >> FIRST WE'LL GO TO YOU THEN BACK. THANKS. SORRY. >> MAYBE MY QUESTION COULD GO ALONG THE LINES OF DR. -- IN THIS CASE WOULD BE IN TERMS OF IN THE CONTEXT OF HEALTH DISPARITIES, AND WORKING OR ADDRESSING THESE ISSUES WITH THE AFRICAN-AMERICAN AND LATINO COMMUNITY. I WORK FOR AN ORGANIZATION THAT PROVIDES SERVICES FOR -- THAT WORK WITH THESE COMMUNITIES. WE STARTED AN AGING PROGRAM TWO YEARS AGO, AND ONE OF THE THINGS THAT I WANT TO BE VERY INTENTIONAL AND CAREFUL ABOUT, AND PUT ATTENTION IS THE FACT THAT WHEN WHICH TALK ABOUT WE TALK ABOUT A LL THESE COMORBIDITIES, WHEN WE GO TO THESE COMMUNITIES THAT ALREADY HAVE PRE-EXPOSURE TO DIABETES, CARD JOE CARDIOVASCULAR DISEASE AND THEY ARE HIV-POSITIVE, HOW CAN I WORK WITH THAT FACTOR OF -- WITHIN HIV IN TERMS OF HE PREVENTING COMORBIDITIES, IN TERMS OF, LIKE -- I MEAN, ONE OTHER THING I'M THINKING IS WE TALKED ABOUT INFLAMMATION, BUT IN THESE COMMUNITIES SOMETIMES, EVEN WE HAVE TO ADDRESS THE TRADITIONAL, AND HOW THAT CORRELATES TO THE IMPLEMENTATION PART OF WHAT YOU'RE DOING, IF THERE WAS ANY SPECIFIC APPROACHES THAT YOU WILL USE TO ADDRESS THE SPECIFIC NEEDS OF THESE COMMUNITIES, WOULD YOU HAVE NN OPINION OR HAVE ANY OPINION OR COMMENT ON THAT? >> I JUST WANTED TO GO BACK TO THE SLIDE FOR JUST A MOMENT BECAUSE WHAT YOU'RE DESCRIBING DID COME UP AS AN IMPORTANT AREA OF FOCUS FOR THE INSTITUTE AND SEVERAL OF THE WORKING GROUP ACTIVITIES WE KIND OF ADDED IT IN THIS IMPLEMENTATION SCIENCE -- THE ISSUE THAT WAS REALLY DISCUSSED WAS THAT IF YOU ALREADY HAVE CERTAIN COMMUNITIES WITH HEIGHTENED RATES OF RISK FACTORS OR BURDEN OF RISK FACTOR FACTORS, AND THEN THERE'S AN INTERSECTION IN TERMS OF THINKING ABOUT THE RATES WITHIN THE POPULATION THAT ARE REALLY GROWING IN TERMS OF PEOPLE LIVING WITH HIV, THAT YOU MAY START TO SEE THESE INTERSECTIONS THAT BECOME IMPORTANT TO UNDERSTAND AS TO HOW THEY RELATE TO THE CO-MORBIDITY DEVELOPMENT. SO WE DO SEE THAT AS PART OF A MISSION THAT FITS WITHIN THE NHLBI RESEARCH VISION, AND ARE ACTIVELY ANTICIPATING THAT THAT WOULD BE AN AREA THAT COULD BE PURSUED EVEN UNDER THE NEW INITIATIVE THAT I HAD MENTIONED THAT PRECLUDE INITIATIVE THAT'S COMING OUT TO FOCUS ON IMPLEMENTATION SCIENCE. SO IT'S A REALLY IMPORTANT POINT THAT YOU RAISE, AND I THINK THE COG SANS OF IT -- IT'S ON OUR RADAR, IT DOESN'T MEAN THAT WE HAVE THE ANSWERS YET AND THAT'S WHY WE THINK WE REALLY NEED IT TO STIMULATE MORE RESEARCH IN THIS AREA. >>ITE I'M GLAD I'M GLAD TO SEE THE INTERSECTION POINT. ONE OF THE THINGS WE DID SOME NEED ASSESSMENT WITH A PROGRAM WE HAVE CALLED STRONG COMMUNITIES, AND WHAT WE LOOKED EXACTLY WAS AT THE IMPORTANCE OF INTERSECTIONS NOW, THAT WE CANNOT JUST LOOK AT ONE POINT OR THE OTHER, BUT WHAT REALLY CREATE A LAYER OF MORE INTERVENTION IS THE INTERSECTION THAT HAPPENED BETWEEN RACE OR BETWEEN STRUCTURAL ISSUES, ALL THOSE INTERSECTIONS WILL HAVE A LOT OF VALUE NOW WHEN WE THINK ABOUT IMPLEMENTING ANY PROGRAMMATIC INTERVENTIONS. SO I'M GLAD TO HEAR THAT'S HAPPENING. >> SO I'D LIKE TO ADD A LITTLE TO PRISCILLA'S RESPONSE TO TRIP'S -- OF COURSE WE CAN'T IGNORE THE TRADITIONAL RISK FACTORS AND WE REALLY HAVE TO ADDRESS THEM, BUT THERE'S SOMETHING REALLY INTERESTING GOING ON, FOR EXAMPLE, THE ACCELERATED MORBIDITY OF OUR SMOKING PATIENTS REALLY DOES SUGGEST THERE'S SOMETHING ABOUT HIV DISEASE AND PLAUSIBLY IT'S AN INFLAMMATORY ISSUE THAT THAT ACCELERATES THE MORBID COURSES IN THESE PATIENTS, AND I DON'T THINK ANYBODY KNOWS HOW THAT TAKES PLACE, AND I THINK THAT COULD BE A REAL FERTILE AREA OF INVESTIGATION. >> I'M A LITTLE OUT OF MY DEPTH WITH THIS QUESTION BUT IT'S ABOUT THE REPRIEVE STUDY, AND THE USE OF THE STATIN AND I JUST WONDERED WHAT SCREENING AND SAFETY MEASURES WERE IN PLACE FOR STATIN-INDUCED MYOPATHIES, EITHER THE -- IF YOU WILL THE TOXIC KIND OR THE IMMUNE-MEDIATED KIND OF STATIN-INDUCED MYOTOXICITY. >> SO I DON'T HAVE THE DETAILS OF THAT SAFETY MONITORING PLAN. >> PERHAPS I CAN COMMENT SINCE THE AIDS CLINICAL TRIAL GROUP IS CO-SPONSORING THE STUDY. THE STATIN IS PANABINISTAT, AN APPROVED STATIN THAT HAS AN EXCELLENT SAFETY RECORD, PATIENTS ARE UNDERGOING STANDARD CLINICAL MONITORING AS YOU WOULD FOR ANY -- THE PARTICIPANTS ARE UNDERGOING STANDARD MONITORING AS YOU WOULD FOR ANY PATIENT PRESCRIBED A STATIN, SO THEY HAVE ROUTINE SAFETY LABORATORIES BEING DETERMINED AS WELL AS LABORATORY MONITORING, AND OF COURSE THE INCIDENCE OF ADVERSE EVENTS INCLUDING MYOPATHY-RELATED AIDS IS BEING TABULATED BY THE INVESTIGATORS. >> AND PRESENTED TO A SAFETY AND DATA MONITORING BOARD THAT MAKES RECOMMENDATIONS TO THE INSTITUTE ABOUT ANY SIGNALS RELATED TO PARTICIPANT SAFETY. >> JUST TO ADD, BECAUSE IT MAY NOT HAVE BEEN CLEAR, THAT STUDY IS FOR PEOPLE WHO WOULDN'T HAVE A STATIN INDICATED BY HYPERLIPIDEMIA ORDINARILY. BY NORMAL MALOR,OR, QUOTE, NORMAL GUIDELINES. >> I WOULD BE INTERESTED TO HEAR A LITTLE BIT MORE ABOUT THE LEVEL OF INTEREST THAT NHLBI HAS IN CHARACTERIZING AND MITIGATING COMORBIDITIES AND INTERNATIONAL RESOURCE LIMITED SETTINGS, PARTICULARLY SUB-SAHARAN AFRICA. AS BEST I CAN TELL, UNLESS THE PATIENT IS PASSING OUT IN FRONT OF YOU, NO ONE IS EVEN TAKING BLOOD PRESSURE IN THE STANDARD VISIT. >> IT'S A VERY GOOD POINT, AND I DID RECOGNIZE THAT IN SEVERAL OF OUR EARLY PRIORITIES, WE DID HAVE MORE OF A DOMESTIC FOCUS, BUT WE DID WANT TO MAKE SURE THAT WE HAD THE OPPORTUNITY TO THINK ABOUT THE GLOBAL FOCUS. THIS, AGAIN, PARTICULARLY CAME OUT WHEN WE WERE TALKING ABOUT IMPLEMENTATION SCIENCE OPPORTUNITIES BECAUSE OUR CENTER FOR TRANSLATION RESEARCH AND IMPLEMENTATION SCIENCE IS ALSO WHERE OUR GLOBAL HEALTH PORTFOLIO RESIDES AS AN INSTITUTE, WE'VE ACTUALLY BEEN LOOKING AT THAT INTERSECTION OF GLOBAL HEALTH RESEARCH AND IMPLEMENTATION SCIENCE AND SAW SOME NATURAL ALIGNMENT, WHICH IS ALLUDED TO HERE AS WELL AROUND IMPLEMENTATION BARRIERS AND TREATMENT AND PREVENTION GLOBALLY, HOWEVER, WE RECOGNIZE THAT IT'S COSTLY TO DO GLOBAL WORK AND WE WOULD LIKE TO LEVERAGE INFRASTRUCTURE WHERE IT'S POSSIBLE TO DO SO, SO THAT'S ACTUALLY ONE OF THE STRATEGIES THAT WE WERE LOOKING AT FROM THIS APPROACH, IS HOW DO WE WORK WITH OTHER INSTITUTES, OTHER AGENCIES THAT ARE ALREADY IN CERTAIN AREAS BUILDING CAPACITY WHERE WE MAY BE ABLE TO PARTNER AND THINK ABOUT THE OPPORTUNITIES IN THE COMORBIDITIES RESEARCH ARENA, THAT MAKES SENSE FOR US AS NHLBI. >> IF I COULD JUST ADD A NOTE ABOUT THAT MORE BROADLY, THERE'S BEEN SOME DISCUSSION OF HOW WE CAN TAKE ADVANTAGE OF INFRASTRUCTURE THAT'S BEING DEVELOPED TO ADDRESS HIV IN SUB-SAHARAN AFRICA TO ADDRESS OTHER CHRONIC CONDITIONS MORE BROADLY OUTSIDE THE POPULATION LIVING WITH HIV, SO SOME OF THE SAME INFRASTRUCTURE IN TERMS OF MEDICAL INFRASTRUCTURE, DRUG DELIVERY INFRASTRUCTURE COULD ALSO BE USED TO ADDRESS ISSUES LIKE, FOR EXAMPLE, HIGH BLOOD PRESSURE IN UNINFECTED POPULATIONS. SO I THINK THERE'S A LOT OF INTEREST IN THESE SORTS OF ISSUES WITHIN OUR INSTITUTE. >> JUST WONDERING IF YOU HAD ANY PARTICULAR INITIATIVES THAT LOOK AT THE INVOLVEMENT OF BONE MARROW ITSELFAND ANY OF THE OTHER COMORBIDITIES AND COMPLICATION. >> SO OUR NHLBI AIDS COORDINATOR IS IN THE AUDIENCE, AND HE WORKS WITH THE BLOOD PORTFOLIO SPECIFICALLY, TO MAYBE HE CAN JUST SPEAK TO THAT QUESTION FOR US. >> WE DON'T HAVE ANYTHING SPECIFIC YET. WE USED TO HAVE AS NAKELA MENTIONED A MORE GENERIC INITIATIVE, THAT'S WHAT I THINK ABOUT RIGHT NOW, MORE FOCUSED GAPS, AREAS THAT I LOOK AT. >> I JUST WANT TO RETURN BRIEFLY TO THE INTERNATIONAL QUESTION, YOU MENTIONED YOU HAVE AN RFA THAT WILL BE COMING OUT SHORTLY FOR IMPLEMENTATION, BUT THAT IT'S -- IMPLEMENTATION RESEARCH BUT IT'S DOMESTIC. GIVEN THAT THERE IS A HUGE PLATFORM OF RESEARCH PROGRAMS INTERNATIONALLY THAT ARE FUNDED BY OTHER INSTITUTES, MAKING IT OPEN TO INTERNATIONAL INVESTIGATORS, BUILDING ON THOSE PLATFORMS MIGHT MAKE SENSE. >> I THINK THIS IS THE ONE YOU WERE REFERRING TO. WE CAN DEFINITELY GO BACK AND DISCUSS FURTHER WHAT THE OPPORTUNITIES MAY BE. >> I JUST WANT TO ECHO DICK'S RECOMMENDATION TO CONSIDER INTERNATIONAL OPPORTUNITIES FOR RFA, AND I'M REALLY PLEASED THAT INTERNATIONAL RESEARCH PRIORITIES ARE STILL ON YOUR AGENDA, AND I'D LIKE TO PUT THAT FORWARD FOR OTHER ICs AS WELL. CLEARLY THERE'S DISCUSSION ABOUT THE ELIMINATION OF THE FOGARTY INTERNATIONAL CENTER. THE FACT THAT THE MAJORITY OF HIV INFECTIONS OCCUR IN LOWER AND MIDDLE INCOME COUNTRIES, THAT IS OF GRAVE CONCERN TO MANY OF US. >> I WAS JUST GOING TO QUICKLY COMMENT THAT OUR GLOBAL RESEARCH AGENDA HAS A HEAVY FOCUS ON LOW AND MIDDLE INCOME COUNTRIES, SO IN THE GENERAL PORTFOLIO OF GLOBAL HEALTH RESEARCH IN NHLBI AND FOCUSES ON CAPACITY BUILDING AND LEVERAGING OTHER INFRASTRUCTURE SIMILAR TO WHAT DR. DP. GO FSM F HAVE SAID, SO WHERE THERE MAY BE RIPE OPPORTUNITIES FOR INTERSECTION, OUR GLOBAL RESEARCH AGENDA IS BROAD ENOUGH TO INCORPORATE THAT. >> SO THIS IS AN OPPORTUNITY FOR JUST A MINUTE MORE IF ANYONE HAS ANY OTHER QUESTIONS OF ANYTHING THAT WE'VE HEARD SINCE THE BREAK. DR. KIM, DR. BROWN OR NHLBI? OKAY. WE ARE RIGHT ON TIME THEN TO BREAK FOR LUNCH, AND IT'S EXACTLY 11:45, SO PLEASE BE BACK AT EXACTLY 12:45 SO THAT WE CAN START ON TIME. THANK YOU. >> WE'RE GOING TO RESTART. ACTUALLY THERE'S WEATHER OUT THERE SO WE'RE GOING TO TRY TO END ON TIME, EARLY IF WE CAN, EVEN THOUGH I THINK UNFORTUNATELY THE WEATHER IS IMPACTING FLIGHTS ADVERSELY THE OTHER WAY AND DELAYS AND SO FORTH BUT WE'RE REALLY GOING TO TRY TO END ABSOLUTELY ON TIME, 15 MINUTES EARLY IF WE CAN. SO THE NEXT PART OF THE AFTERNOON REALLY IS AROUND THE PRESENTATIONS OF THE AFTERNOON, THE IMPACT OF THE MICROBIOME. AND FIRST I'M GOING TO INTRODUCE DR. CARRINGTON-LAWRENCE, STACY CARRINGTON-LAWRENCE, WHO WILL GIVE AN INTRODUCTION TO THIS SECTION. DR. CARRINGTON-LAWRENCE IS HEALTH SCIENCE ADMINISTRATOR AND COORDINATOR FOR ETIOLOGY AND PATHOGENESIS RESEARCHERS IN THE OAR, PRIOR TO 2007 WAS IN THE NIH OFFICE OF SCIENCE POLICY WORKING ON PUBLIC/PRIVATE PARTNERSHIPS FOLLOWING POSTDOC, ON THE IMPACT OF THE MICROBIOME ON HIV, PATHOGENESIS AND PREVENTION. >> THANK YOU, MONICA. SO I HAVE THE PLEASURE OF INTRODUCING THE TOPICS FOR THE SCIENTIFIC SESSION OF OARAC. I'M NOT A MICROBIOME EXPERT, I AM AN ENTHUSIAST, LOOKIN FORWARD TO SOME OF THE EXCITING PRESENTATIONS IN THIS EMERGING AREA OF RESEARCH. WE'RE NOT ALL BAD. THAT'S VERY TRUE. WE'RE USED TO THINKING OF BACTERIA, VIRUSES, FUNGI IN A PATHOGENESIS TYPE OF MODEL, AND TRULY THEY HELP IN A LOT OF AREAS OF OUR SURVIVAL. SO THE DEFINITION OF A MICROBIOME, I SORT OF PULLED THIS OFF OF THE INTERNET, IT'S A NOUN, MICROORGANISMS IN A PARTICULAR ENVIRONMENT INCLUDING THE BODY OR PARTS OF THE BODY, OR THE COMBINED GENETIC MATERIAL OF MICRO ORGANISMS IN A PARTICULAR ENVIRONMENT AND HUMAN MICROBIOTA IS SORT OF AN AGGREGATE OF MICROORGANISMS, THAT RESIDE ON THE SURFACE OF THE SKIN, IN THE MOUTH, RESPIRATORY, GASTROINTESTINAL AND URU-GENITAL TRACT INCLUDING BACTERIA, FUNGI, BACTERIA, VIRUS, THE ENVIRONMENTS ON YOUR BODY EXPOSED TO THE EXTERNAL OR OUTSIDE. IN CONJUNCTION WITH YOUR GENES AND MAKEUP, DIET, LIFESTYLE, THE ENVIRONMENT ALL WORK TOGETHER TO SORT OF REGULATE METABOLISM, AND SO THE OBSERVABLE CHARACTERISTICS OF AN INDIVIDUAL IS REGULATED BY THESE ORGANISMS, AND THE FACTORS THAT ARE RELEASED BY THE MICROBIOME HAVE PROFOUND IMPACT ON HOST METABOLISM AND IMMUNE RESPONSES. THE HUMAN MICROBIOME IS CONSTANTLY IN FLUX. AND ALTHOUGH THERE ARE SOME CHANGES OVER TIME, THE BODY TRIES TO MAINTAIN SORT OF A METABOLIC HOMEOSTASIS. AND SO FUNCTIONALLY, ALTHOUGH THE MICROBIOME IS CHANGING, THE IMMUNE SYSTEM AND METABOLISM SO DR. BUSHMAN IS GOING TO PRESENT WAYS TO MEASURE BOTH OF COMPOSITION AND FUNCTION OF THE MICROBIOME USING A SYSTEMS BIOLOGY APPROACH, AND THERE BY ALLOWING TO US HAVE A MORE COMPREHENSIVE EXAMINATION OF THE IMPACT OF THE HIV INFECTION ON THE HOST. SO, THE MICROBIOME IS SORT OF A BROAD CATEGORY OF RESEARCH. AND FOR A LONG TIME THE NIH HAS BEEN DOING STUDIES THAT WASN'T NECESSARILY CALLED MICROBIOME RESEARCH, BUT IN 2008 THE NIH COMMON FUND ESTABLISHED THE HUMAN MICROBIOME PROJECT WITH THE MISSION OF GENERATING RESEARCH RESOURCES ENABLING COMPREHENSIVE CHARACTERIZATION OF THE HUMAN MICROBIOME, AND COORDINATING THIS EFFORT ACROSS THE NIH. SO, THERE WERE TWO PHASES, THE FIRST PHASE, LIKE I SAID, THEY WERE GENERATING RESEARCH RESOURCES BUT FROM THE SECOND PHASE TERMED THE INTEGRATIVE HMP EXAMINING SPECIFIC MICROBIOME-ASSOCIATED DISEASES, SPECIFICALLY IBD, DIABETES, PRE-TERM BIRTH AND THAT WILL BE DISCUSSED IN THE PRESENTATION FOLLOWING THIS ONE. IN ADDITION TO AN NIH EFFORT THERE WAS A NATIONAL EFFORT ON THE MICROBIOME, WHICH WAS TERMED THE NATIONAL MICROBIOME INITIATIVE. ON MAY 13, 2016, THE WHITE HOUSE OFFICE ANNOUNCED TO STUDY THE MICROBIOME ACROSS DIFFERENT ECOSYSTEMS. THERE WAS A COMMITMENT OF A COMBINED INVESTMENT ACROSS U.S. AGENCIES AS WELL AS SOME PUBLIC AND PRIVATE ORGANIZATIONS OF $121 MILLION IN FISCAL YEARS 2016 AND 2017, AND THE NIH COMMITMENT TO THIS WAS $20 MILLION. THE STATED GOALS OF THE NATIONAL MICROBIOME INITIATIVE WAS TO SUPPORT INTERDISCIPLINARY RESEARCH, IN ORDER TO ANSWER FUNDAMENTAL QUESTIONS ABOUT MICROBIOMES AND DIVERSE ECOSYSTEMS. TO DEVELOP PLATFORM TECHNOLOGIES, TO GENERATE INSIGHTS AND HELP SHARE KNOWLEDGE ABOUT MICROBIOMES IN DIVERSE ECOSYSTEMS, AND THEN TO EXPAND THE MICROBIOME WORK FORCE THROUGH CITIZEN SCIENCE PUBLIC ENGAGEMENT AND EDUCATION OPPORTUNITIES. AND LEADA CAN SPEAK TO THIS INITIATIVE AS WELL. SO THE OAR HAD AN INTEREST IN THE MICROBIOME FOR QUITE A WHILE, STARTED IN 2007, AND NCI HAD A MICROBIOME HIV AND CANCER WORKSHOP AND AT THIS WORKSHOP IT WAS PRETTY CLEAR AT LEAST TO US HERE IN THE OAR THAT A LOT OF WORK STILL NEEDED TO BE DONE IN THIS AREA. IT LOOKED PROMISING, FOR SURE. THERE WAS CLEARLY AN IMPACT OF HIV INFECTION ON THE MICROBIOME, BUT THERE WERE NO STANDARDS, THERE WAS NO WAY TO COMPARE WHAT WAS GOING ON IN THE BODY, WHETHER OR NOT IT WAS HIV CAUSING THIS DYSBIOSIS OR SOMETHING ELSE AND HOW THAT IMPACTED CANCER. SO IN 2008 A MICROBIOME FOCUS WAS ADDED TO THE PLAN AND THE WORKING GROUP IN SUBSEQUENT YEARS OF THE PLAN EXPANDED ON THAT. SO IN ADDITION, NHLBI RELEASED AN RFA ON MICROBIOME OF THE LUNG AND RESPIRATORY TRACT IN HIV-INFECTED INDIVIDUALS AND ON AFFECTED CONTROLS AND AS FAR AS I CAN TELL THIS WAS THE FIRST RFA SPECIFIC FOR HIV IN THE MICROBIOME. AND THEN WE HAVE THIS LONG GAP OF ABOUT SIX YEARS WHERE I THINK WE WERE WAITING FOR INFORMATION FROM THE HUMAN MICROBIOME PROJECT TO SORT OF INFORM OUR PROVIDE ADDITIONAL RESOURCES FOR THIS FIELD IN TERMS OF BEING ABLE TO STANDARDIZE OR LOOK AT HEALTHY CONTROLS FOR THE MICROBIOME, AND AROUND 2012, BETWEEN 2012 AND 2013 WE REALLY SAW THIS FIELD EXPANDING IN HIV. THERE WERE A COUPLE MORE RFAs RELEASED HERE AT NIH. WE HAD A CFAR SUPPLEMENT ON THE IMPACT OF THE MICROBIOME AND HIV INFECTION AND PATHOGENESIS, OAR PROVIDED ADDITIONAL FUNDS, SUPPLEMENTAL FUNDS FOR MICROBIOME RESEARCH PROJECTS, WHICH WERE ADDED TO SEVERAL IC BUDGET ALLOCATIONS IN FY 2015. IN ADDITION, NIH SUPPORTED THE FIRST INTERNATIONAL MICROBIOME AND HIV PATHOGENESIS AND PREVENTION AND TREATMENT MEETING WHICH THE SECOND ONE THIS PAST NOVEMBER, 2016, AND THAT'S CHAIRED BY ALLEN LANDAI, ALSO CHAIR OF THE ETIOLOGY AND PATHOGENESIS NIH PLAN. APPARENTLY THERE IS ONE RFA THAT'S ACTIVE, IT'S MULTI-I.C., AND IT'S LOOKING AT ADVANCING TRANSLATIONAL PROBIOTIC AND PRE-BIOTIC RESEARCH AND INCLUDES COMPONENT OF HIV, THIS LEADS US TO THIS OARAC TODAY. SO A LITTLE BIT ABOUT THE MICROBIOME PORTFOLIO, IN OAR, OR IN NIH, SO BETWEEN 2012 AND 2016 WE LOOKED TO SEE WHAT THE PORTFOLIO LOOKED LIKE, WITH HIV AND MICROBIOME RESEARCH. AND STARTING IN 2012 THE INVESTMENT, TOTAL INVESTMENT, WAS $13.5 MILLION. THAT'S BALLOONED TO ALMOST THREE