1 00:00:15,341 --> 00:00:19,545 THE BASIC PROGRAM HERE AT 2 00:00:19,545 --> 00:00:26,204 DADS AND WE'LL HEAR FROM REACH 3 00:00:26,204 --> 00:00:29,474 AND THE ACRONYM STANDS FOR 4 00:00:29,474 --> 00:00:31,743 RESEARCH ENTERPRISE TO ADVANCE 5 00:00:31,743 --> 00:00:33,512 THE CURATOR HIV. 6 00:00:33,512 --> 00:00:42,521 THE CO-P.I.s ARE BRAD JONES AT 7 00:00:42,521 --> 00:00:43,421 WEILL CORNELL AND BRAD IS IS 8 00:00:43,421 --> 00:00:44,923 GOING TO GIVE THE OVERVIEW SO 9 00:00:44,923 --> 00:00:50,328 NOW I WILL TURN IT OVER TO BRAD 10 00:00:50,328 --> 00:00:56,468 AND -- OH, MARINA IS GOING TO 11 00:00:56,468 --> 00:00:59,237 GIVE THE OVERVIEW. 12 00:00:59,237 --> 00:01:03,575 >> I'LL BRIEFLY INTRODUCE -- 13 00:01:03,575 --> 00:01:04,943 GOOD MORNING, EVERYONE. 14 00:01:04,943 --> 00:01:06,845 PLEASE COME IN. 15 00:01:06,845 --> 00:01:08,547 I'LL BRIEFLY INTRODUCE OUR 16 00:01:08,547 --> 00:01:08,880 COLLABORATORY. 17 00:01:08,880 --> 00:01:11,850 THE STRUCTURE OF OUR LEADERSHIP 18 00:01:11,850 --> 00:01:17,222 AS MENTIONED I CO-LEAD THIS WITH 19 00:01:17,222 --> 00:01:19,457 BRAD AND IN OUR EXECUTIVE 20 00:01:19,457 --> 00:01:21,893 COMMITTEE WE HAVE 21 00:01:21,893 --> 00:01:26,731 REPRESENTATIVES FROM THE THREE 22 00:01:26,731 --> 00:01:28,533 RX AND WE HAVE OUR PARTNERS AND 23 00:01:28,533 --> 00:01:30,569 OUR COMMUNITY ENGAGEMENT TEAM. 24 00:01:30,569 --> 00:01:33,972 THIS IS HAVE THE ORGANIZATION 25 00:01:33,972 --> 00:01:35,273 STRUCTURE OF OUR COLLABORATORY 26 00:01:35,273 --> 00:01:36,641 UNDER RF1. 27 00:01:36,641 --> 00:01:41,446 WE HAVE BEEN APPLYING DIFFERENT 28 00:01:41,446 --> 00:01:44,216 METHODS IN AN ATTEMPT TO DEFINE 29 00:01:44,216 --> 00:01:46,918 THE RELATIONSHIP BETWEEN HIV 30 00:01:46,918 --> 00:01:48,920 RESERVOIRS, T CELLS AND REBOUND 31 00:01:48,920 --> 00:01:49,321 VIRUSES. 32 00:01:49,321 --> 00:01:51,590 UNDER RF2 THE UNDER ARCHING GOAL 33 00:01:51,590 --> 00:01:54,192 IS TO HARNESS THE CELLS TO 34 00:01:54,192 --> 00:01:58,663 DIFFERENT IMMUNOLOGIC APPROACHES 35 00:01:58,663 --> 00:02:01,099 AND BUILD THE DISCOVERY TO 36 00:02:01,099 --> 00:02:02,801 TRANSLATION PIPELINE TRYING TO 37 00:02:02,801 --> 00:02:04,536 UNCOVER MECHANISMS AND IDENTIFY 38 00:02:04,536 --> 00:02:05,670 APPROACHES THAT CAN OVERCOME 39 00:02:05,670 --> 00:02:06,605 BARRIERS TO ELIMINATING 40 00:02:06,605 --> 00:02:09,507 RESERVOIRS. 41 00:02:09,507 --> 00:02:12,177 THIS PAST YEAR WE TRIED TO 42 00:02:12,177 --> 00:02:14,045 LEVERAGE THE FLEXIBILITY OF THIS 43 00:02:14,045 --> 00:02:16,014 GRANT MECHANISM AND WERE ABLE TO 44 00:02:16,014 --> 00:02:19,284 ALLOCATE FUNDS THAT ALLOWED US 45 00:02:19,284 --> 00:02:21,953 TO SUPPORT HIGH PRIORITY 46 00:02:21,953 --> 00:02:27,692 PROJECTS AND WE BROUGHT ON 47 00:02:27,692 --> 00:02:28,827 INVESTIGATORS AND FOR EXAMPLE WE 48 00:02:28,827 --> 00:02:31,696 WERE ABLE TO ALLOW MECHANISMS OF 49 00:02:31,696 --> 00:02:33,965 CONTROL THROUGH THE STUDIES 50 00:02:33,965 --> 00:02:34,733 CONDUCTED. 51 00:02:34,733 --> 00:02:38,336 WE HAVE SUPPORTED A SERIES OF 52 00:02:38,336 --> 00:02:39,437 PUBLICATIONS BUT PERHAPS WHAT 53 00:02:39,437 --> 00:02:41,973 WE'RE MOST PROUD OF IS WE HAVE 54 00:02:41,973 --> 00:02:47,078 ALSO TRIED TO FOSTER NEW 55 00:02:47,078 --> 00:02:48,780 COLLABORATIONS, BRING IN NEW 56 00:02:48,780 --> 00:02:50,015 INVESTIGATORS AND STRENGTHEN 57 00:02:50,015 --> 00:02:50,749 EXISTING COLLABORATORS. 58 00:02:50,749 --> 00:02:54,419 WHAT WE'RE TRYING TO ILLUSTRATE 59 00:02:54,419 --> 00:02:55,954 IS OUR PROGRESS OVER TIME IN 60 00:02:55,954 --> 00:02:56,921 BRINGING INVESTIGATORS TOGETHER. 61 00:02:56,921 --> 00:02:59,691 WHERE YOU SEE THE LINES BECOME 62 00:02:59,691 --> 00:03:03,061 THICKER AND THE KNOBS BECOME 63 00:03:03,061 --> 00:03:06,731 DARKER REPRESENTING THE 64 00:03:06,731 --> 00:03:10,168 DIFFERENT COLLABORATION. 65 00:03:10,168 --> 00:03:13,371 RF1 IS LED BY THESE PEOPLE AND A 66 00:03:13,371 --> 00:03:17,108 BIG COMPONENT IS OUR PARTNERSHIP 67 00:03:17,108 --> 00:03:19,644 WITH THE HEALTH SCIENCES 68 00:03:19,644 --> 00:03:20,245 PROGRAM. 69 00:03:20,245 --> 00:03:25,784 AS MANY KNOW UGANDA WAS THE 70 00:03:25,784 --> 00:03:29,554 EPICENTER OF THE HIV EPIDEMIC IN 71 00:03:29,554 --> 00:03:29,788 UGANDA. 72 00:03:29,788 --> 00:03:31,523 DESPITE ALL THE STRIDES MADE IN 73 00:03:31,523 --> 00:03:33,425 TERMS OF HIV TREATMENT AND 74 00:03:33,425 --> 00:03:35,060 PREVENTION STRATEGIES IT LEFT A 75 00:03:35,060 --> 00:03:36,528 LARGE POPULATION OF PEOPLE WITH 76 00:03:36,528 --> 00:03:38,029 HIV AND SIGNIFICANT SOCIAL 77 00:03:38,029 --> 00:03:38,396 BURDENS. 78 00:03:38,396 --> 00:03:40,131 SO TRYING TO BRING HIV CARE 79 00:03:40,131 --> 00:03:42,500 EFFORTS TO THE REGION HAS BEEN 80 00:03:42,500 --> 00:03:42,801 CHALLENGING. 81 00:03:42,801 --> 00:03:44,769 ONE OF THE CHALLENGES BEING THAT 82 00:03:44,769 --> 00:03:46,738 ONE COULD NOT RELY ON THE 83 00:03:46,738 --> 00:03:50,709 ORIGINAL IPDA. 84 00:03:50,709 --> 00:03:52,610 SO WE WORKED TO DEVELOP 85 00:03:52,610 --> 00:03:54,379 SUCCESSFULLY WERE ABLE TO 86 00:03:54,379 --> 00:03:56,815 DEVELOP THE NEW ADAPTED IPDA 87 00:03:56,815 --> 00:04:03,188 WITH NEW PRIMERS AND PROBES THAT 88 00:04:03,188 --> 00:04:03,355 FIT. 89 00:04:03,355 --> 00:04:08,226 THIS TOGETHER WITH RESEARCH 90 00:04:08,226 --> 00:04:10,495 FUNDED EQUIPMENT NOW SUPPORT 91 00:04:10,495 --> 00:04:13,631 RESEARCH TO HAPPEN ON SITE FOT 92 00:04:13,631 --> 00:04:15,700 ONLY BECAUSE OF THE EQUIPMENT 93 00:04:15,700 --> 00:04:17,769 BUT BECAUSE RESOURCES WENT INTO 94 00:04:17,769 --> 00:04:19,704 TRAINING OF DIFFERENT UGANDAN 95 00:04:19,704 --> 00:04:21,906 ADVOCATORS REALLY ABLE TO CARRY 96 00:04:21,906 --> 00:04:27,979 OUT RESERVOIR MEASUREMENTS IN 97 00:04:27,979 --> 00:04:29,247 PARALLEL WITH RESPONSE 98 00:04:29,247 --> 00:04:31,716 ASSESSMENTS LEVERAGING FROM 99 00:04:31,716 --> 00:04:35,253 THEIR COHORT AND IN ANOTHER AREA 100 00:04:35,253 --> 00:04:40,091 UNDER RF1 IS ADDRESSING THE 101 00:04:40,091 --> 00:04:41,960 QUESTION OF HOW IS HIV 102 00:04:41,960 --> 00:04:45,330 INTEGRATION AFFECTS PERSISTENCE 103 00:04:45,330 --> 00:04:48,633 BY DIFFERENT METHODS AND WORK 104 00:04:48,633 --> 00:04:50,468 CARRIED OUT AND YOU'LL HEAR MORE 105 00:04:50,468 --> 00:04:53,138 ABOUT THIS IN THE NEW TALKS. 106 00:04:53,138 --> 00:04:57,342 ONE SUCH METHODS COMES FROM THIS 107 00:04:57,342 --> 00:05:02,280 STRATEGY THAT WAS DEVELOP TO 108 00:05:02,280 --> 00:05:05,350 ISOLATE CD4 CELLS IN VIRUSES AND 109 00:05:05,350 --> 00:05:12,657 NOT ONLY ISOLATED BUT CAN BE 110 00:05:12,657 --> 00:05:16,027 EXPAN 111 00:05:16,027 --> 00:05:17,962 EXPANDED IN VITRO AND NOW 112 00:05:17,962 --> 00:05:20,532 THEY'VE BECOME VALUABLE TOOLS TO 113 00:05:20,532 --> 00:05:22,534 INVESTIGATE LATENCY AND TEST 114 00:05:22,534 --> 00:05:23,835 APPROACHES TO OVERCOME LATENCY 115 00:05:23,835 --> 00:05:26,871 AND TRY TO UNDERSTAND AND 116 00:05:26,871 --> 00:05:29,974 IMPROVE HOW IMMUNOLOGIC PRESSURE 117 00:05:29,974 --> 00:05:33,645 TO ELIMINATE RESERVOIRS. 118 00:05:33,645 --> 00:05:35,013 WE'RE TRYING DIFFERENT 119 00:05:35,013 --> 00:05:36,314 IMMUNOLOGIC APPROACHES. 120 00:05:36,314 --> 00:05:39,551 ONE OF THE THINGS WE INTEREST TO 121 00:05:39,551 --> 00:05:41,853 LEVERAGE IS THE VARIOUS BNAB 122 00:05:41,853 --> 00:05:45,457 STUDY WE CONDUCTED OR IN 123 00:05:45,457 --> 00:05:47,959 PROGRESS AND ASK HOW THE 124 00:05:47,959 --> 00:05:49,694 STRATEGY MAY INTERFERE WITH 125 00:05:49,694 --> 00:05:51,095 DYNAMICS AND PERHAPS MEDIATE 126 00:05:51,095 --> 00:05:51,796 CONTROL. 127 00:05:51,796 --> 00:05:55,366 ONE SUCH STUDY WAS THE STUDY 128 00:05:55,366 --> 00:06:00,672 YOU'RE ALL FAMILIAR WITH AND 129 00:06:00,672 --> 00:06:03,675 TESTED BNAB DOING ART 130 00:06:03,675 --> 00:06:03,975 INITIATION. 131 00:06:03,975 --> 00:06:05,810 IF YOU REMEMBER FROM THE 132 00:06:05,810 --> 00:06:09,514 PUBLICATION AMONG PARTICIPANTS 133 00:06:09,514 --> 00:06:11,316 WHO HAD BEEN WITH THE VIRUS FROM 134 00:06:11,316 --> 00:06:13,117 THE START OBSERVED IN BLUE IN 135 00:06:13,117 --> 00:06:15,687 THE GRAPH ARE OBSERVED THE DELAY 136 00:06:15,687 --> 00:06:17,956 IN REBOUND BUT ALSO THE BLUNTED 137 00:06:17,956 --> 00:06:20,225 VIRAL REBOUND CURVES. 138 00:06:20,225 --> 00:06:21,593 THIS ALSO INCLUDED ONE 139 00:06:21,593 --> 00:06:25,997 PARTICIPANT WHO MAINTAINED FULL 140 00:06:25,997 --> 00:06:30,635 VIRUS SUPPRESSION OVER FOUR 141 00:06:30,635 --> 00:06:31,603 YEARS NOW. 142 00:06:31,603 --> 00:06:33,972 THEY KNOW THE RESERVOIR IS 143 00:06:33,972 --> 00:06:37,342 DYNAMIC AND INDUCIBLE. 144 00:06:37,342 --> 00:06:38,910 INTERESTINGLY OVER TIME HAS 145 00:06:38,910 --> 00:06:41,746 HIGHER PROPORTIONS OF THE VIRUS 146 00:06:41,746 --> 00:06:44,682 IN THE HETEROCHROMATIN REGIONS 147 00:06:44,682 --> 00:06:48,052 AND HAS POTENT CD 8 T CELLS. 148 00:06:48,052 --> 00:06:50,688 TRYING TO UNDERSTAND CTL 149 00:06:50,688 --> 00:06:54,192 PRESSURE SPECIFICALLY IN THIS 150 00:06:54,192 --> 00:06:57,962 PARTICIPANT WHAT HE DID USING 151 00:06:57,962 --> 00:07:03,768 THE MODELS HE HAD HE USED 152 00:07:03,768 --> 00:07:06,604 SAMPLES AND TRANSFERRED INTO THE 153 00:07:06,604 --> 00:07:11,309 MOUSE MODEL WHICH WAS FOLLOWED 154 00:07:11,309 --> 00:07:13,444 BY REBOUND HERE IN THE GRAPH. 155 00:07:13,444 --> 00:07:15,179 HE WAS ABLE TO THEN ISOLATE THE 156 00:07:15,179 --> 00:07:17,649 REBOUND VIRUSES AND TRANSFER TO 157 00:07:17,649 --> 00:07:18,516 NEW MICE. 158 00:07:18,516 --> 00:07:21,953 WHAT THIS GRAPH SHOWS WITHOUT 159 00:07:21,953 --> 00:07:28,593 ANY CD8 PRESSURE THE VIRUS GOES 160 00:07:28,593 --> 00:07:30,461 UP AND HERE THE VIRUS IS IN BLUE 161 00:07:30,461 --> 00:07:33,998 AND RISES AND STAYS UP AND AT 162 00:07:33,998 --> 00:07:38,369 THE SAME TIME WHEN CD 8 T CELLS 163 00:07:38,369 --> 00:07:43,241 ARE TRANSFERRED THERE'S A RISE 164 00:07:43,241 --> 00:07:49,147 LEEKED TO A SIGNIFICANT EXTENT 165 00:07:49,147 --> 00:07:53,017 AND SHOWS THE PRESSURE THE T 166 00:07:53,017 --> 00:07:56,054 CELLS HAVE PUTTING ON AND WE CAN 167 00:07:56,054 --> 00:08:03,861 DO THESE TYPES OF INTERVENTIONS. 168 00:08:03,861 --> 00:08:09,601 HERE THE IDEA IS THROUGH A 169 00:08:09,601 --> 00:08:17,976 SERIES OF DIFFERENT METHODS TO 170 00:08:17,976 --> 00:08:20,211 HAVE CD 8 T CELL KILLING AROUND 171 00:08:20,211 --> 00:08:21,980 HERE'S THE MOLECULES IDENTIFIED 172 00:08:21,980 --> 00:08:23,915 WITH POTENTIAL TO DO SO AND BRAD 173 00:08:23,915 --> 00:08:26,351 WILL TALK MORE ABOUT THE 174 00:08:26,351 --> 00:08:29,587 INHIBITOR AND HOW IT HAS BEEN 175 00:08:29,587 --> 00:08:32,991 SHOWN AT LEAST IN VIVO MODELS TO 176 00:08:32,991 --> 00:08:34,959 ENHANCE CTL KILL. 177 00:08:34,959 --> 00:08:36,628 WITH THAT I'LL PASS IT OVER TO 178 00:08:36,628 --> 00:08:44,569 JESSICA. 179 00:08:44,569 --> 00:08:46,237 >> I'M GO TO GO OVER QUICKLY 180 00:08:46,237 --> 00:08:48,473 WHAT WE'VE BEEN DOING IN THE 181 00:08:48,473 --> 00:08:48,740 COMMUNITY. 182 00:08:48,740 --> 00:08:50,842 REACH IS FOCUSSED AROUND THE NEW 183 00:08:50,842 --> 00:08:54,212 YORK CITY AREA AND LEAN INTO 184 00:08:54,212 --> 00:08:56,414 THAT AND HAVE A LOCALIZED 185 00:08:56,414 --> 00:08:58,149 PROGRAM AND TALK ABOUT WHAT 186 00:08:58,149 --> 00:09:00,652 WE'VE BEEN DOING STATESIDE AND 187 00:09:00,652 --> 00:09:09,460 WE HAVE HAD A WEBINAR SERIES AND 188 00:09:09,460 --> 00:09:11,796 BEGUN TO LEVERAGE CAT INPUT IN 189 00:09:11,796 --> 00:09:16,801 SEPTEMBER WE HELD A SPECIFIC 190 00:09:16,801 --> 00:09:26,044 MEETING AND AROUND THE EVH AND 191 00:09:26,044 --> 00:09:28,946 LOOKED AT HUMAN CRITICAL TRIALS. 192 00:09:28,946 --> 00:09:30,948 THE CAB HAD AN EXTENSIVE PROCESS 193 00:09:30,948 --> 00:09:32,517 TO LEARN WHAT THE DRUG IS AND 194 00:09:32,517 --> 00:09:35,753 TAKE IT THROUGH THE HISTORY. 195 00:09:35,753 --> 00:09:39,924 WE HAD DR. GRAMATTICA COME IN 196 00:09:39,924 --> 00:09:42,260 AND LEAD PRESENTATIONS AND GO 197 00:09:42,260 --> 00:09:44,829 THROUGH THE Q&A AND CAB ASKED 198 00:09:44,829 --> 00:09:49,967 ABOUT THE DOSAGE, TOXICITY, 199 00:09:49,967 --> 00:09:51,636 TISSUE SAMPLE AND HAS ANYTHING 200 00:09:51,636 --> 00:09:53,404 BEEN DONE AND AT THE END OF THE 201 00:09:53,404 --> 00:09:56,007 DAY DECIDED TO MOVE IT FORWARD 202 00:09:56,007 --> 00:09:57,709 INTO THE -- THEY WOULD THINK IT 203 00:09:57,709 --> 00:10:01,479 CAN MOVE INTO HUMAN TRIALS AND 204 00:10:01,479 --> 00:10:04,215 SKIP NHP MODELS. 205 00:10:04,215 --> 00:10:05,983 THE CAB IS DRAFTING A LETTER TO 206 00:10:05,983 --> 00:10:09,754 THE BOARD AND IT'S LED BY OUR 207 00:10:09,754 --> 00:10:12,523 TWO REPRESENTATIVES ROB WALKER. 208 00:10:12,523 --> 00:10:15,893 WE'RE EXCITED TO SEE THIS MODEL 209 00:10:15,893 --> 00:10:18,463 MOVE FORWARD AS THE CAB AS A 210 00:10:18,463 --> 00:10:18,963 CONSULTATION. 211 00:10:18,963 --> 00:10:20,064 I WANTED TO HIGHLIGHT SOMETHING 212 00:10:20,064 --> 00:10:21,966 WE'RE EXCITED ABOUT AND THE IDEA 213 00:10:21,966 --> 00:10:24,469 OF CONNECTING THE BENCH TO THE 214 00:10:24,469 --> 00:10:24,702 CLINIC. 215 00:10:24,702 --> 00:10:26,003 WE KNOW WE DON'T DO CLINICAL 216 00:10:26,003 --> 00:10:29,974 TRIALS WITHIN THE STRUCTURE BUT 217 00:10:29,974 --> 00:10:32,009 THERE'S ACTIVITY AND 218 00:10:32,009 --> 00:10:34,879 COLLABORATION WITH CLINICAL 219 00:10:34,879 --> 00:10:39,617 TRIALS AROUND AND WE HELD A 220 00:10:39,617 --> 00:10:40,551 COMMUNITY EVENT IN AFRICAN 221 00:10:40,551 --> 00:10:45,056 AMERICAN SERVICES IN HARLEM TO 222 00:10:45,056 --> 00:10:47,625 REACH THE IMMIGRANT POPULATION 223 00:10:47,625 --> 00:10:48,960 OR BLACK AMERICANS LIVING IN NEW 224 00:10:48,960 --> 00:10:49,160 YORK. 225 00:10:49,160 --> 00:10:53,598 WHERE HE HAD THE COORDINATOR 226 00:10:53,598 --> 00:10:56,601 FROM THE HARLEM CENTER ADDS AN 227 00:10:56,601 --> 00:10:59,337 AUDIENCE MEMBER. 228 00:10:59,337 --> 00:11:04,108 WE HAD A FANTASTIC EVENT AND WE 229 00:11:04,108 --> 00:11:06,444 HAD A BLACK TRANS FEMALE AND SHE 230 00:11:06,444 --> 00:11:07,345 WAS ABLE TO COME UP. 231 00:11:07,345 --> 00:11:12,617 HER INTERACTION AND ENGAGEMENT 232 00:11:12,617 --> 00:11:14,452 LED TO HER INTEREST TO RESEARCH 233 00:11:14,452 --> 00:11:16,988 AND LED HER TO CONNECT WITH 234 00:11:16,988 --> 00:11:17,355 JONATHAN. 235 00:11:17,355 --> 00:11:18,723 WHILE HE'S WELL VERSED IN THE 236 00:11:18,723 --> 00:11:20,591 CLINICAL TRIALS WAS NOT AS WELL 237 00:11:20,591 --> 00:11:21,359 VERSED IN THE COMMUNITY 238 00:11:21,359 --> 00:11:24,896 ENGAGEMENT APPROACHES OR THE 239 00:11:24,896 --> 00:11:25,730 LARGER LITERACY. 240 00:11:25,730 --> 00:11:27,965 HE STARTED ATTENDING HER SUPPORT 241 00:11:27,965 --> 00:11:28,399 GROUP. 242 00:11:28,399 --> 00:11:31,169 I WORKED WITH JONATHAN TO 243 00:11:31,169 --> 00:11:31,903 DEVELOP THE LITERACY TOOLS AND 244 00:11:31,903 --> 00:11:36,407 MATERIALS TO WORK THROUGH THE 245 00:11:36,407 --> 00:11:39,076 STRATEGIES AND ABLE TO CULTIVATE 246 00:11:39,076 --> 00:11:40,978 THE LEADERSHIP THAT DOESN'T TO A 247 00:11:40,978 --> 00:11:42,513 CLINICAL TRIAL FOR EXCLUSIONARY 248 00:11:42,513 --> 00:11:44,515 REASONS BUT LED TO HER AND 249 00:11:44,515 --> 00:11:45,249 SEVERAL MEMBERS OF THAT SUPPORT 250 00:11:45,249 --> 00:11:47,718 GROUP ENROLLING IN TRANS CARE 251 00:11:47,718 --> 00:11:48,085 STUDIES. 252 00:11:48,085 --> 00:11:50,154 SO WE CAN REALLY SEE WHEN WE 253 00:11:50,154 --> 00:11:52,456 ESTABLISH THESE LINKAGES WITH 254 00:11:52,456 --> 00:11:54,625 THE COORDINATORS OF CLINICAL 255 00:11:54,625 --> 00:11:57,395 CENTERS WE CAN BUILD BRIDGES AND 256 00:11:57,395 --> 00:11:59,463 INVOLVE NEW INDIVIDUALS AND I 257 00:11:59,463 --> 00:12:00,965 THINK THAT CAME UP YESTERDAY 258 00:12:00,965 --> 00:12:01,999 HIGHLIGHTED BY THE COMMUNITY 259 00:12:01,999 --> 00:12:03,067 ADVISORY BOARD THE NEED TO BRING 260 00:12:03,067 --> 00:12:05,136 IN NEW VOICES AND THIS IS ONE 261 00:12:05,136 --> 00:12:06,737 WAY IN THE I WANTED TO 262 00:12:06,737 --> 00:12:07,038 ILLUSTRATE. 263 00:12:07,038 --> 00:12:11,509 ANOTHER WAY TO BRING IN NEW 264 00:12:11,509 --> 00:12:14,312 VOICES IS IT'S WORKED WELL WITH 265 00:12:14,312 --> 00:12:16,614 THE INTERNATIONAL AIDS SOCIETY 266 00:12:16,614 --> 00:12:17,315 TO HAVE AN INTERNATIONAL 267 00:12:17,315 --> 00:12:19,417 ADVOCACY GROUP AND WE LIKE TO DO 268 00:12:19,417 --> 00:12:20,885 THAT IN THE UNITED STATES AND 269 00:12:20,885 --> 00:12:21,919 CURE WORKSHOP. 270 00:12:21,919 --> 00:12:25,523 IN PARTNERSHIP WITH OTHER 271 00:12:25,523 --> 00:12:26,791 COLLABORATORIES WE'RE LAUNCHING 272 00:12:26,791 --> 00:12:29,994 A U.S. CURE WORKSHOP BASED ON 273 00:12:29,994 --> 00:12:33,130 THE MODEL OF NATIONAL AIDS 274 00:12:33,130 --> 00:12:33,364 SOCIETY. 275 00:12:33,364 --> 00:12:34,532 PULLING CIVIL SOCIETY AND 276 00:12:34,532 --> 00:12:35,399 ADVOCATES FROM AROUND THE UNITED 277 00:12:35,399 --> 00:12:36,834 STATES ONE THE GOAL OF GETTING 278 00:12:36,834 --> 00:12:39,237 THEM UP TO SPEED AND BRINGING IN 279 00:12:39,237 --> 00:12:43,608 NEW VOICES INTO THIS 280 00:12:43,608 --> 00:12:43,941 CONVERSATION. 281 00:12:43,941 --> 00:12:46,677 SO WE WILL BE FOLDING THIS 282 00:12:46,677 --> 00:12:49,046 FEBRUARY 24 THROUGH FEBRUARY 26 283 00:12:49,046 --> 00:12:51,949 IN PHILADELPHIA NEXT YEAR. 284 00:12:51,949 --> 00:12:54,619 APPLICATIONS WILL OFFICIALLY 285 00:12:54,619 --> 00:12:55,953 LAUNCH NEXT WEEK AND EXCITED 286 00:12:55,953 --> 00:12:58,422 ABOUT THE ABILITY TO SPREAD THIS 287 00:12:58,422 --> 00:13:02,627 FAR AND WIDE AND PARTNER WITH 288 00:13:02,627 --> 00:13:04,929 GROUPS TO DIVERSIFY THE 289 00:13:04,929 --> 00:13:07,131 INDIVIDUALS COMING OUT WITH AN 290 00:13:07,131 --> 00:13:08,866 EMPHASIS ON TRANSLATING SCIENCE 291 00:13:08,866 --> 00:13:10,201 AND THE COMMUNICATION BEING 292 00:13:10,201 --> 00:13:11,168 FORWARD. 293 00:13:11,168 --> 00:13:13,971 I WANTED TO HIGHLIGHT TWO 294 00:13:13,971 --> 00:13:14,205 MEMBERS. 295 00:13:14,205 --> 00:13:21,445 THEY'RE NOT HERE TODAY BUT JOHN 296 00:13:21,445 --> 00:13:24,348 SCHOEPP AND GAYLE DORSKY THEY'RE 297 00:13:24,348 --> 00:13:28,152 NEW TO THIS WORK BUT HAVE DONE A 298 00:13:28,152 --> 00:13:30,488 FANTASTIC JOB FACILITATING 299 00:13:30,488 --> 00:13:32,290 CONNECTIONS WITH NEW YORK CITY 300 00:13:32,290 --> 00:13:33,391 AND RECRUITMENT. 301 00:13:33,391 --> 00:13:36,794 THEY HELPED FACILITATE OUR 302 00:13:36,794 --> 00:13:40,631 JUNIOR MEMBER AND WE BROUGHT IN 303 00:13:40,631 --> 00:13:43,401 MENTAL HEALTH TRAINING. 304 00:13:43,401 --> 00:13:45,469 VVNTS AROUND HOMELESSNESS AND 305 00:13:45,469 --> 00:13:46,671 KEEP US UP TO DATE WITH WHAT'S 306 00:13:46,671 --> 00:13:48,105 FUN AND HAPPENING IN NEW YORK 307 00:13:48,105 --> 00:13:48,639 CITY. 308 00:13:48,639 --> 00:13:51,709 WANTED TO HIGHLIGHT THE AMAZING 309 00:13:51,709 --> 00:13:53,511 WORK THEY DO AND I KNOW THEY'RE 310 00:13:53,511 --> 00:13:55,279 ONLINE TODAY AND THANK YOU FOR 311 00:13:55,279 --> 00:13:57,982 YOUR EFFORTS AND WITH THAT I'LL 312 00:13:57,982 --> 00:14:02,987 HAND IT TO PAUL. 313 00:14:02,987 --> 00:14:05,923 >> GOOD MORNING. 314 00:14:05,923 --> 00:14:08,192 THE REASON WE'RE GATHERED HERE 315 00:14:08,192 --> 00:14:10,328 FUNDAMENTALLY IS BECAUSE THERAPY 316 00:14:10,328 --> 00:14:12,263 REVEALS THE PRESENCE OF A SMALL 317 00:14:12,263 --> 00:14:14,332 SUB POPULATION OF VIRUSES THAT 318 00:14:14,332 --> 00:14:15,900 ADOPTED A DIFFERENT LIFESTYLE 319 00:14:15,900 --> 00:14:20,571 THAT IS REPLICATING NOT BY 320 00:14:20,571 --> 00:14:21,706 CONVENTIONAL MECHANISMS BUT 321 00:14:21,706 --> 00:14:25,977 PIGGY BACKING ON CELL DIVISION 322 00:14:25,977 --> 00:14:29,513 MAKING THEM IMPERVIOUS AND I'M 323 00:14:29,513 --> 00:14:30,748 TALKING ABOUT MODEL SYSTEM TO 324 00:14:30,748 --> 00:14:33,451 ADVOCATE THE FACTORS THAT THE 325 00:14:33,451 --> 00:14:34,852 GOVERNMENT DECISION OF A PRO 326 00:14:34,852 --> 00:14:37,588 VIRUS TO ENTER THIS SORT OF 327 00:14:37,588 --> 00:14:41,492 ALTERNATIVE STYLE OF REPLICATION 328 00:14:41,492 --> 00:14:43,894 BY OTHER RETROVIRUSES AND IN 329 00:14:43,894 --> 00:14:46,530 PARTICULAR WHETHER THE SITE OF 330 00:14:46,530 --> 00:14:47,131 INTEGRATIONS INFLUENCES THE 331 00:14:47,131 --> 00:14:49,667 DECISION AND POTENTIALLY 332 00:14:49,667 --> 00:14:50,534 IMPACTED CELL DIVISION 333 00:14:50,534 --> 00:14:52,703 PROPAGATION OF THE RESERVOIR. 334 00:14:52,703 --> 00:14:55,206 SO THE MODEL SYSTEMS BASED IN 335 00:14:55,206 --> 00:14:58,509 PART ON A REPORTER PROVIRUS THAT 336 00:14:58,509 --> 00:15:01,479 MAINTAINS NATIVE MECHANISMS OF 337 00:15:01,479 --> 00:15:02,179 HIV GENE REGULATION. 338 00:15:02,179 --> 00:15:04,648 WE SIMPLY REPLACE ONE OF THE HIV 339 00:15:04,648 --> 00:15:07,318 GENES WITH A REPORTER GENE THAT 340 00:15:07,318 --> 00:15:10,688 PLACES A SURFACE MARKER ON CELLS 341 00:15:10,688 --> 00:15:12,156 ENABLING THEM TO BE PURIFIED AT 342 00:15:12,156 --> 00:15:13,758 LARGE SCALE INTO POPULATIONS 343 00:15:13,758 --> 00:15:16,627 THAT HAVE ACTIVE OR LATENT 344 00:15:16,627 --> 00:15:16,927 PROVIRUSES. 345 00:15:16,927 --> 00:15:22,233 SO WHAT WE DO IS WE TAKE CELLS 346 00:15:22,233 --> 00:15:25,269 FROM AND SUPPORT HIM HAD IN THE 347 00:15:25,269 --> 00:15:28,139 VIRUS AND PURIFY THE INFECTED 348 00:15:28,139 --> 00:15:31,242 CELLS AND INGRAFT MICE WITH 349 00:15:31,242 --> 00:15:32,777 ABOUT 5 MILLION CELLS EACH 350 00:15:32,777 --> 00:15:36,781 CONTAINING A PRESUMPTIVE INTACT 351 00:15:36,781 --> 00:15:38,315 TRANSCRIPTIONALLY ACTIVE PRO 352 00:15:38,315 --> 00:15:38,649 VIRUS. 353 00:15:38,649 --> 00:15:39,917 THE CELLS THEN LIVE IN THE MOUSE 354 00:15:39,917 --> 00:15:40,618 FOR MONTHS. 355 00:15:40,618 --> 00:15:41,986 IMPORTANT TO RECOGNIZE THERE IS 356 00:15:41,986 --> 00:15:43,721 NO CONVENTIONAL HIV REPLICATION 357 00:15:43,721 --> 00:15:45,322 GOING ON HERE. 358 00:15:45,322 --> 00:15:46,991 THERE IS NO IMMUNE SELECTION. 359 00:15:46,991 --> 00:15:51,629 THE PROVIRUS IS FREE TO DECIDE 360 00:15:51,629 --> 00:15:54,632 ITS OWN FATE UNENCUMBERED BY 361 00:15:54,632 --> 00:15:58,135 SELECTION PRESSURES SO THE CELLS 362 00:15:58,135 --> 00:16:01,772 GRAFT AND GROW AND THE 363 00:16:01,772 --> 00:16:02,640 PROVIRUSES SOME MAINTAIN 364 00:16:02,640 --> 00:16:03,074 EXPRESSION. 365 00:16:03,074 --> 00:16:05,176 SOME GO TO A STATE OF LATENCY. 366 00:16:05,176 --> 00:16:07,745 MONTHS LATER WE CAN RECOVER 367 00:16:07,745 --> 00:16:10,915 DECENT NUMBERS OF HUMAN CELLS 368 00:16:10,915 --> 00:16:11,715 FROM MOUSE TISSUES IN THIS 369 00:16:11,715 --> 00:16:13,217 PARTICULAR EXAMPLE THE MAJORITY 370 00:16:13,217 --> 00:16:15,886 OF THOSE CELLS HAVE LOST THE 371 00:16:15,886 --> 00:16:17,855 REPORTER GENE EXPRESSION INTO 372 00:16:17,855 --> 00:16:20,624 THE STATE OF LATENCY. 373 00:16:20,624 --> 00:16:24,895 WE DEVELOPED AN ASSAY BASED ON 374 00:16:24,895 --> 00:16:27,565 NUMEROUS PARALLEL INTEGRATION 375 00:16:27,565 --> 00:16:31,202 SITE DERM DETERMINATIONS TO 376 00:16:31,202 --> 00:16:32,436 QUANTIFY TO GENES. 377 00:16:32,436 --> 00:16:34,438 WE FIND IN THE PRE-INFUSION 378 00:16:34,438 --> 00:16:36,907 SAMPLE WE RECOVER MOST THE 379 00:16:36,907 --> 00:16:37,975 INTEGRATIONS THAT BASED ON THE 380 00:16:37,975 --> 00:16:40,377 NUMBER OF PROVIRUSES THAT GET 381 00:16:40,377 --> 00:16:41,679 INTO THE ASSAY. 382 00:16:41,679 --> 00:16:45,549 MOST OF THE INTEGRATIONS ARE IN 383 00:16:45,549 --> 00:16:45,950 GENES. 384 00:16:45,950 --> 00:16:47,017 HOWEVER IN THE MOUSE GRAFT WHILE 385 00:16:47,017 --> 00:16:50,387 WE FIND THE EXPECTED NUMBER OF 386 00:16:50,387 --> 00:16:53,757 TOTAL INTERGRANTS THE NUMBER OF 387 00:16:53,757 --> 00:16:54,825 TOTAL ARE FAR FEWER BECAUSE 388 00:16:54,825 --> 00:16:58,462 THERE HAS BEEN A VERY EXTENSIVE 389 00:16:58,462 --> 00:17:01,966 DEGREE OF CLONAL EXPANSION OF 390 00:17:01,966 --> 00:17:05,970 INDIVIDUAL CLONES IN THE MOUSE 391 00:17:05,970 --> 00:17:08,139 GRAFT HETEROGENEOUS EXPANSION 392 00:17:08,139 --> 00:17:09,473 SOME ARE GROWING BETTER THAN 393 00:17:09,473 --> 00:17:14,078 OTHERS FOLLOWING ENDRAGRAFTMENT 394 00:17:14,078 --> 00:17:16,747 THE MOUSE. 395 00:17:16,747 --> 00:17:20,551 DOES THE SITE IMPACT THE ABILITY 396 00:17:20,551 --> 00:17:25,656 TO PROLIFERATE IN PREFERENCE TO 397 00:17:25,656 --> 00:17:29,593 OTHER CLONES IN THE GRAFT? 398 00:17:29,593 --> 00:17:32,163 THE ANSWER IS TENTATIVELY, NO. 399 00:17:32,163 --> 00:17:34,565 THOUGH THERE IS QUITE A BIT OF 400 00:17:34,565 --> 00:17:36,767 OVERLAP IN THE GENES WE FIND 401 00:17:36,767 --> 00:17:38,068 BEARING PROVIRUSES IN DIFFERENT 402 00:17:38,068 --> 00:17:41,605 MICE, IF YOU LOOK AT THESE 403 00:17:41,605 --> 00:17:43,541 CHARTS WHERE EACH DATA POINT 404 00:17:43,541 --> 00:17:45,910 REPRESENTS AN INDIVIDUAL GENE 405 00:17:45,910 --> 00:17:48,112 WITH AN INTEGRATED PRO VIRUS. 406 00:17:48,112 --> 00:17:50,548 THE NUMBER OF MICE IN WHICH WE 407 00:17:50,548 --> 00:17:52,383 FIND INTEGRATION TO ANY GIVEN 408 00:17:52,383 --> 00:17:54,518 GENE IS NOT PREDICTED BY THE 409 00:17:54,518 --> 00:17:57,855 ASSOCIATION OF THAT GENE WITH 410 00:17:57,855 --> 00:17:59,056 HIGH LEVELS OF CLONAL EXPANSION. 411 00:17:59,056 --> 00:18:01,392 ALSO, IF WE COUNT THE NUMBER OF 412 00:18:01,392 --> 00:18:05,262 TIMES A GENE CARRIES A PROVIRUS 413 00:18:05,262 --> 00:18:06,830 IN A MOUSE GRAPH MONTHS LATER, 414 00:18:06,830 --> 00:18:08,799 THAT NUMBER IS QUITE STRONGLY 415 00:18:08,799 --> 00:18:10,834 PREDICTED BY THE NUMBER OF 416 00:18:10,834 --> 00:18:13,070 INTEGRATIONS WE HAVE IN THE VERY 417 00:18:13,070 --> 00:18:15,306 SAME GENE IMMEDIATELY FOLLOWING 418 00:18:15,306 --> 00:18:17,308 INFECTION WHERE THERE HAS BEEN 419 00:18:17,308 --> 00:18:19,510 NO OPPORTUNITY FOR SELECTION. 420 00:18:19,510 --> 00:18:24,715 WE SIMPLY DON'T FIND GENES WHERE 421 00:18:24,715 --> 00:18:27,184 INTEGRATION IN THAT GENE FAVORS 422 00:18:27,184 --> 00:18:28,018 SURVIVAL IN THE GRAFT ITSELF IN 423 00:18:28,018 --> 00:18:28,686 THE MOUSE. 424 00:18:28,686 --> 00:18:31,355 IN FACT, WHAT PREDICTS WHETHER A 425 00:18:31,355 --> 00:18:33,324 GENE CARRIES A PRO VIRUS OR NOT 426 00:18:33,324 --> 00:18:35,726 IS ITS SIZE AND EXPRESSION 427 00:18:35,726 --> 00:18:36,760 LEVEL. 428 00:18:36,760 --> 00:18:38,596 FACTORS WELL KNOWN TO FAVOR 429 00:18:38,596 --> 00:18:41,065 INTEGRATION IN THE ABSENCE OF 430 00:18:41,065 --> 00:18:42,499 ANY OTHER SELECTION QUESTION AND 431 00:18:42,499 --> 00:18:44,435 THAT'S TRUE BOTH IN THE 432 00:18:44,435 --> 00:18:47,705 PREINFUSION SAMPLE AND MONTHS 433 00:18:47,705 --> 00:18:48,973 LATER IN THE MOUSE GRAPH. 434 00:18:48,973 --> 00:18:51,108 SO QUITE STRONG EVIDENCE AT 435 00:18:51,108 --> 00:18:53,510 LEAST IN THIS MODEL THAT THE HIV 436 00:18:53,510 --> 00:18:54,778 PROVIRUS IS ACTING VERY MUCH AS 437 00:18:54,778 --> 00:18:59,016 A PASSENGER AND NOT A DRIVER OF 438 00:18:59,016 --> 00:19:00,718 CELL SURVIVAL OF CLONAL 439 00:19:00,718 --> 00:19:02,653 EXPANSION. 440 00:19:02,653 --> 00:19:05,923 SO TO QUESTION TWO, DOES THE 441 00:19:05,923 --> 00:19:07,224 SITE OF INTEGRATION INFLUENCE 442 00:19:07,224 --> 00:19:09,960 WHETHER THAT PROVIRUS IS GOING 443 00:19:09,960 --> 00:19:11,729 TO ENTER LATENCY. 444 00:19:11,729 --> 00:19:14,164 SO THE WAY WE ADDRESS THIS IS TO 445 00:19:14,164 --> 00:19:17,368 HARVEST THE TISSUE AND APPLY 446 00:19:17,368 --> 00:19:18,002 ARTIFICIAL SELECTION PRESSURE 447 00:19:18,002 --> 00:19:26,677 WITH A MAGNET OR FLOW CYTOMETER 448 00:19:26,677 --> 00:19:30,214 AND WHEN WE DO THAT WE SEE IN 449 00:19:30,214 --> 00:19:32,516 THIS EXAMPLE MOUSE THE TYPICAL 450 00:19:32,516 --> 00:19:35,786 PATTERN OF CLONAL EXPANSION BOTH 451 00:19:35,786 --> 00:19:37,955 IN THE ACTIVE PROVIRUS 452 00:19:37,955 --> 00:19:39,890 POPULATION AND IN THE LATENT 453 00:19:39,890 --> 00:19:41,492 POPULATION. 454 00:19:41,492 --> 00:19:45,796 KEY POINT THOUGH IS THE LATENT 455 00:19:45,796 --> 00:19:48,532 POPULATION IS ALMOST 456 00:19:48,532 --> 00:19:49,133 NON-OVERLAPPING. 457 00:19:49,133 --> 00:19:51,135 FOR EXAMPLE THE PROVIRUS, THIS 458 00:19:51,135 --> 00:19:52,636 CLONE WHICH REPRESENTS NEARLY 459 00:19:52,636 --> 00:19:54,872 HALF THE LATENT PROVIRUS 460 00:19:54,872 --> 00:19:57,541 POPULATION AND INCIDENTALLY AS 461 00:19:57,541 --> 00:20:03,314 INTEGRATION IN A ZINC FINGER 462 00:20:03,314 --> 00:20:05,215 GENE IN CHROMOSOMAL 19 IS 463 00:20:05,215 --> 00:20:06,417 VIRTUALLY ABSENT FROM THE 464 00:20:06,417 --> 00:20:06,717 POPULATION. 465 00:20:06,717 --> 00:20:09,720 IN FACT IF YOU LOOK AT 466 00:20:09,720 --> 00:20:11,055 PROVIRUSES AS A TOTAL ONE THAT 467 00:20:11,055 --> 00:20:13,290 MAINTAIN ACTIVITY INTERFREIGHTED 468 00:20:13,290 --> 00:20:18,162 MOST INTEGRATED MOST IN GENES 469 00:20:18,162 --> 00:20:19,296 THAT ARE LATENT MOST ARE NOT IN 470 00:20:19,296 --> 00:20:21,165 GENES. 471 00:20:21,165 --> 00:20:22,599 A FEW ARE. 472 00:20:22,599 --> 00:20:25,602 IF WE LOOK AT CHROMOSOME MARKS 473 00:20:25,602 --> 00:20:27,304 AROUND ACTIVE AND LATENT 474 00:20:27,304 --> 00:20:28,839 PROVIRUSES USING DATA FROM 475 00:20:28,839 --> 00:20:30,941 ENCODE ANALYSIS OF MEMORY T 476 00:20:30,941 --> 00:20:33,010 CELLS, LATENT PROVIRUSES ARE 477 00:20:33,010 --> 00:20:37,948 ENRICHED FOR THE MARK ASSOCIATED 478 00:20:37,948 --> 00:20:45,556 WITH HETEROCHROMATIN. 479 00:20:45,556 --> 00:20:47,825 WE HAVE MODELS THAT SEEMS TO 480 00:20:47,825 --> 00:20:49,360 REASONABLY WELL RECAPITULATE THE 481 00:20:49,360 --> 00:20:53,597 PICTURES ASSOCIATED WITH THE 482 00:20:53,597 --> 00:20:54,698 LATENT RESERVOIR IN HUMANS. 483 00:20:54,698 --> 00:20:57,368 IN REACH WE HAVE THE UNIQUE 484 00:20:57,368 --> 00:20:58,435 OPPORTUNITY TO COMPARE WHAT WE 485 00:20:58,435 --> 00:21:02,573 DO IN OUR MODEL WITH CELLS THAT 486 00:21:02,573 --> 00:21:05,943 COME FROM THE RESERVOIR. 487 00:21:05,943 --> 00:21:16,487 FROM THE INGENIUS BRUTE FORCE 488 00:21:18,021 --> 00:21:24,061 OF OUR LAB WE HAD THE CLONES AND 489 00:21:24,061 --> 00:21:25,662 HAVE INTERESTING PROPERTIES AND 490 00:21:25,662 --> 00:21:31,568 THE FACT THEY ALL HAVE AN INTACT 491 00:21:31,568 --> 00:21:32,636 PROVIRUS FEW EXPRESS AND YOU SEE 492 00:21:32,636 --> 00:21:37,941 THE CELL PROLIFERATING AND A 493 00:21:37,941 --> 00:21:40,077 SMALL PERCENTAGE OF THEM MAKING 494 00:21:40,077 --> 00:21:42,446 GAG AND THE PROCESS OF VIRAL 495 00:21:42,446 --> 00:21:43,547 GENE EXPRESSION HAS BECOME 496 00:21:43,547 --> 00:21:44,848 NEARLY COMPLETELY UNCOUPLED FROM 497 00:21:44,848 --> 00:21:48,218 THE PROCESS OF CELL DIVISION AND 498 00:21:48,218 --> 00:21:48,585 CELL ACTIVATION. 499 00:21:48,585 --> 00:21:55,959 AND IF WE LOOK AT THE HISTONE 500 00:21:55,959 --> 00:21:58,362 MARKS THIS IS FROM ANALYSIS AND 501 00:21:58,362 --> 00:22:01,965 YOU CAN SEE THE SAME HISTONE 502 00:22:01,965 --> 00:22:05,969 MARK AROUND THE AUTHENTIC 503 00:22:05,969 --> 00:22:06,336 RESERVOIR CLONE. 504 00:22:06,336 --> 00:22:08,305 SO ANOTHER PROPERTY THAT SEEMS 505 00:22:08,305 --> 00:22:10,941 TO BE ASSOCIATED WITH THESE 506 00:22:10,941 --> 00:22:12,709 AUTHENTIC RESERVOIR CLONES IS IF 507 00:22:12,709 --> 00:22:15,012 YOU TREAT THEM WITH CONVENTIONAL 508 00:22:15,012 --> 00:22:17,247 LATENCY REVERSING AGENTS AND 509 00:22:17,247 --> 00:22:20,184 HERE'S A WHOLE PANEL WITH 510 00:22:20,184 --> 00:22:21,151 DIFFERENT MECHANISMS OF ACTION 511 00:22:21,151 --> 00:22:22,619 THEY ARE HAVE LITTLE TO ANY 512 00:22:22,619 --> 00:22:25,189 EFFECT ON THE OF THE PRO VIRUS. 513 00:22:25,189 --> 00:22:27,124 WE HAVE GAG AFFECTS THE TWO SUCH 514 00:22:27,124 --> 00:22:30,794 CLONES WITH INTEGRATIONS AT 515 00:22:30,794 --> 00:22:32,663 DIFFERENT -- THEY JUST DON'T 516 00:22:32,663 --> 00:22:32,996 RESPOND WELL. 517 00:22:32,996 --> 00:22:35,732 SO THERE'S OUR MODEL. 518 00:22:35,732 --> 00:22:36,667 WE CAPITULATE LIKE THIS. 519 00:22:36,667 --> 00:22:38,402 IT'S A LOT OF WORK TO ISOLATE 520 00:22:38,402 --> 00:22:41,171 EVEN ONE CLONE FROM AN INFECTED 521 00:22:41,171 --> 00:22:42,239 INDIVIDUAL BUT FROM OUR MICE WE 522 00:22:42,239 --> 00:22:43,607 CAN IN PRINCIPLE DO THIS MANY 523 00:22:43,607 --> 00:22:44,308 TIMES OVER. 524 00:22:44,308 --> 00:22:45,676 WE'RE IN THE EARLY STAGES OF 525 00:22:45,676 --> 00:22:48,579 DOING THAT SO I'M GOING TO SHOW 526 00:22:48,579 --> 00:22:49,880 YOU A PILOT EXPERIMENT. 527 00:22:49,880 --> 00:22:54,017 SO WHAT WE FIND IS IF WE GET 50 528 00:22:54,017 --> 00:22:55,285 POSITIVE WELLS WITH HUMAN CELLS 529 00:22:55,285 --> 00:23:00,190 GROWING FROM A COUPLE ANIMALS WE 530 00:23:00,190 --> 00:23:01,959 FIND ABOUT A QUARTER OF THOSE 531 00:23:01,959 --> 00:23:04,928 CLONES FROM ANIMALS AND ONLY 532 00:23:04,928 --> 00:23:06,663 LATENT PROVIRUS. 533 00:23:06,663 --> 00:23:08,999 UNFORTUNATELY IN THIS EXPERIMENT 534 00:23:08,999 --> 00:23:09,967 WE UNDERESTIMATED THE EFFICIENCY 535 00:23:09,967 --> 00:23:11,468 WITH WHICH OUR CLOTH PROCEDURES 536 00:23:11,468 --> 00:23:13,470 WILL WORK. 537 00:23:13,470 --> 00:23:19,009 MANY WELLS HAVE MORE THAN ONE 538 00:23:19,009 --> 00:23:20,978 CLONING BUT HAVE NUMBERS WE 539 00:23:20,978 --> 00:23:22,846 THINK THERE'S AN A SINGLE CELL 540 00:23:22,846 --> 00:23:24,848 WITH ONE INTACT AND A MIXTURE 541 00:23:24,848 --> 00:23:27,818 AND LATENT PROVIRUSES. 542 00:23:27,818 --> 00:23:29,786 NOW IF WE TAKE ONE SUCH CLONE. 543 00:23:29,786 --> 00:23:32,222 HERE'S AN EXAMPLE WHERE 15% OF 544 00:23:32,222 --> 00:23:35,158 THE CLONES IS GFP POSITIVE AND 545 00:23:35,158 --> 00:23:45,536 ADOPT A KITCHEN SINK APPROACH 546 00:23:45,536 --> 00:23:48,672 AND THERE'S MANIPULATION TO GET 547 00:23:48,672 --> 00:23:50,807 IT TO EXPRESS. 548 00:23:50,807 --> 00:23:51,842 THAT'S TRUE OF SEVERAL CLONES 549 00:23:51,842 --> 00:23:53,844 WHERE WE APPLIED THE PROCEDURE 550 00:23:53,844 --> 00:23:54,811 AND WITH DIFFERENT STARTING 551 00:23:54,811 --> 00:23:56,647 LEVELS OF EXPRESSION. 552 00:23:56,647 --> 00:24:00,751 THEY SIMPLY DON'T RESPOND WELL. 553 00:24:00,751 --> 00:24:02,486 AND SO TO SUMMARIZE AT LEAST IN 554 00:24:02,486 --> 00:24:07,157 OUR MODEL, HIV INTEGRATION DOES 555 00:24:07,157 --> 00:24:09,159 NOT SEEM TO CELL DRIVE SURVIVAL 556 00:24:09,159 --> 00:24:12,496 OR EXPANSION BUT SEEMS TO BE 557 00:24:12,496 --> 00:24:13,363 VIRTUALLY DETERMINISTIC OF THE 558 00:24:13,363 --> 00:24:15,933 DECISION TO ENTER LATENCY. 559 00:24:15,933 --> 00:24:21,371 AND COMMONLY USED LRAs DO NOT 560 00:24:21,371 --> 00:24:23,540 ACTIVATE LATENT IN OUR MODEL AND 561 00:24:23,540 --> 00:24:24,942 REAL RESERVOIR CLONES. 562 00:24:24,942 --> 00:24:26,476 DIFFERENCE IS WE CAN NOW GROW 563 00:24:26,476 --> 00:24:32,482 THE CELLS TO HUNDREDS OF 564 00:24:32,482 --> 00:24:33,917 MILLIONS AND DO CHEMISTRY TO 565 00:24:33,917 --> 00:24:35,519 LEARN EXACTLY ABOUT THE 566 00:24:35,519 --> 00:24:37,054 MECHANISMS THAT GOVERN THE 567 00:24:37,054 --> 00:24:40,457 DECISION AND CHANGE THEM TO 568 00:24:40,457 --> 00:24:40,924 ACHIEVE THIS UP HERE. 569 00:24:40,924 --> 00:24:51,435 LET ME CLOSE BY ACKNOWLEDGING 570 00:24:53,604 --> 00:24:53,837 V 571 00:24:53,837 --> 00:24:55,272 VIRENDER PAL AND FRAUK AND MARIE 572 00:24:55,272 --> 00:24:56,840 AND BRAD JONES AND HIS TEAM FOR 573 00:24:56,840 --> 00:25:00,177 THE WORK ON THE AUTHENTIC 574 00:25:00,177 --> 00:25:01,478 RESERVOIR CLONES AND MICHAEL 575 00:25:01,478 --> 00:25:02,079 BETTS AND HIS GROUP DID THE 576 00:25:02,079 --> 00:25:02,346 ANALYSIS. 577 00:25:02,346 --> 00:25:12,522 THANK YOU. 578 00:25:16,193 --> 00:25:17,527 >> GOOD MORNING. 579 00:25:17,527 --> 00:25:20,497 I'M GOING TO FOLLOW UP ON THAT 580 00:25:20,497 --> 00:25:27,004 WITH WHAT WE'RE TRYING TO DO. 581 00:25:27,004 --> 00:25:30,807 SO, WHAT WE'VE BEEN DOING IS 582 00:25:30,807 --> 00:25:32,843 TRYING TO UNDERSTAND THE ROLE OF 583 00:25:32,843 --> 00:25:35,345 ANTIBODIES AS THERAPIES FOR HIV. 584 00:25:35,345 --> 00:25:36,813 AND THE REASON WE'RE DOING THIS 585 00:25:36,813 --> 00:25:40,784 IS ILLUSTRATED ON THE SLIDE IS 586 00:25:40,784 --> 00:25:43,820 THAT ANTIBODIES HAVE TWO ENDS AN 587 00:25:43,820 --> 00:25:47,090 FAB SIDE AND FC SIDE. 588 00:25:47,090 --> 00:25:50,394 AND WHEREAS THE FAB SIDE CAN ACT 589 00:25:50,394 --> 00:25:53,196 LIKE A BLOCKER AND PREVENT 590 00:25:53,196 --> 00:25:53,597 INFECTION. 591 00:25:53,597 --> 00:25:55,699 THE FC SIDE ENABLES THE ANTIBODY 592 00:25:55,699 --> 00:25:57,968 TO HAVE ADDITIONAL FEATURES AND 593 00:25:57,968 --> 00:26:00,804 THOSE ARE ILLUSTRATED ON THE 594 00:26:00,804 --> 00:26:01,838 SLIDE SO FOR EXAMPLE CLEARING 595 00:26:01,838 --> 00:26:04,274 THE VIRUS, KILLING INFECTED 596 00:26:04,274 --> 00:26:08,078 CELLS AND POTENTIALLY MAKING 597 00:26:08,078 --> 00:26:09,279 IMMUNOCOMPLEXES WHICH ENHANCE 598 00:26:09,279 --> 00:26:10,647 POST IMMUNE RESPONSES. 599 00:26:10,647 --> 00:26:13,316 WE'VE DONE THIS WITH TWO 600 00:26:13,316 --> 00:26:19,089 ANTIBODIES THAT WERE CLONED IN 601 00:26:19,089 --> 00:26:24,761 OUR LAB 3BNC117 AND ONE ANOTHER 602 00:26:24,761 --> 00:26:26,997 AND WE'VE DONE QUITE A BIT OF 603 00:26:26,997 --> 00:26:29,966 WORK ON THESE ANTIBODIES AND 604 00:26:29,966 --> 00:26:31,868 HOST IMMUNITY TO HIV. 605 00:26:31,868 --> 00:26:35,572 FIRST IN MICE AND THEN IN 606 00:26:35,572 --> 00:26:37,974 MACAQUES IN COLLABORATION WITH 607 00:26:37,974 --> 00:26:39,109 MALCOLM MARTIN AND HIS 608 00:26:39,109 --> 00:26:40,544 COLLEAGUES AND PLA REFLA CASKEY 609 00:26:40,544 --> 00:26:43,513 HAS TAKEN THIS TO HUMANS. 610 00:26:43,513 --> 00:26:47,984 WE'VE LEARNED A GREAT DEAL ABOUT 611 00:26:47,984 --> 00:26:51,088 ANTIBODIES AND IN PARTICULAR 612 00:26:51,088 --> 00:26:56,827 THEIR SAFETY IN PEOPLE THAT ARE 613 00:26:56,827 --> 00:26:57,427 LIVING WITH HIV. 614 00:26:57,427 --> 00:26:59,863 AND THEIR PROPERTIES IN TERMS OF 615 00:26:59,863 --> 00:27:03,767 THEIR ANTIVIRAL PROPERTIES. 616 00:27:03,767 --> 00:27:07,304 AND JUST TO SUMMARIZE THE 617 00:27:07,304 --> 00:27:08,638 ANTIBODIES ARE SAFE AND SUPPRESS 618 00:27:08,638 --> 00:27:11,842 VIREMIA IN PEOPLE WHO CARRY 619 00:27:11,842 --> 00:27:14,745 VIRUSES THAT ARE SENSITIVE. 620 00:27:14,745 --> 00:27:17,914 MONOCLONAL ANTIBODY THERAPY JUST 621 00:27:17,914 --> 00:27:22,252 LIKE MONOCLONAL DRUG THERAPY IS 622 00:27:22,252 --> 00:27:24,521 ASSOCIATED WITH EMERGENCE 623 00:27:24,521 --> 00:27:29,159 ASSISTANCE AND COMBINATIONS CAN 624 00:27:29,159 --> 00:27:29,793 MAINTAIN VIRAL SUPPRESSION IN 625 00:27:29,793 --> 00:27:38,335 PEOPLE WHO LAR HARBOR VIRUSES 626 00:27:38,335 --> 00:27:42,806 AND JUST LIKE DRUGS IF 627 00:27:42,806 --> 00:27:45,976 ANTIBODIES BECOME 628 00:27:45,976 --> 00:27:50,781 SUBTHERAPEUTIC, PEOPLE LIVING 629 00:27:50,781 --> 00:27:52,149 WITH HIV REBOUND. 630 00:27:52,149 --> 00:27:55,652 AND THE REASON THEY REBOUND, WE 631 00:27:55,652 --> 00:27:57,687 BELIEVE, ALL OF US, IS BECAUSE 632 00:27:57,687 --> 00:27:58,889 THEY CONTAIN THIS RESERVOIR. 633 00:27:58,889 --> 00:28:01,658 SO WHAT IS THIS THING? 634 00:28:01,658 --> 00:28:03,493 TURNED OUT WE'VE LEARNED QUITE A 635 00:28:03,493 --> 00:28:05,061 BIT ABOUT THE RESERVOIR AS A 636 00:28:05,061 --> 00:28:06,496 COMMUNITY OVER THE LAST FIVE OR 637 00:28:06,496 --> 00:28:07,564 SO YEARS. 638 00:28:07,564 --> 00:28:09,733 IN FACT I BELIEVE WE'RE SORT OF 639 00:28:09,733 --> 00:28:15,172 AT AN INFLEXION POINT IN 640 00:28:15,172 --> 00:28:17,107 UNDERSTANDING WHAT THIS IS FIRST 641 00:28:17,107 --> 00:28:20,110 OF ALL UNIQUE CELLS WITH UNIQUE 642 00:28:20,110 --> 00:28:21,978 PROVIRAL INTEGRATIONS BUT 643 00:28:21,978 --> 00:28:28,118 COMPOSED OF CLONES OF CD4 T 644 00:28:28,118 --> 00:28:28,351 CELLS. 645 00:28:28,351 --> 00:28:32,255 THESE CELLS ARE RARE AND HAVE NO 646 00:28:32,255 --> 00:28:33,957 MARKERS TO SPECIFICALLY PULL THE 647 00:28:33,957 --> 00:28:44,134 CELLS OUT. 648 00:28:48,705 --> 00:28:49,873 AND A CONTRACTION OF HALF LIFE 649 00:28:49,873 --> 00:28:52,742 AND THERE'S INTACT VIRUSES AND 650 00:28:52,742 --> 00:28:54,711 DEFECTIVE VIRUSES AND THEY'RE 651 00:28:54,711 --> 00:28:56,546 QUITE DIFFERENT IN THE WAY THEY 652 00:28:56,546 --> 00:28:57,948 BEHAVE WHEREAS THE IMPACT 653 00:28:57,948 --> 00:29:00,050 VIRUSES HAVE A HALF LIFE AND 654 00:29:00,050 --> 00:29:01,117 DEFECTIVE ONES DON'T SEEM TO. 655 00:29:01,117 --> 00:29:04,521 THEY JUST STAY THERE. 656 00:29:04,521 --> 00:29:10,060 AND THIS THING IS DYNAMIC. 657 00:29:10,060 --> 00:29:11,361 THE CLONES EXPAND AND CONTRACT 658 00:29:11,361 --> 00:29:12,562 AND SOME UNDERSTANDING OF THAT 659 00:29:12,562 --> 00:29:14,030 IS RELATED TO THE FACT THAT 660 00:29:14,030 --> 00:29:19,836 THESE T CELLS ARE BEHAVING LIKE 661 00:29:19,836 --> 00:29:21,504 NORMAL CD4 T CELLS AND 662 00:29:21,504 --> 00:29:24,474 RESPONDING TO ANTIGEN. 663 00:29:24,474 --> 00:29:28,078 NOW, IF IN FACT THESE VIRUSES 664 00:29:28,078 --> 00:29:30,413 ARE RESPONDING TO IMMUNOLOGIC 665 00:29:30,413 --> 00:29:32,949 PRESSURE IT MAY BE BECAUSE 666 00:29:32,949 --> 00:29:35,352 THEY'RE BEING EXPRESSED AND SO 667 00:29:35,352 --> 00:29:40,423 ANTIBODIES HAVE THE POTENTIAL OF 668 00:29:40,423 --> 00:29:43,326 RECOGNIZING THESE PROVIRAL 669 00:29:43,326 --> 00:29:44,594 INTEGRATIVE T CELLS. 670 00:29:44,594 --> 00:29:50,033 SO WHAT WE'VE BEEN TRYING TO 671 00:29:50,033 --> 00:30:00,477 UNDERSTAND IS AND WE TAKE 672 00:30:04,581 --> 00:30:07,050 AUTHENTIC INTEGRATION SITES. 673 00:30:07,050 --> 00:30:12,956 THINGS WE, AMY KLINE UP OUR LAB 674 00:30:12,956 --> 00:30:18,895 AND MATIAS IN THEIR LAB AND 675 00:30:18,895 --> 00:30:21,498 REPRODUCE THEM. 676 00:30:21,498 --> 00:30:25,969 FIRST BY CRISPR METHODS AND USE 677 00:30:25,969 --> 00:30:28,972 IT TO INDICATE AN INDICATOR 678 00:30:28,972 --> 00:30:29,706 VIRUS EXACTLY IN THE SAME 679 00:30:29,706 --> 00:30:34,444 POSITION, NUCLEOTIDE FOR 680 00:30:34,444 --> 00:30:36,513 NUCLEOTIDE WHERE WE KNOW 681 00:30:36,513 --> 00:30:37,781 AUTHENTIC LATENT VIRUSES COME 682 00:30:37,781 --> 00:30:40,717 FROM AND THEN ASK HOW DO THEY 683 00:30:40,717 --> 00:30:43,420 ARE BEHAVE. 684 00:30:43,420 --> 00:30:45,622 THIS IS ILLUSTRATED IN THE PAPER 685 00:30:45,622 --> 00:30:47,557 THAT WAS RECENTLY PUBLISHED AND 686 00:30:47,557 --> 00:30:49,392 HERE ARE SIX DIFFERENT 687 00:30:49,392 --> 00:30:56,099 INTEGRATION SITES AUTHENTIC 688 00:30:56,099 --> 00:31:01,805 SITES REPRODUCED -- HERE FOR 689 00:31:01,805 --> 00:31:04,774 EXAMPLE YOU SEE THE PINK SHOWS 690 00:31:04,774 --> 00:31:06,509 IN THIS PARTICULAR INTEGRATION 691 00:31:06,509 --> 00:31:07,210 PROVIRUSES EXPRESS. 692 00:31:07,210 --> 00:31:10,981 IN THIS ONE IT'S NOT. 693 00:31:10,981 --> 00:31:13,683 IN THIS ONE IT'S NOT BUT WHEN WE 694 00:31:13,683 --> 00:31:17,087 ACTIVATE IT YOU CAN SEE THAT IT 695 00:31:17,087 --> 00:31:18,688 IS EXPRESSED. 696 00:31:18,688 --> 00:31:28,765 SO, THESE SIX ARE BEHAVING IN 697 00:31:28,765 --> 00:31:29,799 TWO OR THREE DIFFERENT WAYS. 698 00:31:29,799 --> 00:31:30,834 SOME EXPRESSED AT BASELINE, 699 00:31:30,834 --> 00:31:31,701 OTHERS ARE NOT. 700 00:31:31,701 --> 00:31:34,838 THE LEVEL OF EXPRESSION IS SHOWN 701 00:31:34,838 --> 00:31:39,943 HERE COMPARED TO AN AUTHENTIC IN 702 00:31:39,943 --> 00:31:42,245 VITRO EXPRESSION YU2 AUTHENTIC 703 00:31:42,245 --> 00:31:45,081 VIRUS AND SEE THE LEVEL OF 704 00:31:45,081 --> 00:31:46,850 EXPRESSION IN THE ONES 705 00:31:46,850 --> 00:31:53,957 EXPRESSING IS MUCH LOWER BY LOGS 706 00:31:53,957 --> 00:31:56,226 THAN THE ACTIVE. 707 00:31:56,226 --> 00:31:58,928 WHEN WE TRIED TO LOOK AT THE 708 00:31:58,928 --> 00:32:00,764 RELATIONSHIP BETWEEN THE GENE 709 00:32:00,764 --> 00:32:03,133 AND SITE OF INTEGRATION AND THE 710 00:32:03,133 --> 00:32:05,201 EXPRESSION OF THE PRO VIRUS WHAT 711 00:32:05,201 --> 00:32:06,903 WE SEE IS SOMETHING LINEAR WHICH 712 00:32:06,903 --> 00:32:09,939 IS SIMILAR TO WHAT PAUL WAS 713 00:32:09,939 --> 00:32:11,207 TALKING ABOUT WHICH IS THE 714 00:32:11,207 --> 00:32:13,977 PROVIRUS EXPRESSION IS DICTATED 715 00:32:13,977 --> 00:32:17,781 BY THE GENE AND NOT VICE VERSA. 716 00:32:17,781 --> 00:32:19,315 AND THE VIRUS HERE IS NOT 717 00:32:19,315 --> 00:32:25,155 CHANGING THE EXPRESSION OF THE 718 00:32:25,155 --> 00:32:26,623 GENE. 719 00:32:26,623 --> 00:32:30,260 THE SECOND APPROACH IS TO CLONE 720 00:32:30,260 --> 00:32:34,364 OUT THE ACTUAL CELL THAT CARE 721 00:32:34,364 --> 00:32:36,232 RID THE PROVIRUS. 722 00:32:36,232 --> 00:32:39,302 THE IMPACT PROVIRUS AND THIS IS 723 00:32:39,302 --> 00:32:41,104 THE APPROACH WE'VE TAKEN IN 724 00:32:41,104 --> 00:32:42,338 COLLABORATION WITH BRAD AND 725 00:32:42,338 --> 00:32:47,777 BASED ON OUR OWN WORK ON T CELL 726 00:32:47,777 --> 00:32:49,946 RECEPTOR EXPRESSION IN CLONES OF 727 00:32:49,946 --> 00:32:51,347 CELLS BASED ON T CELL RECEPTOR 728 00:32:51,347 --> 00:32:57,120 WHICH ENRICHED THE POPULATION 729 00:32:57,120 --> 00:33:00,156 THAT WE WANT AND THEN GO AHEAD 730 00:33:00,156 --> 00:33:00,990 AND CLONE IT. 731 00:33:00,990 --> 00:33:04,794 WHAT WE'VE LEARNED BY COMPARING 732 00:33:04,794 --> 00:33:05,395 EX VIVO CELLS. 733 00:33:05,395 --> 00:33:06,863 CELLS STRAIGHT OUT OF THE 734 00:33:06,863 --> 00:33:10,500 INDIVIDUAL AND CELLS THAT WE'VE 735 00:33:10,500 --> 00:33:12,469 GROWN IN CULTURE BY 10X IS 736 00:33:12,469 --> 00:33:13,603 THEY'RE RELATIVELY SIMILAR IN 737 00:33:13,603 --> 00:33:14,871 TERMS OF GENE EXPRESSION. 738 00:33:14,871 --> 00:33:15,538 SO WE HAVEN'T CHANGED THEM VERY 739 00:33:15,538 --> 00:33:18,808 MUCH. 740 00:33:18,808 --> 00:33:22,378 AND THE OTHER THING THAT WE'VE 741 00:33:22,378 --> 00:33:25,081 LEARNED IS HIV IS EXPRESSED IN 742 00:33:25,081 --> 00:33:28,451 THESE CELLS BUT AT VERY FAR 743 00:33:28,451 --> 00:33:31,855 LOWER LEVELS THAN AN AUTHENTIC 744 00:33:31,855 --> 00:33:32,222 INFECTION. 745 00:33:32,222 --> 00:33:34,657 AND AGAIN THE PROVIRAL 746 00:33:34,657 --> 00:33:36,826 INTEGRATION IS NOT CHANGING THE 747 00:33:36,826 --> 00:33:37,927 EXPRESSION OF THE GENE TO WHICH 748 00:33:37,927 --> 00:33:39,596 THEY ARE EXPRESSED. 749 00:33:39,596 --> 00:33:46,603 THIS IS A SMALL NUMBER. 750 00:33:46,603 --> 00:33:52,308 IF ALL OF NA -- THAT IS TRUE IS 751 00:33:52,308 --> 00:33:57,013 THE BASIS OF WHAT WE'RE TRYING 752 00:33:57,013 --> 00:33:58,515 TO UNDERSTAND THE INFUSION OF 753 00:33:58,515 --> 00:34:00,583 CELLS IN TRIALS THEY'RE DOING 754 00:34:00,583 --> 00:34:01,751 IMPACTING THE RESERVOIR AND 755 00:34:01,751 --> 00:34:05,655 WHETHER OR NOT THE INFUSION OF 756 00:34:05,655 --> 00:34:10,360 ANTIBODIES CAN HELP TO 757 00:34:10,360 --> 00:34:12,195 ACCELERATE THE RESERVOIR. 758 00:34:12,195 --> 00:34:16,833 I MENTIONED THE WORK WAS HEADED 759 00:34:16,833 --> 00:34:19,802 BY AND WE HAVE HELP FROM A 760 00:34:19,802 --> 00:34:24,841 NUMBER OF OTHER PEOPLE AND 761 00:34:24,841 --> 00:34:31,447 COLLABORATED TO GROW CELLS IN 762 00:34:31,447 --> 00:34:39,022 VITRO. 763 00:34:39,022 --> 00:34:48,398 >> SO PAUL AND MICHEL HAVE 764 00:34:48,398 --> 00:34:52,368 TALKED ABOUT THE IDEA THAT SOME 765 00:34:52,368 --> 00:34:54,571 CELLS CAN CONTINUE TO BE 766 00:34:54,571 --> 00:34:56,673 RECOGNIZED BY HIV AND RESIST 767 00:34:56,673 --> 00:34:57,340 BEING KILLED. 768 00:34:57,340 --> 00:34:59,676 FOR A LONG TIME WE'VE BEEN 769 00:34:59,676 --> 00:35:03,746 STRUGGLING HOW TO STUDY THE RARE 770 00:35:03,746 --> 00:35:05,181 CELLS AND HAVE A SOLUTION THAT'S 771 00:35:05,181 --> 00:35:07,817 BEEN TALKED ABOUT THROUGH A LOT 772 00:35:07,817 --> 00:35:09,619 OF EFFORT AND LOVE WE CAN GROW 773 00:35:09,619 --> 00:35:11,888 CLONES, TENS OF MILLIONS OF 774 00:35:11,888 --> 00:35:22,432 CELLS FROM HARBORING CELLS FROM 775 00:35:22,699 --> 00:35:26,202 THEM AND STUDY THEM AND THIS 776 00:35:26,202 --> 00:35:27,403 EXPRESSES HIV AND COMES FROM A 777 00:35:27,403 --> 00:35:29,505 PERSON LIVING WITH HIV IN 778 00:35:29,505 --> 00:35:32,275 CONTRAST TO OTHER LATENT CLONES. 779 00:35:32,275 --> 00:35:34,244 HOWEVER, IT'S MASSIVELY EXPANDED 780 00:35:34,244 --> 00:35:34,911 IN THE INDIVIDUAL. 781 00:35:34,911 --> 00:35:45,455 SO WHY IS THIS CLONE PERSISTING? 782 00:36:11,047 --> 00:36:13,716 THE QUESTION IS DOES THE 783 00:36:13,716 --> 00:36:17,153 INFECTED CELL SURVIVE THE ATTACK 784 00:36:17,153 --> 00:36:19,289 COMPARED TO THE UNINFECTED CELL 785 00:36:19,289 --> 00:36:20,490 AND WE HAVE THE CELLS IN THE 786 00:36:20,490 --> 00:36:22,292 SAME WELL TO SERVE AS A NICE 787 00:36:22,292 --> 00:36:22,525 CONTROL. 788 00:36:22,525 --> 00:36:24,027 SO WITH ALL THAT THIS IS WHAT 789 00:36:24,027 --> 00:36:24,994 THE RESULT LOOKS LIKE. 790 00:36:24,994 --> 00:36:27,497 WE'RE VERY EXCITED TO SEE THIS. 791 00:36:27,497 --> 00:36:30,466 SO WHEN YOU ADD CTL THE PEP SIDE 792 00:36:30,466 --> 00:36:32,168 PULSE CELLS ARE KILLED OFF 793 00:36:32,168 --> 00:36:33,803 EFFICIENTLY AND THE ONLY 794 00:36:33,803 --> 00:36:35,738 SURVIVORS YOU SEE ARE THE 795 00:36:35,738 --> 00:36:36,572 INFECTED CLONE. 796 00:36:36,572 --> 00:36:38,341 THERE'S NO SURVIVORS FROM THE 797 00:36:38,341 --> 00:36:39,275 SAME WELL. 798 00:36:39,275 --> 00:36:40,843 THAT'S ONE WELL. 799 00:36:40,843 --> 00:36:42,945 THESE ARE MULT PRAL SUB CLONES 800 00:36:42,945 --> 00:36:45,114 THE OF THE SAME CLONE FROM AN 801 00:36:45,114 --> 00:36:48,251 INDIVIDUAL AND AFTER CTL KILLING 802 00:36:48,251 --> 00:36:54,757 WE HAVE MULTIPLE SURVIVE. 803 00:36:54,757 --> 00:36:56,492 WE CAN NOW STUDY THIS CLONE 804 00:36:56,492 --> 00:36:59,329 SINCE WE HAVE IT ISOLATED. 805 00:36:59,329 --> 00:37:00,630 THIS ONE DOESN'T GROW QUITE AS 806 00:37:00,630 --> 00:37:01,964 WELL AS WE'D LIKE BUT CAN GET 807 00:37:01,964 --> 00:37:02,865 SOME ANSWERS. 808 00:37:02,865 --> 00:37:05,234 THE FIRST THING WE OBSERVED IS 809 00:37:05,234 --> 00:37:08,471 THE OVEREXPRESSED FAMILY MEMBER 810 00:37:08,471 --> 00:37:12,508 BCLXL A PROSURVIVAL MECHANISM 811 00:37:12,508 --> 00:37:13,943 MAY HELP THE CELL SURVIVE AND 812 00:37:13,943 --> 00:37:16,179 WORK FROM OTHERS SHOWED IT CAN 813 00:37:16,179 --> 00:37:17,880 BE OVEREXPRESSED IN CELLS THAT 814 00:37:17,880 --> 00:37:19,615 HARBOR THE HIV RESERVOIR AND 815 00:37:19,615 --> 00:37:20,483 THERE'S CLINICAL TRIALS ONGOING 816 00:37:20,483 --> 00:37:22,952 TO TEST WHETHER BCL2 INHIBITORS 817 00:37:22,952 --> 00:37:24,387 CAN REDUCE THE RESERVOIRS. 818 00:37:24,387 --> 00:37:26,789 WHAT JUMPED OUT TO US FROM THE 819 00:37:26,789 --> 00:37:30,860 SEQUENCING DATA WAS THIS CLONE 820 00:37:30,860 --> 00:37:36,299 IS HIGHLY CYTOTOXIC COMPARED TO 821 00:37:36,299 --> 00:37:37,900 UNINFECTED CELLS CLONED IN 822 00:37:37,900 --> 00:37:42,105 PARALLEL AND EXPRESSED AN NK 823 00:37:42,105 --> 00:37:46,876 MARKER AND AN NK CD4 T CELL. 824 00:37:46,876 --> 00:37:47,977 WE'LL COME BACK TO THAT BUT WHAT 825 00:37:47,977 --> 00:37:49,946 WE WANT TO DO IS HAVE 826 00:37:49,946 --> 00:37:51,781 THERAPEUTIC TARGETS TO OVERCOME 827 00:37:51,781 --> 00:37:55,318 CTL RESISTANCE. 828 00:37:55,318 --> 00:38:00,857 WE CAN GET CLUES FROM PROFILING 829 00:38:00,857 --> 00:38:05,661 THE RESERVOIR CLONE AND NEED TO 830 00:38:05,661 --> 00:38:09,599 KNOW WHAT THEY LOOK LIKE AND 831 00:38:09,599 --> 00:38:10,933 HOPE IT WILL HELP THE FIELD AND 832 00:38:10,933 --> 00:38:14,771 HERE'S HOW WE DEFINE AND 833 00:38:14,771 --> 00:38:17,340 CHARACTERIZE CTL RESISTANCE 834 00:38:17,340 --> 00:38:19,542 CELLS IN GENERAL AND BEGAN WITH 835 00:38:19,542 --> 00:38:22,378 MEMORY CELLS AND INFECT WILL 836 00:38:22,378 --> 00:38:27,517 THEM WITH WILD TYPE HIV OR ONE 837 00:38:27,517 --> 00:38:31,020 POINT HIV IDENTIFY BY A CLONE 838 00:38:31,020 --> 00:38:33,089 AND CHALLENGED AND WE KILL MOST 839 00:38:33,089 --> 00:38:36,859 THE CELLS THAT HAVE WILD TYPE 840 00:38:36,859 --> 00:38:38,528 VIRUS TRARGETED AND DON'T KILL 841 00:38:38,528 --> 00:38:40,129 THE BY STANDARDS AND ARE THE 842 00:38:40,129 --> 00:38:41,931 CELLS THAT SURVIVE THE FIRST HIT 843 00:38:41,931 --> 00:38:43,699 RESISTANT OR LUCKY IN THE FIRST 844 00:38:43,699 --> 00:38:44,000 ROUND? 845 00:38:44,000 --> 00:38:47,537 TO TEST THAT WE COME IN WITH THE 846 00:38:47,537 --> 00:38:49,906 SECOND CLONE THAT TARGETS THE 847 00:38:49,906 --> 00:38:52,642 EPITOPE AND NOW EVERYTHING'S A 848 00:38:52,642 --> 00:38:52,875 TARGET. 849 00:38:52,875 --> 00:38:54,177 THE CELLS NOT CHALLENGED IN THE 850 00:38:54,177 --> 00:38:55,178 FIRST ROUND ARE KILLED. 851 00:38:55,178 --> 00:38:57,547 WHEREAS THE CELLS THAT SURVIVED 852 00:38:57,547 --> 00:38:59,782 AND SELECTED IN THE FIRST ROUND 853 00:38:59,782 --> 00:39:01,050 CONTINUE TO SURVIVE. 854 00:39:01,050 --> 00:39:02,585 SO DIRECT EVIDENCE THE CELLS 855 00:39:02,585 --> 00:39:06,422 HAVE SOME ABILITY TO RESIST CITO 856 00:39:06,422 --> 00:39:09,025 TOXIC T CELL AND WE CAN 857 00:39:09,025 --> 00:39:10,693 CHARACTERIZE WHAT MAKES THE CELL 858 00:39:10,693 --> 00:39:11,661 SPECIAL. 859 00:39:11,661 --> 00:39:19,101 THIS IS BULK RNA SEQ AND THERE'S 860 00:39:19,101 --> 00:39:23,573 A DISTINCT PROFILE AND THE 861 00:39:23,573 --> 00:39:26,876 SINGLE CELL LETS US DIVE IN THE 862 00:39:26,876 --> 00:39:29,579 HETEROGENEITY AND IT DEFINES 11 863 00:39:29,579 --> 00:39:29,846 CLUSTERS. 864 00:39:29,846 --> 00:39:32,315 WHEN WE EXPOSED THE CTL WE SEE 865 00:39:32,315 --> 00:39:33,950 THE SURVIVORS HAVE ENRICHMENTS 866 00:39:33,950 --> 00:39:37,253 IN SOME CLUSTERS AND DEPLETIONS 867 00:39:37,253 --> 00:39:38,554 IN OTHERS. 868 00:39:38,554 --> 00:39:40,623 THERE'S VARIABILITY IN THEIR 869 00:39:40,623 --> 00:39:42,258 SUSCEPTIBILITY TO CTL. 870 00:39:42,258 --> 00:39:44,093 THEY'RE FLOW STARTED BASED ON 871 00:39:44,093 --> 00:39:46,462 THE EXPRESSION BEFORE GOING INTO 872 00:39:46,462 --> 00:39:46,662 THIS. 873 00:39:46,662 --> 00:39:47,897 THEY'RE ALL EXPRESSING HIV. 874 00:39:47,897 --> 00:39:50,500 AS THE NOT ABOUT LATENCY AND NON 875 00:39:50,500 --> 00:39:53,269 LATENCY IN THE EXPERIMENT. 876 00:39:53,269 --> 00:39:54,871 THE SURVIVING CELLS ARE ALL 877 00:39:54,871 --> 00:39:55,404 EXPRESSING HIV. 878 00:39:55,404 --> 00:39:58,241 SO WHAT CAN BE LEARNED ABOUT THE 879 00:39:58,241 --> 00:39:58,508 CLUSTERS. 880 00:39:58,508 --> 00:39:59,775 THE CLUSTER THAT WAS MOST 881 00:39:59,775 --> 00:40:02,411 CONSISTENTLY ENRICHED IS THE 882 00:40:02,411 --> 00:40:04,747 CLUSTER 9 AND IF YOU ASK WHAT 883 00:40:04,747 --> 00:40:07,817 THE TRANSCRIPTOMIC DATA AND WHAT 884 00:40:07,817 --> 00:40:17,927 POPS OUT IS ITS CYTOTOXIC CD4T 885 00:40:17,927 --> 00:40:25,201 CELLS AND THE REAL CELLS IS 886 00:40:25,201 --> 00:40:26,469 RE-ENRICHED IN THESE CELLS AND 887 00:40:26,469 --> 00:40:29,438 USING THE SAME MODEL TO DEFINE 888 00:40:29,438 --> 00:40:30,873 THIS CLUSTER THE CELLS 889 00:40:30,873 --> 00:40:35,411 EXPRESSING RNA IN VIVO ARE 890 00:40:35,411 --> 00:40:37,246 ENRICHED WITH THE CLUSTER OF 891 00:40:37,246 --> 00:40:38,147 CELLS WE ARE STUDYING. 892 00:40:38,147 --> 00:40:40,650 HERE'S THE FIRST THING AT THE 893 00:40:40,650 --> 00:40:47,023 CENTER OF THIS VEN DIAGRAM 894 00:40:47,023 --> 00:40:48,224 CYTOTOXIC CELLS ARE 895 00:40:48,224 --> 00:40:49,959 HETEROGENEOUS AND ASSOCIATED 896 00:40:49,959 --> 00:40:53,629 WITH CELLS THAT RESIST TL 897 00:40:53,629 --> 00:40:54,096 KILLING. 898 00:40:54,096 --> 00:40:59,268 SO WHY ARE CD4 CELLS CYTOTOXIC. 899 00:40:59,268 --> 00:41:01,938 THEIR JOB IS TO KILL OTHER CELLS 900 00:41:01,938 --> 00:41:04,640 AND DON'T WANT TO SELF-DESTRUCT 901 00:41:04,640 --> 00:41:07,777 SO IT'S LIKE A FLAKE BEING 902 00:41:07,777 --> 00:41:11,647 IMMUNE TO IT'S OWN VENOM LIKE A 903 00:41:11,647 --> 00:41:13,950 SNAKE THAT BITES ITS OWN TONGUE. 904 00:41:13,950 --> 00:41:15,651 HOW DO THEY PROTECT THEMSELVES. 905 00:41:15,651 --> 00:41:18,955 SO ONE OF THE MECHANISMS THAT'S 906 00:41:18,955 --> 00:41:23,159 BEEN IN THE FIELD'S 907 00:41:23,159 --> 00:41:24,860 CONSCIOUSNESS HAS BEEN AN 908 00:41:24,860 --> 00:41:29,298 INHIBITOR FOUND TO BE EXPRESSED 909 00:41:29,298 --> 00:41:31,567 IN CD4 T CELLS AND WORK HAS 910 00:41:31,567 --> 00:41:33,502 SHOWN IF YOU KNOCK THIS OUT YOU 911 00:41:33,502 --> 00:41:36,806 DO NOT IMPROVE KILLING OF THE 912 00:41:36,806 --> 00:41:37,173 CELLS. 913 00:41:37,173 --> 00:41:40,042 SO IT SEEMS TO NOT BE THE MAJOR 914 00:41:40,042 --> 00:41:40,810 THING. 915 00:41:40,810 --> 00:41:42,378 HOWEVER, THE RESERVOIR CLONE DES 916 00:41:42,378 --> 00:41:44,614 PLAYS TWO KNOWN MECHANISMS BY 917 00:41:44,614 --> 00:41:48,050 WHICH CYTOTOXIC T CELLS PREVENT 918 00:41:48,050 --> 00:41:48,451 SELF-DESTRUCTION. 919 00:41:48,451 --> 00:41:50,786 IF YOU LOOK AT THE CELLS THAT 920 00:41:50,786 --> 00:41:57,560 RECEIVED A HIT THE UNINFECTED 921 00:41:57,560 --> 00:41:58,694 CLONE DIES AND ESSENTIALLY IT 922 00:41:58,694 --> 00:42:01,063 GETS A HIT AND HITS BACK. 923 00:42:01,063 --> 00:42:03,332 AND IT'S KNOWN TO BE MECHANISM 924 00:42:03,332 --> 00:42:06,502 BY WHICH NATURAL KILLER CELLS 925 00:42:06,502 --> 00:42:08,871 PROTECT THEMSELVES FROM CELLS IN 926 00:42:08,871 --> 00:42:10,106 ENZYME. 927 00:42:10,106 --> 00:42:14,276 AND SOME CELLS RELEASE INTO THE 928 00:42:14,276 --> 00:42:16,345 SYNAPSE TO PROTECT THE CELL. 929 00:42:16,345 --> 00:42:18,814 IF WHERE HE LOOK AT THE 930 00:42:18,814 --> 00:42:20,650 RESERVOIR CELL IT OVEREXPRESSES 931 00:42:20,650 --> 00:42:26,656 AND EXPOSES IT AT THE SURFACE 932 00:42:26,656 --> 00:42:28,324 AND IT GRANULATES. 933 00:42:28,324 --> 00:42:29,725 THE NEXT STEP IS TRYING TO 934 00:42:29,725 --> 00:42:33,929 OVERCOME AND SEE IF WE CAN 935 00:42:33,929 --> 00:42:36,332 IMPROVE KILLING OF THIS CLONE. 936 00:42:36,332 --> 00:42:38,768 I CAN'T TELL YOU JUST ABOUT THE 937 00:42:38,768 --> 00:42:41,037 ONE CLUSTER SO WHAT'S THE MOST 938 00:42:41,037 --> 00:42:43,673 DIFFERENT THING ABOUT ALL THE 939 00:42:43,673 --> 00:42:44,874 CELLS. 940 00:42:44,874 --> 00:42:52,381 SURVIVE ARE METABOLICALLY QUI -- 941 00:42:52,381 --> 00:42:54,216 QUIESCENT AND THEY HAVE LESS 942 00:42:54,216 --> 00:42:57,853 REACTIVE OXYGEN SPECIES AND CAN 943 00:42:57,853 --> 00:43:02,158 DO FUNCTIONAL ASSAYS AND SEE THE 944 00:43:02,158 --> 00:43:04,827 SURVIVORS HAVE LESS CAPACITY AS 945 00:43:04,827 --> 00:43:07,263 WELL AS LESS GLUCOSE DEPENDENT 946 00:43:07,263 --> 00:43:08,664 METABOLISM AND SELECTED FOR 947 00:43:08,664 --> 00:43:15,304 CELLS LOW FOR THIS TOXIC 948 00:43:15,304 --> 00:43:17,907 BYPRODUCT AND WE CONSISTENTLY 949 00:43:17,907 --> 00:43:18,808 SEE THAT. 950 00:43:18,808 --> 00:43:20,976 WHY IS METABOLISM IMPORTANT? 951 00:43:20,976 --> 00:43:22,545 WE THINK THIS IS THE REASON. 952 00:43:22,545 --> 00:43:24,914 SO WHEN A CYTOTOXIC T CELL 953 00:43:24,914 --> 00:43:29,585 DELIVERED A HIT TO A TARGET CELL 954 00:43:29,585 --> 00:43:32,254 ENZYMES REACT MITOCHONDRIA AND 955 00:43:32,254 --> 00:43:33,589 THESE DAMAGE DNA IS A BIG PART 956 00:43:33,589 --> 00:43:34,724 OF WHY THE CELL DIES. 957 00:43:34,724 --> 00:43:37,493 IF THE CELL DOESN'T HAVE ENOUGH 958 00:43:37,493 --> 00:43:40,796 OF THESE IT CAN EXPLAIN WHY IT 959 00:43:40,796 --> 00:43:41,630 LIVES. 960 00:43:41,630 --> 00:43:44,967 THE DRUG WE SHOWED IMPROVE LEVEL 961 00:43:44,967 --> 00:43:48,404 OF RE-OXYGEN SPECIES IN CELLS 962 00:43:48,404 --> 00:43:50,473 AND IMPROVES KILLING OF CELLS. 963 00:43:50,473 --> 00:43:52,875 SO HERE WE'RE SEEING MORE THAN 964 00:43:52,875 --> 00:44:00,716 98% KILLING OF HIV INFECTED CD4 965 00:44:00,716 --> 00:44:03,252 CELLS AND I'VE BEEN DOING 966 00:44:03,252 --> 00:44:04,620 KILLING ASSAYS FOR YEARS AND 967 00:44:04,620 --> 00:44:07,289 THIS IS THE MOST POTENT KILLING 968 00:44:07,289 --> 00:44:07,723 I'VE SEEN. 969 00:44:07,723 --> 00:44:09,225 I'M PRETTY EXCITED ABOUT THIS. 970 00:44:09,225 --> 00:44:11,794 THIS IS FROM PUBLISHED WORK AND 971 00:44:11,794 --> 00:44:16,432 THE CELLS THAT TRANSCRIBE IN 972 00:44:16,432 --> 00:44:20,636 VIVO ALIGN IN MANY WAYS WITH THE 973 00:44:20,636 --> 00:44:22,638 METABOLIC QUIESCENT PROFILE OF 974 00:44:22,638 --> 00:44:25,207 OUR CELLS AND MAY BE AFFECTING 975 00:44:25,207 --> 00:44:26,375 HOW THESE SURVIVE. 976 00:44:26,375 --> 00:44:28,911 SO, MARINA MENTIONED WE'RE IN 977 00:44:28,911 --> 00:44:30,446 THE DISCOVERY TO TRANSLATION 978 00:44:30,446 --> 00:44:30,713 PIPELINE. 979 00:44:30,713 --> 00:44:32,281 I DON'T HAVE TIME TO TALK ABOUT 980 00:44:32,281 --> 00:44:34,583 SOME MUCH THESE TODAY AND WANTED 981 00:44:34,583 --> 00:44:36,819 TO TALK ABOUT THE LEADING EDGE 982 00:44:36,819 --> 00:44:38,487 OF OUR WORK SHOWING IN VITRO AND 983 00:44:38,487 --> 00:44:39,789 IN THE LAST 30 SECONDS OR SO I 984 00:44:39,789 --> 00:44:44,693 WANT TO GIVE A NOD TO THE 985 00:44:44,693 --> 00:44:47,830 INHIBITER METASTAT WE THINK IS 986 00:44:47,830 --> 00:44:49,832 POISED FOR CLINICAL TRANSLATION. 987 00:44:49,832 --> 00:44:51,167 THOUGH I'M NOT GIVING MUCH TIME 988 00:44:51,167 --> 00:44:53,335 TO IT TODAY THERE'S A POSTER 989 00:44:53,335 --> 00:44:56,672 HERE AS WELL AND THIS IS A CLOSE 990 00:44:56,672 --> 00:44:57,940 COLLABORATION WITH THE HIV 991 00:44:57,940 --> 00:45:01,343 COLLABORATORY ALSO. 992 00:45:01,343 --> 00:45:06,916 WHAT DOES TESMETASTAT DO? 993 00:45:06,916 --> 00:45:12,788 WE SEE SELECTION FOR CELLS LOW 994 00:45:12,788 --> 00:45:16,492 TO CYTOTOXIC T CELLS AND IT ACT 995 00:45:16,492 --> 00:45:20,930 TO INCREASE MHC1 ON THE SURFACE 996 00:45:20,930 --> 00:45:22,464 OF INFECTED CELLS IMPROVING 997 00:45:22,464 --> 00:45:24,166 KILLING FOR T CELLS IN VITRO. 998 00:45:24,166 --> 00:45:27,570 A FEW SNIPPETS FROM THE MOUSE 999 00:45:27,570 --> 00:45:29,939 MODEL GIVING IT AT THE TIME OF 1000 00:45:29,939 --> 00:45:32,107 INITIATION WE SEE LESS RESERVOIR 1001 00:45:32,107 --> 00:45:33,943 SEATING AND THE MOST REMARKABLY 1002 00:45:33,943 --> 00:45:36,879 WE SEE PROFOUND REDUCTIONS IN PD 1003 00:45:36,879 --> 00:45:39,014 1 ON CD 8 T CELLS IN THE MICE 1004 00:45:39,014 --> 00:45:40,816 AND THEY'RE SUSTAINED FOR WEEKS 1005 00:45:40,816 --> 00:45:42,718 AFTER THE DRUG IS GONE. 1006 00:45:42,718 --> 00:45:44,587 WE'RE NOT SURE IF THAT'S ANTIGEN 1007 00:45:44,587 --> 00:45:45,955 LOAD OR PROGRAMMING OF THE 1008 00:45:45,955 --> 00:45:46,589 CELLS. 1009 00:45:46,589 --> 00:45:48,023 SORRY TO DO THAT QUICKLY BUT 1010 00:45:48,023 --> 00:45:48,891 PLEASE SEE THE POSTER. 1011 00:45:48,891 --> 00:45:50,626 TO WRAP UP I WANT TO ACKNOWLEDGE 1012 00:45:50,626 --> 00:45:52,695 THE TERRIFIC COLLABORATIONS WITH 1013 00:45:52,695 --> 00:45:55,798 EVERYONE IN REACH AND THE WORK 1014 00:45:55,798 --> 00:46:01,203 IS ONLY POSSIBLE BECAUSE OF WORK 1015 00:46:01,203 --> 00:46:02,805 WITH THE LABS AND ISABELLA LEADS 1016 00:46:02,805 --> 00:46:05,941 THE TEAM DOING THE GREAT WORK 1017 00:46:05,941 --> 00:46:08,744 WITH THE CLONES AND OTHERS 1018 00:46:08,744 --> 00:46:12,915 LEADING THE HCH2 PROJECT AND 1019 00:46:12,915 --> 00:46:23,425 THANK YOU FOR YOUR ATTENTION. 1020 00:46:24,627 --> 00:46:26,528 >> WE HAVE ABOUT 15 MINUTES FOR 1021 00:46:26,528 --> 00:46:26,829 DISCUSSION. 1022 00:46:26,829 --> 00:46:29,331 ANYONE WITH A QUESTION, PLEASE 1023 00:46:29,331 --> 00:46:31,600 STEP UP TO THE MICROPHONE AND 1024 00:46:31,600 --> 00:46:32,601 SAY WHO YOU ARE AND WHERE YOU'RE 1025 00:46:32,601 --> 00:46:33,936 FROM AND LET'S GO AHEAD. 1026 00:46:33,936 --> 00:46:35,204 I CAN'T SEE YOU VERY WELL FROM 1027 00:46:35,204 --> 00:46:37,606 HERE SO GO AHEAD. 1028 00:46:37,606 --> 00:46:39,341 >> HI, MIKE BETTS FROM 1029 00:46:39,341 --> 00:46:41,277 UNIVERSITY OF PENNSYLVANIA. 1030 00:46:41,277 --> 00:46:42,811 FIRST COMPLEMENTS TO ALL OF YOU. 1031 00:46:42,811 --> 00:46:46,582 IT'S FANTASTIC WORK. 1032 00:46:46,582 --> 00:46:48,584 MY QUESTION IS FOR PAUL. 1033 00:46:48,584 --> 00:46:49,985 IT'S INTERESTING DATA ABOUT THIS 1034 00:46:49,985 --> 00:46:51,020 MOUSE MODEL. 1035 00:46:51,020 --> 00:46:53,188 I'M CURIOUS AS YOU FLASH BY THE 1036 00:46:53,188 --> 00:46:54,623 INTEGRATION SITES AND THINKING 1037 00:46:54,623 --> 00:46:57,960 WHAT THE GENES WERE I DIDN'T 1038 00:46:57,960 --> 00:46:59,929 NOTICE A LOT OF OFFICE 1039 00:46:59,929 --> 00:47:01,497 IMMUNOLOGICAL GENE INTEGRATIONS 1040 00:47:01,497 --> 00:47:06,001 WHICH MADE ME WONDER IN YOUR NSG 1041 00:47:06,001 --> 00:47:11,106 MOUSE MODEL WHICH IS A CLEAN 1042 00:47:11,106 --> 00:47:16,545 FACILITY CAN YOU ALTER A MORE 1043 00:47:16,545 --> 00:47:18,280 PHYSIOLOGICAL MODEL TO US WOULD 1044 00:47:18,280 --> 00:47:26,822 THAT THEN CHANGE YOUR PROFILES? 1045 00:47:26,822 --> 00:47:29,425 >> SO, SINCE WE'RE THINKING OF 1046 00:47:29,425 --> 00:47:30,926 PROVIRUSES VERY MUCH A 1047 00:47:30,926 --> 00:47:31,727 PASSENGER, ANYTHING THAT WOULD 1048 00:47:31,727 --> 00:47:33,929 CHANGE THE PROFILE OF THE CELLS 1049 00:47:33,929 --> 00:47:38,534 THAT PROLIFERATE WOULD LIKELY 1050 00:47:38,534 --> 00:47:41,070 CHANGE THE SPECTRUM OF CLONES 1051 00:47:41,070 --> 00:47:42,338 THAT GROW OUT. 1052 00:47:42,338 --> 00:47:44,273 I STILL THOUGH THAT IF 1053 00:47:44,273 --> 00:47:47,176 INTEGRATION IN THE GENE HAD SOME 1054 00:47:47,176 --> 00:47:52,681 INTRINSIC ABILITY TO DRIVE 1055 00:47:52,681 --> 00:47:54,016 PROLIFERATION WOULD COME OUT IN 1056 00:47:54,016 --> 00:48:04,393 THE CLEAN ENVIRONMENT. 1057 00:48:06,528 --> 00:48:10,699 >> THIS IS FOR PAUL AND JOE. 1058 00:48:10,699 --> 00:48:12,634 WHATEVER GETS EXPRESSED ON THE 1059 00:48:12,634 --> 00:48:15,804 CELLS IN THE MICE, IS THAT 1060 00:48:15,804 --> 00:48:17,439 IMMUNOGENIC IN THE MICE? 1061 00:48:17,439 --> 00:48:19,675 >> THEY'RE NFG MICE THEY 1062 00:48:19,675 --> 00:48:21,877 SHOULDN'T CARE WITH BINDING 1063 00:48:21,877 --> 00:48:22,111 PEPTIDE. 1064 00:48:22,111 --> 00:48:25,748 >> OKAY. 1065 00:48:25,748 --> 00:48:29,651 >> JIM RILEY, UNIVERSITY OF 1066 00:48:29,651 --> 00:48:30,819 PENNSYLVANIA. 1067 00:48:30,819 --> 00:48:33,956 I'M SORRY BUT WHY DIDN'T HIV 1068 00:48:33,956 --> 00:48:36,525 COME OUT? 1069 00:48:36,525 --> 00:48:39,328 LIKE WHAT HIV DID YOU PUT IN? 1070 00:48:39,328 --> 00:48:40,896 >> IT DOESN'T HAVE STRUCTURAL 1071 00:48:40,896 --> 00:48:42,765 GENES IT HAS REPORTER GENES 1072 00:48:42,765 --> 00:48:43,732 INSTEAD. 1073 00:48:43,732 --> 00:48:49,104 >> AND HAVE YOU CONSIDERED THE 1074 00:48:49,104 --> 00:48:52,174 REASON -- WELL, THAT WAS 1075 00:48:52,174 --> 00:48:52,408 COVERED. 1076 00:48:52,408 --> 00:48:55,277 THE CULTURE, RIGHT, AFFECTS 1077 00:48:55,277 --> 00:48:57,713 WHAT'S GOING ON, RIGHT. 1078 00:48:57,713 --> 00:49:00,082 I'M SURE THEY'RE CULTURED MORE 1079 00:49:00,082 --> 00:49:02,217 MONTHS GOING FROM ONE CELL TO 1080 00:49:02,217 --> 00:49:03,352 BILLIONS. 1081 00:49:03,352 --> 00:49:04,386 >> YEAH. 1082 00:49:04,386 --> 00:49:08,323 >> SO ARE YOU SELECTING FOR -- 1083 00:49:08,323 --> 00:49:12,594 IS THERE A PROCESS BY ONES THAT 1084 00:49:12,594 --> 00:49:14,863 WOULD COME OUT ARE LIMITED IS 1085 00:49:14,863 --> 00:49:15,631 WHAT I'M ASKING. 1086 00:49:15,631 --> 00:49:17,299 >> THERE'S NO MECHANISM FOR 1087 00:49:17,299 --> 00:49:17,966 ELIMINATION OF CELLS IN THE 1088 00:49:17,966 --> 00:49:21,403 MOUSE WE KNOW ABOUT. 1089 00:49:21,403 --> 00:49:24,740 >> ARE YOU ASKING ABOUT THE IN 1090 00:49:24,740 --> 00:49:26,175 VITRO CLONE CULTURES? 1091 00:49:26,175 --> 00:49:34,550 >> KIND OF BOTH, RIGHT? 1092 00:49:34,550 --> 00:49:36,585 IN VITRO -- 1093 00:49:36,585 --> 00:49:39,288 >> FOR THE AUTHENTIC CELLS WE 1094 00:49:39,288 --> 00:49:41,256 TRY TO HAVE A LOOK AT THEM WHEN 1095 00:49:41,256 --> 00:49:43,926 THEY'RE BRAND NEW IN CULTURE AND 1096 00:49:43,926 --> 00:49:47,596 HAD RECENT CLONES WE SAW EXPAND 1097 00:49:47,596 --> 00:49:49,798 50 FOLD IN THREE DAYS AND THE 1098 00:49:49,798 --> 00:49:52,167 MOST GAG EXPRESSION WE SAW IS 1099 00:49:52,167 --> 00:49:52,367 .3%. 1100 00:49:52,367 --> 00:49:54,570 SO WE DO CULTURE THEM FOR A LONG 1101 00:49:54,570 --> 00:49:56,605 TIME BUT WE HAVE AN OPPORTUNITY 1102 00:49:56,605 --> 00:50:00,909 TO LOOK WHEN THEY'RE RELATIVELY 1103 00:50:00,909 --> 00:50:04,513 NEW AND AS MICHEL SHOWED THE 1104 00:50:04,513 --> 00:50:06,348 TRANSCRIPTIONAL PROFILE IS IN 1105 00:50:06,348 --> 00:50:06,582 VIVO. 1106 00:50:06,582 --> 00:50:10,752 >> OBVIOUSLY THERE HAS TO BE 1107 00:50:10,752 --> 00:50:12,254 CLONES WHERE HIV COMES 1108 00:50:12,254 --> 00:50:16,225 IMMEDIATELY OR DO YOU -- OR DID 1109 00:50:16,225 --> 00:50:17,860 YOU NOT SURVEY THOSE? 1110 00:50:17,860 --> 00:50:19,394 >> THEY DO VARY IN THE CLONES 1111 00:50:19,394 --> 00:50:21,930 THAT WE GROW IN VITRO. 1112 00:50:21,930 --> 00:50:23,866 THE ONES THAT EXPRESS LET'S SAY 1113 00:50:23,866 --> 00:50:26,401 10% IS MAYBE THE HIGHEST WE'VE 1114 00:50:26,401 --> 00:50:30,539 SEEN AND THOSE DO TEND TO NOT 1115 00:50:30,539 --> 00:50:31,273 STICK AROUND AS LONG AS THE 1116 00:50:31,273 --> 00:50:35,310 OTHERS ARE HARDER TO GROW WHERE 1117 00:50:35,310 --> 00:50:38,447 ONES THAT EXPRESSION 1% OR 2% 1118 00:50:38,447 --> 00:50:41,083 ARE WE MISSING SOME THAT EXPRESS 1119 00:50:41,083 --> 00:50:44,620 HIGHER PERCENTAGES? 1120 00:50:44,620 --> 00:50:45,621 THAT'S POSSIBLE. 1121 00:50:45,621 --> 00:50:49,358 >> REMEMBER TO RECEDE 1122 00:50:49,358 --> 00:50:51,593 REPLICATION YOU ONLY NEED ONE 1123 00:50:51,593 --> 00:50:51,793 CELL. 1124 00:50:51,793 --> 00:50:54,029 1% WILL DO IT. 1125 00:50:54,029 --> 00:50:54,696 >> DAVE. 1126 00:50:54,696 --> 00:50:57,132 >> DAVE, USC. 1127 00:50:57,132 --> 00:50:57,933 THAT WAS BEAUTIFUL AND A LOT OF 1128 00:50:57,933 --> 00:50:59,334 DATA SO I'M SURE I MISSED 1129 00:50:59,334 --> 00:50:59,902 SOMETHING. 1130 00:50:59,902 --> 00:51:02,471 I HAVE A CHICKEN AND THE EGG 1131 00:51:02,471 --> 00:51:04,973 QUESTION IN THAT YOU GET TO A 1132 00:51:04,973 --> 00:51:06,742 CELL THAT'S METABOLICALLY 1133 00:51:06,742 --> 00:51:10,445 INACTIVE OR LESS ACTIVE BEING 1134 00:51:10,445 --> 00:51:10,712 RESISTANT. 1135 00:51:10,712 --> 00:51:15,217 IS IT THE CELLS OR THE CELL'S 1136 00:51:15,217 --> 00:51:16,151 EXPRESSION OF THE VIRUS? 1137 00:51:16,151 --> 00:51:18,253 IN YOUR CONTROL WHERE YOU PULSE 1138 00:51:18,253 --> 00:51:21,323 WITH PEPTIDE, HOW DID YOU 1139 00:51:21,323 --> 00:51:22,090 COMPARE PRESENTATION IN PULSE 1140 00:51:22,090 --> 00:51:25,427 CELLS TO THE OTHER CELLS TO SEE 1141 00:51:25,427 --> 00:51:31,867 THEY ARE WERE MRAATCHED TO BE YR 1142 00:51:31,867 --> 00:51:32,367 CONTROL. 1143 00:51:32,367 --> 00:51:33,835 >> IN THE PULSE CELLS IN VITRO 1144 00:51:33,835 --> 00:51:36,638 THEY EXPRESSED SIMILAR AMOUNTS 1145 00:51:36,638 --> 00:51:37,739 OF MHC1. 1146 00:51:37,739 --> 00:51:39,975 I CAN'T SAY WE HAVE A PEPTIDE TO 1147 00:51:39,975 --> 00:51:41,843 DIRECTLY QUANTIFY THAT. 1148 00:51:41,843 --> 00:51:44,613 WE HAVE LARGE EXPRESSES OF 1149 00:51:44,613 --> 00:51:54,590 PEPTIDE, 10 MOLAR AND WE CAN 1150 00:51:54,590 --> 00:51:57,926 LOOK AT GAG EXPRESSION IN THE 1151 00:51:57,926 --> 00:52:00,796 10X OR SORRY, HIV TRANSCRIPTION 1152 00:52:00,796 --> 00:52:04,266 IN THE 10X AND DON'T SEE A 1153 00:52:04,266 --> 00:52:05,267 RELATIONSHIP BETWEEN THE AMOUNT 1154 00:52:05,267 --> 00:52:06,969 OF HIV TRANSCRIPTION AND THE 1155 00:52:06,969 --> 00:52:08,604 METABOLIC STATE WITHIN THIS POOL 1156 00:52:08,604 --> 00:52:14,710 OF CELLS THAT ARE EXPRESSING 1157 00:52:14,710 --> 00:52:14,876 HIV. 1158 00:52:14,876 --> 00:52:16,511 >> BECAUSE THE FOUR QUADRANTS 1159 00:52:16,511 --> 00:52:18,380 YOU HAD BOTTOM LEFT THERE WAS A 1160 00:52:18,380 --> 00:52:20,115 LITTLE BIT OF SIGNAL AND NO 1161 00:52:20,115 --> 00:52:22,751 SIGNAL IN THE BOTTOM RIGHT AND 1162 00:52:22,751 --> 00:52:24,620 THE TOP ETCETERA. 1163 00:52:24,620 --> 00:52:27,256 SO IS THE PRESENTATION OF TARGET 1164 00:52:27,256 --> 00:52:27,956 IN THE PULSE CELLS? 1165 00:52:27,956 --> 00:52:29,925 HOW DO YOU NORMALIZE THAT 1166 00:52:29,925 --> 00:52:31,126 AGAINST PRESENTATION OF TARGET 1167 00:52:31,126 --> 00:52:32,294 IN THE UPPER CELLS. 1168 00:52:32,294 --> 00:52:35,097 >> YEAH, SO WHAT I CAN TELL YOU 1169 00:52:35,097 --> 00:52:40,235 IS WE DO DEGRANULATION WITH THE 1170 00:52:40,235 --> 00:52:42,804 PEPTIDE PULSE INFECTED OR 1171 00:52:42,804 --> 00:52:45,440 UNINFECTED CLONE AND IT 1172 00:52:45,440 --> 00:52:50,112 DEGRANULATES IN RESPONSE TO B 1173 00:52:50,112 --> 00:52:55,017 BOTHPLBOTH 1174 00:52:55,017 --> 00:52:58,420 MAXIMALLY RESPONDS AND CAN'T SAY 1175 00:52:58,420 --> 00:53:00,889 THERE'S YOU CAN'T TRIGGER THE 1176 00:53:00,889 --> 00:53:01,757 CELL. 1177 00:53:01,757 --> 00:53:03,058 IT'S A BODY OF WORK I DIDN'T 1178 00:53:03,058 --> 00:53:05,560 HAVE A CHANCE TO PRESENT TODAY 1179 00:53:05,560 --> 00:53:10,098 BUT THEY'RE LOADED WITH EXCESS 1180 00:53:10,098 --> 00:53:15,804 PEPTIDE AND CAUSE DEGRANULATION 1181 00:53:15,804 --> 00:53:16,204 IN ISOLATION. 1182 00:53:16,204 --> 00:53:20,842 >> I JUST WANTED TO CLARIFY 1183 00:53:20,842 --> 00:53:21,043 THIS. 1184 00:53:21,043 --> 00:53:23,078 SO ARE YOU SAYING AS THE 1185 00:53:23,078 --> 00:53:25,814 RESISTANT CELLS INHERENTLY 1186 00:53:25,814 --> 00:53:28,150 EXPRESS LOWER LEVELS OF MHC AND 1187 00:53:28,150 --> 00:53:32,854 THAT'S THE BASIC MECHANISM FOR 1188 00:53:32,854 --> 00:53:33,555 RESISTANCE TO KILLING? 1189 00:53:33,555 --> 00:53:38,360 >> YEAH, THAT IS ONE OF THE 1190 00:53:38,360 --> 00:53:44,900 MECHANISMS AND 10X LET'S US 1191 00:53:44,900 --> 00:53:47,002 TEASE THESE A PART TO SEE THE 1192 00:53:47,002 --> 00:53:52,240 LOW AND HIGH SURVIVORS AND 1193 00:53:52,240 --> 00:53:53,875 THERE'S A LOT OF SURVIVORS THAT 1194 00:53:53,875 --> 00:53:56,712 ARE MCH1 HIGH SO TRAZ NOT JUST 1195 00:53:56,712 --> 00:54:02,417 ABOUT MCH1 HOUR YOU'RE RIGHT, 1196 00:54:02,417 --> 00:54:06,855 MHC1 IS AN ISSUE AND WE TREAT TO 1197 00:54:06,855 --> 00:54:08,623 WE SEE BETTER KILLING AND THAT 1198 00:54:08,623 --> 00:54:10,258 THE ONLY THE CASE WITH WILD TYPE 1199 00:54:10,258 --> 00:54:12,127 VIRUS. 1200 00:54:12,127 --> 00:54:14,463 WE DON'T SEE AN IMPROVEMENT WITH 1201 00:54:14,463 --> 00:54:17,966 THE DELTA F VIRUS BUT SEEMS 1202 00:54:17,966 --> 00:54:21,937 DRIVING MHC1 PLAY COUNTER 1203 00:54:21,937 --> 00:54:22,838 BALANCE BY DOWN REGULATION. 1204 00:54:22,838 --> 00:54:24,439 >> I WAS THINKING IT MAKES A 1205 00:54:24,439 --> 00:54:26,808 NICE STORY FOR HOW THE CELLS 1206 00:54:26,808 --> 00:54:29,678 TRANSITION TO LATENCY AND ESCAPE 1207 00:54:29,678 --> 00:54:31,947 THE IMMUNE KILLING AS A MODEL. 1208 00:54:31,947 --> 00:54:33,448 >> RIGHT. 1209 00:54:33,448 --> 00:54:37,652 THEY ARE START OFF WITH LESS 1210 00:54:37,652 --> 00:54:37,986 ANTIGENICITY. 1211 00:54:37,986 --> 00:54:44,359 I DON'T THINK LATENCY AND 1212 00:54:44,359 --> 00:54:47,729 SURVIVABILITY ARE MUTUALLY 1213 00:54:47,729 --> 00:54:48,363 EXCLUSIVE. 1214 00:54:48,363 --> 00:54:49,531 >> THIS IS AN EXCELLENT 1215 00:54:49,531 --> 00:54:50,332 PRESENTATION, THANK YOU GUYS FOR 1216 00:54:50,332 --> 00:54:55,036 THAT. 1217 00:54:55,036 --> 00:54:56,805 LOOKING FORWARD TO HOW WILL IT 1218 00:54:56,805 --> 00:55:00,308 BE TRANSLATED TO THE COMMUNITY 1219 00:55:00,308 --> 00:55:01,443 MEMBERS WHO WILL HOPEFULLY 1220 00:55:01,443 --> 00:55:04,646 RECEIVE THIS AMAZING WORK YOU 1221 00:55:04,646 --> 00:55:05,013 GUYS ARE DOING? 1222 00:55:05,013 --> 00:55:07,015 >> SO THE WORKSHOP THE IDEA IS 1223 00:55:07,015 --> 00:55:09,351 TO BRING IN INDIVIDUALS AND ONE 1224 00:55:09,351 --> 00:55:10,786 OF THE REQUIREMENTS IS THAT 1225 00:55:10,786 --> 00:55:13,922 THERE'S A TRANSLATION COMPONENT. 1226 00:55:13,922 --> 00:55:16,358 SO WE WILL HAVE RESERVOIR SPACE 1227 00:55:16,358 --> 00:55:18,193 FOR ONE CAB MEMBER FROM EACH OF 1228 00:55:18,193 --> 00:55:19,294 THE COLLABORATORIES 1229 00:55:19,294 --> 00:55:20,962 PARTICIPATING AND I THINK 1230 00:55:20,962 --> 00:55:22,464 THERE'S STILL ROOM FOR 1231 00:55:22,464 --> 00:55:23,999 ADDITIONAL COLLABORATION IF 1232 00:55:23,999 --> 00:55:24,633 OTHERS ARE INTERESTED IN 1233 00:55:24,633 --> 00:55:25,167 PARTNERING THERE. 1234 00:55:25,167 --> 00:55:28,003 BUT THE IDEA IS FOR THOSE WHO 1235 00:55:28,003 --> 00:55:29,938 ATTEND WILL GAIN SKILLS IN 1236 00:55:29,938 --> 00:55:31,106 SCIENCE TRANSLATION AND BE ABLE 1237 00:55:31,106 --> 00:55:35,444 TO COMMUNICATE THAT VIA A BLOG 1238 00:55:35,444 --> 00:55:36,578 OR ADDITIONAL SOCIAL MEDIA 1239 00:55:36,578 --> 00:55:37,612 COMPONENTS BUT HAVE AN ACTIVE 1240 00:55:37,612 --> 00:55:48,056 OUTREACH COMPONENT TO IT. 1241 00:55:50,058 --> 00:55:55,997 >> AND WE HAVE HDA2. 1242 00:55:55,997 --> 00:55:58,333 DO YOU KNOW IF IT PLAYS A ROLE 1243 00:55:58,333 --> 00:56:01,736 ACTING ON THE SAME CELL OR BY 1244 00:56:01,736 --> 00:56:07,008 TARGETING THE SPOT YOU CAN 1245 00:56:07,008 --> 00:56:07,609 TARGET DIFFERENT CELLS? 1246 00:56:07,609 --> 00:56:09,811 >> IT'S A REALLY GREAT QUESTION 1247 00:56:09,811 --> 00:56:13,014 AND IT'S SOMETHING THAT WE WANT 1248 00:56:13,014 --> 00:56:15,784 TO TEASE OUT WITH OUR 10X DATA 1249 00:56:15,784 --> 00:56:17,819 AND HAVE DONE SOME WORK ON THAT. 1250 00:56:17,819 --> 00:56:18,954 WHAT I CAN SAY AT THIS POINT IS 1251 00:56:18,954 --> 00:56:21,957 BOTH WE NEED TO DO MORE AND IT'S 1252 00:56:21,957 --> 00:56:23,725 ALSO NOT CUT AND DRY LIKE YOU 1253 00:56:23,725 --> 00:56:27,062 LOOK AT THE U MAP AND HERE'S THE 1254 00:56:27,062 --> 00:56:29,998 BCL2 POSITIVE CLUSTER THAT 1255 00:56:29,998 --> 00:56:40,509 SURVIVED AND THE MHC1 CLUSTER. 1256 00:56:41,676 --> 00:56:42,944 THERE'S MORE AND THE BEST ANSWER 1257 00:56:42,944 --> 00:56:45,013 I CAN GIVE FOR NOW IS I THINK 1258 00:56:45,013 --> 00:56:47,983 EACH OF THE AGENTS WILL PROBABLY 1259 00:56:47,983 --> 00:56:50,785 IMPACT SOME OF THE TARGET CELLS 1260 00:56:50,785 --> 00:56:53,321 BUT YOU YOU'LL NEED COMBINATIONS 1261 00:56:53,321 --> 00:56:54,789 TO GET A LOT OF THEM. 1262 00:56:54,789 --> 00:56:55,557 THERE'S A LOT OF VARIATION IN 1263 00:56:55,557 --> 00:56:56,358 THE DIFFERENT CLONES. 1264 00:56:56,358 --> 00:56:56,958 THEY ARE ALL HAVE THEIR OWN 1265 00:56:56,958 --> 00:57:00,295 PERSONAL AMOUNTS. 1266 00:57:00,295 --> 00:57:01,930 -- PERSONALITIES. 1267 00:57:01,930 --> 00:57:04,699 >> JOHN, MIKE BETTS AGAIN. 1268 00:57:04,699 --> 00:57:06,668 A QUESTION FOR MICHEL. 1269 00:57:06,668 --> 00:57:07,602 YOU SHOWED SORT OF THE MODEL 1270 00:57:07,602 --> 00:57:11,273 WHAT YOU'RE LOOKING FOR 1271 00:57:11,273 --> 00:57:12,908 RECOGNIZING LATENTLY INFECTED 1272 00:57:12,908 --> 00:57:14,676 CELLS THAT PLAY EXPRESS BUT YOU 1273 00:57:14,676 --> 00:57:21,316 DIDN'T TELL US ABOUT ANY DATA. 1274 00:57:21,316 --> 00:57:23,084 ARE YOU ABLE TO SEE SOME 1275 00:57:23,084 --> 00:57:23,385 RECOGNITION? 1276 00:57:23,385 --> 00:57:26,755 >> THE BEST DATA WE HAVE COMES 1277 00:57:26,755 --> 00:57:30,292 FROM MOUSE STUDY THAT WERE 1278 00:57:30,292 --> 00:57:32,694 PUBLISHED SOME TIME AGO THAT 1279 00:57:32,694 --> 00:57:33,862 ANTIBODIES HELPED CLEAR INFECTED 1280 00:57:33,862 --> 00:57:37,065 CELLS AND FROM ONGOING CLINICAL 1281 00:57:37,065 --> 00:57:43,505 STUDY WHERE WE SEE ACCELERATED 1282 00:57:43,505 --> 00:57:45,540 RESERVOIR CLEARANCE. 1283 00:57:45,540 --> 00:57:45,740 YEAH. 1284 00:57:45,740 --> 00:57:46,708 >> OKAY. 1285 00:57:46,708 --> 00:57:49,077 THIS WILL BE THE LAST QUESTION I 1286 00:57:49,077 --> 00:57:49,411 THINK. 1287 00:57:49,411 --> 00:57:49,678 GO AHEAD. 1288 00:57:49,678 --> 00:57:55,917 >> I MAY HAVE MISSED IT BUT DID 1289 00:57:55,917 --> 00:57:57,652 YOU THINK ABOUT THE SPECIFIC 1290 00:57:57,652 --> 00:57:59,454 AUTHENTIC RESERVOIR CLONES? 1291 00:57:59,454 --> 00:58:01,089 >> I'M SO GLAD YOU ASKED. 1292 00:58:01,089 --> 00:58:03,625 WE HAVE ONE AND EVA SPECIFIC AND 1293 00:58:03,625 --> 00:58:08,630 IT'S REALLY GOOD AT KILLING EVB 1294 00:58:08,630 --> 00:58:10,465 TRANSFORMED LYMPHOMA CELL LINES. 1295 00:58:10,465 --> 00:58:13,268 SO IT'S A CELL THAT HAS AN HIV 1296 00:58:13,268 --> 00:58:17,939 PROVIRUS AND CAN FUNCTION AND DO 1297 00:58:17,939 --> 00:58:24,112 IT JOB AND KILL LYMPHOMA CELLS 1298 00:58:24,112 --> 00:58:25,580 WHICH ARE INTERESTED AND THE 1299 00:58:25,580 --> 00:58:27,282 ONES WE FOUND AND ISABELLA HAS A 1300 00:58:27,282 --> 00:58:29,618 POSTER THAT WILL SHOW SOME OF 1301 00:58:29,618 --> 00:58:33,221 THE EVB SPECIFICITY RESULTS. 1302 00:58:33,221 --> 00:58:33,755 >> OKAY. 1303 00:58:33,755 --> 00:58:35,023 I THINK THAT WILL BE ABOUT IT 1304 00:58:35,023 --> 00:58:35,690 FOR THIS PRESENTATION. 1305 00:58:35,690 --> 00:58:37,926 I JUST WANT THE TO THANK THE 1306 00:58:37,926 --> 00:58:38,893 REACH GROUP. 1307 00:58:38,893 --> 00:58:41,930 IT'S A REAL PLEASURE TO BE THEIR 1308 00:58:41,930 --> 00:58:42,297 PROGRAM OFFICER. 1309 00:58:42,297 --> 00:58:44,866 AND THANKS TO THE AUDIENCE FOR 1310 00:58:44,866 --> 00:58:46,001 ALL THEIR REALLY GREAT 1311 00:58:46,001 --> 00:58:46,301 QUESTIONS. 1312 00:58:46,301 --> 00:58:51,239 SO I TURN IT OVER NOW TO DIANNE 1313 00:58:51,239 --> 00:59:01,716 LAWRENCE AND THE DARE GROUP. 1314 00:59:10,358 --> 00:59:12,060 >> A QUICK REMINDER IF YOU HAVE 1315 00:59:12,060 --> 00:59:17,232 NOT ORDERED LUNCH YOU CAN GO OR 1316 00:59:17,232 --> 00:59:25,240 GO TO CHAT TO DROP DOT AND PLACE 1317 00:59:25,240 --> 00:59:26,007 YOUR ORDER. 1318 00:59:26,007 --> 00:59:29,944 IT'S VERY QUICK. 1319 00:59:29,944 --> 00:59:38,119 FEEL FREE TO DO THAT. 1320 00:59:38,119 --> 00:59:44,359 I'M DIANNE LAWRENCE IN THE 1321 00:59:44,359 --> 00:59:47,362 BRANCH OF THE DIVISION OF AIDS 1322 00:59:47,362 --> 00:59:49,731 AND DARE STANDS FOR THE DELANEY 1323 00:59:49,731 --> 00:59:51,700 AIDS RESEARCH ENTERPRISE AND 1324 00:59:51,700 --> 00:59:53,968 THIS TRAEM HAS BEEN IN PLACE 1325 00:59:53,968 --> 00:59:58,940 SINCE THE FIRST ITERATION OF THE 1326 00:59:58,940 --> 00:59:59,641 PROGRAM. 1327 00:59:59,641 --> 01:00:03,511 SO, THE DARE TEAM IS BASED IN 1328 01:00:03,511 --> 01:00:05,680 SAN FRANCISCO LED BY STEVEN 1329 01:00:05,680 --> 01:00:12,954 DEEKS, LOUIS PICKER AND SHARON 1330 01:00:12,954 --> 01:00:13,254 LEWIN. 1331 01:00:13,254 --> 01:00:15,857 >> THANK YOU, DIANE. 