TIMES THE AMOUNT IN 2016, SO OVER THAT 4-YEAR PERIOD WE'VE SEEN INCREASING INTEREST AND INCREASING SUPPORT HERE AT NIH FOR MICROBIOME RESEARCH. IF WE LOOK AT FUNDING BY INSTITUTES AND CENTERS YOU CAN SEE THAT BETWEEN 2012 AND 2016 NIAID, HERE IN LIGHT BLUE, INVESTED QUITE HEAVILY IN THE AREA, THE LARGEST INSTITUTE TO SUPPORT THE RESEARCH BUT WE HAVE SMALLER INSTITUTES CONTRIBUTING AS WELL. NICHD, WHICH IS IN THE ORANGE, HAS PROVIDED SUPPORT FOR THESE TYPES OF STUDIES. HEART, LUNG AND BLOOD THAT RELEASED THE FIRST RFA IN 2007 HAVE QUITE A BIT OF SUPPORT AS WELL, IT'S TRAILED OFF A LITTLE BIT SINCE THE INITIAL INVESTMENT. BUT WE'VE ALSO SEEN AN INCREASE IN THE NUMBER OF INSTITUTES SUPPORTING THIS TYPE OF RESEARCH OVER TIME. AND MOST OF THESE STUDIES ARE -- THEY WERE PART OF LARGER STUDIES, SO SUPPLEMENTS TO CENTER GRANTS, SUPPLEMENTS TO LARGER U01s. THERE WEREN'T VERY MANY INVESTIGATOR-INITIATED, AT LEAST NOT EARLY ON, SOME WERE IN RESPONSE TO FOAs, BUT THE VAST MAJORITY WERE PARTS OF LARGER EFFORTS BUT WHAT WE'RE SEEING IN 2016 IS MORE INVESTIGATOR-INITIATED AND MORE AREAS BEING COVERED AS WELL. AND I'LL SHOW THAT IN THE NEXT SLIDE. SO THE INVESTMENTS BY NIH PRIORITY AREAS, AS YOU CAN SEE, AND IT'S PROBABLY NO SURPRISE, MOST OF THE RESEARCH THAT'S BEING DONE HAS BEEN BASIC RESEARCH, THE DARK BLUE BAR ON THE TOP, FOLLOWED BY COMORBIDITIES AND REDUCING INCIDENCE. A LOT OF THESE STUDIES ARE LOOKING AT, YOU KNOW, HOW THE MICROBIOME IMPACTS IMMUNITY, THE GASTROINTESTINAL TRACT, THERAPEUTICS, HOW THE MICROBIOME IMPACTS THE PHARMACOKINETICS, PHARMACODYNAMICS OF ARTs, AND SO ON AND SO FORTH. AND THERE'S IN 2016 THERE WAS ACTUALLY ONE PROJECT ON CURE AND A FEW ON VACCINES AS WELL. SO SOME CURRENT RESEARCH THAT'S CURRENTLY BEING CONDUCTED IN THIS AREA THAT I JUST PULLED OFF OF PubMed THAT SEEMS REALLY INTERESTING AND SORT OF EXPANDED UPON SORT OF THE INFORMATION THAT WE CURRENTLY KNOW ABOUT HIV AND THE MICROBIOME, AND ONE WAS ON ANAEROBIC BACTERIAL FERMENTATION PRODUCTS, LOOKING AT SHORT CHAIN STUDY ASSETS WHICH WILL PROBABLY COME UP AGAIN AND AGAIN AS AN IMPORTANT METABOLITE, FROM ACTIVE MICROBES IN THE GUT, THEY ARE GOOD FOR THE IMMUNE SYSTEM, THEY INDUCE T CELL REGULATORY -- T REGULATORY CELLS. BUTERATE, THE BY-PRODUCT, IS AN ENERGY SOURCE FOR GUT EPITHELIAL CELLS, PROMOTES IMMUNE TOLERANCE, AND SO ON AND SO FORTH. AND WHAT THESE INVESTIGATORS FOUND ACTUALLY WAS THAT IN HIV-INFECTED ART-TREATED INDIVIDUALS, IN RESPONSE TO TB ANTIGEN STIMULATION THERE WAS A DOWNREGULATION OF INTERFERON ALPHA AND IL-17A WHICH MADE THEM MORE SUSCEPTIBLE TO INFECTION, SO WHILE SHORT CHAIN STUDY ASSAYS AND BUTERATE ARE GOOD ON ONE HAND IT CAN AFFECT SUSCEPTIBILITY ON ANOTHER. ANOTHER AREA OR STUDY THAT RECENTLY IS PUBLISHED WITH HIV INFECTION AND COMPRISED, COMPROMISED MUCOSAL IMMUNITY, LOOKING AT THE ORAL MICROBIOME, AND HOW IT INFLUENCED -- ART INFLUENCES ORAL MICROBIOME IN WAYS THAT THE INTEGRITY OF THE ORAL MUCOSAL TISSUE AND INNATE IMMUNE COMPONENTS OF ORAL CAVITY ARE ASSOCIATED WITH THE INDUCTION OF CHRONIC INFLAMMATION IN HIV-INFECTED INDIVIDUALS. SO I WON'T GO INTO THE LAST ONE BUT IN JUST THIS PAST YEAR, AT AIDS 2016, R4P AND CROI THERE WERE STUDIES DISCUSSING EFFECT OF MICROBIOME ON GENITAL TRACT MICROBIOME AND TRANSMISSION, IMMUNE ACTIVATION, VACCINE EFFICACY AND ISSUES REGARDING ROLE OF ART METABOLISM AND PREVENTION. DOUG IS NOT HERE UNFORTUNATELY BUT SOME OF THESE STUDIES MAY BE PRESENTED THIS AFTERNOON AS WELL. SO THE GOALS OF TODAY'S OARAC MEETING, AS YOU CAN SEE, MICROBIOME RESEARCH IS VERY BROAD AND IT'S RELEVANT TO A WHOLE HOST OF AREAS AND DISCIPLINES WITHIN HIV SO I THINK IT'S IMPORTANT FOR US HERE AT OAR TO BE ABLE TO HEAR FROM YOU, TO INFORM US ON SORT OF THE GAPS AND OPPORTUNITIES IN THE AREA, AS WELL AS GET YOUR RECOMMENDATIONS ON THE BEST WAYS FOR US TO MOVE FORWARD AND PRIORITIZING THIS RESEARCH IN THE FIELD. SO JUST SORT OF THE AGENDA FOR THE AFTERNOON, LITA PROCTOR WILL GIVE US AN OVERVIEW, WE'LL LARRY FROM RICK BUSHMAN, JACQUES RAVEL WITH THE INFLUENCE OF BIOLOGICAL SPECS, DOUG KWAN WHO UNFORTUNATELY COULD NOT MAKE IT WAS GOING TO TALK ABOUT THE ROLE OF THE MICROBIOME MUCOSA, SYSTEMIC IMMUNITY, THIS MAY COME UP DURING THE PANEL DISCUSSION THIS AFTERNOON. AND THEN FINALLY BETSY HAROLD FILLING IN FOR GENIE MORAAK, IMPACT OF MICROBIOME ON PHARMACODYNAMICS AND PHARMACOKINETICS AND A DISCUSSION ON THE MICROBIOME FIELD AND HOW TO CAPITALIZE ON THE OPPORTUNITIES. SO WITH THAT I THINKLY TURN IT BACK OVER TO MONICA TO INTRODUCE THE FIRST SPEAKER. >> OKAY. THANK YOU. SO NEXT IS DR. LITA PROCTOR WHO WILL GIVE AN INTRODUCTION TO THE MICROBIOME, PROGRAM DIRECTOR IN DIVISION OF GENOMIC SCIENCES AT THE NATIONAL INSTITUTE OF GENOME RESEARCH -- NATIONAL HUMAN GENOME INSTITUTE, A COMMON FUND PROGRAM WITH THE MISSION OF GENERATING THE HUMAN MICROBIOME AND ROLE OF MICROBIOME IN HUMAN HEALTH. SHE'S FORMERLY TRAINED IN MICROBIAL ECOLOGY AND PRIOR TO WORK AT THE NIH HELD APPOINTMENT AT FLORIDA STATE UNIVERSITY AND UNIVERSITY OF CALIFORNIA-SANTA CRUZ. THANK YOU. >> THANK YOU, THANK YOU. STACY ASKED ME TO PROVIDE A BROAD OVERVIEW OF THE HUMAN MICROBIOME. SHE STARTED WITH HER SLIDES BUT I'M HOPING TO ADD MORE COLOR TO THE IDEAS BECAUSE I COORDINATE THE HUMAN MICROBIOME PROJECT, WHAT WE'RE TRYING TO ACCOMPLISH WITHIN THAT PROGRAM AS WELL. THIS IS, I UNDERSTAND FROM STACY, A VERY BROAD GROUP OF DISCIPLINES. FOR SOME THIS WILL BE TOTALLY BORING. HOPEFULLY THOUGH FOR SOME OF YOU IT WILL BE USEFUL. LET'S SEE. OKAY. SO EVERYWHERE WE LOOK AND BY THE WAY I'M OFTEN FEELING INHIBITED BEHIND BIG PODIA LIKE THIS. HOPEFULLY YOU CAN SEE MY, NOT JUST A TALKING HEAD. IT'S EPITHELIAL SURFACES BUT EVERYWHERE WE LOOK WE FIND MICROBES ASSOCIATED WITH HEALTHY HUMAN TISSUES. I WON'T READ NUMBERS BUT YOU CAN SEE THEY VERY LARGE DEPENDING ON THE SITE. IN SOME CASES DATA ARE PRELIMINARY. THERE'S SOME DISCUSSION ABOUT BREAST MILK HAVING A COMMUNITY BUT WE EVENTUAL FINALIZED, AND WHETHER THE PLACENTA MIGHT HAVE AN ASSOCIATED MICROBIAL COMMUNITY. THE POINT IS ALL HEALTHY TISSUES TO SOME DEGREE OR ANOTHER HAVE AN ASSOCIATED MICROBIAL COMMUNITY. I'M GOING TO USE THE WORD MICROBE A LOT. IT JUST MEANS MICROBIAL, IT'S A SLOPPY TERM BUT DOES INCLUDE ALL MANNER OF MICROBIAL, BACTERIA, EUKARYOTIC, AND MICROBIOME MEANS ALL THAT MICROBIAL LIFE AND GENETIC AND METABOLIC CAPABILITY. SO JUST BE AWARE HOW WE TRY TO USE THAT PHRASE. TO GIVE YOU KIND OF A COUPLE TAKEHOME CONCEPTS TO GET A SENSE OF THE MAGNITUDE OF MICROBIOME THE GUT MICROBIOME, THE LARGEST MICROBIAL COMMUNITY OF OUR BODIES, AND IN THE ADULTS WEIGH 3 TO 5 POUNDS. SO THAT'S ABOUT THE SIZE OF YOUR BRAIN. YOU GOT A SENSE FOR HOW LARGE THE GUT MICROBIOME IS. AND ANOTHER PARAMETER IS THE METABOLIC CAPACITY OF THE GUT MICROBIOME, ABOUT EQUIVALENT TO OUR LIVER. SO IN OTHER WORDS VERY HIGH METABOLIC ACTIVITY. I'M GOING TO WALK THROUGH KIND OF NATURAL HISTORY OF THE MICROBIOME BECAUSE YOU SHOULD BE AWARE THAT WE ACQUIRE OUR MICROBIOTA NEW EACH GENERATION. THESE ARE CLUSTER PLOTS, YOU'VE SEEN PLENTY OF THEM. THEY ARE MEANT TO DESCRIBE IN THIS ONE PANEL COMPARING WHERE MICROBES COME FROM FOR THE NEWBORN, WHETHER THE CHILD IS BORN BY CESEAREAN, A VERY COMMON PROCEDURE IN MODERN SOCIETY, VERSUS BIRTH CANAL. THE POINT I WANT TO MAKE IN THIS ONE FIGURE, OH BY THE WAY IF YOU EVER WANT TO READ THESE PAPERS I TRY ALWAYS REMEMBER TO INCLUDE THE CITATION FOR EACH FIGURE SO IF YOU CHASE DOWN THE PRIMARY LITERATURE. CHILDREN THAT ARE BORN VAGINALLY ACQUIRE THEIR INITIAL INNOCULUM FROM THE BIRTH CANAL, AND THE OTHERS FROM TEND TO BE SKIN MICROBES FROM NOBODY'S HANDLING THE BABY. IT OBTAINS INNOCULUM FROM THE MOTHER, THEY ARE MAGNETS. THE SECOND POINT IS THERE'S A DYNAMIC PROCESS THAT OCCURS OVER ABOUT THE FIRST TWO YEARS OF LIFE. YEAR-AND-A-HALF, TWO YEARS OF LIFE. DOESN'T MATTER THAT YOU CAN'T READ THE LEGEND ON THE RIGHT. FOLLOW THE COLORS. YOU SEE THERE'S THE INITIAL INNOCULUM IS LOW DIVERSITY INNOCULUM AND AS HE DEVELOPS HE STARTS SEEING MICROBIAL COMMUNITIES MOVING IN, IN A SERIES OF SUCCESSIONAL EVENTS, A YEAR-AND-A-HALF TO TWO YEARS. YOU CAN SEE AT THE VERY TOP OF THAT FIGURE IT STARTS WITH MECONIUM, ENDS AT DAY 54, YOU CAN -- DAY 454, ONE TO TWO YEARS. WHAT'S OCCURRING IS THE COMMUNITY IS COMING TOGETHER AND ASSEMBLING AND BECOMING IN FACT MORE ADULT-LIKE OVER THE FIRST TWO YEARS OF LIFE. THAT RED ARROW IS MINE SUPER-IMPOSED ON A GRAPH PUBLISH THE IN THE 2007 PAPER. OVER THAT PERIOD, 500 DAYS OR SO, THE CHILD'S MICROBIOME BECOMES MORE ADULT-LIKE IN MAKEUP AND COMPOSITION, THE ADULT THERE BEING THE MOTHER. THEN IF A CHILD IS BREASTFED, SO BREAST MILK HAS A ROLE IN THIS DEVELOPMENT, THE HUMAN MILK OLIGO MICRO, THE BABY IS NOT FEEDING OFF THE SUGARS, INSTEAD IT'S BEING FERMENTED BY THE BIOME, HUNDREDS OF DIFFERENT KINDS OF HMOs, THERE'S ALWAYS BEEN THIS QUESTION, WHY IS BREASTING MILK SO COMPLEX, IT'S NURTURING THE MICROBES. THESE HMOs ARE APPEARING AS MOLECULAR DECOYS THAT ACT AS MOLECULAR SPONGES TO REMOVE PATHOGENS THAT MAY BE ENTERING THE INFANT AS THE INFANT'S OWN IMMUNE SYSTEM IS DEVELOPING. SO IT'S A KIND OF FIRST LAYER OF PROTECTION, IF YOU WILL. YOU KNOW THIS. THIS IS ALSO ALL OCCURRING DURING THE TIME WHEN THE CHILD'S IMMUNE SYSTEM IS DEVELOPING. SO THIS KIND OF FIGURE HERE SHOWS YOU NEWBORN, THREE MONTHS, ONE YEAR AND SIX YEARS OLD. THAT NEWBORN NOW HAS SOME OF THE MOTHER'S MATERNALLY ACQUIRE IMMUNITY, PASSIVE IMMUNITY, NOW BREAST MILK IS ANOTHER PART OF THAT PASSIVE IMMUNITY, PROTECTING THE CHILD FROM INVADING PATHOGENS, BY THE FIRST YEAR DEVELOPED 15-20% OF ANTIBODY COMPARED TO ADULT. FIRST YEAR IMMUNE SYSTEM IS DEVELOPING AND CHILD'S MICROBIOME IS DEVELOPING DURING THE SAME TIME. AND TOGETHER THEN THE MICROBIOTA AND HOST INTERACT TO REGULATE OUR HEALTH. I'VE INDICATED THE IMMUNE SYSTEM HAS TO DEVELOP IN THE PRESENCE OF THIS DEVELOPING MICROBIOME BECAUSE IT EDUCATES THE IMMUNE SIS TO RECOGNIZE CELLS FROM NON-CELLS, NEEDS TO ACQUIRE BENEFICIAL MICROBES AND NOT ASSUME THEY ARE PATHOGENS. THE GUT MICROBIOME PLAYS A ROLE IN DIGESTING INDIGESTIBLES LIKE VEGETABLE, WE REQUIRE ACTIVITY OF OUR GUT MICROBIOME. STACY ALREADY MENTIONED ENERGY SUBSTRATES FOR HOST CELLS, SHORT CHAIN FATTY ACID INCLUDING BUTERATE. THEY METABOLIZE DRUGS. THERE'S SOME DISCUSSION ABOUT THE ROLE OF THE GUT MICROBIOME IN METABOLIZING DRUGS THAT LEAD TO ACTIVE TO DRUG, DEACTIVATE THE DRUG, TURN IT INTO A TOXIC BY-PRODUCT OR METABOLIZE SO FAST IT'S HARD TO FIGURE OUT HOW MUCH OF A DOSE YOU SHOULD GIVE A PATIENT IN ORDER TO HAVE AN EFFICACIOUS DOES, ALL A MATTER OF BENEFICIAL COMPOUNDS. MANY VITAMINS HAVE TO BE ISN'T SIZED. SIZED -- SYNTHESIZED. MANY REASONS HAVE AN ASSOCIATED MICROBIA L COMMUNITY. THEY ALLS IT AS A WAY TO MAINTAIN NICHE PRESENCE AND SO ANTIMICROBIALS ALSO PRODUCE SIGNALING MOLECULES, COMMUNICATE WITH HOST, ALL MANNER OF SIGNALING MOLECULES THAT INTERACT WITH THE HOST AND FINALLY A VERY HOT AREA YOU'RE NOT GOING TO TALK ABOUT DURING THIS COUNCIL BUT THE GUT MICROBIOME IS THE SOURCE OF MANY APPARENTLY NEUROTRANSMITTERS AND THERE'S A LOT OF WORK TO FIGURE OUT HOW DOES THE GUT MICROBIOME AND ITS METABOLITES COMMUNICATE WITH THE BRAIN BUT APPARENTLY THERE'S QUITE A BIT OF -- THERE'S A LARGE ROLE FOR THE GUT MICROBIOME IN BRAIN DEVELOPMENT AND SUBSEQUENT BEHAVIOR. LOOK AT JUST THE GENE COMPLEMENT, GENE CATALOG OF THE MICROBIOME, THE HUMAN MICROBIOME IS THOUGHT TO EITHER AUGMENT OR EXTEND THE HUMAN GENOME. WHY DO WE SAY THAT? MOST OF US, ALL OF US ARE HOST TO THOUSANDS OF BACTERIAL SPECIES, NEVER MIND THE OTHER MICROBIAL LIFE, WHICH IF YOU ADD UP ALL THE GENES ASSOCIATED WITH THOSE MICROBES ADDS UP TO OKAY? HUMAN GENOME, WE'RE AT 20 OR 23,000 GENES. SO IT'S QUITE CLEAR THAT THE MICROBIAL MEMBERS OF OUR BODIES CONTRIBUTE HUNDREDS OF TIMES MORE GENE INPUT INTO OUR SYSTEMS THAN JUST OUR OWN HUMAN GENOME. I COME FROM THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE, SO SOMETIMES THIS SLIDE DOESN'T GET A LOT OF FAVOR. BUT HERE IS WHERE WE ARE. 2017. THERE'S BEEN A CALL NOW FOR A WHILE THAT PRACTICES, IMPORTANT PRACTICES IN MODERN SOCIETY, MAY BE UNINTENTIONAL LEADING TO IMPOVERISHED OR DYSFUNCTIONAL OR DYSBIOTIC MICROBIOME. COMMON CONTEMPORARY PRACTICES WHICH WE RELY ON INCLUDE SANITATION, FRESH FOOD, COOKING OUR FOOD, CLEAN WATER, BATHING, ANTIBIOTIC USE, CESEAREAN BIRTH, FORMULA FEEDING AND SO ON. THOSE ARE ALL IMPORTANT TO US IN CONTEMPORARY SOCIETY. YET THERE MAY BE AN UNINTENDED CONSEQUENCE TO THAT, IN THAT WE MAY BE UNINTENTIONALLY REMOVING TRANSFER -- THE TRANSFER OPPORTUNITY OF MICROBES BETWEEN GENERATIONS AND OR KILLING OFF MICROBES BECAUSE OF THESE VARIOUS ACTIVITIES. AND I LOVE THIS QUOTE FROM DOMINGUEZ FELLOW, SHE SAYS HEALTHY BRAZILIAN AMER INDIANS HAVE 30% MORE MICROBES IN THEIR MICRO BIOPSY THAN SO-CALLED HEALTHY AMERICANS. I'LL GET TO THOSE DATA IN A MINUTE. SO THE THING THAT MAY BE EVEN MORE CONCERNING IS NOT JUST AS IF IT HITS ONE GENERATION. IF IN FACT OUR MAJOR MODE OF TRANSFER OF MICROBES IS AT BIRTH, AND IF THE PREVIOUS GENERATIONS HAVE AN IMPOVERISHED MICROBIOME THERE'S THE CONCEPT EACH GENERATION THEN HAS FEWER AND FEWER OF NECESSARY MICROBES TO MAKE UP WHAT WOULD BE THE ROBUST OR HEALTHY MICROBIOME. THESE ARE ALL IDEAS THAT ARE BEING TESTED AND EXAMINED BUT IT'S AN IMPORTANT CONCEPT TO KEEP IN MIND STUDYING CONTEMPORARY POPULATION IN THE U.S. THE LIST OF POSTULATED MICROBIOME-ASSOCIATED DISEASE AND DISORDER IS EXPLODING. THERE'S A LOT OF EVIDENCE GROWING CARDIOVASCULAR DISEASE HAS A ROLE FROM THE MICROBIOME BECAUSE OF PARTICULAR MICROBIL PRODUCTS, A LIST OF GUT CONDITIONS THAT APPEAR TO HAVE A CONNECTION. IT LEADS TO CHRONIC LOW LEVEL INFLAMMATION THAT CAN LEAD TO CARCINOGENIC CASCADE, MANY KINDS OF SYSTEMIC MODERN CONDITIONS LIKE OBESITY APPEARS TO HAVE A MICROBIOME ROLE AND SKIN, LUNG, VAGINA, JACQUES IS GOING TO TALK ABOUT THIS, I BELIEVE RICK IS GOING TO TALK ABOUT LUNG CONDITIONS, VARIOUS KINDS OF LIVER DISEASES AND FINALLY AS I MENTIONED BRAIN AND BEHAVIOR, A NUMBER OF MENTAL CONDITIONS MAY BE CLOSELY TIED TO THE, QUOTE, HEALTH OF THE MICROBIOME. SO THAT WAS MY QUICK SURVEY OF THE TOPICS THAT ARE BEING DISCUSSED IN THE MICROBIOME FIELD. BUT I WANT TO TAKE A COUPLE MINUTES AND TALK ABOUT THE HUMAN MICROBIOME PROJECT BECAUSE IT WAS A FUNDAMENTAL INVESTMENT BY THE NIH OVER TEN YEARS TO DEVELOP THE RESOURCES AND TOOLS TO ENABLE GROWTH OF THIS FIELD. SO WHAT WERE SOME CATALYSTS TEN YEARS AGO THAT PROMOTED THE -- THAT ENCOURAGED NIH TO TAKE ON THE MICROBIOME PROJECT? FIRSTLY EPIDEMIOLOGISTS WERE SHOWING US BECAUSE OF ANTIBIOTICS, BECAUSE OF VACCINES, BECAUSE OF THOSE KINDS OF PUBLIC HEALTH PRACTICES THAT MANY KINDS OF INFECTIOUS DISEASES WERE DECREASING RAPIDLY. THAT TIME FRAME IS FROM ROUGHLY 1950 TO 2000. AT THE SAME TIME THOUGH THIS PAPER DEMONSTRATED MANY AUTOIMMUNE DISEASES STARTED TO REALLY INCREASE, BUT THE KINDS SHOWN HERE ARE JUST EXAMPLES, ASTHMA, TYPE 1 DIABETES, CROHN'S DISEASE, MULTIPLE SCLEROSIS, ADD MANY MORE CONTEMPORARY AUTOIMMUNE AND ALLERGIC DISEASE BUT IT'S A MIRROR IMAGE, NOT AS IF THE HUMAN GENOME IS MUTATING AT THAT RATE. THERE'S SOME OTHER ENVIRONMENTAL IMPACTS THAT'S OCCURRING CAUSING DEVELOPMENT, POTENTIAL DEVELOPMENT OF AUTOIMMUNE DISEASES. THAT'S ONE DATA POINT THAT ACT AS A CATALYST FOR HMP. THE SECOND, RECOGNIZING WE KNOW THERE'S AROUND A LITTLE OVER A THOUSAND HUMAN PATHOGENS, THERE ARE MILLIONS AND MILLIONS OF MICROBIAL SPECIES ON EARTH, MOST OF WHICH ARE BENEFICIAL, AND THAT CONCEPT REALLY STARTED TO COME FROM THE ECOLOGICAL FIELD RECOGNIZING MICROBES PLAYED A CRITICAL ROLE IN ECOSYSTEM HEALTH AND STABILITY. AND THE THIRD IS THE HUMAN GENOME PROJECT DEVELOPED MANY KINDS OF TOOLS THAT ALLOWED NIH TO SAY, YOU KNOW WHAT, I THINK WE CAN