1332 01:00:15,857 --> 01:00:17,892 I'M GOING TO PRESENT ON BEHALF 1333 01:00:17,892 --> 01:00:18,760 OF THE DARE COLLABORATORY. 1334 01:00:18,760 --> 01:00:20,295 SINCE THE FIRST EDITION OF THE 1335 01:00:20,295 --> 01:00:21,663 GROUP WE'VE BEEN LARGELY 1336 01:00:21,663 --> 01:00:24,666 FOCUSSED ON THE CONCEPT OF USING 1337 01:00:24,666 --> 01:00:26,267 IMMUNOTHERAPY TO REDUCE 1338 01:00:26,267 --> 01:00:29,938 RESERVOIR AND CONTROL WHAT'S 1339 01:00:29,938 --> 01:00:30,638 LEFT. 1340 01:00:30,638 --> 01:00:33,007 THAT'S BEEN THE MAIN THEME 1341 01:00:33,007 --> 01:00:34,409 THROUGH THE THREE OR SO 1342 01:00:34,409 --> 01:00:35,477 COLLABORATORIES INCLUDING THE 1343 01:00:35,477 --> 01:00:38,079 WORK WE'LL PRESENT TODAY. 1344 01:00:38,079 --> 01:00:42,951 AND WE DO THIS LARGELY THROUGH A 1345 01:00:42,951 --> 01:00:44,219 CORE GROUP OF CLINICAL 1346 01:00:44,219 --> 01:00:47,822 ADVOCATORS, VIROLOGIST AND 1347 01:00:47,822 --> 01:00:49,691 IMMUNOLOGISTS MANY OF WHOM HAVE 1348 01:00:49,691 --> 01:00:52,026 BEEN WORKING TOGETHER MANY YEARS 1349 01:00:52,026 --> 01:00:53,561 NOW AND I DON'T HAVE TIME TO GO 1350 01:00:53,561 --> 01:00:54,662 THROUGH THE STRUCTURE BUT WE 1351 01:00:54,662 --> 01:00:55,997 HAVE FOUR WORKING GROUPS. 1352 01:00:55,997 --> 01:01:00,502 THE FIRST IS LED BY LILLY COHEN 1353 01:01:00,502 --> 01:01:05,940 AND FOCUSSING ON THE ACTIVE 1354 01:01:05,940 --> 01:01:08,643 RESERVOIR PROLIFERATION. 1355 01:01:08,643 --> 01:01:10,612 SECOND IS LOOKING AT THE 1356 01:01:10,612 --> 01:01:11,579 MECHANISMS OF POST INVENTION 1357 01:01:11,579 --> 01:01:13,314 CONTROL AND POST TREATMENT 1358 01:01:13,314 --> 01:01:13,715 CONTROL. 1359 01:01:13,715 --> 01:01:16,985 YOU'LL HEAR ABOUT SOME OF THIS 1360 01:01:16,985 --> 01:01:20,288 TODAY AND LOUIS PICKER LEADS THE 1361 01:01:20,288 --> 01:01:24,292 RF2 TEAM USING THE MONKEY MODEL 1362 01:01:24,292 --> 01:01:26,761 TO DEVELOP IMMUNOTHERAPIES AND 1363 01:01:26,761 --> 01:01:33,134 OTHERS HAVE BEEN LEADING EFFORTS 1364 01:01:33,134 --> 01:01:35,370 ON THE DRUG UPDATES WE HAVE 1365 01:01:35,370 --> 01:01:35,970 TODAY. 1366 01:01:35,970 --> 01:01:38,006 THE THEME OF TODAY THING IS 1367 01:01:38,006 --> 01:01:38,907 GOING TO BE TRANSLATION. 1368 01:01:38,907 --> 01:01:42,310 THE WORK WE DO TO TAKE IDEAS 1369 01:01:42,310 --> 01:01:43,711 FROM THE LAB THROUGH THE ANIMAL 1370 01:01:43,711 --> 01:01:46,314 MODELS INTO THE CLINIC AND BACK. 1371 01:01:46,314 --> 01:01:48,616 AND THIS IS SOMETHING THAT WE'VE 1372 01:01:48,616 --> 01:01:49,818 BEEN DOING PRETTY CONSISTENTLY 1373 01:01:49,818 --> 01:01:52,520 ALL ALONG. 1374 01:01:52,520 --> 01:01:54,222 OUR CURRENT SUITE OF APPROACHES 1375 01:01:54,222 --> 01:01:57,091 IN TERMS OF REDUCING THE 1376 01:01:57,091 --> 01:01:59,494 RESERVOIR ARE LISTED HERE 1377 01:01:59,494 --> 01:02:02,397 FOCUSSING ON LRAs AND DRUGS WE 1378 01:02:02,397 --> 01:02:04,165 THINK CAN ACCELERATE CELL DEATH. 1379 01:02:04,165 --> 01:02:08,803 THIS HAS BEEN THE FOCUS OF WORK 1380 01:02:08,803 --> 01:02:10,505 SHARON WILL PRESENT IN THE R3. 1381 01:02:10,505 --> 01:02:13,808 I THINK WE MADE PROGRESS AS WE 1382 01:02:13,808 --> 01:02:15,176 HEAR ABOUT THINGS WE SHOULD MOVE 1383 01:02:15,176 --> 01:02:17,111 FORWARD TO THE CLINIC AND SHOULD 1384 01:02:17,111 --> 01:02:17,445 NOT. 1385 01:02:17,445 --> 01:02:20,114 AGAIN, SINCE DAY ONE WE'VE BEEN 1386 01:02:20,114 --> 01:02:22,951 FOCUSSED ON IMMUNOTHERAPY 1387 01:02:22,951 --> 01:02:26,120 FOCUSSING THROUGHOUT THE ENTIRE 1388 01:02:26,120 --> 01:02:29,357 LIFE SPAN OF THEIR THERAPEUTIC 1389 01:02:29,357 --> 01:02:31,626 VACCINES VERSUS VECTORS AND 1390 01:02:31,626 --> 01:02:33,595 WE'LL HEAR UPDATES ON THE LATTER 1391 01:02:33,595 --> 01:02:35,430 AND HAVE DONE WORK LOOKING AT 1392 01:02:35,430 --> 01:02:37,765 THE ROLE OF ANTIBODIES IN PEOPLE 1393 01:02:37,765 --> 01:02:42,237 AND NOW WE'RE DOING WORK IN THE 1394 01:02:42,237 --> 01:02:43,171 NON-HUMAN PRIMATES AND 1395 01:02:43,171 --> 01:02:47,242 THROUGHOUT THE PROGRAM WORKING 1396 01:02:47,242 --> 01:02:49,644 ON DIFFERENT CYTOKINES AND 1397 01:02:49,644 --> 01:02:53,348 MIXING AND MATCHING THEM IN THE 1398 01:02:53,348 --> 01:02:56,718 MONKEY MODELS AND DO CLINICAL 1399 01:02:56,718 --> 01:03:00,922 TRIALS AND SHARON HAS DONE 1400 01:03:00,922 --> 01:03:01,823 CLINICAL TRIALS AND MOVE SAMPLE 1401 01:03:01,823 --> 01:03:03,725 BACK AND FORM AND THAT'S HOW WE 1402 01:03:03,725 --> 01:03:03,958 WORK. 1403 01:03:03,958 --> 01:03:06,160 IN DEVELOPING NEW THERAPEUTIC 1404 01:03:06,160 --> 01:03:08,029 APPROACHES WE'VE HAD A FAIR 1405 01:03:08,029 --> 01:03:09,931 AMOUNT OF APPROACH ON WAYS TO 1406 01:03:09,931 --> 01:03:11,532 MEASURE WHAT WE'RE DOING AND 1407 01:03:11,532 --> 01:03:12,367 DEVELOP ASSAYS. 1408 01:03:12,367 --> 01:03:14,369 I THINK RACHEL WILL PRESENT 1409 01:03:14,369 --> 01:03:16,738 EXCITING DATA TO USE T CELL 1410 01:03:16,738 --> 01:03:18,506 PROLIFERATION AS A POTENTIAL WAY 1411 01:03:18,506 --> 01:03:20,909 TO PREDICT IMMUNOTHERAPY AND 1412 01:03:20,909 --> 01:03:24,746 WHAT WILL WORK AND WON'T WORK 1413 01:03:24,746 --> 01:03:29,951 AND WE'VE WORKED IN DEVELOPING 1414 01:03:29,951 --> 01:03:32,987 DIFFERENT WAYS TO MEASURE THE 1415 01:03:32,987 --> 01:03:35,390 INTACT RESERVOIR. 1416 01:03:35,390 --> 01:03:38,459 ALL RIGHT, SO TODAY YOU'RE GOING 1417 01:03:38,459 --> 01:03:40,695 TO HEAR THREE PRESENTATIONS. 1418 01:03:40,695 --> 01:03:43,998 THE FIRST WILL BE BY LEWIS. 1419 01:03:43,998 --> 01:03:47,068 WE'LL TALK ABOUT HOW WE TEST 1420 01:03:47,068 --> 01:03:49,103 INTERVENTIONS IN THE MONKEY 1421 01:03:49,103 --> 01:03:51,205 MODEL AND DOES DEEP DIVE IN THE 1422 01:03:51,205 --> 01:03:53,174 MECHANISM AND HOW WE'VE BEEN 1423 01:03:53,174 --> 01:03:56,744 USING THAT TO INFORM THE NEXT 1424 01:03:56,744 --> 01:03:58,713 STEP MOVING THIS STEP. 1425 01:03:58,713 --> 01:04:03,584 AND THEN YOU'LL HEAR BY RACHEL 1426 01:04:03,584 --> 01:04:05,853 WHO WILL SUMMARIZE SOME CLINICAL 1427 01:04:05,853 --> 01:04:08,856 TRIALS WE'VE DIDN'T DOING AND 1428 01:04:08,856 --> 01:04:09,724 EFFORTS WITHIN AND WITHOUT DARE 1429 01:04:09,724 --> 01:04:11,993 POST INVENTION CONTROLLERS AND 1430 01:04:11,993 --> 01:04:12,994 USING THAT TO DEVELOP POTENTIAL 1431 01:04:12,994 --> 01:04:14,729 BIOMARKERS WE CAN USE TO GUIDE 1432 01:04:14,729 --> 01:04:17,332 FUTURE DRUG DEVELOPMENT AND 1433 01:04:17,332 --> 01:04:19,701 FINALLY SHARON WILL FOCUS ON HER 1434 01:04:19,701 --> 01:04:23,004 WORK LOOKING AT DRUGS AND 1435 01:04:23,004 --> 01:04:28,443 REVERSE LATENCY AND LYNNE -- 1436 01:04:28,443 --> 01:04:38,953 LYNDA WILL END WITH AN UPDATE. 1437 01:04:51,132 --> 01:04:53,501 >> FIRST I'LL START WITH THE 1438 01:04:53,501 --> 01:04:57,939 WORK OF THE GROUP AND BE 1439 01:04:57,939 --> 01:04:59,640 REPRESENTATIVE HERE. 1440 01:04:59,640 --> 01:05:00,641 OKAY. 1441 01:05:00,641 --> 01:05:02,844 SO IN TERMS OF THE COMMUNITY 1442 01:05:02,844 --> 01:05:04,946 SLIDE, WHAT IS IT WE'RE TRYING 1443 01:05:04,946 --> 01:05:06,280 TO DO? 1444 01:05:06,280 --> 01:05:07,849 FIRST, WE'RE TRYING TO 1445 01:05:07,849 --> 01:05:10,885 UNDERSTAND HOW THE IMMUNE SYSTEM 1446 01:05:10,885 --> 01:05:13,187 PARTICULARLY THE ADAPTIVE T CELL 1447 01:05:13,187 --> 01:05:16,190 SYSTEM INTERCEPTS THE ACTIVATING 1448 01:05:16,190 --> 01:05:19,193 VIRUS AFTER THE VIRUS IS 1449 01:05:19,193 --> 01:05:20,762 DISCONTINUED AND BY 1450 01:05:20,762 --> 01:05:21,362 UNDERSTANDING THE PROCESS TO 1451 01:05:21,362 --> 01:05:25,166 IMPROVE UPON IT TO BE ABLE TO 1452 01:05:25,166 --> 01:05:28,703 HAVE IMMUNOTHERAPEUTICS THAT 1453 01:05:28,703 --> 01:05:32,140 MANIPULATE T CELL SYSTEM AND 1454 01:05:32,140 --> 01:05:34,142 VACCINE THAT ALLOWS FOR POST 1455 01:05:34,142 --> 01:05:35,443 CONTROL. 1456 01:05:35,443 --> 01:05:40,615 WE'VE BEEN WORKING ON THIS 1457 01:05:40,615 --> 01:05:50,792 SYSTEM 1458 01:05:51,059 --> 01:05:55,963 SYSTEMATE -- AND INSETERCEPTED 1459 01:05:55,963 --> 01:05:57,165 THE VIRAL REBOUND AND WHETHER 1460 01:05:57,165 --> 01:06:07,708 THE THERAPEUTIC VACCINE CAN LEA 1461 01:06:36,204 --> 01:06:36,671 OKAY. 1462 01:06:36,671 --> 01:06:38,339 SO WE DID EXPERIMENTS A NUMBER 1463 01:06:38,339 --> 01:06:41,676 OF YEARS AGO TO ASK WHAT THE 1464 01:06:41,676 --> 01:06:44,045 NATURAL T CELL RESPONSE DOES IN 1465 01:06:44,045 --> 01:06:48,182 THE POST ART CESSATION REBOUND 1466 01:06:48,182 --> 01:06:49,750 SITUATION AND SHOWED PRETTY 1467 01:06:49,750 --> 01:06:53,721 CLEARLY THE T CELLS DO 1468 01:06:53,721 --> 01:06:57,058 CONTRIBUTE TO PLATEAU LEVEL OF 1469 01:06:57,058 --> 01:06:58,226 VIRAL REPLICATION BUT THEY ARE 1470 01:06:58,226 --> 01:06:59,293 DO NOT ACTUALLY SHOW ANY EFFECT 1471 01:06:59,293 --> 01:07:00,695 ON THE TIME TO REBOUND. 1472 01:07:00,695 --> 01:07:03,998 SO THEY APPEAR TO INTERCEPT THE 1473 01:07:03,998 --> 01:07:08,936 RESPONSE LATE AND AFFECT A 1.5 1474 01:07:08,936 --> 01:07:10,705 LOG REDUCTION IN VIRAL 1475 01:07:10,705 --> 01:07:11,005 REPLICATION. 1476 01:07:11,005 --> 01:07:12,273 SO THEY'RE EFFECTIVE BUT APPEAR 1477 01:07:12,273 --> 01:07:15,776 TO COME TOO LATE TO EFFECT THE 1478 01:07:15,776 --> 01:07:17,211 POST REBOUND SITUATION AND OTHER 1479 01:07:17,211 --> 01:07:19,213 DATA THAT SUPPORTS THIS AND IF 1480 01:07:19,213 --> 01:07:22,416 AND IF YOU LOOK AT THE 1481 01:07:22,416 --> 01:07:24,418 PROTECTIVE ALEELS ON TIME TO 1482 01:07:24,418 --> 01:07:27,121 REBOUND SET POINT VIRAL LOW WE 1483 01:07:27,121 --> 01:07:29,690 SEE A SIGNIFICANT EFFECT ON SET 1484 01:07:29,690 --> 01:07:37,498 TIME VIRAL LOAD BUT NO EFFECT ON 1485 01:07:37,498 --> 01:07:44,539 TIME TO REBOUND. 1486 01:07:44,539 --> 01:07:46,040 AND THEY'RE UNABLE TO INTERCEPT 1487 01:07:46,040 --> 01:07:47,341 THE PROCESS PRIOR TO VIRUS. 1488 01:07:47,341 --> 01:07:49,844 WE ASKED THE SIMPLE QUESTION. 1489 01:07:49,844 --> 01:07:53,114 ON THE TOP IS WHAT WE THINK IS 1490 01:07:53,114 --> 01:07:53,848 HAPPENING WITH THE NATURAL T 1491 01:07:53,848 --> 01:07:59,387 CELL RESPONSE DURING THE 1492 01:07:59,387 --> 01:08:03,758 INFECTION PERIOD AND CAN WE 1493 01:08:03,758 --> 01:08:06,761 CHANGE THE DYNAMICS SO IT PEAKS 1494 01:08:06,761 --> 01:08:17,305 PRIOR AND CAN IT HAVE AN EFFECT. 1495 01:09:16,931 --> 01:09:22,570 AND THERE'S VIRAL EXPRESSION AND 1496 01:09:22,570 --> 01:09:24,538 WE HAVE A PRIMING OF DOSING 1497 01:09:24,538 --> 01:09:26,874 EVERY THREE WEEKS AND CAME BACK 1498 01:09:26,874 --> 01:09:30,611 WITH ANOTHER DOSE AND TIMED IT 1499 01:09:30,611 --> 01:09:32,680 PRIOR TO REGARD RELEASE WITH THE 1500 01:09:32,680 --> 01:09:37,151 HOPE OF INCREASING THE PEAK 1501 01:09:37,151 --> 01:09:38,052 RESPONSES PRIOR TO VIRAL 1502 01:09:38,052 --> 01:09:38,552 OUTGROWTH. 1503 01:09:38,552 --> 01:09:40,688 IN FACT THE GROUPS WERE VERY 1504 01:09:40,688 --> 01:09:44,191 COMPARABLE IN TERMS OF THE 1505 01:09:44,191 --> 01:09:46,761 CONTROL GROUP WHICH IS GOING THE 1506 01:09:46,761 --> 01:09:53,801 RABIES VIRUS VERSUS THE GAG 1507 01:09:53,801 --> 01:10:04,111 EXPRESSION VIRUS. 1508 01:10:14,488 --> 01:10:17,858 AND THIS IS 20% AT PEAK IN TERMS 1509 01:10:17,858 --> 01:10:21,128 OF GAG RESPONSES. 1510 01:10:21,128 --> 01:10:25,800 AND THE ACD8 RESPONSES ARE 1511 01:10:25,800 --> 01:10:27,134 CONSIDERABLY HIGHER AND WE SEE 1512 01:10:27,134 --> 01:10:29,136 THE SAME INCREASES AND RESPONSES 1513 01:10:29,136 --> 01:10:33,107 IN PERIPHERAL LYMPH NODES AND 1514 01:10:33,107 --> 01:10:34,041 THE RESPONSE IS GOOD THE VACCINE 1515 01:10:34,041 --> 01:10:44,118 IS DOING WHAT WE HOPED. 1516 01:10:44,118 --> 01:10:47,955 WE'RE TRYING THE FINAL BOOST SO 1517 01:10:47,955 --> 01:10:48,622 THE PEAK RESPONSE OCCURS IN THE 1518 01:10:48,622 --> 01:10:52,293 WEEK AFTER AFTER THE REWHERE WE 1519 01:10:52,293 --> 01:10:57,832 KNOW THE VIRUS IS GOING TO BEGIN 1520 01:10:57,832 --> 01:11:03,437 TO COME OUT AND WE DID A GOOD 1521 01:11:03,437 --> 01:11:04,372 JOB COMPARED TO THE NATURAL 1522 01:11:04,372 --> 01:11:05,940 RESPONSE WHICH PEAKS LOWER AND 1523 01:11:05,940 --> 01:11:16,050 LATER. 1524 01:11:20,955 --> 01:11:25,726 AND WE SEE BLUE DOTS ARE HIGHER 1525 01:11:25,726 --> 01:11:26,927 THEN THE GREEN DOTS. 1526 01:11:26,927 --> 01:11:29,630 THIS IS PRIOR TO AND 18 DAYS 1527 01:11:29,630 --> 01:11:31,966 POST RELEASE AND THE REBOUND HAS 1528 01:11:31,966 --> 01:11:33,934 BEEN COVERED WITH HIGHER T 1529 01:11:33,934 --> 01:11:37,938 CELLS. 1530 01:11:37,938 --> 01:11:39,140 HEARS WHAT WE FOUND. 1531 01:11:39,140 --> 01:11:42,276 THIS IS THE FIRST TIME WE'VE 1532 01:11:42,276 --> 01:11:44,645 EVER SEEN A DELAY OF NINE DAYS 1533 01:11:44,645 --> 01:11:45,312 IN VIRAL REBOUND. 1534 01:11:45,312 --> 01:11:47,181 THIS MODEL WHICH WAS DEVELOPED 1535 01:11:47,181 --> 01:11:57,091 WITH JEFF AND BRANDON IS TIGHT 1536 01:11:57,091 --> 01:11:57,725 REBOUNDING KINETICS. 1537 01:11:57,725 --> 01:12:03,464 AND THERE'S A SIGNIFICANT DELAY 1538 01:12:03,464 --> 01:12:13,674 IN REBOUND. 1539 01:12:41,402 --> 01:12:43,871 WE HAD A GOOD EFFECT WITH THIS 1540 01:12:43,871 --> 01:12:44,305 VACCINE. 1541 01:12:44,305 --> 01:12:48,209 WE HAD A 2 LOG OF PEAK VIRAL 1542 01:12:48,209 --> 01:12:53,314 LOAD MAINTAINED FOR SIX WEEKS 1543 01:12:53,314 --> 01:12:55,416 OVER TIME AND THE CONTROL GROUP 1544 01:12:55,416 --> 01:13:05,559 MERGED. 1545 01:13:05,993 --> 01:13:08,529 AND THIS IS A STEP TOWARDS THE 1546 01:13:08,529 --> 01:13:11,665 GOAL BUT WE HAVE NOT ACHIEVED 1547 01:13:11,665 --> 01:13:13,434 WITH THIS VACCINE ALONE THE 1548 01:13:13,434 --> 01:13:16,704 RESULTS WE HOPED FOR. 1549 01:13:16,704 --> 01:13:17,805 THIS IS INTERESTING THOUGH AND 1550 01:13:17,805 --> 01:13:19,773 IF YOU LOOK AT THE RESPONSES 1551 01:13:19,773 --> 01:13:21,408 VERSUS THE VIRAL OUTGROWTH WE 1552 01:13:21,408 --> 01:13:24,278 DID ACHIEVE THE GOAL WE WANTED 1553 01:13:24,278 --> 01:13:26,146 TO HAVING THE RESPONSES PEAK 1554 01:13:26,146 --> 01:13:28,315 BEFORE THE VIRUS CAME OUT 1555 01:13:28,315 --> 01:13:29,149 OPPOSED TO THE RESPONSES 1556 01:13:29,149 --> 01:13:31,852 FOLLOWING THE VIRUS COMING OUT 1557 01:13:31,852 --> 01:13:32,453 IN THE CONTROL GROUP. 1558 01:13:32,453 --> 01:13:35,055 THE QUESTION IS HOW DO WE MAKE 1559 01:13:35,055 --> 01:13:35,623 THIS BETTER? 1560 01:13:35,623 --> 01:13:38,792 WE HAVEN'T YET ACHIEVED THE GOAL 1561 01:13:38,792 --> 01:13:49,270 OF THE POTENT VIRUS AND WE'RE 1562 01:13:49,270 --> 01:13:51,872 TRYING TO ADD ADJUNCTIVE 1563 01:13:51,872 --> 01:13:55,776 THERAPIES TO FIT THE GOAL. 1564 01:13:55,776 --> 01:13:59,213 ANTI-PD1 DID NOT HELP IN FACT IT 1565 01:13:59,213 --> 01:14:09,757 SEEMED TO HURT THE OUTCOME AND 1566 01:14:10,791 --> 01:14:12,893 OTHER PRODUCTS CAN'T HELP AND A 1567 01:14:12,893 --> 01:14:15,796 LITTLE BIT NEGATIVE EFFECTS 1568 01:14:15,796 --> 01:14:20,167 OPPOSED TO THE GAG VACCINE AND 1569 01:14:20,167 --> 01:14:25,439 SHARON WILL PROVIDE OTHER DATA. 1570 01:14:25,439 --> 01:14:35,149 THAT'S IT FOR ME.% 1571 01:14:35,149 --> 01:14:38,986 >> UM, NICE TO BE HERE TODAY. 1572 01:14:38,986 --> 01:14:41,355 SO, IN DARE AND OUR WORK IN OUR 1573 01:14:41,355 --> 01:14:43,324 LAB VERY MUCH COMPLIMENTS THE 1574 01:14:43,324 --> 01:14:45,192 WORK THAT LOUIS PRESENTED EXCEPT 1575 01:14:45,192 --> 01:14:51,599 WE STUDY HUMANS AND WORK WITH 1576 01:14:51,599 --> 01:15:02,142 STEVE DEEKS AND MICHAEL PELUSO 1577 01:15:02,810 --> 01:15:05,546 AND UNDERSTANDING WHAT DEFINES 1578 01:15:05,546 --> 01:15:07,414 EFFECTIVE IMMUNE RESPONSES 1579 01:15:07,414 --> 01:15:16,690 AGAINST HIV REBOUND AND CAN WE 1580 01:15:16,690 --> 01:15:21,929 ILLICIT THAT AND WHAT IS 1581 01:15:21,929 --> 01:15:23,530 RESPONDING IS MOST IMPORTANT AS 1582 01:15:23,530 --> 01:15:24,698 LOUIS ALLUDED TO AND I LIKE TO 1583 01:15:24,698 --> 01:15:28,268 THINK OF THIS AS A CAT READY TO 1584 01:15:28,268 --> 01:15:30,971 POUNCE AND AS WE UNDERSTAND THE 1585 01:15:30,971 --> 01:15:32,973 MECHANISMS BETTER WE CAN INFORM 1586 01:15:32,973 --> 01:15:34,008 FUTURE ITERATIVE STUDIES FOR 1587 01:15:34,008 --> 01:15:35,242 GETTING CLOSER TO A CURE. 1588 01:15:35,242 --> 01:15:39,413 AND SO AS ALL OF YOU KNOW, RARE 1589 01:15:39,413 --> 01:15:41,882 INDIVIDUALS WHO ARE WITH HIV CAN 1590 01:15:41,882 --> 01:15:45,486 CONTROL THE INFECTION EITHER 1591 01:15:45,486 --> 01:15:46,720 SPONTANEOUSLY PRIOR IT STARTING 1592 01:15:46,720 --> 01:15:49,089 THE ART, VERY RARELY AND IN SOME 1593 01:15:49,089 --> 01:15:53,661 CASES AFTER STOPPING ART WITHOUT 1594 01:15:53,661 --> 01:15:56,363 ADDITIONAL INTERVENTION BEYOND 1595 01:15:56,363 --> 01:15:56,530 ART. 1596 01:15:56,530 --> 01:15:58,966 THOSE INDIVIDUALS OF COURSE ARE 1597 01:15:58,966 --> 01:16:01,335 QUITE RARE AND OCCUR AT HIGHER 1598 01:16:01,335 --> 01:16:04,505 RATES THAN INDIVIDUALS WITH LOW 1599 01:16:04,505 --> 01:16:06,140 RESERVOIRS SO PEOPLE TREATED 1600 01:16:06,140 --> 01:16:08,976 EARLIER IN INFECTION BUT DON'T 1601 01:16:08,976 --> 01:16:11,145 ACHIEVE HIGH LEVELS AND SOME 1602 01:16:11,145 --> 01:16:13,414 MECHANISMS MIGHT CONTRIBUTE TO 1603 01:16:13,414 --> 01:16:15,015 CONTROL IN THE NATURAL SETTING 1604 01:16:15,015 --> 01:16:17,551 THAT MAY CONTRIBUTE TO 1605 01:16:17,551 --> 01:16:18,686 INTERVENTION CONTROL. 1606 01:16:18,686 --> 01:16:20,654 THE SMALLER RESERVOIR MAY BE 1607 01:16:20,654 --> 01:16:21,455 SOMETHING ESTABLISHED AT THE 1608 01:16:21,455 --> 01:16:23,757 TIME OF INFECTION AND MAYBE 1609 01:16:23,757 --> 01:16:24,758 INTERVENE ON AND CONTRIBUTE TO 1610 01:16:24,758 --> 01:16:26,894 POST INTERVENTION CONTROL 1611 01:16:26,894 --> 01:16:29,263 INCLUDING INNATE AND ADAPTIVE 1612 01:16:29,263 --> 01:16:30,731 MECHANISMED AND OUR LAB AND 1613 01:16:30,731 --> 01:16:33,067 OTHERS HAVE BEEN FOCUSSED ON 1614 01:16:33,067 --> 01:16:35,969 UNDERSTANDING THE ROLE OF CD 8 T 1615 01:16:35,969 --> 01:16:39,506 CELLS IN PARTICULAR PROLIFE 1616 01:16:39,506 --> 01:16:40,541 PROLIFERATIVE CAPACITY TO 1617 01:16:40,541 --> 01:16:41,809 RESPOND TO THE VIRUS. 1618 01:16:41,809 --> 01:16:45,913 OUR LAB IS FOCUSSED ON THE TCF1 1619 01:16:45,913 --> 01:16:49,817 THAT PROMOTES THIS CAPACITY AND 1620 01:16:49,817 --> 01:16:53,120 HAVE TWO POSTERS PRESENTING ON 1621 01:16:53,120 --> 01:16:57,324 NHP STUDY AND CHARLIE IS 1622 01:16:57,324 --> 01:17:01,428 PRESENTING A STUDY FOCUSSED ON 1623 01:17:01,428 --> 01:17:04,431 THE PROLIFERATIVE CAPACITY. 1624 01:17:04,431 --> 01:17:07,201 SO HOW DO WE PROMOTE THIS OR 1625 01:17:07,201 --> 01:17:09,837 HAVE AN IMMUNE RESPONSE FOR 1626 01:17:09,837 --> 01:17:10,771 CONTROL AND HAVE THERAPEUTIC 1627 01:17:10,771 --> 01:17:11,839 VACCINE STUDIES. 1628 01:17:11,839 --> 01:17:15,576 THE NHP STUDY IS THE MOST 1629 01:17:15,576 --> 01:17:19,413 STRIKING TO SHOW THAT AND THE 1630 01:17:19,413 --> 01:17:21,949 STUDY SHOWED AN INTERESTING 1631 01:17:21,949 --> 01:17:23,951 SIGNAL ABOUT THE POSSIBILITY 1632 01:17:23,951 --> 01:17:26,220 THEY COULD ELICIT RESPONSES THAT 1633 01:17:26,220 --> 01:17:27,988 CAN CONTRIBUTE TO BETTER CONTROL 1634 01:17:27,988 --> 01:17:29,723 AFTER TREATMENT INTERRUPTION. 1635 01:17:29,723 --> 01:17:33,393 WE'VE PUT BEEN INTRIGUED BY THE 1636 01:17:33,393 --> 01:17:35,028 INDIVIDUALS WHO HAVE BEEN SHOWN 1637 01:17:35,028 --> 01:17:37,531 TO INDUCE SOME CONTROL TO HAVE 1638 01:17:37,531 --> 01:17:40,634 SOME INDUCE CONTROL AFTER 1639 01:17:40,634 --> 01:17:42,736 RECEIVING BROADLY RECEIVING 1640 01:17:42,736 --> 01:17:43,437 ANTIGEN ANTIBODYING DURING HIGH 1641 01:17:43,437 --> 01:17:46,106 LEVEL OF ANTIGEN AT THE TIME OF 1642 01:17:46,106 --> 01:17:47,708 ART OR AFTER ART IS STOPPED IN 1643 01:17:47,708 --> 01:17:49,409 SEVERAL STUDIES. 1644 01:17:49,409 --> 01:17:51,645 AND STILL LIKE LOW NUMBERS OF 1645 01:17:51,645 --> 01:17:52,379 INDIVIDUALS RELATIVELY LOW RATES 1646 01:17:52,379 --> 01:17:54,081 OF POTENTIAL CONTROL AND NOT A 1647 01:17:54,081 --> 01:17:54,882 LOT OF UNDERSTANDING ABOUT WHAT 1648 01:17:54,882 --> 01:17:59,186 THE MECHANISMS ARE. 1649 01:17:59,186 --> 01:18:00,888 THE STUDY I'LL TALK ABOUT I 1650 01:18:00,888 --> 01:18:04,792 THINK MANY ARE FAMILIAR WITH IS 1651 01:18:04,792 --> 01:18:08,061 COMBINATION IMMUNOTHERAPY WAS IN 1652 01:18:08,061 --> 01:18:10,330 THREE STAGES RAN IN SAN 1653 01:18:10,330 --> 01:18:10,597 FRANCISCO. 1654 01:18:10,597 --> 01:18:12,933 THEY WERE THERAPEUTIC VACCINE 1655 01:18:12,933 --> 01:18:16,670 STUDY AND DELIVERED THERAPEUTIC 1656 01:18:16,670 --> 01:18:17,938 VACCINE REGIMENT FOR CONSERVED 1657 01:18:17,938 --> 01:18:19,840 ELEMENTS OF HIV WITHIN GAG. 1658 01:18:19,840 --> 01:18:21,408 A SECOND STAGE IN WHICH THERE 1659 01:18:21,408 --> 01:18:23,143 WAS INTENDED RESERVOIR REDUCTION 1660 01:18:23,143 --> 01:18:27,648 AN ADMINISTRATION OF TWO BROADLY 1661 01:18:27,648 --> 01:18:28,882 NEUTRALIZING ANTIBODIES ON ART 1662 01:18:28,882 --> 01:18:31,151 AND AT THE TIME OF ART 1663 01:18:31,151 --> 01:18:32,085 INTERRUPTION THE TWO WERE GIVEN 1664 01:18:32,085 --> 01:18:34,254 AND THE HOPE WAS THAT WE WOULD 1665 01:18:34,254 --> 01:18:36,356 SEE CONTROL OF REBOUND. 1666 01:18:36,356 --> 01:18:38,058 AND WE PRESENTED THE CLINICAL 1667 01:18:38,058 --> 01:18:42,930 RESULTS AND THINK IT'S STRIKING 1668 01:18:42,930 --> 01:18:44,565 THAT THERE'S NO PLACEBO ARM BUT 1669 01:18:44,565 --> 01:18:46,099 HAVE 10 INDIVIDUALS WITH HIV ON 1670 01:18:46,099 --> 01:18:50,137 ART GIVEN THE REGIMENT AND THREE 1671 01:18:50,137 --> 01:18:53,073 REBOUNDED NORMALLY BUT SEVEN 1672 01:18:53,073 --> 01:18:54,641 PEOPLE HAD UNUSUAL LEVEL OF POST 1673 01:18:54,641 --> 01:18:55,943 INTERVENTION CONTROL. 1674 01:18:55,943 --> 01:18:57,578 ONE PERSON DOESN'T REBOUND AND 1675 01:18:57,578 --> 01:19:00,480 SIX PEOPLE FELL INTO THE LOW 1676 01:19:00,480 --> 01:19:01,215 LEVEL OF SET POINT. 1677 01:19:01,215 --> 01:19:03,283 YOU LOOK AT THE ACCESS IS WEEKS 1678 01:19:03,283 --> 01:19:04,418 FROM THE BEGINNING OF REBOUND 1679 01:19:04,418 --> 01:19:06,787 AND THE TOP TWO YOU HAVE TWO 1680 01:19:06,787 --> 01:19:08,555 PEOPLE WHO WENT OUT SLOWLY IN 1681 01:19:08,555 --> 01:19:10,891 THE VIRAL LOADS OVER MANY WEEKS 1682 01:19:10,891 --> 01:19:13,927 AND FOUR PEOPLE WHO WENT UP TO 1683 01:19:13,927 --> 01:19:16,396 1,000 COPIES PER MILL AND 1684 01:19:16,396 --> 01:19:17,831 MAINTAIN WHICH IS A RATE OF POST 1685 01:19:17,831 --> 01:19:21,635 ART CONTROL THAT IS ABOVE A 1686 01:19:21,635 --> 01:19:22,369 BACKGROUND RATE OF POST 1687 01:19:22,369 --> 01:19:26,506 TREATMENT CONTROL SEEN IN 1688 01:19:26,506 --> 01:19:27,441 SIMILAR INDIVIDUALS. 1689 01:19:27,441 --> 01:19:28,542 SORRY THIS IS BLURRY. 1690 01:19:28,542 --> 01:19:29,710 ONE THING WE THINK IS IMPORTANT 1691 01:19:29,710 --> 01:19:31,211 OF THE POST INTERVENTION 1692 01:19:31,211 --> 01:19:33,914 CONTROLLERS SO THESE ARE THE 1693 01:19:33,914 --> 01:19:37,918 INDIVIDUALS IN BLUE AND GRAY ON 1694 01:19:37,918 --> 01:19:38,151 HERE. 1695 01:19:38,151 --> 01:19:39,987 WHEN WE COMPARED THE SET POINT 1696 01:19:39,987 --> 01:19:41,655 VIRAL LOAD SO THIS IS THE 1697 01:19:41,655 --> 01:19:43,590 AVERAGE VIRAL LOAD AFTER THEIR 1698 01:19:43,590 --> 01:19:45,926 PEAK, AFTER COMING OFF ART IT 1699 01:19:45,926 --> 01:19:47,694 WAS SIGNIFICANTLY LOWER THAN THE 1700 01:19:47,694 --> 01:19:49,162 VIRAL LOADS THAT WERE MEASURED 1701 01:19:49,162 --> 01:19:50,430 PRIOR TO STARTING ART. 1702 01:19:50,430 --> 01:19:52,366 WE THINK THIS IS IMPORTANT WE 1703 01:19:52,366 --> 01:19:53,600 SHIFT THE NEEDLE ON WHAT THEIR 1704 01:19:53,600 --> 01:19:55,035 SET POINT IS AND THIS WAS NOT 1705 01:19:55,035 --> 01:19:56,937 DIFFERENT IN THE INDIVIDUALS WHO 1706 01:19:56,937 --> 01:19:58,305 WERE NON CONTROLLERS. 1707 01:19:58,305 --> 01:20:01,308 SO REALLY THE QUESTION IS WHAT 1708 01:20:01,308 --> 01:20:03,277 CAUSED THE POST-ART SET POINTS 1709 01:20:03,277 --> 01:20:04,745 TO BE LOWER? 1710 01:20:04,745 --> 01:20:06,647 WHAT WAS THE OUTPUT FROM THE 1711 01:20:06,647 --> 01:20:06,980 INTERVENTIONS? 1712 01:20:06,980 --> 01:20:09,316 I DON'T HAVE ALL THE ANSWERS 1713 01:20:09,316 --> 01:20:09,716 TODAY. 1714 01:20:09,716 --> 01:20:10,651 WE ARE DOING WILL A LOT OF 1715 01:20:10,651 --> 01:20:10,884 THINGS. 1716 01:20:10,884 --> 01:20:13,553 WE'RE TRYING TO PUT TOGETHER THE 1717 01:20:13,553 --> 01:20:15,689 ANTIBODY PK WITH THE RESERVOIR 1718 01:20:15,689 --> 01:20:17,457 MEASUREMENTS WITH A HOST OF 1719 01:20:17,457 --> 01:20:18,558 IMMUNOLOGIC MEASURES TO TRY TO 1720 01:20:18,558 --> 01:20:19,259 UNDERSTAND THIS. 1721 01:20:19,259 --> 01:20:21,261 BUT THE DATA I'LL PRESENT 1722 01:20:21,261 --> 01:20:22,329 FOCUSES ON SEVERAL TIME POINTS. 1723 01:20:22,329 --> 01:20:24,765 WE WOULD WANT TO KNOW ARE THERE 1724 01:20:24,765 --> 01:20:25,632 DIFFERENCES AT BASELINE BETWEEN 1725 01:20:25,632 --> 01:20:29,469 CONTROLLERS AND NON CONTROLLERS 1726 01:20:29,469 --> 01:20:30,704 THROUGH THE VACCINE PHASE AND 1727 01:20:30,704 --> 01:20:32,039 THEN THE MAJOR TIME POINTS WE'RE 1728 01:20:32,039 --> 01:20:33,774 LOOKING AT ARE RIGHT BEFORE 1729 01:20:33,774 --> 01:20:36,310 TREATMENT INTERRUPTION AND THEN 1730 01:20:36,310 --> 01:20:41,915 AS THEY ARE B NAPS ARE WARN OFF 1731 01:20:41,915 --> 01:20:45,152 BEFORE KEY TIME POINT AND RIGHT 1732 01:20:45,152 --> 01:20:46,920 INTO REBOUND. 1733 01:20:46,920 --> 01:20:47,988 AS YOU PRESSURE TEST THE IMMUNE 1734 01:20:47,988 --> 01:20:49,489 SYSTEM YOU HAVE TO DO SOMETHING. 1735 01:20:49,489 --> 01:20:53,961 WHAT IS IT DOING AND HOW DOES IT 1736 01:20:53,961 --> 01:20:54,962 DIFFER BETWEEN PEOPLE 1737 01:20:54,962 --> 01:20:57,597 CONTROLLING AND NOT AND HAVE A 1738 01:20:57,597 --> 01:20:59,466 SAMPLING TIME POINT FOR 1739 01:20:59,466 --> 01:21:00,100 INDIVIDUALS AT THE RELATIVELY 1740 01:21:00,100 --> 01:21:01,501 LOW VIRAL LOADS WITHIN THE FIRST 1741 01:21:01,501 --> 01:21:04,438 MONTH OF REBOUND WHERE WE WERE 1742 01:21:04,438 --> 01:21:08,508 ABLE TO ASSESS HOW THE IMMUNE 1743 01:21:08,508 --> 01:21:10,944 SYSTEM WAS RESPONDING AND 1744 01:21:10,944 --> 01:21:12,045 THERE'S A LOT OF DATA HERE I 1745 01:21:12,045 --> 01:21:14,681 DON'T HAVE TIME TO SHOW BUT 1746 01:21:14,681 --> 01:21:17,651 HAPPY TO GO THROUGH WITH ANYBODY 1747 01:21:17,651 --> 01:21:22,823 AND WE SHOWED THE B NAB, PK AS 1748 01:21:22,823 --> 01:21:25,125 EXPECTED CORRELATED WITH TIME 1749 01:21:25,125 --> 01:21:30,130 AND NOT THE PORT-ART SET POINT 1750 01:21:30,130 --> 01:21:33,600 SO BNAB WASN'T RELATED TO THOSE 1751 01:21:33,600 --> 01:21:35,802 WITH LOWER SET POINTS AND THE 1752 01:21:35,802 --> 01:21:37,938 RESERVOIR LEVEL SHOWED MOST 1753 01:21:37,938 --> 01:21:40,640 INDIVIDUALS HAVE RELATIVELY LOW 1754 01:21:40,640 --> 01:21:44,511 RESERVOIR LEVEL AND FROM 1755 01:21:44,511 --> 01:21:46,813 PERIPHERAL BLOOD CD4 T CELLS THE 1756 01:21:46,813 --> 01:21:48,181 NON-REBOUNDER HAD LOW LEVELS OF 1757 01:21:48,181 --> 01:21:50,250 RESERVOIR AND HAPPY TO COMMENT 1758 01:21:50,250 --> 01:21:53,720 MORE BUT NO CORRELATION WITH SET 1759 01:21:53,720 --> 01:21:56,490 POINTS AND THE VACCINES 1760 01:21:56,490 --> 01:21:58,392 FANTASTIC VACCINE REGIMENT 1761 01:21:58,392 --> 01:21:59,793 ELICITED T CELL RESPONSES 1762 01:21:59,793 --> 01:22:01,528 AGAINST THE REGIONS. 1763 01:22:01,528 --> 01:22:04,131 THE MAGNITUDE IS MEASURE BY ICS 1764 01:22:04,131 --> 01:22:05,432 DIDN'T CORRELATE WITH THE 1765 01:22:05,432 --> 01:22:05,699 OUTCOMES. 1766 01:22:05,699 --> 01:22:09,536 WE'VE GOTTEN A LOT OF MILEAGE 1767 01:22:09,536 --> 01:22:17,344 OUT OF USING MASS CYTOMETRY AND 1768 01:22:17,344 --> 01:22:19,546 LOOKED AT CELLS THAT RELATE TO 1769 01:22:19,546 --> 01:22:20,013 OUTCOMES. 1770 01:22:20,013 --> 01:22:23,116 OUR PANELS ARE DESIGN TO LOOK AT 1771 01:22:23,116 --> 01:22:28,388 INNATE AND ADAPTIVE IMMUNE CELLS 1772 01:22:28,388 --> 01:22:32,626 AND THIS IS NOT ANTIGEN SPECIFIC 1773 01:22:32,626 --> 01:22:33,994 CELLS AT THIS LEVEL BUT IS 1774 01:22:33,994 --> 01:22:37,164 IMPORTANT FOR CAPTURING THE 1775 01:22:37,164 --> 01:22:37,364 CELLS. 1776 01:22:37,364 --> 01:22:38,765 SO, ONE THING I WANTED TO SAY IS 1777 01:22:38,765 --> 01:22:40,567 WHEN WE USE THE PANELS AND 1778 01:22:40,567 --> 01:22:41,902 SORRY, I DIDN'T REALIZE THIS WAS 1779 01:22:41,902 --> 01:22:45,205 SO BLURRY BUT WE LOOKED -- THIS 1780 01:22:45,205 --> 01:22:47,107 IS LOOKING THE HEAT PERHAPS ARE 1781 01:22:47,107 --> 01:22:48,175 MEANT TO REPRESENT WHAT HAPPENS 1782 01:22:48,175 --> 01:22:50,744 ACROSS THE COURSE OF THE TRIAL 1783 01:22:50,744 --> 01:22:51,611 AND BASELINE AND POST REBOUND 1 1784 01:22:51,611 --> 01:22:54,014 AND WE'RE LOOKING AT POPULATIONS 1785 01:22:54,014 --> 01:22:56,416 ACTIVATED IN INNATE AND ADAPTIVE 1786 01:22:56,416 --> 01:22:58,318 IMMUNE CELLS AND WHAT'S 1787 01:22:58,318 --> 01:23:00,153 HAPPENING IN THE CONTROLLERS WE 1788 01:23:00,153 --> 01:23:01,588 DECIDED TO LOOK AT AND SEE THE 1789 01:23:01,588 --> 01:23:03,390 POPULATIONS GO UP IN FREQUENCY. 1790 01:23:03,390 --> 01:23:05,725 NOT SURPRISING AT THE TIME POINT 1791 01:23:05,725 --> 01:23:06,893 WHEN THEY'RE RESPONDING TO 1792 01:23:06,893 --> 01:23:07,127 VIRUS. 1793 01:23:07,127 --> 01:23:08,962 YOU SEE A LOT OF THEM GOING UP 1794 01:23:08,962 --> 01:23:10,697 AT THE PRE-REBOUND TIME POINT 1795 01:23:10,697 --> 01:23:11,965 AND SEE THEY'RE ALREADY STARTING 1796 01:23:11,965 --> 01:23:13,567 TO COME UP BEFORE PEOPLE HAVE 1797 01:23:13,567 --> 01:23:14,801 STARTED TO REBOUND. 1798 01:23:14,801 --> 01:23:16,536 THIS HAPPENS TO BE TRUE IN BOTH 1799 01:23:16,536 --> 01:23:20,407 THE CONTROLLERS IN BLUE AND NON 1800 01:23:20,407 --> 01:23:21,007 CONTROLLERS IN RED. 1801 01:23:21,007 --> 01:23:21,875 WHAT'S THE DIFFERENCE BETWEEN 1802 01:23:21,875 --> 01:23:25,011 THE CONTROLLERS AND 1803 01:23:25,011 --> 01:23:26,213 NON-CONTROLLERS. 1804 01:23:26,213 --> 01:23:28,682 LOOKING THROUGH HUNDREDS ME AND 1805 01:23:28,682 --> 01:23:31,485 MY GRADUATE STUDENT, DEMI, 1806 01:23:31,485 --> 01:23:32,152 LOOKING THROUGH HUNDREDS OF 1807 01:23:32,152 --> 01:23:35,455 IMMUNE FEATURES AT A TIME. 1808 01:23:35,455 --> 01:23:38,792 THE ABSOLUTELY MOST STRIKING 1809 01:23:38,792 --> 01:23:40,360 THING I LOVE CD 8 T CELLS BUT 1810 01:23:40,360 --> 01:23:41,795 ABOUT WHAT IS STRIKING THE 1811 01:23:41,795 --> 01:23:44,798 CONTROLLERS WHEN THEY HIT THE 1812 01:23:44,798 --> 01:23:47,534 POST REBOUND 1 TIME POINT HAVE 1813 01:23:47,534 --> 01:23:49,569 IN INCREASE IN THEIR CYCLING OF 1814 01:23:49,569 --> 01:23:51,872 THE POSITIVE CD 8 CELLS STRIKING 1815 01:23:51,872 --> 01:23:53,974 COMPARED TO THE NON-CONTROLLERS 1816 01:23:53,974 --> 01:23:55,642 WHO WERE AT A HIGHER VIRAL LOAD 1817 01:23:55,642 --> 01:23:57,911 AND ON THEIR WAY TO START LOSING 1818 01:23:57,911 --> 01:24:00,380 CONTROL AND COULDN'T CATCH UP IS 1819 01:24:00,380 --> 01:24:02,482 OUR INTERPRETATION OF THIS. 1820 01:24:02,482 --> 01:24:03,450 THERE'S A NICE NEGATIVE 1821 01:24:03,450 --> 01:24:05,118 CORRELATION AND THE INDIVIDUALS 1822 01:24:05,118 --> 01:24:07,988 WHO HAVE HIGHER CYCLING NON-CD 8 1823 01:24:07,988 --> 01:24:09,923 T CELLS ARE THE ONE THAT GO ON 1824 01:24:09,923 --> 01:24:12,159 TO HAVE LOWER SET POINT AND 1825 01:24:12,159 --> 01:24:12,993 SUSTAIN MORE SET POINTS OVER 1826 01:24:12,993 --> 01:24:15,562 MANY MONTHS. 1827 01:24:15,562 --> 01:24:17,864 WE THINK IT'S REALLY INTERESTING 1828 01:24:17,864 --> 01:24:20,867 WITHIN THESE CYCLING CD 8 T 1829 01:24:20,867 --> 01:24:24,471 CELLS THE INDIVIDUALS WHO HAVE 1830 01:24:24,471 --> 01:24:27,040 INTERVENTION CONTROL HAVE A HIGH 1831 01:24:27,040 --> 01:24:29,109 CYCLING THAT EXPRESS THE 1832 01:24:29,109 --> 01:24:31,645 IMPORTANT TCF1 IMPORTANT FOR 1833 01:24:31,645 --> 01:24:33,246 MAINTAINING PROLIFERATIVE 1834 01:24:33,246 --> 01:24:33,747 CAPACITY. 1835 01:24:33,747 --> 01:24:40,453 AND AGAIN THERE'S A CORRELATION 1836 01:24:40,453 --> 01:24:41,922 WITH THE VIRAL LOADS AND IT'S 1837 01:24:41,922 --> 01:24:43,323 INTERESTING THE OTHER STRIKING 1838 01:24:43,323 --> 01:24:45,825 POPULATION WE SEE IS NOT AN 1839 01:24:45,825 --> 01:24:52,232 INCREASE OR UNIQUE INCREASE IN 1840 01:24:52,232 --> 01:24:53,967 PLA 1841 01:24:53,967 --> 01:24:55,402 PLASMA BLASTS WHICH PUMP OUT 1842 01:24:55,402 --> 01:24:58,505 ANTIBODIES AND WE UNIQUELY SEE 1843 01:24:58,505 --> 01:25:02,442 THE PLASMA BLASTS FOR MAKING AN 1844 01:25:02,442 --> 01:25:04,077 ANTIVIRAL RESPONSE GOING UP IN 1845 01:25:04,077 --> 01:25:04,711 IN THE CONTROLLERS COMPARED TO 1846 01:25:04,711 --> 01:25:06,846 THE NON CONTROLLERS AND IN THE B 1847 01:25:06,846 --> 01:25:09,449 CELL AND T CELL WORK WE'RE 1848 01:25:09,449 --> 01:25:10,951 TRYING TO UNDERSTAND HIV 1849 01:25:10,951 --> 01:25:13,687 SPECIFICITY AND INTEGRATING THE 1850 01:25:13,687 --> 01:25:15,488 RESPONSES WITH OTHER THINGS. 1851 01:25:15,488 --> 01:25:17,958 SO WE HAVE MORE DATA. 1852 01:25:17,958 --> 01:25:19,559 HAPPY TO CHAT MORE ABOUT THAT 1853 01:25:19,559 --> 01:25:21,928 BUT THE CLINICAL OUTCOMES IT'S 1854 01:25:21,928 --> 01:25:23,363 AN INTERESTING CLINICAL TRIAL WE 1855 01:25:23,363 --> 01:25:27,200 THINK THE COMBINATION ALTERED 1856 01:25:27,200 --> 01:25:29,769 NATURAL HIV REBOUND AND PEOPLE 1857 01:25:29,769 --> 01:25:32,606 WITH BETTER CONTROLS HAVE IN A 1858 01:25:32,606 --> 01:25:34,174 PRESSURE TEST SETTING A BETTER 1859 01:25:34,174 --> 01:25:37,077 ABILITY TO POUNCE ON THE VIRUS. 1860 01:25:37,077 --> 01:25:38,812 THERE MAY BE A DISTINCT 1861 01:25:38,812 --> 01:25:40,780 MECHANISM OF CONTROL RELATE THE 1862 01:25:40,780 --> 01:25:45,952 TO RESERVOIR INDIVIDUALS AND WE 1863 01:25:45,952 --> 01:25:47,320 HAVE COLLABORATORS INVOLVED FROM 1864 01:25:47,320 --> 01:25:49,389 BEGINNING TO NOW AND ONGOING BUT 1865 01:25:49,389 --> 01:25:50,991 WANTED TO SHOW YOU MEMBERS OF MY 1866 01:25:50,991 --> 01:25:53,026 LAB AND SOME OF OUR 1867 01:25:53,026 --> 01:25:53,660 COLLABORATORS INVOLVED IN THE 1868 01:25:53,660 --> 01:25:54,060 WORK I PRESENTED. 1869 01:25:54,060 --> 01:26:04,237 THANK YOU. 1870 01:26:19,986 --> 01:26:22,656 >> THANKS VERY MUCH. 1871 01:26:22,656 --> 01:26:26,126 OUR LAB IS LARGELY FOCUSSED ON 1872 01:26:26,126 --> 01:26:27,327 APOPTOTIC DRUGS BUT TODAY I'M 1873 01:26:27,327 --> 01:26:29,562 GOING TO TALK TO YOU ABOUT OUR 1874 01:26:29,562 --> 01:26:34,034 FINDINGS ON THE IMPACT OF 1875 01:26:34,034 --> 01:26:37,804 MONOVMO 1876 01:26:37,804 --> 01:26:41,908 MONOVALENT REVERSAL AND CD 8 T 1877 01:26:41,908 --> 01:26:44,644 CELL FUNCTION. 1878 01:26:44,644 --> 01:26:46,413 WE WERE INTERESTED IN THE EFFECT 1879 01:26:46,413 --> 01:26:48,081 OF CANCER DRUGS AS MANY 1880 01:26:48,081 --> 01:26:48,648 LABORATORIES ARE AND THEIR 1881 01:26:48,648 --> 01:26:53,887 EFFECT ON THE RESERVOIR AND 1882 01:26:53,887 --> 01:26:56,022 WHETHER THEY ARE EFFECT THE 1883 01:26:56,022 --> 01:27:00,060 VIRUS AND HAVE AN EFFECT ON THE 1884 01:27:00,060 --> 01:27:00,694 IMMUNE RESPONSE? 1885 01:27:00,694 --> 01:27:03,263 THEY ARE CAN REVERSE HIV LATENCY 1886 01:27:03,263 --> 01:27:07,500 BUT HAVE LIMITED POTENCY IN 1887 01:27:07,500 --> 01:27:14,174 USING PRIMARY CD4 T CELLS. 1888 01:27:14,174 --> 01:27:17,911 AND FOUND THE CELL KILLED IN 1889 01:27:17,911 --> 01:27:21,548 VITRO AND IN ANIMAL MODEL 1890 01:27:21,548 --> 01:27:22,515 RESULTING IN HIGHER VIRAL 1891 01:27:22,515 --> 01:27:25,785 REBOUND AFTER NATI. 1892 01:27:25,785 --> 01:27:36,296 SO WHAT ARE THE IMPLICATIONS? 1893 01:27:40,133 --> 01:27:41,801 HAVE ADVERSE EFFECTS AND FEEL IT 1894 01:27:41,801 --> 01:27:43,970 SHOULD BE USED WITH CAUTION IN 1895 01:27:43,970 --> 01:27:46,906 REDUCING CONTROL PURE STRATEGIES 1896 01:27:46,906 --> 01:27:49,776 THAT INVOLVE CD 8 T CELLS AND 1897 01:27:49,776 --> 01:27:51,745 MORE POTENT LESS TOXIC HIV 1898 01:27:51,745 --> 01:27:53,980 SPECIFIC AGENTS ARE STILL NEEDED 1899 01:27:53,980 --> 01:28:04,324 TO REVERSE LATENCY. 1900 01:28:14,567 --> 01:28:16,603 AND WE'VE BEEN PARTICULARLY 1901 01:28:16,603 --> 01:28:17,470 INTERESTED IN THESE TWO 1902 01:28:17,470 --> 01:28:23,042 COMPOUNDS THAT WERE GIVEN TO US 1903 01:28:23,042 --> 01:28:28,281 BY GDCO152 AND 0197 AND 1904 01:28:28,281 --> 01:28:32,051 INTERESTED IN THE MONOVALENT 1905 01:28:32,051 --> 01:28:33,486 BECAUSE THEY'VE BEEN SHOWN TO 1906 01:28:33,486 --> 01:28:37,257 HAVE REDUCED TOXICITY BUT IT'S 1907 01:28:37,257 --> 01:28:41,027 WELL KNOWN THE BIVALENCE HAVE 1908 01:28:41,027 --> 01:28:43,997 BETTER POTENCY. 1909 01:28:43,997 --> 01:28:46,166 THO 1910 01:28:46,166 --> 01:28:48,802 HAVE BEEN INVESTIGATED BY 1911 01:28:48,802 --> 01:28:49,803 OTHERS SOME IN THE ROOM TODAY. 1912 01:28:49,803 --> 01:28:54,507 WE STARTED LOOKING AT THE THE 1913 01:28:54,507 --> 01:28:58,178 MONOVALENT AND VALENTS RAND THE 1914 01:28:58,178 --> 01:29:00,847 CELL LINE UNDER THE CONTROL OF 1915 01:29:00,847 --> 01:29:03,616 AN HIV LTR. 1916 01:29:03,616 --> 01:29:06,853 AND AS DESCRIBED EARLIER BY 1917 01:29:06,853 --> 01:29:17,397 OTHERS CLEARLY THE BIVALENCE AND 1918 01:29:29,175 --> 01:29:30,543 IT'S 10% OF THE CELLS AND THE 1919 01:29:30,543 --> 01:29:35,615 HIGHER CONCENTRATIONS THERE'S 1920 01:29:35,615 --> 01:29:38,718 CLEARLY EVIDENCE OF CITO 1921 01:29:38,718 --> 01:29:49,062 TOXICITY SHOWN HERE. 1922 01:29:49,262 --> 01:29:52,332 AND THEY WERE TREATED EX VIVO 1923 01:29:52,332 --> 01:29:54,634 WITH AND WITHOUT T AND L ALPHA 1924 01:29:54,634 --> 01:29:56,636 AND I WON'T SHOW THAT DATA 1925 01:29:56,636 --> 01:29:57,237 TODAY. 1926 01:29:57,237 --> 01:30:01,741 AND WE USED THE HIV 1927 01:30:01,741 --> 01:30:03,743 TRANSCRIPTIONAL PROFILING ASSAY 1928 01:30:03,743 --> 01:30:05,044 INITIALLY DESCRIBED AND RECENTLY 1929 01:30:05,044 --> 01:30:07,647 ADAPTED BY MY GROUP TO USE IN 1930 01:30:07,647 --> 01:30:12,485 THE SETTING OF DIGITAL PCR 1931 01:30:12,485 --> 01:30:17,190 OPPOSED TO DROPLET PCR FOR 1932 01:30:17,190 --> 01:30:17,857 HIGHER THROUGHPUT. 1933 01:30:17,857 --> 01:30:19,692 INTERESTING IN THE PROFILING 1934 01:30:19,692 --> 01:30:21,995 ASSAY BECAUSE IT TELLS US ALL 1935 01:30:21,995 --> 01:30:24,664 STAGES OF TRANSCRIPTION 1936 01:30:24,664 --> 01:30:26,900 INITIATION AND ELONGATION AND 1937 01:30:26,900 --> 01:30:32,438 COMPLETION AND MOST IMPORTANTLY 1938 01:30:32,438 --> 01:30:32,739 SPLICING. 1939 01:30:32,739 --> 01:30:36,476 ONLY SPLICED RNA ALLOWS FOR 1940 01:30:36,476 --> 01:30:39,779 PROTEIN PRODUCTION AND AMPLIFIED 1941 01:30:39,779 --> 01:30:43,082 INCOMPLETE TRANSCRIPTS. 1942 01:30:43,082 --> 01:30:44,083 WHAT DID WE FIND? 1943 01:30:44,083 --> 01:30:46,286 HERE'S THE DATA FOR 1944 01:30:46,286 --> 01:30:47,887 TRANSCRIPTIONAL INITIATION. 1945 01:30:47,887 --> 01:30:51,958 BLACK SHOWING MONOVALENCE AND 1946 01:30:51,958 --> 01:30:55,795 BIVALENCE AND SEE THE GDC 1947 01:30:55,795 --> 01:31:00,767 COMPOUNDS 0197 AND SHOWED 1948 01:31:00,767 --> 01:31:08,608 INCREASE IN TRANSCRIPTIONAL 1949 01:31:08,608 --> 01:31:08,908 INITIATION. 1950 01:31:08,908 --> 01:31:13,112 WHEN WE LOOK AT POLY A 1951 01:31:13,112 --> 01:31:16,816 COMPLETION THE 8852 GOES ON TO 1952 01:31:16,816 --> 01:31:18,618 SIGNIFICANTLY COMPLETE 1953 01:31:18,618 --> 01:31:22,155 TRANSCRIPTS WHILE THE MONOVALENT 1954 01:31:22,155 --> 01:31:23,423 COMPOUNDS SHOWED NO SIGNIFICANT 1955 01:31:23,423 --> 01:31:23,690 INCREASE. 1956 01:31:23,690 --> 01:31:25,191 WHEN WE LOOKED AT SPLICING THERE 1957 01:31:25,191 --> 01:31:29,929 WAS NO SIGNIFICANT INCREASE IN 1958 01:31:29,929 --> 01:31:33,900 SPLICED RNA WHEN TREATED WITH 1959 01:31:33,900 --> 01:31:41,240 THE MONOVALENT OR AZD5582. 1960 01:31:41,240 --> 01:31:47,814 MONOVALENT AND BIVALENT DOES NOT 1961 01:31:47,814 --> 01:31:50,116 INDUCE SPLICING. 1962 01:31:50,116 --> 01:31:55,054 WHY DO WE SEE BLIPS IN MACAQUES 1963 01:31:55,054 --> 01:31:58,558 IN THOSE TREATED WITH A ZD5582 1964 01:31:58,558 --> 01:32:00,560 AND COULD THIS BE EXPLAINED WITH 1965 01:32:00,560 --> 01:32:08,735 THE IMMUNOLOGICAL EFFECTS OF 1966 01:32:08,735 --> 01:32:12,138 SMAC AND CAN THEY PLAY IN CURE 1967 01:32:12,138 --> 01:32:12,472 STRATEGIES? 1968 01:32:12,472 --> 01:32:16,643 THERE'S DATA IN THE REGULATORY 1969 01:32:16,643 --> 01:32:23,416 EFFECTS OF SMAC MIMETICS AND 1970 01:32:23,416 --> 01:32:29,422 INHIBITORS OF ATPOPTOSIS PROTEIS 1971 01:32:29,422 --> 01:32:33,092 WERE REQUIRED FOR EXPANSION AND 1972 01:32:33,092 --> 01:32:35,595 SURVIVAL DURING ANTIVIRAL 1973 01:32:35,595 --> 01:32:40,400 IMMUNITY IN MOUSE SO FAVORABLE 1974 01:32:40,400 --> 01:32:45,905 EFFECTS OF THE SMAC MIMETIC AND 1975 01:32:45,905 --> 01:32:50,910 SHOWED TO ENHANCE SURVIVAL OF 1976 01:32:50,910 --> 01:32:54,547 ANTI-TUMOR T CELLS AND THE 1977 01:32:54,547 --> 01:32:55,948 BLOCKADE TO PROMOTE TUMOR 1978 01:32:55,948 --> 01:32:56,616 IMMUNITY. 1979 01:32:56,616 --> 01:32:59,118 WE'RE INTERESTED REALLY IN THE 1980 01:32:59,118 --> 01:33:07,360 FAVORABLE EFFECTS OF SMAC MIM 1981 01:33:07,360 --> 01:33:07,827 ETIET 1982 01:33:07,827 --> 01:33:08,161 IB 1983 01:33:08,161 --> 01:33:08,361 ICES. 1984 01:33:08,361 --> 01:33:11,297 WE TOOK PEOPLE ON ANTIRETROVIRAL 1985 01:33:11,297 --> 01:33:16,569 THERAPY AND ADDED HIV PEPTIDE TO 1986 01:33:16,569 --> 01:33:19,105 INCREASE THE CELLS AND QUANTIFY 1987 01:33:19,105 --> 01:33:21,574 THE CELLS THAT HAVE UNDER GONE 1988 01:33:21,574 --> 01:33:22,875 PROLIFERATION. 1989 01:33:22,875 --> 01:33:26,112 WE THEN INCUBATED THOSE IN THE 1990 01:33:26,112 --> 01:33:28,748 PRESENCE OF SMAC MIMETICS AND 1991 01:33:28,748 --> 01:33:37,023 LOOKED AT PROLIFERATION AND THE 1992 01:33:37,023 --> 01:33:40,193 TOTAL CELLS AND HIV SPECIFIC 1993 01:33:40,193 --> 01:33:45,765 CELLS LABELLED WITH TETRAMERS 1994 01:33:45,765 --> 01:33:48,367 AND COULD QUANTIFY HIV SPECIFIC 1995 01:33:48,367 --> 01:33:53,773 AND TOTAL CD 8 T CELLS. 1996 01:33:53,773 --> 01:34:04,250 SO THIS GRAPH SHOWS YOU AND 1997 01:34:05,618 --> 01:34:07,987 POSITIVE CONTROL A DRUG 1998 01:34:07,987 --> 01:34:12,391 INTERESTED IN IN ITS ENHANCING 1999 01:34:12,391 --> 01:34:14,660 AFFECTS OF HIV CD T CELLS. 2000 01:34:14,660 --> 01:34:18,898 IT'S SHOWN IN GRAY AND THE DATA 2001 01:34:18,898 --> 01:34:20,867 IS RELATIVE AND PLOTTED AT 1. 2002 01:34:20,867 --> 01:34:24,670 AND YOU CAN SEE ABOVE THE LINE 2003 01:34:24,670 --> 01:34:28,608 ALL THE MONOVALENCE SMAC 2004 01:34:28,608 --> 01:34:31,544 MIMETICS SHOW AFTER PROLONGED 2005 01:34:31,544 --> 01:34:35,081 CULTURE IN VITRO AFTER DAY 7 YOU 2006 01:34:35,081 --> 01:34:36,716 SEE THE PROGRESSIVE INCREASE IN 2007 01:34:36,716 --> 01:34:41,921 HIV SPECIFIC T CELLS WHICH FOR 2008 01:34:41,921 --> 01:34:46,025 SOME MONOVALENCE T CELLS 0917 IS 2009 01:34:46,025 --> 01:34:47,193 QUITE SIGNIFICANT. 2010 01:34:47,193 --> 01:34:50,730 IN CONTRAST YOU SEE THE RED LINE 2011 01:34:50,730 --> 01:34:52,098 IN THE PRESENCE WHERE THERE'S IN 2012 01:34:52,098 --> 01:34:56,702 FACT NO EXPANSION OF THE HIV 2013 01:34:56,702 --> 01:34:58,037 SPECIFIC T CELLS AND CELL LOSS. 2014 01:34:58,037 --> 01:35:00,339 THESE FINDINGS WERE SIMILAR BUT 2015 01:35:00,339 --> 01:35:05,178 LESS DRAMATIC IN CD 8 T CELLS. 2016 01:35:05,178 --> 01:35:07,680 SHOWN HERE IN A DIFFERENT WAY 2017 01:35:07,680 --> 01:35:10,883 YOU SEE THE LOSS OF LOSS 2018 01:35:10,883 --> 01:35:13,519 SPECIFIC CD 8 T CELLS WAS PRETTY 2019 01:35:13,519 --> 01:35:15,054 DRAMATIC AND MORE PRONOUNCED 2020 01:35:15,054 --> 01:35:18,591 THAN WHAT YOU WOULD SEE WITH THE 2021 01:35:18,591 --> 01:35:20,793 LOSS OF JUST TOTAL CD 8 T CELLS. 2022 01:35:20,793 --> 01:35:27,166 WE THINK THIS IS A CLEARLY 2023 01:35:27,166 --> 01:35:33,172 ADVERSE EFFECT OF AZD5582 AND 2024 01:35:33,172 --> 01:35:35,508 EFFECT ON CD4 AND CD 8 T CELLS I 2025 01:35:35,508 --> 01:35:37,944 WON'T GO INTO NOW. 2026 01:35:37,944 --> 01:35:40,580 AT THE SAME TIME WE HAD THE 2027 01:35:40,580 --> 01:35:42,815 OPPORTUNITY TO ASK THE QUESTION 2028 01:35:42,815 --> 01:35:49,255 IN COLLABORATION WITH LOUIS AND 2029 01:35:49,255 --> 01:35:50,656 HIS TEAM BECAUSE AS SHOWED 2030 01:35:50,656 --> 01:35:56,095 EARLIER WERE LOOKING AT THE 2031 01:35:56,095 --> 01:36:00,666 EFFECTS OF mRNA IN THE PRESENCE 2032 01:36:00,666 --> 01:36:05,872 OF SIV. 2033 01:36:05,872 --> 01:36:10,243 THEY COMPARED AN mRNA VACCINE 2034 01:36:10,243 --> 01:36:12,445 THAT EXPRESSED GAG AND THE 2035 01:36:12,445 --> 01:36:13,779 FAVORABLE AFFECTS THE 2036 01:36:13,779 --> 01:36:16,315 VACCINATION HAD ON HIV SPECIFIC 2037 01:36:16,315 --> 01:36:18,351 T CELLS AND TIME TO REBOUND AND 2038 01:36:18,351 --> 01:36:20,353 VIRAL SET POINT. 2039 01:36:20,353 --> 01:36:23,422 AT THE SAME TIME THE TEAM DID 2040 01:36:23,422 --> 01:36:25,758 THE IDENTICAL STUDY BUT ALSO 2041 01:36:25,758 --> 01:36:35,401 INCLUDED MULTIPLE DOSES OF 2042 01:36:35,401 --> 01:36:36,502 AZD5582. 2043 01:36:36,502 --> 01:36:41,307 THE INITIAL HYPOTHESIS WAS AZD 2044 01:36:41,307 --> 01:36:43,776 WOULD ENHANCE THE VACCINE AND 2045 01:36:43,776 --> 01:36:47,613 MAKE THEM MORE VISIBLE TO THE 2046 01:36:47,613 --> 01:36:49,115 NEWLY GENERATED CD 8 T CELLS. 2047 01:36:49,115 --> 01:36:52,485 SO WHAT DID THEY FIND? 2048 01:36:52,485 --> 01:36:55,288 WELL, AS YOU'D EXPECT AZD DID 2049 01:36:55,288 --> 01:36:57,723 INDEED INDUCE BLIPS YOU SEE IN 2050 01:36:57,723 --> 01:37:00,726 BOTH ARMS OF THE STUDY WITH THE 2051 01:37:00,726 --> 01:37:05,564 MONKEYS RECEIVED AN SIV GAG 2052 01:37:05,564 --> 01:37:07,066 VACCINE IN THE PRESENCE THEY ARE 2053 01:37:07,066 --> 01:37:09,669 WERE BLIPS AND MORE TIME POINTS 2054 01:37:09,669 --> 01:37:10,937 WHERE THE VIRAL LOAD WAS GREATER 2055 01:37:10,937 --> 01:37:14,674 THAN THE AMOUNT OF DETECTION. 2056 01:37:14,674 --> 01:37:19,545 WHAT HAPPENED TO THE HIV 2057 01:37:19,545 --> 01:37:22,648 SPECIFIC T CELL RESPONSE? 2058 01:37:22,648 --> 01:37:25,484 I'M SHOWING THE mRNA VACCINE 2059 01:37:25,484 --> 01:37:28,287 DATA WITH AZD IN THE SOLID AND 2060 01:37:28,287 --> 01:37:29,221 WITHOUT IN THE DASH LINE. 2061 01:37:29,221 --> 01:37:32,959 FROM LEFT TO RIGHT YOU SEE THE 2062 01:37:32,959 --> 01:37:34,260 GAG SPECIFIC CD 8 T CELLS IN THE 2063 01:37:34,260 --> 01:37:36,696 PRESENCE OF AZD. 2064 01:37:36,696 --> 01:37:38,831 THEY WERE REDUCED GAG SPECIFIC 2065 01:37:38,831 --> 01:37:40,166 CD 8 T CELLS. 2066 01:37:40,166 --> 01:37:45,938 IN THE PRESENCE OF AZD THE 2067 01:37:45,938 --> 01:37:47,974 BENEFICIAL EFFECT OF THE mRNA 2068 01:37:47,974 --> 01:37:55,848 VACCINE WAS AB ROW GRW -- ABROG 2069 01:37:55,848 --> 01:38:00,119 AND THERE WAS A HIGHER PEAK 2070 01:38:00,119 --> 01:38:01,721 VIRAL LOAD AND VIRAL SET POINT. 2071 01:38:01,721 --> 01:38:05,191 THESE FINDINGS WERE THE SAME IN 2072 01:38:05,191 --> 01:38:08,728 THE CONTROL ARM MEANING WHEN WE 2073 01:38:08,728 --> 01:38:11,197 PREPARED THE CONTROL ARM WITHOUT 2074 01:38:11,197 --> 01:38:13,599 AZD IN THE DASH LINE AND THE 2075 01:38:13,599 --> 01:38:16,402 SOLID LINE YOU CAN SEE LOWER GAG 2076 01:38:16,402 --> 01:38:17,670 SPECIFIC CD 8 T CELLS. 2077 01:38:17,670 --> 01:38:19,905 NO DIFFERENCE IN TIME TO VIRAL 2078 01:38:19,905 --> 01:38:22,608 REBOUND BUT THIS IS REALLY 2079 01:38:22,608 --> 01:38:23,709 INTERESTING THAT IN THE PRESENCE 2080 01:38:23,709 --> 01:38:27,313 OF AZD YOU ACTUALLY HAD A HIGHER 2081 01:38:27,313 --> 01:38:31,884 SET POINT THAN WITHOUT AZD. 2082 01:38:31,884 --> 01:38:37,123 SO, IN SUMMARY WE'VE SHOWN 2083 01:38:37,123 --> 01:38:41,027 MIMETICS REVERSE LATENCY WIN 2084 01:38:41,027 --> 01:38:48,401 PEOPLE WITH HIV IN ART AND EX 2085 01:38:48,401 --> 01:38:49,602 VIVO MIMETICS CAN ENHANCE 2086 01:38:49,602 --> 01:38:51,637 SPECIFIC T CELLS WHICH WE THINK 2087 01:38:51,637 --> 01:38:53,639 IS A FAVORABLE FEATURE AND THAT 2088 01:38:53,639 --> 01:38:54,306 WAS SIGNIFICANT TOXICITY. 2089 01:38:54,306 --> 01:38:57,910 WE DON'T KNOW IF THIS IS A CLASS 2090 01:38:57,910 --> 01:39:03,416 EFFECT OF ALL BIVALENCE AND 2091 01:39:03,416 --> 01:39:04,784 WE'RE INVESTIGATING WITH THE 2092 01:39:04,784 --> 01:39:07,720 PANEL AND ELIMINATED ANY 2093 01:39:07,720 --> 01:39:11,123 EXPANSION OF CD 8 T CELLS AND 2094 01:39:11,123 --> 01:39:13,459 UNFAVORABLE OUTCOME. 2095 01:39:13,459 --> 01:39:16,395 THE ADDITIONAL OF AZD ABROGATED 2096 01:39:16,395 --> 01:39:18,397 IN A BENEFICIAL EFFECT OF THE 2097 01:39:18,397 --> 01:39:21,367 VACCINE AND RESULTS IN A HIGHER 2098 01:39:21,367 --> 01:39:23,969 VIRAL LOAD SET POINT FOLLOWING 2099 01:39:23,969 --> 01:39:26,305 ATI WITH OR WITHOUT THE VACCINE 2100 01:39:26,305 --> 01:39:29,175 AND THOUGH NOT DIRECTLY SAVED AN 2101 01:39:29,175 --> 01:39:31,911 IN THE STUDY ONE POSSIBLE 2102 01:39:31,911 --> 01:39:33,712 EXPLANATION FOR PRODUCING VIRAL 2103 01:39:33,712 --> 01:39:35,581 BLIPS IN NON-HUMAN PRIMATE 2104 01:39:35,581 --> 01:39:38,651 MODELS COULD BE A RESULT OF 2105 01:39:38,651 --> 01:39:40,186 DEPLETING HIV SPECIFIC T CELLS 2106 01:39:40,186 --> 01:39:41,320 RATHER THAN DIRECTLY ACTING ON 2107 01:39:41,320 --> 01:39:43,756 THE LATENT INFECTED CELLS. 2108 01:39:43,756 --> 01:39:49,295 WE THINK MORE POTENT, LESS TOXIC 2109 01:39:49,295 --> 01:39:52,031 LRAs ARE STILL NEEDED AND WE'VE 2110 01:39:52,031 --> 01:39:54,333 BECOME VERY INTERESTED IN THE 2111 01:39:54,333 --> 01:39:56,502 ROLE OF mRNA AND DREW YOUR 2112 01:39:56,502 --> 01:39:59,738 ATTENTION AND LOOK AT THE POSTER 2113 01:39:59,738 --> 01:40:03,642 PRESENTED BY MICHAEL MOSO FOR 2114 01:40:03,642 --> 01:40:07,813 HIV LATENCY REVERSION USING THE 2115 01:40:07,813 --> 01:40:08,080 PARTICLES. 2116 01:40:08,080 --> 01:40:15,621 I'D LIKE TO ACKNOWLEDGE ALL THE 2117 01:40:15,621 --> 01:40:17,990 PEOPLE INVOLVED IN THE WORK AND 2118 01:40:17,990 --> 01:40:21,560 A FANTASTIC PARTNERSHIP WITH 2119 01:40:21,560 --> 01:40:28,634 OHSU AND JAKE, LEWIS AND THE GDC 2120 01:40:28,634 --> 01:40:29,101 DRUGS FROM GENENTECH. 2121 01:40:29,101 --> 01:40:39,445 THANK YOU VERY MUCH. 2122 01:40:40,312 --> 01:40:42,882 >> HI, EVERYBODY. 2123 01:40:42,882 --> 01:40:44,250 GOOD MORNING. 2124 01:40:44,250 --> 01:40:46,852 SO, LET'S GO TODAY I'M GOING TO 2125 01:40:46,852 --> 01:40:47,887 TALK PRIMARILY ABOUT OUR 2126 01:40:47,887 --> 01:40:50,322 COMMUNITY ENGAGEMENT ACTIVITIES 2127 01:40:50,322 --> 01:40:53,926 IN A LONG-TERM SURVIVORS' 2128 01:40:53,926 --> 01:40:54,693 RESEARCH PROJECT BUT BEFORE I 2129 01:40:54,693 --> 01:40:58,230 GET STARTED, MICHAEL AND DEREK 2130 01:40:58,230 --> 01:41:00,666 WOULD YOU STAND UP, PLEASE. 2131 01:41:00,666 --> 01:41:02,968 WE COULDN'T DO ANY OF THIS 2132 01:41:02,968 --> 01:41:04,136 WITHOUT OUR MEMBERS. 2133 01:41:04,136 --> 01:41:06,939 I THINK MOST KNOW MICHAEL. 2134 01:41:06,939 --> 01:41:10,676 AND THERE'S OUR NEW CO-CHAIR. 2135 01:41:10,676 --> 01:41:12,578 I DON'T WANT TO FORGET THEM 2136 01:41:12,578 --> 01:41:13,345 BECAUSE THEY'RE INSTRUMENTAL. 2137 01:41:13,345 --> 01:41:15,548 AT THIS POINT WE HAVE HALF OUR 2138 01:41:15,548 --> 01:41:17,850 PEOPLE ON OUR CAB ARE PEOPLE OF 2139 01:41:17,850 --> 01:41:28,394 COLOR AND MANY PEOPLE -- NAURD 2140 01:41:29,995 --> 01:41:30,095 -- 2141 01:41:30,095 --> 01:41:30,362 [NO AUDIO] 2142 01:41:30,362 --> 01:41:30,429 2143 01:41:32,431 --> 01:41:32,631 [NO AUDIO] 2144 01:41:32,631 --> 01:41:33,866 2145 01:41:34,867 --> 01:41:37,536 WE ALSO INCLUDED LIFE TIME 2146 01:41:37,536 --> 01:41:37,903 SURVIVE. 2147 01:41:37,903 --> 01:41:38,971 WE DID THAT LAST YEAR. 2148 01:41:38,971 --> 01:41:41,907 THIS YEAR WE DECIDED TO TALK 2149 01:41:41,907 --> 01:41:43,542 ABOUT THE RESERVOIRS. 2150 01:41:43,542 --> 01:41:46,278 AND EVERY YEAR WE'VE LEARNED 2151 01:41:46,278 --> 01:41:47,279 SOMETHING FROM THIS. 2152 01:41:47,279 --> 01:41:51,250 I THINK WE EXTEND THE SESSIONS 2153 01:41:51,250 --> 01:41:52,518 AND MADE THEM NOT JUST 2154 01:41:52,518 --> 01:41:52,851 INVESTIGATORS. 2155 01:41:52,851 --> 01:41:55,054 WE INCLUDED AT LEAST TWO 2156 01:41:55,054 --> 01:41:57,256 COMMUNITY PEOPLE BESIDES A CHAT 2157 01:41:57,256 --> 01:41:58,157 BEFORE WE CAN HAVE LIVE 2158 01:41:58,157 --> 01:42:00,059 INTERACTION WITH PEOPLE AND THAT 2159 01:42:00,059 --> 01:42:00,526 REALLY HELPS. 2160 01:42:00,526 --> 01:42:02,561 WE'VE INITIALLY STARTED WITH TWO 2161 01:42:02,561 --> 01:42:04,530 NEW INVESTIGATORS AND SO WE'RE 2162 01:42:04,530 --> 01:42:06,565 TRYING TO GET THEM ACCLIMATED 2163 01:42:06,565 --> 01:42:07,833 LIKE WE ARE THE REST OF THE 2164 01:42:07,833 --> 01:42:08,100 COMMUNITY. 2165 01:42:08,100 --> 01:42:11,370 AND YOU CAN SEE WHAT WE'VE DONE. 2166 01:42:11,370 --> 01:42:14,440 SO, WHAT I'M GOING TO DO INSTEAD 2167 01:42:14,440 --> 01:42:17,676 OF STALK -- TALKING ABOUT THE 2168 01:42:17,676 --> 01:42:25,918 DIFFERENT TOPICS IS WHAT WE DO. 2169 01:42:25,918 --> 01:42:36,095 [NO AUDIO] 2170 01:42:39,465 --> 01:42:43,969 AND WE DECIDED TO PRESENT AT THE 2171 01:42:43,969 --> 01:42:44,270 SESSIONS. 2172 01:42:44,270 --> 01:42:47,840 WE'VE GOT THIS FORMULA WHERE WE 2173 01:42:47,840 --> 01:42:49,108 ALWAYS INCLUDE ABLE WHICH MEANS 2174 01:42:49,108 --> 01:42:51,310 LIFE TIME AND LONG-TERM SURVIVE 2175 01:42:51,310 --> 01:42:53,512 AND ALWAYS INCLUDE WOMEN. 2176 01:42:53,512 --> 01:42:55,714 WE DO AN INTRODUCTION INITIALLY. 2177 01:42:55,714 --> 01:42:59,118 WE HAD A GREAT SESSION WITH A 2178 01:42:59,118 --> 01:43:01,720 NEW RESERVOIR RESEARCH BY 2179 01:43:01,720 --> 01:43:01,954 MATIAS. 2180 01:43:01,954 --> 01:43:05,057 WE LOVED THAT AND WE HAD A GREAT 2181 01:43:05,057 --> 01:43:09,595 SESSION IN NOVEMBER EARLIER THIS 2182 01:43:09,595 --> 01:43:13,032 MONTH WITH THE TWO CAB LEADS AT 2183 01:43:13,032 --> 01:43:16,802 HOPE AND RUBIN IS ALSO A NEW 2184 01:43:16,802 --> 01:43:17,303 INVESTIGATOR. 2185 01:43:17,303 --> 01:43:19,138 SO WE'RE TRYING TO INCLUDE 2186 01:43:19,138 --> 01:43:21,006 EVERYBODY IN OUR EDUCATION 2187 01:43:21,006 --> 01:43:22,308 PROCESS, INVESTIGATORS AND 2188 01:43:22,308 --> 01:43:23,509 COMMUNITY PEOPLE ALIKE. 2189 01:43:23,509 --> 01:43:26,312 AND IN DECEMBER WE'RE GOING TO 2190 01:43:26,312 --> 01:43:30,582 HAVE A BEHAVIORAL STUDY SESSION. 2191 01:43:30,582 --> 01:43:31,350 FLAUD 2192 01:43:32,785 --> 01:43:38,057 [NO AUDIO] 2193 01:43:38,057 --> 01:43:38,857 [NO AU 2194 01:43:38,857 --> 01:43:49,034 [NO AUDIO] 2195 01:44:05,651 --> 01:44:12,358 BE A BIG SESSION BECAUSE WE 2196 01:44:12,358 --> 01:44:15,461 ALSO HAVE ONE OF THE LEADS 2197 01:44:15,461 --> 01:44:21,400 RESEARCH PEOPLE AT THE NATIONAL 2198 01:44:21,400 --> 01:44:22,434 MINORITY AIDS COUNCIL AND WE 2199 01:44:22,434 --> 01:44:25,971 HAVE PAUL A COMMUNITY PARTNER 2200 01:44:25,971 --> 01:44:27,873 AND AIDS BALTIMORE IS ALSO A 2201 01:44:27,873 --> 01:44:28,273 COMMUNITY PARTNER. 2202 01:44:28,273 --> 01:44:31,777 HERE'S ANALYTICS. 2203 01:44:31,777 --> 01:44:33,912 SO FAR WE'VE HAD 224 PEOPLE ON 2204 01:44:33,912 --> 01:44:36,382 THE CALLED, YOUTUBE AND FACEBOOK 2205 01:44:36,382 --> 01:44:39,385 HITS AND AT 70% HIGHLY SATISFIED 2206 01:44:39,385 --> 01:44:40,419 AND THAT GETS BETTER EVERY TIME 2207 01:44:40,419 --> 01:44:43,021 WE DO THIS BECAUSE AS I SAY 2208 01:44:43,021 --> 01:44:46,358 WE'VE LEARNED FROM EACH ONE OF 2209 01:44:46,358 --> 01:44:46,625 THESE. 2210 01:44:46,625 --> 01:44:48,627 SO WE'RE GOING TO TAKE THE LEAD 2211 01:44:48,627 --> 01:44:52,998 ON THE LAST GIFT STUDY UPDATE 2212 01:44:52,998 --> 01:44:53,932 AND 2213 01:44:53,932 --> 01:45:04,109 [NO AUDIO] 2214 01:45:30,836 --> 01:45:33,038 ONE THING HE SAYS IS WE NEED TO 2215 01:45:33,038 --> 01:45:33,672 COLLABORATE WITH OTHER GROUPS 2216 01:45:33,672 --> 01:45:35,374 AND OTHER PEOPLE AND THAT'S WHAT 2217 01:45:35,374 --> 01:45:39,278 WE DO. 2218 01:45:39,278 --> 01:45:41,513 IT'S EASIER I THINK WE HAVE A 2219 01:45:41,513 --> 01:45:44,383 LEG UP NOT ONLY END WITH THE 2220 01:45:44,383 --> 01:45:46,118 FIRST ROUND OF SITES BUT MOST OF 2221 01:45:46,118 --> 01:45:47,986 US IN THE GROUP HAVE KNOWN EACH 2222 01:45:47,986 --> 01:45:49,087 OTHER 20, 25 YEARS. 2223 01:45:49,087 --> 01:45:53,158 WE'RE VERY USED TO WORKING 2224 01:45:53,158 --> 01:45:55,561 TOGETHER WITH EVERYTHING FROM 2225 01:45:55,561 --> 01:45:57,729 THE BAD OLD DAYS TO WHAT IS NOW 2226 01:45:57,729 --> 01:46:01,133 TURNING INTO THE NEW BAD OLD 2227 01:46:01,133 --> 01:46:01,900 DAYS. 2228 01:46:01,900 --> 01:46:03,001 HOPEFULLY I'M WRONG BUT I'M 2229 01:46:03,001 --> 01:46:04,837 USUALLY NOT WRONG ABOUT THAT 2230 01:46:04,837 --> 01:46:05,037 STUFF. 2231 01:46:05,037 --> 01:46:08,440 THIS IS HOW WE GET NEW PEOPLE IN 2232 01:46:08,440 --> 01:46:09,208 FROM DIFFERENT GROUP AND 2233 01:46:09,208 --> 01:46:10,876 DIFFERENT COLLABORATORIES AND 2234 01:46:10,876 --> 01:46:13,912 IT'S REALLY BEEN VERY VERY 2235 01:46:13,912 --> 01:46:18,684 REWARDING. 2236 01:46:18,684 --> 01:46:21,119 THIS IS CARRINE'S STUDY. 2237 01:46:21,119 --> 01:46:31,296 [NO AUDIO] 2238 01:47:28,887 --> 01:47:30,556 INTERESTINGLY 32 PEOPLE WERE 2239 01:47:30,556 --> 01:47:30,822 RECRUITED. 2240 01:47:30,822 --> 01:47:33,258 69 YEARS OLD WAS THE MEDIAN AGE 2241 01:47:33,258 --> 01:47:35,260 AND WHAT WE ARE TRYING TO DO IS 2242 01:47:35,260 --> 01:47:38,263 MAKE THAT 65 CUT AND PASTE 2243 01:47:38,263 --> 01:47:38,997 NUMBER HIGHER. 2244 01:47:38,997 --> 01:47:40,699 IF PEOPLE ARE OTHERWISE HEALTHY 2245 01:47:40,699 --> 01:47:44,469 AND NOT PRECLUDED BY THE 2246 01:47:44,469 --> 01:47:45,470 INCLUSION OR EXCLUSION CRITERIA 2247 01:47:45,470 --> 01:47:49,174 THEY SHOULD BE INCLUDED IN THE 2248 01:47:49,174 --> 01:47:52,077 TRIALS IT'S A POLICY THING WE 2249 01:47:52,077 --> 01:47:53,512 ARE PUSHING FOR THE POPULATION. 2250 01:47:53,512 --> 01:47:57,916 WE HAVE 50% MEN NOT A SURPRISED 2251 01:47:57,916 --> 01:48:00,285 AND 47% CISGENDER WOMAN AND 2252 01:48:00,285 --> 01:48:03,221 TRANS WOMAN AND 30% OF THE 2253 01:48:03,221 --> 01:48:03,922 PEOPLE WERE AFRICAN AMERICAN OR 2254 01:48:03,922 --> 01:48:04,256 BLACK. 2255 01:48:04,256 --> 01:48:05,557 THE THING IS WE KNOW THIS IS 2256 01:48:05,557 --> 01:48:05,824 HARD. 2257 01:48:05,824 --> 01:48:08,093 IT WAS HARD FOR US BUT WE'RE 2258 01:48:08,093 --> 01:48:09,861 SHOWING YOU THAT IT CAN BE DONE 2259 01:48:09,861 --> 01:48:12,965 AND IT'S NOT A HUGE STUDY BUT 2260 01:48:12,965 --> 01:48:14,633 YOU KNOW NONE OF OUR STUDIES ARE 2261 01:48:14,633 --> 01:48:16,602 REALLY HUGE AT THIS POINT. 2262 01:48:16,602 --> 01:48:19,871 I MEAN THIS IS THE WAY TO DO IT 2263 01:48:19,871 --> 01:48:24,209 AND HOW WE DID IT WAS I 2264 01:48:24,209 --> 01:48:26,211 ALWAYS -- I'M GOOD AT MAKING THE 2265 01:48:26,211 --> 01:48:27,145 TRAINS RUN. 2266 01:48:27,145 --> 01:48:29,848 I GOT MONEY FROM EACH ONE OF 2267 01:48:29,848 --> 01:48:31,717 THESE INSTITUTIONS FROM CRISPR, 2268 01:48:31,717 --> 01:48:32,584 DARE AND GRID. 2269 01:48:32,584 --> 01:48:37,189 WE MADE A CONTRACT WITH U.C. SAN 2270 01:48:37,189 --> 01:48:39,358 DIEGO AND DID THE STUDY. 2271 01:48:39,358 --> 01:48:40,025 IT WAS INTERESTING. 2272 01:48:40,025 --> 01:48:44,396 IT WASN'T REALLY HARD BECAUSE 2273 01:48:44,396 --> 01:48:45,897 INVESTIGATORS WERE BEHIND US AND 2274 01:48:45,897 --> 01:48:49,901 HELPED GET THE MONEY OUT THE 2275 01:48:49,901 --> 01:49:00,012 DOOR. 2276 01:49:15,827 --> 01:49:17,896 AND EVERY TIME WE'VE DONE A 2277 01:49:17,896 --> 01:49:19,998 PRESENTATION IN FRONT OF PEOPLE 2278 01:49:19,998 --> 01:49:21,233 THAT ARE LONG-TERM SURVIVORS OR 2279 01:49:21,233 --> 01:49:23,268 EVEN PEOPLE THAT ARE NOT, OKAY, 2280 01:49:23,268 --> 01:49:24,202 I'M GOING TO BE CURED. 2281 01:49:24,202 --> 01:49:27,372 MY SUPPORT GROUPS ARE GOING TO 2282 01:49:27,372 --> 01:49:28,073 GO AWAY. 2283 01:49:28,073 --> 01:49:30,108 MY DRUG COVERAGE IS GOING TO GO 2284 01:49:30,108 --> 01:49:30,342 AWAY. 2285 01:49:30,342 --> 01:49:31,943 I WON'T HAVE MEDICAL CARE. 2286 01:49:31,943 --> 01:49:34,446 WE REALLY NEED TO THINK ABOUT IF 2287 01:49:34,446 --> 01:49:36,314 WE'RE SUCCESSFUL WHAT ARE THE 2288 01:49:36,314 --> 01:49:37,949 RAMIFICATIONS OF THAT AND I 2289 01:49:37,949 --> 01:49:47,392 THINK THAT'S VERY IMPORTANT. 2290 01:49:47,392 --> 01:49:51,463 AND AS FAR AS THE WEBINARS WE 2291 01:49:51,463 --> 01:49:52,798 COME TOGETHER TO TRY AND DECIDE 2292 01:49:52,798 --> 01:49:53,799 THESE THINGS AND HOW WE'RE GOING 2293 01:49:53,799 --> 01:49:59,304 TO DO IT AND WHO THE SPEAKERS 2294 01:49:59,304 --> 01:50:02,107 ARE GOING TO BE AND THERE'S 2295 01:50:02,107 --> 01:50:05,811 CONFIRMATIONS CONTRACT WITH THE 2296 01:50:05,811 --> 01:50:06,445 ADVOCATORS AND MAKE THE TRAIN 2297 01:50:06,445 --> 01:50:16,788 RUN MAKE IT HAPPEN. 2298 01:50:17,989 --> 01:50:19,958 AND IT'S A COLLABORATION WITHIN 2299 01:50:19,958 --> 01:50:22,094 DARE AND THE MDC COLLABORATORY. 2300 01:50:22,094 --> 01:50:32,471 IS THAT SEVEN MINUTES? 2301 01:50:33,872 --> 01:50:34,606 >> THANK YOU. 2302 01:50:34,606 --> 01:50:37,909 I'D LIKE TO ASK QUESTIONS OF THE 2303 01:50:37,909 --> 01:50:44,783 DARE TEAM. 2304 01:50:44,783 --> 01:50:46,051 >> QUESTION FOR LOUIS. 2305 01:50:46,051 --> 01:50:52,824 I REALLY LIKED SEEING THE 2306 01:50:52,824 --> 01:50:56,361 RESPONSE IN THE mRNA GROUP 2307 01:50:56,361 --> 01:50:58,630 COMPARED TO THE CONTROL GROUP 2308 01:50:58,630 --> 01:51:04,503 AND DO YOU SEE RESPONSES TO THE 2309 01:51:04,503 --> 01:51:06,371 CTL PRESSURE? 2310 01:51:06,371 --> 01:51:09,174 >> YOU MEAN THE SEQUENCE THE 2311 01:51:09,174 --> 01:51:10,108 VIRUS POST ART RELEASE? 2312 01:51:10,108 --> 01:51:11,376 >> YES. 2313 01:51:11,376 --> 01:51:12,344 >> WE HAVEN'T DONE THAT YET. 2314 01:51:12,344 --> 01:51:19,117 THAT'S SOMETHING ON OUR LIST. 2315 01:51:19,117 --> 01:51:23,321 >> I HAD A COUPLE QUESTIONS. 2316 01:51:23,321 --> 01:51:24,489 TERRIFIC PRESENTATIONS. 2317 01:51:24,489 --> 01:51:27,292 FIRST FOR LOUIS, WERE YOU ABLE 2318 01:51:27,292 --> 01:51:29,895 TO IDENTIFY A BIOMARKER THAT WAS 2319 01:51:29,895 --> 01:51:32,130 CORRELATED WITH THE DELAYED 2320 01:51:32,130 --> 01:51:36,401 REBOUND OF NINE DAYS WITH THE 2321 01:51:36,401 --> 01:51:36,835 mRNA VACCINE? 2322 01:51:36,835 --> 01:51:40,806 IN OTHER WORDS, DO YOU THINK THE 2323 01:51:40,806 --> 01:51:43,408 LOWER LEVELS OF VIRUS EXPRESSING 2324 01:51:43,408 --> 01:51:44,342 CELLS AND TISSUES WITH THE 2325 01:51:44,342 --> 01:51:45,310 VACCINATION STRATEGY IS WHAT 2326 01:51:45,310 --> 01:51:47,112 ACCOUNTED FOR THE DELAY IN 2327 01:51:47,112 --> 01:51:50,148 REBOUND OR DIRECTLY RELATED TO 2328 01:51:50,148 --> 01:51:53,385 HIV SPECIFIC OR HIV SPECIFIC CD 2329 01:51:53,385 --> 01:51:54,119 8 T CELLS? 2330 01:51:54,119 --> 01:52:01,092 >> THE ONLY WAY TO ANSWER THAT 2331 01:52:01,092 --> 01:52:05,897 IS REALLY TO SEE CD 8 T CELL 2332 01:52:05,897 --> 01:52:08,600 DEPLETION AND THE VACCINE WAS 2333 01:52:08,600 --> 01:52:09,868 OTHERWISE IDENTICAL. 2334 01:52:09,868 --> 01:52:12,704 WE'RE COMPARING IT TO THE 2335 01:52:12,704 --> 01:52:14,139 CONTROL VACCINE. 2336 01:52:14,139 --> 01:52:15,807 SO THE INMATE IMMUNE RESPONSES 2337 01:52:15,807 --> 01:52:17,576 SHOULD BE THE SAME. 2338 01:52:17,576 --> 01:52:19,444 I THINK THE DATA STRONGLY 2339 01:52:19,444 --> 01:52:21,913 SUPPORT THIS IS THE ADAPTIVE 2340 01:52:21,913 --> 01:52:24,416 RESPONSE ELICITED BY THE VACCINE 2341 01:52:24,416 --> 01:52:26,151 WHICH I MEAN THE VACCINE DOES 2342 01:52:26,151 --> 01:52:30,355 MAKE ANTIBODIES BUT THE 2343 01:52:30,355 --> 01:52:33,825 ANTIBODIES ARE TO GAG SO THERE'S 2344 01:52:33,825 --> 01:52:35,227 ALSO CD4 T CELLS THERE YOU CAN'T 2345 01:52:35,227 --> 01:52:38,129 RULE OUT THEY DON'T HAVE AN 2346 01:52:38,129 --> 01:52:41,566 EFFECT BUT THE MOST LIKELY 2347 01:52:41,566 --> 01:52:45,070 PREDICT IF WE DEPLETE CD T CELLS 2348 01:52:45,070 --> 01:52:51,343 WE'D LOSE THE DELAY AND CONTROL. 2349 01:52:51,343 --> 01:52:54,279 >> YOU ALLUDED TO CONTROL BEING 2350 01:52:54,279 --> 01:52:54,913 ASSOCIATED WITH LOW RESERVOIR 2351 01:52:54,913 --> 01:52:56,915 SIZE AND WONDER IF YOU CAN GIVE 2352 01:52:56,915 --> 01:52:59,651 US A QUANTITATIVE RANGE FOR WHAT 2353 01:52:59,651 --> 01:53:03,421 YOU CONSIDER LOW SIZE IN YOUR 2354 01:53:03,421 --> 01:53:05,223 COHORT. 2355 01:53:05,223 --> 01:53:08,593 >> YEAH, SO WHEN I SAY LOWER 2356 01:53:08,593 --> 01:53:12,163 RESERVOIR SIZE THE ONLY 2357 01:53:12,163 --> 01:53:15,000 MEASUREMENTS HAVE BEEN DNA WITH 2358 01:53:15,000 --> 01:53:21,907 IPDA INTACT MEASUREMENTS AND 2359 01:53:21,907 --> 01:53:29,180 CELL RNA AND THE RESERVOIRS I'M 2360 01:53:29,180 --> 01:53:31,850 NOT RECALLING -- LIKE I CAN'T 2361 01:53:31,850 --> 01:53:35,487 GIVE EXACTLY THE NUMBER BUT WHEN 2362 01:53:35,487 --> 01:53:42,394 WE COMPARED THE IN TACT DNA FROM 2363 01:53:42,394 --> 01:53:43,428 EARLY TREATED PEOPLE THEY FELL 2364 01:53:43,428 --> 01:53:46,531 IN THE RANGE OF PEOPLE WHO 2365 01:53:46,531 --> 01:53:49,100 TYPICALLY WHO RECEIVED EARLY ART 2366 01:53:49,100 --> 01:53:51,069 EARLY AFTER HIV ACQUISITION. 2367 01:53:51,069 --> 01:53:53,538 SO I CAN LOOK AT THAT WITH YOU 2368 01:53:53,538 --> 01:53:56,107 LATER TO GIVE YOU A PRECISE 2369 01:53:56,107 --> 01:53:56,341 NUMBER. 2370 01:53:56,341 --> 01:54:01,179 >> TEN OR A HUNDRED OR A 2371 01:54:01,179 --> 01:54:01,446 THOUSAND. 2372 01:54:01,446 --> 01:54:05,250 >> SO, MANY OF THE NUMBERS ARE 2373 01:54:05,250 --> 01:54:07,052 EVEN LOWER THAN SO AND AT TIMES 2374 01:54:07,052 --> 01:54:09,921 UNDETECTABLE AND OTHER TIMES 2375 01:54:09,921 --> 01:54:11,756 DETECT 2376 01:54:11,756 --> 01:54:12,057 DETECTABLE. 2377 01:54:12,057 --> 01:54:13,224 THE ONE INDIVIDUAL THAT DIDN'T 2378 01:54:13,224 --> 01:54:16,061 REBOUND AND SEVERAL MEASUREMENTS 2379 01:54:16,061 --> 01:54:18,530 UNDETECTABLE AND IN OTHER 2380 01:54:18,530 --> 01:54:23,735 STUDIES WITH DIFFICULT TO ELICIT 2381 01:54:23,735 --> 01:54:25,170 PRODUCTIVE INFECTION IN S. 2382 01:54:25,170 --> 01:54:26,571 WE DIDN'T DO THAT IN THE STUDY. 2383 01:54:26,571 --> 01:54:28,707 >> AND THE THIRD QUESTION IS FOR 2384 01:54:28,707 --> 01:54:29,107 SHARON. 2385 01:54:29,107 --> 01:54:36,481 REALLY AMAZING WORK ON THE SMAC 2386 01:54:36,481 --> 01:54:38,149 MIMETICS AND I THINK I REMEMBER 2387 01:54:38,149 --> 01:54:39,684 A SIMILAR EFFECT IN INHIBITORS 2388 01:54:39,684 --> 01:54:45,090 WHERE IT DID IMPACT ON HIV CD 8 2389 01:54:45,090 --> 01:54:45,357 RESPONSES. 2390 01:54:45,357 --> 01:54:48,393 AND I WONDERED TO WHAT EXTENT 2391 01:54:48,393 --> 01:54:50,662 YOU THINK THIS IS A LARGER 2392 01:54:50,662 --> 01:54:55,600 PHENOMENON OF LATENCY REVERSAL 2393 01:54:55,600 --> 01:55:00,638 LEADING TO CD 8 T CELL 2394 01:55:00,638 --> 01:55:01,439 EXHAUSTION PERHAPS AND LOSS IN 2395 01:55:01,439 --> 01:55:05,710 THE SETTING. 2396 01:55:05,710 --> 01:55:08,413 >> YEAH, YOU'RE RIGHT. 2397 01:55:08,413 --> 01:55:10,582 THEY WERE SHOWN TO AFFECT 2398 01:55:10,582 --> 01:55:11,049 FUNCTION ACTUALLY. 2399 01:55:11,049 --> 01:55:13,485 I THINK IT'S A CONSEQUENCE OF 2400 01:55:13,485 --> 01:55:15,487 THESE NOT BEING HIV SPECIFIC. 2401 01:55:15,487 --> 01:55:17,088 THEY HAVE OFF TARGET EFFECTS. 2402 01:55:17,088 --> 01:55:23,428 I THINK THE MECHANISMS OF WHY 2403 01:55:23,428 --> 01:55:28,600 INHIBITORS HIT AZD AND SMAC 2404 01:55:28,600 --> 01:55:29,367 MIMETICS ARE PROBABLY DIFFERENT. 2405 01:55:29,367 --> 01:55:32,771 I THINK IT'S A CONSEQUENCE OF 2406 01:55:32,771 --> 01:55:37,909 USING DRUGS SPECIFIC THAT 2407 01:55:37,909 --> 01:55:41,279 THEREFORE IMPACT CELL DEATH 2408 01:55:41,279 --> 01:55:42,580 PATHWAYS FOR AZD. 2409 01:55:42,580 --> 01:55:45,016 >> I THINK IT'S GREAT YOU WERE 2410 01:55:45,016 --> 01:55:48,253 ABLE TO COME TO A CONCLUSION IN 2411 01:55:48,253 --> 01:55:49,888 TERMS OF CONSIDERATION OF USE 2412 01:55:49,888 --> 01:55:51,156 THE MOLECULES. 2413 01:55:51,156 --> 01:55:53,691 WHAT WOULD YOUR RECOMMENDATION 2414 01:55:53,691 --> 01:55:54,092 BE? 2415 01:55:54,092 --> 01:55:58,363 CAN WE SAY GO, NO GO FOR THE 2416 01:55:58,363 --> 01:55:59,931 BASED ON THESE FINDINGS. 2417 01:55:59,931 --> 01:56:03,535 >> YEAH, I THINK OUR FINDINGS 2418 01:56:03,535 --> 01:56:05,570 AROUND THE ADVERSE EFFECT OF 2419 01:56:05,570 --> 01:56:12,477 SMAC MIMETICS ARE LIMITED TO 2420 01:56:12,477 --> 01:56:13,978 AZD5582 AND THERE'S BEEN EFFECTS 2421 01:56:13,978 --> 01:56:17,916 AS SHOWN BEFORE IN THE CANCER 2422 01:56:17,916 --> 01:56:20,151 LITERATURE. 2423 01:56:20,151 --> 01:56:24,856 AND WHETHER THIS EFFECT IS FOR 2424 01:56:24,856 --> 01:56:35,567 ALL BUY V -- BIVEIL -- BIVALENS 2425 01:56:37,969 --> 01:56:44,142 AND IT'S INTRIGUED ME WHY IT 2426 01:56:44,142 --> 01:56:46,911 LOOKS DIFFERENT IN VIVO AND EX 2427 01:56:46,911 --> 01:56:47,345 VIVO. 2428 01:56:47,345 --> 01:56:48,880 >> THANK YOU. 2429 01:56:48,880 --> 01:56:51,716 RICK DUNHAM. 2430 01:56:51,716 --> 01:56:52,417 THANK YOU. 2431 01:56:52,417 --> 01:57:02,961 GREAT SET OF STUDIES AND PRETTY 2432 01:57:03,461 --> 01:57:05,330 DISTINCT AND IT DOESN'T JIVE 2433 01:57:05,330 --> 01:57:08,099 FROM OTHER DATA SETS IN TERMS OF 2434 01:57:08,099 --> 01:57:10,201 ATM AFTER AZD TREATMENT SO 2435 01:57:10,201 --> 01:57:11,569 INTERESTED TO TALK THROUGH THE 2436 01:57:11,569 --> 01:57:13,905 DIFFERENCES AND SEE IF WE CAN 2437 01:57:13,905 --> 01:57:16,040 UNDERSTAND THIS AND FIGURE OUT A 2438 01:57:16,040 --> 01:57:26,484 WAY TO PUSH THIS FORWARD. 2439 01:57:28,386 --> 01:57:30,722 THE BIVALENCE IS VERY SHORT 2440 01:57:30,722 --> 01:57:37,662 MAYBE ONE HOUR FOR THESE 2441 01:57:37,662 --> 01:57:39,964 PERIODS. 2442 01:57:39,964 --> 01:57:43,568 IN VITRO WERE YOU SIMULATING 2443 01:57:43,568 --> 01:57:44,469 EXPOSURE TO THE DRUG? 2444 01:57:44,469 --> 01:57:47,772 >> I'M PRETTY SURE IT WAS 2445 01:57:47,772 --> 01:57:48,072 CONTINUOUS. 2446 01:57:48,072 --> 01:57:52,410 >> DO YOU SEE VERY DIFFERENT 2447 01:57:52,410 --> 01:57:53,945 OUTCOMES WITH SHORT EXPOSURES 2448 01:57:53,945 --> 01:57:56,080 AND TALK THROUGH THAT. 2449 01:57:56,080 --> 01:57:59,417 >> WE HAVEN'T LOOKED AT THAT BUT 2450 01:57:59,417 --> 01:58:02,187 IN IN VIVO I ASSUME YOU'RE 2451 01:58:02,187 --> 01:58:04,422 GIVING CONTINUOUS BECAUSE YOU'RE 2452 01:58:04,422 --> 01:58:04,689 REDOSING. 2453 01:58:04,689 --> 01:58:06,758 NO, SINGLE DOSE. 2454 01:58:06,758 --> 01:58:09,894 WE WERE DOING CONTINUOUS DOSING 2455 01:58:09,894 --> 01:58:11,029 IN THE EX VIVO STUDY. 2456 01:58:11,029 --> 01:58:15,767 >> MY NAME IS KARLY FROM THE 2457 01:58:15,767 --> 01:58:17,735 UNIVERSITY OF WASHINGTON. 2458 01:58:17,735 --> 01:58:19,270 MY QUESTION IS FOR SHARON AND 2459 01:58:19,270 --> 01:58:21,706 CURIOUS WHAT YOU THINK ABOUT THE 2460 01:58:21,706 --> 01:58:26,711 ALTERNATIVE HYPOTHESIS THAT 2461 01:58:26,711 --> 01:58:29,881 AZD5582 IS RESENSITIZING THE 2462 01:58:29,881 --> 01:58:30,915 CELLS LEADING TO A HIGHER SET 2463 01:58:30,915 --> 01:58:33,251 POINT AND NOT SURE IF THERE'S 2464 01:58:33,251 --> 01:58:35,920 WAYS TO ADD BACK IN THE HIV 2465 01:58:35,920 --> 01:58:37,855 SPECIFIC CD 8 CELLS TO FULLY 2466 01:58:37,855 --> 01:58:40,658 LINK THOSE CELLS TO THE 2467 01:58:40,658 --> 01:58:42,126 PHENOTYPE OR NOT. 2468 01:58:42,126 --> 01:58:45,463 >> SO I THINK YOU'RE REFERRING 2469 01:58:45,463 --> 01:58:47,098 TO THE LAST DATA THE PIECE OF 2470 01:58:47,098 --> 01:58:48,600 DATA WE SHOWED WHICH WAS A 2471 01:58:48,600 --> 01:58:49,901 HIGHER SET POINT IN THE MONKEYS 2472 01:58:49,901 --> 01:58:54,839 THAT RECEIVED THE CONTROL 2473 01:58:54,839 --> 01:58:59,544 VACCINE WITH AZD WITH CONTROL 2474 01:58:59,544 --> 01:59:01,246 WITHOUT AND THEY DO RECEIVE THE 2475 01:59:01,246 --> 01:59:03,414 CONTROL VACCINE. 2476 01:59:03,414 --> 01:59:08,152 I THOUGHT THAT TOO MAYBE YOU'RE 2477 01:59:08,152 --> 01:59:11,022 INCREASING THE POOL OF 2478 01:59:11,022 --> 01:59:12,957 TRANSCRIPTIONALLY ACTIVE CELLS 2479 01:59:12,957 --> 01:59:17,795 ONCE YOU STOP ATI AND 2480 01:59:17,795 --> 01:59:18,830 THEORETICALLY WE ALWAYS SAID 2481 01:59:18,830 --> 01:59:21,599 WHEN YOU REVERSE AGENTS ON ART 2482 01:59:21,599 --> 01:59:24,135 THAT DOESN'T EXPAND THE 2483 01:59:24,135 --> 01:59:24,869 RESERVOIR BECAUSE YOU EXPAND THE 2484 01:59:24,869 --> 01:59:27,272 VIRAL REPLICATION BUT YOU PLAY 2485 01:59:27,272 --> 01:59:29,641 BE INCREASING ALL THE CELLS 2486 01:59:29,641 --> 01:59:32,110 RECALL TO FIRE UP FAST. 2487 01:59:32,110 --> 01:59:33,911 THAT'S A POTENTIALLY REASONABLE 2488 01:59:33,911 --> 01:59:34,212 EXPECTATION. 2489 01:59:34,212 --> 01:59:36,614 HAVE WE ADDED BACK IN CTL? 2490 01:59:36,614 --> 01:59:36,981 NO. 2491 01:59:36,981 --> 01:59:38,883 BUT I THINK THERE'S MORE 2492 01:59:38,883 --> 01:59:41,419 MECHANISTIC STUDIES WE COULD DO 2493 01:59:41,419 --> 01:59:45,123 IN MONKEYS IF I CAN CONVINCE 2494 01:59:45,123 --> 01:59:46,891 LOUIS TO SPEND MORE ON THIS 2495 01:59:46,891 --> 01:59:48,826 MONKEY WORK WHICH IS ALWAYS HARD 2496 01:59:48,826 --> 01:59:49,927 TO CONVINCE BUT WE COULD 2497 01:59:49,927 --> 01:59:52,730 PROBABLY TEASE IT OUT MORE IN 2498 01:59:52,730 --> 01:59:52,964 MONKEYS. 2499 01:59:52,964 --> 01:59:55,099 >> I DON'T WANT TO CUT TOO MUCH 2500 01:59:55,099 --> 01:59:57,535 IN THE BREAK SO QUICK QUESTIONS. 2501 01:59:57,535 --> 01:59:59,404 >> SURE. 2502 01:59:59,404 --> 02:00:01,906 JUST FOR LOUIS CAN YOU COMMENT 2503 02:00:01,906 --> 02:00:04,509 ON CELL ASSOCIATED RNA WHICH IT 2504 02:00:04,509 --> 02:00:07,378 WAS ALTERED WITH THE DIFFERENT 2505 02:00:07,378 --> 02:00:09,314 VACCINE OR HAD ANY RELATIONSHIP 2506 02:00:09,314 --> 02:00:11,015 TO REBOUND RATES? 2507 02:00:11,015 --> 02:00:13,885 >> I THINK LOUIS WOULD KNOW THE 2508 02:00:13,885 --> 02:00:15,320 MONKEY STUDY I THINK WE SHOWED 2509 02:00:15,320 --> 02:00:17,822 SOME OF THAT. 2510 02:00:17,822 --> 02:00:21,893 >> IN MONKEYS ESPECIALLY MONKEYS 2511 02:00:21,893 --> 02:00:24,329 GIVEN THE DNA IT'S A GOOD 2512 02:00:24,329 --> 02:00:25,897 REFLECTION OF REPLICATION 2513 02:00:25,897 --> 02:00:27,131 COMPETENT VIRUS. 2514 02:00:27,131 --> 02:00:29,334 THE PEAK VIRAL LOADS WERE 2515 02:00:29,334 --> 02:00:32,603 IDENTICAL IN BOTH GROUPS AND SO 2516 02:00:32,603 --> 02:00:37,041 THEN WE DIDN'T SEE DIFFERENCES 2517 02:00:37,041 --> 02:00:38,843 IN CELLS ASSOCIATED DNA IN THE 2518 02:00:38,843 --> 02:00:41,913 ART VACCINE. 2519 02:00:41,913 --> 02:00:44,182 >> LOUIS ASSOCIATED WITH AND 2520 02:00:44,182 --> 02:00:46,317 WITHOUT AZD IN THE VACCINATED 2521 02:00:46,317 --> 02:00:46,517 GROUP. 2522 02:00:46,517 --> 02:00:48,853 DO YOU REMEMBER THAT? 2523 02:00:48,853 --> 02:00:53,458 >> I DON'T REMEMBER THERE BEING 2524 02:00:53,458 --> 02:00:53,758 DIFFERENCES. 2525 02:00:53,758 --> 02:01:00,732 THE AZD WAS ANOTHER STUDY. 2526 02:01:00,732 --> 02:01:03,000 >> WE HAVE THAT DATA AND I'LL 2527 02:01:03,000 --> 02:01:04,569 CHECK IT FOR YOU BECAUSE IT WAS 2528 02:01:04,569 --> 02:01:07,105 DONE IN ALL FOUR ARMS. 2529 02:01:07,105 --> 02:01:13,911 WE CAN'T SHOW YOU AZD VERSUS NOT 2530 02:01:13,911 --> 02:01:16,314 BUT WE HAVE THAT. 2531 02:01:16,314 --> 02:01:18,483 >> MAYBE THIS WILL CARRY INTO 2532 02:01:18,483 --> 02:01:19,617 THE BREAK BUT THANKS FOR 2533 02:01:19,617 --> 02:01:20,551 PRESENTING THIS WORK. 2534 02:01:20,551 --> 02:01:24,055 IT WAS INTERESTING AND AS I'M 2535 02:01:24,055 --> 02:01:25,123 SURE YOU KNOW WE HAVE QUITE 2536 02:01:25,123 --> 02:01:29,427 DIFFERENT RESULTS WHEN WE TREAT 2537 02:01:29,427 --> 02:01:37,135 IN VIVO NON HUMAN PRIMATES WITH 2538 02:01:37,135 --> 02:01:39,303 SMAC MIMETICS AND WHEN WE 2539 02:01:39,303 --> 02:01:40,772 PUBLISHED IN NATURE AND MEDICINE 2540 02:01:40,772 --> 02:01:43,074 LAST YEAR WE FOUND THE 2541 02:01:43,074 --> 02:01:45,910 COMBINATION WITH HIV SPECIFIC 2542 02:01:45,910 --> 02:01:46,711 ENVELOPE TARGETING ANTIBODIES 2543 02:01:46,711 --> 02:01:50,715 ACTUALLY LED TO AN INCREASE IN 2544 02:01:50,715 --> 02:01:53,918 SIV GAMMA PRODUCING T CELLS SO 2545 02:01:53,918 --> 02:01:56,788 MAYBE RELATED TO WHAT YOU'RE 2546 02:01:56,788 --> 02:02:01,426 COMBINING AZD IN TERMS OF THE 2547 02:02:01,426 --> 02:02:03,461 EFFECTIVE ANTIBODIES AND THE 2548 02:02:03,461 --> 02:02:05,329 EFFECT OF THE mRNA VACCINE AND 2549 02:02:05,329 --> 02:02:07,398 I'M WONDERING IF YOU HAVE 2550 02:02:07,398 --> 02:02:09,400 MECHANISTIC DATA IN TERMS OF THE 2551 02:02:09,400 --> 02:02:11,669 RESULTS IN TERMS OF THE EFFECT 2552 02:02:11,669 --> 02:02:17,809 ON THE CD 8 T CELLS AND WHAT THE 2553 02:02:17,809 --> 02:02:20,077 SMAC MIMETIC WAS CHANGING TO 2554 02:02:20,077 --> 02:02:22,180 HELP US TEASE OUT DIFFERENCES 2555 02:02:22,180 --> 02:02:23,314 BETWEEN MULTIPLE EXPERIMENTS. 2556 02:02:23,314 --> 02:02:28,553 >> I THINK IT'S A GOOD POINT. 2557 02:02:28,553 --> 02:02:32,757 DEPENDING ON WHAT CYOUR CONTROL 2558 02:02:32,757 --> 02:02:34,892 AND THE T CELL VACCINE AND SAW 2559 02:02:34,892 --> 02:02:36,127 ABROGATION OF THE EFFECT AND MAY 2560 02:02:36,127 --> 02:02:37,929 NOT TRANSLATE TO OTHER 2561 02:02:37,929 --> 02:02:40,565 INTERVENTIONS AS YOU'VE 2562 02:02:40,565 --> 02:02:42,767 PUBLISHED WITH ANTIBODIES. 2563 02:02:42,767 --> 02:02:48,473 WE HAVE GOT SOME SINGLE CELL RNA 2564 02:02:48,473 --> 02:02:49,841 DATA AND GOING THROUGH THAT TO 2565 02:02:49,841 --> 02:02:52,510 UNDERSTAND THE EFFECT. 2566 02:02:52,510 --> 02:02:56,147 IT MAY BE MY CURRENT HYPOTHESIS 2567 02:02:56,147 --> 02:03:00,284 IS THE EXPRESSION OF PROTEINS IN 2568 02:03:00,284 --> 02:03:05,289 THE SPECIFIC T CELLS MAKING THEM 2569 02:03:05,289 --> 02:03:08,159 VULNERABLE TO CELL TOGETHER BUT 2570 02:03:08,159 --> 02:03:16,200 THAT'S PRELIMINARY. 2571 02:03:16,200 --> 02:03:19,170 >> THE WE SEE A BENEFICIAL 2572 02:03:19,170 --> 02:03:20,571 EFFECT THE VIRAL LOADS ARE LOWER 2573 02:03:20,571 --> 02:03:21,939 DURING TREATMENT. 2574 02:03:21,939 --> 02:03:27,378 YOU DO THE SAME WITH VACCINE AND 2575 02:03:27,378 --> 02:03:29,013 DO THE OPPOSITE AND HARM THE 2576 02:03:29,013 --> 02:03:34,719 OUTCOME OPPOSED TO HELPING. 2577 02:03:34,719 --> 02:03:37,455 AND WE BOOST RESPONSE THAT IS 2578 02:03:37,455 --> 02:03:38,756 SHOWING VULNERABILITY THAT MAY 2579 02:03:38,756 --> 02:03:41,859 NOT BE THE SAME IN ALL YOU'VE 2580 02:03:41,859 --> 02:03:42,059 DONE. 2581 02:03:42,059 --> 02:03:42,527 >> GREAT, THANK YOU. 2582 02:03:42,527 --> 02:03:48,332 LET'S GIVE A ROUND OF APPLAUSE. 2583 02:03:48,332 --> 02:03:49,400 AND THANK YOU SO MUCH. 2584 02:03:49,400 --> 02:03:53,771 RIGHT NOW WE HAVE A BREAK. 2585 02:03:53,771 --> 02:03:55,907 LOSE ENJOY THE COFFEE SPONSORED 2586 02:03:55,907 --> 02:04:02,179 BY THE COLLABORATORY P.I.s AND 2587 02:04:02,179 --> 02:04:07,685 SNACKS PERFECT -- ARE PROVIDED 2588 02:04:07,685 --> 02:04:08,653 BY THE PROGRAM OFFICERS. 2589 02:04:08,653 --> 02:04:11,565 WE'LL RECONVENE PROMPTLY AT 11:00. 2590 02:04:11,565 --> 02:04:13,000 SINCE WE ARE ABOUT HALFWAY 2591 02:04:13,000 --> 02:04:15,736 THROUGH WE'VE HAD FIVE NDCs AND 2592 02:04:15,736 --> 02:04:17,604 HAVE FIVE LEFT. 2593 02:04:17,604 --> 02:04:22,209 I JUST WANT TO REMIND EVERYONE 2594 02:04:22,209 --> 02:04:26,780 TO BE COGNIZANT OF THE NIAID 2595 02:04:26,780 --> 02:04:29,082 LANGUAGE GUIDE. 2596 02:04:29,082 --> 02:04:31,985 INSTEAD OF SUBJECT WE CAN SAY 2597 02:04:31,985 --> 02:04:34,621 PARTICIPANT OR INFECTED 2598 02:04:34,621 --> 02:04:35,956 INDIVIDUAL PEOPLE LIVING WITH 2599 02:04:35,956 --> 02:04:36,590 HIV. 2600 02:04:36,590 --> 02:04:39,626 WITH THAT I'D LIKE TO INTRODUCE 2601 02:04:39,626 --> 02:04:43,130 THE BEAT HIV COLLABORATORY LEAD 2602 02:04:43,130 --> 02:04:47,367 BY THE LUIS AND JIM AT U-PEN AND 2603 02:04:47,367 --> 02:04:50,070 JOHN AT JOHNS HOPKINS. 2604 02:04:50,070 --> 02:04:54,308 WITH THAT I'LL LET LUIS TAKE IT 2605 02:04:54,308 --> 02:04:54,608 AWAY. 2606 02:04:54,608 --> 02:04:55,375 >> THANK YOU. 2607 02:04:55,375 --> 02:04:57,144 IT'S EXCITING TO SHARE WITH YOU 2608 02:04:57,144 --> 02:04:58,979 THE PROGRESS THE GROUP HAS BEEN 2609 02:04:58,979 --> 02:05:00,580 MAKING AND IT WAS HARD TO CHOOSE 2610 02:05:00,580 --> 02:05:02,149 THE TALKS WE'RE GOING TO PRESENT 2611 02:05:02,149 --> 02:05:05,919 BUT THEY'RE ALL REALLY EXCITING 2612 02:05:05,919 --> 02:05:08,522 AND REALLY IMPACTFUL ACROSS THE 2613 02:05:08,522 --> 02:05:10,223 WORK OF ALL THE COLLABORATORIES. 2614 02:05:10,223 --> 02:05:13,026 THE COLLABORATORY AS A WHOLE 2615 02:05:13,026 --> 02:05:15,696 STILL MAINTAINS AN ACTIVE GROUP 2616 02:05:15,696 --> 02:05:16,029 OF PEOPLE. 2617 02:05:16,029 --> 02:05:21,301 THANK YOU FOR PARTICIPATING IN 2618 02:05:21,301 --> 02:05:24,638 THE WORKING GROUPS. 2619 02:05:24,638 --> 02:05:27,407 AND WE'RE FOCUSSED ON THE FOUR 2620 02:05:27,407 --> 02:05:34,181 CENTRAL SEN -- TENETS IN 2621 02:05:34,181 --> 02:05:36,049 STRATEGY FOR CONTROL OR 2622 02:05:36,049 --> 02:05:36,350 ERADICATION. 2623 02:05:36,350 --> 02:05:39,653 ONE THING OUR COLLABORATORY IS 2624 02:05:39,653 --> 02:05:41,188 DISTINCT FOR IS THE EMPHASIS ON 2625 02:05:41,188 --> 02:05:43,991 THE SOCIAL SCIENCE AGENDA. 2626 02:05:43,991 --> 02:05:46,026 WE'VE DEVELOPED THE CAB WITH 2627 02:05:46,026 --> 02:05:47,260 SOCIAL SCIENCE AND ONE PROJECT 2628 02:05:47,260 --> 02:05:48,662 HAS JUST BEEN ACCEPTED FOR 2629 02:05:48,662 --> 02:05:50,464 PUBLICATION AND WE'LL HEAR ABOUT 2630 02:05:50,464 --> 02:06:00,307 IT TODAY. 2631 02:06:00,307 --> 02:06:01,508 AND PROGRAMS FEATURED TODAY AND 2632 02:06:01,508 --> 02:06:04,478 TODAY AND WE KEEP A CLOSE TRACK 2633 02:06:04,478 --> 02:06:09,916 RECORD OF THE COLLABORATORY AND 2634 02:06:09,916 --> 02:06:14,054 TRYING TO MAKE CERTAIN YOU HOW 2635 02:06:14,054 --> 02:06:18,058 INTEGRATIVE THE COLLABORATIVE IS 2636 02:06:18,058 --> 02:06:24,364 AND THE GRANTS THAT EMERGE. 2637 02:06:24,364 --> 02:06:28,935 I THINK THE HIGHLIGHTS ARE HERE 2638 02:06:28,935 --> 02:06:35,175 AND THE LATENT RESERVOIR IS 2639 02:06:35,175 --> 02:06:38,178 BUILDING AN INVENTORY OF 2640 02:06:38,178 --> 02:06:42,082 INDIVIDUALS WITH APHERESIS AND 2641 02:06:42,082 --> 02:06:44,484 TIME POINTS AND EXPANDING THE 2642 02:06:44,484 --> 02:06:45,786 TISSUE ACCESS TO THESE 2643 02:06:45,786 --> 02:06:46,086 INDIVIDUALS. 