NOW AFFORD TO TRY TO ANALYZE AND CHARACTERIZE THE HUMAN MICROBIOME. MANY KINDS OF SEQUENCE TECHNOLOGIES AND COMPUTATIONAL ANALYSES WERE COMING OF AGE DURING THE HUMAN GENOME PROJECT. I THINK I'LL WALK THROUGH SOME. THERE ARE WAYS TO APPLY A SPECIFIC MARKER TO LOOK FOR PARTICULAR SPECIES AND GENERAL END SAMPLES, ABILITY TO SEQUENCE ENTIRE MICROBIAL GENOMES AND THE POTENTIALLY MORE RECENT APPROACH, METAGENOMIC SEQUENCE, YOU CAN SEQUENCE AND ENTIRE COMMUNITY AND REASSEMBLE AND MAKE SENSE OF THIS SEQUENCE GATHERED FROM AN ENTIRE COMMUNITY. AND IN FACT OTHER OMICS, PROTEOMICS, METABOLOMICS, YES, WE CAN SUPPORT THIS WORK. HMP IS A TEN-YEAR INVESTMENT, ALL COMMON FUND ARE 10 YEARS LONG. IT'S UP TO THE REST OF NIH TO TAKE IT OVER. THAT BEGINNING DATE IS BACK AND FORTH. THERE'S AN EARLY JUMP START INVESTMENT PERIOD SO THEY TEND TO INCLUDE 2007, IT'S BEEN ABOUT TEN YEARS, BUILDING A COMMUNITY RESOURCE, BUILDING ALL UNNECESSARY FUNDAMENTAL RESOURCES TO HELP KICK START A FIELD. AND I LIKE THIS GRAPHIC, THIS LOGO OF LOGOS, BECAUSE I WANT TO EXPLAIN AND DEMONSTRATE HOW MANY DIFFERENT MEDICAL SCHOOLS AND UNIVERSITIES AND OTHER ORGANIZATIONS CAME TOGETHER AROUND THIS TEN-YEAR PERIOD TO HELP BUILD THESE RESOURCES. AND THERE ARE TWO PHASES TO THIS ACTIVITY. PHASE 1 AND PHASE 2, NOT VERY SEXY, BUT IT'S WHAT WE CALLED IT, DESIGNED TO BUILD RESOURCES. PHASE 1 WAS THE BIGGER AND BETTER FUNDED PHASE, IT WENT ON FOR -- OH, THAT'S NOT GOOD. THAT'S NOT GOOD. THAT'S LIKE A TORNADO THING (WEATHER TONE PLAYING) SHALL I CONTINUE? WE'RE IN A BASEMENT SO WE'RE IN A VERY SAFE SPACE. >> NO WINDOWS. >> AND WE'RE IN A BASEMENT SO I'LL KEEP GOING. FIVE YEARS, PHASE 1 WAS FIVE YEARS. IT'S OKAY IF I KEEP ON GOING? OKAY, THANK YOU. IT REALLY WAS A SURVEY. IT'S IN BLUE. WHO IS THERE? THAT WAS THE QUESTION. WE ONLY DID HUMAN CORD STUDIES, DIDN'T DO ANIMAL STUDIES. ONE WAS THE FAMOUS HEALTHY CORE STUDY IN WHICH 300 ADULT MEN AND WOMEN WERE SAMPLED ACROSS FIVE MAJOR BODY REGIONS SIMULTANEOUSLY, HAD TO PASS ALL KINDS OF EXCLUSION CRITERIA, COULDN'T TAKE PROBIOTICS, ANTIBIOTIC IT'S, IMMUNE MODULATORS, COULDN'T BATHE 24 HOURS BEFORE EVENT, TO CAPTURE ACROSS FIVE REGIONS OF THE BODY AND THEY WERE REPEATEDLY VISITED OVER ABOUT TWO YEARS OF TIME. THE GOAL THERE WAS TO FIND THE REFERENCE FOR HEALTHY MICROBIOME. A SECOND SET OF PROJECTS, DEMONSTRATE PROJECTS, MEANT TO DEMONSTRATE WHETHER THERE WAS A CHARACTERISTIC MICROBIOME ASSOCIATED WITH PARTICULAR CONDITIONS OR DISEASES, YOU CAN SEE HERE PRIMARILY FOCUSED ON SKIN, G.I., ORAL URI GENITAL AREA. IT WAS A SURVEY OF HEALTH AND DISEASE CONDITIONS TO SEE WHETHER A CHARACTERISTICS MICROBIOME EMERGED FROM THE STUDIES. HERE IS ONE FIGURE FROM A PAPER. EVERYTHING OKAY? OKAY. THE BUILDING IS STANDING. OH, I SEE. I THOUGHT YOU WERE CHECKING THE TORNADO. YEAH, I WANT TO POINT OUT SOMEONE PUT TOGETHER A VERY NICE COUNCIL BOOKLET WITH ALL THE PAPERS IN IT AND I KNOW THIS PAPER AND THE OTHER COMPANION PAPER FROM 2012 FROM PHASE 1 IS IN THERE AS IS THE MARKER PAPER FOR PHASE 2. THIS IS ANOTHER CLUSTER ANALYSIS SHOWING HOW EACH BODY REGION HAD ITS -- HAS ITS OWN UNIQUE MICROBIAL COMMUNITY SO THAT MEANS ALL OF US IN OUR ROOM, IN THIS ROOM HERE, OUR GUT MICROBIOMES ARE MORE ALIKE THAN MY SKIN MICROBIOME IS TO MY MOUTH MICROBIOME. THAT'S BECAUSE ENVIRONMENT SELECTS. BUT THERE ARE OTHER -- IN THIS CASE 2012 WE CAME UP WITH THOUSANDS OF BACTERIAL SPECIES AND MILLIONS OF BACTERIAL GENES, BUT IN FACT BECAUSE WE DON'T -- BECAUSE THERE'S MOVEMENT OF MICROBES BETWEEN HUMANS, THE TOTAL POOL MAY BE ON THE ORDER OF 10,000 DIFFERENT BACTERIAL SPECIES AND MILLIONS, 8 MILLION BACTERIAL GENES, ASSOCIATED WITH HEALTHY ADULTS. THIS ALL HAS TO DO WITH HEALTH HERE. MICROBES, WE'RE ALL HEALTHY AND NEED THEM. IN GENERAL AN IMPORTANT TAKEHOME FROM PHASE 1 IS THAT MICROBIAL COMPOSITION EVEN THOUGH I SHOWED YOU THE CLUSTER ANALYSIS, IT IS HIGHLY VARIABLE AND THIS IS A VERY TRICKY GRAPH. I WANT TO TAKE A MINUTE TO WALK YOU THROUGH THIS. I THINK I DID THIS RIGHT. YES. OKAY. THE Y-AXIS IS PROPORTION AND THE X-AXIS IS INDIVIDUAL SUBJECTS IS THIS A POINTER MAYBE? THERE'S 200 SUBJECTS ALONG THE AXIS, THEY ARE ALL FROM THE SAME COHORT, SO THEY SHOULD HAVE THE SAME PROPERTIES. YOU CAN SEE THAT'S A PROPORTION OF DIFFERENT MICROBES, DIFFERENT IN PATIENT 1 OR SUBJECT 1 VERSUS SUBJECT 200. THAT WAS CONFUSING INITIALLY TO SOME PEOPLE. BUT WE DID FURTHER ANALYSIS, NOW METAGENOMIC ANALYSIS THAT THE SEQUENCE OF THE ENTIRE MICROBIAL COMMUNITY TAKING THOSE DATA, TURNING AROUND AND TRYING TO PREDICT THE MAJOR METABOLIC PATHWAYS ASSOCIATED WITH THOSE COMMUNITIES. WHAT YOU SHOULD SEE, I KNOW YOU CANNOT SEE THE LEGEND, EVERYTHING OKAY? HERE IT IS. I SEE IT. EVEN THOUGH YOU CAN'T READ THIS, THESE ARE DIFFERENT METABOLIC PATHWAYS, NOT JUST CORE METABOLISMS, THESE ARE OTHER KINDS OF METABOLISMS. THERE'S A LOT MORE -- I'LL GO BACK TO THE GUT. THERE'S A LOT MORE SIMILARITY IN THE METABOLIC -- PREDICTED METABOLIC PATHWAYS MICROBIOME IN SUBJECT 1 VERSUS SUBJECT 200, SO THE THINKING HERE IS THAT METABOLIC POTENTIAL OF EACH MICROBIOME IS LESS VARIABLE AND THAT A CORE MICROBIAL COMOSITION MAY NOT NECESSARILY CORRELATE WITH HOST PHENOTYPE BUT A CORE METAGENOMIC OR FUNCTIONAL PROFILE MAY CORRELATE WITH HOST PHENOTYPE. I'M GOING TO SKIP THIS PART, OKAY? SO THAT FORMED THE BASIS OF OUR THINKING FOR PHASE 2. WE CAN'T JUST STOP AT MEASURING COMPOSITION BECAUSE IT'S NOT GOING TO GET US THE BIOMARKER WE NEED. WE NEED TO START REALLY LOOKING AT OTHER BIOLOGICAL PROPERTIES OF THE MICROBIOME. JACQUES AND RICK ARE BOTH GOING TO TALK ABOUT HOW THEY ARE DOING THIS KIND OF WORK SO PHASE 2 WHICH WE CALL THE INTEGRATIVE HMP IS ANOTHER ACTIVITY TO ANALYZE BIOLOGICAL PROCESS OF MICROBIOME AND HOST TO LOOK AT DISEASE, WE FUNDED THREE MODEL CONDITIONS. YOU MAY NOT CARE ABOUT PREGNANCY AND PRE-TERM BIRTH BUT THIS SHOULD BE OF USE TO THE ENTIRE COMMUNITY, WHAT SHOULD WE ANALYZE WHEN WE MEASURE? PREGNANCY AND PRE-TERM BIRTH, IBD, ONSET OF TYPE 2 DIABETES, AND THE OTHER PAPER IN YOUR COUNCIL BOOK IS WHAT WE CALL THE MARKER PAPER, A HOLDOVER FROM THE HUMAN GENOME PROJECT. IF YOU HAVE A LARGE ACTIVITY WHICH YOU'RE GOING TO RELEASE A LOT OF DATA AND WANT RESEARCH COMMUNITY TO KNOW ABOUT IT, YOU PROBABLY SHOULD HAVE A MARKER PAPER, A PAPER WITHOUT DATA IN IT BUT IT'S A PAPER ABOUT THE DATA THAT'S GOING TO COME OUT AND WHERE YOU'RE GOING TO DEPOSIT IT AND HOW PEOPLE WITH ACCESS IT. THE OTHER PEOPLE IS THE IHMP MARKER PAPER PUBLISHED IN 2014. ALL THESE FIGURES, THE REASON I WANT TO CALL UP A FEW TO SEE HOW COMPLEX THESE STUDIES ARE. THEY SAMPLE MANY DIFFERENT TYPES OF TISSUES. THEY ARE GOING TO CONDUCT MANY, MANY KINDS OF ASSAYS, AND SOME ASSAYS ARE JUST FOR A MICROBIAL PROPERTY, OTHER ASSAYS ARE JUST COMING FROM THE HOST, AND YET THIRD CLASS OF ASSAYS WILL BE COMEING FROM THE MICROBIOME AND HOST, AN AMAZINGLY RICH RESOURCE COMING OUT SOON OUT OF THE PHASE 2 HMP, -- IHMP. IF YOU'RE INTERESTED, READ THE PAPER IN THE PACKET. I PULLED OUT ONE DATASET FROM THE PREGNANCY AND PRE--TERM BIRTH STUDY IN WHICH THEY ARE TRACKING CYTOKINES AND LIPID PROFILES IN THE MICRO BIOME OF WOMEN AT RISK FOR PRE-TERM BIRTH AND FOUND PRETTY INTERESTING CORRELATIONS THAT ALLOW THEM TO DISCRIMINATE THE DIFFERENT VAGINA. I'M NOT GOING TO TALK ABOUT VAGINAL TIMES, JACQUES WILL. THERE'S DIFFERENT COMMUNITIES, NOT JUST ONE KIND, THERE'S SOME PRETTY INTERESTING CORRELAIONS BETWEEN ONE COMMUNITY TYPE, MICROBIAL COMMUNITY TYPE AND PARTICULAR CYTOKINES AND LIPID PROFILES. SO THAT METABOLIC PROPERTIES IN COMBINATION WITH MICROBIOME SHOW EARLY PROMISE AS BIOMARKERS FOR DISCRIMINATING HEALTH STATUS. THAT'S ALL I'M GOING TO TALK ABOUT WITH HMP. THIS IS HAPPENING IN A LARGER CONTEXT. THERE ARE 27 INSTITUTES AND CENTERS AT THE NIH. BEFORE THE HMP STARTED THERE WERE FOUR OR FIVE, BY 2012 THERE WERE 18 FUNDING. SO A HUGE EXPLOSION OF INTEREST AND WE WENT FROM LIKE MAYBE $5 MILLION A YEAR TO AROUND $100 OR $150 MILLION A YEAR AND DECIDED TO FOUND A COMMITTEE ACROSS THE NIH CALLED THE TRANS-NIH MICROBIOME WORKING GROUP ESTABLISHED IN 2012, MADE UP OF INTRAMURAL STAFF. A COUPLE THINGS YOU SHOULD CARE ABOUT. NUMBER ONE, WE HELD A VERY SUCCESSFUL NIH-WIDE MICROBIOME WORKSHOP IN 2013, ANOTHER ONE IN 2017. WE DEVELOPED A PANEL AT CSR TO SEE WERE A MICROBIOME EXCLUSIVE PANEL WORKS BETTER FOR MICROBIOME APPLICATIONS VERSUS ONES THAT GO TO REGULAR STUDY SECTIONS. WE ACT AS A CENTRAL RESOURCE FOR THE LARGER RESEARCH COMMUNITY, NIH IS A VERY LARGE PLACE TO NAVIGATE SO I'VE GOT A KEY POINT OF CONTACT AT EACH INSTITUTE. AND THIS LINK HERE WILL TAKE YOU TO THIS TABLE, IF YOU WANT TO LEARN ABOUT MICROBIOME RESEARCH AT ANY ONE OF THESE INSTITUTES GO TO THAT PERSON AND THEY WILL HELP YOU, EITHER ADDRESS THE QUESTION OR DIRECT YOU TO THE RIGHT PERSON. THIS IS A VERY IMPORTANT TABLE TO DEVELOP. OTHER ACTIVITIES THAT REALLY SPEAK TO THE MATURING OF THE MICROBIOME FIELD IS JUST LAST YEAR NIST, ANOTHER FEDERAL AGENCY, NATIONAL INSTITUTE FOR STANDARDS AND TECHNOLOGY, HELD A JOINT WORKSHOP WITH NIH AROUND STANDARDS DEVELOPMENT SO ONCE YOU SEE PEOPLE TALKING ABOUT STANDARDS YOU KNOW THE FIELD IS STARTING TO MATURE, RIGHT? OKAY. THAT PAPER IS GOING TO COME OUT PRETTY SOON IN BMC STANDARDS AND GENOMIC STANDARDS, THEY ARE PRETTY FAR ALONG. OVER THIS 10-YEAR SPAN, NOW I'VE GOT 2006-2016, THE RED BARS ARE THE -- HERE IT IS. THE RED BARS ARE THE HMP INVESTMENT. IT'S BEEN $225 MILLION OVER TEN YEARS BUT YOU SHOULD SEE RIGHT AWAY WHAT CATALYTIC ACTIVITY WAS, STARTING IN 2011, 2012 SEEING TREMENDOUS GROWTH BY THE OTHER 18 ICs AT THE NIH. CURRENTLY WE'RE WRITING A PAPER, DEEM ANALYSIS OVER THE LAST FIVE YEARS, 2012-2016, TRYING TO DISSECT WHERE THE RESEARCH IS GOING, WHERE THE GAPS ARE, HOPING THAT WILL COME OUT IN THE NEXT YEAR. TMWG IS ORGANIZING AND HOSTING A THREE-DAY WORKSHOP IN AUGUST, TO REALLY TAKE STOCK OF WHERE IS THE FIELD AFTER 10-YEAR INVESTMENT BY THE HMP, NOT ONLY THAT BUT TO IDENTIFY KNOWLEDGE GAPS, TECHNICAL CHALLENGES AND NEW APPROACHES NEEDED FOR THE NEXT DECADE. WHAT DO WE NEED? WHAT ARE THE HOLES STILL? WE HAVE 500 PARTICIPANTS SELECTED BY THE COMMITTEE OUT OF THE NIH GRANTEE POOL FUNDED MORE MICROBIOME RESEARCH, 40 SPEAKERS, WE'LL CLOSE WITH AN AGENCY PANEL BECAUSE NOT ONLY NIH BUT OTHER AGENCIES NOW ARE FUNDING MICROBIOME RESEARCH OR VERY INTERESTED IN WHAT THE NIH IS DOING LIKE THE FDA OR CDC SO THEY WANT TO HEAR WHAT WE'RE DOING AND SEE IF THERE'S OPPORTUNITY FOR COLLABORATION BETWEEN THESE AGENCIES AROUND MICROBIOME RESEARCH. I SEE IT'S FLASHING. I THINK I'M GOING TO BE OKAY. >> WE'RE ACTUALLY RUNNING OVER, SO A COUPLE MORE MINUTES MORE. >> I'M GOING TO SKIP OVER THIS. >> THANK YOU. SORRY. >> OKAY. I WANT YOU TO KNOW THAT THIS MICROBIOME RESEARCH ON THE HUMAN IS HAPPENING IN A LARGER CONTEXT, OKAY? RECENTLY THE WHITE HOUSE IDENTIFIED ABOUT $900 MILLION FOR ONLY 3 YEARS OF SUPPORT ACROSS THE FEDERAL GOVERNMENT, FEDERAL AGENCIES ARE AT THE BOTTOM SO YOU CAN SEE IF YOU THINK ABOUT THE WORD MICROBIOME IN A LARGER CONTEXT, MICROBIAL COMMUNITIES MAINTAIN THE ECOSYSTEM, THERE'S QUITE A BIT OF INTEREST. THE REASON YOU SHOULD CARE IS NOW THERE IS A MICROBIOME INTERAGENCY WORKING GROUP. WE NOW HAVE A FORMALIZED STRUCTURE, WE'VE BEEN WORKING ON A YEAR, SUBMIT TO THE NEW ADMINISTRATION AND IF APPROVED WE'LL FLESH OUT THE OUTLINES. SO ALL THIS MICROBIOME WORK IS HAPPENING IN A LARGER CONTEXT SO IT'S ONLY HEALTHY FOR THE GROWTH OF THE FIELD. AND THAT I'M DONE. ANY QUESTIONS? [APPLAUSE] MAYBE I COULD -- >> WE'RE GOING TO HOLD QUESTIONS, SORRY, BECAUSE WE'RE GOING TO GET BACK ON TRACK. THANK YOU SO MUCH. SO THE NEXT TALK IS INTERROGATING THE MICROBIOME, A SYSTEM OF BIOLOGY APPROACH, DR. RICK BUSH MAN IS PROFESSOR THE MICROBIOLOGY AT UNIVERSITY OF PENNSYLVANIA, CHAIRMAN EVER THE DEPARTMENT THERE, FOCUSING ON HOST MICROBE INTERACTION AND HEALTH AND DISEASE AND INCLUDES STUDIES OF THE HUMAN MICROBIOME HIV PATHOGENESIS AND DNA INTEGRATION, MUCH OF DR. BUSHMANS WORK IS DRIVEN THAT ALLOWS INDEPENDENTS ANALYSIS OF MICROBIAL POPULATIONS. THANK YOU. >> THANK YOU VERY MUCH. IN A SENSE, HIV RESEARCH WAS MICROBIOME RESEARCH BEFORE IT WAS HIV RESEARCH. AS WE HEARD THIS MORNING, THE DISEASE WAS IDENTIFIED BY OPPORTUNISTIC INFECTIONS THAT OCCURRED IN HIV POSITIVE PEOPLE SO THE ORGANIZATION GOES BACK TO EVEN BEFORE THE VIRUS WAS ISOLATED. MORE MICROBIOME RESEARCH AS YOU KNOW WHAT WE'VE COME TO MEAN IS COMPREHENSIVE STUDIES OF COMMUNITIES OR ALL THE METHODS ARE BIASED, MOST OF WHAT'S IN A COMMUNITY USING NEW DEEP SEQUENCING METHODS. IN MY 20 MINUTES PLEASE GIVE ME, IF I GO TOO LONG, I'M GOING TO GO OVER SPECIFICS ABOUT HIV AND THE MICROBIOME, IN A FEW AREAS, SOME WE'VE BEEN INVOLVED IN, BUT I'LL TRY TO SORT OF TALK ABOUT THE PROGRESSION OF IDEAS, THE QUESTIONS IN EACH OF THESE AREAS. OOPS. AND THEN END ON SOME COMMENTS ON WHAT LOOK LIKE AT LIKE A FEW AREAS THAT MIGHT WARRANT FUTURE STUDIES AT THE INTERFACE BETWEEN HIV AND MICROBIOME RESEARCH. SO THE FIRST TOPIC WILL BE HIV OR SIV INFECTION AND GUT BACTERIAL MICROBIOME AND HIV AND THE VIRON, AND THE LUNG, VAGINAL MICROBIOME, I WON'T SAY MUCH BECAUSE JACQUES IS ONE OF THE WORLD LEADERS AND WILL FOLLOW. HIV MICROBIOME AND METABOLOMES, GETTING TO MORE CONSEQUENCES. MICROBIOME, ACTION. MICROBIOME AND EFFECTOR MOLECULES AND NEW DIRECTIONS. WE GOT INTO THIS AREA THROUGH STUDIES IN THE MACAQUE A COLLABORATION WITH ANDREW LACKNER WHO PASSED AWAY IN THE LAST FEW DAYS, A WONDERFUL MAN. THIS WAS 2008, A YEAR OR TWO AFTER DANNY DUIK PROPOSED MICROBIAL TRANSLOCATION MIGHT BE IMPORTANT IN PATHOGENESIS IN DEVELOPMENT OF HIV DISEASE. WE WANTED TO SET UP TOOLS TO STUDY THIS USING THE NEW THEN BRAND NEW PYRO SEQUENCING METHODS AND SET UP WAYS TO AMPLIFY GENES, SET UP METHODS FOR DNA BARCODING, SO WE COULD DO A WHOLE BUNCH OF THESE TAGS IN A SINGLE SEQUENCING RUN AND USE THEM TO READ OUT SOME OF THE MICROBES PRESENT IN A SAMPLE. WE -- I MET ROB KNIGHT WHEN HE WAS SETTING UP HIS OWN LAB, WET BEHIND THE EARS YOUNG SCIENTIST, NOW ONE OF THE STARS OF THE AREA. AND WE PUBLISHED WHAT WAS ONE OF THE FIRST PAPERS ON 454 SEQUENCING OF TAGS TO TRACK WHAT'S GOING ON IN THE MICROBIOME AND GUT OF MACAQUES AS THEY PROGRESS THROUGH EXPERIMENTAL SIV INFECTION. WE EXPECTED THERE WOULD BE BIG FAT CHANGES IN THE BUGS THAT WERE THERE. AS ANDREW AND OTHERS SHOWED THERE ARE DAMAGE TO LYMPHOID TISSUE IMMUNE CELLS THAT LINE THE GUT AND SO WHAT WE ANTICIPATED THAT IF THEY ARE CONTROLLING MICROBES IN THE GUT THERE WOULD BE HUGE EFFECTS. WE FOUND QUITE THE OPPOSITE. WE HAD A HARD TIME FINDING ANY CHANGES IN THE GUT MICROBIOTA OF MACAQUES ASSOCIATED WITH SIV. IF WE WAITED UNTIL THEY HAD TO BE PUT DOWN FOR COLITIS WE COULD SEE DIFFERENCES BUT SAW REGARDLESS OF SOURCE OF COLITIS, SIV PLUS OR MINUS. WE CAME AWAY THINKING THE GUT MICROBIOME WAS TOUGH, IT LIKED IT THERE, DIDN'T YIELD TO THE FIELD EASILY AND SIV INFECTION WAS RELATIVELY MINOR PERTURBATION COMPARED TO STABILITY OF GUT MICROBIOTA THAT WAS THERE. THIS WAS CONTRARY TO EXPECTATION BUS A FEW YEARS LATER SKIP VIRGIN'S LAB MENTIONED IN PASSING THEY HAD A SIMILAR RESULT. THEY WERE AFTER THE VIROME, I'LL SAY MORE IN A MINUTE. THEY FOUND NO EFFECT OF SIV INFECTION IN THE GUT MICROBIOME OF MACAQUES. A FEW YEARS LATER THERE WERE NUMEROUS PAPERS SUGGESTING THAT INFLUENCE OF HIV INFECTION ON HUMAN GUT MICROBIOME, SO A VARIETY OF GROUPS PUBLISHED THEY COULD SEE DIFFERENCES IN THE GUT MICRO BY MICROBIOTA IN POSITIVE VERSUS NEGATIVE CONTROL SUBJECTS, ENRICHMENT OF PREVITELLA, WE WESTERNERS ARE HIGH IN BACTEROIDES, ASSOCIATED WITH HIV WAS INCREASE IN PREVITELLA, DEPLETION OF BACTEROIDES AND INCREASE OF ENTEROBACTERIAAE. THERE'S A STRONG TREND IN HEALTHY PEOPLE GLOBALLY, URBAN DWELLINGERS ARE HIGH