2644 02:06:46,086 --> 02:06:49,056 THE BIOLOGICAL AGING ASPECT AND 2645 02:06:49,056 --> 02:06:50,123 BIOMARKER WORK CONTINUES TO MOVE 2646 02:06:50,123 --> 02:06:56,563 FORWARD AND THE FOCUS ON 2647 02:06:56,563 --> 02:06:58,165 STRATEGIES. 2648 02:06:58,165 --> 02:07:03,603 T 2649 02:07:03,603 --> 02:07:06,606 THE EVENT OF STRATEGIES WE DON'T 2650 02:07:06,606 --> 02:07:09,109 HAVE TIME TO PRESENT ALL BUT 2651 02:07:09,109 --> 02:07:10,944 THEY'RE ALL EXCITING AND 2652 02:07:10,944 --> 02:07:14,081 DEVELOPING NOVEL STRATEGIES IN 2653 02:07:14,081 --> 02:07:15,916 EACH ONE OF THESE TO HAVE A TALK 2654 02:07:15,916 --> 02:07:18,185 ON EACH ONE OF THEM AS TIME 2655 02:07:18,185 --> 02:07:20,187 WOULD ALLOW. 2656 02:07:20,187 --> 02:07:21,922 BUT MY TANK IS TO BE QUICK 2657 02:07:21,922 --> 02:07:23,657 BECAUSE WE HAVE FOUR STORIES I 2658 02:07:23,657 --> 02:07:26,293 WANT TO ALLOW TIME FOR BUT AS 2659 02:07:26,293 --> 02:07:27,427 THE OTHER COLLABORATORIES 2660 02:07:27,427 --> 02:07:31,698 CONTINUE TO EVOLVE AND THESE ARE 2661 02:07:31,698 --> 02:07:33,733 FUNDING AND CONTRACTS THAT HAVE 2662 02:07:33,733 --> 02:07:34,968 COME UP HIGHLIGHTING THE 2663 02:07:34,968 --> 02:07:36,636 EVOLUTION OF STRATEGIES AND NEW 2664 02:07:36,636 --> 02:07:38,338 INVESTIGATORS COMING ON BOARD 2665 02:07:38,338 --> 02:07:39,940 WITH THE COLLABORATORY. 2666 02:07:39,940 --> 02:07:41,508 TWO OF WHICH WE'LL HERE FROM 2667 02:07:41,508 --> 02:07:42,642 TODAY AS NEW INVESTIGATORS THAT 2668 02:07:42,642 --> 02:07:44,811 ARE NOW SUPPORTED BY THE 2669 02:07:44,811 --> 02:07:45,145 COLLABORATORY. 2670 02:07:45,145 --> 02:07:49,349 WE'RE ALSO EXCITED TO ENGAGE IN 2671 02:07:49,349 --> 02:07:53,753 AN INITIATIVE TO OPEN A NEW HIV 2672 02:07:53,753 --> 02:07:55,021 CURE AND VIRAL CENTER AND 2673 02:07:55,021 --> 02:07:58,024 EVALUATING PROGRAMS SO IF YOU 2674 02:07:58,024 --> 02:07:59,693 KNOW ANYONE INTERESTED IN 2675 02:07:59,693 --> 02:08:01,628 DEVELOPING THIS AREA AND 2676 02:08:01,628 --> 02:08:04,064 RELOCATED SEE ME AFTERWARDS. 2677 02:08:04,064 --> 02:08:06,500 FOR TODAY WE'LL TALK ABOUT TWO 2678 02:08:06,500 --> 02:08:08,835 ESTABLISHED PROGRAMS AND TWO NEW 2679 02:08:08,835 --> 02:08:09,102 PROGRAMS. 2680 02:08:09,102 --> 02:08:11,171 AND THESE TWO TALKS WE'LL HEAR 2681 02:08:11,171 --> 02:08:17,777 ABOUT FROM BOB AND MIKE ARE 2682 02:08:17,777 --> 02:08:20,213 REALLY CENTERED ON AREAS UNDER 2683 02:08:20,213 --> 02:08:22,149 STUDIED OR OVERLOOKED. 2684 02:08:22,149 --> 02:08:23,350 AS THE DISCUSSION MOVES FORWARD 2685 02:08:23,350 --> 02:08:27,454 YOU'LL SEE WHAT I MEAN REGARDING 2686 02:08:27,454 --> 02:08:28,722 THE POWERFUL ANTIBODIES THE 2687 02:08:28,722 --> 02:08:33,093 TEAMS AT PENN ARE CHASING AND 2688 02:08:33,093 --> 02:08:34,327 OUR CONTINUED DESIRE TO 2689 02:08:34,327 --> 02:08:36,563 UNDERSTAND WHERE IS THE 2690 02:08:36,563 --> 02:08:38,098 PERSISTENT VIRUS AND HOW BEST TO 2691 02:08:38,098 --> 02:08:41,601 MEASURE IT AND THE 2692 02:08:41,601 --> 02:08:43,336 PROPORTIONALITY OF THE RESERVOIR 2693 02:08:43,336 --> 02:08:46,706 BETWEEN THE SUBSETS OF THE CD4 2694 02:08:46,706 --> 02:08:47,374 CELL. 2695 02:08:47,374 --> 02:08:49,242 WITH RESPECT TO NEW PROGRAMS 2696 02:08:49,242 --> 02:08:51,778 COMING THERE'S AN EXCITING 2697 02:08:51,778 --> 02:08:53,346 DEVELOPMENT FROM CAR T CELL AS 2698 02:08:53,346 --> 02:08:57,217 NEW THERAPY APPROACH THAT SHOW 2699 02:08:57,217 --> 02:08:59,753 THE POTENCY OF BROADLY 2700 02:08:59,753 --> 02:09:01,821 NEUTRALIZING ANTIBODIES AS THE 2701 02:09:01,821 --> 02:09:03,623 STRATEGY FOR DETECTION AND 2702 02:09:03,623 --> 02:09:07,827 DR. CLAIBORNE WILL TELL US ABOUT 2703 02:09:07,827 --> 02:09:08,862 THAT. 2704 02:09:08,862 --> 02:09:09,763 ANOTHER UNDER STUDIED SOCIAL 2705 02:09:09,763 --> 02:09:11,698 SCIENCE SIDE IS WE TALK ABOUT 2706 02:09:11,698 --> 02:09:13,066 OUTREACH TO THE COMMUNITIES AND 2707 02:09:13,066 --> 02:09:15,502 WE HAVE THE PROVIDERS WHICH ARE 2708 02:09:15,502 --> 02:09:17,671 GATE KEEPERS TO THE PEOPLE 2709 02:09:17,671 --> 02:09:19,072 LIVING WITH HIV WHEN THEY LEARN 2710 02:09:19,072 --> 02:09:22,209 AND TRY TO SIPHON AND UNDERSTAND 2711 02:09:22,209 --> 02:09:29,115 WHAT'S DEVELOPING WHETHER IT'S A 2712 02:09:29,115 --> 02:09:30,617 DEVELOPMENT AND HOW BEST TO 2713 02:09:30,617 --> 02:09:31,718 ENGAGE THE COMMUNITY FOR THE 2714 02:09:31,718 --> 02:09:32,986 BENEFIT OF MOVING THE SCIENCE 2715 02:09:32,986 --> 02:09:34,154 FORWARD. 2716 02:09:34,154 --> 02:09:38,425 SO WITH THAT, I WE'LL DO A 2717 02:09:38,425 --> 02:09:44,097 VIRTUAL TRANSFER TO BOB AND 2718 02:09:44,097 --> 02:09:49,603 AFTER THAT MIKE AND THE LAST ONE 2719 02:09:49,603 --> 02:09:52,806 WILL BE VIRTUAL IF WE CAN 2720 02:09:52,806 --> 02:09:55,542 TRANSFER THE PRESENTATION TO HIS 2721 02:09:55,542 --> 02:09:55,775 LAPTOP. 2722 02:09:55,775 --> 02:09:57,010 WE PRACTICED THIS DURING THE 2723 02:09:57,010 --> 02:09:58,311 BREAK SO WE SHOULD BE GOOD. 2724 02:09:58,311 --> 02:10:00,647 >> CAN YOU SEE MY SLIDES? 2725 02:10:00,647 --> 02:10:07,554 >> YES. 2726 02:10:07,554 --> 02:10:14,728 I'LL TALK ABOUT AUTOLOGOUS 2727 02:10:14,728 --> 02:10:15,061 ANTIBODY. 2728 02:10:15,061 --> 02:10:21,701 PEOPLE WITH HIV MAKE A RESPONSE 2729 02:10:21,701 --> 02:10:25,305 AND THEY NEUTRALIZE THE VIRUS 2730 02:10:25,305 --> 02:10:28,008 AND WE ARE EXPLORING THE ROLE OF 2731 02:10:28,008 --> 02:10:29,109 THE ANTIBODIES IN HIV STRATEGIES 2732 02:10:29,109 --> 02:10:30,477 AN IN SOME SITUATIONS THEY MAY 2733 02:10:30,477 --> 02:10:33,980 BE ABLE TO MEDIATE A FUNCTIONAL 2734 02:10:33,980 --> 02:10:34,180 CURE. 2735 02:10:34,180 --> 02:10:35,749 NOW WE BECAME INTERESTED IN THE 2736 02:10:35,749 --> 02:10:37,050 ANTIBODIES THROUGH THE 2737 02:10:37,050 --> 02:10:38,184 CONSIDERATION OF THE CLONAL 2738 02:10:38,184 --> 02:10:40,053 NATURE OF THE HIV RESERVOIR. 2739 02:10:40,053 --> 02:10:42,155 IT'S CLEAR REPEATED EXPOSURE TO 2740 02:10:42,155 --> 02:10:44,791 THE AIM ANTIGEN CAN GENERATE 2741 02:10:44,791 --> 02:10:47,627 LARGE CLONES OF HIV INFECTED 2742 02:10:47,627 --> 02:10:48,895 CELLS TRANSFORMING THE RESERVOIR 2743 02:10:48,895 --> 02:10:54,634 FROM A COLLECTION OF QUIESCENT 2744 02:10:54,634 --> 02:10:57,504 CELLS DOMINATED BY CLONES AND 2745 02:10:57,504 --> 02:10:59,506 REBOUND AND INTERRUPTION WILL 2746 02:10:59,506 --> 02:11:01,708 COME FROM THE LARGE CLONES. 2747 02:11:01,708 --> 02:11:03,043 INTERESTINGLY, TWO RECENT 2748 02:11:03,043 --> 02:11:05,145 STUDIES HAVE SHOWN EVEN WHEN THE 2749 02:11:05,145 --> 02:11:07,714 RESERVOIR IS DOMINATED BY A 2750 02:11:07,714 --> 02:11:09,716 SINGLE CLONE TREATMENT AND 2751 02:11:09,716 --> 02:11:12,719 INTERRUPTION COMES FROM 2752 02:11:12,719 --> 02:11:13,586 PHYLOGENETICALLY DISTINCT 2753 02:11:13,586 --> 02:11:14,020 VARIANTS. 2754 02:11:14,020 --> 02:11:16,990 HERE'S A STUDY BY MICHEL. 2755 02:11:16,990 --> 02:11:19,659 IN THINKING ABOUT THIS IT'S 2756 02:11:19,659 --> 02:11:24,631 USEFUL TO CONSIDER THE RESERVOIR 2757 02:11:24,631 --> 02:11:28,468 ON THE LOG SCALE SHOWING THE 2758 02:11:28,468 --> 02:11:31,971 DIFFICULTY IN REDUCTION GIVEN 2759 02:11:31,971 --> 02:11:34,107 RAPID EXPONENTIAL VARIANTS CAN 2760 02:11:34,107 --> 02:11:36,643 COME FROM A SINGLE CELL. 2761 02:11:36,643 --> 02:11:38,311 WE NEED TO EXPLAIN WHY DOESN'T 2762 02:11:38,311 --> 02:11:40,747 REBOUND COME FROM THE DOMINANT 2763 02:11:40,747 --> 02:11:41,648 CLONES? 2764 02:11:41,648 --> 02:11:43,116 HYPOTHESES WERE PUT FORWARD AND 2765 02:11:43,116 --> 02:11:45,285 WE FAVORED A SIMPLER ONE THE 2766 02:11:45,285 --> 02:11:47,354 LARGE CLONES CANNOT CAUSE 2767 02:11:47,354 --> 02:11:52,292 REBOUND BECAUSE THE VIRUS IS 2768 02:11:52,292 --> 02:11:56,863 ALREADY NEUTRALIZING BY THE 2769 02:11:56,863 --> 02:12:02,168 AUTOLOGOUS ANTIBODY RESPONSE AND 2770 02:12:02,168 --> 02:12:05,405 IT'S TYPE SPECIFIC AND RESULTS 2771 02:12:05,405 --> 02:12:06,639 SHOW IT'S EFFECTIVE AND MAY HOLD 2772 02:12:06,639 --> 02:12:09,476 THE KEY TO A CURE. 2773 02:12:09,476 --> 02:12:12,645 NOW, TO TEST THE HYPOTHESIS 2774 02:12:12,645 --> 02:12:15,248 AUTOLOGOUS NEUTRALIZING 2775 02:12:15,248 --> 02:12:16,516 ANTIBODIES CAN PREVENT REBOUND 2776 02:12:16,516 --> 02:12:18,218 FROM THE LARGE CLONES WE CARRIED 2777 02:12:18,218 --> 02:12:20,153 OUT LARGE GROWTH ASSAYS IN THE 2778 02:12:20,153 --> 02:12:22,222 PRESENCE AND ABSENCE OF LOW 2779 02:12:22,222 --> 02:12:24,424 CONCENTRATIONS OF AUTOLOGOUS 2780 02:12:24,424 --> 02:12:26,760 CONTEMPORANEOUS IGG ANTIBODIES 2781 02:12:26,760 --> 02:12:30,263 AND SHOWED ONLY A SUBSET OF 2782 02:12:30,263 --> 02:12:32,999 RESERVOIR VIRUSES COULD GO OUT 2783 02:12:32,999 --> 02:12:35,368 IN THE PRESENCE OF AUTOLOGOUS 2784 02:12:35,368 --> 02:12:35,535 IGG. 2785 02:12:35,535 --> 02:12:38,638 THE VIRUSES ACCUMULATED 2786 02:12:38,638 --> 02:12:39,606 MUTATIONS IN THE FIVE VARIABLE 2787 02:12:39,606 --> 02:12:42,108 REGIONS OF THE ENVELOPE GENE. 2788 02:12:42,108 --> 02:12:43,810 IF WE LOOK AT THE ENVELOPE 2789 02:12:43,810 --> 02:12:44,911 TRIMER THEY'RE LOCATED IN THE 2790 02:12:44,911 --> 02:12:48,148 PART OF THE TRIMER AND LOOKING 2791 02:12:48,148 --> 02:12:53,686 FROM THIS PERSPECTIVE YOU CAN 2792 02:12:53,686 --> 02:13:00,627 SEE THE VARIABLE REGIONS 2793 02:13:00,627 --> 02:13:03,830 ENCOMPASS THE TRIMER AND THE 2794 02:13:03,830 --> 02:13:08,668 REGIONS ARE BOUNDED BY CYSTEINE 2795 02:13:08,668 --> 02:13:09,769 RESIDUES BOUND TO EACH OTHER AND 2796 02:13:09,769 --> 02:13:13,072 THE RESIDUE BETWEEN THE 2797 02:13:13,072 --> 02:13:15,141 CYSTEINES CAN VARY IN NUMBER, 2798 02:13:15,141 --> 02:13:16,776 SEQUENCE AND GLYCOSYLATION AND 2799 02:13:16,776 --> 02:13:20,547 IT'S LIKELY THE CAPACITY FOR 2800 02:13:20,547 --> 02:13:23,416 VARIATION EVOLVED TO ALLOW 2801 02:13:23,416 --> 02:13:25,685 ESCAPE FROM THE AUTOLOGOUS 2802 02:13:25,685 --> 02:13:27,020 NEUTRALIZING ANTIBODY RESPONSE 2803 02:13:27,020 --> 02:13:30,857 WHICH NORMALLY TARGETS THIS 2804 02:13:30,857 --> 02:13:34,027 REGION. 2805 02:13:34,027 --> 02:13:41,434 IT'S THE AND THE ASSAYS SHOWED 2806 02:13:41,434 --> 02:13:43,503 THE VIRUSES GROWING OUT IN THE 2807 02:13:43,503 --> 02:13:46,172 PRESENCE OF AUTOLOGOUS IGG WERE 2808 02:13:46,172 --> 02:13:48,641 HIGHLY RESISTANT AS EXPECTED BUT 2809 02:13:48,641 --> 02:13:53,847 OTHER VIRUSES FROM THE SAME 2810 02:13:53,847 --> 02:13:56,416 DONOR IN THE LARGE CLONES WERE 2811 02:13:56,416 --> 02:13:58,151 HIGHLY SENSITIVE AND LYNN WENT 2812 02:13:58,151 --> 02:14:05,758 ON TO SHOW THE VIRUSES THAT ARE 2813 02:14:05,758 --> 02:14:09,996 RESISTANT ARE CONNECTED TO VIRUS 2814 02:14:09,996 --> 02:14:11,598 IN REBOUND IN VIVO AND IT'S 2815 02:14:11,598 --> 02:14:13,633 STILL EFFECTIVE IN PREVENTING 2816 02:14:13,633 --> 02:14:16,970 REBOUND FROM A SUBSET OF 2817 02:14:16,970 --> 02:14:18,171 RESERVOIR VIRUSES. 2818 02:14:18,171 --> 02:14:21,541 THE FRACTION OF VIRUS NEUTRALIZE 2819 02:14:21,541 --> 02:14:24,644 VARY TREMENDOUSLY FROM PERSON TO 2820 02:14:24,644 --> 02:14:24,878 PERSON. 2821 02:14:24,878 --> 02:14:29,048 THE FRACTION OF VIRUS NEUTRALIZE 2822 02:14:29,048 --> 02:14:36,322 CORRELATE WITH TIME TO VIRAL 2823 02:14:36,322 --> 02:14:40,827 REBOUND AND IN A STUDY AFTER 2824 02:14:40,827 --> 02:14:50,503 ACCOUNTING FOR BNAB WASH OUT. 2825 02:14:50,503 --> 02:14:54,173 THEY'RE STABLE AND SHOWING 2826 02:14:54,173 --> 02:14:54,874 SENSIT 2827 02:14:54,874 --> 02:14:57,577 SENSITIVE ISOLATES FROM DONORS 2828 02:14:57,577 --> 02:14:59,212 ON ART OVER 20 YEARS. 2829 02:14:59,212 --> 02:15:00,113 SO REBOUND IS A SELECTION 2830 02:15:00,113 --> 02:15:01,714 PROCESS. 2831 02:15:01,714 --> 02:15:03,550 ANTIGENS ARE CONSTANTLY 2832 02:15:03,550 --> 02:15:06,185 ACTIVATING RESERVOIR CELLS AND 2833 02:15:06,185 --> 02:15:11,424 GIVES RISE TO THE RESIDUAL 2834 02:15:11,424 --> 02:15:11,658 VIREMIA. 2835 02:15:11,658 --> 02:15:14,360 MANY HAVE A RESPONSE AND REBOUND 2836 02:15:14,360 --> 02:15:17,397 REQUIRES ACTIVATION OF A CELL 2837 02:15:17,397 --> 02:15:18,631 CARRYING A NEUTRALIZATION 2838 02:15:18,631 --> 02:15:20,033 RESISTANT VIRUS. 2839 02:15:20,033 --> 02:15:22,201 ONLY A SUBSET OF RESERVOIR 2840 02:15:22,201 --> 02:15:24,137 VIRUSES CAN CAUSE REBOUND. 2841 02:15:24,137 --> 02:15:26,372 NOW, THE EVOLUTION OF ESCAPE 2842 02:15:26,372 --> 02:15:28,575 VARIANTS IS A PROCESS THAT 2843 02:15:28,575 --> 02:15:30,643 PREDATES AND ORTHOGONAL TO 2844 02:15:30,643 --> 02:15:31,544 CLONAL EXPANSION. 2845 02:15:31,544 --> 02:15:34,948 IN SOME DONORS, THE LARGE CLONES 2846 02:15:34,948 --> 02:15:38,184 ARE ACTUALLY NEUTRALIZATION 2847 02:15:38,184 --> 02:15:38,618 RESISTANT. 2848 02:15:38,618 --> 02:15:39,986 NEVERTHELESS THE FINDING AN 2849 02:15:39,986 --> 02:15:42,155 ANTIBODY RESPONSE GENERATED 2850 02:15:42,155 --> 02:15:44,390 YEARS AGO CAN STILL PREVENT 2851 02:15:44,390 --> 02:15:48,661 REBOUND FROM A SUBSET OF 2852 02:15:48,661 --> 02:15:54,167 RESERVOIR VIRUSES IS FROM RECENT 2853 02:15:54,167 --> 02:16:01,074 YEARS. 2854 02:16:01,074 --> 02:16:04,110 IT CAN BE ANALYZED IN THE 2855 02:16:04,110 --> 02:16:05,411 MACAQUE MODEL AND WE HAVE AN 2856 02:16:05,411 --> 02:16:06,713 ADVANTAGE TO KNOW WHAT THE 2857 02:16:06,713 --> 02:16:13,419 STARTING CONSEQUENCE SEQUENCE 2858 02:16:13,419 --> 02:16:15,521 AND HERE'S A SINGLE ANIMAL OVER 2859 02:16:15,521 --> 02:16:19,058 36 WEEKS PRIOR TO THE INITIATION 2860 02:16:19,058 --> 02:16:19,492 OF ART. 2861 02:16:19,492 --> 02:16:20,960 THE VIRAL LOAD IS EXTREMELY HIGH 2862 02:16:20,960 --> 02:16:21,628 AT THIS TIME. 2863 02:16:21,628 --> 02:16:25,264 AT THE TIME OF INITIATION THE 2864 02:16:25,264 --> 02:16:27,600 VIRUS IS REPLICATING IS IN BLACK 2865 02:16:27,600 --> 02:16:30,870 AND ACCUMULATED MUTATIONS IN THE 2866 02:16:30,870 --> 02:16:32,705 ENVELOPE GENE CONSISTENT WITH 2867 02:16:32,705 --> 02:16:35,108 ESCAPE FROM AUTOLOGOUS 2868 02:16:35,108 --> 02:16:36,609 NEUTRALIZING ANTIBODIES. 2869 02:16:36,609 --> 02:16:40,713 ANCESTRAL VARIANTS WITH FEWER 2870 02:16:40,713 --> 02:16:41,848 MUTATIONS ARE PRESERVED IN THE 2871 02:16:41,848 --> 02:16:46,586 RESERVOIR AND ABSENT FROM THE 2872 02:16:46,586 --> 02:16:49,656 PLASMA AT THE TIME OF VARIATION 2873 02:16:49,656 --> 02:16:51,557 DESPITE FITNESS SHOWN BY THE 2874 02:16:51,557 --> 02:16:55,895 VIREMIA EARLY ON AND THIS LIKELY 2875 02:16:55,895 --> 02:16:58,164 REFLECTS THE NEUTRALIZATION BY 2876 02:16:58,164 --> 02:17:02,435 AUTOLOGOUS NEUTRALIZING 2877 02:17:02,435 --> 02:17:02,835 ANTIBODIES. 2878 02:17:02,835 --> 02:17:05,905 THIS SUGGESTS A CURES STRATEGY. 2879 02:17:05,905 --> 02:17:07,473 INSTEAD OF REDUCING THE 2880 02:17:07,473 --> 02:17:10,610 RESERVOIR BY MANY LOGS, WHICH WE 2881 02:17:10,610 --> 02:17:13,713 DON'T KNOW HOW TO DO, WE CAN 2882 02:17:13,713 --> 02:17:15,581 SUPPLY OR GENERATE ANTIBODIES TO 2883 02:17:15,581 --> 02:17:20,920 THE ANAB RESISTANT SUBSET OF 2884 02:17:20,920 --> 02:17:21,154 VIRUSES. 2885 02:17:21,154 --> 02:17:21,754 CAN THEY PRODUCE A FUNCTIONAL 2886 02:17:21,754 --> 02:17:22,789 CURE? 2887 02:17:22,789 --> 02:17:25,925 AND I'D LIKE TO CONCLUDE WITH A 2888 02:17:25,925 --> 02:17:30,363 CASE THAT SUGGESTS THE ANSWER 2889 02:17:30,363 --> 02:17:32,765 MAY BE YES. 2890 02:17:32,765 --> 02:17:36,969 THIS IS A PARTICIPANT IN A STUDY 2891 02:17:36,969 --> 02:17:38,571 OF A 45-YEAR-OLD MALE STARTED 2892 02:17:38,571 --> 02:17:41,174 ART TWO MONTHS AFTER INFECTION. 2893 02:17:41,174 --> 02:17:43,643 AT THAT TIME THE VIRAL LOAD WAS 2894 02:17:43,643 --> 02:17:48,681 VERY HIGH AND NO PROTECTIVE HLA 2895 02:17:48,681 --> 02:17:48,915 ALLELES. 2896 02:17:48,915 --> 02:17:54,320 HE RECEIVED AN LRA AND BNAB AT 2897 02:17:54,320 --> 02:17:56,589 THE TIME OF INITIATION AND AFTER 2898 02:17:56,589 --> 02:17:57,990 ONE YEAR IT WAS STOPPED AND 2899 02:17:57,990 --> 02:17:59,859 REBOUND DID NOT OCCUR AND IT'S 2900 02:17:59,859 --> 02:18:02,328 NOW BEEN OVER SIX YEARS WITHOUT 2901 02:18:02,328 --> 02:18:06,232 A VIRAL REBOUND. 2902 02:18:06,232 --> 02:18:08,634 THIS IS DESPITE THE PRESENCE OF 2903 02:18:08,634 --> 02:18:12,705 REPLICA 2904 02:18:12,705 --> 02:18:17,310 REPLICATION COMPETENT RESERVOIR. 2905 02:18:17,310 --> 02:18:20,780 AND WE ASKED WHETHER THE CONTROL 2906 02:18:20,780 --> 02:18:24,550 COULD BE DUE TO AUTOLOGOUS 2907 02:18:24,550 --> 02:18:26,385 NEUTRALIZING ANTIBODIES. 2908 02:18:26,385 --> 02:18:29,388 THIS IS AN HIV NEGATIVE DONOR. 2909 02:18:29,388 --> 02:18:31,624 AT THE TIME OF INITIATION 2910 02:18:31,624 --> 02:18:33,226 THERE'S NO NEUTRALIZING ACTIVITY 2911 02:18:33,226 --> 02:18:36,395 IN THIS PARTICIPANT'S PLASMA BUT 2912 02:18:36,395 --> 02:18:37,964 AFTER THREE MONTHS STRONG 2913 02:18:37,964 --> 02:18:40,767 NEUTRALIZATION IS DETECTED AND 2914 02:18:40,767 --> 02:18:42,668 AFTER SIX MONTHS AND ALL 2915 02:18:42,668 --> 02:18:44,537 SUBSEQUENT TIME POINTS THERE'S 2916 02:18:44,537 --> 02:18:45,838 VERY STRONG NEUTRALIZING 2917 02:18:45,838 --> 02:18:46,239 ACTIVITY. 2918 02:18:46,239 --> 02:18:52,445 THE IC50 IS ONE MICROGRAM PER 2919 02:18:52,445 --> 02:18:54,547 MIL AND ONLY A MINUTE FRACTION 2920 02:18:54,547 --> 02:18:58,117 OF WHICH IS COMPRISED OF HIV 2921 02:18:58,117 --> 02:18:58,885 SPECIFIC ANTIBODIES. 2922 02:18:58,885 --> 02:19:00,553 AND I'LL ALSO POINT OUT THE 2923 02:19:00,553 --> 02:19:05,324 NORMAL PLASMA IGG CONCENTRATION 2924 02:19:05,324 --> 02:19:15,835 IS 10 MISSION -- MIGS PER MIL 2925 02:19:16,135 --> 02:19:18,171 AND WE CAN COMPARE THE 2926 02:19:18,171 --> 02:19:24,143 NEUTRALIZING ACTIVITY IN THIS 2927 02:19:24,143 --> 02:19:26,612 PARTICIPANT'S PLASMA TO ART 2928 02:19:26,612 --> 02:19:28,815 REGIMENTS AND THEY INDIVIDUALLY 2929 02:19:28,815 --> 02:19:31,851 PRODUCE LESS THAN 3 LOGS OF 2930 02:19:31,851 --> 02:19:33,386 INHIBITION WHEREAS EFFECTIVE 2931 02:19:33,386 --> 02:19:36,222 REGIMENTS PRODUCE ABOVE 5 LOGS 2932 02:19:36,222 --> 02:19:37,990 OF INHIBITION. 2933 02:19:37,990 --> 02:19:41,327 AND LOOKING AT THE AUTOLOGOUS 2934 02:19:41,327 --> 02:19:44,630 NEUTRALIZING ANTIBODIES IN THIS 2935 02:19:44,630 --> 02:19:48,701 PARTICIPANTS PLASMA ONCE THEY 2936 02:19:48,701 --> 02:19:53,539 ARE ARISE THEY ACHIEVE A LEVEL 2937 02:19:53,539 --> 02:19:55,675 OF INHIBITION COMPARABLE TO ART. 2938 02:19:55,675 --> 02:19:58,711 BY THE TIME THE ANTIBODIES AROSE 2939 02:19:58,711 --> 02:20:00,079 THE PARTICIPANT WAS ALREADY ON 2940 02:20:00,079 --> 02:20:02,315 ART SO THERE WAS NO CHANCE FOR 2941 02:20:02,315 --> 02:20:07,320 ESCAPE MUTATIONS. 2942 02:20:07,320 --> 02:20:11,624 AND INTERESTINGLY IF YOU LOOK AT 2943 02:20:11,624 --> 02:20:15,027 THE ANTIBODIES FOR PEOPLE WITH 2944 02:20:15,027 --> 02:20:16,762 HIV THERE'S NO ACROSS 2945 02:20:16,762 --> 02:20:17,096 NEUTRALIZING. 2946 02:20:17,096 --> 02:20:19,398 THE ANTIBODIES ARE LIKELY 2947 02:20:19,398 --> 02:20:24,337 DIRECTED AT THE VARIABLE 2948 02:20:24,337 --> 02:20:24,604 REGIONS. 2949 02:20:24,604 --> 02:20:28,507 SO WORKING WITH DUKE WE HAVE NOW 2950 02:20:28,507 --> 02:20:29,876 OBTAINED A CRYO EM STRUCTURE OF 2951 02:20:29,876 --> 02:20:31,177 THE ENVELOPE FROM THIS 2952 02:20:31,177 --> 02:20:33,112 PARTICIPANT AND WE'RE PULLING 2953 02:20:33,112 --> 02:20:35,248 OUT THE ANTIBODIES IN HOPES WE 2954 02:20:35,248 --> 02:20:38,150 CAN LEARN FROM THIS EXTREMELY 2955 02:20:38,150 --> 02:20:41,354 POTENT BUT HIGHLY SPECIFIC 2956 02:20:41,354 --> 02:20:42,154 RESPONSE. 2957 02:20:42,154 --> 02:20:46,225 SOME INSIGHTS TO HELP DEVELOP A 2958 02:20:46,225 --> 02:20:52,365 GENERAL CURE STRATEGY. 2959 02:20:52,365 --> 02:20:53,966 MY WIFE AND I HAVE LAD THE 2960 02:20:53,966 --> 02:20:55,801 PLEASURE OF WORKING WITH A 2961 02:20:55,801 --> 02:20:57,370 REMARKABLE GROUP OF GRADUATE 2962 02:20:57,370 --> 02:20:58,170 STUDENTS AND MENTIONED THEM IN 2963 02:20:58,170 --> 02:21:03,042 THE WORK AND WOULD LIKE TO THANK 2964 02:21:03,042 --> 02:21:07,580 MANY COLLABORATORS FROM THE 2965 02:21:07,580 --> 02:21:09,849 COLLABORATORIES AND A GROUP FROM 2966 02:21:09,849 --> 02:21:20,126 DUKE UNIVERSITY. 2967 02:21:31,971 --> 02:21:32,939 >> THANK YOU, EVERYBODY. 2968 02:21:32,939 --> 02:21:35,908 I'M HAPPY TO BE HERE IN MULTIPLE 2969 02:21:35,908 --> 02:21:39,312 WAYS TO PRESENT THIS WORK TO YOU 2970 02:21:39,312 --> 02:21:41,480 FROM OUR LAB THROUGH THE B 2971 02:21:41,480 --> 02:21:41,814 KWLABTRY. 2972 02:21:41,814 --> 02:21:46,986 WHAT I' -- COLLABORATORY. 2973 02:21:46,986 --> 02:21:48,721 AND WHAT WE'LL START WITH THE 2974 02:21:48,721 --> 02:21:50,723 PLAIN LANGUAGE IS WHERE IS HIV? 2975 02:21:50,723 --> 02:21:54,160 WHAT I MEAN IS WHAT TYPE OF CELL 2976 02:21:54,160 --> 02:21:59,565 IS HARBORING HIV IN PEOPLE 2977 02:21:59,565 --> 02:22:02,668 LIVING WITH HIV AND TISSUES 2978 02:22:02,668 --> 02:22:04,704 WHERE WE KNOW THE PREDOMINANCE 2979 02:22:04,704 --> 02:22:08,374 OF THE RESERVOIR RESIDE AND WHAT 2980 02:22:08,374 --> 02:22:13,813 CELLS ARE IN LYMPH NODE AND IS 2981 02:22:13,813 --> 02:22:16,849 THE VIRUS LATENT IN TISSUES 2982 02:22:16,849 --> 02:22:17,616 DURING ART. 2983 02:22:17,616 --> 02:22:22,755 WE FOUND THE HIV RESERVOIR IN 2984 02:22:22,755 --> 02:22:23,756 LYMPH NODES HAVE DIFFERENT 2985 02:22:23,756 --> 02:22:25,925 PROPERTIES AND MAY NOT ENTIRELY 2986 02:22:25,925 --> 02:22:28,027 BE LATENT AND WHY IS THIS 2987 02:22:28,027 --> 02:22:29,362 IMPORTANT? 2988 02:22:29,362 --> 02:22:31,998 AS WE THINK OF DIFFERENT TYPES 2989 02:22:31,998 --> 02:22:34,800 OF CELLS MAY PRESENT UNIQUE 2990 02:22:34,800 --> 02:22:36,102 CHALLENGES FOR CURE ESPECIALLY 2991 02:22:36,102 --> 02:22:39,672 WHEN THE CELLS WITH HIV MAY NOT 2992 02:22:39,672 --> 02:22:40,606 DIFFER VERY MUCH HENCE THE 2993 02:22:40,606 --> 02:22:41,841 WHERE'S WALDO PICTURE. 2994 02:22:41,841 --> 02:22:47,346 THE STUDY GOAL WAS TO DEFINE THE 2995 02:22:47,346 --> 02:22:49,882 HIV RESERVOIR AND TREAT PEOPLE 2996 02:22:49,882 --> 02:22:50,182 WITH HIV. 2997 02:22:50,182 --> 02:22:54,720 WE WANTED TO LOOK AT THE 2998 02:22:54,720 --> 02:22:58,157 TRANSCRIPTOMIC AND EPITOPE IN 2999 02:22:58,157 --> 02:23:00,126 LYMPH NODESES OF PEOPLE WITH ART 3000 02:23:00,126 --> 02:23:02,895 AND USED A TECHNIQUE FIRST USED 3001 02:23:02,895 --> 02:23:06,232 IN THE CONTEXT OF HIV CALLED 3002 02:23:06,232 --> 02:23:09,668 DOGMA SEQ PUBLISHED I GUESS LATE 3003 02:23:09,668 --> 02:23:10,202 LAST YEAR. 3004 02:23:10,202 --> 02:23:13,572 WE WANTED TO DETERMINE WHERE THE 3005 02:23:13,572 --> 02:23:18,177 PREDOMINANT CELL SUBSETS 3006 02:23:18,177 --> 02:23:19,879 HARBORING IN THE ART TREATED 3007 02:23:19,879 --> 02:23:22,214 LYMPH NODES AND THE MOST THING 3008 02:23:22,214 --> 02:23:23,582 YOU'LL THINK ABOUT IS HELPER 3009 02:23:23,582 --> 02:23:23,783 CELLS. 3010 02:23:23,783 --> 02:23:26,385 AND WE WANT THE TO FIGURE OUT IF 3011 02:23:26,385 --> 02:23:33,459 THAT WAS REALLY THE CASE. 3012 02:23:33,459 --> 02:23:36,395 WE WANTED TO DETERMINE IF THE 3013 02:23:36,395 --> 02:23:41,000 CD4 T CELLS HARBORING HIV WERE 3014 02:23:41,000 --> 02:23:42,701 QUIESCENT OR TRANSCRIPTIONALLY 3015 02:23:42,701 --> 02:23:46,172 ACTIVE AND IF THERE WERE 3016 02:23:46,172 --> 02:23:46,972 DIFFERENT CHARACTERISTICS 3017 02:23:46,972 --> 02:23:48,374 THEREOF AND IN THIS PRESENTATION 3018 02:23:48,374 --> 02:23:49,842 WE WON'T BE ABLE TO GET TO THE 3019 02:23:49,842 --> 02:23:51,744 LAST POINT DUE TO TIME. 3020 02:23:51,744 --> 02:23:53,913 WE USED A TECHNIQUE CALLED DOGMA 3021 02:23:53,913 --> 02:23:55,414 SEQ I WON'T GO THROUGH THE 3022 02:23:55,414 --> 02:23:56,649 ENTIRE PROCEDURE OUT OF TIME. 3023 02:23:56,649 --> 02:23:59,351 THE MAIN POINT TO TAKE HOME ARE 3024 02:23:59,351 --> 02:24:00,786 ESSENTIALLY WHAT WERE THE CELLS 3025 02:24:00,786 --> 02:24:03,189 WE STARTED WITH AND SO PAY 3026 02:24:03,189 --> 02:24:05,925 ATTENTION TO THE TOP PART OF 3027 02:24:05,925 --> 02:24:09,862 THIS FIGURE WHERE WE INSTEAD OF 3028 02:24:09,862 --> 02:24:12,031 USING BEAD MEDIATED SELECTION AS 3029 02:24:12,031 --> 02:24:17,670 DONE TO PURIFY CELLS WE USED 3030 02:24:17,670 --> 02:24:20,072 FLOW SORTING TO LIVE SORT CELLS 3031 02:24:20,072 --> 02:24:29,548 AND PARTICULARLY TO INCLUDE CD 3032 02:24:29,548 --> 02:24:31,951 5RA IN THE SELECTION. 3033 02:24:31,951 --> 02:24:37,289 WE HAD SAMPLES I'LL DESCRIBE IN 3034 02:24:37,289 --> 02:24:40,459 THE NEXT SLIDE FROM INDIVIDUALS 3035 02:24:40,459 --> 02:24:41,460 OFF VEREMIC CHRONIC INFECTION 3036 02:24:41,460 --> 02:24:44,763 AND THOSE ON THERAPY. 3037 02:24:44,763 --> 02:24:48,701 AND WE DIFFERENTIALLY CHOSE 3038 02:24:48,701 --> 02:24:51,070 CELLS BASED ON THE FREQUENTED 3039 02:24:51,070 --> 02:24:52,404 CELLS FROM HIV. 3040 02:24:52,404 --> 02:24:56,475 THE CHRONIC SAMPLES WE USED A 3041 02:24:56,475 --> 02:24:57,977 LITTLE OVER 25,000 CELLS FOR 3042 02:24:57,977 --> 02:24:59,912 DONOR AND FOR THE ART A LITTLE 3043 02:24:59,912 --> 02:25:03,549 OVER 50,000 CELLS PER DONOR THE 3044 02:25:03,549 --> 02:25:07,520 TOTAL CELLS WE ANALYZED THAT 3045 02:25:07,520 --> 02:25:11,290 PASSED WERE GREATER THAN 400,000 3046 02:25:11,290 --> 02:25:12,591 SINGLE CELLS AND WE HAVE 3047 02:25:12,591 --> 02:25:14,593 ADDITIONAL DATA NOT ADDED TO 3048 02:25:14,593 --> 02:25:16,562 THIS WE'VE BEEN ANALYZING AS WE 3049 02:25:16,562 --> 02:25:17,963 HAVE BEEN SITTING IN HERE THAT 3050 02:25:17,963 --> 02:25:20,399 BRINGS US TO ABOUT 650,000 3051 02:25:20,399 --> 02:25:20,733 SINGLE CELLS. 3052 02:25:20,733 --> 02:25:24,203 BUT THE CONCLUSIONS HAVE NOT 3053 02:25:24,203 --> 02:25:34,547 CHANGED FORTUNATELY. 3054 02:25:34,847 --> 02:25:36,515 AND THESE ARE INDIVIDUALS LIVING 3055 02:25:36,515 --> 02:25:41,754 WITH HIV EITHER TREATED OR 3056 02:25:41,754 --> 02:25:47,259 UNTREATED WHO DONATED SAMPLES 3057 02:25:47,259 --> 02:25:48,227 TYPICALLY CERVICAL LYMPH NODES 3058 02:25:48,227 --> 02:25:49,728 FOR DIAGNOSTIC PURPOSES. 3059 02:25:49,728 --> 02:25:51,630 YOU CAN SEE WE HAVE 10 3060 02:25:51,630 --> 02:25:54,166 INDIVIDUALS ON ART, 10 3061 02:25:54,166 --> 02:25:55,034 INDIVIDUALS WHO HAD NOT YET 3062 02:25:55,034 --> 02:26:05,544 BEGUN ART AT THE TIME OF THE 3063 02:26:06,212 --> 02:26:16,689 LYMPH NODES BIOPSY AND SUFFICE 3064 02:26:19,758 --> 02:26:22,161 TO SAY WE WERE ABLE TO CLEARLY 3065 02:26:22,161 --> 02:26:26,165 DEFINE AROUND 23 OR SO DIFFERENT 3066 02:26:26,165 --> 02:26:29,401 CLUSTERS OF CELLS FROM THE LYMPH 3067 02:26:29,401 --> 02:26:30,703 NODES OF THE INDIVIDUALS AND 3068 02:26:30,703 --> 02:26:32,738 COMPRISED SUBSETS AS DETAILED 3069 02:26:32,738 --> 02:26:34,173 HERE. 3070 02:26:34,173 --> 02:26:35,874 SO IMPORTANTLY FOR EXAMPLE TWO 3071 02:26:35,874 --> 02:26:36,709 DIFFERENT SUBSETS OF HELPER 3072 02:26:36,709 --> 02:26:38,811 CELLS AND I WON'T GO THROUGH THE 3073 02:26:38,811 --> 02:26:39,044 REST. 3074 02:26:39,044 --> 02:26:49,588 MANY DIFFERENT SUBSETS OF CELLS 3075 02:26:55,995 --> 02:26:57,730 AND WE'LL HAVE MORE IN A FEW 3076 02:26:57,730 --> 02:26:58,030 MOMENTS. 3077 02:26:58,030 --> 02:27:01,634 THE KEY ISSUE IS COULD WE FIND 3078 02:27:01,634 --> 02:27:03,936 HIV CELLS HARBORING HIV AND WE 3079 02:27:03,936 --> 02:27:08,340 CAN DETECT THOSE BOTH BY 3080 02:27:08,340 --> 02:27:10,142 DETECTING VIRAL DNA AND RNA 3081 02:27:10,142 --> 02:27:12,344 AFTER ALIGNING THE SEQUENCING 3082 02:27:12,344 --> 02:27:12,544 DATA. 3083 02:27:12,544 --> 02:27:15,080 WE'RE ABLE TO FIND DNA AND RNA 3084 02:27:15,080 --> 02:27:16,215 POSITIVE SAMPLES IF YOU LOOK AT 3085 02:27:16,215 --> 02:27:18,150 THE LEFT SIDE OF THE SLIDES IN 3086 02:27:18,150 --> 02:27:24,023 BOTH THE ART TREATED AND CHRONIC 3087 02:27:24,023 --> 02:27:27,159 INDIVIDUALS WE OBTAINED 400 3088 02:27:27,159 --> 02:27:29,395 SINGLE CELLS IN THE ART TREATED 3089 02:27:29,395 --> 02:27:31,864 INDIVIDUALS AND ABOUT 1200 OR 3090 02:27:31,864 --> 02:27:34,033 MORE -- SORRY, 1300 OR MORE FROM 3091 02:27:34,033 --> 02:27:35,334 THE CHRONIC INDIVIDUALS AND 3092 02:27:35,334 --> 02:27:38,003 WE'RE ABLE TO DETECT DNA AND RNA 3093 02:27:38,003 --> 02:27:41,240 POSITIVE CELLS AND YOU CAN SEE 3094 02:27:41,240 --> 02:27:43,309 FROM THE MAPS THE RED CELLS OVER 3095 02:27:43,309 --> 02:27:48,380 THE U MAPS ARE THE CELLS THAT 3096 02:27:48,380 --> 02:27:53,585 HAVE DETECTABLE PROVIRAL OR RNA 3097 02:27:53,585 --> 02:28:04,129 READ AND WE MAY NOT BE ABLE TO 3098 02:28:07,466 --> 02:28:11,437 LOOK AT THE MODALITY AND THE 3099 02:28:11,437 --> 02:28:13,272 DEFICIENCY IS ABOUT 50%. 3100 02:28:13,272 --> 02:28:15,207 WHAT ARE THE TAKE-HOME MESSAGES 3101 02:28:15,207 --> 02:28:18,410 FROM THE DATA SET? 3102 02:28:18,410 --> 02:28:20,879 I WON'T GET INTO DIFFERENTLY 3103 02:28:20,879 --> 02:28:22,181 EXPRESSED GENE ANALYSIS AND LOOK 3104 02:28:22,181 --> 02:28:24,583 AT SUBSETS HARBORING HIV. 3105 02:28:24,583 --> 02:28:26,518 WE'LL TALK ABOUT THESE IN THREE 3106 02:28:26,518 --> 02:28:28,320 GROUPS. 3107 02:28:28,320 --> 02:28:30,723 FIRST, FOCUSSING ON THE VIREMIC 3108 02:28:30,723 --> 02:28:31,290 INDIVIDUALS. 3109 02:28:31,290 --> 02:28:33,759 THE FIRST AND WHAT THE PLOT IS 3110 02:28:33,759 --> 02:28:35,661 SHOWING HERE IS IF WE TAKE ALL 3111 02:28:35,661 --> 02:28:38,864 OF THE IN THIS CASE PROVIRAL DNA 3112 02:28:38,864 --> 02:28:40,632 POSITIVE CELLS SET THAT TO 100% 3113 02:28:40,632 --> 02:28:42,901 AND ASK WHERE ARE THEY FOUND 3114 02:28:42,901 --> 02:28:46,171 WITHIN THE SUBSETS WE DEFINE. 3115 02:28:46,171 --> 02:28:49,541 THAT'S THE PROPORTIONALITY AND 3116 02:28:49,541 --> 02:28:52,010 SEE FIRST IT'S VERY 3117 02:28:52,010 --> 02:28:52,344 HETEROGENEOUS. 3118 02:28:52,344 --> 02:28:56,248 MANY CD4 SUBSETS IN THE LYMPH 3119 02:28:56,248 --> 02:28:57,850 NODE PLAY HAVE A PROVIRAL AID. 3120 02:28:57,850 --> 02:28:59,518 SO ABOUT WHAT ARE THE KEY THINGS 3121 02:28:59,518 --> 02:29:01,687 WE THINK ABOUT? 3122 02:29:01,687 --> 02:29:05,424 FIRST WE THINK OF CELLS AND 3123 02:29:05,424 --> 02:29:09,061 IDENTIFIED TWO TFH WE CAN GET TO 3124 02:29:09,061 --> 02:29:11,130 IN THE Q&A TO UNDERSTAND THE 3125 02:29:11,130 --> 02:29:12,531 DIFFERENCES AND IN COMBINATION 3126 02:29:12,531 --> 02:29:15,968 THEY ACCOUNTED FOR NEARLY 17% OF 3127 02:29:15,968 --> 02:29:17,069 THE TOTAL PROVIRAL DNA CELLS. 3128 02:29:17,069 --> 02:29:20,372 THEY WEREN'T THE LARGEST 3129 02:29:20,372 --> 02:29:20,672 POPULATION. 3130 02:29:20,672 --> 02:29:23,709 LARGEST WAS JUST A BORING 3131 02:29:23,709 --> 02:29:26,078 CENTRAL MEMORY CD4 POPULATION 3132 02:29:26,078 --> 02:29:27,946 ABOUT 35%. 3133 02:29:27,946 --> 02:29:29,548 THIS POPULATION HAS INTERESTING 3134 02:29:29,548 --> 02:29:29,915 CHARACTERISTICS. 3135 02:29:29,915 --> 02:29:35,053 I CALLED IT BORING BUT IT'S NOT 3136 02:29:35,053 --> 02:29:35,788 THAT BORING. 3137 02:29:35,788 --> 02:29:39,391 ONE OF THE TOP DIFFERENTLY 3138 02:29:39,391 --> 02:29:41,693 EXPRESSED GENES NEGATIVELY RECTS 3139 02:29:41,693 --> 02:29:44,163 TGF BETA YOU HEARD ABOUT IN THE 3140 02:29:44,163 --> 02:29:44,596 TALKS. 3141 02:29:44,596 --> 02:29:47,199 THERE'S ANOTHER MARKER CALLED OX 3142 02:29:47,199 --> 02:29:48,100 40 INDUCED UPON ACTIVATION. 3143 02:29:48,100 --> 02:29:49,968 THIS LOOKS LIKE IT MAY HAVE 3144 02:29:49,968 --> 02:29:51,336 ACTIVATION MARKERS. 3145 02:29:51,336 --> 02:29:54,173 IT'S ALSO NOT A RESIDENT 3146 02:29:54,173 --> 02:29:56,809 POPULATION SO IT'S A POPULATION 3147 02:29:56,809 --> 02:29:58,143 THAT WILL LEAVE THE LYMPH NODES 3148 02:29:58,143 --> 02:30:08,687 OUT TO THE BLOOD AND COME BACK. 3149 02:30:09,955 --> 02:30:10,989 THE LITERATURE HAS BEEN MIXED 3150 02:30:10,989 --> 02:30:13,392 WHETHER THE T CELLS ARE A MAJOR 3151 02:30:13,392 --> 02:30:14,626 CONTRIBUTOR TO THE RESERVOIR 3152 02:30:14,626 --> 02:30:15,294 UNDER ART. 3153 02:30:15,294 --> 02:30:17,563 IN OUR CASE FOR OUR SAMPLES WE 3154 02:30:17,563 --> 02:30:20,199 FIND IT IS NOT. 3155 02:30:20,199 --> 02:30:24,002 IN THESE SAMPLES ONLY 8% OF THE 3156 02:30:24,002 --> 02:30:26,171 TOTAL RESERVOIR WAS FOUND TO BE 3157 02:30:26,171 --> 02:30:28,006 IN CELLS DEFINED AS HELPER 3158 02:30:28,006 --> 02:30:28,207 CELLS. 3159 02:30:28,207 --> 02:30:31,043 WE FOUND TWO OTHER MEMORY 3160 02:30:31,043 --> 02:30:33,178 POPULATIONS THAT HIGHER 3161 02:30:33,178 --> 02:30:37,149 PROPORTIONS OF PROVIRAL DNA. 3162 02:30:37,149 --> 02:30:42,154 ONE WAS A NON-ACTIVATED CIRCUIT 3163 02:30:42,154 --> 02:30:44,423 POPULATION A CD4 CELL AGAIN THAT 3164 02:30:44,423 --> 02:30:45,824 WILL GO TO THE BLOOD. 3165 02:30:45,824 --> 02:30:47,259 AND THEN WE FOUND ANOTHER 3166 02:30:47,259 --> 02:30:48,861 POPULATION WHICH HAS NOT BEEN 3167 02:30:48,861 --> 02:30:51,730 DEFINED THAT WE KNOW OF AND IT'S 3168 02:30:51,730 --> 02:30:54,166 UNFORTUNATELY THE AN PLACE IS 3169 02:30:54,166 --> 02:30:59,037 CUT OFF THE DESCRIPTION OF IT 3170 02:30:59,037 --> 02:31:00,806 AND THE A41 POSITIVE POPULATION 3171 02:31:00,806 --> 02:31:02,074 I'LL TALK ABOUT IN A MOMENT 3172 02:31:02,074 --> 02:31:03,742 BECAUSE IT TURNS OUT TO BE AN 3173 02:31:03,742 --> 02:31:04,243 INTERESTING SUBSET. 3174 02:31:04,243 --> 02:31:06,144 BEFORE I TALK ABOUT THAT THOUGH 3175 02:31:06,144 --> 02:31:07,312 LET'S GO TO THE THIRD SMALL 3176 02:31:07,312 --> 02:31:09,748 STORY WHICH IS WHAT ABOUT THE 3177 02:31:09,748 --> 02:31:10,983 TRANSCRIPTIONALLY ACTIVE CELL? 3178 02:31:10,983 --> 02:31:14,553 I'VE TALKED ABOUT THE DNA ACTIVE 3179 02:31:14,553 --> 02:31:16,688 CELLS AND NOW THE RNA POSITIVE 3180 02:31:16,688 --> 02:31:16,889 CELLS. 3181 02:31:16,889 --> 02:31:18,790 ONLY IN THE ART TREATED 3182 02:31:18,790 --> 02:31:19,424 INDIVIDUALS THE CHRONIC 3183 02:31:19,424 --> 02:31:20,459 INDIVIDUALS COULD BE A FOURTH WE 3184 02:31:20,459 --> 02:31:21,760 WON'T TALK ABOUT BUT THE 3185 02:31:21,760 --> 02:31:23,896 QUESTION WAS WHAT ARE THE HELPER 3186 02:31:23,896 --> 02:31:25,297 CELLS DOING IN THIS CASE? 3187 02:31:25,297 --> 02:31:27,399 ONLY 5% OF THE RNA POSITIVE 3188 02:31:27,399 --> 02:31:31,336 CELLS ARE COMING OUT OF THE T 3189 02:31:31,336 --> 02:31:32,571 HELPER CELLS. 3190 02:31:32,571 --> 02:31:34,540 AGAIN IT'S THE POSITIVE 3191 02:31:34,540 --> 02:31:38,010 POPULATION THAT'S THE DOMINANT 3192 02:31:38,010 --> 02:31:42,281 POPULATION OF THE NR4A1 AND 2 3193 02:31:42,281 --> 02:31:42,681 POPULATION. 3194 02:31:42,681 --> 02:31:46,018 THEY'RE APPROXIMATELY 10% OF THE 3195 02:31:46,018 --> 02:31:49,521 TOTAL CD4s IN THE TREATED LYMPH 3196 02:31:49,521 --> 02:31:53,926 NODES IRRESPECTIVE OF TREATED OR 3197 02:31:53,926 --> 02:31:54,192 UNTREATED. 3198 02:31:54,192 --> 02:31:56,161 WHAT ARE THE CELLS? 3199 02:31:56,161 --> 02:32:00,499 THEY APPEAR CENTRAL MEMORY CD 28 3200 02:32:00,499 --> 02:32:02,601 AND CD HIGH AND THEY DO NOT 3201 02:32:02,601 --> 02:32:05,571 DISPLAY MARKERS OF RESIDENCY. 3202 02:32:05,571 --> 02:32:07,706 THEY'RE CD 69 LOW AND GO FROM A 3203 02:32:07,706 --> 02:32:10,042 LYMPH NODES TO THE BLOOD. 3204 02:32:10,042 --> 02:32:12,811 THEY APPEAR TO BE RESTING. 3205 02:32:12,811 --> 02:32:19,184 SO THEY'RE HLA NEGATIVE AND CD 3206 02:32:19,184 --> 02:32:21,119 38 NEGATIVE AND CD 3 LOW WHICH 3207 02:32:21,119 --> 02:32:24,056 SUGGEST THEY COULD BE ACTIVATED. 3208 02:32:24,056 --> 02:32:30,796 AND SUPPORTED BY THE TOP 3209 02:32:30,796 --> 02:32:32,664 EXPRESSED GENES. 3210 02:32:32,664 --> 02:32:34,232 THEY'RE TRANSCRIPTION FACTOR 3211 02:32:34,232 --> 02:32:37,869 THAT REQUIRES T CELL RECEPTOR 3212 02:32:37,869 --> 02:32:40,572 TRIGGERING WITHIN 3 TO 18 HOURS. 3213 02:32:40,572 --> 02:32:41,607 FROM MOUSE DATA AND COMMONLY 3214 02:32:41,607 --> 02:32:44,209 USED AS A REPORTER SYSTEM FOR 3215 02:32:44,209 --> 02:32:45,744 TCR ACTIVATION. 3216 02:32:45,744 --> 02:32:48,046 IT'S NOT INDUCED BY STANDARD 3217 02:32:48,046 --> 02:32:48,347 ACTIVATION. 3218 02:32:48,347 --> 02:32:51,850 IT'S A SPECIFIC EFFECT HAPPENING 3219 02:32:51,850 --> 02:32:54,553 BY CELLS GETTING TRIGGERED AND 3220 02:32:54,553 --> 02:32:55,921 THE RNA POSITIVE CELLS AND 3221 02:32:55,921 --> 02:32:59,524 THERE'S MULTIPLE FUNCTIONS 3222 02:32:59,524 --> 02:33:02,160 THAT'S A TRANSCRIPTION FACTOR 3223 02:33:02,160 --> 02:33:04,196 FACILITATE APOPTOSIS AND DRIVE 3224 02:33:04,196 --> 02:33:06,798 TOLERANCE. 3225 02:33:06,798 --> 02:33:12,371 AND THESE CELLS HAVE HIGH CD 69 3226 02:33:12,371 --> 02:33:17,542 RNA BUT HAVE LOW 69 PROTEIN OF 3227 02:33:17,542 --> 02:33:26,151 THE RNA TOE TO THE PROTEIN AND 3228 02:33:26,151 --> 02:33:34,526 APPEARS TO BE PHENOTYPICALLY 3229 02:33:34,526 --> 02:33:37,095 RESTING AND CELLS IN VIREMIA AND 3230 02:33:37,095 --> 02:33:37,262 ART. 3231 02:33:37,262 --> 02:33:38,630 I THINK I DON'T KNOW WHERE I AM 3232 02:33:38,630 --> 02:33:41,066 IN TERMS OF TIME. 3233 02:33:41,066 --> 02:33:45,237 I COVERED A LOT OF THIS. 3234 02:33:45,237 --> 02:33:47,806 THE RESERVOIR IS HETEROGENEOUS 3235 02:33:47,806 --> 02:33:48,340 IN ART. 3236 02:33:48,340 --> 02:33:52,210 WE SEE OTHER POPULATIONS THAT 3237 02:33:52,210 --> 02:33:54,279 PLAY HAVE LARGER CONTRIBUTIONS. 3238 02:33:54,279 --> 02:33:56,048 WE ARE SOMEWHAT LIMITED AND CAN 3239 02:33:56,048 --> 02:33:59,051 ONLY STAND FOR ONE OR TWO LYMPH 3240 02:33:59,051 --> 02:33:59,951 NODES AND THERE'S OVER 600 IN 3241 02:33:59,951 --> 02:34:01,853 THE BODY AND COULD BE 3242 02:34:01,853 --> 02:34:04,056 DIFFERENCES IN THE RESERVOIR 3243 02:34:04,056 --> 02:34:04,856 ACROSS THOSE TISSUES. 3244 02:34:04,856 --> 02:34:08,960 AND ONE REALLY IMPORTANT POINT 3245 02:34:08,960 --> 02:34:11,463 IS AND THIS HAS BEEN FOR EXAMPLE 3246 02:34:11,463 --> 02:34:13,265 MELANIE'S PRESENTATION SAYING 3247 02:34:13,265 --> 02:34:17,436 THE LATENT RESERVOIR IS NOT 3248 02:34:17,436 --> 02:34:19,271 TOTALLY LATENT THEY'RE 3249 02:34:19,271 --> 02:34:22,040 TRANSCRIPTIONALLY ACTIVE AND SEE 3250 02:34:22,040 --> 02:34:24,810 RNA POSITIVE CELLS THE VIRUSES 3251 02:34:24,810 --> 02:34:26,478 CONTINUALLY TRYING TO REACTIVATE 3252 02:34:26,478 --> 02:34:28,680 ALL THE TIME EVEN UNDER ART. 3253 02:34:28,680 --> 02:34:30,148 AND I'LL STOP THERE. 3254 02:34:30,148 --> 02:34:33,351 THE VAST MAJORITY OF ALL THIS 3255 02:34:33,351 --> 02:34:40,826 WORK WAS DONE BY VINCENT WU A 3256 02:34:40,826 --> 02:34:42,327 POSTDOC IN MY LAB AND I LIKE 3257 02:34:42,327 --> 02:34:43,929 WHEN PEOPLE SAY IT TAKES A 3258 02:34:43,929 --> 02:34:45,397 VILLAGE TO DO THIS. 3259 02:34:45,397 --> 02:34:47,365 IT TAKES OR CITY OR GLOBAL 3260 02:34:47,365 --> 02:34:50,502 AMOUNT OF FUNDING TO DO THESE 3261 02:34:50,502 --> 02:34:51,336 ASSAYS BECAUSE THEY'RE 3262 02:34:51,336 --> 02:34:52,204 INCREDIBLY EXPENSIVE SO THANK 3263 02:34:52,204 --> 02:35:02,748 YOU TO ALL THE FUNDING SOURCES. 3264 02:35:06,384 --> 02:35:07,119 >> ALL RIGHT. 3265 02:35:07,119 --> 02:35:09,888 SO, I'M EXCITED TO SHARE SOME 3266 02:35:09,888 --> 02:35:12,958 WORK THAT HAS BEEN A PROJECT 3267 02:35:12,958 --> 02:35:14,760 WE'VE BEEN DEVELOPING HEAVILY IN 3268 02:35:14,760 --> 02:35:17,662 THE PAST YEAR HALF LOOKING HOW 3269 02:35:17,662 --> 02:35:20,098 TO FURTHER DEVELOP T CELLS FOR 3270 02:35:20,098 --> 02:35:20,332 HIV. 3271 02:35:20,332 --> 02:35:22,768 FOR PLAIN LANGUAGE SUMMARY OUR 3272 02:35:22,768 --> 02:35:24,803 KEY QUESTION IS WHAT PARTS OF 3273 02:35:24,803 --> 02:35:27,939 HIV SPECIFICALLY THE ENVELOPE 3274 02:35:27,939 --> 02:35:31,777 ARE THE BEST TO TARGET AND WHY? 3275 02:35:31,777 --> 02:35:34,613 ENGINEERED T CELLS HAVE SHOWN TO 3276 02:35:34,613 --> 02:35:43,889 BE A VIABLE PART AND WE HAVE A 3277 02:35:43,889 --> 02:35:47,259 CAR T CELL AND ENVELOPE THAT CAN 3278 02:35:47,259 --> 02:35:49,961 BE TARGETED BY ANTIBODIES OR V 3279 02:35:49,961 --> 02:35:51,163 NABS AND DOES IT MATTER WHICH 3280 02:35:51,163 --> 02:35:58,170 ONE YOU TARGET AND WHY? 3281 02:35:58,170 --> 02:36:00,005 AND IT HAPPENS TO BE MORE DISTAL 3282 02:36:00,005 --> 02:36:03,041 ONES TOWARDS THE TOP OF THAT 3283 02:36:03,041 --> 02:36:03,441 TRIMER. 3284 02:36:03,441 --> 02:36:06,812 WE ALSO IMPLICATED CAR BINDING 3285 02:36:06,812 --> 02:36:09,514 THE STRENGTH WITH WHICH I BINDS 3286 02:36:09,514 --> 02:36:12,818 THE ENVELOPE TRIMER AS ONE 3287 02:36:12,818 --> 02:36:14,686 ASPECT DICTATING POTENCY AND 3288 02:36:14,686 --> 02:36:15,921 DEFINED COMBINATION OF CARS WE 3289 02:36:15,921 --> 02:36:18,657 THINK WE NEED IF WE'RE GOING TO 3290 02:36:18,657 --> 02:36:20,659 RESTRICT THE INCREDIBLE ABILITY 3291 02:36:20,659 --> 02:36:24,796 TO EVOLVE FROM ALL OF OUR 3292 02:36:24,796 --> 02:36:25,063 THERAPIES. 3293 02:36:25,063 --> 02:36:27,332 SO, AS I WAS SAYING WE WANT TO 3294 02:36:27,332 --> 02:36:28,800 KNOW WHAT PARTS OF THE HIV 3295 02:36:28,800 --> 02:36:30,802 TRIMER ARE THE BEST TO TARGET 3296 02:36:30,802 --> 02:36:32,304 AND WHY. 3297 02:36:32,304 --> 02:36:33,805 AND A LOT OF THE WORK WE'VE DONE 3298 02:36:33,805 --> 02:36:36,041 IN THE PAST HAS BEEN USING THE 3299 02:36:36,041 --> 02:36:38,910 PART YOU SEE ON THE LEFT. 3300 02:36:38,910 --> 02:36:41,446 IT'S A POTENT CAR T CELL AND HAS 3301 02:36:41,446 --> 02:36:42,681 GOOD IN VIVO SAFETY PROFILES AND 3302 02:36:42,681 --> 02:36:43,915 CAN'T ANSWER THE QUESTION 3303 02:36:43,915 --> 02:36:45,383 BECAUSE IT ONLY BINDS TO THE 3304 02:36:45,383 --> 02:36:46,318 BINDING SITE. 3305 02:36:46,318 --> 02:36:47,052 WE TOOK THE INCREDIBLE 3306 02:36:47,052 --> 02:36:49,421 LITERATURE AND FINDINGS FROM THE 3307 02:36:49,421 --> 02:36:50,555 BROADLY NEUTRALIZING ANTIBODY 3308 02:36:50,555 --> 02:36:54,793 FIELD AND MADE A LARGE PANEL OF 3309 02:36:54,793 --> 02:37:00,799 CAR T CELLS AND THAT ARE GET ALL 3310 02:37:00,799 --> 02:37:05,804 THE SIX MOST WIDELY DESCRIBED 3311 02:37:05,804 --> 02:37:08,607 AUTOLOGOUS NEUTRALIZING EPITOPES 3312 02:37:08,607 --> 02:37:10,175 AND THIS FORMS OUR TOOLBOX BY 3313 02:37:10,175 --> 02:37:12,811 WHICH WE CAN ASK QUESTIONS. 3314 02:37:12,811 --> 02:37:15,447 SO ONE OF THE FIRST AND SIMPLEST 3315 02:37:15,447 --> 02:37:18,783 THINGS IS HOW WELL DO THE 3316 02:37:18,783 --> 02:37:20,952 VARIOUS T CELLS KILL. 3317 02:37:20,952 --> 02:37:24,956 WE USED A KILLING ASSAY AND USED 3318 02:37:24,956 --> 02:37:26,324 TARGET RATIOS EXPRESSING HIV 3319 02:37:26,324 --> 02:37:30,295 ENVELOPE AND MONITOR REAL TIME 3320 02:37:30,295 --> 02:37:31,663 KILLING IN THE SYSTEM. 3321 02:37:31,663 --> 02:37:32,898 HERE YOU SEE THERE'S QUITE A 3322 02:37:32,898 --> 02:37:35,967 SPREAD AND THE ABILITY OF 3323 02:37:35,967 --> 02:37:37,569 VARIOUS CAR T CELLS TO KILL THE 3324 02:37:37,569 --> 02:37:39,671 TAR GETS AND IF WE DO THIS MANY 3325 02:37:39,671 --> 02:37:43,775 TIMES AND LOOK AT ACTUALLY FOR 3326 02:37:43,775 --> 02:37:45,043 VERY SPECIFIC EPITOPE CLASSES 3327 02:37:45,043 --> 02:37:47,012 HOW WELL ON AVERAGE THEY KILL WE 3328 02:37:47,012 --> 02:37:48,713 CAN SEE THERE IS HIERARCHY HERE. 3329 02:37:48,713 --> 02:37:50,649 IT'S NOT JUST A FLAT LINE. 3330 02:37:50,649 --> 02:37:52,350 CERTAIN ONES KILL BETTER OR NOT. 3331 02:37:52,350 --> 02:37:53,885 AND ONE THING WE NOTICE IS IF 3332 02:37:53,885 --> 02:37:55,820 YOU TALK THE RELATIVE DISTANCE 3333 02:37:55,820 --> 02:37:58,089 FROM THE PLASMA MEMBRANE AND 3334 02:37:58,089 --> 02:37:59,291 COMPARE THAT TO THE KILLING 3335 02:37:59,291 --> 02:38:01,693 SCORE IT DOES APPEAR THOSE MOST 3336 02:38:01,693 --> 02:38:03,194 DISTAL OR FURTHER FROM THE 3337 02:38:03,194 --> 02:38:04,930 ENVELOPE ARE ASSOCIATED WITH 3338 02:38:04,930 --> 02:38:07,866 ENHANCED KILLING POTENCY. 3339 02:38:07,866 --> 02:38:10,168 WE THEN WANTED TO CORROBORATE 3340 02:38:10,168 --> 02:38:14,172 THE FINDINGS BY PERFORMING A 3341 02:38:14,172 --> 02:38:15,974 MORE STRINGENT STRATEGY WITH T 3342 02:38:15,974 --> 02:38:18,576 CELLS AND REPLICATION COMPETENT 3343 02:38:18,576 --> 02:38:22,347 HIV AND MIX TARGET RATIOS WITH 3344 02:38:22,347 --> 02:38:23,448 CAR T CELLS AND IT'S MEASURING 3345 02:38:23,448 --> 02:38:27,052 THE CULTURE BY LOOKING AT THE 3346 02:38:27,052 --> 02:38:28,453 STAINING AND DO THIS FOR THE 3347 02:38:28,453 --> 02:38:30,789 FULL PANEL TO SEE WHAT THE 3348 02:38:30,789 --> 02:38:31,790 RESOLUTION IS. 3349 02:38:31,790 --> 02:38:34,592 AT HIGH EFFECTER TARGET RATIOS 3350 02:38:34,592 --> 02:38:38,997 MOST OF THE CARS ARE ABLE TO 3351 02:38:38,997 --> 02:38:40,765 EXPRESS VIRUS REPLICATION AND 3352 02:38:40,765 --> 02:38:46,538 THOSE TARGETING THE GP INTERFACE 3353 02:38:46,538 --> 02:38:48,707 APPEAR TO MAY BE LESS POTENT BUT 3354 02:38:48,707 --> 02:38:52,510 ALL IN ALL ARE POTENT AT TARGET 3355 02:38:52,510 --> 02:38:52,711 RATIO. 3356 02:38:52,711 --> 02:38:55,080 WE INCREASED THE RATIO OR 3357 02:38:55,080 --> 02:38:56,982 DECREASE THE NUMBER OF CARS PER 3358 02:38:56,982 --> 02:39:00,218 TARGET WE SEE A DIFFERENT STORY. 3359 02:39:00,218 --> 02:39:06,157 HERE MOST OF THE CARS AREN'T 3360 02:39:06,157 --> 02:39:08,960 ABLE TO SUPPRESS AND 3361 02:39:08,960 --> 02:39:14,165 CORROBORATES SOME DETE -- DATA 3362 02:39:14,165 --> 02:39:17,102 WE JUST SHOWED. 3363 02:39:17,102 --> 02:39:21,806 WITHIN AN EPITOPE WHAT DICTATES 3364 02:39:21,806 --> 02:39:22,040 POTENCY? 3365 02:39:22,040 --> 02:39:25,410 THERE'S GREATEST RANGE FROM 3366 02:39:25,410 --> 02:39:27,345 THOSE THAT ARE QUITE POTENT AND 3367 02:39:27,345 --> 02:39:28,346 WE ASKED THE QUESTION. 3368 02:39:28,346 --> 02:39:36,621 IN THIS BINDING ASSAY WE HAVE 3369 02:39:36,621 --> 02:39:37,989 NANO PARTICLES AND WASHED THEM 3370 02:39:37,989 --> 02:39:42,127 OFF AND CAN IMAGE CELLS TO SEE 3371 02:39:42,127 --> 02:39:43,294 HOW MANY ARE LEFT OVER AND THINK 3372 02:39:43,294 --> 02:39:46,398 IT'S A FUNCTION OF THE BINDING 3373 02:39:46,398 --> 02:39:46,965 AFFINITY. 3374 02:39:46,965 --> 02:39:49,501 WE GET A NIGHT SPREAD SUGGESTING 3375 02:39:49,501 --> 02:39:51,036 YES THERE'S HETEROGENEITY FOR 3376 02:39:51,036 --> 02:39:52,704 THE PHENOTYPE AND IF WE LOOK AT 3377 02:39:52,704 --> 02:39:54,372 TWO FUNCTIONAL WITHOUT PUTS OF 3378 02:39:54,372 --> 02:39:57,108 THE CARS LOOKING AT THEIR 3379 02:39:57,108 --> 02:40:01,946 ABILITY TO KILL TARGET CELLS OR 3380 02:40:01,946 --> 02:40:03,848 IL2 ON THE RIGHT AND REGRESS 3381 02:40:03,848 --> 02:40:05,583 THOSE AGAINST THE BINDING SCORES 3382 02:40:05,583 --> 02:40:09,521 IT APPEARS TO BE A FAIRLY ABOUT 3383 02:40:09,521 --> 02:40:11,689 PREDICTOR BETWEEN EP EPITOPES. 3384 02:40:11,689 --> 02:40:16,528 HOW TIGHTLY THE CARS BIND 3385 02:40:16,528 --> 02:40:16,761 APPEARS. 3386 02:40:16,761 --> 02:40:22,167 NOW WE HAVE SOME T CELLS. 3387 02:40:22,167 --> 02:40:23,334 WHAT HAPPENS IN VIVO? 3388 02:40:23,334 --> 02:40:24,969 WE HAVE A MOUSE MODEL TO TEST 3389 02:40:24,969 --> 02:40:28,940 THIS AND TAKE MICE AND 3390 02:40:28,940 --> 02:40:29,941 ADOPTIVELY TRANSFER THE T CELL 3391 02:40:29,941 --> 02:40:32,177 PRODUCTS AND LOOK AT WHAT 3392 02:40:32,177 --> 02:40:32,410 HAPPENS. 3393 02:40:32,410 --> 02:40:36,815 THESE ARE SOME OF THE MOST P 3394 02:40:36,815 --> 02:40:41,119 POTENT AND DO NOT EXPRESS VIRAL 3395 02:40:41,119 --> 02:40:41,352 LOAD. 3396 02:40:41,352 --> 02:40:50,662 THEY'LL ESCAPE MUTATIONS AND WE 3397 02:40:50,662 --> 02:40:53,298 SEQUENCED THE MICE AND SEE CON 3398 02:40:53,298 --> 02:40:58,336 ANTICAL CONTEXT SITES AND THE 3399 02:40:58,336 --> 02:41:03,141 LOSS OF GLYCAN AND THE CARS AT 3400 02:41:03,141 --> 02:41:04,342 DIFFERENT POSITION SELECT FOR 3401 02:41:04,342 --> 02:41:12,550 ESCAPE AND ALL THE GLYCAN AND 3402 02:41:12,550 --> 02:41:16,187 THIS SUGGESTS WE CAN DEFINE CAR 3403 02:41:16,187 --> 02:41:19,224 T CELL PRODUCT HAVE ORTHOGONAL 3404 02:41:19,224 --> 02:41:20,792 ESCAPE PATTERNS AND WE CAN 3405 02:41:20,792 --> 02:41:22,193 COMBINE THEM AND GET A DIFFERENT 3406 02:41:22,193 --> 02:41:32,337 RESULT. 3407 02:41:35,473 --> 02:41:37,809 AND FOR THE OTHER COHORTS WE 3408 02:41:37,809 --> 02:41:41,713 PERFORMED A MIXTURE AND HAVE THE 3409 02:41:41,713 --> 02:41:44,883 SAME NUMBER OF CAR T CELLS 3410 02:41:44,883 --> 02:41:46,484 AGAINST EPITOPES AND WE SEE 3411 02:41:46,484 --> 02:41:47,852 CONTROLLERS. 3412 02:41:47,852 --> 02:41:52,090 WE'RE ABLE TO FULLY SUPPRESS IN 3413 02:41:52,090 --> 02:41:52,557 THE MODEL. 3414 02:41:52,557 --> 02:41:53,825 WHAT'S MORE INTERESTING IS WHEN 3415 02:41:53,825 --> 02:41:55,693 WE TAKE THEM OUT AND JUST LOOK 3416 02:41:55,693 --> 02:41:57,262 AT MICE THAT HAVE HIGH VIREMIA 3417 02:41:57,262 --> 02:42:00,665 WE SEE AI LOG REDUCTION IN VIRAL 3418 02:42:00,665 --> 02:42:04,402 LOAD RELATIVELY DURABLE 3419 02:42:04,402 --> 02:42:06,137 SUGGESTING THE COMBINATION OF 3420 02:42:06,137 --> 02:42:07,472 CAR T IS DOING SOMETHING 3421 02:42:07,472 --> 02:42:08,740 IMPORTANT WE THINK IS PREVENTING 3422 02:42:08,740 --> 02:42:12,810 OR SLOWING THE KINETICS OF 3423 02:42:12,810 --> 02:42:13,478 ESCAPE. 3424 02:42:13,478 --> 02:42:17,549 TO FORMALLY INTERROGATE THAT WE 3425 02:42:17,549 --> 02:42:22,053 SEQUENCED AND LOOKED AT LOSS OF 3426 02:42:22,053 --> 02:42:23,755 THE GLYCAN BECAUSE THIS IS 3427 02:42:23,755 --> 02:42:25,156 COMMON AMONG THE COHORTS AND 3428 02:42:25,156 --> 02:42:27,392 LOOK AT THE RATE AT WHICH THE 3429 02:42:27,392 --> 02:42:29,561 GLYCAN IS LOST AND THE MICE THAT 3430 02:42:29,561 --> 02:42:33,498 GET THE MIXTURE OF CAR T CELLS 3431 02:42:33,498 --> 02:42:35,466 HAVE A LOWER RATE AND THINK IT'S 3432 02:42:35,466 --> 02:42:37,936 IMPORTANT BECAUSE THE RATE THAT 3433 02:42:37,936 --> 02:42:39,871 IT'S LOSS IS RELATED TO 3434 02:42:39,871 --> 02:42:43,141 CUMULATIVE VIRAL LOADS AND IF WE 3435 02:42:43,141 --> 02:42:44,842 CAN RESTRICT ESCAPE MAYBE WE CAN 3436 02:42:44,842 --> 02:42:46,578 GET BETTER CONTROL. 3437 02:42:46,578 --> 02:42:48,813 BECAUSE MIXTURES SEEM TO MAKE A 3438 02:42:48,813 --> 02:42:56,187 BIG DIFFERENCE INSTEAD OF MAKING 3439 02:42:56,187 --> 02:43:00,725 MIXTURES MAKE A CAR WHERE THEY 3440 02:43:00,725 --> 02:43:04,762 EXPRESS THE VARIOUS CAR T CELLS 3441 02:43:04,762 --> 02:43:07,966 AND AT LEAST THESE ARE NOT 3442 02:43:07,966 --> 02:43:11,869 INFERIOR OR MORE POTENT WHEN WE 3443 02:43:11,869 --> 02:43:17,075 LOOK AT THE KILLING ASSAY AND 3444 02:43:17,075 --> 02:43:18,142 SECRETE LEVELS SUGGESTING THESE 3445 02:43:18,142 --> 02:43:21,779 ARE EQUALLY AS POTENT. 3446 02:43:21,779 --> 02:43:24,749 AND SOME OF THIS LED TO US 3447 02:43:24,749 --> 02:43:27,085 BELIEVE MAYBE THE CAR T CELLS 3448 02:43:27,085 --> 02:43:29,487 HAVE GREATER ANTIGEN SENSITIVITY 3449 02:43:29,487 --> 02:43:31,222 AND EXPAND BETTER IN VIVO AND 3450 02:43:31,222 --> 02:43:33,057 CAN FORMALLY TEST IN OUR 3451 02:43:33,057 --> 02:43:33,491 SYSTEMS. 3452 02:43:33,491 --> 02:43:36,294 IN THIS SCENARIO INSTEAD OF 3453 02:43:36,294 --> 02:43:37,962 USING ONE TO TRANSDUCE WE USED 3454 02:43:37,962 --> 02:43:42,166 THREE WHICH GIVES A COMPLICATED 3455 02:43:42,166 --> 02:43:49,841 PRE-TRANSFER PRODUCT BUT AT 3456 02:43:49,841 --> 02:43:50,375 LEAST WE HAVE DIFFERENT 3457 02:43:50,375 --> 02:43:53,945 FREQUENCIES AND WE TAKE THE 3458 02:43:53,945 --> 02:43:54,846 AUTOLOGOUS CAR T CELL PRODUCT 3459 02:43:54,846 --> 02:43:57,148 AND TRANSMIT IT TO MICE AND LOOK 3460 02:43:57,148 --> 02:44:00,752 RAT WHAT HAPPENS TO CAR 3461 02:44:00,752 --> 02:44:04,856 EXPANSION OVER TIME. 3462 02:44:04,856 --> 02:44:06,591 THIS SHOWS THE RELATIVE 3463 02:44:06,591 --> 02:44:07,825 FREQUENCIES OF THE TOTAL T CELL 3464 02:44:07,825 --> 02:44:10,128 COMPARTMENT OF THE MICE IN THE 3465 02:44:10,128 --> 02:44:11,429 BOTTOM YOU SEE THE NUMBERS 3466 02:44:11,429 --> 02:44:12,897 GIVING THE PRODUCTS AND IT WAS 3467 02:44:12,897 --> 02:44:15,667 CLEAR TO SEE WE DO SEE CAR 3468 02:44:15,667 --> 02:44:17,535 EXPANSION AND IN THE MICE THAT 3469 02:44:17,535 --> 02:44:19,370 DON'T SEE CAR EXPANSION THESE 3470 02:44:19,370 --> 02:44:21,673 TWO HERE BECAUSE THEY'RE 3471 02:44:21,673 --> 02:44:23,374 CONTROLLING THEIR VIRAL LOAD AND 3472 02:44:23,374 --> 02:44:24,609 SUSPECT THERE'S NOT ENOUGH TO 3473 02:44:24,609 --> 02:44:26,044 DRIVE PROLIFERATION. 3474 02:44:26,044 --> 02:44:29,080 ONE THING THAT'S ENCOURAGING 3475 02:44:29,080 --> 02:44:31,683 THAT DUAL AND SPECIFIC T CELLS 3476 02:44:31,683 --> 02:44:32,317 MAY HAVE GREATER SENSITIVITY AND 3477 02:44:32,317 --> 02:44:35,119 LOOK AT THE FULL CHANGE IN 3478 02:44:35,119 --> 02:44:40,591 RELATIVE CAR T CELL TO THE 3479 02:44:40,591 --> 02:44:42,727 TRANSFER PRODUCT WE SEE ROBUST 3480 02:44:42,727 --> 02:44:45,096 AND PROFOUNDLY ENHANCED 3481 02:44:45,096 --> 02:44:50,735 EXPANSION OF THE DUAL AND TRI 3482 02:44:50,735 --> 02:44:53,204 SPECIFIC AND WE'LL FOLLOW-UP 3483 02:44:53,204 --> 02:44:54,605 WITH MORE IN VIVO EXPERIMENTS 3484 02:44:54,605 --> 02:44:56,974 BUT IT'S ENCOURAGING. 3485 02:44:56,974 --> 02:45:02,046 TO SUMMARIZE IT APPEARS DISTAL 3486 02:45:02,046 --> 02:45:03,348 EPITOPES ARE ASSOCIATED WITH 3487 02:45:03,348 --> 02:45:05,583 SUPERIOR CAR POTENCY IT MAY BE 3488 02:45:05,583 --> 02:45:07,118 ABOUT EPITOPE ACCESS BUT WE'RE 3489 02:45:07,118 --> 02:45:11,322 ACTIVELY IN TER GETTING THAT. 3490 02:45:11,322 --> 02:45:15,760 WE KNOW CAR AVIDITY IS MOST 3491 02:45:15,760 --> 02:45:18,763 STRONG IN CARS THAT BIND TO THE 3492 02:45:18,763 --> 02:45:21,899 SAME EPITOPE. 3493 02:45:21,899 --> 02:45:25,370 RESTRICTING HIV ESCAPE SEEMS TO 3494 02:45:25,370 --> 02:45:28,272 BE A VIABLE STRATEGY FOR MORE 3495 02:45:28,272 --> 02:45:30,174 ENHANCED AN ROBUST SUPPRESSION 3496 02:45:30,174 --> 02:45:31,509 OF VIRAL LOAD BUT THERE'S STILL 3497 02:45:31,509 --> 02:45:32,043 WORK TO BE DONE. 3498 02:45:32,043 --> 02:45:34,712 RIGHT NOW WE'RE TRYING TO MAKE 3499 02:45:34,712 --> 02:45:42,787 HIGH ENOUGH NUMBERS OF A PURE 3500 02:45:42,787 --> 02:45:45,456 TRI VALENT CAR PRODUCT AND MAY 3501 02:45:45,456 --> 02:45:48,459 BE ABLE TO SUSTAIN AND HAVE 3502 02:45:48,459 --> 02:45:49,527 BETTER VIRAL LOAD IN VIVO. 3503 02:45:49,527 --> 02:45:51,295 I WANTED TO THANK EVERYONE IN MY 3504 02:45:51,295 --> 02:45:52,363 LAB BECAUSE EVERYONE'S 3505 02:45:52,363 --> 02:45:54,899 CONTRIBUTED TO THE PROJECT AND 3506 02:45:54,899 --> 02:45:56,801 HIGHLIGHT THE TALENTED GRADUATE 3507 02:45:56,801 --> 02:46:00,538 STUDENT IN MY LAB WHO 3508 02:46:00,538 --> 02:46:01,372 SPEARHEADED HIS AND HAS A POSTER 3509 02:46:01,372 --> 02:46:10,248 IF YOU WANT TO LOOK AT THAT. 3510 02:46:10,248 --> 02:46:13,484 >> OUR NEXT PRESENTATION IS 3511 02:46:13,484 --> 02:46:20,358 VIRTUAL IF THE A/V CAN SPOTLIGHT 3512 02:46:20,358 --> 02:46:20,892 STEVEN. 3513 02:46:20,892 --> 02:46:23,361 >> ARE YOU THERE? 3514 02:46:23,361 --> 02:46:24,162 >> I'M HERE. 3515 02:46:24,162 --> 02:46:25,663 >> EXCELLENT. 3516 02:46:25,663 --> 02:46:26,697 JUST TELL ME WHEN TO ADVANCE. 3517 02:46:26,697 --> 02:46:29,100 >> I CAN'T SEE THE SLIDES. 3518 02:46:29,100 --> 02:46:30,902 NOW I CAN. 3519 02:46:30,902 --> 02:46:34,705 GOOD AFTERNOON, GOOD MORNING, 3520 02:46:34,705 --> 02:46:34,972 EVERYONE. 3521 02:46:34,972 --> 02:46:43,815 I'M STEVEN MEANLEY AND HIV 3522 02:46:43,815 --> 02:46:45,249 PROVIDER SURVEY REVEALS GAP IN 3523 02:46:45,249 --> 02:46:47,452 CURE RESEARCH AWARENESS AND BY 3524 02:46:47,452 --> 02:46:50,955 THE ENGAGEMENT GROUP AND BOARD. 3525 02:46:50,955 --> 02:46:52,390 SO OUR STUDY FOCUSSED ON 3526 02:46:52,390 --> 02:46:55,993 UNDERSTANDING THE ATTITUDES OF 3527 02:46:55,993 --> 02:46:57,929 CLINICAL PROVIDERS TOWARDS 3528 02:46:57,929 --> 02:46:59,430 DISCUSSING HIV CURE RESEARCH 3529 02:46:59,430 --> 02:47:01,432 WITH THEIR PATIENTS IN TREATMENT 3530 02:47:01,432 --> 02:47:07,772 INTERRUPTIONS OR ATIs. 3531 02:47:07,772 --> 02:47:10,741 HOW WILLING ARE THE PROVIDERS TO 3532 02:47:10,741 --> 02:47:11,742 DISCUSS HIV CURE STUDY 3533 02:47:11,742 --> 02:47:12,343 OPPORTUNITIES WITH THEIR 3534 02:47:12,343 --> 02:47:16,414 PATIENTS AND WHAT INFLUENCES 3535 02:47:16,414 --> 02:47:18,916 THEIR WILLINGNESS WHEN ATIs ARE 3536 02:47:18,916 --> 02:47:19,183 REQUIRED. 3537 02:47:19,183 --> 02:47:21,185 TO INVESTIGATE WE ENDED UP 3538 02:47:21,185 --> 02:47:22,520 REACHING 64 CLINICAL PROVIDERS 3539 02:47:22,520 --> 02:47:25,823 WHO WORK WITH PATIENTS WITH HIV 3540 02:47:25,823 --> 02:47:30,561 INCLUSIVE OF MDs MPs AND RNs 3541 02:47:30,561 --> 02:47:32,163 ACROSS EIGHT CLINICS IN 3542 02:47:32,163 --> 02:47:34,065 PHILADELPHIA AND EACH COMPLETED 3543 02:47:34,065 --> 02:47:34,866 A ONE TIME SURVEY. 3544 02:47:34,866 --> 02:47:38,669 WE FOCUSSED ON CLINICAL 3545 02:47:38,669 --> 02:47:41,005 PROVIDERS AND PRE-COVID SURVEY 3546 02:47:41,005 --> 02:47:43,274 OF PATIENTS WITH HIV IN 3547 02:47:43,274 --> 02:47:45,009 PHILADELPHIA AND THEY WERE 3548 02:47:45,009 --> 02:47:49,380 DEMONSTRATING A HIGH WILL 3549 02:47:49,380 --> 02:47:52,350 WILLINGNESS TO PROVIDER AND WE 3550 02:47:52,350 --> 02:47:56,087 KNOW PROVIDERS ARE TRUSTED 3551 02:47:56,087 --> 02:47:59,490 SOURCES WHEN MAKING HEALTH 3552 02:47:59,490 --> 02:48:02,159 DECISIONS AND PROVIDERS WERE OUR 3553 02:48:02,159 --> 02:48:05,897 BRIDGE TO PATIENT POPULATIONS. 3554 02:48:05,897 --> 02:48:07,231 PROVIDER BUY-IN IS GOING TO BE 3555 02:48:07,231 --> 02:48:07,665 IMPORTANT. 3556 02:48:07,665 --> 02:48:11,002 WE NEED TO UNDERSTAND WHAT MAKES 3557 02:48:11,002 --> 02:48:12,436 PROVIDERS HESITANT OR COMPETENT 3558 02:48:12,436 --> 02:48:13,337 ABOUT DISCUSSING STRATEGIES TO 3559 02:48:13,337 --> 02:48:16,841 HELP EQUIP THEM WITH THE RIGHT 3560 02:48:16,841 --> 02:48:20,645 TOOLS AND STRATEGY TO 3561 02:48:20,645 --> 02:48:22,179 COLLABORATE AND SO ULTIMATELY TO 3562 02:48:22,179 --> 02:48:24,916 ENSURE MORE PATIENTS HAVE ACCESS 3563 02:48:24,916 --> 02:48:28,352 TO THE RESEARCH OPPORTUNITIES. 3564 02:48:28,352 --> 02:48:30,888 IN TERMS OF AWARENESS OF HIV 3565 02:48:30,888 --> 02:48:33,124 CURE RESEARCH WE FOCUSSED ON THE 3566 02:48:33,124 --> 02:48:35,192 SCIENTIFIC APPROACHES AND WE 3567 02:48:35,192 --> 02:48:36,327 WERE DESIGNING THE SURVEY WE 3568 02:48:36,327 --> 02:48:41,499 LOOKED AT THE WEBSITE WHERE THEY 3569 02:48:41,499 --> 02:48:48,906 DESCRIBED THE THIRD ERA OF THIS 3570 02:48:48,906 --> 02:48:59,450 AND AND THE APPROACH WAS AROUND 3571 02:49:17,335 --> 02:49:17,468 85%. 3572 02:49:17,468 --> 02:49:19,870 WE DIDN'T FIND A WHOLE LOT OF 3573 02:49:19,870 --> 02:49:21,906 DIFFERENCES IN PROVIDER 3574 02:49:21,906 --> 02:49:22,273 CHARACTERISTICS. 3575 02:49:22,273 --> 02:49:25,142 WE DIDN'T DO ANY OF THE ANALYSIS 3576 02:49:25,142 --> 02:49:28,879 BY SPECIFIC APPROACH BUT AS A 3577 02:49:28,879 --> 02:49:30,348 WHOLE. 3578 02:49:30,348 --> 02:49:31,949 UNSURPRISINGLY PROVIDERS WHO HAD 3579 02:49:31,949 --> 02:49:36,087 SPECIALIZED TRAINING IN HIV 3580 02:49:36,087 --> 02:49:41,592 REPORTED MORE FAMILIARITY XAU 3581 02:49:41,592 --> 02:49:42,693 COMPARED TO THOSE WITHOUT 3582 02:49:42,693 --> 02:49:43,160 SPECIALIZED TRAINING. 3583 02:49:43,160 --> 02:49:45,763 OTHER HIGHLIGHTS THERE WAS 3584 02:49:45,763 --> 02:49:48,032 ENTHUSIASM FOR OUTREACH AND HIV 3585 02:49:48,032 --> 02:49:49,100 CURE RESEARCH. 3586 02:49:49,100 --> 02:49:53,337 THEY THEMSELVES WOULD BE OR 3587 02:49:53,337 --> 02:49:54,672 LIKELY TO RECOMMEND TO 3588 02:49:54,672 --> 02:49:55,873 PARTICIPATE IN HIV RESEARCH. 3589 02:49:55,873 --> 02:50:00,111 WHILE THAT'S GREAT NEWS WE FOUND 3590 02:50:00,111 --> 02:50:05,583 THIS ENTHUSIASM DROPPED IF HEIs 3591 02:50:05,583 --> 02:50:08,319 WERE REQUIRED. 3592 02:50:08,319 --> 02:50:17,995 HALF SAID THEY'D BE WILL TO 3593 02:50:17,995 --> 02:50:20,097 RECOMMEND AND THE EXPERIENCE WAS 3594 02:50:20,097 --> 02:50:21,065 ASSOCIATED WITH PATIENT 3595 02:50:21,065 --> 02:50:24,535 WILLINGNESS AND LOOKING AT 3596 02:50:24,535 --> 02:50:26,637 WILLINGNESS THE ONLY FACTOR 3597 02:50:26,637 --> 02:50:28,372 ASSOCIATED WITH HIV WAS HIGHER 3598 02:50:28,372 --> 02:50:29,807 LEVELS OF EXPERIENCE WITH 3599 02:50:29,807 --> 02:50:31,409 PATIENT OUTREACH EXPERIENCE. 3600 02:50:31,409 --> 02:50:34,045 AND THEN THE LAST WE ASKED 3601 02:50:34,045 --> 02:50:37,281 PROVIDERS WHICH RESOURCES TRADE 3602 02:50:37,281 --> 02:50:39,517 THEY'D PREFER TO HAVE ON STAYING 3603 02:50:39,517 --> 02:50:41,852 UP TO DATE ON PATIENT RESEARCH 3604 02:50:41,852 --> 02:50:42,186 OPPORTUNITIES. 3605 02:50:42,186 --> 02:50:44,388 WEBINARS AND PUBLICATIONS AND 3606 02:50:44,388 --> 02:50:45,556 CONFERENCES AND UPDATES ALL 3607 02:50:45,556 --> 02:50:46,924 RECEIVED ENDORSEMENT FROM AT 3608 02:50:46,924 --> 02:50:52,396 LEAST 60% OF PROVIDERS. 3609 02:50:52,396 --> 02:50:56,934 A 3610 02:50:56,934 --> 02:50:59,003 AND THERE'S POTENTIAL FOR 3611 02:50:59,003 --> 02:50:59,970 COLLABORATORS IN PHILADELPHIA. 3612 02:50:59,970 --> 02:51:02,440 MOST THE PROVIDERS WE SURVEYED 3613 02:51:02,440 --> 02:51:09,613 WERE FROM ACADEMIC CLINIC AND IN 3614 02:51:09,613 --> 02:51:10,981 BUILDING THE COLLABORATIONS IT 3615 02:51:10,981 --> 02:51:12,883 WOULD BE HELPFUL TO LEVERAGE THE 3616 02:51:12,883 --> 02:51:14,952 PREFERRED RESOURCES LIKE 3617 02:51:14,952 --> 02:51:16,153 WEBINARS, PUBLICATIONS AN EMAIL 3618 02:51:16,153 --> 02:51:16,420 SUMMARIES. 3619 02:51:16,420 --> 02:51:19,190 IN TERMS OF WHAT THIS RESOURCES 3620 02:51:19,190 --> 02:51:20,324 SHOULD ADDRESS WE THINK THAT IT 3621 02:51:20,324 --> 02:51:22,193 WILL BE REALLY IMPORTANT TO 3622 02:51:22,193 --> 02:51:24,428 ALERT PROVIDERS TO THE DIFFERENT 3623 02:51:24,428 --> 02:51:26,030 APPROACHES BEING INVESTIGATED 3624 02:51:26,030 --> 02:51:27,765 ESPECIALLY WITHIN JURISDICTIONS 3625 02:51:27,765 --> 02:51:30,835 THAT HAVE AN MDC PRESENT LIKE 3626 02:51:30,835 --> 02:51:31,168 PHILADELPHIA. 3627 02:51:31,168 --> 02:51:32,203 AND IN PROVING AND UNDERSTANDING 3628 02:51:32,203 --> 02:51:35,973 THE NECESSITY AND ETHICS AROUND 3629 02:51:35,973 --> 02:51:37,041 IMPLEMENTING HIV WITHIN CURES 3630 02:51:37,041 --> 02:51:39,710 STUDY AND BUILDING SKILLS AND 3631 02:51:39,710 --> 02:51:42,079 SELF EFFICACY FOR OUTREACH AND 3632 02:51:42,079 --> 02:51:47,151 PATIENT SUPPORT AS PATIENTS 3633 02:51:47,151 --> 02:51:48,586 PARTICIPATE IN STUDIES. 3634 02:51:48,586 --> 02:51:50,955 THAT WRAPS UP MY PART OF THE 3635 02:51:50,955 --> 02:51:51,155 PANEL. 3636 02:51:51,155 --> 02:51:51,455 . 3637 02:51:51,455 --> 02:51:52,623 ON BEHALF OF OUR TEAM, THANK YOU 3638 02:51:52,623 --> 02:51:54,792 TO OUR FUNDERS AND OUR 3639 02:51:54,792 --> 02:51:58,129 PARTICIPANTS AND THANK YOU FOR 3640 02:51:58,129 --> 02:51:58,596 YOUR ATTENTION TO THE 3641 02:51:58,596 --> 02:52:08,839 PRESENTATION. 3642 02:52:09,540 --> 02:52:16,280 >> WE'LL GO TO QUESTIONS IF YOU 3643 02:52:16,280 --> 02:52:18,849 CAN SPOT STEVEN AND BOB THEY'LL 3644 02:52:18,849 --> 02:52:20,151 UNMUTE AND IF YOU ADDRESS 3645 02:52:20,151 --> 02:52:21,986 QUESTIONS ONLINE DO SO IN THE 3646 02:52:21,986 --> 02:52:22,620 BEGINNING SO THEY CAN UNMUTE AND 3647 02:52:22,620 --> 02:52:28,025 ANSWER. 3648 02:52:28,025 --> 02:52:30,928 >> THIS IS A QUESTION FOR BOB. 3649 02:52:30,928 --> 02:52:33,330 PHENOMENAL STUDY AS ALWAYS. 3650 02:52:33,330 --> 02:52:35,299 FASCINATING DATA. 3651 02:52:35,299 --> 02:52:41,038 YOU HAD SHOWN IN THE CONTROLLER 3652 02:52:41,038 --> 02:52:43,841 THAT THE VIRAL ASSAY WAS FAIRLY 3653 02:52:43,841 --> 02:52:45,509 EASILY ABLE TO GROW OUT VIRUS. 3654 02:52:45,509 --> 02:52:49,313 TO CONFIRM THE RESPONSE IS TRULY 3655 02:52:49,313 --> 02:52:49,947 CONTRIBUTING TO THE CONTROL I 3656 02:52:49,947 --> 02:52:53,384 WOULD ASSUME YOU ADDED 3657 02:52:53,384 --> 02:52:58,756 AUTOLOGOUS IGG TO SUPPRESS ALL 3658 02:52:58,756 --> 02:52:59,056 OUT GROWTH. 3659 02:52:59,056 --> 02:53:00,825 IS THAT SOMETHING YOU FOUND? 3660 02:53:00,825 --> 02:53:05,162 >> THANKS FOR THE QUESTION. 3661 02:53:05,162 --> 02:53:08,199 SO TO DO THE VIRAL OUTGROWTH 3662 02:53:08,199 --> 02:53:11,569 ASSAYS THAT WE HAVE DONE IN THE 3663 02:53:11,569 --> 02:53:17,608 PAST WITH AUTOLOGOUS IGG WE NEED 3664 02:53:17,608 --> 02:53:19,543 LARGE NUMBER OF CELLS BECAUSE 3665 02:53:19,543 --> 02:53:22,179 NEED THREE OUTGROWTH ASSAYS 3666 02:53:22,179 --> 02:53:24,515 PARALLEL WITH NO CONTROL IGG OR 3667 02:53:24,515 --> 02:53:26,483 PATIENT IGG. 3668 02:53:26,483 --> 02:53:28,752 SO THAT'S A DIFFICULT THING TO 3669 02:53:28,752 --> 02:53:28,919 DO. 3670 02:53:28,919 --> 02:53:35,559 BUT WHAT WE CAN DO IS TAKE THE 3671 02:53:35,559 --> 02:53:37,194 ENVELOPES AND IN THIS INDIVIDUAL 3672 02:53:37,194 --> 02:53:40,030 IT WAS ACTUALLY LIMITED 3673 02:53:40,030 --> 02:53:41,298 DIVERSIFICATION OF THE ENVELOPE 3674 02:53:41,298 --> 02:53:42,233 BECAUSE OF THE TREATMENT. 3675 02:53:42,233 --> 02:53:45,636 SO WE CAN TAKE THOSE AND DO 3676 02:53:45,636 --> 02:53:46,904 PSEUDO VIRUS NEUTRALIZATION 3677 02:53:46,904 --> 02:53:47,972 ASSAYS AND ESSENTIALLY LOOKED AT 3678 02:53:47,972 --> 02:53:50,708 THREE ENVELOPES THAT DIFFER 3679 02:53:50,708 --> 02:53:53,611 SLIGHTLY AND ALL OF THEM ARE 3680 02:53:53,611 --> 02:53:56,580 VERY EFFECTIVELY NEUTRALIZED BY 3681 02:53:56,580 --> 02:53:57,448 THE PARTICIPANTS IGG. 3682 02:53:57,448 --> 02:54:02,186 >> THANKS. 3683 02:54:02,186 --> 02:54:05,222 >> I HAVE A COMMENT AND QUESTION 3684 02:54:05,222 --> 02:54:07,024 AND RESPONSE TO BOB'S BEAUTIFUL 3685 02:54:07,024 --> 02:54:07,791 PRESENTATION. 3686 02:54:07,791 --> 02:54:10,928 JUST TO MAKE THE CONNECTION, THE 3687 02:54:10,928 --> 02:54:13,597 DATA THAT MARINA SHOWED IN THE 3688 02:54:13,597 --> 02:54:16,033 MICE WITH THE REMARKABLE CD 8 3689 02:54:16,033 --> 02:54:20,938 CONTROL WAS THE SAME DONOR WITH 3690 02:54:20,938 --> 02:54:24,942 REMARKABLE AUTOLOGOUS 3691 02:54:24,942 --> 02:54:27,444 NEUTRALIZING ANTIBODIES. 3692 02:54:27,444 --> 02:54:37,454 COMMENT IS PERHAPS THEY'RE 3693 02:54:37,454 --> 02:54:38,656 SUPPRESSED PUT MIGHT IT FOSTER 3694 02:54:38,656 --> 02:54:42,159 AN ENVIRONMENT FOR DEVELOPMENT 3695 02:54:42,159 --> 02:54:48,165 OF EFFECTIVE CD 8 AND THE EFFECT 3696 02:54:48,165 --> 02:54:54,138 IS IMPACTED IN ANTIBODIES DOING 3697 02:54:54,138 --> 02:54:55,673 THIS IN THIS DONOR? 3698 02:54:55,673 --> 02:55:02,212 >> YEAH, THANKS. 3699 02:55:02,212 --> 02:55:04,782 THIS IS THE SAME PARTICIPANT AND 3700 02:55:04,782 --> 02:55:06,750 MARINA MENTION THE SAME CD 8 3701 02:55:06,750 --> 02:55:08,852 RESPONSE IN THIS PARTICIPANT. 3702 02:55:08,852 --> 02:55:09,720 IT'S INTERESTING TO CONSIDER 3703 02:55:09,720 --> 02:55:10,821 ABOUT WHAT IS CRITICAL FOR 3704 02:55:10,821 --> 02:55:11,121 CONTROL. 3705 02:55:11,121 --> 02:55:15,592 ALL WE CAN SAY IS THAT THE LEVEL 3706 02:55:15,592 --> 02:55:17,494 OF NEUTRALIZING ACTIVITY IN THE 3707 02:55:17,494 --> 02:55:20,331 PATIENT'S PLASMA IS COMPARABLE 3708 02:55:20,331 --> 02:55:22,333 TO ART REGIMENT. 3709 02:55:22,333 --> 02:55:24,468 BY ITSELF IS SUFFICIENT TO 3710 02:55:24,468 --> 02:55:26,303 MEDIATE CONTROL. 3711 02:55:26,303 --> 02:55:29,573 IT'S LIKELY THE CD 8 RESPONSE IS 3712 02:55:29,573 --> 02:55:33,510 ALSO INVOLVED AND HOW THEY'RE 3713 02:55:33,510 --> 02:55:35,746 RELATED AND WHETHER THE STRONG 3714 02:55:35,746 --> 02:55:36,413 NEUTRALIZING ANTIBODY RESPONSE 3715 02:55:36,413 --> 02:55:38,849 HAS ANYTHING TO DO ONE THE 3716 02:55:38,849 --> 02:55:42,152 STRENGTH OF THE CD RESPONSE IS 3717 02:55:42,152 --> 02:55:44,355 A 3718 02:55:44,355 --> 02:55:47,057 GOOD QUESTION AND I DON'T HAVE 3719 02:55:47,057 --> 02:55:50,928 AN ANSWER FOR THAT BUT TO LOUIS' 3720 02:55:50,928 --> 02:55:52,863 EARLIER PRESENTATION SUBJECTING 3721 02:55:52,863 --> 02:55:56,500 A STRONG CTL RESPONSE CAN DELAY, 3722 02:55:56,500 --> 02:55:58,002 SLIGHTLY REBOUND AND LOWER SET 3723 02:55:58,002 --> 02:55:58,268 POINT. 3724 02:55:58,268 --> 02:55:59,670 THIS IS A DIFFERENT SITUATION. 3725 02:55:59,670 --> 02:56:01,071 THIS IS NO REBOUND. 3726 02:56:01,071 --> 02:56:03,474 AND SO THIS IS I THINK THE 3727 02:56:03,474 --> 02:56:06,910 REASON WE THINK THE ANTIBODY 3728 02:56:06,910 --> 02:56:07,511 RESPONSE IS PROBABLY A MAJOR 3729 02:56:07,511 --> 02:56:16,520 FACTOR. 3730 02:56:16,520 --> 02:56:18,522 >> IT WOULD BE A GREAT 3731 02:56:18,522 --> 02:56:19,690 OPPORTUNITY FOR STUDY ON THE 3732 02:56:19,690 --> 02:56:23,427 SAME SAID OF CONTROLLERS MAYBE 3733 02:56:23,427 --> 02:56:25,529 WE MAYBE START TO DISENTANGLE 3734 02:56:25,529 --> 02:56:26,063 SOME OF THIS. 3735 02:56:26,063 --> 02:56:28,165 >> ABSOLUTELY. 3736 02:56:28,165 --> 02:56:28,766 >> FREDERICK NATIONAL LAB FOR 3737 02:56:28,766 --> 02:56:32,936 MIKE. 3738 02:56:32,936 --> 02:56:38,075 REGARDING THE SHIFT IN FREQUENCY 3739 02:56:38,075 --> 02:56:42,079 OF HEL PER CELLS BETWEEN THE 3740 02:56:42,079 --> 02:56:44,815 VEREMIC AND TREATED INDIVIDUAL 3741 02:56:44,815 --> 02:56:46,950 THERE'S TATE IN THE LITERATURE 3742 02:56:46,950 --> 02:56:48,018 SUGGESTING IT CAN FUNCTION OVER 3743 02:56:48,018 --> 02:56:51,555 TIME AS A DURATION ON ART AND 3744 02:56:51,555 --> 02:56:53,290 TRYING TO REBOUND IT SEEMED LIKE 3745 02:56:53,290 --> 02:56:57,394 IF I'M REBOUNDING CORRECTLY YOUR 3746 02:56:57,394 --> 02:56:59,029 COHORT MAY HAVE BEEN SKEWED 3747 02:56:59,029 --> 02:57:06,437 TOWARD A LONGER DURATION AND 3748 02:57:06,437 --> 02:57:07,504 SHIFT IN THE FREQUENCY. 3749 02:57:07,504 --> 02:57:10,074 >> THE LITERATURE THERE'S QUITE 3750 02:57:10,074 --> 02:57:12,776 SMALL AMOUNTS OF DATA IN THE 3751 02:57:12,776 --> 02:57:15,379 LITERATURE THAT SAY AN ART THAT 3752 02:57:15,379 --> 02:57:18,949 TFH CELLS ARE THE PREDOMINANT 3753 02:57:18,949 --> 02:57:19,783 RESERVOIR. 3754 02:57:19,783 --> 02:57:21,852 MATIAS HAS A NICE FIGURE IN HIS 3755 02:57:21,852 --> 02:57:23,787 PAPERS THAT SHOW THAT OTHERWISE 3756 02:57:23,787 --> 02:57:30,961 ALL THE DATA ARE FROM VIREMIC 3757 02:57:30,961 --> 02:57:34,031 LYMPH NODES AND THE DONOR ON 20 3758 02:57:34,031 --> 02:57:35,332 YEARS OF ART WE BARELY FOUND AN 3759 02:57:35,332 --> 02:57:37,935 CELLS WITH THE VIRUS SO WE CAN'T 3760 02:57:37,935 --> 02:57:40,337 MAKE MUCH OF A CONCLUSION THERE. 3761 02:57:40,337 --> 02:57:46,143 WHAT WE THINK HAPPENS FROM THE 3762 02:57:46,143 --> 02:57:54,952 DATA IN VIREMIC CELL THEY'RE 3763 02:57:54,952 --> 02:57:58,021 HIGHLY DEPLETED TO THE SAME 3764 02:57:58,021 --> 02:58:06,697 POPULATION UNDER ART ALBEIT IN 3765 02:58:06,697 --> 02:58:08,699 DIFFERENT INDIVIDUALS BUT HAS A 3766 02:58:08,699 --> 02:58:11,268 HIGH BURDEN OF VIRAL RNA. 3767 02:58:11,268 --> 02:58:13,570 WE THINK THAT POPULATION IS JUST 3768 02:58:13,570 --> 02:58:15,772 BEING KILLED BY THE VIRUS AND 3769 02:58:15,772 --> 02:58:18,642 CAN NEVER ESTABLISH A RESERVOIR 3770 02:58:18,642 --> 02:58:21,512 ONCE THE PERSON WOULD GO ON ART. 3771 02:58:21,512 --> 02:58:23,347 AND SO I THINK WHAT WE'RE SEEING 3772 02:58:23,347 --> 02:58:27,151 HERE IS ESSENTIALLY AN EFFECT 3773 02:58:27,151 --> 02:58:30,154 THAT THOSE CELLS ALL TFA ARE 3774 02:58:30,154 --> 02:58:32,589 HIGHLY SUSCEPTIBLE. 3775 02:58:32,589 --> 02:58:34,224 WE KNOW THAT FROM MANY STUDIES. 3776 02:58:34,224 --> 02:58:35,692 THEY DON'T FORM A RESERVOIR 3777 02:58:35,692 --> 02:58:36,994 BECAUSE THE CELLS DON'T SURVIVE 3778 02:58:36,994 --> 02:58:42,166 INFECTION. 3779 02:58:42,166 --> 02:58:44,801 >> THANKS. 3780 02:58:44,801 --> 02:58:47,738 >> SANDY AND BRAD JUST ASKED THE 3781 02:58:47,738 --> 02:58:48,972 SAME QUESTION I WAS GOING TO 3782 02:58:48,972 --> 02:58:55,712 ASK. 3783 02:58:55,712 --> 02:59:00,117 THE TWO MECHANISMS IF YOU HAVE 3784 02:59:00,117 --> 02:59:02,853 POTENT ANABS ON BOARD IT TAKES 3785 02:59:02,853 --> 02:59:08,325 MORE TIME FOR T CELLS TO TALK 3786 02:59:08,325 --> 02:59:11,728 EFFECT IN THE STEVE DEEKS 3787 02:59:11,728 --> 02:59:12,930 INTERCEPT HE SAW IN HIS TRIAL. 3788 02:59:12,930 --> 02:59:15,199 AND I WAS STRUCK BY THE FINDING 3789 02:59:15,199 --> 02:59:16,700 ABOUT PROVIDERS NOT BEING 3790 02:59:16,700 --> 02:59:27,244 WILLING TO REFER TO ATI TRIALS. 3791 02:59:28,812 --> 02:59:39,289 AND USE CLINICAL CARE PROVIDERS. 3792 02:59:39,990 --> 02:59:44,127 >> BOB, BEAUTIFUL DATA. 3793 02:59:44,127 --> 02:59:46,129 YOU SAID RNA LEVELS WERE 3794 02:59:46,129 --> 02:59:46,496 SUPPRESSED. 3795 02:59:46,496 --> 02:59:53,070 CAN YOU DETECT ANY VIREMIA AT 3796 02:59:53,070 --> 02:59:53,937 ALL? 3797 02:59:53,937 --> 02:59:54,738 >> THANKS. 3798 02:59:54,738 --> 02:59:57,874 NO, WE HAVEN'T DONE SINGLE COPY 3799 02:59:57,874 --> 02:59:58,075 ASSAY. 3800 02:59:58,075 --> 03:00:00,544 THERE WAS A BLIP OF 29 ASSAYS 3801 03:00:00,544 --> 03:00:05,949 YEAR TWO OR SOMETHING BUT IT'S 3802 03:00:05,949 --> 03:00:16,493 NOW AND ARE THESE ALL RESEARCH 3803 03:00:30,707 --> 03:00:33,110 AND IS THERE INTERPATIENT 3804 03:00:33,110 --> 03:00:34,111 VARIATION? 3805 03:00:34,111 --> 03:00:36,213 IS IT GREATER FOR CERVICAL LYMPH 3806 03:00:36,213 --> 03:00:39,950 NODES BECAUSE WE'VE HAD THAT 3807 03:00:39,950 --> 03:00:41,718 EXPERIENCE AND SOMETHING LIKE 3808 03:00:41,718 --> 03:00:43,353 XLA IS MORE UNIFORM BUT MAYBE 3809 03:00:43,353 --> 03:00:45,622 IT'S NOT THE CASE. 3810 03:00:45,622 --> 03:00:47,624 >> THE LYMPH NODES ARE PRIMARILY 3811 03:00:47,624 --> 03:00:50,494 TAKEN FOR DIAGNOSTIC PURPOSES. 3812 03:00:50,494 --> 03:00:53,430 SO THE REMAINING SAMPLE THAT'S 3813 03:00:53,430 --> 03:00:55,132 OBTAINED IS THEN CRYO OBSERVED 3814 03:00:55,132 --> 03:00:57,401 FOR RESEARCH PURPOSES. 3815 03:00:57,401 --> 03:00:58,669 THE CERVICAL LYMPH NODES TURN 3816 03:00:58,669 --> 03:01:00,137 OUT TO BE ME MOST ACCESSIBLE 3817 03:01:00,137 --> 03:01:03,774 ONES FOR THE CLINIC WHICH IS 3818 03:01:03,774 --> 03:01:05,142 PREDOMINANTLY A RESPIRATORY 3819 03:01:05,142 --> 03:01:07,778 DISEASES CLINIC AND LOOKING TO 3820 03:01:07,778 --> 03:01:10,147 MAKE SURE THERE'S NOT TB OR 3821 03:01:10,147 --> 03:01:14,951 THINGS LIKE THIS. 3822 03:01:14,951 --> 03:01:18,655 WE DO HAVE ONE LYMPH NODE SAMPLE 3823 03:01:18,655 --> 03:01:22,059 AND ADDED FOUR MORE LYMPH NODES 3824 03:01:22,059 --> 03:01:23,694 FROM THE SAME DEMOGRAPHIC COHORT 3825 03:01:23,694 --> 03:01:26,129 JUST TO TRY TO DEAL WITH THIS 3826 03:01:26,129 --> 03:01:29,466 ISSUE THAT MAYBE A MUCOSAL 3827 03:01:29,466 --> 03:01:30,267 DRAINING SITE WILL HAVE 3828 03:01:30,267 --> 03:01:31,968 DIFFERENT SUBSETS OF CELLS WHICH 3829 03:01:31,968 --> 03:01:34,538 IS VERY REASONABLE TO ASSUME 3830 03:01:34,538 --> 03:01:38,141 HIGHER LEVELS OF ACTIVATION AND 3831 03:01:38,141 --> 03:01:45,449 MORE MUCOSAL DRAINING SITE. 3832 03:01:45,449 --> 03:01:49,353 AND WE HAVE NOT OVERTLY CHANGED 3833 03:01:49,353 --> 03:01:51,455 THE CONTRIBUTION OF CD4 HELPER 3834 03:01:51,455 --> 03:01:55,058 CELLS TO THE RESERVOIR BY ADDING 3835 03:01:55,058 --> 03:01:56,560 THOSE LYMPH NODES. 3836 03:01:56,560 --> 03:01:58,328 >> YOU FIND A WAY OF NORMALIZING 3837 03:01:58,328 --> 03:02:00,697 FOR THE ACTIVATION THAT MAY BE 3838 03:02:00,697 --> 03:02:02,699 PRESENT BY TOTAL NUMBER OF CELLS 3839 03:02:02,699 --> 03:02:04,267 OR SOMETHING LIKE THAT? 3840 03:02:04,267 --> 03:02:06,169 THAT WOULD BE USEFUL FOR 3841 03:02:06,169 --> 03:02:09,239 EVERYBODY TO KNOW WHAT DIVIDE 3842 03:02:09,239 --> 03:02:09,606 BY. 3843 03:02:09,606 --> 03:02:11,007 >> YEAH. 3844 03:02:11,007 --> 03:02:15,312 I WOULD LOVE TO TALK TO YOU 3845 03:02:15,312 --> 03:02:18,048 ABOUT THIS AFTERWARD AND ONE OF 3846 03:02:18,048 --> 03:02:20,283 THE PROBLEMS OF THE PROCEDURES 3847 03:02:20,283 --> 03:02:25,489 WHICH IS 50% EFFICIENT ANYWAY. 3848 03:02:25,489 --> 03:02:28,725 WE KNOW WE'RE MISSING CELLS WITH 3849 03:02:28,725 --> 03:02:29,226 PROVIRAL READ. 3850 03:02:29,226 --> 03:02:32,496 THE OTHER IS SENSITIVE. 3851 03:02:32,496 --> 03:02:34,097 >> AND I KNOW THEY'RE SUPPORTING 3852 03:02:34,097 --> 03:02:37,033 THE TISSUE REPOSITORY OF THAT 3853 03:02:37,033 --> 03:02:41,905 MIKE USED SO IF ANYONE ELSE HAS 3854 03:02:41,905 --> 03:02:51,314 AN INTEREST IN LYMPH NODE 3855 03:02:51,314 --> 03:02:51,548 BIOPSY. 3856 03:02:51,548 --> 03:02:52,682 >> MY QUESTION FOR DANIEL. 3857 03:02:52,682 --> 03:02:53,817 THANK YOU FOR THE GREAT TALK. 3858 03:02:53,817 --> 03:02:58,755 A TON OF WORK. 3859 03:02:58,755 --> 03:03:01,024 BIG CHALLENGE FOR CAR T CELL IS 3860 03:03:01,024 --> 03:03:06,229 ANTIGEN BURDEN AND PEOPLE ON 3861 03:03:06,229 --> 03:03:09,232 ART. 3862 03:03:09,232 --> 03:03:10,934 HAVE YOU DONE WORK LOOKING AT 3863 03:03:10,934 --> 03:03:13,069 THE PROXIMAL MIXTURES IN THE 3864 03:03:13,069 --> 03:03:17,240 SETTING OF MICE ON ART AND LOW 3865 03:03:17,240 --> 03:03:18,341 RAN TI GEN SETTING? 3866 03:03:18,341 --> 03:03:20,677 >> NO, WE HAVEN'T BUT 3867 03:03:20,677 --> 03:03:21,778 SENSITIVITY IS OUR MAIN 3868 03:03:21,778 --> 03:03:23,146 TECHNICAL QUESTIONS WE WANT TO 3869 03:03:23,146 --> 03:03:24,247 ANSWER HOW MUCH ENVELOPE DO YOU 3870 03:03:24,247 --> 03:03:25,649 HAVE TO HAVE ON THE SURFACE. 3871 03:03:25,649 --> 03:03:27,350 IT'S GETTING TO YOUR QUESTION 3872 03:03:27,350 --> 03:03:28,485 WHICH IS CRITICAL FOR THE FIELD 3873 03:03:28,485 --> 03:03:30,153 AND HOW THIS WOULD WORK IN THE 3874 03:03:30,153 --> 03:03:31,555 CLINIC. 3875 03:03:31,555 --> 03:03:33,924 ART MODEL SYSTEMS ARE BASED ON 3876 03:03:33,924 --> 03:03:36,726 IF WE HAVE A VIREMIC MOUSE CAN 3877 03:03:36,726 --> 03:03:39,229 WE FULLY SUPPRESS VIREMIA 3878 03:03:39,229 --> 03:03:40,464 WITHOUT ANYTHING ELSE ON BOARD 3879 03:03:40,464 --> 03:03:41,598 IS VERY STRINGENT, RIGHT. 3880 03:03:41,598 --> 03:03:43,033 BUT IN THE CASE WE'RE TALKING 3881 03:03:43,033 --> 03:03:44,701 ABOUT IS WHY WE THINK CERTAIN 3882 03:03:44,701 --> 03:03:47,471 CARS ARE MORE POTENT TO SEE LOW 3883 03:03:47,471 --> 03:03:50,440 LEVELS OF ANTIGEN AND THOSE MAY 3884 03:03:50,440 --> 03:03:52,309 BE MOST SUITED FOR A CLINICAL 3885 03:03:52,309 --> 03:03:54,144 SCENARIO TO HAVE ART ON BOARD 3886 03:03:54,144 --> 03:03:57,147 WITH MAYBE AN LRA AND GET LOW 3887 03:03:57,147 --> 03:04:00,317 LEVELS OF ENVELOPE ON THE 3888 03:04:00,317 --> 03:04:00,550 SURFACE. 3889 03:04:00,550 --> 03:04:05,622 WE'RE DOING MICRO SCSCOPY TO SE 3890 03:04:05,622 --> 03:04:07,224 HOW MUCH IS ON INFECTED CELLS 3891 03:04:07,224 --> 03:04:09,426 AND HAVEN'T DONE ANYTHING FOR 3892 03:04:09,426 --> 03:04:16,266 INFECTED CELLS. 3893 03:04:16,266 --> 03:04:20,337 >> MY QUESTION IS -- 3894 03:04:20,337 --> 03:04:23,095 >> THANK YOU. 3895 03:04:23,095 --> 03:04:27,967 HELLO, MY NAME IS TANIA LOMBO 3896 03:04:27,967 --> 03:04:29,335 FOR THE PEDIATRIC RESEARCH 3897 03:04:29,335 --> 03:04:30,703 BRANCH AT THE DIVISION OF AIDS 3898 03:04:30,703 --> 03:04:34,873 AND HAVE THE PLEASURE TO 3899 03:04:34,873 --> 03:04:37,676 INTRODUCE THE MDC TEAM TODAY. 3900 03:04:37,676 --> 03:04:41,146 IT STANDS FOR THE PEDIATRIC 3901 03:04:41,146 --> 03:04:43,649 ADOLESCENT VIRUS ELIMINATION AND 3902 03:04:43,649 --> 03:04:46,719 THE COLLABORATORY IS THE ONLY 3903 03:04:46,719 --> 03:04:49,455 ONE FOR THE PEDIATRIC 3904 03:04:49,455 --> 03:04:50,389 POPULATIONS LIVING WITH HIV. 3905 03:04:50,389 --> 03:04:54,360 IT HAS THE UNIQUENESS OF POOR 3906 03:04:54,360 --> 03:04:59,465 RESEARCH FOCUS THE OTHERS DON'T 3907 03:04:59,465 --> 03:04:59,865 HAVE. 3908 03:04:59,865 --> 03:05:02,134 THAT'S WHY WE'LL SPAEND A LITTLE 3909 03:05:02,134 --> 03:05:11,143 BIT MORE TIME SPEND A LITTLE BIT 3910 03:05:11,143 --> 03:05:14,880 MORE TIME AND LED BY THIS TEAM 3911 03:05:14,880 --> 03:05:16,081 AND THE ANN WELL LEAD THE 3912 03:05:16,081 --> 03:05:17,750 OVERVIEW AND INTRODUCTIONS TO 3913 03:05:17,750 --> 03:05:21,720 THE TEAM. 3914 03:05:21,720 --> 03:05:22,221 THANK YOU. 3915 03:05:22,221 --> 03:05:24,323 >> THANK YOU, TANIA. 3916 03:05:24,323 --> 03:05:26,325 HOPEFULLY EVERYONE IS AWAKE 3917 03:05:26,325 --> 03:05:28,394 AFTER AN EXCITING POSTER 3918 03:05:28,394 --> 03:05:28,627 SESSION. 3919 03:05:28,627 --> 03:05:31,297 DEBBIE AND I DECIDED IN THE 3920 03:05:31,297 --> 03:05:35,034 OVERVIEW TO FOCUS ON SOME OF THE 3921 03:05:35,034 --> 03:05:37,703 NEW THINGS THAT HAPPENED IN LAST 3922 03:05:37,703 --> 03:05:39,038 YEAR IN PAVE AS WELL AS TO 3923 03:05:39,038 --> 03:05:40,506 EXPRESS OUR GRATITUDE TO ALL THE 3924 03:05:40,506 --> 03:05:41,140 PEOPLE THAT CONTRIBUTE TO THE 3925 03:05:41,140 --> 03:05:51,383 WORK OF PAVE. 3926 03:05:53,519 --> 03:05:55,454 SO, JUST TO KIND OF GIVE AN 3927 03:05:55,454 --> 03:05:57,656 OVERVIEW FOR THE NEXT I GUESS A 3928 03:05:57,656 --> 03:06:01,660 LITTLE BIT OVER AN HOUR. 3929 03:06:01,660 --> 03:06:04,396 WE HAVE PRESENTERS SEATED HERE 3930 03:06:04,396 --> 03:06:05,230 AS WELL AS A COUPLE VIRTUAL 3931 03:06:05,230 --> 03:06:08,033 PRESENTERS AND JESSICA WILL 3932 03:06:08,033 --> 03:06:10,135 START US AND WE HAVE KATHERINE 3933 03:06:10,135 --> 03:06:12,538 AND PHILLIP VIRTUALLY AND 3934 03:06:12,538 --> 03:06:15,307 FOLLOWED BY LESLEY AND MAURICIO 3935 03:06:15,307 --> 03:06:17,042 HERE IN THE ROOM. 3936 03:06:17,042 --> 03:06:19,845 THE PAVE MISSION TO REMIND 3937 03:06:19,845 --> 03:06:25,684 EVERYBODY IS TO USE CUTTING EDGE 3938 03:06:25,684 --> 03:06:28,721 SCIENCE TO DEVELOP AND LOOKING 3939 03:06:28,721 --> 03:06:39,231 AT RESERVOIRS TO PAVE THE WAY 3940 03:06:39,998 --> 03:06:41,734 FOR FUTURE INTERVENTIONAL 3941 03:06:41,734 --> 03:06:43,669 STUDIES THROUGH A LIFE TIME OF 3942 03:06:43,669 --> 03:06:43,969 REMISSION. 3943 03:06:43,969 --> 03:06:46,472 AND WE'RE HOPING TO ADVANCE SOME 3944 03:06:46,472 --> 03:06:49,675 OF THE WORK WE'VE BEEN DOING IN 3945 03:06:49,675 --> 03:06:52,344 THE INTERVENTIONAL STUDIES IN 3946 03:06:52,344 --> 03:06:53,345 THE NOT TOO DISTANT FUTURE. 3947 03:06:53,345 --> 03:06:55,581 THESE ARE FOLKS LISTED HERE. 3948 03:06:55,581 --> 03:06:58,650 IT'S A BIG GROUP AS TANNIA 3949 03:06:58,650 --> 03:07:00,085 MENTIONED WE'RE THE ONLY HIV 3950 03:07:00,085 --> 03:07:03,555 PEDIATRIC COLLABORATORY AND TRY 3951 03:07:03,555 --> 03:07:03,922 TO BE INCLUSIVE. 3952 03:07:03,922 --> 03:07:09,695 WE HAVE NEW MEMBERS LISTED THERE 3953 03:07:09,695 --> 03:07:12,698 FROM THE PAST YEAR. 3954 03:07:12,698 --> 03:07:14,633 WE'RE GRATEFUL TO THE SUPPORT 3955 03:07:14,633 --> 03:07:15,834 AND HELP OF OUR ADVISORY BOARD. 3956 03:07:15,834 --> 03:07:23,342 SEE THE FOLKS LISTED AND SHOWN. 3957 03:07:23,342 --> 03:07:25,978 LUIS JOINED AS AN AD HOC MEMBER 3958 03:07:25,978 --> 03:07:27,780 THIS YEAR AND IS A GREAT 3959 03:07:27,780 --> 03:07:28,113 ADDITION. 