IN BACTEROIDES BUT REAL PEOPLE WITH TRADITION LIFESTYLES ARE HIGH IN PREVITELLA, IN MANY CONTINENTS AROUND THE WORLD, GETTING AT SOMETHING SURPRISING AND DEEP. AND CONTRARY TO WHAT WE HAD SEEN WITH EXPERIMENTAL SIV INFECTION. MAYBE THERE'S SOMETHING ABOUT HIV INFECTED SUBJECTED, OTHER MEDICATIONS THEY ARE TAKING, WHATEVER. BEATRICE HAHN WANTED TO STUDY CHIMPANZEES, WE LOOK AT MICROBIOTA, THERE WASN'T MUCH EFFECT OF BEING SIV PLUS, TWO CASES OF ANIALS THAT WERE ON THE EDGE OF DEATH WHERE THEY WERE ABLE TO GET A SAMPLE DUE TO ASSOCIATED WITH HIV INFECTION OR SIV INFECTION IN ANIMALS, THEY DID SHOW SOME DIFFERENCES. BUT IN GENERAL THEY DIDN'T SEE MUCH IN THE WAY OF DIFFERENCES OTHERWISE. SO THAT LED TO THE IDEA THAT, WELL, MAYBE WHEN THE ANIMALS ARE STARTING TO GET SICK THAT'S THE ONLY TIME YOU SEE A DIFFERENCE, AND THEN LIKE A LEOPARD GETS THEM OR SOMETHING, MAYBE IN THE WILD THEY DIE QUICKLY ONCE THEY START TO DECLINE SO THERE'S NO OPPORTUNITY TO SEE MUCH EFFECT OF SIV. A REMARKABLE TWIST WITH THE FINDING FROM ROGERS'S LAB THAT THE HIGH PREVITELLA SIGNATURE WS ASSOCIATED WITH MEN WHO HAVE SEX WITH MEN AND NOT HIV INFECTION, THAT IS ROGER HAD COHORTS OF MSM PLUS AND MINUS, BOTH HIGH IN PREVITELLA AND SHOWED OTHER SIGNS ASSOCIATED WITH INFECTION LEADING TO THE IDEA THAT MAYBE HUMANS ARE MORE LIKE THE CHIMPS AND MACAQUES THAN -- IT'S SOMETHING ABOUT MSM THAT'S NOT FULLY RECOGNIZED IN THIS AREA. AND I THINK AT LEAST ONE OTHER GROUP HAS GOTTEN THIS RESULT ALSO. >> JUST TO BE CLEAR, THESE ARE SAYING THERE'S A TORNADO BUT WE'RE SAFE. SO EVERYONE'S SAFE. >> OKAY. IF I SHOULD LIKE RUN FOR MY LIFE OR SOMETHING LET ME KNOW >> WIZARD OF OZ, IT CAN'T TAKE US. >> OKAY. SO I'LL GO ON UNLESS YOU TELL ME TO FLEE OR SOMETHING. ALL RIGHT. SO IT TURNED OUT MSM HAD HIGH PREVITELLA CHARACTERISTICS. MORE RECENTLY ANOTHER PAPER FROM SKIP VERSION'S LAB LOOKING AT A DEVELOPING WORLD COHORT, UGANDA, DIDN'T SEE HIGH PRIVATELLA BUT SAW ASSOCIATIONS OF HIV INFECTION AND CHANGES IN THE GUT MICROBIOTA. THAT'S WHERE IT STANDS. THERE'S BEEN THIS BACKING AND FORTHING IN LITERATURE WHETHER HIV, SIV INFECTION HAS MUCH EFFECT ON COMPOSITION OF GUT MICROBIOTA. AN INTERESTING AREA THAT MIGHT WARRANT INVESTIGATION IN SICKER COHORTS. HIV AND THE VIROME IS ANOTHER AREA CLOSEY STUDIED, SKIP'S LAB AND ALSO BEATRICE. SKIP LOOKED AT SERIES OF COHORTS OF SIV INFECTED MACAQUES, EACH ROW IS A VIRUS, EACH COLUMN IS ANIMAL, EACH BLOCK IS A COHORT. SIV ON THIS SIDE CONTROLS ON THE LEFT. YOU CAN SEE THERE'S A LOT MORE DIFFERENT VIRUSES DETECTED IN THE SIV-INFECTED MACAQUES. SEEMED LIKE IT WAS EASIER TO FIND SPREADING VIRAL INFECTIONS IN THESE SIV INFECTED ANIMALS THAN CHANGES IN THE GUT MICROBIOTA, AN INTERESTING OBSERVATION. THEY HAD ANOTHER PAPER IN THIS AREA AND SOME INDICATION THEY COULD SEE PARALLEL EFFECTS IN HUMANS AT LEAST ADENOVIRUS. WITH THE GAMBHI CHIMPS WE DIDN'T SEE ANY DIFFERENCE IN VIROME IN THE CHIMPS, POSSIBLY AGAIN THE IDEA IF AN ANIMAL IS GOING DOWN WITH SIV IN THE WILD THEY ARE QUICKLY CAUGHT BY PREDATORS AND KILLED OR SOMETHING. SO AGAIN DEPENDING ON WHAT YOU THINK IS IMPORTANT TO STUDY A LOT MORE COULD BE DONE WITH INTERSECTION OF HIV AND THE VIROME. HIV AND THE LUNG MICROBIOME, HERE I WORKED WITH MY CLOSE COLLEAGUE RON COLEMAN TO STUDY COLONIZATION OF THE LUNG. THIS WAS THE LUNG HIV MICROBIOME PROJECT AFTER THE HUMAN MICROBIOME PROJECT BY NHLBI, A MULTI-CENTER STUDY IN HUMANS, FOCUSING ON HIV-POSITIVE SUBJECTS AND HEALTHY CONTROLS. BRONCHOALVEOLA AND OTHER SAMPLES. FOR BODY SITES WITH A LOT OF MICROBES LIKE MOUTH OR STOOL, TAKE STUFF, MAKE DNA AND VOILA SEQUENCE MICROBES. LOW IS A DIFFERENT KETTLE OF FISH. YOU HAVE SPARSE MICROBES, THE LUNG WASH, THE CARRYOVER IS A BIG DEAL, AMOUNT OF DNA COMING WITH YOUR REAGENTS, WITH DUST IS A BIG DEAL. AND SO EARLY STAGES OF THIS PROJECT, THERE WAS QUITE A WRESTLING MATCH TO UNDERSTAND HOW TO DEAL WITH THESE LOW BIOMASS SAMPLES IN A WAY THAT YIELDED USEFUL DATA. SO AFTER A BUNCH OF STUDYING CAME TO THE CONCLUSION THE PATTERN OF COLONIZATION IN THE LUNG IS PROBABLY LARGELY MICRO ASPIRATION OF ORAL BACTERIA, THERE'S VERY LITTLE THAT LIVES DOWN THERE NORMALLY, AT LEAST THAT'S WHAT I THINK. HOWEVER, WE WERE ABLE TO FIND ONE BUG THAT DID SEEM TO BE ENRICHED IN LUNG EVEN IN RELATIVELY HEALTHRY RESEARCH SUBJECTS, TROPHERYMA WHIPPLEI, PROMINENT IN SUBJECTS, DIMINISHED WITH COLONIZATION WITH TERP. WE STUDY THE WHIPPLEI, IT'S HARD TO GROW, WE WERE ABLE TO GET GENOME SEQUENCES. THERE ARE UNIQUE GENES FOUND IN THE LUNG VARIANTS, UNIQUE GENES FOUND IN ANY PAIR OF VARIANTS YOU ISOLATE FROM A HUMAN SO IT'S NOT CLEAR IN WE GOT ANYTHING SPECIFIC SO THE LUNG OR HIV. SO WE DID GET A BUNCH OF INTERESTING SORT OF DRAFT GENOME SEQUENCES. AND THAT'S PRETTY MUCH WHERE THAT STANDS. I THINK THIS IS ANOTHER AREA WHERE IT WOULD BE INTERESTING TO UNDERSTAND MORE AND WHIPPLEI AND OTHER COMMUNITY MEMBERS. SO HIV IN THE VAGINAL MICROBIOME, SO BRIEFLY THIS IS A VERY WELL STUDIED AREA, 121 PAPERS, WHEN I SEARCHED ON HIV VAGINAL AND MICROBIOME AS IT DESERVEDLY SHOULD BE BECAUSE OF IMPORTANCE OF TRANSMISSION, IN VAGINA LOW DIVERSITY COMMUNITY ASSOCIATED WITH HEALTH, THERE'S SOME DEBATE. JACQUES CAN SAY MORE. BACTERIAL VAGINOSIS IS ASSOCIATED WITH HIGH DIVERSITY, RACIALLY DISPARATE DISEASE AND ONE FACTOR THAT MAY BE OF CONSEQUENCE, BV IS A RISK FACTOR FOR TRANSMISSION AND MAY HAVE A BEARING ON GLOBAL EPIDEMIC. LOTS OF QUESTIONS ABOUT THE MECHANISM OF THIS ASSOCIATION. BV PROMOTE INFLAMMATION WHICH PROVIDES MORE CELLS FOR HIV TO INFECT OR IS THERE SOME OTHER MECHANISM, INTERESTING AND IMPORTANT SET OF QUESTIONS. DOES HIV INFECTION ALTER MICRO BIOTIC COMMUNITY STRUCTURE, DIFFERENT AMONG STUDIES AND COHORTS. A CHRONIC PROBLEM WITH HIV RESEARCH IN THE U.S. AS YOU PROBABLY WELL KNOW IS PEOPLE WHO MAKE GOOD RESEARCH SUBJECTS ARE GENERALLY PRETTY HEALTHY. THEY ARE TAKING DRUGS, DOING WELL, SHOW UP FOR APPOINTMENTS. THERE ARE PEOPLE DOING POORLY WITH HIV IN THE UNITED STATES BUT THEY DON'T MAKE GOOD RESEARCH SUBJECTS, THEY DON'T COME TO THE CLINIC SO THEY ARE UNDERSAMPLES SO WE'RE OFTEN STUDYING HIV POSITIVES WHO ARE RELATIVELY HEALTHY, NOT THAT MUCH DIFFERENT FROM NORMALS. SO IN HIV, AT LEAST IN SOME OF THESE STUDIES, IT WAS DEVELOPING WORLD SAMPLES WHERE THERE WAS MORE ASSOCIATION OF HIV AND ALTERED COMMUNITY STRUCTURE THAN IN THE U.S. POSSIBLY BECAUSE OF THIS SAMPLING THING. WE PUBLISHED A PAPER IN THIS AREA RECENTLY WITH TOM HOPE. ONE THING WE NOTICED WAS THAT WE SAW BACTERIAL VAGINOSIS IN WOMEN SAMPLED MEANS YEARS AFTER HIV INFECTION, WE SAW THE ASSOCIATE BUT LONG AFTER INFECTION, SUGGESTING A PERSISTENT STATE MORE LIKELY TO HAVE BV AND BE HIV INFECTED, WHAT'S THE DEAL WITH THIS PERSISTENT STATE MIGHT BE WORTH STUDYING. HIV, THE MICROBIOME AND METABOLOME, SO RETURNING TO MY TITLE, THE SYSTEMS BIOLOGY AND MECHANISMS, ONE COLLECTION OF WAYS THAT MICROBIOME MAY BE INFLUENCING HEALTH IS VIA PRODUCTION OF SMALL MOLECULES OR MODIFICATION OF SMALL MOLECULES THAT ARE ALREADY MADE BY THE HOST. AND SO MANY LABS ARE REALLY INTERESTED IN UNDERSTANDING WHAT THE METABOLOME IS AND HOW IT'S ALTERED IN DISEASE STATES INCLUDING HIV INFECTION. SO THIS IS AN AREA THAT'S GETTING GOING. THERE SEEMS TO BE SOME IMPORTANT RESULTS ALREADY. SO THIS IS ABOUT SEARCHING FOR EFFECTORS PRODUCED BY MICROBIOTA. THERE HAVE BEEN A FEW GLOBAL STUDIES PUBLISHED LOOKING AT LUNG, PLASMA AND IDENTIFYING MICROBES ASSOCIATED WITH MENTAL CONDITIONS, DISEASE PROGRESSION, AND OTHER FACTORS. SO THERE'S STARTING TO BE A CATALOG OF SMALL MOLECULES AND THEIR EFFECTS DERIVED OR MODIFIED BY MICROBIOME AND EFFECTS ON HEALTH. A SPECIFIC SET OF IMPORTANT PROPOSALS CENTERS ON CARDIOVASCULAR DISEASE, WHERE DAN HAZEN COME UP WITH A SERIES OF REALLY BEAUTIFUL STUDIES, STARTING WITH METABOLOMICS WHERE HE FOUND TRIMETHYL AMINE AND TRIMETHYL AMINE OXIDE WITH POSSIBLY ASSOCIATED WITH ATHEROSCLEROSIS AND GUT MICROBIOTA WERE SPECIFICALLY INVOLVED IN METABOLISM THAT MANUFACTURED ACTIVE MOLECULES AND THIS HAS BEEN OBSERVED AND MAY BE AN IMPORTANT EFFECTOR IN THE HIV CASE AS WELL. THE INCREASE IN HIV-RELATED CARDIOVASCULAR DISEASE MAY IN PART GO THROUGH THESE MOLECULES. LET ME JUST TELL BUT ONE WAY WE'RE TRYING TO STUDY THIS AT PENN GOING FORWARD WITH MY COLLEAGUES GARY WU AND JIM LEWIS TAKING THE LEAD WITH THIS. THE NAME. STUDY IS FOOD AND RESTING MICROBIAL METABOLITES, OR FARM. A LARGE CONSORTIUM WITH CROHN'S AND COLITIS FOUNDATION, THE IDEA TO WEED OUT SMALL MOLECULES MADE BY MICROBIOTA OR MODIFIED IN ONE FELL SWOOP, 30 SUBJECTS SEQUESTERED IN THE HOSPITAL, WITH SPECIFIC DIETS, ONE USED AS THERAPY FOR CROHN'S DISEASE, DENSE SAMPLING BY SHOTGUN METAGENOMICS OF SCHOOL, DENSE METABOLOMICS FOR STOOL AND FECAL MOLECULES, IN THE MIDDLE OF THIS TIME PERIOD WE GIVE THE SUBJECTS A BOWEL PURGE AND STRONG DOSE OF ANTIBIOTICS TO ELIMINATE THE MICROBIOME, AND ASK WHAT COMPOUNDS GO DOWN AND THEN COME BACK, THOSE WOULD BE ONES MADE BY THE MICROBIOME, OR GO UP, SUBSTRATES THAT AREN'T MODIFIED. WE GOT THIS GIGANTIC DATASET THAT SHOW THESE PATTERNS, TRYING TO READ OUT MOLECULES MADE BY DIFFERENT GUT BUGS AND THEN PHASE 2 WHICH WE'RE JUST STARTING IS TO GET PURIFIED MA TABLOIDS, PURIFIED REPRESENTATIVES OF MOLECULES, PUT THEM IN TRAYS, HIGH-THROUGHPUT SCREENING ASSAYS TO BEGIN RUNNING MULTIPLE DIFFERENT KINDS OF ASSAYS INCLUDING HIV INFECTION AND OTHER SORTS OF ASSAYS TO SEE WHAT THESE MOLECULES ARE DOING IN LOTS OF DIFFERENT BIOLOGICAL SETTINGS. SO THAT'S JUST GETTING GOING. >> RICK, I'M SORRY, A MINUTE MORE. >> MY VERY LAST SLIDE, I'LL STOP AFTER THIS I SWEAR. STUFF TO DO, STUDIES OF MICROBES IN GLOBAL POPULATIONS WHERE THERE'S PERHAPS MORE SEVERE EFFECTS OF DISEASE TO HELP MAGNIFY EFFECTS ON THE MICROBIOME OF HIV INFECTION. THIS ISSUE OF GUT MICROBIOME IN MSM, AND WHIPLEI, THERE'S PROPOSALS AND EXAMPLES FROM OTHER STUDIES, VAGINAL MICROBIOME, CARDIOVASCULAR DISEASE, SHAPING IMMUNE RESPONSES TO LENTIVIRAL INFECTION, AND ALTERATIONS IN THE MICROBIOME AND HOW IT AFFECTS METABOLOME AND ONE SPECIFIC THING TO DO HERE OFTEN YOU HAVE PEAKS THAT YOU DON'T KNOW WHAT THE MOLECULE IS. YOU HAVE TO SYNTHESIZE CANDIDATES TO SEE IF THEY CO-FRACTIONATE WITH THOSE PEAKS. BUT THEN YOU HAVE THE SYNTHETIC PRODUCT AND KNOW WHAT IT IS. WHAT WE NEED FOR THE FOLLOWING UP ON THE LAST EXPERIMENT I DESCRIBED IS LOTS OF CHEMICAL SYNTHESIS AND THEN MASS SPEC ANALYSIS TO FIGURE OUT UNMONEY MOLECULES, THE VAST MAJORITY. I'LL STOP AND THANK RON COLEMAN IN LUNG, GARY WORKS AND JIM LEWIS AND BEATRICE. >> WE'LL DO QUESTIONS AFTER. NEXT IS DR. JACQUES RAVEL TALKING ABOUT HOW BIOLOGICAL SEX INFLUENCES MICROBIOME, PROFESSOR AT INSTITUTE FOR GENOMIC SCIENCES IN UNIVERSITY OF MARYLAND. RESEARCH PROGRAM IS ON A APPLYING SYSTEMS BIOLOGY APPROACHES TO STUDY THE HUMAN MICROBIOME. AND HE IS GOING TO LOOK AT MODELING INTERACTION BETWEEN THE HUMAN MICROBIOME, HUMAN HOST, ENVIRONMENT AND STRONG FOCUS ON WOMEN'S HEALTH INCLUDING PREGNANCY OUTCOMES AND SEXUALLY TRANSMITTED INFECTIONS. >> THANK YOU. I WAS TASKED TO -- ASSIGNED THIS TITLE. IT'S NOT QUITE MINE BUT IT LITERALLY TOUCHES A LOT INTO WHAT I STUDY IN MANY WAYS. A LOT OF IT WILL BE SOME REVIEW OF THE LITERATURE OF WHAT'S GOING ON IN THIS AREA. AND I JUST WANT TO START RIGHT AWAY. I THINK THAT QUESTION IS UNANSWERABLE BECAUSE WE DON'T HAVE A CLUE HOW THAT WORKS, DOES THAT INFLUENCE THE MICROBIOME IN TERMS OF MECHANISM. BUT THERE ARE CORRELATION AND ASSOCIATION WE CAN MAKE, THAT'S WHAT WE'RE GOING TO BE DISCUSSING. SO SOMEBODY KIND THE TERM MICRO GENDEROME, THE MICROBIOME UNIQUE TO ONE GENDER OR ANOTHER. A STUDY WAS PUBLISHED IN 2013, BASICALLY THE FIRST STUDY IN THIS AREA, WHERE IT WAS AN ANIMAL, IN MICE, THEY LOOKED AT PUBERTY AND FOUND THE COMPOSITION OF THE GUT MICROBIOTA OF FEMALE AND FEMALE ANIMAL DIVERGED AND FOUND THERE WAS AN IMPACT OF SEXUAL MATURATION AND CHANGING HORMONES ON THE GUT MICROBIOTA DRIVEN BY THE AMOUNT OF TESTOSTERONE THAT WAS IN CIRCULATING WHICH WAS DRIVING A SPECIFIC COMPOSITION OF THE MICROBIOTA AND DRIVING MATURATION AND SUSCEPTIBILITY TO DIABETES. THE FIRST STUDY ABLE TO ASSOCIATE MICROBIOME -- SORRY, MICROBIOME ARE BIOLOGICAL SEX AND SUSCEPTIBILITY FOR DISEASE SO ONE OF THE PLAYERS INTO THAT RELATIONSHIP. SO -- OOPS. IT'S REALLY SHOWED THE ABILITY OF THE GUT MICROBIOTA ON AFFECT HUMAN AND HORMONAL PATHWAYS IN TYPE 1 DIABETES. THERE ARE A LOT OF STUDY AND LITA MENTIONED THE BRAIN GUT ACCESS, THERE ARE A LOT OF STUDY ON BIOLOGICAL SEX AND I LISTED SOME OF THE PAPERS IN A ARE DEALING WITH THIS. BASICALLY THIS MICRO GENDEROME, I DON'T KNOW IF I LIKE THAT TITLE, PROVIDES A PARADIGM SHIFT THAT HIGHLIGHT THE ROLE OF SEX IN HOST MICROBIOME INTERACTION, RELEVANT SO FATHER SHOWN FOR IMMUNE DISEASE AND THIS NEUROIMMUNE CONDITION. BUT THIS IS REALLY A BIDIRECTIONAL INTERACTION, OKAY? IT COMMUNICATES FROM THE BRAIN TO GUT AND GUT TO BRAIN, OKAY? AND THAT RELATIONSHIP IS EMERGED AS A FACTOR THAT INFANTS IMMUNITY, METABOLISM, IN THE GUT, NEURODEVELOPMENT AND BEHAVIOR AND A LOT OF STUDIES ARE DONE IN THOSE CONTEXT, ESPECIALLY WHEN IT STARTS FROM BIRTH, AND THAT IN THE CONTEXT OF SEX DIFFERENCES. SO REALLY WHAT THIS IS -- WHERE THIS IS GOING, IT APPLIED AND MECHANISTIC RESEARCH REALLY NEEDED TO CONSIDER SEX INTERACTION WHEN LOOKING AT THE COMPETITION AND FUNCTION OF THE GUT MICROBIOTA. THERE'S ANOTHER ASPECT. I MENTIONED TESTOSTERONE. ESTROGEN IS JUST AS IMPORTANT IN DRIVING OR BEING MODIFIED BY THE MICROBIOME AND THERE'S A CONCEPT CALLED THE ESTROBOLOME. ESTROGEN IS PRODUCED BY MOSTLY OVARIES, BUT OTHER ORGANS, IT GOES INTO BLOOD AND LIVER, GETS CONJUGATED, REJECTED IN BILE, ALSO REJECTED IN URINE. BILE GOES DIRECTLY INTO YOUR (INDISCERNIBLE) DISCERN AND WE HAVE A LOT OF CONJUGATED ESTROGEN, READY TO BE EXCRETED AND WE HAVE THIS ESTROBOLOME CORRESPONDING TO THE BACTERIAL GENES THAT ARE CAPABLE IF YOU WANT DECONJUGATING ESTROGEN, THEY CAN BE WE REABSORBED AND GO BACK INTO ENTEROPATHIC CIRCULATION. NOW WE HAVE A SYSTEM IF YOU WANT TO FINE TUNE ESTROGEN IN THE BODY, THAT CAN HAVE SOME MAJOR IMPACT. SO WE HAVE SOMETHING THAT'S VERY SEX SPECIFIC. OKAY. THAT HAS EFFECT ON THE ORGANISM THAT'S POSSIBLY -- AFFECTED BY THE ORGANISMS PRESENT IN THE GUT AND HAVE HAVE EFFECT FURTHER AWAY THAN THE GUT, AND SOME OF THE PAPERS THAT ARE IN THIS AREA OFTEN TALK ABOUT INCREASING ARTIFICIALLY AMOUNT OF ESTROGEN IN THE BLOODSTREAM WHEN THE CURE IS TRYING TO GET RID OF IT. SO ESTROGEN IS ALSO VERY IMPORTANT IN DRIVING THE DEVELOPMENT OF THE VAGINAL MICROBIOTA FROM BIRTH ALL THE WAY TO MENOPAUSE. AT BIRTH WE HAVE A BABY GIRL, WHICH IS THOUGHT TO HAVE A STERILE VAGINA, OKAY? WHAT WE OBSERVE, LONG TIME AGO PEOPLE HAVE OBSERVED, IT'S MORE DIFFICULT NOWADAYS, LACTOBACILLUS IS COLONIZING FOR ABOUT THREE TO FOUR WEEKS A BABY GIRL'S VAGINA, OKAY? THAT'S MOSTLY DUE BECAUSE THERE'S MATERNAL ESTROGEN CIRCULATING IN THE BABY GIRL. AFTER THREE OR FOUR WEEKS WHEN THAT MATERNAL ESTROGEN IS GONE WE GO INTO PRE-PUBERTY WHERE WE DON'T HAVE ESTROGEN, LACTOBACILLUS IS LOOK, AND ANEROBES TO PUBERTY, NOW PRODUCED BY THE GIRL'S OVARY AND OTHER TISSUE AND WE START SEEING IN GENERAL LACTOBACILLUS COMES BACK AND STARTS TO DOMINATE VAGINAL MICROBIOTA. AND WE HAVE MAINTENANCE OF LACTOBACILLUS, WE'LL SEE THAT IN A MINUTE, BUT A LOT IS DRIVEN BY ESTROGEN, INITIATING MATURATION OF VAGINAL EPITHELIUM AND GLYCOGEN BROKEN DOWN BY ALPHA ANYLASE, BENEFICIAL TO GROWTH OF LACTOBACILLUS, PRODUCING LACTIC ACID, SOLIDIFIES HAVE VAGINA AND HOMEOSTASIS, PREGNANCY BEING AN EXCEPTION WHERE YOU HAVE AN EXTREME WHERE YOU HAVE HIGH ESTROGEN DURING PREGNANCY AND LACK TOE BAY SILL LACTOBACILLUS IS DOMINANT DURING PREGNANCY AND OPPOSITE AT MENOPAUSE. WHAT DOES THE VAGINAL MICROBIOME LOOK LIKE? NO, ONE MORE THING. THIS IS ANOTHER HYPOTHESIS WHERE WE CAN NOW START THINKING A ROLE FOR SEX HORMONES IN COMMUNICATION BETWEEN THE GUT AND THE VAGINAL MICROBIOTA. ENZYMES ARE IN THE GUT AND SOME CAN DECONJUGATE ESTROGEN. ESTROGEN PRODUCED BY OVARIES, GO IN THE LIVER, BILE, IN RED. THEY CAN BE DECONJUGATED AND REABSORBED, THAT BECOMES THE E HERE AND WHAT WE HAVE HERE, WE HAVE A LOT OF ESTROGENA LOT OF GLYCOGEN AND LACTOBACILLUS IN THE VAGINA. IF THE GUT THAT'S DRIVEN BY THE GUT MICROBIOME, IF YOU DON'T HAVE THIS ESTROMALONE YOU COULD HAVE POOR CONJUGATION, YOU DON'T AS MANY LACTOBACILLUS AND HIGHER Ph AND LOW GLYCOGEN, SEX HORMONES COULD PLAY A ROLE IN COMMUNICATION. SO WHAT DOES THE VAGINAL MICROBIOTA LOOK LIKE? WE PUBLISHED A PAPER BACK IN 2011 WHERE WE DESCRIBED WHAT WAS CALLED EARLIER VAGINOTYPE, WHICH WE DON'T USE, IMMUNE STATE TYPE, WHAT HAPPENED HERE YOU CAN SEE EACH LINE CORRESPONDS TO ONE WOMAN. HERE WE HAVE 5,000 SAMPLE, ONE SAMPLE, FROM 800 WOMEN, COMPOSITION OF THE PARTICULAR'S WOMAN'S MICROBIOTA SHOWN IN COLORS. RED BEING CLOSE TO 100%, YELLOW CLOSE TO 0%. THERE ARE SOME GROUPINGS THAT APPEAR VERY READILY, AND FOUR OF THOSE MAJOR GROUPINGS ARE COMPRISED OF DOMINANT LACTOBACILLUS SPECIES, SO WE HAVE THOSE FOUR GROUPINGS, IS BE SUBGROUPED, SMALLER GROUPS, AND THEN WE HAVE ANOTHER SET OF TWO GROUPS HERE WHICH WE CALL CST 4 A AND B, WHICH LACK SIGNIFICANT AMOUNT OF LACTOBACILLUS AND HAVE A MUCH HIGHER DIVERSITY AND TEND TO BE DOMINATED BY THIS VAGINALIS. SO WE HAVE THIS STRUCTURE WHERE WE CAN GROUP WOMEN WHICH IS VERY GOOD WHEN YOU START DOING LARGE EPIDEMIOLOGIC STUDIES. IF YOU LOOK AT THE LONGITUDINAL ASPECT HOW THE MICROBIOTA CHANGES OVER TIME YOU SEE THREE MAJOR GROUPS. WOMEN WHO ARE CONSTANTLY DOMINATED BY ONE SPECIES, OR TWO SPECIES OF LACTOBACILLUS, AND YOU CAN SEE RED AND ORANGE, THAT WAS A STUDY ON 160 WOMEN WHICH SAMPLED DAILY FOR ABOUT 10 WEEKS. THEN HAVE YOU 20% OF WOMEN WHO HAVE PATTERNS LIKE THIS, YOU DON'T SEE LACTOBACILLUS. THEY GO FOR 10 WEEKS, DON'T REPORT OBVIOUS SYMPTOMS BUT THEY DON'T HAVE LACTOBACILLUS. THEY HAVE A WIDE ARRAY OF ANAEROBES, AND THIS WOMAN HAS MOSTLY VAGINALIS AND SIGNS OF LACTOBACILLUS, AND YOU HAVE ANOTHER GROUP OF WOMEN THAT CONSTITUTE 30% OF THEM WHICH HAVE VERY ERRATIC PATTERN, YOU CAN SEE SOUGHT LACTOBACILLUS BUT THOSE LACTOBACILLUS ARE NEVER JUST GOOD ENOUGH TO MAINTAIN DOMINANTS IN THAT COMMUNITY JUST LIKE THOSE WOMEN. SO WE TRIED TO MODEL THIS AND TRIED TO UNDERSTAND WHAT DRIVES THOSE CHANGES AND ONE OF THE THINGS THAT WE FOUND BACK AGAIN TO SEX HORMONES, SEX HORMONES ARE VERY IMPORTANT IN DRIVING CHANGES, AMOUNT OF CHANGES YOU SEE IN THE COMMUNITY. SO OVER NORMALIZED MENSTRUAL CYCLE, THIS IS THE AMOUNT OF CHANGE, HIGHER DURING MENSES, LOWER TWICE DURING RIGHT AT 14 DAYS WHEN ESTROGEN IS HIGHER AND 21 DAYS WHEN HAVE YOU PROGESTERONE AND ESTROGEN. AGAIN, A ROLE FOR SEXUAL HORMONES IN DRIVING CHANGES THAT HAPPEN IN THE VAGINAL MICROBIOTA. SO THIS COMMUNITY CST IV IS VERY INTERESTING, WHEN HAVE YOU ABOUT 25, 30 POPULATION THAT CARRY A STATE LIKE THIS, WE CAN'T SAY 30 OR 40% IS SICK AND DISEASED. THERE'S GOT TO BE A REASON THAT WE DON'T UNDERSTAND. BUT BASICALLY ANY GIVEN TIME AT LEAST IN A U.S. POPULATION WE HAVE 25% OF WOMEN WHO ARE IN THIS STATE. ONE THING WE KNOW, THIS STATE IS ASSOCIATED WITH VERY HIGH NUGENT CORE, GRAM STAINED ASSAY THAT ALLOWS YOU TO DIAGNOSE VAGINALOSIS, PEOPLE HAVE USED IT IN EPIDEMIOLOGY FOR A LONG TIME, AND LARGE NUMBER OF SAMPLES, USING THE NUGENT SCORE THAT STRONGLY SO IF YOU WANT I CALL IT NUGENT BACTERIAL VAGINOSIS, ASSOCIATED WITH RISK FOR HIV. THEY MAY BE ASYMPTOMATIC, APPARENTLY HEALTHY, POTENTIALLY AT INCREASED RISK OF STI OF OTHER ADVERSE OUTCOMES, WE SEE IT A LOT IN FOR EXAMPLE SIMILAR STATES IN AFRICAN WOMAN. I THINK THERE'S A CRITICAL NEED TO START THINKING ABOUT REVIEWING HOW DOES THE MANAGEMENT OF ASYMPTOMATIC CONDITION LIKE THIS ARE DONE, AND WAYS TO RESTORE A COMMUNITY. WE ALL KNOW THAT WHEN WE HAVE LACTOBACILLUS THERE'S PROTECTION, WHEN IT'S NOT THERE THERE'S SUSCEPTIBILITY, BUT WE'RE TRYING TO -- THE GUIDELINES FOR TREATING BV, IT'S ONLY IF THERE ARE SYMPTOMS SO WE'RE MISSING OUT A BIG PORTION OF WOMEN STILL AT WORK, THAT PUT THEMSELF IN SUCH SITUATION, BUT WHEN THERE ARE CIRCULATING VIRUSES AND SO ON THAT MIGHT BE AN ISSUE. SO THEY NEVER DEAL WITH THE PENIS. THEY HAVE THE VAGINA, DIDN'T HAVE THE PENIS, EVEN THOUGH THEY HAD MEN IN THE STUDY. WE DID STUDY ON THE PENILE MICROBIOTA, ANOTHER COMPONENT OF THAT TRANSMISSION FOR HIV IN MANY WAYS. SO A STUDY WE DID WITH CINDY LIU AND LANCE PRICE AND RON GRAY AT HOPKINS, WE LOOKED AT EFFECT OF MALE CIRCUMCISION ON THE PENILE MICROBIOTA, A SIMPLE STUDY WHERE MEN HIV NEGATIVE RANDOMIZED TO CONTROL ARM AND INTERVENTION ARM AND FOR -- WE LOOKED AT BASELINE AND ONE YEAR AFTER CIRCUMCISION. SO THE IDEA BEHIND ALL THIS WAS PRETTY SIMPLE. WE FELT THAT MALE CIRCUMCISION JUST LIKE THE TRIAL HAD SHOWN THAT IT WAS BENEFICIAL, PROVIDED PROTECTION AGAINST HIV, SO IT GOES WHERE YOU GET DECREASE IN CYTOKINE AND CHEMOKINE, IMMUNE CHANGES, CORRESPOND TO PROTECTION AGAINST HIV. ONE THING THAT WAS VERY IMPORTANT IN THIS, WE NOT ONLY LOOKED AT THIS 16S GENE FOR PROPORTION BUT ALSO PERFORMED BACTERIAL qPCR, HOW MUCH BACTERIA IN THE SAMPLE, AN OPPORTUNITY TO STUDY WHAT WE CALL ABSOLUTE ABUNDANCE FOR EACH SPECIES, WE DISCOVERED, WE IDENTIFY IN THE MICROBIOTA. WHEN YOU DO THIS AND LOOK AT ABSOLUTE ABUNDANCE AND DON'T SEE ANY SIGNAL WHEN YOU LOOK AT RELATIVE ABUNDANCE AT BASELINE BASICALLY IN THE CONTROL AND ONE YEAR LATER YOU DON'T SEE ANY DIFFERENT, WHEN YOU LOOK AT INTERVENTION, THE MICRO MICROBIOTA OF THE MEN WHO UNDERWENT CIRCUMCISION ARE VERY DIFFERENT. SO WHAT IS VERY DIFFERENT? WE SEE A MAJOR DECREASE IN ANAEROBES, BASICALLY WAS E XPECTED BECAUSE OF CHANGE IN PHYSICAL ENVIRONMENT. PREVOTELLA AND POREPHYROMONAS WERE AFFECTED, INCREASE OF NON-AEROBES ON THE PENIS OF THOSE THAT GOT CIRCUMCISED. SO THEN WE WENT A LITTLE FURTHER WITH THE STUDY, ACTUALLY CINDY AND LANCE PUBLISHED -- SHOULD BE PUBLISHED SOON, LOOKED AT THE PENILE MICROBIOME, INFLAMMATION AND RISK OF HIV SEROCONVERSION TO FULFILL THEIR HYPOTHESES. IN UNCIRCUMCISED MEN WE LOOKED AT BASAL CORONAL SULCUS SWABS. AGAIN, A LOT OF THE SAME PLAYERS STARTED TO SHOW UP, AND WE LOOKED AT THE PREVOTELL ASSOCIATED WITH SEROCONVERSION. CINDY PERFORMED A STUDY LOOKING AT PENILE MICROBIOTA IN CONTEXT OF FEMALE PARTNERS WITH VAGINOSIS, HERE THE SAME CONCEPT WHERE WE GROUP DIFFERENT SAMPLES BASED ON COMPOSITION, BUT ALSO COMPOSITION BUT ALSO ABUNDANCE OF THAT PARTICULAR BACTERIA PRESENT IN THE SAMPLE. SEVEN COMMUNITY TYPES, THOSE IN HIGHER COLORS ARE HIGHER ABUNDANCE OF MICROBES, OKAY? AND SO WHAT SHE FOUND IS THAT MEN WHO ARE IN THOSE LAST ONE WITH THE HIGHEST ABUNDANCE WAS SIGNIFICANTLY MORE LIKELY TO HAVE SINGLE PARTNER WITH HIGH NUGENT SCORE AND FEMALE PARTNER, SO IF SHE WAS NUGENT BV, SIGNIFICANTLY ASSOCIATED WITH DIFFERENT PENILE MICROBIOTA, ESPECIALLY PREVOTELLA. THEY ARE FOLLOWING THIS LANCE PRICE AND CINDY LIU ARE FOLLOWING THIS. FROM A MECHANISTIC ANGLE BUT WE REALLY WANT TO UNDERSTAND THAT MECHANISTIC, HOW DO THE MICROBES DO AND ACTIVATE ALL THOSE CELLS. SO HOW CAN YOU THINK ABOUT IT THIS WAY, SO WE KNOW THAT WE HAVE THIS ANAEROBIC DYSBIOSIS, SIMILAR OCCURRING IN WOMEN, WITH BACTERIAL VAGINOSIS. IN MAN RESOLVED UPON CIRCUMCISION, THE ANAEROBIC CORRELATING WITH SEXUAL PARTNERS, THE POSSIBILITY DYSBIOSIS BY ITSELF IS SEXUALLY TRANSMISSIBLE, A VERY CONTROVERSIAL AREA RIGHT NOW BUT SEXUAL TRANSMISSIBILITY OF DYSBIOSIS, THAT GOES BOTH WAYS, IT DOESN'T JUST GO FROM THE WOMAN TO THE MAN WHICH IS WHAT THE OTHER STUDY WAS SUGGESTING WITH CORRESPONDING NUGENT SCORE BUT ALSO GOING FROM THE MAN TO THE WOMAN, WHERE HERE WE HAVE AN EXAMPLE OF A WOMAN SO THIS IS THE SAME PATTERN, SOMEBODY WHO HAD LACTOBACILLUS CRISPOSATUS DOMINATING MOST THE TIME, DURING THE 10-WEEK STUDY HAD ONE NEW SEXUAL PARTNER, UNPROTECTED SEX, RIGHT THERE. WHAT HAPPENED RIGHT AFTER THAT SEX EVENT, SHE BASICALLY EXPERIENCED VAGINOSIS AND HER MICROBIOTA WAS AFFECTED, NOT COMING BACK THE SAY WAY. WE DID EVERYTHING TO DETECT THE MICROBES PRIOR TO THE SEX ACT AND COULD NOT FIND THEM, SO THE MICROBES WERE CERTAINLY TRANSFERRED BY HER SEXUAL PARTNER ON THAT EVENT. SO JUST TO FINISH, I WANT TO SHOW YOU HORMONES ARE VERY IMPORTANT. PHYSICAL BARRIER OF THE DIFFERENT SEX IS ALSO VERY IMPORTANT. THERE'S NOTHING THAT'S KNOWN ABOUT THE MEN BUT IN WOMEN WE KNOW CERVICAL VAGINAL MUCUS IS VERY IMPORTANT SO WE WANTED TO KNOW IF THE BACTERIA THAT LIVES ON TOP OF IT OR IN IT COULD AFFECT ITS PROPERTY AND ACTUALLY AFFECT SUSCEPTIBILITY TO HIV. WITH THE COLLABORATORS OF MINE, AT THE UNIVERSITY OF NORTH CAROLINA, WE COLLECTED 31 CVM FROM 31 WOMEN AND MEASURED MOBILITY OF HIV, VERY NICE, A VERY NICE ASSAY, WITH PARTICLES THAT ARE FLUORESCENT, CAN TRACE THEM IN THE MUCOUS, MOBILE OR NOT. 17 SPECIFICALLY STUCK IN SPACE, 14 MOBILE. WE LOOKED AT EVERY FACTOR THAT COULD EXPLAIN THIS. THERE'S ONE FACTOR THAT COULD EXPLAIN IT, THE MICROBIOTA. WE SAMPLED IN THREE GROUPS, GROUP ONE DOMINATED BY LACTOBACILLUS, THE LOWEST DIFFUSIBILITY, LOWEST MOBILITY. THE PRODUCTION OF D LACTIC'S A IT, LACTOBACILLUS DOES PRODUCE LACTIC ACID, D LACTIC ACID. THIS LACK WAS EXPLAINING THE MOBILITY OF THE VARIANT IN THE MUCUS. JUST TO FINISH, FOR THE SAKE OF TIME I CAN SKIP THIS. I WANT TO GO BACK TO THIS. I THINK THE WHOLE IDEA OF ENVIRONMENT HOST MICROBIOME HAS GOT A LOT MORE COMPLEX AND WHEN WE START PUTTING THE HOST AND ITS GENDER WE START TO COME UP WITH A LOT OF ARROWS THAT START POINTING TO A LOT OF DIFFERENT ASPECTS AND EVEN THE GUT, AND THE GUT, IF IT'S AFFECTED BY ESTROGEN, CAN BE VERY IMPORTANT BECAUSE OF SUSCEPTIBILITY TO HIV, A SITE OF INFECTION IN MEN THE SAME WAY SO THERE'S A LOT MORE GOING ON IN THOSE CORRELATIONS THAN WE ORIGINALLY THOUGHT AND A LOT MORE QUESTIONS THAT'S GOING TO NEED TO BE ANSWERED. THAT'S IT. [APPLAUSE] >> THANK YOU SO MUCH, JACQUES. WE'RE GOING TO ANNOUNCE A CHANGE IN SCHEDULE. DOUG KWAN FROM THE REAGAN INSTITUTE COULD NOT COME BECAUSE OF THE WEATHER. SO UNFORTUNATELY WE ARE GOING TO SKIP THAT TALK. AND BECAUSE WE WANT TO HAVE A LONGER TIME FOR DISCUSSION AND CONSOLIDATED, WE'RE GOING TO HAVE THE NEXT TALK FIRST BEFORE THE BREAK AND THEN WE'RE GOING TO TAKE A BREAK AND HAVE THE PANEL AND THE DISCUSSION SIMULTANEOUSLY. AND ANOTHER ANNOUNCEMENT OR OR CHANGE IS DR. HAZUDA COULDN'T COME BALLS OF WEATHER SO BETSY HAROLD WILL TALK. AND DR. HAROLD IS DIRECTOR OF TRANSLATIONAL RESEARCH CENTER FROM ALBERT EINSTEIN, AND SHE'S GOING TO GIVE THIS TALK FOR ALL OF US, WE'RE GOING TO BREAK AND HAVE OUR DISCUSSION. >> OKAY. THANKS VERY MUCH. I AM GOING TO BE DOUG, JEANNE AND MYSELF. JEANNE SENT MY SLIDES BUT HALF CAME FROM MY LAB SO I KNOW THOSE. THE OTHERS I'LL FAKE MY WAY THROUGH. JEANNE STARTED WITH FOUR QUESTIONS. I LIKE THIS ACRONYM. IS THERE AN INTERACTION BETWEEN ARV AND HUMAN MICROBIOME, THE ANSWER IS YES. DOES IT DIFFER IN THE VAGINA AND GUT? THE ANSWER IS PROBABLY. DIFFERENT BY OUT OF ADMINISTRATION? YES. ARE THERE SPECIFIC INTERACTION RELATIVE TO INDIVIDUAL DRUGS? WE'LL GET TO THAT. ARE THERE OTHER ASPECTS THAT MIGHT AMPLIFY AND WHAT ELSE CAN ACT AS INTERMEDIARIES. JACQUES ADDRESSED HORMONES, ESTROGEN, I WON'T DO THAT BUT WE'LL BRING IT UP IN DISCUSSION. THIS IS A SLIDE EVERYONE IN THE PREP FIELD HAS SEEN, SHOWING IF YOU ADHERE TO PrEP PRODUC, THIS IS LOOKING PREDOMINANT AT AT ORAL PrEP, IF YOU ADHERE YOU'RE PROTECT THE, IF NOT YOU'RE NOT PROTECT THE. WHEN ADHERENCE IS, QUOTE, 100%, AND WHAT THAT'S BASED ON DEPENDS ON THE STUDY, BUT THE EFFICACY IS ALWAYS LESS. MANY BEGAN TO ASK IS THERE A BIOLOGICAL ROLE AS WELL, NOT SIMPL ADHERENCE BUT ADHERENCE PLUS BIOLOGY, THIS IS CAME OUT OF A STUDY IN SOUTH AFRICA, ONE OF THE EARLY STUDIES THAT LOOKED AT QUOTE/UNQUOTE BEING INFLAMED. I HATE THAT WORD BUT I THINK IT'S A GOOD DESCRIPTOR, THAT WOMEN WITH MORE INCREASED INFLAMMATORY CYTOKINES, BUT REMEMBER MANY HAVE DIVERSE ACTIVITIES SO WE'RE DIE COT MIZING, WERE MORE LIKELY TO ACQUIRE HIV, SHOWS THIS IN THE STUDY, THE WOMEN WITH DESCRIBED GENITAL INFLAMMATION, A SCORE OF INFLAMMATORY CYTOKINES, GREATER RISK OF HIV ACQUISITION, 19 TO 6, COMPARED TO WHEN NOT PRESENT YOU HAD FEWER EPISODES OF HIV ACQUISITION, IN THE CONTEXT OF OF THE GEL IN THE STUDY. JOANNE LED THIS PART OF THE STUDY, THEY PULLED OUT 119 WOMEN, AGAIN THE GEL STUDY, WHAT WAS ASSOCIATED AND USED THE TYPICAL 16S RIBOSOMAL RNA APPROACH AND FOUND IF YOU HAD INFLAMMATION WHICH IS THE HC THERE, AND YOU HAD PREVOTELLA, YOU WERE 19 TIMES MORE LIKELY TO HAVE INFLAMMATION, WHICH IS DRIVING WHICH WE DON'T KNOW IF YOU IF YOU'RE INFLAMES YOU HAVE MORE PREVOTELLA AND 13 TIMES MORE LIKELY TO GET HIV. AND THEY WENT ON AND THE REASON THIS IS IMPORTANT TO MENTION THEY LOOKED AT MECHANISM AND MECHANISM THEY PICKED WAS WHETHER LPS WAS BEING SYNTHESIZED BY PREVOTELLAE KNOWN TO ACTIVATE NF-KAPPAB PATHWAY AND THAT WAS AN ASSOCIATION. SO THAT'S THE ASSOCIATION PART. SUBSEQUENT STUDIES THAT WERE DONE BY ADAM BURGENNER AND NIKKI KLATT TOOK A DIFFERENT APPROACH, THEY DID NOT DO 16S RIBOSOMAL RNA. THEY SERVE CVL, THE FLUID YOU WASH OUT OF A GENITAL TRACT AND THEY LOOKED BY PROTEOME INCORPORATION FOR SIGNATURES AND DIVIDED WOMEN INTO TWO GROUPS, GE VAGINALIV DOMINANT, FOCUSING ON G VAG AND THOSE THAT WERE LACTOBACILLUS DOMINANT. LACTOBACILLUS DOMINANT GROUP IN THIS COHORT, THIS REFLECTS SOME OF WHAT JACQUES WAS SAYING EARLIER, DON'T ALL INCREASE OR DECREASE Ph, ET CETERA, BUT THEY DIVIDED THEM INTO GUARDRELLA VERSUS PREDOMINANTLY LACTOBACILLUS AND IT LOOKS SIMILAR TO THE EARLIER STUDY DIVIDED BY PREVOTELLO, IN WOMEN ON THE TENOFOVIL GEL, 56% ON THE FAR LEFT, IF YOU WERE LACTOBACILLUS DOMINANT EVEN LOOKED BETTER, 78% EFFICACY, FOUR CASES OF HIV ACQUISITION IN THE TENOFOVIL ARM, 15 IN PLACEBO ARM. IF YOU WERE IN THE GARDNERELLA ARM OR DIDN'T HAVE A LOT OF LACTOBACILLUS YOU DIDN'T HAVE MUCH PROTECT, IN FACT YOU HAD ESSENTIALLY NO PROTECTION. OKAY? SO THAT'S WHAT GOT PEOPLE THINKING ABOUT THIS IN THE FIELD. THEY ALSO WENT ON TO DO A LITTLE BIT OF MECHANISTIC DATA AND MIXED DIFFERENT BACK DEARA, INERS OR GARDNERELLA DRUG, SPUN AND ASKED WAS THE DRUG ASSOCIATED WITH BACTERIA OR DID THE DRUG STAIN THE SUPER NATANT, THE DRUG DID SEEM TO ASSOCIATE WITH GARDNERELLA BUT NOT INERS. LOOK AT THE AXIS, THE DOSING WHEN YOU'RE USING TENOFOVIL GEL IS 40 MILLIGRAMS PER DOSE, A TINY BIT, MAYBE GARDNERELLA IS BINDING TAKING UP ABSORBING, EATING, WHATEVER WORD BECAUSE WE DON'T HAVE ALL THE MECHANISMS WORKED OUT. ONE OTHER STUDY THAT HAS LOOKED AT THIS, AND I'LL GET INTO MECHANISTIC DATA, WHAT CAME FROM THE SAME STUDY OF TENOFIVIR FILM, THIS WAS RAISING CONCERNS ABOUT IS TENOFIVIR THE RIGHT DRUG TO MOVE FORWARD WITH, WENT BACK AND LOOKED AT DATA, A SMALL COHORT THAT APPLIED TENOFOVIR FILM THAT OBSERVED APPLICATION SO SEVEN DOSES OF FILM OF TENOFOVIR AND THEY WENT BACK AND CORRELATED BASED ON NUGENT SCORES OR QUANTITATIVE PCR LOOKING IT'S A LACTOBACILLUS AND IN GENERAL. WITH DOMINANCE, GREATER THAN 10 TO THE 8th, GARDNERELLA, YOU SEE DECREASE OF TENOFOVIR IN THE BLOOD AND CERVICAL TISSUE. INERS DID NOTHING. AND ADIPOBIUM IN THE SAME DIRECTION. THERE'S ONE STUDY IN ORAL PREP I'M GOING TO GO QUICKLY THROUGH, THAT ASKED WAS ORAL PrEP EQUALLY EFFECTIVE IN CLINICAL STUDY GOING BACK, SEGREGATING WOMEN BASED ON NUGENT SCORE, YES. ORAL PrEP, DIFFERENT THAN WHAT I JUST SHOWED YOU, THE EFFICACY WAS THE SAME WHETHER YOU HAD NUGENT SCORE OF 0-3 NORMAL, ENTIRE IMMEDIATEAT OR CONSISTENT WITH VAGINOSIS. CLINICALLY WE HAVEN'T SHOWN A DIFFERENCE IN PrEP, VAGINAL PrEP EXCEPT IN THE CAPRICE TRIAL WITH SEVERAL CORRELATES. SO TENOFOVIR LEVELS MAYBE BEING LOWER. SO CAN WE THINK ABOUT THE