3960 03:07:28,113 --> 03:07:30,883 WE WANT TO GIVE A SHOUT OUT TO 3961 03:07:30,883 --> 03:07:32,518 OUR PAVE NIH OFFICERS AND 3962 03:07:32,518 --> 03:07:33,952 PARTNERS WHO ATTEND ALL OUR 3963 03:07:33,952 --> 03:07:35,454 CALLS AND HAVE BEEN FANTASTIC 3964 03:07:35,454 --> 03:07:40,159 CHAMPIONS OF THE WORK WE DO. 3965 03:07:40,159 --> 03:07:41,093 WE HAVE SEVERAL INDUSTRY 3966 03:07:41,093 --> 03:07:43,362 PARTNERS LISTED HERE AND JUST AS 3967 03:07:43,362 --> 03:07:47,332 AN UPDATE FROM THE PAST YEAR WE 3968 03:07:47,332 --> 03:07:51,069 ADDED A NEW INDUSTRY PARTNER FOR 3969 03:07:51,069 --> 03:07:53,138 THE IG WORK WITH ALL THE 3970 03:07:53,138 --> 03:07:56,675 OPTIMIZATION THEY'VE BEEN DOING. 3971 03:07:56,675 --> 03:07:57,643 ANOTHER SORT OF THING WE'RE 3972 03:07:57,643 --> 03:07:59,545 PROUD OF AND EXCITED TO SUPPORT 3973 03:07:59,545 --> 03:08:01,180 IN PAVE ARE A NUMBER OF 3974 03:08:01,180 --> 03:08:04,082 DIFFERENT CLINICAL COHORTS AND 3975 03:08:04,082 --> 03:08:07,352 BIO BANKS ACROSS THE WORLD 3976 03:08:07,352 --> 03:08:07,686 BASICALLY. 3977 03:08:07,686 --> 03:08:09,822 WE HAVE SOME THROUGH THE IMPACT 3978 03:08:09,822 --> 03:08:10,189 NETWORK. 3979 03:08:10,189 --> 03:08:12,858 WE HAVE SOME PREVIOUSLY 3980 03:08:12,858 --> 03:08:17,129 SUPPORTED AND NOW THROUGH A 3981 03:08:17,129 --> 03:08:18,797 SUPPLEMENT IN THE BEGINNING OF 3982 03:08:18,797 --> 03:08:22,568 YEAR FOUR TO SUPPORT CLINICAL 3983 03:08:22,568 --> 03:08:25,671 COHORTS IN SOUTH AFRICA, 3984 03:08:25,671 --> 03:08:31,009 MOZAMBIQUE AND CONTINUED 3985 03:08:31,009 --> 03:08:37,683 COLLABORATION WITH THE EPI-CAL 3986 03:08:37,683 --> 03:08:41,186 AND PHACS ENHANCING OUR ABILITY 3987 03:08:41,186 --> 03:08:43,188 TO STUDY HIV RESERVOIRS ACROSS 3988 03:08:43,188 --> 03:08:44,823 THE AGE SPECTRUM. 3989 03:08:44,823 --> 03:08:47,493 AS ONE EXAMPLE OF THE PEDIATRIC 3990 03:08:47,493 --> 03:08:48,894 OF THE COHORT AND SOME 3991 03:08:48,894 --> 03:08:51,096 ADDITIONAL WORK THAT PAVE HAS 3992 03:08:51,096 --> 03:08:53,098 BEEN ABLE TO DO THAT'S BUILDING 3993 03:08:53,098 --> 03:08:55,701 OFF OF WORK IN THE IMPACT 3994 03:08:55,701 --> 03:08:58,303 NETWORK, DEBBIE PRESENTED SOME 3995 03:08:58,303 --> 03:08:59,605 EXCITING WORK AT THE CURRENT 3996 03:08:59,605 --> 03:09:01,540 CONFERENCE LAST YEAR ON FOUR 3997 03:09:01,540 --> 03:09:07,546 CASES OF REMISSION IN VERY EARLY 3998 03:09:07,546 --> 03:09:10,382 TREATED CHILDREN AND SAW THIS 3999 03:09:10,382 --> 03:09:12,417 BEAUTIFUL ARTWORK THAT WAS 4000 03:09:12,417 --> 03:09:13,819 DEMONSTRATING I GUESS DETECTING 4001 03:09:13,819 --> 03:09:24,129 THE PARTICIPANTS. 4002 03:09:27,533 --> 03:09:34,773 AND JING WEN WITH ANN HAS A 4003 03:09:34,773 --> 03:09:39,044 SUPPLEMENT TO STUDY CNS DELIVERY 4004 03:09:39,044 --> 03:09:41,146 AND LOOKING AT THIS IN NON HUMAN 4005 03:09:41,146 --> 03:09:45,684 PRY MIGHTS AND TO FURTHER IMAGE 4006 03:09:45,684 --> 03:09:48,854 THAT USING IMMUNOPET. 4007 03:09:48,854 --> 03:09:51,390 AND WE'VE BEEN PRODUCTIVE IN THE 4008 03:09:51,390 --> 03:09:52,925 LAST YEAR AND HAVE A LOT OF 4009 03:09:52,925 --> 03:09:53,258 PUBLICATIONS. 4010 03:09:53,258 --> 03:09:55,360 FOUR ARE HIGHLIGHTED HERE. 4011 03:09:55,360 --> 03:09:57,629 THESE ARE ALL FROM VARIOUS 4012 03:09:57,629 --> 03:09:59,498 CLINICAL COHORT AND YOU'LL HEAR 4013 03:09:59,498 --> 03:10:00,432 A LITTLE BIT MORE ABOUT THOSE 4014 03:10:00,432 --> 03:10:06,004 AND FROM SOME OF THE TALKS 4015 03:10:06,004 --> 03:10:06,972 TODAY. 4016 03:10:06,972 --> 03:10:10,342 WE'RE LOOKING FORWARD TO NPH 4017 03:10:10,342 --> 03:10:15,314 MOVING TO PUBLICATION IN THE 4018 03:10:15,314 --> 03:10:15,547 FUTURE. 4019 03:10:15,547 --> 03:10:19,918 THE RESEARCH HIGHLIGHTS THE 4020 03:10:19,918 --> 03:10:23,622 BULLETS MARK WITH THE THREE 4021 03:10:23,622 --> 03:10:28,226 ASTERISKS AND BREAK IT UP BY 4022 03:10:28,226 --> 03:10:31,663 NONHUMAN PRIMATE AND HUME 4023 03:10:31,663 --> 03:10:35,367 ANRELATED COHORT AND WE'VE BEEN 4024 03:10:35,367 --> 03:10:36,435 INVESTIGATING ADOLESCENTS AND 4025 03:10:36,435 --> 03:10:43,308 YOUNG ADULTS AND WHO ACQUIRED IT 4026 03:10:43,308 --> 03:10:50,282 PERI-NATNATALLY AND THERE'S BEE 4027 03:10:50,282 --> 03:10:53,652 COHORT WITH ACQUISITION AND 4028 03:10:53,652 --> 03:10:56,221 RESERVOIR SIZE AND WE'VE NOTED 4029 03:10:56,221 --> 03:10:58,824 OVER THE PAST FEW YEARS OF PAVE 4030 03:10:58,824 --> 03:11:03,261 IN INFANTS EXPOSED AND ACQUIRED 4031 03:11:03,261 --> 03:11:06,598 THERE'S NK CELLS SEEN IN 4032 03:11:06,598 --> 03:11:08,934 MULTIPLE COHORTS WE'RE 4033 03:11:08,934 --> 03:11:09,835 SYNERGIZING AND PUTTING THAT 4034 03:11:09,835 --> 03:11:10,702 DATA TOGETHER. 4035 03:11:10,702 --> 03:11:18,844 A COUPLE OF OTHER THINGS JUST TO 4036 03:11:18,844 --> 03:11:25,050 AND AN ABUNDANCE OF INTACT 4037 03:11:25,050 --> 03:11:26,551 VIRUSES AND IDENTIFYING FACTORS 4038 03:11:26,551 --> 03:11:27,953 CONTRIBUTING TO VIRAL CONTROL. 4039 03:11:27,953 --> 03:11:30,489 A NUMBER OF COMPLEMENTARY 4040 03:11:30,489 --> 03:11:33,692 APPROACHES TO SCREEN NOVEL 4041 03:11:33,692 --> 03:11:36,895 LATENCY REVERSING AGENTS AND 4042 03:11:36,895 --> 03:11:39,398 FURTHER STUDIES USING ORGANOIDS. 4043 03:11:39,398 --> 03:11:44,536 IN TERMS OF THE NON-ORGANOID 4044 03:11:44,536 --> 03:11:48,306 EXPERIMENTS YOU'LL HEAR ABOUT 4045 03:11:48,306 --> 03:11:49,608 BIOLOGICS WITH LONG-TERM VIRAL 4046 03:11:49,608 --> 03:11:51,810 EXPRESSION OF THE ART IN HUMAN 4047 03:11:51,810 --> 03:11:55,147 AND NONHUMAN PRIMATES AND HAVE 4048 03:11:55,147 --> 03:11:59,017 GIVEN IT AT 7 WEEKS OF LIFE AT 4049 03:11:59,017 --> 03:12:04,322 RF2 AND 3 AND SIV INFECTED 4050 03:12:04,322 --> 03:12:07,492 INFANTS AND HAVE BEEN LEARNING 4051 03:12:07,492 --> 03:12:10,395 NUMEROUS LESSONS FROM ANTIBODIES 4052 03:12:10,395 --> 03:12:12,998 THAT ARE INITIATION IN INFANT 4053 03:12:12,998 --> 03:12:15,000 MACAQUES AND DOING DOSING 4054 03:12:15,000 --> 03:12:18,670 STUDIES TO FOCUS IN ON PEDIATRIC 4055 03:12:18,670 --> 03:12:22,441 SPECIFIC DOSING FORI AP 4056 03:12:22,441 --> 03:12:23,475 INHIBITORS AND AGONISTS AS WELL 4057 03:12:23,475 --> 03:12:26,745 AS A NUMBER OF STUDIES WITH 4058 03:12:26,745 --> 03:12:28,146 IMMUNOPET OPTIMIZATION. 4059 03:12:28,146 --> 03:12:31,349 AND JESSICA WILL TALK WITH US 4060 03:12:31,349 --> 03:12:34,419 ABOUT OUR STAKEHOLDER ENGAGEMENT 4061 03:12:34,419 --> 03:12:38,657 AND THE EXCITING KNOWLEDGE 4062 03:12:38,657 --> 03:12:40,325 DISSEMINATION TO PROVIDERS AND 4063 03:12:40,325 --> 03:12:41,059 POLICY MAKERS. 4064 03:12:41,059 --> 03:12:42,761 HOPEFULLY YOU ALL HAD A CHANCE 4065 03:12:42,761 --> 03:12:45,664 TO VISIT THE POSTERS OF THESE 4066 03:12:45,664 --> 03:12:47,866 WONDERFUL ESI SCHOLARSHIP 4067 03:12:47,866 --> 03:12:50,736 RECIPIENTS AND WE'RE GRATEFUL 4068 03:12:50,736 --> 03:12:53,138 FOR THE SUPPORT OF NIAID TO 4069 03:12:53,138 --> 03:12:53,672 BRING THEM HERE. 4070 03:12:53,672 --> 03:12:55,741 WITHIN CAME ALL THE WAY FROM 4071 03:12:55,741 --> 03:12:57,209 SOUTH AFRICA IF YOU HAVE THE 4072 03:12:57,209 --> 03:12:58,810 CHANCE TO TALK TO THEM AT 4073 03:12:58,810 --> 03:13:00,645 ANOTHER BREAK, PLEASE DO SO. 4074 03:13:00,645 --> 03:13:04,082 AND FINALLY FOR ME WE JUST 4075 03:13:04,082 --> 03:13:05,584 WANTED TO THANK OUR PROGRAM 4076 03:13:05,584 --> 03:13:05,884 MANAGERS. 4077 03:13:05,884 --> 03:13:08,153 WE HAD A FEW WITH US FROM ALMOST 4078 03:13:08,153 --> 03:13:12,157 THE BEGINNING OR THE VERY 4079 03:13:12,157 --> 03:13:14,493 BEGINNING FROM JOHNS HOPKINS AND 4080 03:13:14,493 --> 03:13:16,228 NEW ONES AT EMERY UNIVERSITY AND 4081 03:13:16,228 --> 03:13:19,498 TO THANK ALL THE PAVE 4082 03:13:19,498 --> 03:13:21,333 INVESTIGATORS AND MEMBERS AS 4083 03:13:21,333 --> 03:13:21,533 WELL. 4084 03:13:21,533 --> 03:13:23,301 WITH THAT I'LL TURN IT OVER TO 4085 03:13:23,301 --> 03:13:29,875 JESSICA. 4086 03:13:29,875 --> 03:13:38,517 >> YOU WANTED TO START WITH OUR 4087 03:13:38,517 --> 03:13:39,017 CORE LEADERSHIP. 4088 03:13:39,017 --> 03:13:41,686 SO WE REACHED A NUMBER OF NEW 4089 03:13:41,686 --> 03:13:43,855 STAKEHOLDERS THIS YEAR AND HAVE 4090 03:13:43,855 --> 03:13:49,227 BEEN FOCUSSED ON BROADENING OUR 4091 03:13:49,227 --> 03:13:50,929 REACH. 4092 03:13:50,929 --> 03:13:52,531 MOST OUR REACH IS IN SOUTH 4093 03:13:52,531 --> 03:13:56,601 AFRICA BUT HERE YOU SEE SPECIFIC 4094 03:13:56,601 --> 03:13:57,669 THINGS. 4095 03:13:57,669 --> 03:13:59,905 ONE PARTNER IS THE SOUTHERN 4096 03:13:59,905 --> 03:14:01,139 AFRICAN AMERICAN CLINICIAN 4097 03:14:01,139 --> 03:14:01,373 SOCIETY. 4098 03:14:01,373 --> 03:14:03,375 THEY HELD THEIR FIRST PEDIATRIC 4099 03:14:03,375 --> 03:14:05,744 CARE SYMPOSIUM IN 2023 AT THEIR 4100 03:14:05,744 --> 03:14:06,378 ANNUAL MEETING. 4101 03:14:06,378 --> 03:14:12,350 WE'VE BEEN WORKING WITH THE 4102 03:14:12,350 --> 03:14:14,152 INDIVIDUALS TO INCLUDED AND 4103 03:14:14,152 --> 03:14:16,621 EXCITED TO SEE THE LIFE TIME 4104 03:14:16,621 --> 03:14:18,690 SURVIVORS SHOW UP IN OTHER 4105 03:14:18,690 --> 03:14:19,658 PARTNERS' WORK AS WELL. 4106 03:14:19,658 --> 03:14:21,927 WE HAD A NUMBER OF VIDEOS AND 4107 03:14:21,927 --> 03:14:23,461 ONLINE VIDEO PARTNERSHIPS THAT 4108 03:14:23,461 --> 03:14:27,032 POPPED UP AND IN PARTICULAR 4109 03:14:27,032 --> 03:14:30,168 TRYING TO WORK WITH SOCIAL MEDIA 4110 03:14:30,168 --> 03:14:33,505 INFLUENCERS TO GET THE WORD OUT 4111 03:14:33,505 --> 03:14:36,808 AND THINKING ABOUT SPECIFIC 4112 03:14:36,808 --> 03:14:38,443 TOPICS THAT MIGHT BE OF INTEREST 4113 03:14:38,443 --> 03:14:41,146 LIKE UTIs AND AGING AND YOU SEE 4114 03:14:41,146 --> 03:14:41,746 THE PICTURES AND POSTERS AS 4115 03:14:41,746 --> 03:14:45,183 WELL. 4116 03:14:45,183 --> 03:14:46,751 SO AGAIN SUPPORTING KNOWLEDGE 4117 03:14:46,751 --> 03:14:47,085 DISSEMINATION. 4118 03:14:47,085 --> 03:14:49,321 WE'VE HAD A NUMBER OF WEBINARS 4119 03:14:49,321 --> 03:14:54,426 AND FORTUNATE TO WORK WITH THE 4120 03:14:54,426 --> 03:15:00,866 EGPAF AND HAVE BEEN ABLE TO HOLD 4121 03:15:00,866 --> 03:15:03,702 WEBINARS WITH EGPAF TO HIGHLIGHT 4122 03:15:03,702 --> 03:15:05,403 THE RESULTS IN THE COHORT WORK. 4123 03:15:05,403 --> 03:15:07,906 AND THE OTHER THING WE'VE BEEN 4124 03:15:07,906 --> 03:15:10,408 TARGETING IS THINKING ABOUT 4125 03:15:10,408 --> 03:15:13,144 BROADENING OUR STAKEHOLDER BASE. 4126 03:15:13,144 --> 03:15:15,380 NOT JUST WORKING ON THOSE LIVING 4127 03:15:15,380 --> 03:15:17,682 WITH HIV BUT FOCUSSING ON 4128 03:15:17,682 --> 03:15:18,884 CLINICIANS AND PROVIDERS. 4129 03:15:18,884 --> 03:15:22,153 AND WE HAVE AN ARTICLE OUT WITH 4130 03:15:22,153 --> 03:15:23,355 NURSING MATTERS THIS YEAR AND 4131 03:15:23,355 --> 03:15:30,095 THEY PUT OUT A GLOSSARY AS WELL 4132 03:15:30,095 --> 03:15:33,098 AND THINKING HOW TO EXPAND. 4133 03:15:33,098 --> 03:15:34,165 OUR GROUP DOES ADVOCACY. 4134 03:15:34,165 --> 03:15:35,533 A NUMBER OF GROUPS FOCUSSED ON 4135 03:15:35,533 --> 03:15:38,703 THE ADULT POPULATION AND WE 4136 03:15:38,703 --> 03:15:41,306 THOUGHT HOW WE CAN BEGIN TO 4137 03:15:41,306 --> 03:15:43,675 TARGET AND HOW WE BRING IN 4138 03:15:43,675 --> 03:15:44,442 ADMINISTRATIVE HEALTH AND 4139 03:15:44,442 --> 03:15:47,913 REGULATORS INTO THE 4140 03:15:47,913 --> 03:15:50,282 CONVERSATIONS. 4141 03:15:50,282 --> 03:15:54,052 THE CAB CHAIR DR. CARIBE IS 4142 03:15:54,052 --> 03:15:57,122 THERE WITH PARTNERS FOCUSSED ON 4143 03:15:57,122 --> 03:15:58,757 HOW DO YOU GET THESE INDIVIDUALS 4144 03:15:58,757 --> 03:16:01,693 INVOLVED IN TALKING ABOUT MANY 4145 03:16:01,693 --> 03:16:02,761 HIV PEER RESEARCH EARLY. 4146 03:16:02,761 --> 03:16:05,497 AND FEATURED AT THE CONSENSUS 4147 03:16:05,497 --> 03:16:09,834 MEETING AND HAVE BEGUN TO THINK 4148 03:16:09,834 --> 03:16:12,804 ABOUT HOW WE COLLABORATE WITH 4149 03:16:12,804 --> 03:16:15,407 MAURICIO AND HIS WORK AND 4150 03:16:15,407 --> 03:16:17,108 THERE'S BEEN A VOICES PROJECT. 4151 03:16:17,108 --> 03:16:19,444 THIS IS WHERE THEY'RE COLLECTING 4152 03:16:19,444 --> 03:16:23,114 DATA FROM STAKEHOLDERS WHO ARE 4153 03:16:23,114 --> 03:16:25,283 PEOPLE WITH PERINATAL HIV AND 4154 03:16:25,283 --> 03:16:25,817 CAREGIVERS AND VARIOUS 4155 03:16:25,817 --> 03:16:26,785 REGULATORS AND HERE ON THE 4156 03:16:26,785 --> 03:16:28,620 SCREEN IS A QUOTE FROM ONE OF 4157 03:16:28,620 --> 03:16:30,989 THE VOICES PROJECTS AND ON THE 4158 03:16:30,989 --> 03:16:34,125 SCREEN BEFORE I DIDN'T POINT OUT 4159 03:16:34,125 --> 03:16:35,760 BUT IT'S ONE OF THE YOUNG WOMEN 4160 03:16:35,760 --> 03:16:37,662 TALKING ABOUT WHY IT'S SO 4161 03:16:37,662 --> 03:16:37,929 IMPORTANT. 4162 03:16:37,929 --> 03:16:39,064 SO TOWARDS THE FIRST QUARTER OF 4163 03:16:39,064 --> 03:16:41,266 NEXT YEAR WE HOPE TO HAVE 4164 03:16:41,266 --> 03:16:42,500 SEVERAL INDIVIDUAL VIDEO 4165 03:16:42,500 --> 03:16:44,336 PROJECTS THAT FEATURE THESE 4166 03:16:44,336 --> 03:16:54,879 VOICES FROM AROUND SUB-SAHARAN 4167 03:16:55,080 --> 03:16:55,747 AFRICA. 4168 03:16:55,747 --> 03:16:58,183 AND THE COMMUNITY PLAYS AN 4169 03:16:58,183 --> 03:16:59,451 IMPORTANT ROLE AND HERE THERE'S 4170 03:16:59,451 --> 03:17:03,321 BEEN FANTASTIC WORK AND WE HAVE 4171 03:17:03,321 --> 03:17:08,860 A MEMBER TRANSITIONING TO ONE OF 4172 03:17:08,860 --> 03:17:10,528 OUR PAVE MEMBERS AND FEATURED ON 4173 03:17:10,528 --> 03:17:12,630 A PANELIST AT THE STRATEGIES 4174 03:17:12,630 --> 03:17:14,833 MEETING AND PRESENTED ABOUT 4175 03:17:14,833 --> 03:17:20,205 PERINATAL HIV AND THE NATIONAL 4176 03:17:20,205 --> 03:17:28,013 AIDS COMMISSION IN COUNTRIES AND 4177 03:17:28,013 --> 03:17:31,816 SHE HELD THE FIRST SYMPOSIUM IN 4178 03:17:31,816 --> 03:17:40,125 MALL -- MALAWI AND JUST REALLY 4179 03:17:40,125 --> 03:17:41,559 EXCITED FOR ALL THE WORK THAT 4180 03:17:41,559 --> 03:17:43,628 SHE'S BUILT AND CONTINUES TO DO 4181 03:17:43,628 --> 03:17:47,766 IN COLLABORATION TRULY WITH THE 4182 03:17:47,766 --> 03:17:48,666 ENTIRE CAB. 4183 03:17:48,666 --> 03:17:53,505 I KNOW SOME OF YOU HEARD ABOUT 4184 03:17:53,505 --> 03:17:55,073 THE EVENT AND WE WON'T PLAY THE 4185 03:17:55,073 --> 03:17:59,177 WHOLE VIDEO WE CAB MAKE SURE 4186 03:17:59,177 --> 03:18:01,346 PEOPLE HAVE ACCESS BUT SUCH A 4187 03:18:01,346 --> 03:18:03,281 NICE PICTURE OF SOME EVENTS THAT 4188 03:18:03,281 --> 03:18:07,819 HAPPENED. 4189 03:18:07,819 --> 03:18:18,296 DEBBIE IS THERE AND OTHERS. 4190 03:18:51,329 --> 03:18:54,332 I'M NOT GOING TO PLAY THE WHOLE 4191 03:18:54,332 --> 03:18:57,936 VIDEO BUT IT HAS DANCING AND A 4192 03:18:57,936 --> 03:18:59,871 FEATURE OF THE ART EXHIBIT THAT 4193 03:18:59,871 --> 03:19:01,673 SHOWS NOT JUST PARTICIPANTS BUT 4194 03:19:01,673 --> 03:19:04,642 ALL THE FANTASTIC ART AND IT'S A 4195 03:19:04,642 --> 03:19:05,844 FANTASTIC COLLABORATION. 4196 03:19:05,844 --> 03:19:09,280 I KNOW OTHER COLLABORATORIES ARE 4197 03:19:09,280 --> 03:19:12,083 REALLY BRINGING IN UGANDA SO 4198 03:19:12,083 --> 03:19:17,155 IT'S NICE TO SEE EVERYBODY COME 4199 03:19:17,155 --> 03:19:18,456 TOGETHER AND WITH THAT -- SEE, 4200 03:19:18,456 --> 03:19:19,090 THEY WANT YOU TO SEE THE WHOLE 4201 03:19:19,090 --> 03:19:29,200 VIDEO. 4202 03:19:39,010 --> 03:19:43,515 SO, KATHERINE. 4203 03:19:43,515 --> 03:19:44,849 >> THANK YOU, JESSICA. 4204 03:19:44,849 --> 03:19:47,452 IT'S A HARD ACT TO FOLLOW. 4205 03:19:47,452 --> 03:19:50,455 I'M PLEASED TO PRESENT ON BEHALF 4206 03:19:50,455 --> 03:19:53,191 OF PAVE RESEARCH FOCUS GROUPS 1 4207 03:19:53,191 --> 03:19:57,262 AND 3 INVESTIGATORS AND OUR 4208 03:19:57,262 --> 03:19:58,363 INVESTIGATORS FOCUS ON 4209 03:19:58,363 --> 03:20:00,198 CHARACTERIZING THE EVOLUTION OF 4210 03:20:00,198 --> 03:20:02,734 THE HIV RESERVOIR OVER TIME 4211 03:20:02,734 --> 03:20:05,470 FOLLOWING VIRAL SUPPRESSION ON 4212 03:20:05,470 --> 03:20:08,306 EARLY ART AND THEN SECONDLY 4213 03:20:08,306 --> 03:20:09,674 UNDERSTANDING HOST IMMUNE 4214 03:20:09,674 --> 03:20:10,909 RESPONSES THAT SHAPE THE 4215 03:20:10,909 --> 03:20:11,209 RESERVOIR. 4216 03:20:11,209 --> 03:20:12,744 AND TODAY I'M GOING TO SPEAK 4217 03:20:12,744 --> 03:20:15,880 ABOUT SOME OF OUR STUDIES THAT 4218 03:20:15,880 --> 03:20:16,848 CHARACTERIZE THE EVOLUTION OF 4219 03:20:16,848 --> 03:20:19,984 THE RESERVOIR OVER DECADES OF 4220 03:20:19,984 --> 03:20:21,686 VIRAL SUPPRESSION AFTER EARLY 4221 03:20:21,686 --> 03:20:25,690 ART. 4222 03:20:25,690 --> 03:20:28,760 SO HERE'S OUR PLAIN LANGUAGE 4223 03:20:28,760 --> 03:20:28,993 SUMMARY. 4224 03:20:28,993 --> 03:20:35,833 WHAT IS THEYY -- THE KEY 4225 03:20:35,833 --> 03:20:36,401 QUESTION. 4226 03:20:36,401 --> 03:20:39,337 WHAT DOES IT LOOK LINE IN 4227 03:20:39,337 --> 03:20:40,805 CHILDREN AFTER LONG PERIODS 4228 03:20:40,805 --> 03:20:44,409 BEING UNDETECTABLE IN ART. 4229 03:20:44,409 --> 03:20:46,711 LOW LEVELS OF INTACT HIV CAPABLE 4230 03:20:46,711 --> 03:20:48,780 OF REPLICATION HAVE BEEN 4231 03:20:48,780 --> 03:20:50,648 DETECTED IN INDIVIDUALS STUDIED 4232 03:20:50,648 --> 03:20:53,184 AFTER DECADES OF BEING 4233 03:20:53,184 --> 03:20:55,220 UNDETECTABLE AND THE RESERVOIR 4234 03:20:55,220 --> 03:20:57,488 APPEARS TO BE LESS STABLE AND 4235 03:20:57,488 --> 03:20:59,524 EASIER FOR THE IMMUNE SYSTEM TO 4236 03:20:59,524 --> 03:21:00,892 CLEAR. 4237 03:21:00,892 --> 03:21:01,926 AND WHY SHOULD THE COMMUNITY BE 4238 03:21:01,926 --> 03:21:03,928 ENCOURAGED ABOUT THE RESULTS OR 4239 03:21:03,928 --> 03:21:04,862 PROGRESS PRESENTED? 4240 03:21:04,862 --> 03:21:06,731 WE FEEL IMPROVED UNDERSTANDING 4241 03:21:06,731 --> 03:21:08,833 OF HIV RESERVOIRS AND THE IMMUNE 4242 03:21:08,833 --> 03:21:10,702 RESPONSES THAT SHAPE THEM OVER 4243 03:21:10,702 --> 03:21:12,670 TIME CAN INFORM TARGETED 4244 03:21:12,670 --> 03:21:14,739 REMISSION STRATEGIES FOR 4245 03:21:14,739 --> 03:21:15,707 CHILDREN AND YOUTH LIVING WITH 4246 03:21:15,707 --> 03:21:22,046 HIV. 4247 03:21:22,046 --> 03:21:23,147 SO THE VERY FIRST EARLY 4248 03:21:23,147 --> 03:21:25,650 COMBINATION STUDIES WERE STARTED 4249 03:21:25,650 --> 03:21:31,122 29 YEARS AGO AND SINCE THEN 4250 03:21:31,122 --> 03:21:32,890 EARLY DIAGNOSIS AND 4251 03:21:32,890 --> 03:21:33,992 ANTIRETROVIRAL THERAPIES HAVE 4252 03:21:33,992 --> 03:21:35,660 BEEN STANDARD OF CARE. 4253 03:21:35,660 --> 03:21:41,199 AND THEY HAVE DEMONSTRATED THAT 4254 03:21:41,199 --> 03:21:43,935 EARLY ART CAN MARKEDLY REDUCE 4255 03:21:43,935 --> 03:21:46,871 THE SIZE OF THE RESERVOIR AND 4256 03:21:46,871 --> 03:21:50,108 REDUCE THE IMMUNE FUNCTION AND 4257 03:21:50,108 --> 03:21:51,943 REDUCE MORBIDITY AND MORTALITY. 4258 03:21:51,943 --> 03:21:54,412 THE NUMBER OF CHILDREN GROWING 4259 03:21:54,412 --> 03:21:56,247 WITH HIV INTO ADULTHOOD OFFERS 4260 03:21:56,247 --> 03:21:58,516 THE OPPORTUNITY TO EVALUATE HOW 4261 03:21:58,516 --> 03:22:01,686 THE HIV RESERVOIR EVOLVES OVER 4262 03:22:01,686 --> 03:22:02,053 TIME. 4263 03:22:02,053 --> 03:22:11,696 AND THE HIV COHORT WAS ONE STUDY 4264 03:22:11,696 --> 03:22:13,765 AND THEY LOOKED AT NINE 4265 03:22:13,765 --> 03:22:16,067 INDIVIDUALS ALL BUT ONE OF WHOM 4266 03:22:16,067 --> 03:22:19,137 STARTED ART LESS THAN SIX MONTHS 4267 03:22:19,137 --> 03:22:21,306 OF AGE. 4268 03:22:21,306 --> 03:22:23,207 THESE CHILDREN EXPERIENCED 8 TO 4269 03:22:23,207 --> 03:22:24,175 25 YEARS OF VIRAL SUPPRESSION 4270 03:22:24,175 --> 03:22:26,644 AND SINCE THEY ARE WERE OLDER 4271 03:22:26,644 --> 03:22:31,015 AND LARGER THEY ARE WERE ABLE TO 4272 03:22:31,015 --> 03:22:35,520 DO LEUKOPHORESIS TO OBTAIN LARGE 4273 03:22:35,520 --> 03:22:39,691 NUMBER OF CELLS AND 86 MILLION 4274 03:22:39,691 --> 03:22:41,192 PBMC WERE INVESTIGATED PER 4275 03:22:41,192 --> 03:22:42,193 INDIVIDUAL. 4276 03:22:42,193 --> 03:22:45,663 AND WHAT THIS STUDY SHOWED A 4277 03:22:45,663 --> 03:22:48,599 LONG STORY SHORT IS THAT IT 4278 03:22:48,599 --> 03:22:52,136 SHOWED A SIGNIFICANTLY LOWER 4279 03:22:52,136 --> 03:22:56,207 NUMBERS OF INTACT HIV PER 4280 03:22:56,207 --> 03:22:58,876 MILLION PBMC AND LOWER PORTIONS 4281 03:22:58,876 --> 03:23:00,611 OF INTACT PROVIRUS IN THE 4282 03:23:00,611 --> 03:23:03,214 CHILDREN COMPARED TO LEAD 4283 03:23:03,214 --> 03:23:05,817 CONTROLLERS OR ADULT INDIVIDUALS 4284 03:23:05,817 --> 03:23:16,260 WHO WERE EXPRESSED ON ART. 4285 03:23:18,296 --> 03:23:22,100 WE HAVE DONE A STUDY AND WHAT WE 4286 03:23:22,100 --> 03:23:26,771 HAD THE OPPORTUNITY TO DO WAS TO 4287 03:23:26,771 --> 03:23:31,876 STUDY LONGITUDINAL SAMPLES TAKEN 4288 03:23:31,876 --> 03:23:34,345 FROM TWINS LIVING WITH HIV 4289 03:23:34,345 --> 03:23:37,882 INFECTION AND THIS FOLLOWED THEM 4290 03:23:37,882 --> 03:23:40,852 FROM INITIATION OF 4291 03:23:40,852 --> 03:23:41,519 ANTIRETROVIRAL THERAPY THROUGH 4292 03:23:41,519 --> 03:23:43,855 28 YEARS OF AGE. 4293 03:23:43,855 --> 03:23:53,197 THE FIRST SAMPLES EVALUATE D THY 4294 03:23:53,197 --> 03:23:57,668 EXPERIENCED WHY INTRAPARTUM 4295 03:23:57,668 --> 03:23:59,570 TRANSMISSION AND ART WAS 4296 03:23:59,570 --> 03:24:06,110 INITIATED AT 10 WEEKS OF AGE. 4297 03:24:06,110 --> 03:24:10,581 THE P1042 HAD DETECTION AT SIX 4298 03:24:10,581 --> 03:24:15,086 MONTHS ON ART AND THE RIGHT 4299 03:24:15,086 --> 03:24:19,123 PANEL HAD DETECTION AT 1 1/2 4300 03:24:19,123 --> 03:24:22,527 MONTHS AT ART AND THE FIRST 4301 03:24:22,527 --> 03:24:24,328 SAMPLES AT EIGHT MONTHS AND 12 4302 03:24:24,328 --> 03:24:26,030 YEARS, 20 YEARS AND 28 YEARS AND 4303 03:24:26,030 --> 03:24:29,200 THE SAMPLES TAKEN AT 28 YEARS 4304 03:24:29,200 --> 03:24:32,236 WERE DONE BY THE LEUKOPHORESIS 4305 03:24:32,236 --> 03:24:33,971 TO GIVE US LARGE NUMBERS OF 4306 03:24:33,971 --> 03:24:34,839 CELLS. 4307 03:24:34,839 --> 03:24:38,443 WHAT WE FOUND IN THE SAMPLES THE 4308 03:24:38,443 --> 03:24:41,078 PHORESIS SAMPLES AT 28 YEARS WE 4309 03:24:41,078 --> 03:24:44,148 WERE ABLE TO ANALYZE ABOUT A 4310 03:24:44,148 --> 03:24:46,617 BILLION CELLS FROM EACH OF THESE 4311 03:24:46,617 --> 03:24:46,918 INDIVIDUALS. 4312 03:24:46,918 --> 03:24:50,354 WE DID NOT FIND ANY INTACT 4313 03:24:50,354 --> 03:24:56,394 SEQUENCES FROM P10 42 AND FOUND 4314 03:24:56,394 --> 03:24:59,630 ONE INTACT FROM P1043. 4315 03:24:59,630 --> 03:25:02,033 AND WHEN WE LOOKED AT 4316 03:25:02,033 --> 03:25:04,001 LONGITUDINAL SAMPLES WE SAW AN 4317 03:25:04,001 --> 03:25:09,140 ALMOST FOUR LOG DECREASE IN 4318 03:25:09,140 --> 03:25:12,176 INTACT HIV DNA COPY NUMBER AND 4319 03:25:12,176 --> 03:25:14,912 THAT WAS COMPARED TO ABOUT A 1-2 4320 03:25:14,912 --> 03:25:19,183 LOG DECREASE IN DEFECTIVE HIV 4321 03:25:19,183 --> 03:25:24,388 DNA COPY NUMBER FROM EIGHT 4322 03:25:24,388 --> 03:25:28,826 MONTHS TO 28 YEARS. 4323 03:25:28,826 --> 03:25:33,898 AND THE LEVELS OF INTACT 4324 03:25:33,898 --> 03:25:35,099 PROVIRUSES WERE 80 FOLD LOWER 4325 03:25:35,099 --> 03:25:41,706 THAN THOSE DETECTED IN 4326 03:25:41,706 --> 03:25:45,042 CONTROLLERS AND 6700 TIMES LOWER 4327 03:25:45,042 --> 03:25:47,078 THAN THOSE MEASURED IN ADULT 4328 03:25:47,078 --> 03:25:53,184 INDIVIDUALS WHO INITIATED ART 4329 03:25:53,184 --> 03:25:54,585 DURING ESTABLISHED INFECTION. 4330 03:25:54,585 --> 03:25:57,321 AND THEN IN TERMS OF DETECTIVE, 4331 03:25:57,321 --> 03:26:00,691 WE ALSO SAW A TODAY CREASE BUT 4332 03:26:00,691 --> 03:26:05,196 NOT QUITE SO MUCH AND THE 4333 03:26:05,196 --> 03:26:07,198 DEFECTIVE PROVIRAL LEVELS WERE 4334 03:26:07,198 --> 03:26:08,266 24 FOLD LESS THAN THOSE MEASURED 4335 03:26:08,266 --> 03:26:13,304 IN ELITE CONTROLLERS AND 160 4336 03:26:13,304 --> 03:26:16,541 FOLD LESS THAN ADULTS THAT 4337 03:26:16,541 --> 03:26:25,683 INITIATED ART WITH THE 4338 03:26:25,683 --> 03:26:26,150 ESTABLISHED INFECTION. 4339 03:26:26,150 --> 03:26:26,284 DEF 4340 03:26:29,053 --> 03:26:30,755 THIS SHOWED INTACT IN 4341 03:26:30,755 --> 03:26:34,058 INDIVIDUALS AND THE INTACT 4342 03:26:34,058 --> 03:26:40,398 PROVIRAL COPY NUMBER DECREASED 4343 03:26:40,398 --> 03:26:43,768 FROM 8,000 FOLD AND BY CONTRACT 4344 03:26:43,768 --> 03:26:45,236 DEFECTIVE PROVIRAL LEVELS 4345 03:26:45,236 --> 03:26:47,405 DECREASED BY 64 FOLD OVER THAT 4346 03:26:47,405 --> 03:26:54,011 TIME PERIOD. 4347 03:26:54,011 --> 03:26:57,248 IN THIS LEVEL IT DECREASED BY 4348 03:26:57,248 --> 03:26:59,517 13,000 FOLD AND PROVIRUS LEVELS 4349 03:26:59,517 --> 03:27:03,254 DECREASED BY 98 FOLD AND BODY 4350 03:27:03,254 --> 03:27:05,189 WEIGHT INCREASED AGAIN THE TWO 4351 03:27:05,189 --> 03:27:07,792 SAMPLING TIME POINTS INCREASED 4352 03:27:07,792 --> 03:27:13,664 ONLY 8 TO 9 TIMES AND SINCE THE 4353 03:27:13,664 --> 03:27:16,834 NUMBER OF LYMPHOCYTES ARE 4354 03:27:16,834 --> 03:27:20,171 ROUGHLY PROPORTIONAL TO BODY 4355 03:27:20,171 --> 03:27:24,909 WEIGHT WE DO NOT THINK THE 4356 03:27:24,909 --> 03:27:27,912 DECREASE IN PROVIRAL LEVELS IS 4357 03:27:27,912 --> 03:27:36,621 SIMPLY DUE TO A DILUTIONAL 4358 03:27:36,621 --> 03:27:36,854 EFFECT. 4359 03:27:36,854 --> 03:27:44,996 WE THEN WENT WE USED 298 MILLION 4360 03:27:44,996 --> 03:27:51,402 CD8 CELLS IN AN ASSAY AND DID 4361 03:27:51,402 --> 03:27:57,074 NOT OBSERVE -- WERE NOT ABLE TO 4362 03:27:57,074 --> 03:27:58,609 RECOVER VIRUS FROM EITHER 4363 03:27:58,609 --> 03:27:58,909 INDIVIDUAL. 4364 03:27:58,909 --> 03:28:01,912 WE BEGAN TO LOOK AT THE PROVIRAL 4365 03:28:01,912 --> 03:28:06,951 LANDSCAPE OVER TIME AND WHILE WE 4366 03:28:06,951 --> 03:28:10,321 DETECTED EXPANSION OF INTACT AT 4367 03:28:10,321 --> 03:28:16,560 THE FIRST TIME POINT IN BOTH 4368 03:28:16,560 --> 03:28:17,294 INDIVIDU 4369 03:28:17,294 --> 03:28:20,331 INDIVIDUALS AND WE DID NOT 4370 03:28:20,331 --> 03:28:24,602 DETECT EXPANSION OR ANY INTACT 4371 03:28:24,602 --> 03:28:26,103 CLONE SUBSEQUENTLY. 4372 03:28:26,103 --> 03:28:29,173 IN P1043 WE DETECTED A SMALL 4373 03:28:29,173 --> 03:28:31,976 CLONE AT 12 YEARS BUT NOT 4374 03:28:31,976 --> 03:28:32,309 SUBSEQUENTLY. 4375 03:28:32,309 --> 03:28:36,547 AND OVER ALL WE OBSERVED LIMITED 4376 03:28:36,547 --> 03:28:38,315 GENOMIC DIVERSITY AND SAW 4377 03:28:38,315 --> 03:28:41,185 LIMITED EXPANSION OF DEFECTIVE 4378 03:28:41,185 --> 03:28:41,719 CLONES AT THE LATER TIME 4379 03:28:41,719 --> 03:28:47,992 PERIODS. 4380 03:28:47,992 --> 03:28:49,660 BOTH INDIVIDUALS WERE ANTIBODY 4381 03:28:49,660 --> 03:28:52,296 NEGATIVE AT THE TIME OF TESTING 4382 03:28:52,296 --> 03:28:53,731 AT 28 YEARS. 4383 03:28:53,731 --> 03:28:58,769 THEY PRE-ART WERE ABLE TO DETECT 4384 03:28:58,769 --> 03:29:02,940 CD 8 T CELL AND MAP CD 8 T CELL 4385 03:29:02,940 --> 03:29:04,008 RESPONSES IN THEM AFTER VIRAL 4386 03:29:04,008 --> 03:29:08,245 EXPRESSION AND RESPONSES WERE 4387 03:29:08,245 --> 03:29:13,384 NOT DETECTED BY DIRECT EX VIVO 4388 03:29:13,384 --> 03:29:17,221 OR INTRACELLULAR CYTOKINE SAERS 4389 03:29:17,221 --> 03:29:20,491 BUT WERE ABLE TO DETECT CD4 AND 4390 03:29:20,491 --> 03:29:23,894 CD 8 T CELL RESPONSES WHICH 4391 03:29:23,894 --> 03:29:26,530 INDICATE THEY HAD MEMORY. 4392 03:29:26,530 --> 03:29:29,200 THEY PRESERVE MEMORY RESPONSES 4393 03:29:29,200 --> 03:29:33,571 THROUGH 28 YEARS OF AGE AND TO 4394 03:29:33,571 --> 03:29:36,373 GAG AND A POOL OF PEP SIDES. 4395 03:29:36,373 --> 03:29:39,176 -- PEPTIDES. 4396 03:29:39,176 --> 03:29:43,214 IN SUMMARY AFTER DECADES OF 4397 03:29:43,214 --> 03:29:49,587 EXPRESSIVE ART WE OBSERVED MARK 4398 03:29:49,587 --> 03:29:50,421 REDUCTION IN THE MANY DNA AND 4399 03:29:50,421 --> 03:29:54,325 THE SEQUENCES WERE EXTREMELY LOW 4400 03:29:54,325 --> 03:29:58,729 AND DECREASED OF INTACT PROVIRAL 4401 03:29:58,729 --> 03:30:01,165 VIRUSES EXCEEDED THAT OF 4402 03:30:01,165 --> 03:30:01,599 DEFECTIVE SEQUENCES. 4403 03:30:01,599 --> 03:30:04,602 WE DID NOT SEE EXPANSION OF 4404 03:30:04,602 --> 03:30:08,906 CLONES WITH INTACT FOR VIRAL 4405 03:30:08,906 --> 03:30:11,375 SEQUENCES OVER TIME AND THE DATA 4406 03:30:11,375 --> 03:30:13,677 SUGGEST A LONG-TERM STABILITY 4407 03:30:13,677 --> 03:30:18,482 AND INCREASED IMMUNOLOGIC 4408 03:30:18,482 --> 03:30:20,785 PROVIRUSES STARTING IN EARLY 4409 03:30:20,785 --> 03:30:21,685 INFANCY. 4410 03:30:21,685 --> 03:30:25,156 AGAIN WE WERE ABLE TO DETECT 4411 03:30:25,156 --> 03:30:33,597 PERSISTENT HIV SPECIFIC T CELL 4412 03:30:33,597 --> 03:30:35,232 RESPONSES AND WE ALLUDED TO ARE 4413 03:30:35,232 --> 03:30:39,236 NOT GOING TO FOCUS ON INNATE AND 4414 03:30:39,236 --> 03:30:41,605 K CELL FUNCTIONS AND LESLEY WILL 4415 03:30:41,605 --> 03:30:43,007 BE SPEAKING MORE ABOUT THAT IN 4416 03:30:43,007 --> 03:30:43,674 HER PRESENTATION LATER ON THIS 4417 03:30:43,674 --> 03:30:47,511 AFTERNOON. 4418 03:30:47,511 --> 03:30:50,147 SO BEFORE I CLOSE I'D LIKE TO 4419 03:30:50,147 --> 03:30:53,217 ACKNOWLEDGE STUDY PARTICIPANTS 4420 03:30:53,217 --> 03:30:55,753 AND THEIR FAMILIES AS WELL AS 4421 03:30:55,753 --> 03:30:56,821 MEMBERS OF THE LABS. 4422 03:30:56,821 --> 03:31:04,562 MY LAB, THE POWER LAB, LESLEY DE 4423 03:31:04,562 --> 03:31:09,333 ARMAS AND MEMBERS OF THE 4424 03:31:09,333 --> 03:31:10,134 CHILDREN'S HOSPITAL AND I THINK 4425 03:31:10,134 --> 03:31:10,501 I'LL STOP THERE. 4426 03:31:10,501 --> 03:31:20,878 THANK YOU VERY MUCH. 4427 03:31:20,878 --> 03:31:22,279 >> THANK YOU, KATHERINE. 4428 03:31:22,279 --> 03:31:27,518 PHILLIP ARE YOU ON? 4429 03:31:27,518 --> 03:31:29,553 >> YES. 4430 03:31:29,553 --> 03:31:33,524 MY TALK IS EARLY LIFE IMMUNE SEX 4431 03:31:33,524 --> 03:31:35,326 DIFFERENCES IN HIV CURE 4432 03:31:35,326 --> 03:31:35,826 POTENTIAL. 4433 03:31:35,826 --> 03:31:38,062 AND THESE ARE THE PEOPLE 4434 03:31:38,062 --> 03:31:41,398 INVOLVED IN THE HUMAN STUDIES 4435 03:31:41,398 --> 03:31:42,666 COMPONENT OF RESEARCH FOCUS 2 4436 03:31:42,666 --> 03:31:46,737 AND 3 AND I'LL BE SPEAKING ABOUT 4437 03:31:46,737 --> 03:31:49,173 PART OF THIS WORK IN THE NEXT 4438 03:31:49,173 --> 03:31:49,406 MINUTES. 4439 03:31:49,406 --> 03:31:52,042 IN TERMS OF PLAIN LANGUAGE 4440 03:31:52,042 --> 03:31:52,376 SUMMARY. 4441 03:31:52,376 --> 03:31:53,844 THE KEY QUESTION CAN CURE 4442 03:31:53,844 --> 03:32:04,388 REMISSION BE ACHIEVED BY EARLY 4443 03:32:05,356 --> 03:32:06,123 ANTIRETROVIRAL SYSTEM AND DO 4444 03:32:06,123 --> 03:32:08,859 IMMUNE SEX DIFFERENCES PLAY A 4445 03:32:08,859 --> 03:32:09,426 ROLE? 4446 03:32:09,426 --> 03:32:11,562 SINCE SEX DIFFERENCES DO AFFECT 4447 03:32:11,562 --> 03:32:15,566 OUTCOME, THIS WORK ADVANCES OUR 4448 03:32:15,566 --> 03:32:17,234 FIELD BECAUSE IT MEANS THAT 4449 03:32:17,234 --> 03:32:18,702 IMPLIES SEX SPECIFIC 4450 03:32:18,702 --> 03:32:20,905 INTERVENTIONS MAY BE IMPORTANT 4451 03:32:20,905 --> 03:32:22,806 TO ADVANCE CURE POTENTIAL AMONG 4452 03:32:22,806 --> 03:32:23,073 CHILDREN. 4453 03:32:23,073 --> 03:32:24,308 WHY SHOULD THE COMMUNITY BE 4454 03:32:24,308 --> 03:32:25,476 ENCOURAGED ABOUT THE RESULTS? 4455 03:32:25,476 --> 03:32:26,577 WE IDENTIFIED FIVE CHILDREN IN 4456 03:32:26,577 --> 03:32:32,116 THE STUDY WHO REMAINED 4457 03:32:32,116 --> 03:32:35,185 UNDETECTABLE FOR UNSCHEDULED 4458 03:32:35,185 --> 03:32:36,186 ANTIRETROVIRAL INTERRUPTION AND 4459 03:32:36,186 --> 03:32:38,956 EIGHT CHILDREN TO A PROSPECTIVE 4460 03:32:38,956 --> 03:32:41,225 STUDY AND FOUR CHILDREN REMAINED 4461 03:32:41,225 --> 03:32:43,460 UNDETECTABLE MORE THAN A YEAR 4462 03:32:43,460 --> 03:32:49,667 AND OTHER FINDINGS JUST MENTION 4463 03:32:49,667 --> 03:32:57,675 ED INDICATE THE POTENTIAL TO 4464 03:32:57,675 --> 03:33:00,577 CURE CHILDREN AND BROADLY 4465 03:33:00,577 --> 03:33:01,946 NEUTRALIZING ANTIBODIES CAN BE 4466 03:33:01,946 --> 03:33:02,246 IMPLEMENTED. 4467 03:33:02,246 --> 03:33:07,785 THE STUDY I'LL TALK ABOUT WAS 4468 03:33:07,785 --> 03:33:11,155 THE BABY CURE PROJECT WE STARTED 4469 03:33:11,155 --> 03:33:16,593 10 YEARS AGO IN NORTHERN EASTERN 4470 03:33:16,593 --> 03:33:20,064 PART OF AFRICA FOR THE STUDY 4471 03:33:20,064 --> 03:33:28,973 SITES SHOWN HERE. 4472 03:33:28,973 --> 03:33:33,544 THERE'S 320 CHILD PAIRS 4473 03:33:33,544 --> 03:33:44,088 FOLLOWING IN UTERO TRANSMISSION 4474 03:33:44,655 --> 03:33:50,527 AND THEY ARE HAVE REMISSION 4475 03:33:50,527 --> 03:33:51,862 FOLLOWING EARLY ANTIRETROVIRAL 4476 03:33:51,862 --> 03:33:53,664 AND LOOK AT THE CURE REMISSION 4477 03:33:53,664 --> 03:33:57,234 IN THESE INSTANCES. 4478 03:33:57,234 --> 03:33:58,602 THE SEX DIFFERENCES CAME FROM 4479 03:33:58,602 --> 03:34:01,438 SOME OF THE TWINS WE STUDIES IN 4480 03:34:01,438 --> 03:34:05,676 THE COHORT AND WE'VE COME ACROSS 4481 03:34:05,676 --> 03:34:07,644 FIVE SEX DISCORDANT TWINS WHERE 4482 03:34:07,644 --> 03:34:14,818 ONE HAS BECOME INFECTED AND IT 4483 03:34:14,818 --> 03:34:19,156 WAS THE FEMALE AND THE 4484 03:34:19,156 --> 03:34:29,666 HISTORICAL CODE IN MALAWI AND 4485 03:34:41,545 --> 03:34:43,881 THE SUSCEPTIBILITY TO 4486 03:34:43,881 --> 03:34:45,382 ACQUISITION IS GONE TO RECENT 4487 03:34:45,382 --> 03:34:48,352 MATERNAL INFECTION LOOKING AT 4488 03:34:48,352 --> 03:34:51,388 MOTHERS WHO HAD CONVERTED BEFORE 4489 03:34:51,388 --> 03:34:52,923 PREGNANCY THERE WAS NO 4490 03:34:52,923 --> 03:34:54,291 TRANSMISSION TO MALES AND 4491 03:34:54,291 --> 03:34:59,763 FEMALES BUT IN THE MOTHERS WHO 4492 03:34:59,763 --> 03:35:08,338 CONVERTED DURING PREGNANCY AND 4493 03:35:08,338 --> 03:35:11,275 THE MECHANISM CAME FROM ADULT 4494 03:35:11,275 --> 03:35:12,609 STUDIES WHICH HAS SHOWN THE 4495 03:35:12,609 --> 03:35:21,685 VIRUS IS TRANSMITTED TO ADULTS 4496 03:35:21,685 --> 03:35:32,229 FOR RESIST JANS AND THIS BECOMES 4497 03:35:32,229 --> 03:35:33,664 AND MOTHERS RECENTLY INFECTED IN 4498 03:35:33,664 --> 03:35:35,566 THE COURSE OF PREGNANCY WILL BE 4499 03:35:35,566 --> 03:35:40,671 MORE LIKELY TO HARBOR RESISTANT 4500 03:35:40,671 --> 03:35:42,106 VIRUSES AND HYPOTHESIZED LIKE 4501 03:35:42,106 --> 03:35:44,842 FEMALE CHILDREN AND FEMALE 4502 03:35:44,842 --> 03:35:48,612 ADULTS THE FEMALE FETUSES MAKE 4503 03:35:48,612 --> 03:35:51,081 STRONGER RESPONSES THAN MALE 4504 03:35:51,081 --> 03:35:51,548 COUNTERPARTS. 4505 03:35:51,548 --> 03:36:01,125 FRALE FETUSES ARE MORE RESISTANT 4506 03:36:01,125 --> 03:36:04,394 AND THE RESISTANT VIRUSES ARE 4507 03:36:04,394 --> 03:36:08,298 HARBORED BY THE MALES AND FEMALE 4508 03:36:08,298 --> 03:36:11,835 FETUS ARE MORE SUSCEPTIBLE THAN 4509 03:36:11,835 --> 03:36:14,304 MALES IN UTERO. 4510 03:36:14,304 --> 03:36:19,243 WE LOOKED AT SOME SEX DISCORDANT 4511 03:36:19,243 --> 03:36:22,379 TWINS BORN TO HIV-NEGATIVE 4512 03:36:22,379 --> 03:36:25,015 MOTHERS AND THE STIMULATED GENES 4513 03:36:25,015 --> 03:36:31,288 WAS HIGHER IN CD4 CELLS IN 4514 03:36:31,288 --> 03:36:33,624 FEMALES VERSUS MALES AND THE 4515 03:36:33,624 --> 03:36:35,392 LEVEL OF ACTIVATION IN THESE 4516 03:36:35,392 --> 03:36:40,430 WERE HIGHER AMONG THE FEMALES 4517 03:36:40,430 --> 03:36:44,868 AND THE LEVELS WERE CORRELATED 4518 03:36:44,868 --> 03:36:51,041 WITH THE ABILITY TO INFECT THE 4519 03:36:51,041 --> 03:36:54,378 CELLS IN VITRO WITH HIV. 4520 03:36:54,378 --> 03:36:58,248 I WANTED TO SHOW YOU THE VIRUSES 4521 03:36:58,248 --> 03:36:59,650 TRANSMITTED TO MALES AND FEMALES 4522 03:36:59,650 --> 03:37:01,518 IN THE STUDIES WE'VE BEEN DOING 4523 03:37:01,518 --> 03:37:09,660 AND SHOWING ON THE LEFT PANEL 4524 03:37:09,660 --> 03:37:12,095 VIRUSES TEND TO BE HIGHER 4525 03:37:12,095 --> 03:37:13,864 CAPACITY ON THE Y AXIS AND 4526 03:37:13,864 --> 03:37:15,999 INTERFERON SENSITIVE ON THE X 4527 03:37:15,999 --> 03:37:16,366 AXIS. 4528 03:37:16,366 --> 03:37:20,070 AND BY CONTRACT THE VIRUS IS 4529 03:37:20,070 --> 03:37:21,738 TRANSMITTED TO FEMALES BUT THE 4530 03:37:21,738 --> 03:37:25,676 MAJORITY OF THEM ARE IN THE LOW 4531 03:37:25,676 --> 03:37:28,779 RIGHT HAND QUADRANT WITH LOWER 4532 03:37:28,779 --> 03:37:29,046 CAPACITY. 4533 03:37:29,046 --> 03:37:31,615 THESE ARE VIRUSES THAT YOU 4534 03:37:31,615 --> 03:37:37,621 RARELY SEE TRANSMITTED TO MALES. 4535 03:37:37,621 --> 03:37:41,291 AND MOST TRANSMITTED TO FEMALES 4536 03:37:41,291 --> 03:37:48,799 WERE TRANSMITTED IN THE SETTING 4537 03:37:48,799 --> 03:37:51,401 AND HAVING SEEN MOST THE VIRUS 4538 03:37:51,401 --> 03:37:54,137 WERE TRANSMITTED TO MALES ARE 4539 03:37:54,137 --> 03:37:59,343 TRANSMITTED AND FIT VIRUSES WE 4540 03:37:59,343 --> 03:38:02,779 HAVE ALSO OBSERVED TYPICAL MALES 4541 03:38:02,779 --> 03:38:05,048 WITH VIREMIA FOR SUBSTANTIAL 4542 03:38:05,048 --> 03:38:06,450 PERIODS UP TO 10 MONTHS 4543 03:38:06,450 --> 03:38:06,950 FOLLOWING UNSCHEDULED 4544 03:38:06,950 --> 03:38:13,523 INTERRUPTION. 4545 03:38:13,523 --> 03:38:15,325 WE WERE ABLE TO CHARACTERIZE 4546 03:38:15,325 --> 03:38:18,095 VIRUSES IN THE TYPICAL CASES AND 4547 03:38:18,095 --> 03:38:23,267 SHOWED THEY'RE UNUSUALLY LOW IN 4548 03:38:23,267 --> 03:38:33,143 TERMS OF THE CAPACITY IN MAIL 4549 03:38:33,143 --> 03:38:34,544 INFANTS AND SUGGESTING IN MALES 4550 03:38:34,544 --> 03:38:40,150 THE VIRUSES TRANSMITTED AND 4551 03:38:40,150 --> 03:38:45,656 SUSTAI 4552 03:38:45,656 --> 03:38:48,091 SUSTAINED FOLLOWING CHILD BIRTH 4553 03:38:48,091 --> 03:38:50,327 ARE AT CAPACITY IN MALES. 4554 03:38:50,327 --> 03:38:54,965 AND WE HAVE ALSO INITIATED SOME 4555 03:38:54,965 --> 03:38:57,701 PERSPECTIVE STUDIES IN EIGHT OF 4556 03:38:57,701 --> 03:39:03,140 THE CHILDREN AND FOUR WE HEARD 4557 03:39:03,140 --> 03:39:04,941 FROM THE PAST FOUR WEEKS AND 4558 03:39:04,941 --> 03:39:08,111 OTHERS REMAINED IN REMISSION AND 4559 03:39:08,111 --> 03:39:12,983 OTHERS OCCURRED AT 18 MONTHS. 4560 03:39:12,983 --> 03:39:15,085 I'D LIKE TO FINISH BY 4561 03:39:15,085 --> 03:39:16,286 ACKNOWLEDGING ALL THE PEOPLE WHO 4562 03:39:16,286 --> 03:39:17,721 PARTICIPATED IN THE STUDY 4563 03:39:17,721 --> 03:39:19,456 PARTICULARLY THE STUDY 4564 03:39:19,456 --> 03:39:24,094 PARTICIPANTS AND CLINICAL TEAMS. 4565 03:39:24,094 --> 03:39:26,930 THE TEAM THAT PARTICIPATED IN 4566 03:39:26,930 --> 03:39:29,166 THE WORK I DESCRIBED AND NAMED 4567 03:39:29,166 --> 03:39:32,436 ON THE LEFT AND ALSO THE FUNDERS 4568 03:39:32,436 --> 03:39:34,471 THE PAVE IN PARTICULAR AND 4569 03:39:34,471 --> 03:39:36,473 STUDIES THEMSELVES WERE FUNDED 4570 03:39:36,473 --> 03:39:37,674 BY WELCOME TRUST. 4571 03:39:37,674 --> 03:39:47,851 THANK YOU. 4572 03:39:55,392 --> 03:39:58,028 >> I'M HERE TO PRESENT DATA ON 4573 03:39:58,028 --> 03:40:00,797 BEHALF OF THE INVESTIGATORS NOT 4574 03:40:00,797 --> 03:40:03,166 JUST MYSELF. 4575 03:40:03,166 --> 03:40:06,303 THIS IS THE RF4 TEAM OF HUMAN 4576 03:40:06,303 --> 03:40:07,270 STUDIES. 4577 03:40:07,270 --> 03:40:08,372 I'M NOT PRESENTING WORK FULLY 4578 03:40:08,372 --> 03:40:12,175 FROM THIS GROUP BUT FOCUSSING ON 4579 03:40:12,175 --> 03:40:14,778 THE IMMUNOLOGICAL ASSAYS WE ARE 4580 03:40:14,778 --> 03:40:15,078 DEVELOPING. 4581 03:40:15,078 --> 03:40:18,682 WE HAVE TWO MAIN QUESTIONS. 4582 03:40:18,682 --> 03:40:22,853 ONE IS CAN WE MEASURE NATURAL 4583 03:40:22,853 --> 03:40:27,391 KILLER WITH PERINATAL HIV WITH 4584 03:40:27,391 --> 03:40:31,862 SAMPLE AVAILABILITY AND WHICH 4585 03:40:31,862 --> 03:40:32,729 CHARACTERISTIC ASSOCIATES WITH 4586 03:40:32,729 --> 03:40:35,165 VIRUS CONTROL IN THE POPULATION. 4587 03:40:35,165 --> 03:40:37,534 HOW DOES THIS WORK ADVANCE THE 4588 03:40:37,534 --> 03:40:40,570 FIELD AND MK CELLS ARE 4589 03:40:40,570 --> 03:40:41,671 COMPONENTS OF THE INNATE 4590 03:40:41,671 --> 03:40:46,109 IMMUNITY AND PLAY A ROLE IN THE 4591 03:40:46,109 --> 03:40:48,812 ANTIVIRAL IMMUNITY AND DRIVING 4592 03:40:48,812 --> 03:40:51,081 NK KILLING POTENTIAL IN HIV AND 4593 03:40:51,081 --> 03:40:51,381 INFANTS. 4594 03:40:51,381 --> 03:40:52,482 THE COMMUNITY SHOULD BE 4595 03:40:52,482 --> 03:40:55,585 ENCOURAGED ABOUT RESULTS AND 4596 03:40:55,585 --> 03:40:59,122 PROGRESS BECAUSE IT CAN DELAY TO 4597 03:40:59,122 --> 03:41:02,025 THE DECAY OF THE HIV RESERVOIR 4598 03:41:02,025 --> 03:41:03,560 AND THERE'S STUDIES IN PEDIATRIC 4599 03:41:03,560 --> 03:41:04,828 POPULATIONS WHERE WE HAVE 4600 03:41:04,828 --> 03:41:05,629 LIMITED VOLUMES. 4601 03:41:05,629 --> 03:41:09,366 AND THE FINDINGS ARE EXPECTED TO 4602 03:41:09,366 --> 03:41:11,601 PROVIDE INSIGHT TO STRATEGIES TO 4603 03:41:11,601 --> 03:41:13,670 BOOST HIV IMMUNITY TO TARGET THE 4604 03:41:13,670 --> 03:41:16,273 RESERVOIR. 4605 03:41:16,273 --> 03:41:19,443 OUR WORK IN DOING IMMUNOLOGIC 4606 03:41:19,443 --> 03:41:24,548 PROFILING AND PERINATAL HIV IS 4607 03:41:24,548 --> 03:41:25,449 TRYING TO DETERMINE WHAT 4608 03:41:25,449 --> 03:41:29,519 RESPONSE IS PRESENTS AND/OR 4609 03:41:29,519 --> 03:41:31,688 EFFECTIVE PRE AND POST OUR 4610 03:41:31,688 --> 03:41:32,155 INITIATION. 4611 03:41:32,155 --> 03:41:34,658 WE HAVE THREE MAIN TOOLS WE USED 4612 03:41:34,658 --> 03:41:37,394 TO INTERROGATE AT THE SYSTEM. 