MECHANISM? NOT KNOWING THAT ANY OF THESE PEOPLE WERE DOING THIS I HAD A GRAD STUDENT COME INTO THE LAB, THIS IS ALL HER DATA WHO WANTED TO ASK THE QUESTION, DO OTHER FACTORS AFFECT DRUG PK AND FOCUSED ON THE MICROBIOME. THE FIRST THING SHE DID, THIS IS IMPORTANT THAT WE ALL HAVE THE SAME BASIC UNDERSTANDING IS FIGURE OUT HOW THE DRUGS GET INSIDE CELLS. WE DID STUDIES IN MANY, MANY WOMEN WITH PrEP AND MEN WITHOUT COMPLETELY KNOWING HOW THESE DRUGS GET INTO THE TARGET CELLS. AND IN FACT WHAT'S KNOWN ABOUT TENOFOVIR IN THE LITERATURE IS WRONG. WHAT'S IN THE LITERATURE ON TENOFOVIR IS CORRECT, THAT ON RENAL CELLS ORGANIC TRANSPORTERS ARE EXPRESSED, THAT'S HOW IT GETS TAKEN BY RENAL CELLS, THAT'S PART OF THE MECHANISM OF RENAL TOXICITY BUT THOSE ORGANIC TRANSPORTERS WITH NOT EXPRESSED BY HUMAN FEMALE VAGINAL EPITHELIAL CELLS, NOR BY CD4 T CELLS IN HUMAN SO WE HAVE THE DNA BUT DON'T EXPRESS THE RNA, DON'T MAKE THE PROTEIN, FIVE GROUPS HAVE SHOWN THIS. TURNS OUT WE SHOWED BASICALLY TENOFOVIR GETS IN CELLS BY A POOR MECHANISM OF ENDOCYTOSIS, THAT'S NOT THE MOST EFFICIENT. TDF AND TAF ARE PRO DRUGS OF TENOFOVIR GET IN BY PASSIVE DIFFUSION, BUT ONCE INSIDE A DEVELOP HAVE TO BE CONVERTED BACK TO TENOFOVIR, CATALYZING THE CHANGE, TWO-STEP PROCESS, I'M LISTING THE FIRST ENZYME. THOSE ENZYMES, SOME CHANGES THE LEVELS, TDF THAT WENT IN CAN'T GET CONVERTED TO TENOFOVIR AND IS GOING RIGHT BACK OUT. AND DEPIVERINE, THE OTHER DRUGS NOT MODIFIED, PASSIVELY DIFFUSING IN AND OUT. SHE ASKED THE QUESTION WHAT HAPPENS IN THE MICROBIOME? WE HAPPENED TO WORK ON HIV, HSV AND INTERACTIONS BETWEEN THOSE SO THE FAR LEFT IS EXAMPLE SIMILAR TO WHAT WAS JUST SHOWN TO YOU, SO THE TOP COHORT THERE ARE HIV NEGATIVE, TWO NEGATIVE WOMEN AND BOTTOM DIVERSITY ARE DOUBLE POSITIVES. WE KNOW H INCREASES HIV RISK, WE ASKED WHAT'S GOING ON WITH RESPECT TO RISK AND WITH RESPECT TO DRUG. YOU RELEASE THE GEL FROM THE RING OR ANYTHING ELSE ECTOPICALLY, IT DOESN'T GO INTO PBS. IT GOES INTO A COMPLEX ENVIRONMENT THAT'S GOT CYTOKINES, BACK MATERIAL FLORA, AND HAS TO GET FROM WHERE RELEASED TO KEEP WITH THIS MORNING, MONOCYTE MACROPHAGE PERHAPS, CD4 T CELLS AND TENOFOVIR HAS TO GET IN EPITHELIAL CELL. WHAT ABOUT Ph? TENOFOVIR GETS IN BY ENDOCYTIC MECHANISM. WHEN YOU MODIFY Ph, CULTURING YOUR CELLS WITH THE DRUG, RADIO-LABELED WAS EASIER THAN MASS SPEC EVERY DAY, INCUBATE AT DIFFERENT PHs, ON THE FAR LEFT YOU CAN SEE THAT THERE'S A MARKED DECREASE IN TENOFOVIR UPTAKE THAT'S MEASURING RADIO-LABELED UPTAKE OVER HERE AS YOU INCREASE Ph AND THESE ARE PHs THAT AFTER SEX EXIST FOR ABOUT 72 HOURS. SEMEN HAS A Ph OF 8, IT'S A REALLY GOOD BUFFER. THESE ARE PHs THAT EXIST IF HAVE YOU BACTERIAL VAGINOSIS, TENOFOVIR IS IMPAIRED AT HIGHER PH, OTHER DRUGS NOT AFFECTED. NEXT SIMILAR TO WHAT NIKKI KLATT DID WITH DIFFERENT RESULTS AND HAVEN'T FIGURED OUT WHY YET. IF YOU TAKE BACTERIA AND GROW THEM IN LIQUID BROTH AND MIX THEM WITH RADIO-LABELED DRUGS, WASH IT OFF, AND YOU SPIN IT DOWN AND ASK HOW MUCH OF THE DRUG IS ASSOCIATED WITH THE BACTERIA AND HOW MUCH IS RETAINED IN THE SUPERNATEN AND GOT SURPRISING RESULTS. IN RED IS TENOFOVIR, THIS BACTERIA WHICH HAPPENS TO BE THE GOOD GUY, LACTOBACILLUS CRISPATUS, TAKES UP, I'LL SHOW YOU IN A SECOND, THE TENOFOVIR DRUG, THE OTHER US DO IT BUT NOT AS MUCH AS CRISPATUS. MOST BACTERIA TO SOME EXTENT. THE PEVARINE IN BLUE, NOT TAKING IT UP, IT'S BINDING BECAUSE WE GET THE SAME RESULT AS 4 DEGREES, AND WE GET THE SAME RESULT IF WE USE HEAT-KILLED BACTERIA. PEVARINE IS STICKY. IT'S A PROBLEM. IF YOU TAKE A RING OUT THAT'S DELIVERING DEPEVARINE, PASSIVELY DIFFUSING GOING IN AND OUT, COMES OUT OF THE CELLS AND STICKS TO YOUR BACTERIA AND EPITHELIUM AND DEBRIS, IT'S STUCK AND IT'S STUCK FOR LIFE. SO THAT'S A PROBLEM IF YOU'RE NOT ADHERENT TO DEPEVARINE. THE PRO DRUG NOT AFFECTED. SO WE WENT TO LOOK MECHANISTICALLY, THIS IS QUICKLY SHOWING YOU IF YOU DO COLD COMPETITION WITH RADIO-LABELED DRUGS, IF IT'S ACTIVE TRANSPORT MECHANISM YOU SHOULD SEE A DECREASE. THIS IS LOOKING AT TENOFOVIR UPTAKE IN CD4 T CELLS, NO COLD COMPETITION BECAUSE IT'S NOT -- IT'S AN ENDOCYTIC PATHWAY AND COLD DOESN'T COMPETE. WHEN YOU LOOK AT THE UPTAKE INTO THE LACTOBACILLUS BACTERIA NOW FOLLOW THE RED AND YOU SEE COMPETITION, THAT SUGGESTED IT'S AN ACTIVE TRANSPORTER THAT'S AVAILABLE IN LACTOBACILLUS, AGAIN THIS IS SHOWING 4 DEGREES IN WHITE NOT BEING TAKEN UP. AND WHEN YOU LOOK FOR WHAT COULD BE THE TRANSPORTER YOU USE A DRUG LIKE PROBENEFID, IT BLOCKS UPTAKE OF TENOFOVIR BY CRISPATUS BUT DOESN'T AFACT JURKAT CELLS. IT DOES A BETTER JOB THAN YOUR T CELL. WE MEASURED METABOLITES, CONVERTS TENOFOVIR INTO MONOPHOSPHATE AND DIPHOSPATE AND DOES IT PRETTY EFFICIENTLY AND AGAIN IT DOES IT MORE EFFICIENTLY, THE WHITE OVER HERE IS THE JURKAT CELL, BUTTER THAN A JURKAT CELL. IS THAT GOOD OR BAD? YOU CAN DECIDE. IT'S EITHER A RESERVOIR SO IT'S TAKING IT UP, METABOLIZING IT BUT EVENTUALLY THAT LACTOBACILLUS IS PROBABLY GOING TO DIE OR POTENTIALLY MY CONVERT BACK TO TENOFOVIR AND RELEASE OR A SINK SUCKING IT UP AND COMPETING FOR THAT DRUG. SO THAT WAS LOOKING AT INDIVIDUAL BACTERIA. SO WE WANTED TO SAY IS THIS RELEVANT BECAUSE WE ADD 10 TO THE 9th, INSTEAD OF ADDING INDIVIDUAL BACTERIA TOOK VAGINAL SWABS FROM 12 HEALTHY WOMEN, MIXED WITH DRUGS, LET THEM INCUBATE FOR SHORT TIME PERIOD, PELLETED OUT BACK BACTERIA, ASKED HOW MANY DRUG IS STILL AVAILABLE. YOU CAN SEE FOR ALL 12 WOMEN, YOU LOSE MOST OF THE DEPEVARINE, STICKS TO BACTERIA AND NOT AVAILABLE. THE TWO PRO DRUGS ARE FINE. THAT'S IMPORTANT. IF YOU DO AN ANTI-VIRAL ASSAY, ADDING DIFFERENT AMOUNTS OF TENOFOVIR IN THE PRESENCE OF NO BACTERIA, HEAT KILLED OR LIVE BACTERIA AND MEASURING HOW MUCH ANTI-HIV ACTIVITY THERE IS, SO THIS IS WHAT YOU WANT, INHIBIT ABOUT 100% OF HIV INFECTIVITY, YOU CAN SEE WITH NO BACTERIA OR HEAT KILLED YOU NEED 5 MICRO MOLARS TO INHIBIT. IF YOU'VE GOT LIVE BACTERIA, THESE GUYS, OVER HERE AROUND, YOU'VE SHIFTED THAT CURVE TO THE RIGHT AND NOW YOU DON'T GET GOOD INHIBITION UNTIL YOU'RE 15 MICROMOLAR. TAF AND TDF, IT LOOKS IDENTICAL. DON'T CARE. YOU GET A BEAUTIFUL DOSE-RESPONSE CURVE, AND NOTE AMOUNT OF TAF OR TDF IS LESS THAN YOU NEED OF TENOFOVIR SO FIT GETS INSIDE A CELL MORE EFFICIENTLY TO INHIBIT HIV-INFECTED AND DEPEVARINE CARES AND HEAT-KILLED AND LIVE SHIFT DOSE-RESPONSE CURVE TO THE RIGHT. THE LAST MECHANISM WAS WHETHER HERE WAS SOMETHING BEING MADE BY BACTERA THAT COULD INTERFERE WITH DRUG METABOLISM OR DRUG UPTAKE. THIS TIME SHE TAKES HER BACTERIA AND PELLETS IT OUT AND COLLECTS SUPERNATANT, WHAT'S BEING RELEASED? IF YOU GET 100% BACK, ITS DOESN'T CHANGE. TDF AND TAF DON'TS CARE ABOUT MICROBIOTA. WHEN YOU ADD TENOFOVIR, THERE'S SOMETHING IN THE SUPERNATANT BLOCKING UPTAKE BY CD4 T CELL, SOMETHING'S BLOCKING, AND INTERESTINGLY THESE BACTERIA ARE ACTUALLY ENHANCING THE UPTAKE, THE SUPERNATANTS ARE ENHANCING IT. WE DECIDED TO FOCUS ON THESE, CONFIRMING IT, GARDNERELLA IS INHIBITING, AND THE SUPERNATANT IS ENHANCING, WHETHER WE WERE TRYING TO GET TENOFOVIR INTO CD4 CELLS, VAGINAL CELLS, FIBROBLASTS, IT'S ALWAYS BLOCKED BY GARDNERELLA NATANT, NOT JUST TENOFOVIR THAT'S AFFECT THE BY DEFOVIR IS ALSO. TENOFOVIR GETS IN BY ENDOCYTOSIS, WE DID A QUICK AND DIRTY ASSAY SO IF YOU USE TRANSFERRIN AS A MARKER IN RED HERE, TRANSFERRIN IS TAKE UP BY ENDOCYTIC PATHWAY. YOU CAN SEE RED, CULTURE IN PRESENCE OF BROTH, USE GARDNERELLA SUPERNATANT YOU SHOULDN'T SEE RED. WHEN YOU ADD ADIPOBIUM YOU GET MORE RED, AND DYNASORE ALSO BLOCKED UP TAKE. GARDNERELLA IS SPITTING OUT ADENENE, INTERFERING WITH CYTOSIS, BLOCKS TENOFOVIR, AND MEASURE OUT OF GARDNERELLA LOOMS IT WENT FROM 60 WHICH WAS IN THE BROTH TO OVER 300, AND INTERESTINGLY ADIPOBIUM IN THE SAME BROTH WENT DOWN TO 5 WHICH SAYS SOMETHING ABOUT BACTERIA. THESE GUYS ALMOST ALWAYS EXIST TODAY SO FOR SOME REASON GARDNERELLA IS MAKING OR SPITTING OUT ADENINE AND ADIPOBIUM WANTS IT. >> YOUR LIGHT IS NOT WORKING WELL BUT A COUPLE MORE MINUTES PLEASE. THANK YOU. >> I'VE GOT NINE MINUTES ACCORDING TO THIS. I'LL FINISH. HERE IS BOTTOM LINE CONCLUSION. TENOFOVIR UPTAKE IS REDUCED AT 5.5, BACTERIA CAN ACT AS SINK BY BINDING OR ACCUMULATING IN THE CASE OF LACTOBACILLUS CRISPATUS AND MAYBE TENOFOVIR AND BACTERIA RELEASE SOMETHING INTO THE SUPERNATANTS THAT CAN BLOCK UPTAKE. I'LL END ON THIS IF YOU WANT ME TO END QUICKLY. THIS IS SORT OF A CONCEPTUAL MODEL WE'RE AT. AND SO THIS IS LOOKING AT LET'S TAKE DEPIVARENE, ANYTIME IT GOES OUT IT CAN BE BOUND BY BACTERIA OR EPITHELIAL CELLS. TENOFOVIR IS MORE COMPLICATED DOWN HERE, IT GETS IN BY ENDOCYTIC PATHWAY THAT'S BLOCKED B ADENINE, Ph INTERFERES WITH ENDOCYTOSIS, AND THE OTHER PART THAT WE HAVE LESS DATA ONCE TENOFOVIR IS IN OR IN THE CASE OF TDF AND TAF ONCE CONVERTED INTO TENOFOVIR IT GETS DEPHOSPHORYLATED AND THAT COMPETES WITH DEOXY ATP TO BLOCK HIV REPLICATION. WE DON'T KNOW THAT BACTERIA MODIFY THIS, BUT WE DO KNOW THAT THE AMOUNT OF DEOXY ATP DIFFERS IN DIFFERENT SITES SO CERVICAL AND VAGINAL EPITHELIUM HAVE HIGHER LEVELS. IF YOU HAVE MORE SUBSTRATE REPLICATION, WE NEED TO METABOLIZE ALL THESE THINGS SO THINGS ARE GOING TO CHANGE ENZYMES REQUIRED HERE, THINGS ARE GOING TO INTERFERE WITH INCREATES YOUR DEOXY ATP, THINGS THAT BLOCK UPTAKE WILL MAKE A DIFFERENCE SO THE BOTTOM LINE, I'LL SKIP THAT CARTOON, GO BACK TO THE FOUR QUESTIONS, IS THERE ENTER ANXIOUS BETWEEN ARV AND HUMAN MICROBIOME? YES. THE EXISTS IN THE VAGINA. THERE'S AN IMPACT. MORE OF A PROBLEM WITH TOPICALLY DELIVERED DRUG INTO THE MICROBIOME. THERE ARE SPECIFIC INTERACTIONS AND WE NEED TO UNDERSTAND THESE, AND WE'VE MENTIONED THESE OTHER THINGS. AND WITH THAT I WILL GO TO THE VERY LAST SLIDE WHICH I THINK OPENS UP THE DISCUSSION AND THEN WE CAN BREAK FOR THE DISCUSSION. I THINK, YOU KNOW, WE NEED TO THINK ABOUT WHAT'S GOING ON, WHAT CHANGES VAGINA OR GUT MICROBIOME THAT INTERACTS, WE DON'T HAVE GOOD DATA BUT WE THINK THINGS ARE CHANGING THE ENDOGENOUS NUCLEOTIDE POOL, THIS IS PROBABLY OVERCOME IF YOU ARE ADHERENT, IF YOU ALWAYS HAVE A HIGH LEVEL DRUG AROUND IT DOESN'T MATTER THAT HAVE YOU ALL THESE THINGS. BUT WHEN YOUR DRUG LEVEL FALLS OR INTERMITTENTL ADHERENT OR PULL YOUR RINGS OUT IT MAKES A DIFFERENCE. WE NEED TO SET UP STUDIES TO ADDRESS THIS EARLY IN CLINICAL DEVELOPMENT, NOT AFTER THE FACT. [APPLAUSE] >> THANK YOU. WE'LL HAVE LOTS OF TIME FOR DISCUSSION AND BREAK. BECAUSE WE WANT TO GET PEOPLE OUT A LITTLE BIT EARLY TODAY BECAUSE THERE IS A TORNADO, WE'RE GOING TO GO AND PLEASE GET YOUR COFFEE. WARNING, SORRY. A WARNING. OH, IT'S GONE. WE'RE OKAY. PLEASE GO GET COFFEE AND TEA AND JUST BRING IT BACK AND WE'LL START ONCE PEOPLE ARE BACK. WE'RE NOT GOING TO TAKE AS LONG OF A BREAK SO WE CAN GET TO THE DISCUSSION AND GET OUT EARLIER TODAY. >> WE'RE GOING TO RESTART. YES, WE'RE ENERGIZED. THE FIRST PART OF THIS IS ANY QUESTIONS THAT CAME UP FROM THE TALKS. WE HAVE MOST OF THE -- WELL, MANY OF THE PEOPLE WHO GAVE THE TALKS AT THE FRONT OF THE ROOM. AND BETSY HAROLD AND JACQUES REVAL, AND ALLOW TWO OTHER PANEL MEMBERS TO INTRODUCE THEMSELVES, EVAN AND CHRISTINE DEPEREZ, WHY DON'T YOU INTRODUCE YOURSELVES. WE KNOW THE OTHER TWO AND THEN WE'LL OPEN IT UP TO ANY QUESTIONS THAT CAME UP IN THE LAST SET OF TALKS ABOUT THE MICROBIOME. >> HI, MICROBIOME EVAN (INDISCERNIBLE) AND I TRAINED AT UCSF WHERE I WAS INVOLVED IN ONE OF THE FIRST SURVEYS OF THE GUT MICROBIOME AND HIV INFECTED INDIVIDUALS COMPARED TO UNINFECTED SUBJECT S IN COLLABORATION WITH DR. LETTERMAN, NOW IN YASMIN'S LAB STUDYING GUT BUGS AND CHRONIC INFLAMMATION AND PUSH DISEASE PROGRESSION. >> I'M DR. DEPARIS FROM THE UNIVERSITY OF NORTH CAROLINA CHAPEL HILL AND TRAINED AS IMMUNOLOGIST AND STARTED IN VAGINAL TRANSMISSION MODEL OF SIV AND NOW WORK EXCLUSIVELY PRETTY MUCH IN THE INFANT MACAQUE MODEL AND I WORK ON HUMAN INFANT IMMUNE DEVELOPMENT BECAUSE OUR GOAL IS TO PREVENT BREAST MILK TRANSMISSION OF HIV AND WORKING IN THE AREA GOT INTRODUCED TO THE MICROBIOME BECAUSE WE INTERESTED IN THE NEWBORN HOW BREASTING MILK AFFECTS THE MICROBIOME AND OTHER FACTORS ESPECIALLY RESOURCE POOR COUNTRIES MAY AFFECT THE MICROBIOME AND THERE BY AFFECT DISEASE OUTCOME. >> OKAY. LET'S OPEN THE DISCUSSION FROM -- I KNOW CHUCK HAD A QUESTION. ANYONE WHO HAD QUESTIONS FROM PREVIOUS TALKS OR COMMENTS. >> BETSY, I WAS REALLY INTERESTED IN YOUR PRESENTATION. YOU SPOKE ABOUT THIS, BUT DO YOU THINK THAT THE VAGINAL MICROBIOME HAS IMPLICATIONS FOR SYSTEMIC PrEP, IT MUST BE TOPICAL PrEP THAT LENDS ITSELF BUT GIVEN WE DON'T KNOW WHERE PrEP AGENTS NEED TO BE TO BE EFFECTIVE DOES IT IMPACT SYSTEMIC PrEP AS WELL. >> WE DEBATED THIS. I'LL SHARE BOTH SIDES OF THE ANSWER TO THIS QUESTION. I THINK THE SIMPLE ANSWER IS YES. I MEAN, IT MAKES NO SENSE IF TENOFOVIR IS TAKEN ORALLY, WHAT ULTIMATE LY GETS IN THE HAVE VAGINA IS TENOFOVIR. THE DIFFERENCE IN PrEP, WHERE IS PROOF HAPPENING. SO I THINK WITH SYSTEMIC PrEP WHETHER WE'RE MOSTLY PROTECTING IS PROBABLY AT THE LYMPH NODE, AMPLIFICATION STEP, THE BLOOD, WHAT HAVE YOU, AND SO VIRUS MAY COME IN THROUGH THE HAVE A VAGINA BUT GOT THERE GOING THROUGH THE BLOODSTREAM THEN THE MICROBIOME ISN'T GOING TO MATTER. IF YOU WERE TRYING TO PROTECT THE FIRST FEW VIRAL PARTICLES THAT ATTACHED TO -- THAT GET INTO A MACROPHAGE, DENDRITIC T CELL IN THE VAGINA, IT WILL HAVE THE SAME APPLICATION. TOPICAL PrEP, LOW PLASMA LEVEL, WE'RE KEEPING IT ALL LOCAL SO THERE THESE EFFECTS ARE MORE APPARENT OR POTENTIALLY MORE DAMAGING IF YOU DON'T KEEP HIGH LEVELS AROUND. I DON'T KNOW IF THAT ANSWERS THE QUESTION. >> JUST A FOLLOW-UP, THE AMOUNT OF DRUG THERE IS SO VASTLY EXCEEDED, RIGHT, WHEN YOU USE IT IN A TOPICAL FORM. >> SO THE AMOUNT THAT'S THERE WHEN YOU USE IT SYSTEMICALLY IN THE GENITAL TRACT, IT WOULD HAVE MORE EFFECT VAGINALLY THERE. YOU'RE RIGHT WHICH IS WHY I THINK PEOPLE HAVE MISCONSTRUED SOME OF THE DATA OUT THERE, MAYBE BECAUSE THE PEOPLE DELIVERING TALKS KIND OF TRY TO -- LEAVE THIS PART OUT BUT WE'RE TALKING ABOUT EFFECTS ONLY IMPORTANT WHEN YOUR DRUG LEVELS ARE LOW BUT WHERE THAT BECOMES IMPORTANT IN PrEP IS WHEN SOMEONE PULLS THE RING OUT OR DOESN'T TAKE GEL FOR A FEW DAYS, THEN IT'S GOING TO MATTER. SO IF YOU HAD YOUR CHOICE, I'D PICK A DRUG WHERE IT'S NOT GOING TO MATTER. YOU KNOW, WHERE THE MICROBIOME ISN'T GOING TO MAKE A DIFFERENCE. I'D USE A DRUG MOST FORGIVEN AND SO I WANT A DRUG THAT Ph DOESN'T MATTER, MICROBIOME DOESN'T MATTER, HAS A LONG INTRACELLULAR LIFE THAT DOESN'T BIND TO SEMEN AND EPITHELIAL CELLS, THAT'S WHAT I WOULD PICK. >> SO TO FOLLOW UP ON TRIPP'S QUESTION, AND I APOLOGIZE IF I MISSED THIS BUT I'VE BEEN WRESTLING WITH UNTIED AIRLINES WILL TRYING TO GET HOME THIS WEEK. >> I'M WITH YOU ON THAT ONE. >> YEAH. SO IT WOULD SEEM THAT WITH TOPICAL PROTECTIONS, THAT THE SITE OF ACTION WOULD BE TISSUE, NOT LUMEN, A DRUG LIKE TENOFOVIR WHERE THERE IS CELLS THAT TAKE IT UP AND ARE PROTECTED FROM REVERSE TRANSCRIPTION. SO WHAT DO YOU KNOW, AND SYSTEMICALLY IT COULD BE ANY OF THE SITES THAT YOU TAKE IT ORALLY, SYSTEMIC ACTIVITY, ALMOST ANYWHERE, IN LYMPHOID TISSUES, INCLUDING THE GENITAL TISSUES AND NEARBY NODES, BUT WHAT DO YOU KNOW ABOUT THE LEVELS OF THESE DRUGS IN TISSUES AS AFFECTED BY THE BUGS WHO YOU'RE ACCUSING OF BEING BAD GUYS? >> SO I'M NOT ACCUSING PARTICULAR BUGS OF BEING BAD DUGS, ALL BUGS CAN MODIFY SOME DRUGS. DATA FROM SHARON'S LOOK BACK AT THEIR CERVICAL BIOPSIES, SHARON HILLIARD'S DATA FROM FAME, A SMALL SAMPLE SIZE WAS LOOKING AT BIOPSIES, THERE WAS AN ASSOCIATION. BUT THE STUFF WE SHOWED IN TERMS OF OUR LAB, IN TERMS OF MECHANISM, DOESN'T HAVE THAT DATA. WE USE VAGINAL SWABS SO YOU'RE RIGHT BUT YOU HAVE TO REMEMBER YES WHEN YOU APPLY A GEL, A GOOD PROPORTION OF THE DRUG OR YOU PUT A RING IN, A GOOD PROPORTION OF THE DRUG GOES INTO THE CELLS. BUT THERE'S A LOT OF DRUG THAT'S NOT GOING INTO THE CELLS THAT IS HANGING OUT IN THE LUMEN. WHEN YOU PULL THE RING OUT OR AS TIME GOES BY, THAT'S WHY WE MEASURE VAGINAL LUMINAL DRUG, WE THINK OF THAT AS A RESERVOIR FOR THE CD4 CELL THAT MIGHT BE RECRUITED IN RESPONSE TO INFLAMMATORY THING, WHATEVER THAT INFLAMMATORY SIGNAL MIGHT BE, SO THAT DRUG IS IMPORTANT AS A RESERVOIR, IF THAT'S GOING TO BE BOUND OR TAKEN UP BY A BACTERIA OR MODIFIED OR BLOCKED IN ITS ABILITY TO BE TAKEN UP LUMINAL DRUG MATTERS. ALL OF THIS MATTERS, BUT YES, NEED TO BE. >> JUST TO FOLLOW UP ON THAT, THIS IS A LOT DIRECTED TOWARDS% YOU, BUT ANGELA'S WORK SHOWS CERTAIN DRUGS LIKE (INDISCERNIBLE) OR OTHER MEDICATIONS NOT USED FOR PrEP BUT USED FOR TREMENDOUS HIGH LEVELS IN CERVICAL VAGINAL TISSUES. I KNOW YOU WANT TO TALK ABOUT EX VIVO MODEL, BUT DRUGS THAT HAVE VERY HIGH CONCENTRATIONS THERE, YOU WOULD FAVOR AS DOING THE WORK THAT YOU DO. YOU WOULD FAVOR THOSE BECAUSE DYSBIOSIS, IF YOU THINK IT'S MECHANISM CHEWS IT UP WOULD BE TRUE OF ANY DRUG THAT'S MAYBE NOT INTRACELLULAR BUT GOES IN AND OUT OF CELLS BIKE DEPIVARINE, YOU FAVOR THOSE. >> ABSOLUTELY. THERE'S TWO LESSONS HERE. IT'S NOT LIKE ONE BAD GUY DRUG AND NOT LIKE ONE BAD GUY BACTERIA WHICH IS MAYBE THE WRONG MESSAGE. THE MESSAGE IS MICROBIOME IS A METABOLICALLY ACTIVE THING LIKE YOU'VE KNOWN ABOUT THE GUT BUT MAYBE IGNORED THE VAGINA THAT CAN MODIFY DRUGS. YOU'RE RIGHT. I WOULDN'T THROW TENOFOVIR AND PRO DRUGS IN THE SAME BASKET BECAUSE PRO DRUGS ARE VERY DIFFERENT BECAUSE THEY ARE NOT CHANGED -- BECAUSE THEY PASSIVELY DIFFUSE AND GET IN SO POTENTLY, AND WE DON'T YET HAVE DATA, THERE MAY BE DATA COME INCOME THE FUTURE, THAT SUGGESTS WE'RE REALLY CHANGING THE LEVEL OF (INDISCERNIBLE) OR WHATEVER ENZYMES YOU NEED TO MODIFY THEM, THOSE WILL BE FINE. ALSO THE NON-PRO DRUG FORM OF TENOFOVIR THAT'S AFFECTED BY A LOT OF THINGS, DRUGS NOT MODIFIED THAT DON'T HAVE A LONG INTRACELLULAR HALF-LIFE THAT WILL BE PROBLEMATIC. WHAT'S GOING ON WITH PROTEASE INHIBITORS, WITH INTEGRASE INHIBITORS, NO ONE HAS DONE THE STUDY. THERE'S A WHOLE STORY OF (INDISCERNIBLE), WHETHER IT GETS INTO CELLS, A SEPARATE ENTITY. YOU'RE RIGHT, WE WANT DRUGS I THINK THE MOST FORGIVING FOR THE REALITY OF HOW A PRODUCT CAN BE USED IN A REAL WORLD SETTING. >> JUST TO FOLLOW UP ON THAT, THE IMPLICATION IS TAF WOULD BE A MUCH BETTER PrEP DRUG, WHERE ARE WE IN TERMS OF CLINICAL TRIALS OF TAF AND PROBIOTIC AND PrEP. >> ORAL TAF MAY NOT BE GETTING INTO THE VAGINAL AREA WELL BUT IF YOU DON'T NEED IT AND YOU NEED IT IN LYMPH NODE IT MAY BE PHONE. AGAIN, WE HAVE SO -- SO MUCH WE DON'T KNOW. IT'S AMAZING, WE DO CLINICAL TRIALS ON THOUSANDS OF PEOPLE WITHOUT KNOWING WHAT WE'RE TALKING ABOUT. SO I DON'T THINK -- I'M NOT SURE THAT -- >> (INAUDIBLE). >> WE'RE ALL GUILTY. WE DO THE BEST WE CAN. THERE ARE QUESTIONS WE CAN GET ANSWERED. I DON'T KNOW THAT TAF IS SUPERIOR TO TDF AS TOPICAL DELIVERY BECAUSE TDF IN OUR HANDS LOOKED IDENTICAL. WE HAVE A TDF RING WE'VE DEVELOPED IN SECOND PHASE 1 STUDY. THERE'S NO TAF RING YET READY TO GO. THERE ARE PEOPLE WORKING ON TAF AS IMPLANT, AND THAT'S ALSO IN PRE-CLINICAL DEVELOPMENT, NOT CLINICAL DEVELOPMENT. I DON'T KNOW OF FORMULATIONS READY FOR THE CLINIC IN TERMS OF TOPICAL. >> THE DISCOVER TRIAL IS ENROLLING MEN AND TRANSGENDER WOMEN. >> ORAL. >> ORAL, CORRECT. >> I'D LIKE FOR A MINUTE TO SHIFT GEARS A LITTLE BIT. DURING RICK BUSHMAN'S -- AND I GUESS HE'S LEFT -- PRESENTATION, HE SPOKE SEVERAL TIMES ABOUT THE VIROME AND HOW THAT IS BEING AFFECTED. I WAS WONDERING FROM THE STANDPOINT GOING FORWARD, IS AS MUCH KNOWN ABOUT THE VIROME AT MUCOSAL SURFACES AS MICROBIOME? I KNEW THAT WAS THE ANSWER. AND BUT WITH THE LITTLE BIT THAT IS KNOWN, HOW UNIQUE OR DISSIMILAR IS IT IN TERMS OF THE TYPES OF QUESTIONS YOU'RE ANSWERING? WHAT CAN YOU TELL US ABOUT THE VIRAL THAT MIGHT BE IMPORTANT IN TERMS OF GENITAL TRACT OR THE GASTROINTESTINAL TRACT? >> THERE'S A LOT MORE DATA ON THE GASTROINTESTINAL TRACT. MUCH EASIER TO -- THE AMOUNT OF SAMPLE YOU GET IS A LOT BETTER, EASIER TO HANDLE WHEN YOU TRY TO LOOK FOR PARTICLES, YOU KNOW, VERY SMALL AND GENOME SIZE, BECAUSE MOST OF THOSE ANALYSIS ARE DONE BY -- NOT BY LOOKING FOR MARKER GENES, THEY ARE DONE BY EXTRACTING ALL THE DNA OR RNA OF THOSE SAMPLES AND SEQUENCING IT BY SHOTGUN TO GET TO -- THERE ARE SOME WAYS YOU CAN GET IT BUT MOSTLY IT'S (INAUDIBLE) SO IT'S VERY CHALLENGING AND ESPECIALLY IN THE VAGINA, WE'VE BEEN TRYING TO DO THIS AND THERE ARE VIRUSES THAT ATTACK, THAT TARGET THE HOST CELLS AND THERE ARE VIRUSES THAT TARGET THE BACTERIA AS WELL. SO THAT'S ANOTHER SET OF THE COMPLICATIONS. SO YOU CAN HAVE DYNAMIC POPULATION IN BACTERIA BECAUSE OF THE VIRUSES THAT ATTACK THE BACTERIA, AND YOU CAN HAVE ISSUES WITH MORE LIKE -- I MEAN IN A VAGINAL TRACT WE SEE HERPES AND, YOU KNOW, WE SEE THEM ALL WHEN WE SEQUENCE ALL THE GENE AND DNA. WHETHER IT HAS AN IMPACT ON ANYTHING, THERE'S LITERALLY NO DATA RIGHT NOW IN THE VAGINAL TRACT. STILL VERY MUCH AN EXPLORED AREA. >> THEORETICALLY IT'S POSSIBLE WITHIN FIVE YEARS THE VIROME MAY BE MUCH MORE IMPORTANT IN REGULATING INNATE IMMUNE SYSTEM THAN THE MICROBIOME, WHAT WE'RE MEASURING IS LOW-HANGING FRUIT. >> IT'S POSSIBLE. IN ITEMS OF ABUNDANCE THERE'S MORE BACTERIA, MANY LOGS OF BACTERIA. >> I DIDN'T REALIZE THAT. >> THEE IS A LITTLE BIT OF VIROME DATA IN DOUG KWAN'S RECENT IMMUNITY PAPER. IT DIDN'T SHOW A DIFFERENCE SO IT DIDN'T GET -- IT WAS ONLY THE ONE FIGURE THAT SHOWS UP, MORE IN SUPPLEMENTED, THAT'S ONE OF THE BETTER STUDIES THAT'S LOOKED AT IT. >> OUT OF INTEREST YOU MENTIONED HERPES. WHAT OTHER VIRUSES ARE IN THE VIROME COMMONLY? >> ALL THE OTHERS THAT WE FIND IS MOSTLY SO YOU SEE HPV, ALL THE KNOWN ONES. AND THE REST IS MOSTLY FOR BACTERIA. IT'S BACTERIA PHAGE. >> IN THE GUT IT'S (INDISCERNIBLE) CHARACTERIZED NOVEL FAMILY OF VIRUSES PEOPLE DON'T KNOW MUCH ABOUT. >> I THINK THAT WAS IN -- ALSO HAVE THE VAGINAL VIROME IN DOUG'S PAPER AS WELL. >> YEAH, THEY SEEMED TO BE ENRICHED IN GENERAL INFLAMMATION, AND ARE ACTUALLY VERY ABUNDANT IN HEALTHY HUMANS AS WELL BUT THERE'S VERY LITTLE KNOWN ABOUT THIS. >> I WANTED TO ASK A QUESTION ABOUT BREAST MILK IMMUNITY AND WE HAD A TALK ABOUT THE HMO HUMAN MILK OLIGOSACCHARIDES, IMPORTANT TO BREAK DOWN THE MICROBIOME TO LEAD TO DIGESTIBLE FOOD FOR THE INFANT, BUT DIDN'T TALK AS MUCH ABOUT THE IMMUNITY THAT'S CONFERRED BY BREAST MILK, SHE TALKED ABOUT PROTECTION FROM PATHOGENS AND THE GOOD -- NOT GOOD OR BAD BUT MICROBES THERE PROTECTING AGAINST PATHOGENS, IF YOU COULD TALK ABOUT THAT A LITTLE BIT. >> ACTUALLY I DON'T KNOW WHICH PATHOGENS IN THE BREAST MILK WOULD PROTECT. BUT OUR INTEREST, I'M LIKE FAIRLY NEW TO THE TOTAL AREA, I WORK WITH JOHN FLEECEMAN AND ACTUALLY MAUREEN, SO IT'S A STUDY BASICALLY FOLLOWING INFANTS FROM BIRTH TO 1 YEAR OF AGE, AND COLLECT SAMPLES FROM MOTHERS AND THE INFANT TO LOOK AT MICROBIOME COMPOSITION AND THE MOM, AND MOMS THAT EITHER EXCLUSIVELY COMMIT TO BREASTFEEDING FOR A SPECIFIED AMOUNT OF TIME AND LOOK AT THE STOOL FLORA IN THE INFANT AND WE HAVE A SEPARATE STUDY WHERE WE HAVE COLLECTED ORAL SWABS FROM INFANT THROUGHOUT THE FIRST YEAR OF LIFE AND WE WANT TO LOOK AT CHANGES IN THE MICROBIOME OVER TIME AND HOW THAT RELATES AND SO THEN THE QUESTION IS AT THE SAME TIME COLLECTING ALL THESE MICROBIOME SAMPLES VIA GETTING TINY BLOOD SAMPLES FROM THESE INFANTS, DR. FLEECEMAN'S LAB IS INTERESTING AND WE'RE MORE INTERESTED IN CD4. WHAT WE HOPE TO DO IN THE END IS SEE HOW IMMUNE FUNCTION CHANGES IN THE FIRST YEAR OF LIFE AND CAN BE CORRELATED WITH MICROBIOME DEVELOPMENT SO THAT'S LIKE THE BIGGER PICTURE AND IT'S DIFFICULT, YOU CAN GET ENOUGH BIOME SAMPLE BUT GETTING BLOOD SAMPLE FOR IMMUNE STUDIES IS FAIRLY DIFFICULT, THE VOLUMES ARE VERY, VERY SMALL. BUT I THINK BECAUSE WE JUST TALKED ABOUT INTERACTIONS BETWEEN BACTERIA AND VIRUSES, BEING INTERESTED IN BREAST MILK TRANSMISSION OF HIV I WANT TO EMPHASIZE AGAIN WE SHOULD NOT FORGET ABOUT THE IMPORTANCE OF HIV INFECTION IN INFANTS BECAUSE WE KNOW THE BIOME, THERE HAVE BEEN A FEW STUDIES, CAN HAVE AN IMPORTANT IMPACT ON THE KIND OF IMMUNITY THAT DEVELOPS. THERE HAVE ALSO BEEN STUDIES IN MACAQUES WHERE THEY COULD SHOW BREASTFED VERSUS NURSERY AT MACAQUES, THE BREASTFED MONKEYS ARE MORE Th17 RESPONSE OR MUCH BETTER INTEGRITY AND YOU COULD FIND BETTER DATA IF YOU LOOK 3 YEARS LATER. THE BIOME ESTABLISHED IN THE FIRST FEW MONTHS UP TO 2 YEARS THAT REALLY DICTATE KIND OF LIKE WHICH PATH YOU GO DOWN IN YOUR IMMUNE RESPONSE TO A BIG PORTION. AND RESOURCE POOR COUNTRIES A LOT OF THE INFANTS WILL BE BREASTFED OBVIOUSLY, THAT BREAST MILK EQUIVALENT, PROBABLY NOT, PROBABLY VERY DIFFERENT, AND THOSE MOMS ARE HIV INFECTED SO THEY HAVE INFLAMMATORY FACTORS BUT HE DON'T UNDERSTAND THE INFLAMMATION ITSELF, BUT THAT ALSO WILL IMPACT THE MICROBIOMES THAT WILL BE ESTABLISHED IN THE INFANT, AND WHAT ARE THE OUTCOMES, (INAUDIBLE) I THINK THERE ARE A LOT OF QUESTIONS THAT WE HAVEN'T ADDRESSED YET. AND THEN THERE WAS ONE TRULY DIFFERENT AREA, BUT I GOT INVOLVED IN PERIPHERALLY, BECAUSE I STARTED TO LOOK AT ORAL MUCOSA, IF YOU LOOK AT DENTAL DISEASE, SO WE TALK ABOUT THE GUT MICROBIOME, VAGINAL MICROBIOME, RECTAL MICROBIOME, , ORAL MICROBIOME IS FORGOTTEN, DENT HEALTH IS NOT INCLUDED IN PRIMARY CARE OF HIV-INFECTED PATIENTS. A DENTIST WHO WAS INSTRUMENTAL AND SHE HAS DONE WONDERFUL STUDIES WHERE SHE COULD SHOW ACTUALLY A PATIENT THAT HAS DENTAL DISEASE, THEIR ORAL FLORA IS DIFFERENT BECAUSE THEY HAVE INFLAMMATION, AND ONCE YOU START TREATING THOSE PATIENTS WITH ART, YOU KNOW INFECTIONS GO AWAY AND ORAL FLORA CHANGES AGAIN. WHY YOU HAVE INFECTION GOING YOU CAN SEE A DIRECT CORRELATION TO INCREASES IN HTV ACTIVATION, CLEAR INTERACTIONS BETWEEN THE DIFFERENT COMMUNITIES THAT WE UNDERSTAND VERY LITTLE ABOUT, AND THAT MIGHT BE INTERESTING TO FOLLOW UP IN THE GUT STUDY, WE HAVE ADOLESCENTS, AND THOSE ADOLESCENTS, TEENAGERS, ARE NORMALLY NOT AS CAREFUL WITH DENTAL HEALTH AND THEN AGAIN YOU HAVE THE PERIOD WHERE YOU HAVE THE ADOLESCENTS TRANSITIONING TO YOUNG ADULTS, THE PERIOD WHEN THEY FALL OUT OF MEDICAL CARE FROM THEIR PARENTS AND DON'T YET HAVE THEIR OWN MEDICAL CARE, THAT THEY WILL ALSO HAVE NO DENTAL CARE. THEY WILL BE CHANGING THE MICROBIOME. I THINK SOME OF THE QUESTIONS, I THINK IT WAS YOU, YOU BROUGHT UP LIKE HOW STABLE IS THE MICROBIOME, YOU KNOW, HOW OFTEN DOES IT CHANGE AND ARE THOSE CHANGES THAT ARE INDUCED, THAT WAS ONE OF THE QUESTIONS I WANTED TO THROW OUT, THROUGH AN INFECTION HOW TRANSIENT ARE THEY OR HOW INSTRUMENTAL ARE THEY TO INDUCE LONG-LASTING CHANGES, PROBABLY DIFFERENT ON PATHOGENESIS AND HOW LONG, THESE ARE ALL QUESTIONS WE REALLY DON'T UNDERSTAND YET AND WE'RE JUST STARTING TO RECOGNIZE. >> SO WE'VE TALKED A BIT ABOUT BACTERIAL SPECIES AND VIRAL SPECIES, WHAT DO WE KNOW ABOUT MUSHROOMS, PEOPLE LOOKING AT FUNGI AND YEAST AND THINGS LIKE THAT AT THESE SIDES? >> PROBABLY EVEN LESS. >> GO AHEAD. >> THERE ARE CLEARLY STUDIES LOOKING AT WHAT THE FUNGI LOOK LIKE. MORE OF THOSE HAVE COME OUT OF THE RESPIRATORY TRACT AND LUNGS THAN GENITAL TRACT. I DON'T KNOW ABOUT THE GUT. >> THERE HAVE BEEN FEW IN HIV LOOKING AT MICROBIOME. ONE CHALLENGE IS TO DISRUPT CELL WALLS, MORE DIFFICULT, TO LIBERATE THE DNA FOR SHOTGUN SEQUENCING IS MORE DIFFICULT, YOU HAVE TO DO THAT INTENTIONALLY IN ORDER TO GET THOSE DATA. SO THE CURRENT DATA SETS PROBABLY AREN'T SUITED TO LOOK AT THAT QUESTION AND I THINK PEOPLE WOULD HAVE TO DO THAT WITH THE INTENTION OF LOOKING AT THE MICROBIOME WHICH HASN'T BEEN DONE, TO MY KNOWLEDGE, FOR GUT. >> WE SHOWED A NUMBER OF YEARS AGO THAT CERVICAL VAGINAL SECRETION HAVE ANTI-CANDIDA ACTIVITY, SUSCEPTIBLE TO NATURALLY OCCURRING AND SECRETED ANTIMICROBIALS PRESENT IN THE GENITAL TRACT. I WANTED TO COME BACK TO A QUESTION TO JACQUES AND TO THE REST OF YOU. >> OBVIOUSLY THAT WORKS FOR SOME, BUT CERTAINLY IN PATIENTS WITH IMMUNE DEFICIENCIES AND DIABETES, IT'S INSUFFICIENT CONTROL CANDIDA. >> I AGREE. IN THE UNHEALTHY INDIVIDUAL. WE'RE TALKING ABOUT SECRETIONS FROM HEALTHY INDIVIDUALS. I THINK THAT THERE'S A MAJOR COMPROMISE AT ALL MUCOSAL SURFACES IN THE IMMUNE COMPROMISED INDIVIDUAL AND OTHERS. >> THE IMPORTANCE OF THOSE INNATE DEFENSES, I'M HEARKENING BACK TO SOME EXPERIMENTS WE DID A MILLION YEARS AGO WHEN OUR PATIENTS HAD MUCOSAL CANDEDIASIS, WE WORRIED WHETHER THAT REFLECTED IMPAIRMENT IN T CELL DEFENSES AGAINST MUCOSAL CANDEDIASIS BECAUSE PEOPLE WITH T CELL IMMUNE DEFICIENCIES ARE AT RISK FOR IT AND TO OUR SURPRISE IT'S SYSTEMIC CD4 T-CELL RESPONSES TO CANDIDA ANTIGENS ARE ONLY ENHANCED IN PERSONS WITH MUCOSAL CANDEDIASIS SUGGESTING ANOTHER MUCOSAL LESION. >> I THINK THAT HIGHLIGHTS WHY IT WOULD BE IMPORTANT TO LOOK AT THE MICROBIOME IN HIV BECAUSE PEOPLE SUCCUMBED TO OPPORTUNISTIC INFECTION FROM FUNGI, THERE COULD BE ENRICHMENT FOR THE CLINICAL SIGNS ARE APPARENT AND THEY COULD BE STIMULATING INFLAMMATION SO I DEFINITELY AGREE FOR THE RECORD THAT THAT SHOULD BE INVESTIGATED. >> FOR THE RECORD. >> WE'VE LOOKED AT THE ASSOCIATION BETWEEN EVEN THE PRESENCE OF CANDIDA WHICH 20% OF ALL WOMEN BASICALLY CARRY CANDIDA ALBICANS OR ANOTHER. AND ANY FEATURE OF THE MICTROBIOTA, IT'S NOT REALLY THE -- THE CARRIAGE IS NOT ASSOCIATED WITH MICTROBIOTA TYPE. OKAY? BUT WHAT'S INTERESTING IS THAT WHEN WE FOLLOWED THOSE WOMEN OBVIOUSLY SOME DEVELOPED CANDIADIIASIS, LIKE A MOVIE WE CAN ROLL THE TAPE, WHAT WAS IT BEFORE. AGAIN, THERE'S NO FEATURES WHEN YOU LOOK AT LET'S SAY SPECIES LEVELS, (INDISCERNIBLE) ASSOCIATED WITH NO DEVELOPMENT OF CANDIDA. THAT'S NOT THE CASE. IT'S STRAIN SPECIFIC. THERE ARE STRAINS OF CRISPATUS REALLY GOOD AT KILLING CANDIDA AND THERE ARE STRAINS OF CRISPATUS THAT DON'T DO ANYTHING. FEATURES THAT ARE MORE ANTI-FUNGAL ARE VERY STRAIN SPECIFIC. I THINK THAT'S GOING TO BE A FEATURE FOR CONTROLLING CANDIDA, FOR CONTROLLING BV ASSOCIATED ORGANISM, IT'S A FEATURE THAT ALL THE METHODS WE USE SPECIFICALLY MISS BECAUSE WE DON'T GO DEEP ENOUGH INTO THE CHARACTERIZATION. >> THE QUESTION I WANTED TO ASK WAS YOU SHOWED US VERY ELEGANT FINDINGS OF THE CORRELATION BETWEEN THE MICROBIOME AND THE PENIS, AND IN THE VAGINA. HAVE YOU OR ANYBODY LOOKED AT THE MICROBIOME IN THE INTESTINAL RECTAL TRACT OF THESE WOMEN AND COMPARED IT TO WHAT IS PRESENT IN THE VAGINA? DOES IT CHANGE DURING THE MENSTRUAL CYCLE AND IS THIS TRANSFERABLE? IT'S A REAL PROBLEM GIVEN SOME OF THE EVIDENCE, CLEAR EVIDENCE, THAT SHARON HILLIER SHARED WITH US ABOUT DIFFERENT PATHWAYS OF ENTRY IN SEXUAL ACTIVITY, SOMETIMES IT'S JUST VAGINAL. IN ANY SINGLE ACT SOMETIMES IT'S VAGINAL, THEN RECTAL. FRONT DOOR, BACK DOOR, OTHER TIMES BACK DOOR, FRONT DOOR. I'M WONDERIN DO THE BUGS KNOW WHAT'S GOING ON? >> I DON'T KNOW OF ANY STUDIES THAT FOLLOWED VAGINAL AND RECTAL OR EVEN INTESTINAL, AT A RESOLUTION THAT WILL ALLOW YOU TO SEE THIS KIND OF THING. >> YEAH. SO THERE ARE PEOPLE THAT ARE STARTING TO LOOK AT THAT, A COUPLE STUDIES THAT LOOKED AT BOTH THE ORAL MICROBIOME, VAGINAL MICROBIOME AND RECTAL MICROBIOME CURRENTLY OUT THERE SMALL SAMPLE NUMBERS WITH CORRELATION BETWEEN THOSE. LARGE STUDIES HAVEN'T BEEN DONE. I WOULD BE SURPRISED IF THEY DON'T MOVE IT TOGETHER IN CERTAIN TRENDS. I WANT TO MAKE A COMMENT ON YOUR COMMENT BECAUSE IT'S ANOTHER ONE OF THOSE THINGS THAT, YOU KNOW, YES RECEPTIVE AGE INTERCOURSE OH COURSE BUT PRIMARY IS VAGINAL, IMPORTANT TO UNDERSTAND BECAUSE THERE'S A LOT OF RUMOR. >> WHETHER THE MICROBIOME IS WHAT WE'RE LEARNING FROM THE REAR DOOR MAY INCREASE INCREASE SUSCEPTIBILITY TO FRONT DOOR. >> YOU RARELY SEE - - (INDISCERNIBLE) EVEN LACTOBACILLUS, THERE'S A SITE SPECIFICITY IN TERMS OF WHAT MICROBES CAN COLONIZE OR ARE EXCLUDED. >> YOU LOOK FOR ENTEROBACTEERI AND E. COLI. THERE ARE VERY FEW. IF YOU LOOK AT PEOPLE, IN THE VAGINA THERE'S VERY LITTLE THERE. WE SUGGESTED SOME REFLECTS VAGINAL SECRETION, ANTIMICROBIAL PEPTIDES, THAT HELPS KEEP IT OUT. >> PH 3.5 WILL DO THAT. PH OF 3.5 WILL DO THAT, KEEPING E. COLI OUT. >> I FEEL COMPELLED TO MAKE A COMMENT, GIVEN WE HAVE THE EMINENT MINDS OF OUR FIELD HERE, ABOUT THE GUT MICROBIOME AND HIV. DR. BUSHMAN SHOWED, AND I AGREE WITH HIM, THAT IT WAS REALLY IMPORTANT, THE STUDIES THAT LOOKED AT MSM VERSUS HETEROSEXUAL MEN IN TERMS OF GUT MIKE MOMENT. PREVOTELLA IS INCREASED. TWO STUDIES LOOKED AT MSM VERSUS HETEROSEXUAL. MOST ENRICHED AS DR. BUSHMAN SAID IS PREVOTELLA SIGNATURE. HAVE HAVE BEEN STUDIES LOOKING AT HIV-INFECTED INFECTED INDIVIDUALS, COMPARED TO UNINFECTED, IN WHICH THE CONTROLS HAVE BEEN MSM, CONTROLLED FOR MSM AND THOSE STUDIES AS ONE WOULD PREDICT DO NOT SHOW AN INCREASE OF PREVOTELLA BUT SHOW DIFFERENCES CONSISTENT IN PROTEOBACTERIALA BEING ENRICHED AND DEPLETION OF CLOSTRIDIA MEMBERS, PRODUCING THE ENERGY SOURCE FOR CLONOCYTES AND PRODUCE T-REGS. THERE'S A CONSISTENT DIFFERENCE IN THE HIV-ASSOCIATED GUT MICROBIOME THAT IS INDEPENDENT OF LIFESTYLE AND SEXUAL PRACTICE. YEAH. YEAH, YEAH, YEAH. THESE TRENDS SEEM TO BE CONSISTENT IN STUDIES WHERE PROPERLY CONTROLLED. IT'S KIND OF A POINT OF TENSION BETWEEN THE FOLKS THAT STUDY NON-HUMAN PRIMATES AND HUMAN RESEARCHERS BECAUSE IT'S BEEN SHOWN SEVERAL TIMES THAT NON-HUMAN PRIMATES DO NOT GET CHANGES IN THE MICROBIOME AS A RESULT OF OF SIV INFECTION, THERE MIGHT BE SOMETHING CONFOUNDING THEM BUT I THINK IT'S RELATIVELY CLEAR THAT THERE ARE EFFECTS, INDEPENDENT OF LIFESTYLE AND SEXUAL PRACTICE ASSOCIATED WITH HIV INFECTION IN THE GUT MICROBIME. >> THIS IS FAR TOO COMPLICATED FOR ME TO UNDERSTAND. AND I THINK THAT FROM WHERE I GLEANED FROM THE LITERATURE, JUST -- THERE'S SUCH VARIABILITY IN THE WAY WE LIVE AND WHAT WE EAT, AND THOSE WITH WHOM WE INTERACT, THAT IT'S GOING TO BE A WHILE BEFORE PEOPLE ARE GOING TO BE ABLE TO SORT OUT HOW THESE THINGS INDEPENDENTLY OR THESE BUGS INDEPENDENTLY DO WHAT THEY ARE SUPPOSED TO DO. RICK WAS SAYING HE WAS GOING TO DO -- HE WAS SAYING HIS LAB AND COLLEAGUES IN PHILADELPHIA WERE GOING TO BE APPLYING A VARIETY OF DIFFERENT READOUTS TO SEE IF INDIVIDUAL BUGS DID INTERESTING THINGS AND NOT JUST VIRAL REPLICATION BUT A WHOLE ARRAY OF HUMAN CELL OUTCOMES, SO I THINK THOSE COULD BE PRETTY INFORMATIVE IF HE GETS A GOOD HIT. AND THEN APPLYING THE THINGS THAT YOU'RE DOING TO QUANTIFY SOME OF THESE CHARACTERS, AND SEEING HOW THEY AFFECT SYSTEMIC AND MUCOSAL RESPONSES WILL BE PRETTY EXCITING, BUT I THINK YOU'RE GOING TO BE ABLE TO FEED YOURSELF FOR A LONG TIME ON THE CARRY-IN OF THE MICROBIOME. I MEAN, MAYBE I -- IT'S A FERTILE PLACE FOR WORK. IT'S GOING TO TAKE A WHILE TO SORT IT OUT. MAYBE THAT WAS THE WRONG WORD. I'M SORRY. >> TO FOLLOW UP, I LISTENED TO SOME OF THE TALKS, I WANTED TO ASK AND PROVOKE WOULD IT BE BETTER IF WE STUDY METABOLOMICS AND LOOK AT COMMON PRODUCTS OF THE BACTERIA, WOULD THAT BE -- I MEAN I'M NOT SURE IT WOULD BE EASIER BECAUSE METABOLOMICS ISN'T THAT EASY EITHER. BUT WOULD THAT GIVE US LIKE A MORE STRAIGHTFORWARD ANSWER, BECAUSE DIFFERENT BUGS MAY INTRODUCE THE SAME DAMAGING BYPRODUCTS OR BENEFICIAL PRODUCTS THAT MAY INFLUENCE DISEASE OUTCOME OR NOT. AND I WANTED TO HEAR FROM THE PEOPLE THAT HAVE BEEN WORKING IN THIS AREA LONGER IF THEY SEE THIS AS A POSSIBLE ROUTE AND THEN IF YOU SEE ALWAYS LIKE SIMILAR BYPRODUCTS LIKE BUTERATE OR FATTY ACIDS COMING BACK AND SEE IF THOSE ARE ASSOCIATED WITH SPECIFIC MICROBES. >> I CAN SPEAK FOR THE GUT. I KNOW IN THE VAGINAL TRACT NOW, THAT'S BASICALLY GOING TO BECOME THE NORM. THE COST IS COMING DOWN BECAUSE RIGHT NOW IT'S REALLY DIFFICULT TO DO THOSE STUDIES WELL POWERED BECAUSE IT'S PRETTY EXPENSIVE TO CHARACTERIZE ONE SAMPLE WITH, YOU KNOW, BOTH THE COMPOSITION, THE GENE, THE GENES ARE EXPRESSED AND METABOLOME AND SO THAT'S - THERE'S A COST ASSOCIATED WITH THAT BUT IT IS BECOMING THE NORM. IT IS LESS BIASED, AND A LOT OF THE WAYS WE'VE BEEN DOING IT, IT BRINGS SO MUCH MORE INFLAMMATION. BUT A LOT OF STUDIES EVEN THOSE DONE WITH GENE SEQUENCING I WOULD SAY 80% ARE UNDER POWER TO DO ANYTHING BUT WHAT THEY HAVE BEEN REPORTING IS A LOT OF BACKGROUND AND SO, YOU KNOW, A LOT OF STUDIES HAVE TO BE TAKEN A LITTLE -- LOOK WITH THAT EYE THAT IT'S -- THE POWER IS LOW. AND WE NEED TO DO STUDIES WITH MUCH LARGER SUBJECT ENROLLED. WE JUST -- IT'S A SAMPLING, ALL THE STUDIES, ALL THE METHODS ARE SAMPLING METHODS AND WE ARE SAMPLING POPULATION, THAT CREATES A LOT OF ISSUES. BUT THAT'S BECOMING THE NORM NOW. THAT'S SPECIFICALLY WHAT WE DO ON HUNDREDS IF NOT THOUSANDS OF SAMPLES. >> JUST TO FOLLOW UP WITH AN EXAMPLE FROM THE PART WHERE WE SHOWED GARDNERELLA SEEMED TO BE SECRETING ADENINE INTO THE ENVIRONMENT AND ADENINE WAS BLOCKING TENOFOVIR UPTAKE, OTHER BACTERIAL CULTURES LOOKED LIKE THEY WERE BLOCKING TENOFOVIR, WE MEASURED HOW MUCH ADENINE THEY ARE RELEASING, HIGH ONES ARE BLOCKING, LOW ONES ARE KNOCK, UNCOVERING A PATHWAY. NOW ASK THE QUESTION WHAT ELSE IS ADENINE DOING AND ONE IS WHY ONE BACTERIA SPITTING IT OUT AND THE OTHER EATING IT UP. I DON'T THINK YOU CAN JUST SAY WE'RE GOING TO ONLY LOOK AT METABOLOME. WE NEED ALL OF THIS BUT I THINK THE MOST IMPORTANT THING IS WE NEED MECHANISTIC DATA BECAUSE IF ALL WE HAVE IS DESCRIPTIONS OF THIS BACTERIA ASSOCIATED WITH X, Y OR Z AND THIS NOT WE'LL BE LESS LIKELY TO BE SUCCESSFUL AT MANIPULATING THE SYSTEM TO MAKE PEOPLE HEALTHIER, THAT'S WHAT WE WANT TO DO AT THE END. >> ONE OF THE BIG PROBLEMS, TO FOLLOW ON THIS, TO GO MECHANISTIC WE SEE THINGS IN HUMANS, NOT ALWAYS, WE TAKE IT OUT OF HUMAN AND BRING IT BACK INTO THE LAB. CELL LINE, FOR EXAMPLE, THAT DON'T PRODUCE MUCUS OR THEY ARE NOT EVEN -- YOU KNOW, JUST INDIVIDUAL CELLS, THEY DON'T HAVE ANY STRUCTURE, AND I THINK WE TRIED, WE START MAKING INFERENCE THERE THOSE DATA THAT JUST DON'T GO BACK INTO THE HUMAN. WE NEED TO BE CAREFUL WHEN WE DO THOSE KIND OF THINGS. JUST AS A REMINER, IF WE STUDY VAGINAL MICROBIOTA THERE'S NO ANIMAL WE KNOW OF THAT HAS -- THAT CARRY MICTROBIOTA THAT LOOK LIKE HUMAN. LACTOBACILLUS IS AN ORGANISM THAT COLONIZED HUMAN VAGINA, WE DON'T SEE THAT IN ANIMALS. IT'S HARD TO TAKE OUR FINDING AND GO BACK INTO ANIMAL AND TEST ANY HYPOTHESES. SO WE STILL STUDY IN HUMAN, THAT'S REALLY STILL THE BEST MODEL WE HAVE AND THE MOST RELEVANT. >> METABOLOMEIC AND MECHANISTIC LINES, ONE OF THE THINGS THAT I JUST FOUND FASCINATING IN THE FIELD AND WAS MENTIONED EARLIER IS THE TRIMETHYL AMINE OXIDE STORY OF CARDIOVASCULAR DISEASE. I'LL ASK TWO QUESTIONS SINCE YOU'RE HERE. ONE IS THE CHANGE OR ALTERATION OF THE MICROBIOME THAT PROMOTES THAT, AND SECONDLY HOW SHOULD I CHANGE MY DIET TO AVOID IT? [LAUGHTER] >> RED MEAT. >> WITH A GOOD WINE. [LAUGHTER] >> THE INCREASE IN CARNATINE BUT I DON'T KNOW BACTERIAL WISE BUT RED MEAT WAS THE CARNITINE WITH THE PRODUCT ASSOCIATED. >> THE PRECISE BACTERIA THAT PERFORMED THOSE FUNCTIONS ARE NOT TOTALLY UNDERSTOOD. THERE'S SEVERAL FAMILIES OF LIASES THAT CAN CATALYZE CONVERSION OF CHOLINE AND CARNITINE BUT THEY WEREN'T PRECISELY IDENTIFIED IN THOSE STUDIES. AND WITH REGARDS TO HIV, I BELIEVE, I SWEAR I JUST READ AN ABSTRACT, I THINK THERE WAS NOT A SIGNIFICANT DIFFERENCE IN TAM LEVEL AT LEAST IN HIV IN PERIPHERAL BLOOD PLASMA. YEAH. >> AS LONG AS WE HAVE A DISCUSSION, I CAN BRING UP ANOTHER QUESTION BECAUSE THIS IS THE NIH. IT'S ALSO QUITE OBVIOUS WHEN YOU READ ABOUT THESE STUDIES OR IF YOU TRY TO DO IT YOURSELF THAT THERE'S REALLY -- THERE'S NOT ONLY A CERTAIN LEVEL OF EXPERTISE NEEDED, THAT IS NOT EASY TO GAIN. THERE'S A CERTAIN COST INVOLVED WITH IT, AND THEN IF YOU WANT TO ADD METABOLOMICS YOU NEED ANOTHER EXPERTISE, MORE INSTRUMENTATION AND MORE COST. AND THEN AT THE VERY END HAVE ALL THE BIOINFORMATICS TO DO THE ANALYSIS. I THINK IF WE WANT TO MOVE FORWARD IN THE FIELD WHAT IS ALSO NEEDED IS THAT MAYBE THAT THERE ARE REALLY SOME STANDARDIZED TOOLS LIKE WE THOUGHT BIT IN THE FIRST TALK, STANDARDIZING HOW TO COLLECTING SAMPLES, AND SHOULD WE HAVE LIKE -- I'M NOT REALLY PROMOTING AS AN INDIVIDUAL INVESTIGATOR HAVING MORE HUGE CENTERS WHERE PEOPLE GET EVERYTHING, BUT FOR CERTAIN THINGS I THINK IT'S REALLY IMPORTANT TO HAVE LIKE EXPERT ANALYZING, THE ONES THAT CAN REALLY WORK WITH THE DATA AND CAN INTERPRET THEM IN THE CORRECT WAY. AND MAKE THOSE TOOLS AVAILABLE AND JUST LIKE WE HAVE OTHER NIH-SPONSORED SOURCES THAT PROVIDE FREE AGENTS OR OTHER SURFACES, COULD BE SURFACE CREATED WHERE PEOPLE SEND SAMPLES SO WE DON'T HAVE SMALL SCALE STUDIES YOU KNOW WHERE THIS GROUP HAD SIX HUMAN, OR 20 HUMANS AND THIS GROUP HAD SIX MACAQUES AND NOW THEY WANT TO INTERPRET THE DATA WHICH REALLY DOESN'T MAKE ANY SENSE BUT LIKE REALLY COLLECTING LARGER DATASETS AND THEN PERFORM A MORE USEFUL ANALYSIS THAT WILL ACTUALLY PROVIDE THE COMMUNITY THIS DATA AND THEN GENERATE HYPOTHESIS THAT PEOPLE CAN WORK ON. JUST AN IDEA. >> ACTUALLY MY QUESTION WAS TWO-FOLD. ONE, WHAT ARE THE AVAILABLE NET MODELS IN WHICH ALL THESE THINGS CAN ACTUALLY BE TESTED IN A RATIONAL WAY, AND SECOND, IT WASN'T REALLY CLEAR TO ME WHETHER THE VAGINAL CAVITY WAS SEEDED FIRST AND WHERE EXACTLY THE BACTERIA COME FROM AND WHAT HAPPENS TO THE G.I. AT THE SAME TIME IN THOSE BABIES WHEN THEY ARE FIRST BORN. >> I DIDN'T REALLY GET YOUR FIRST QUESTION BUT I CAN ANSWER THE SECOND ONE. YOU'RE REFERRING TO WHAT LITA PROCTOR PRESENTED. >> REFERRING TO YOUR PRESENTATION. >> OH. >> FROM THE VAGINA, SO WE'VE DONE A STUDY WHERE WE LOOKED AT BABIES, PAIRED WITH THEIR MOMS. THEY GET VAGINAL MICROBE FROM THE MOM AT LEAST FOR VAGINAL DELIVERY. THAT'S WHERE THEY GET IT. THERE'S NO REAL STUDIES, I MEAN THERE ARE STUDIES THAT SHOW THERE'S LACTOBACILLUS BUT THERE'S ACTUALLY NO STUDIES THAT HAVE SHOWN THAT MATERNAL TRANSMISSION DOES EXIST. THERE'S A LOT OF -- THERE'S STUDIES FOR EXAMPLE WHAT LITA PRESENTED, THIS IS ONE HOUR AFTER BIRTH, I SAY IF THEY HAD DUNKED THE BABY IN SOUP THEY WOULD HAVE FOUND SOUP, ONE OUR OUR SIX HOURS, WE DON'T KNOW. THERE'S NO AFFIRMATIVE STUDY THAT SAYS THE MICROBE GOES FROM THE MOM TO BABY AND COLONIZED INTESTINE, FOR EXAMPLE. AND IT'S VERY UNLIKELY THAT VAGINAL MICROBES DO COLONIZE THE INTESTINE. JUST LIKE WE NEVER FIND THEM IN THE VAGINA, YOU DON'T FIND THEM IN THE BABY, MECONIUM OR STOOL A COUPLE DAYS LATER. WHERE DO THEY GET PICKED UP? IT'S STILL A BIG QUESTION. THERE'S A LOT OF CONTACT WITH THE PARENTS AND THEY ARE IN AN ENVIRONMENT FULL OF MICROBES AND THEN THE BODY SITES ITSELF IS GOING TO BE SELECTING FOR THOSE, BUT THIS IS STILL BIG UNKNOWN, VERTICAL TRANSMISSION OF MICROBES. >> AND JUST IN TERMS OF YOUR FIRST QUESTION, I MEAN, THE SIMPLE ANSWER IS THERE PROBABLY IS NO MODEL AND HUMANS ARE REALLY GOOD MODEL, BUT SOMETIMES MORE DIFFICULT TO WORK WITH. I MEAN I THINK THE OTHER APPROACH YOU'RE WELL AWARE OF IS THINGS LIKE USING GERM-FREE MICE AND RECONSTITUTING THEM WITH SPECIFIC BACTERIAL SPECIES AND TESTING YOUR HYPOTHESIS, THAT'S GREAT AS LONG AS YOU UNDERSTAND THAT IT'S HYPOTHESIS GENERATING BUT YOU HAVE TO GO BACK TO THE HUMANS. PEOPLE TRIED TO USE NON-HUMAN PRIMATES AND THEIR MICROBIOME IS QUITE DIFFERENT. GIVEN THE COST OF USING THEM THINK IN MANY RESPECTS SOME OF THESE GERM-FREE MICE AT LEAST ALLOW YOU TO ASK MECHANISTIC QUESTIONS AND TRY TO GO VALIDATE THAT IN YOUR CLINICAL TRIAL. I DON'T THINK WE HAVE A LOT OF GREAT TOOLS OTHERWISE. >> I THINK YOU MADE A VERY GOOD POINT. I'M NOT SURE I AGREE WITH THE FACT HUMANS ARE A GOOD TEST MODEL BECAUSE EVERYONE IS DIFFERENT. AND IN ESSENCE TO BE ABLE TO EXPERIMENTALLY APPROVE A POINT LIKE THIS, EFFECT IN TRANSMISSION OR EFFECT ON PREVENTION IS GOING TO BE REALLY DIFFICULT. >> WE NEED A LARGE SAMPLE SIZE AND CONTROL FOR AS MANY VARIABLES BUT AT THE END OF THE DAY IF WE WANT TO TALK ABOUT HUMAN DISEASE WE NEED TO USE HUMAN. >> FOLLOWING UP ON MATERNAL TRANSFER, NOT ONLY THE BIOTA BUT OTHER MICROBES WILL COLONIZE THE INFANT, THAT PLAYS A ROLE, AND THERE ARE DATA OUT THERE THAT HAVE COMPARED BREAST-FED VERSUS FORMULA-FED INFANTS AND SHOW THEIR COLONIZATION IS DIFFERENT. >> IT'S ACTUALLY THE MAJOR FACTOR THAT DRIVES THE TYPE OF MICROBIOTA YOU'LL SEE IN A BABY AT SIX MONTHS OLD. >> JUST TO COMMENT, IT JUST HIT ME ONE ASPECT WITH ALL THE EXCELLENT WORK WE'VE HEARD TODAY ABOUT MICROBIOME, THERE'S ONE ASPECT WE HAVEN'T TOUCHED ON, IT GOES TO THE ISSUE OF JACQUES, YOUR ONE SLIDE, WHERE THERE WAS A VERY STANDARD VAGINAL POPULATION OF BUGS, A WOMAN HAD SEX WITH A SINGLE MAN AND PROFILE COMPLETELY CHANGED, FOR FIVE OR SIX DAYS BUT THEN CAME BACK. I'M THINKING ABOUT THE SITUATION WHERE LACTOBACILLUS AND OTHER MICROORGANISMS ARE BEING USED GENETICALLY ENGINEERED TO DELIVER VAGINALLY CCR5, OTHERS ANTIMICROBIALS, AND NOW EVEN SOME OF THE MOST RECENT WORK THAT'S BEING DONE WITH DELIVERY OF VACCINE, VACCINES. FROM MY READING AND TELL ME IF I'M WRONG, ONE REAL PROBLEM HERE IS THAT WHATEVER BUG SEEMS TO BE USED, IT DOES NOT BECOME A RESIDENT POPULATION OF THE GENITAL TRACT. JUST LIKE THE PROBLEM. SO I THINK THE AREA THAT REALLY COULD USE SOME WORK WOULD BE NOT ONLY TO UNDERSTAND THE POPULATIONS OF BUGS THAT ARE IN THERE BUT THE ENVIRONMENT WITHIN WHICH THEY LIVE THAT DOES NOT PRECLUDE EVEN AN ORGANISM THAT IS VERY SIMILAR TO EXIST AND DO ITS JOBS. >> I MEAN, THIS IS THE BIG QUESTION. YOU KNOW, LIKE ALL THE PROBIOTICS, WHETHER NON-GENETICALLY MODIFIED OR GENETICALLY MODIFIED WOULD THEY BE ABLE TO COLONIZE? SOME STUDIES THAT "CELL" HAS DONE THAT SHOWS THERE'S SOME COLONIZATION, BUT THAT STRAIN THEY HAVE USED CTBO 5 THAT SHARON DEVELOPED, GOT MAYBE 50% COLONIZATION, SOMETIMES LEFT, BUT WE DON'T HAVE UNDERSTANDING WHY SOME WOMEN WERE COLONIZED, SOME OTHERS DIDN'T. I THINK THAT'S GOING TO BE THE KEY TO BE ABLE TO DEVELOP THOSE FORMULATIONS. BUT THERE'S ALSO THE APPROACH WHICH IS A LITTLE MORE -- IF YOU THINK ABOUT WHAT WE'VE LEARNED FROM FECAL TRANSPLANT AND WHAT COLONIZED, WHAT DOESN'T, THERE ARE WAYS TO DO THIS BECAUSE THE VAGINAL TRACT, WE THINK ONE ORGANISM, BECAUSE WE THINK THE FDA IS GOING TO LIKE IT BETTER, OR IT'S EASIER TO MANUFACTURE, BUT I THINK THERE ARE CONCOCTIONS OF ORGANISMS TO LET THE BODY DECIDE WHICH TO KEEP. THEY ARE ALL EQUALLY THERE. THERE'S A NATURAL SELECTION NO MATTER WHAT. SO LET'S TAKE ADVANTAGE OF THIS. BUT THERE'S STILL NO PRODUCT, NO SUCH PRODUCT ON THE MARKET OR NOT EVEN IN DEVELOPMENT. >> OKAY. THIS ACTUALLY IS THE TIME FOR PUBLIC COMMENTS, AND I'M GOING TO PAUSE FOR A MOMENT. I THINK THERE WEREN'T ANY PUBLIC COMMENTS SUBMITTED. SO THIS IS THE TIME TO ADJOURN, SO THANK YOU SO MUCH. WE FIRST HEARD AN OVERVIEW OF THE OAR, BY OUR DIRECTOR, DR. MAUREEN GOODENOW, FOLLOWED HAVE WITH HHS TREATMENT GUIDELINES BY DR. TRIPP GULIC AND HEZRRA, WORK ON MACROPHAGE INFECTION, IT NEEDS TO BE STUDIED MORE AND WE HEARD ABOUT LISTENING DAY, THAT WAS ORGANIZED FOR THE COMMUNITY BY OAR AND HOW WELL THAT WENT, AND THE REAL FOCUS IN OAR TO LISTEN TO THE COMMUNITY. WE THEN HEARD FROM THE NEW DEPUTY DIRECTOR OF THE OAR, DR. PETER KIM, ON THE NIH AIDS EXECUTIVE COMMITTEE AND THE FY 18 AND THEN 19 TRANS-NIH PLAN TO ENCOURAGE INVESTIGATORS AND COMMUNITY COMMENTS ON BOTH OF THOSE. WE HEARD AN UPDATE FROM THE NHBLI, FROM DR. DAVID GOFF AND DR. NAKILA AND LAUNCHED INTO THE VERY RICH DISCUSSION OF RICH MICROBIOME, THERE'S 4,000 BACTERIAL SPECIES AND THERE'S LIKE WAY MORE GENOME THAT'S BACTERIAL THAN HUMAN IN OUR OWN DNA AND IT WAS FASCINATING, THAT WAS FROM DR. LITA PROCTOR AND DR. RICK BUSHMAN WHO DISCUSSED IMPACT OF HIV IN THE MICROBIOME AND VICE VERSA AND JACQUES REVAL AND BETSY HAROLD AND HAD THIS DISCUSSION. SO THANK YOU SO MUCH. THIS CONCLUDES THE 44th OAR ADVISORY COMMITTEE, AND I HOPE EVERYONE HAS SAFE TRAVELS BACK. [APPLAUSE]