4613 03:41:37,394 --> 03:41:42,499 THE FIRST IS DOING HIGH 4614 03:41:42,499 --> 03:41:45,168 DIMENSIONAL FLOW CYTOMETRY AND 4615 03:41:45,168 --> 03:41:48,038 SECOND IS FUNCTIONAL STUDIES TO 4616 03:41:48,038 --> 03:41:49,706 DETERMINE HOW DIFFERENT CELL 4617 03:41:49,706 --> 03:41:52,175 TYPES RESPOND TO EXTERNAL 4618 03:41:52,175 --> 03:41:55,645 STIMULI AND VIRAL INFECTION AND 4619 03:41:55,645 --> 03:41:57,614 mRNA SEQ TO LOOK AT THE 4620 03:41:57,614 --> 03:41:58,782 UNBIASSED VIEW OF THE LANDSCAPE. 4621 03:41:58,782 --> 03:42:04,855 THE GOAL IS TO OPTIMIZE SAMPLES 4622 03:42:04,855 --> 03:42:08,692 SPARING ASSAYS TO LOOK AT 4623 03:42:08,692 --> 03:42:10,260 COHORTS IN CLINICAL TRIAL AND 4624 03:42:10,260 --> 03:42:12,629 LOOKING AT NK CELL DATA WE 4625 03:42:12,629 --> 03:42:14,130 GENERATED USING THE THREE 4626 03:42:14,130 --> 03:42:14,498 APPROACHES. 4627 03:42:14,498 --> 03:42:19,035 THAT WILL COME FROM TWO 4628 03:42:19,035 --> 03:42:22,973 DIFFERENT AND THE STUDY COMES 4629 03:42:22,973 --> 03:42:25,442 FROM BOTSWANA LED BY ROBERT 4630 03:42:25,442 --> 03:42:28,612 SHAPIRO A TREATMENT WITH ATI IN 4631 03:42:28,612 --> 03:42:30,013 CHILDREN THREE TO FOUR YEARS OF 4632 03:42:30,013 --> 03:42:30,647 AGE. 4633 03:42:30,647 --> 03:42:35,018 THEY WERE TREATED VERY EARLY AND 4634 03:42:35,018 --> 03:42:40,090 WERE ON CONTINUOUS ART SIX WEEKS 4635 03:42:40,090 --> 03:42:45,662 WERE UNDETECTED AND IN M 4636 03:42:45,662 --> 03:42:50,300 MOZAMBIQUE WE WERE FOLLOWING A 4637 03:42:50,300 --> 03:42:54,304 COHORT AND THIS STUDY ENROLLED 4638 03:42:54,304 --> 03:42:57,774 CHILDREN STUDIED EARLY AT 1 TO 2 4639 03:42:57,774 --> 03:43:02,379 MONTHS AND ZERO NEGATIVE INFANTS 4640 03:43:02,379 --> 03:43:06,449 WITH IN UTERO AND WE HAD 4641 03:43:06,449 --> 03:43:08,685 LONGITUDINAL SAMPLING AND 4642 03:43:08,685 --> 03:43:11,621 CLINICAL FOLLOW-UP. 4643 03:43:11,621 --> 03:43:16,893 FIRST TO SHOW THE NK FINDINGS 4644 03:43:16,893 --> 03:43:20,730 AND THIS IS WORK DONE SHOWING 4645 03:43:20,730 --> 03:43:31,241 THE SCHEMATIC OF THE STUDY SO 4646 03:43:31,708 --> 03:43:34,644 CHILDREN WERE GIVEN ART AND THE 4647 03:43:34,644 --> 03:43:40,383 ATI WENT ON 24 WEEKS UNLESS 4648 03:43:40,383 --> 03:43:43,653 VIRUS LOADS WENT ABOVE THE 4649 03:43:43,653 --> 03:43:45,288 THRESHOLD AND WE HAD 14 4650 03:43:45,288 --> 03:43:47,958 REBOUNDERS AND 11 CONTROLLERS SO 4651 03:43:47,958 --> 03:43:49,426 THOSE WHO MAINTAINED EXPRESSION 4652 03:43:49,426 --> 03:43:54,230 FOR THE 24 WEEKS. 4653 03:43:54,230 --> 03:44:04,975 AND MELANIE PERFORMED FLOWCY 4654 03:44:08,445 --> 03:44:08,645 CYTOMETRY. 4655 03:44:08,645 --> 03:44:11,348 AND WE'RE FOCUSSING MAINLY ON 4656 03:44:11,348 --> 03:44:13,149 TWO POPULATIONS THE CD 56 4657 03:44:13,149 --> 03:44:18,688 POSITIVE AND 16 NEGATIVE AND 4658 03:44:18,688 --> 03:44:25,695 CYTOKINE PRODUCING CELLS AND THE 4659 03:44:25,695 --> 03:44:28,264 MAJOR CYTOTOXIC POPULATION AND 4660 03:44:28,264 --> 03:44:32,802 LOOKED AT FREQUENCIES AND THERE 4661 03:44:32,802 --> 03:44:36,940 WAS NO SIGNIFICANT DIFFERENCE IN 4662 03:44:36,940 --> 03:44:39,075 SUBSET FREQUENCIES. 4663 03:44:39,075 --> 03:44:41,444 THEY FOUND SIGNIFICANT DIFFERENT 4664 03:44:41,444 --> 03:44:43,847 IN CELLS EXPRESSING THE NK 4665 03:44:43,847 --> 03:44:46,082 RECEPTOR TO THE L1 AT THE TIME 4666 03:44:46,082 --> 03:44:49,653 OF OUR INITIATION IN BOTH THE NK 4667 03:44:49,653 --> 03:44:53,890 CELL SUBSETS THAT WERE MEASURED 4668 03:44:53,890 --> 03:44:56,760 AND THE LEVEL OF THIS INHIBITORY 4669 03:44:56,760 --> 03:44:59,362 MARKER EXPRESSION ON THE CD 56 4670 03:44:59,362 --> 03:45:01,197 DIM CELLS HAD A NEGATIVE 4671 03:45:01,197 --> 03:45:02,599 CORRELATION WITH WEEKS TO VIRAL 4672 03:45:02,599 --> 03:45:04,901 REBOUND SUBJECTING THE SUBSET 4673 03:45:04,901 --> 03:45:06,870 WAS NOT ABLE TO CONTROL HIV 4674 03:45:06,870 --> 03:45:11,374 REBOUND. 4675 03:45:11,374 --> 03:45:13,543 SO NK CELLS EXPRESS A DIVERSE 4676 03:45:13,543 --> 03:45:18,148 ARRAY OF RECEPTORS THAT DICTATE 4677 03:45:18,148 --> 03:45:20,483 LIGATION WITH DIFFERENT LIGANDS 4678 03:45:20,483 --> 03:45:22,318 ON CD4 AND OTHER CELLS DICTATE 4679 03:45:22,318 --> 03:45:23,219 THEIR FUNCTION WHETHER 4680 03:45:23,219 --> 03:45:28,491 INHIBITORY OR ACTIVATING AND THE 4681 03:45:28,491 --> 03:45:35,765 MAJOR LIGAND FOR KIR IN THE 2DL1 4682 03:45:35,765 --> 03:45:39,469 IS HLA-C. 4683 03:45:39,469 --> 03:45:41,104 AND THE EXPRESSION VARIES AMONG 4684 03:45:41,104 --> 03:45:43,473 TYPE AND MELANIE EVALUATED THE 4685 03:45:43,473 --> 03:45:45,675 DIFFERENT TYPE AND FOUND LOW 4686 03:45:45,675 --> 03:45:48,511 EXPRESSION ALLO TYPES WERE IN 4687 03:45:48,511 --> 03:45:52,982 CONTROLLERS AND HIGH TYPES WERE 4688 03:45:52,982 --> 03:45:57,454 ENRICHED IN REBOUNDERS AND 4689 03:45:57,454 --> 03:46:01,658 IMMUNE MEDIATED CONTROLLERS MAY 4690 03:46:01,658 --> 03:46:09,566 PLAY A ROLE IN VIRAL REBOUND. 4691 03:46:09,566 --> 03:46:12,235 SWITCHING OVER TO THE MANY TARA 4692 03:46:12,235 --> 03:46:12,635 COHORT. 4693 03:46:12,635 --> 03:46:14,204 IT DOES NOT HAVE AN 4694 03:46:14,204 --> 03:46:14,537 INTERVENTION. 4695 03:46:14,537 --> 03:46:16,372 WE'RE LOOKING AT IMMUNOLOGIC 4696 03:46:16,372 --> 03:46:20,343 PROFILES IN RELATION TO AGE, 4697 03:46:20,343 --> 03:46:22,679 VIRAL STATUS AND ART INITIATION. 4698 03:46:22,679 --> 03:46:24,514 AND WE'VE BEEN INTERESTED IN NK 4699 03:46:24,514 --> 03:46:26,382 CELLS BECAUSE WE FOUND SOME 4700 03:46:26,382 --> 03:46:28,351 DIFFERENCES IN SUBSET 4701 03:46:28,351 --> 03:46:29,352 FREQUENCIES AND PHENOTYPES 4702 03:46:29,352 --> 03:46:31,855 BETWEEN AGI AND AGU. 4703 03:46:31,855 --> 03:46:33,957 SO WE WANTED TO DEVELOP AN ASSAY 4704 03:46:33,957 --> 03:46:36,359 TO LOOK AT NK FUNCTION BECAUSE 4705 03:46:36,359 --> 03:46:37,427 WE THINK IT'S CRITICALLY 4706 03:46:37,427 --> 03:46:40,130 IMPORTANT IN INFANCY. 4707 03:46:40,130 --> 03:46:44,901 SO WE DID THIS IN NINE ATU AND 4708 03:46:44,901 --> 03:46:47,103 17ATI AND LOOKED AT ENTRY ONE TO 4709 03:46:47,103 --> 03:46:50,673 TWO MONTHS OF ABLE AND AGAIN AT 4710 03:46:50,673 --> 03:46:53,409 12 MONTHS OF ABLE AND THE ASSAY 4711 03:46:53,409 --> 03:46:58,915 WE START WITH PDMC AND PURIFY NK 4712 03:46:58,915 --> 03:47:01,017 AND CO-CULL CURE WITH TARGET 4713 03:47:01,017 --> 03:47:06,790 CELLS AND PERFORM A 25 COLOR 4714 03:47:06,790 --> 03:47:11,461 FLOW CYTOMETRY ASSAY TO LOOK AT 4715 03:47:11,461 --> 03:47:12,862 CYTOTOXIC FUNCTION AND CYTOKINES 4716 03:47:12,862 --> 03:47:16,366 AND MARKERS OF DEEP GRANULATION. 4717 03:47:16,366 --> 03:47:19,235 THE TARGET CELLS ARE CEM AND KR 4718 03:47:19,235 --> 03:47:25,208 THAT ARE NK RESISTANT AND MHC1 4719 03:47:25,208 --> 03:47:27,610 DEFICIENT AND NK SENSITIVE AND 4720 03:47:27,610 --> 03:47:32,615 HUD 78 A CELL LINE THAT STABLY 4721 03:47:32,615 --> 03:47:33,950 INFECTED WITH SF 2 AND HIV 1 4722 03:47:33,950 --> 03:47:37,420 STRAIN AND THESE CELLS ACTED AS 4723 03:47:37,420 --> 03:47:40,089 OUR HIV INFECTED TARGET CELLS. 4724 03:47:40,089 --> 03:47:41,724 SO THE PRIMARY READOUT OF THIS 4725 03:47:41,724 --> 03:47:45,428 ASSAY IS JUST LOOKING AT 4726 03:47:45,428 --> 03:47:46,362 SPECIFIC KILLING OF DIFFERENT 4727 03:47:46,362 --> 03:47:47,297 CELL LINES. 4728 03:47:47,297 --> 03:47:49,432 WE DID NOT SEE A DIFFERENCE 4729 03:47:49,432 --> 03:47:53,069 BETWEEN AGI AND AGU SUBJECTING 4730 03:47:53,069 --> 03:47:56,840 NO INHERENT DEFECT IN AGI AS FAR 4731 03:47:56,840 --> 03:47:59,275 AS TARGETING CELLS BUT THERE'S 4732 03:47:59,275 --> 03:48:02,045 NO RELATION WITH VIRUS LOAD AT 4733 03:48:02,045 --> 03:48:04,814 THE 1-2 MONTH TIME POINT. 4734 03:48:04,814 --> 03:48:07,717 HOWEVER AT 12 MONTHS WE DID SEE 4735 03:48:07,717 --> 03:48:10,253 A NEGATIVE CORRELATION BETWEEN 4736 03:48:10,253 --> 03:48:17,794 SPECIFIC KILLING OF 78 CELLS AND 4737 03:48:17,794 --> 03:48:21,698 PLASMA VIRUS LOAD AND ONLY 16 4738 03:48:21,698 --> 03:48:23,099 WERE SUPPRESSED AND DID NOT SEE 4739 03:48:23,099 --> 03:48:25,568 ASSOCIATION WITH THE KILLING OF 4740 03:48:25,568 --> 03:48:29,339 K562 SUBJECTING FRO LONGED 4741 03:48:29,339 --> 03:48:33,009 VIREMIA PLAY MEDIATE KILLING OF 4742 03:48:33,009 --> 03:48:34,210 HIV INFECTED CELLS. 4743 03:48:34,210 --> 03:48:38,314 WE WANTED TO LOOK AT WHICH NK 4744 03:48:38,314 --> 03:48:39,816 FEATURES CORRELATED WITH TARGETS 4745 03:48:39,816 --> 03:48:41,150 OF KILLING. 4746 03:48:41,150 --> 03:48:43,453 SO WE DID MIXED EFFECTS MODELS 4747 03:48:43,453 --> 03:48:45,221 WHERE WE LOOKED AT ALL THE 4748 03:48:45,221 --> 03:48:49,158 DIFFERENT PHENOTYPIC MARK FROM 4749 03:48:49,158 --> 03:48:55,231 THE FLOW CYTOMETRY DATA SET AND 4750 03:48:55,231 --> 03:49:01,604 SAW A POSITIVE IMPACT OF CD 25 4751 03:49:01,604 --> 03:49:04,507 EXPRESSION AND THE CELLS AND 4752 03:49:04,507 --> 03:49:07,744 SMALL POSITIVE EFFECT OF LIGAND 4753 03:49:07,744 --> 03:49:10,079 RECEPTOR ON THE CD 56 STEM 4754 03:49:10,079 --> 03:49:10,280 CELLS. 4755 03:49:10,280 --> 03:49:12,582 TO SEE HOW THIS LOOKS IN 4756 03:49:12,582 --> 03:49:14,250 CORRELATION PLOTS WE SEE A NICE 4757 03:49:14,250 --> 03:49:17,353 LINEAR POSITIVE RELATIONSHIP 4758 03:49:17,353 --> 03:49:18,855 BETWEEN LIGAND EXPRESSED AFTER 4759 03:49:18,855 --> 03:49:20,223 THE CULTURE AND FREQUENCY OF 4760 03:49:20,223 --> 03:49:27,597 CELLS THAT WERE KILLED. 4761 03:49:27,597 --> 03:49:30,700 WHEN YOU LOOK AT THE CELLS YOU 4762 03:49:30,700 --> 03:49:34,804 SEE CD 107A AND THE MARKER 4763 03:49:34,804 --> 03:49:35,872 HAVING A STRONG ASSOCIATION AS 4764 03:49:35,872 --> 03:49:38,975 WELL AS THE BETA AND INHIBITORY 4765 03:49:38,975 --> 03:49:41,544 MARKER AT EXPECTED AS A NEGATIVE 4766 03:49:41,544 --> 03:49:41,878 IMPACT. 4767 03:49:41,878 --> 03:49:44,614 SO WE'RE SEEING THE NK 4768 03:49:44,614 --> 03:49:45,815 PHENOTYPES DIVERGE IN 4769 03:49:45,815 --> 03:49:46,549 CO-CULTURES DEPENDING ON THE 4770 03:49:46,549 --> 03:49:49,819 CELLULAR TARGET. 4771 03:49:49,819 --> 03:49:53,623 SO THE EMERGING DATA SO FAR 4772 03:49:53,623 --> 03:49:58,461 SUGGESTING NK RECEPTOR AND CD4 4773 03:49:58,461 --> 03:50:01,998 LIGANDS MAY PLAY A ROLE IN 4774 03:50:01,998 --> 03:50:04,167 CONTROL AND WENT TO A DATA SET 4775 03:50:04,167 --> 03:50:09,205 OF 12ATI AT THE PRE-ART TIME 4776 03:50:09,205 --> 03:50:12,842 POINT AND HAD GENE AND PROTEIN 4777 03:50:12,842 --> 03:50:14,444 EXPRESSION FROM 130 ANTIBODIES 4778 03:50:14,444 --> 03:50:16,012 TO LABEL PDMC. 4779 03:50:16,012 --> 03:50:19,682 WE WERE ABLE TO SEPARATE OUT 4780 03:50:19,682 --> 03:50:21,684 SOME OF OUR HIGH VIRUS VERSUS 4781 03:50:21,684 --> 03:50:24,454 LOW VIRUS LOAD IN INFANTS AND 4782 03:50:24,454 --> 03:50:26,556 THE MAP IS SHOWING CLUSTERS. 4783 03:50:26,556 --> 03:50:30,259 WE IDENTIFIED SEVEN CD4 T CELL 4784 03:50:30,259 --> 03:50:33,663 CLUSTERS WHICH WERE ANNOTATED AS 4785 03:50:33,663 --> 03:50:36,366 NAIVE OR BASED ON A REFERENCE 4786 03:50:36,366 --> 03:50:37,667 DATABASE. 4787 03:50:37,667 --> 03:50:41,771 WE ALSO IDENTIFIED TREGS AND TH2 4788 03:50:41,771 --> 03:50:42,672 POPULATION DUE TO EXPRESSION AND 4789 03:50:42,672 --> 03:50:47,043 THE CLUSTERS YOU CAN SEE THEY 4790 03:50:47,043 --> 03:50:49,379 ALMOST ACROSS THE BOARD HAVE UP 4791 03:50:49,379 --> 03:50:52,815 REGULATED HLA EXPRESSION AND AN 4792 03:50:52,815 --> 03:50:55,251 ANTIBODY THAT DOES NOT 4793 03:50:55,251 --> 03:51:00,957 DISTINGUISH BETWEEN HLA AND CR C 4794 03:51:00,957 --> 03:51:04,827 AND HIGH UPREGULATION AND THE 4795 03:51:04,827 --> 03:51:07,330 FOUR CLUSTERS IDENTIFIED WHICH 4796 03:51:07,330 --> 03:51:11,067 WERE ABLE TO ANNOTATE USING CD 4797 03:51:11,067 --> 03:51:13,102 56 AND CD 66 EXPRESSION. 4798 03:51:13,102 --> 03:51:18,541 WE SEE UP REGULATION OF SOME 4799 03:51:18,541 --> 03:51:24,113 INHIBITORY TEARS HIGH VERSE US 4800 03:51:24,113 --> 03:51:26,449 AND SEE UPREGULATION IN THE 4801 03:51:26,449 --> 03:51:31,821 INDIVIDUALS WITH HIGHER VIREMIA. 4802 03:51:31,821 --> 03:51:34,590 SO THESE RESULTS THE IMMUNE 4803 03:51:34,590 --> 03:51:37,393 PROFILES CONSISTENT WITH REDUCED 4804 03:51:37,393 --> 03:51:41,631 NK FUNCTION IN THE PRESENCE OF 4805 03:51:41,631 --> 03:51:43,299 HIGHER AMOUNT. 4806 03:51:43,299 --> 03:51:48,204 AND THE INHIBITORY MARKERS ARE 4807 03:51:48,204 --> 03:51:49,872 ASSOCIATED WITH THE REBOUND AND 4808 03:51:49,872 --> 03:51:51,874 DIDN'T SHOW THE KG2A AND 4809 03:51:51,874 --> 03:51:55,411 PROLONGED VIREMIA IN INFANTS 4810 03:51:55,411 --> 03:51:58,648 IMPAIRS KILLING OF HIV INFECTED 4811 03:51:58,648 --> 03:52:02,718 CELL LINES BUT THE K562 CELLS 4812 03:52:02,718 --> 03:52:05,655 AND THERE'S A MECHANISM USING 4813 03:52:05,655 --> 03:52:09,892 LIGANDS RATHER THAN A CD107A 4814 03:52:09,892 --> 03:52:11,894 DEGRANLATION AND FAS EXPRESSION 4815 03:52:11,894 --> 03:52:15,565 WAS INCREASED WITH HIGHER VIRUS 4816 03:52:15,565 --> 03:52:18,901 LOAD AND SINGLE CELL RNA SEQ ARE 4817 03:52:18,901 --> 03:52:23,072 FEASIBLE FOR SAMPLES AND XASHG 4818 03:52:23,072 --> 03:52:24,941 TWO SMALL GROUP SUCH AS HIGH LOW 4819 03:52:24,941 --> 03:52:28,544 RESERVOIR OR CLINICAL RESPONSES. 4820 03:52:28,544 --> 03:52:31,414 AND I'LL THANK INDIVIDUALS FROM 4821 03:52:31,414 --> 03:52:36,419 THE LAB WHERE I WORK AND THOSE 4822 03:52:36,419 --> 03:52:43,159 WHO DID THE EXPERIENCE AND THE 4823 03:52:43,159 --> 03:52:44,727 ANALYSIS AND MOZAMBIQUE TOOK 4824 03:52:44,727 --> 03:52:47,463 CARE OF THE INFANTS FOLLOWING 4825 03:52:47,463 --> 03:52:51,767 AND WE APPRECIATE THEIR 4826 03:52:51,767 --> 03:52:54,437 CONTRIBUTIONS AND THEN MATHIAS 4827 03:52:54,437 --> 03:52:57,673 AND MELANIE FOR THE DETE AND THE 4828 03:52:57,673 --> 03:52:59,475 WHOLE TEAM. 4829 03:52:59,475 --> 03:53:01,978 IT WAS A REALLY INTERESTING 4830 03:53:01,978 --> 03:53:12,088 SITE. 4831 03:53:12,555 --> 03:53:14,757 >> GOOD AFTERNOON. 4832 03:53:14,757 --> 03:53:17,360 I'M MAURICIO MARTIN AND TALK 4833 03:53:17,360 --> 03:53:28,304 ABOUT THE AAV-VECT DELIV DELIVE 4834 03:53:28,304 --> 03:53:31,641 INFANT MACAQUES. 4835 03:53:31,641 --> 03:53:35,111 OUR GROUP IS SHOWN HERE. 4836 03:53:35,111 --> 03:53:36,445 I WANT TO MENTION THE STUDY I'LL 4837 03:53:36,445 --> 03:53:39,382 BE TALKING ABOUT NOW WERE 4838 03:53:39,382 --> 03:53:43,452 CONDUCTED UNDER THE SEPARATION 4839 03:53:43,452 --> 03:53:47,089 OF DR. HAYWOOD AND SO MY PLAIN 4840 03:53:47,089 --> 03:53:49,559 LANGUAGE SUMMARY SO THE KEY 4841 03:53:49,559 --> 03:53:51,327 QUESTION WE ADDRESSED IS CAN 4842 03:53:51,327 --> 03:54:01,637 EARLY ART PLUS GENE THERAPY WITH 4843 03:54:01,637 --> 03:54:04,373 HIV-1B NABS ACHIEVE DURABLE 4844 03:54:04,373 --> 03:54:08,611 ART-FREE CONTROL IN VIREMIA IN 4845 03:54:08,611 --> 03:54:11,480 INFANT MACAQUES AND LED TO 4846 03:54:11,480 --> 03:54:13,716 PRODUCTION OF THE MONKEY'S OWN 4847 03:54:13,716 --> 03:54:17,987 CELLS WITHOUT REPEATED 4848 03:54:17,987 --> 03:54:18,354 ADMINISTRATION. 4849 03:54:18,354 --> 03:54:19,589 AFTER STOMP ANTIRETROVIRAL ABOUT 4850 03:54:19,589 --> 03:54:23,359 80% OF THE TREATED MACAQUES 4851 03:54:23,359 --> 03:54:24,594 MAINTAINED BNAB LEVELS THAT 4852 03:54:24,594 --> 03:54:25,328 PREVENTED VIRUS REBOUND. 4853 03:54:25,328 --> 03:54:28,931 WE SHOULD BE EXCITED ABOUT THIS 4854 03:54:28,931 --> 03:54:30,633 FOR TWO REASONS. 4855 03:54:30,633 --> 03:54:35,271 THE BNAB VECTORS IN GENERAL ARE 4856 03:54:35,271 --> 03:54:38,007 HIGHLY STABLE AND ACROSS 4857 03:54:38,007 --> 03:54:39,809 MULTIPLE TEMPERATURES AND 4858 03:54:39,809 --> 03:54:41,978 CONDITIONS MAKING THEM 4859 03:54:41,978 --> 03:54:43,613 ESPECIALLY USEFUL FOR DEPLOYMENT 4860 03:54:43,613 --> 03:54:46,315 TO REMOTE AREAS WHERE A COLD 4861 03:54:46,315 --> 03:54:48,618 CHAIN CANNOT BE RELIABLE. 4862 03:54:48,618 --> 03:54:50,586 AND THE ADMINISTRATIONS CAN BE 4863 03:54:50,586 --> 03:54:54,757 DONE WITHOUT ADVANCED MEDICAL 4864 03:54:54,757 --> 03:54:57,393 TRAINING OR FACILITIES WHICH 4865 03:54:57,393 --> 03:54:59,362 HAVE A PLUS AND BNAB EXPRESSION 4866 03:54:59,362 --> 03:55:02,465 IN INFANCY PLAY PREVENT LATER 4867 03:55:02,465 --> 03:55:04,433 INFECTION IN LIFE. 4868 03:55:04,433 --> 03:55:09,639 WE LIKE THIS APPROACH OF USED 4869 03:55:09,639 --> 03:55:12,642 AAV TO DELIVER B NABS BECAUSE IT 4870 03:55:12,642 --> 03:55:14,510 CAN PERSIST IN THE NUCLEUS OF 4871 03:55:14,510 --> 03:55:18,514 THE CELL WHERE IT CAN MAINTAIN 4872 03:55:18,514 --> 03:55:19,949 PERSISTENT EXPRESSION FOR THE 4873 03:55:19,949 --> 03:55:21,684 CELL LIVE AND WE'RE INTERESTED 4874 03:55:21,684 --> 03:55:25,554 IN TARGETING THESE VECTORS TO 4875 03:55:25,554 --> 03:55:26,956 SKELETAL MUSCLE CELLS BECAUSE OF 4876 03:55:26,956 --> 03:55:28,557 THE LIFE LONG SPAN. 4877 03:55:28,557 --> 03:55:32,328 OUR VISION FOR THE APPROACH IS A 4878 03:55:32,328 --> 03:55:42,838 ONE-TIME INTRAMUSCULAR WOULD 4879 03:55:44,307 --> 03:55:45,875 PROVIDE PROTECTION AND I'LL TALK 4880 03:55:45,875 --> 03:55:47,476 ABOUT THREE STUDIES CONDUCTED OR 4881 03:55:47,476 --> 03:55:51,847 IN THE PROCESS OF CONDUCTING OUR 4882 03:55:51,847 --> 03:55:52,415 . 4883 03:55:52,415 --> 03:55:56,585 OUR 2022 STUDY WE ORALLY 4884 03:55:56,585 --> 03:55:59,488 INFECTED THE INFANT MACAQUES AND 4885 03:55:59,488 --> 03:56:04,560 ONE WEEK LATER WE START THE 4886 03:56:04,560 --> 03:56:06,662 ANIMALS ON ANTIRETROVIRAL AND 4887 03:56:06,662 --> 03:56:14,337 THEY RECEIVED INTRAMUSCULAR 4888 03:56:14,337 --> 03:56:16,439 VERSIONS AND THEN AFTER WEEK 30 4889 03:56:16,439 --> 03:56:18,574 POST INFECTION WE STOPPED ART 4890 03:56:18,574 --> 03:56:20,309 AND ASSESSED VIRUS REBOUND AND 4891 03:56:20,309 --> 03:56:26,315 WE SAW A SIGNIFICANT DELAY OR 4892 03:56:26,315 --> 03:56:29,652 PREVENTION AS SHOWN IN THE TOP 4893 03:56:29,652 --> 03:56:29,985 RIGHT. 4894 03:56:29,985 --> 03:56:32,088 SO I'M GOING TO TO BE TALKING 4895 03:56:32,088 --> 03:56:37,660 ABOUT THE STUDY FIRST. 4896 03:56:37,660 --> 03:56:41,364 THIS IS SHOWING ONE PANEL FOR 4897 03:56:41,364 --> 03:56:45,534 ANIMAL AND I'VE SHOWN THIS 4898 03:56:45,534 --> 03:56:47,269 BEFORE BUT UPDATE WHAT WE'VE 4899 03:56:47,269 --> 03:56:48,437 DONE RECENTLY. 4900 03:56:48,437 --> 03:56:52,608 WE SAW TWO ANIMALS IN THE 2022 4901 03:56:52,608 --> 03:56:54,276 COHORT EXPERIENCED VIRUS REBOUND 4902 03:56:54,276 --> 03:56:55,811 AND INTERESTED IN CHARACTERIZING 4903 03:56:55,811 --> 03:56:58,848 THE SEQUENCE OF THEIR ENVELOPE 4904 03:56:58,848 --> 03:57:00,449 OF VIRUSES AT THE TIME OF 4905 03:57:00,449 --> 03:57:00,683 REBOUND. 4906 03:57:00,683 --> 03:57:05,388 I ALSO WANT TO POINT OUT THAT WE 4907 03:57:05,388 --> 03:57:10,893 IN THE LAST YEAR CONDUCTED 4908 03:57:10,893 --> 03:57:11,727 RECEPTOR BLOCKADE IN VIVO AND 4909 03:57:11,727 --> 03:57:14,463 SAW REBOUND CONSISTENT WITH THE 4910 03:57:14,463 --> 03:57:15,898 DECREASE IN PLASMA 4911 03:57:15,898 --> 03:57:17,700 CONSIDERATIONS OF THE TWO 4912 03:57:17,700 --> 03:57:18,801 BIOLOGICS AND AS THE EXPRESSION 4913 03:57:18,801 --> 03:57:23,372 OF THE BIOLOGICS CAME BACK, 4914 03:57:23,372 --> 03:57:26,509 VIROLOGIC CONTROL WAS 4915 03:57:26,509 --> 03:57:27,777 RE-ESTABLISHED AND PEOPLE 4916 03:57:27,777 --> 03:57:29,512 GETTING THE MOLECULES AND AS FOR 4917 03:57:29,512 --> 03:57:32,782 THE ENVELOPE SEQUENCES WE 4918 03:57:32,782 --> 03:57:33,516 IDENTIFIED WE'RE STILL 4919 03:57:33,516 --> 03:57:35,551 CHARACTERIZING THEM BUT 4920 03:57:35,551 --> 03:57:37,953 IDENTIFIED A NUMBER OF 4921 03:57:37,953 --> 03:57:39,522 POLYMORPHISMS SHARED BETWEEN THE 4922 03:57:39,522 --> 03:57:45,928 ANIMALS ANALYZED AND THE SHARED 4923 03:57:45,928 --> 03:57:46,929 POLYMORPHISM INVOLVED A DELETION 4924 03:57:46,929 --> 03:57:49,899 IN V4 AND THE SEQUENCING DATA 4925 03:57:49,899 --> 03:57:54,904 WAS GENERATED BY DR. BRANDON 4926 03:57:54,904 --> 03:57:57,873 HEEL'S GROUP AND HAVE BEEN 4927 03:57:57,873 --> 03:57:59,809 CHARACTERIZING THE PROVIRAL 4928 03:57:59,809 --> 03:58:02,778 LOADS IN THE ANIMALS AND 4929 03:58:02,778 --> 03:58:03,813 COMPARED THEM BETWEEN THE 4930 03:58:03,813 --> 03:58:06,248 MACAQUES AND THE CONTROL GROUP 4931 03:58:06,248 --> 03:58:07,750 OVER 30 YEARS OF ANTIRETROVIRAL 4932 03:58:07,750 --> 03:58:09,452 IN STUDY AND HADN'T SEEN A 4933 03:58:09,452 --> 03:58:11,654 DIFFERENCE PROBABLY BECAUSE OF 4934 03:58:11,654 --> 03:58:14,123 THE PERIOD OF ART BEING TOO 4935 03:58:14,123 --> 03:58:14,356 SHORT. 4936 03:58:14,356 --> 03:58:17,359 AND WE'RE PLANNING TO ASSESS 4937 03:58:17,359 --> 03:58:18,894 THIS IN THE FUTURE WITH LONGER 4938 03:58:18,894 --> 03:58:20,396 ART PERIODS. 4939 03:58:20,396 --> 03:58:22,598 SO IN THE 2023 STUDY WE HAVE 4940 03:58:22,598 --> 03:58:25,701 STOPPED ART AND SO FAR WE HAVE 4941 03:58:25,701 --> 03:58:27,903 SEEN STABLE CONTROL IN FUF OF 4942 03:58:27,903 --> 03:58:31,340 THE SIX ANIMALS THAT WERE 4943 03:58:31,340 --> 03:58:33,175 ENROLLED. 4944 03:58:33,175 --> 03:58:36,812 WE HAVE A 7th MACAQUE ENROLLED 4945 03:58:36,812 --> 03:58:38,781 BUT THIS IS ENCOURAGING BECAUSE 4946 03:58:38,781 --> 03:58:40,216 IT SHOWS CONTROL CAN BE 4947 03:58:40,216 --> 03:58:42,785 MAINTAINED BY THIS APPROACH IN 4948 03:58:42,785 --> 03:58:45,254 ANIMALS THAT WERE TREATED WITH 4949 03:58:45,254 --> 03:58:49,692 ART AND AAV VECTORS AT 7 AND 21 4950 03:58:49,692 --> 03:58:52,061 DAYS POST INFECTION. 4951 03:58:52,061 --> 03:58:53,395 SO WE'RE IN THE PROCESS OF 4952 03:58:53,395 --> 03:58:56,298 CONDUCTING THIS STUDY WHERE 4953 03:58:56,298 --> 03:59:01,136 WE'RE ANALYZING THE ADVOCACY OF 4954 03:59:01,136 --> 03:59:04,073 THE VERSIONS OF THE 10-1074 AND 4955 03:59:04,073 --> 03:59:08,444 HAVE EXPRESSION OF AT LEAST ONE 4956 03:59:08,444 --> 03:59:10,279 OF THE MOLECULES WITH THE ATI 4957 03:59:10,279 --> 03:59:11,847 PLANNED FOR FEBRUARY OF 2025. 4958 03:59:11,847 --> 03:59:14,917 TO SUMMARIZE WHAT I SAID SO FAR, 4959 03:59:14,917 --> 03:59:17,853 WE SEE PREVENTION OR DELAY OF 4960 03:59:17,853 --> 03:59:24,593 VIRUS REBOUND AND ABOUT 80% OF 4961 03:59:24,593 --> 03:59:27,463 MACAQUES AT WEEK ONE OR THREE 4962 03:59:27,463 --> 03:59:30,499 POST SHIV INFECTION AND WE KNOW 4963 03:59:30,499 --> 03:59:32,735 THAT MANY WE SHOULD TRANSIENTLY 4964 03:59:32,735 --> 03:59:35,804 DEPLETE THE CIRCULATION THROUGH 4965 03:59:35,804 --> 03:59:38,541 BLOCKADE AND THE VIRUS COMES 4966 03:59:38,541 --> 03:59:38,741 BACK. 4967 03:59:38,741 --> 03:59:42,378 WE ARE -- WE JUST DID TWO CD 8 4968 03:59:42,378 --> 03:59:46,815 DEPLETIONS IN THE 2023 COHORT 4969 03:59:46,815 --> 03:59:49,952 AND WE HAVEN'T SEEN THE VIRUS 4970 03:59:49,952 --> 03:59:54,156 COME BACK YET SO THIS IS I THINK 4971 03:59:54,156 --> 03:59:55,691 STRENGTHENS THE CONCLUSION IT'S 4972 03:59:55,691 --> 03:59:57,693 REALLY THE EXPRESSION OF THE TWO 4973 03:59:57,693 --> 03:59:59,395 MOLECULES MAINTAINING CONTROL 4974 03:59:59,395 --> 04:00:05,367 AND SO FAR WE HAVE THE 2024 4975 04:00:05,367 --> 04:00:08,771 COHORT WHERE WE ARE AWAITING 4976 04:00:08,771 --> 04:00:13,709 ANXIOUSLY FOR THE AGI IN 2025. 4977 04:00:13,709 --> 04:00:15,010 AS FOR PLANS FOR THE FUTURE 4978 04:00:15,010 --> 04:00:19,548 WE'RE IN ACTIVE CONVERSATIONS 4979 04:00:19,548 --> 04:00:21,850 ABOUT TRANSLATING TO A CLINICAL 4980 04:00:21,850 --> 04:00:23,886 TRIAL AND CONDUCT THE MONKEY 4981 04:00:23,886 --> 04:00:27,523 STUDY TO ASSESS WHETHER A 4982 04:00:27,523 --> 04:00:31,093 COMBINATION OF VERSIONS OF 4983 04:00:31,093 --> 04:00:32,595 101074 AND IT CAN ACHIEVE THE 4984 04:00:32,595 --> 04:00:35,397 LEVEL OF CONTROL WE HAVE SEEN IN 4985 04:00:35,397 --> 04:00:36,398 STUDIES I JUST DESCRIBED. 4986 04:00:36,398 --> 04:00:38,734 WE ARE CONTEMPLATING USING THIS 4987 04:00:38,734 --> 04:00:40,869 DUAL COMBO FOR THE CLINICAL 4988 04:00:40,869 --> 04:00:43,339 TRIAL AND FOR THIS PARTICULAR 4989 04:00:43,339 --> 04:00:49,178 STUDY WE ARE COLLABORATING WITH 4990 04:00:49,178 --> 04:00:51,447 DR. KATIE BARR AROUND A SHIV 4991 04:00:51,447 --> 04:00:53,182 THEY DEVELOPED AND HAVE INFECTED 4992 04:00:53,182 --> 04:00:55,517 THREE INFANT MACAQUES WITH THE 4993 04:00:55,517 --> 04:00:55,751 VIRUS. 4994 04:00:55,751 --> 04:00:58,821 WE'RE LOOKING AT REPLICATION AND 4995 04:00:58,821 --> 04:01:01,190 HOW THE VIRUSES RESPOND TO 4996 04:01:01,190 --> 04:01:02,891 ANTIRETROVIRAL THERAPY AND ATI 4997 04:01:02,891 --> 04:01:04,460 AND THAT'S SHOWN IN THE GRAPH. 4998 04:01:04,460 --> 04:01:06,595 AND YES, THIS IS MY 4999 04:01:06,595 --> 04:01:08,330 ACKNOWLEDGEMENT SLIDE. 5000 04:01:08,330 --> 04:01:11,400 THANK YOU VERY MUCH FOR ALL 5001 04:01:11,400 --> 04:01:13,068 PARTIES INVOLVED ESPECIALLY THE 5002 04:01:13,068 --> 04:01:15,337 MEMBERS OF MY LAB AND THE ASSAYS 5003 04:01:15,337 --> 04:01:17,373 AND MY COLLEAGUES AT THE CENTER 5004 04:01:17,373 --> 04:01:21,944 WHO DID THE ANIMAL WORK. 5005 04:01:21,944 --> 04:01:32,121 THANK YOU. 5006 04:01:35,457 --> 04:01:36,025 >> THANK YOU. 5007 04:01:36,025 --> 04:01:37,259 WE'RE OPEN FOR QUESTIONS. 5008 04:01:37,259 --> 04:01:47,169 WE HAVE 10, 12 MINUTES. 5009 04:01:47,169 --> 04:01:49,371 HERE WE GO. 5010 04:01:49,371 --> 04:01:52,141 >> QUESTION FOR MAURICIO. 5011 04:01:52,141 --> 04:01:54,977 THE QUESTION OF THE ANTIBODY IN 5012 04:01:54,977 --> 04:01:57,680 SPITE OF EXPRESSION DID YOU SEE 5013 04:01:57,680 --> 04:02:01,450 IMPACT OF THE CD 8 RESPONSE IN 5014 04:02:01,450 --> 04:02:02,051 THE EXPRESSION IN THE 5015 04:02:02,051 --> 04:02:04,553 CONJUNCTION WITH THE RESPONSE OF 5016 04:02:04,553 --> 04:02:04,887 THE ANTIBODY? 5017 04:02:04,887 --> 04:02:07,156 >> SO, I THINK I COVERED THIS A 5018 04:02:07,156 --> 04:02:07,856 BIT TOO QUICKLY. 5019 04:02:07,856 --> 04:02:11,160 WHAT I MEANT TO SAY IS THAT IN 5020 04:02:11,160 --> 04:02:13,896 TWO OF THE 2023 COHORT ANIMALS 5021 04:02:13,896 --> 04:02:17,433 WE TREATED THEM WITH CD 8 ALPHA 5022 04:02:17,433 --> 04:02:20,035 DEPLETING ANTIBODY TO SEE IF THE 5023 04:02:20,035 --> 04:02:21,770 VIRUS WOULD COME BACK AND 5024 04:02:21,770 --> 04:02:23,972 HAVEN'T SEEN ANY VIRUS OF LAST 5025 04:02:23,972 --> 04:02:24,540 WEEK. 5026 04:02:24,540 --> 04:02:26,909 WE HAVE NOT CHARACTERIZED CD 8 T 5027 04:02:26,909 --> 04:02:31,046 CELL RESPONSES IN THE ANIMALS 5028 04:02:31,046 --> 04:02:33,615 BECAUSE OF THEIR LIMITED BLOOD 5029 04:02:33,615 --> 04:02:35,417 AVAILABILITY AND WILL CONTINUE 5030 04:02:35,417 --> 04:02:36,752 MONITORING PLASMA FOR VIRAL 5031 04:02:36,752 --> 04:02:38,387 LOADS IN THE NEXT WEEKS TO SEE 5032 04:02:38,387 --> 04:02:39,822 IF THAT TRIGGERS ANY REPLICATION 5033 04:02:39,822 --> 04:02:47,696 BUT IT HASN'T SO FAR. 5034 04:02:47,696 --> 04:02:51,734 >> AT THE HIV MEETING IT WAS 5035 04:02:51,734 --> 04:02:55,838 SHOWED USING TWO NEUTRALIZING 5036 04:02:55,838 --> 04:02:58,373 ANTIBODIES AND THREE DAYS AFTER 5037 04:02:58,373 --> 04:03:00,375 INFANT MACAQUE INFECTION HE CAN 5038 04:03:00,375 --> 04:03:04,546 CURE SIX OUT OF SIX ANIMALS, I 5039 04:03:04,546 --> 04:03:04,780 BELIEVE. 5040 04:03:04,780 --> 04:03:15,324 YOU ARE PLANNING TO ADD 5041 04:03:15,324 --> 04:03:16,525 ANIRANOMAB IN THE FUTURE? 5042 04:03:16,525 --> 04:03:18,727 >> WE'RE PLANNING TO COLLABORATE 5043 04:03:18,727 --> 04:03:20,562 WITH HIS GROUP. 5044 04:03:20,562 --> 04:03:22,464 AND IN THE NEAR FUTURE LET'S PUT 5045 04:03:22,464 --> 04:03:25,667 IT THIS WAY. 5046 04:03:25,667 --> 04:03:32,374 >> I HAVE A QUESTION FOR 5047 04:03:32,374 --> 04:03:42,551 KATHERINE. 5048 04:03:49,424 --> 04:03:53,595 >> IT SEEMS LIKE I WAS THINKING 5049 04:03:53,595 --> 04:03:55,631 DO YOU THINK PROLIVE TIF 5050 04:03:55,631 --> 04:03:56,965 CAPACITY OF THE SPECIFIC CD 8 T 5051 04:03:56,965 --> 04:03:59,434 CELLS WOULD YOU CALL IT HIGH OR 5052 04:03:59,434 --> 04:04:00,068 CALL IT LOW? 5053 04:04:00,068 --> 04:04:04,940 WHERE WOULD YOU PUT THAT IN THE 5054 04:04:04,940 --> 04:04:06,041 AND THE QUESTION ABOUT THE 5055 04:04:06,041 --> 04:04:09,244 ADULTS AND THE RESERVOIRS AND 5056 04:04:09,244 --> 04:04:12,514 TRYING TO THINK ABOUT HOW THESE 5057 04:04:12,514 --> 04:04:19,488 PROLIVE -- PROLIFERATIVE 5058 04:04:19,488 --> 04:04:21,390 CAPACITY IS HOW STRONG IS? 5059 04:04:21,390 --> 04:04:28,230 >> WE MEASURED IN THE ASSAYS THE 5060 04:04:28,230 --> 04:04:30,265 PROLIFERATIVE CAPACITY TO GAG 5061 04:04:30,265 --> 04:04:31,900 AND THE OTHER WAS COMPARABLE TO 5062 04:04:31,900 --> 04:04:40,442 WHAT WE HAVE SEEN IN ADULTS WITH 5063 04:04:40,442 --> 04:04:41,043 HIV. 5064 04:04:41,043 --> 04:04:43,846 IT WAS A GOOD RESPONSE AND I 5065 04:04:43,846 --> 04:04:45,747 THINK IT MAKES SENSE GIVEN WE 5066 04:04:45,747 --> 04:04:51,220 WERE ABLE TO DETECT HIV SPECIFIC 5067 04:04:51,220 --> 04:04:53,689 AND MAP HIV SPECIFIC CD 8 T 5068 04:04:53,689 --> 04:04:57,559 CELLS PRIOR TO INITIATION OF ART 5069 04:04:57,559 --> 04:04:57,860 IN THE KIDS. 5070 04:04:57,860 --> 04:05:01,430 >> I WAS THINKING THAT IF THE 5071 04:05:01,430 --> 04:05:03,265 QUALITY SEEMS PARTICULARLY GOOD 5072 04:05:03,265 --> 04:05:07,402 LIKE IF THE PROLIFERATIVE 5073 04:05:07,402 --> 04:05:08,704 RESPONSES SEEMED GOOD MIGHT THEY 5074 04:05:08,704 --> 04:05:10,606 RESPOND WELL TO THERAPEUTIC 5075 04:05:10,606 --> 04:05:10,873 VACCINES? 5076 04:05:10,873 --> 04:05:15,544 AND I WAS CURIOUS WHAT THE 5077 04:05:15,544 --> 04:05:16,612 THOUGHTS ARE -- 5078 04:05:16,612 --> 04:05:21,717 >> THEY HAVE RESPONDED NORMALLY 5079 04:05:21,717 --> 04:05:24,553 TO ROUTINE CHILDHOOD VACCINES 5080 04:05:24,553 --> 04:05:26,922 AND WE WOULD EXPECT THAT THEY 5081 04:05:26,922 --> 04:05:29,424 ARE WOULD PROBABLY HAVE A 5082 04:05:29,424 --> 04:05:34,496 SECONDARY RESPONSE OR A GOOD 5083 04:05:34,496 --> 04:05:37,833 RESPONSE TO A THERAPEUTIC 5084 04:05:37,833 --> 04:05:38,734 VACCINE. 5085 04:05:38,734 --> 04:05:39,534 >> LIKE A T CELL BASED 5086 04:05:39,534 --> 04:05:40,502 THERAPEUTIC VACCINE. 5087 04:05:40,502 --> 04:05:41,637 >> EXACTLY. 5088 04:05:41,637 --> 04:05:46,408 >> ARE THERE PLANS FOR THAT? 5089 04:05:46,408 --> 04:05:49,011 >> WELL, WE PLANNED FOR IT 5090 04:05:49,011 --> 04:05:51,647 SEVERAL TIMES OVER THE YEARS. 5091 04:05:51,647 --> 04:05:58,287 THE AVAILABILITY OF VACCINE IS 5092 04:05:58,287 --> 04:06:00,088 LOOKING FOR A VACCINE WE THINK 5093 04:06:00,088 --> 04:06:02,157 IS CAPABLE OF GENERATING THAT 5094 04:06:02,157 --> 04:06:03,659 TYPE OF T CELL RESPONSE. 5095 04:06:03,659 --> 04:06:06,128 >> I CAN ADD TO THAT RACHEL. 5096 04:06:06,128 --> 04:06:11,433 SO THE IMPACT WE HAVE STUDIED 5097 04:06:11,433 --> 04:06:14,002 2039 IN DEVELOPMENT ALREADY 5098 04:06:14,002 --> 04:06:23,011 AGAIN TO REVIEW AND WILL INCLUDE 5099 04:06:23,011 --> 04:06:29,518 THE VACCINE WITH BNAB IN 5 TO 5100 04:06:29,518 --> 04:06:35,791 12-YEAR-OLDS TREATED IN INFANCY. 5101 04:06:35,791 --> 04:06:38,126 >> MAURICIO, I NOTICED IN YOUR 5102 04:06:38,126 --> 04:06:40,862 CONTROL ANIMALS, IF I HAD IT 5103 04:06:40,862 --> 04:06:42,731 RIGHT THE VIREMIA COMES DOWN IN 5104 04:06:42,731 --> 04:06:43,665 THE CONTROL. 5105 04:06:43,665 --> 04:06:45,667 IT LOOKS LIKE YOU HAVE A HIGHER 5106 04:06:45,667 --> 04:06:48,370 RATE OF CONTROL THAN WHAT 5107 04:06:48,370 --> 04:06:53,342 PHILLIP WAS SAYING FOR EXAMPLE 5108 04:06:53,342 --> 04:06:57,012 IN THE HUMAN PEDIATRIC COHORT 5109 04:06:57,012 --> 04:06:57,879 AND MAKES THE LIKE LIKE THE 5110 04:06:57,879 --> 04:07:01,683 MODEL HAS MORE CONTROL AND THE 5111 04:07:01,683 --> 04:07:03,785 ANTIBODIES MAY HAVE MORE EFFECT 5112 04:07:03,785 --> 04:07:05,554 THAN THE SHIV. 5113 04:07:05,554 --> 04:07:06,722 CAN YOU COMMENT? 5114 04:07:06,722 --> 04:07:11,426 >> THAT'S SOMETHING WE SEE OFTEN 5115 04:07:11,426 --> 04:07:17,599 WITH SHIV WHICH REMAINS AN 5116 04:07:17,599 --> 04:07:18,133 IMPERFECT MODEL. 5117 04:07:18,133 --> 04:07:28,577 WE HOPE AND PREVENTION OF 5118 04:07:41,490 --> 04:07:44,860 REBOUND AND IF YOU LOOK AT THE 5119 04:07:44,860 --> 04:07:47,429 PARAMETER ALONE AND IN THE 5120 04:07:47,429 --> 04:07:49,664 PRESENCE OF THE EXPRESSED 5121 04:07:49,664 --> 04:07:51,400 BIOLOGIC WE SEE A SIGNIFICANT 5122 04:07:51,400 --> 04:07:54,302 DELAY IN TERMS OF VIREMIA POST 5123 04:07:54,302 --> 04:07:56,671 ATI WE HAVE FEW ANIMALS, ONLY 5124 04:07:56,671 --> 04:08:00,609 ONE ACTUALLY OF THE 16 SO FAR 5125 04:08:00,609 --> 04:08:03,912 THAT IS VIREMIC AFTER ATI. 5126 04:08:03,912 --> 04:08:06,848 SO WE CONSENT REALLY MAKE THE 5127 04:08:06,848 --> 04:08:09,751 COMPARISON BETWEEN POST ATI 5128 04:08:09,751 --> 04:08:19,961 VIRAL LOADS. 5129 04:08:26,435 --> 04:08:30,806 >> THE DYNAMICS YOU WERE 5130 04:08:30,806 --> 04:08:31,940 DESCRIBING WERE TIGHTLY LINKED 5131 04:08:31,940 --> 04:08:34,843 TO THE WINDOW OF INFECTION OF 5132 04:08:34,843 --> 04:08:36,978 THE MOTHER SO THEREFORE IS IT 5133 04:08:36,978 --> 04:08:40,449 RIGHT TO THEN INTERPRET THE 5134 04:08:40,449 --> 04:08:42,717 ACUTE INFECTION WITH THE VIRUS 5135 04:08:42,717 --> 04:08:47,422 IS MORE INTERFERON RESISTANT IS 5136 04:08:47,422 --> 04:08:49,691 KEY DYNAMIC TO THE PREFERENTIAL 5137 04:08:49,691 --> 04:08:53,361 OF THE FEMALES OR THE INTRINSIC 5138 04:08:53,361 --> 04:08:56,264 BASELINE OF THE RESPONSE ON THE 5139 04:08:56,264 --> 04:08:57,699 FEMALE IS THE DRIVER MEANS IF 5140 04:08:57,699 --> 04:09:00,235 YOU HAVE WOMEN THAT TRANSMIT 5141 04:09:00,235 --> 04:09:03,338 PASSED THE WINDOW OF ACUTE 5142 04:09:03,338 --> 04:09:05,307 INFECTION YOU DON'T SEE THAT 5143 04:09:05,307 --> 04:09:08,610 DIFFERENTIAL ANYMORE? 5144 04:09:08,610 --> 04:09:11,847 >> THAT'S RIGHT. 5145 04:09:11,847 --> 04:09:22,357 I THINK THE DATA IS SAYING IN 5146 04:09:34,870 --> 04:09:37,672 THAT SETTING THERE'S NO 5147 04:09:37,672 --> 04:09:42,944 DIFFERENCE IN TERMS OF MALES TO 5148 04:09:42,944 --> 04:09:44,579 FEMALES AND THAT SETTING IS 5149 04:09:44,579 --> 04:09:45,180 INTERFERON SENSITIVE. 5150 04:09:45,180 --> 04:09:51,186 IF IT'S TRANSMITTED TO MALES IS 5151 04:09:51,186 --> 04:09:52,821 RARELY INTERFERON RESISTANT AND 5152 04:09:52,821 --> 04:09:58,793 THE REASON WE THINK IS TO DO 5153 04:09:58,793 --> 04:10:00,662 WITH THE IMPACT IT HAS ON 5154 04:10:00,662 --> 04:10:01,229 REPLICATE CAPACITY. 5155 04:10:01,229 --> 04:10:08,570 THERE'S A NEGATIVE CORRELATION 5156 04:10:08,570 --> 04:10:10,539 BETWEEN CAPACITY AND YOU NEED A 5157 04:10:10,539 --> 04:10:12,874 REASONABLY FIT VIRUS TO GET 5158 04:10:12,874 --> 04:10:17,112 ACROSS THE TRANSMISSION BO 5159 04:10:17,112 --> 04:10:19,080 BOTTLENECK IN MALES AND THE FEW 5160 04:10:19,080 --> 04:10:23,418 THAT SUCCEEDED ACROSS THOSE ARE 5161 04:10:23,418 --> 04:10:27,389 THE ONES WHERE WE SEE AVIREMIA. 5162 04:10:27,389 --> 04:10:29,157 >> THAT'S WHAT I WAS GOING TO 5163 04:10:29,157 --> 04:10:29,658 FOLLOW UP NEXT. 5164 04:10:29,658 --> 04:10:33,395 YOU THINK THE CLINICAL 5165 04:10:33,395 --> 04:10:34,729 SIGNIFICANCE DURING THE 5166 04:10:34,729 --> 04:10:36,364 SUSCEPTIBILITY TO INFECTION OR 5167 04:10:36,364 --> 04:10:37,666 WILL HAVE A LONG-TERM IMPACT 5168 04:10:37,666 --> 04:10:39,901 HAVING BEEN TRANSMITTED AT THAT 5169 04:10:39,901 --> 04:10:40,835 POINT TO WHAT ACTUALLY HAPPENS 5170 04:10:40,835 --> 04:10:42,170 SUBSEQUENT? 5171 04:10:42,170 --> 04:10:52,547 >> I THINK IT'S BOTH. 5172 04:10:54,082 --> 04:10:57,385 AND IF YOU HAVE A SENSITIVE 5173 04:10:57,385 --> 04:10:59,187 VIRUS YOU'RE LIKELIHOOD OF 5174 04:10:59,187 --> 04:11:01,690 CONTROLLING THAT VIRUS IS GOING 5175 04:11:01,690 --> 04:11:11,933 TO BE HIGHER. 5176 04:11:13,101 --> 04:11:13,835 >> THANK YOU AND NOW WE'LL MOVE 5177 04:11:13,835 --> 04:11:24,045 TO THE NEXT. 5178 04:11:49,704 --> 04:11:55,744 >> SO THUR -- THANK YOU EVERYONE 5179 04:11:55,744 --> 04:11:57,979 I'M IN THE TARGETED 5180 04:11:57,979 --> 04:11:59,881 INTERVENTIONS PROGRAM IN THE 5181 04:11:59,881 --> 04:12:00,515 SCIENCES PROGRAM IN THE DIVISION 5182 04:12:00,515 --> 04:12:03,518 OF AIDS AND OVERSEE THE CRISPR 5183 04:12:03,518 --> 04:12:04,653 FOR CURE COLLABORATORY. 5184 04:12:04,653 --> 04:12:07,689 SOMETIMES YOU SEE IT AS C4C. 5185 04:12:07,689 --> 04:12:18,166 THE CODIRECTORS ARE KAMALL 5186 04:12:18,500 --> 04:12:21,002 KHALILI AND TRICIA BURDO AT 5187 04:12:21,002 --> 04:12:23,438 RUTGERS UNIVERSITY. 5188 04:12:23,438 --> 04:12:33,715 PLEASE GO AHEAD. 5189 04:12:34,816 --> 04:12:36,551 >> THANK YOU VERY MUCH FOR 5190 04:12:36,551 --> 04:12:37,619 INCLUDING US IN THIS EVENT. 5191 04:12:37,619 --> 04:12:42,524 YOU MAY KNOW THE CRISPR FOR CURE 5192 04:12:42,524 --> 04:12:46,494 IS ONE OF THE LATEST PROGRAMS TO 5193 04:12:46,494 --> 04:12:50,632 BECOME PART OF THE MARTIN 5194 04:12:50,632 --> 04:12:54,102 DELANEY CURE PROGRAM FOR HIV. 5195 04:12:54,102 --> 04:12:55,637 IT'S VERY FOCUSSED IN TERMS OF 5196 04:12:55,637 --> 04:12:58,640 THE GOAL AND THE GOAL OF THE 5197 04:12:58,640 --> 04:13:03,878 MARTIN CRISPR FOR CURE IS TO USE 5198 04:13:03,878 --> 04:13:04,979 MOLECULAR GENETIC APPROACH FOR 5199 04:13:04,979 --> 04:13:07,916 REMOVAL OF THE INTEGRATED COPY 5200 04:13:07,916 --> 04:13:16,091 OF THE HIV FROM THE HOST 5201 04:13:16,091 --> 04:13:16,725 CHROMOSOME AND FOR YELL LAR 5202 04:13:16,725 --> 04:13:19,661 GENES WHOSE PRODUCTS ARE 5203 04:13:19,661 --> 04:13:25,100 IMPORTANT FOR VIRAL REPLICATION. 5204 04:13:25,100 --> 04:13:31,272 IT'S THE PLAIN LANGUAGE SUMMARY 5205 04:13:31,272 --> 04:13:33,675 IS SHOWN HERE. 5206 04:13:33,675 --> 04:13:36,911 IT'S A QUESTION WE'RE ASKING CAN 5207 04:13:36,911 --> 04:13:41,383 BE LIMITED HIV DNA INTEGRATED IN 5208 04:13:41,383 --> 04:13:43,051 CELL CHROMOSOME WHICH HAPPENS 5209 04:13:43,051 --> 04:13:48,022 SOON AFTER THE VIRAL INFECTION 5210 04:13:48,022 --> 04:13:50,125 AND ALSO THAT CHROMOSOME SERVES 5211 04:13:50,125 --> 04:13:54,396 AS THE TEMPLATE FOR PRODUCTION 5212 04:13:54,396 --> 04:13:59,434 OF THE NEW VIRAL PROJECT. 5213 04:13:59,434 --> 04:14:04,272 SO THEN KEY FINDINGS AND TAKE 5214 04:14:04,272 --> 04:14:05,407 HOME MESSAGE FROM THE STUDIES WE 5215 04:14:05,407 --> 04:14:08,543 HAVE DONE SO FAR IS THAT CRISPR 5216 04:14:08,543 --> 04:14:13,681 GENE EDITING TECHNIQUES HAVE 5217 04:14:13,681 --> 04:14:15,717 DEMONSTRATED I BELIEVE TO ENTIRE 5218 04:14:15,717 --> 04:14:18,386 VIRAL GENOME AT THE CELL CULTURE 5219 04:14:18,386 --> 04:14:22,624 AND DESIGNATED SEGMENT DICTATED 5220 04:14:22,624 --> 04:14:26,094 BY THE GUIDE RNAs FROM THE HOST 5221 04:14:26,094 --> 04:14:28,496 GENOME YOU SEE IN THE CARTOON ON 5222 04:14:28,496 --> 04:14:30,799 THE RIGHT SIDE. 5223 04:14:30,799 --> 04:14:32,967 AND WHY THIS IS IMPORTANT IS 5224 04:14:32,967 --> 04:14:36,137 IT'S IMPORTANT BECAUSE THIS 5225 04:14:36,137 --> 04:14:37,639 METHOD OFFERS A POTENTIAL 5226 04:14:37,639 --> 04:14:40,475 GENETIC BASED TECHNIQUE FOR THE 5227 04:14:40,475 --> 04:14:42,544 REPLICATION COMPETENT VIRUS 5228 04:14:42,544 --> 04:14:45,680 WHICH IS TO MY KNOWLEDGE IS A 5229 04:14:45,680 --> 04:14:48,983 CRITICAL STEP TOWARD THE YOU'RE. 5230 04:14:48,983 --> 04:14:50,185 AND CURE OF HIV. 5231 04:14:50,185 --> 04:14:53,121 WHY SHOULD WE BE EXCITED ABOUT 5232 04:14:53,121 --> 04:14:53,388 THIS? 5233 04:14:53,388 --> 04:14:57,492 BECAUSE BY DOING THAT THE 5234 04:14:57,492 --> 04:14:59,961 INDIVIDUALS ARE BASICALLY 5235 04:14:59,961 --> 04:15:01,329 INFECTED BY HIV AND DON'T NEED 5236 04:15:01,329 --> 04:15:04,365 TO TAKE ANY ART AND THE 5237 04:15:04,365 --> 04:15:05,567 COMORBIDITY ASSOCIATED WITH THE 5238 04:15:05,567 --> 04:15:12,373 PRESENCE OF THE VIRUS OR THE 5239 04:15:12,373 --> 04:15:13,708 TREATMENT STRATEGIES WILL 5240 04:15:13,708 --> 04:15:17,412 DISAPPEAR AND WON'T BE STIGMA 5241 04:15:17,412 --> 04:15:17,946 ASSOCIATED WITH THE VIRUS 5242 04:15:17,946 --> 04:15:27,088 PRESENCE. 5243 04:15:27,088 --> 04:15:28,690 THIS DEMONSTRATED HAS WE 5244 04:15:28,690 --> 04:15:29,591 STARTED. 5245 04:15:29,591 --> 04:15:31,626 IN 2015 WE USED CRISPR 5246 04:15:31,626 --> 04:15:33,528 TECHNOLOGY FOR THE VIRUS FROM 5247 04:15:33,528 --> 04:15:37,665 THE CELL CULTURE SYSTEM AND SOON 5248 04:15:37,665 --> 04:15:41,970 WE REALIZED IT'S ACTUALLY 5249 04:15:41,970 --> 04:15:46,374 POSSIBLE TO REMOVE ENTIRE VIRAL 5250 04:15:46,374 --> 04:15:49,210 FROM THE LGR IN THE CELL CULTURE 5251 04:15:49,210 --> 04:15:51,813 MODEL AND THIS WAS REPRODUCED 5252 04:15:51,813 --> 04:15:54,115 SEVERAL TIMES IN A NUMBER OF THE 5253 04:15:54,115 --> 04:16:04,659 CELLS AND PUBLISHED IN THE 2014. 5254 04:16:36,457 --> 04:16:41,062 AND CRISPR CAN PROBABLY BE USED 5255 04:16:41,062 --> 04:16:45,300 FOR THE CURE OF HIV AND THEN 5256 04:16:45,300 --> 04:16:49,203 LATER ON IN 2020 WE MOVED WITH 5257 04:16:49,203 --> 04:16:52,106 THE LARGER ANIMAL NONHUMAN 5258 04:16:52,106 --> 04:16:53,441 PRIMATE AND WE USED THIS AS THE 5259 04:16:53,441 --> 04:16:55,710 TOOL FOR THE INFECTION WHICH IS 5260 04:16:55,710 --> 04:16:57,612 AN ABOUT MODEL FOR HIV AS YOU 5261 04:16:57,612 --> 04:17:03,785 ALL KNOW AND THEN WE SHOWED THAT 5262 04:17:03,785 --> 04:17:05,420 THE APPLICATION OF THE CRISPR 5263 04:17:05,420 --> 04:17:09,490 FOR TARGETED REGION RESULTS IN 5264 04:17:09,490 --> 04:17:13,661 THE REMOVAL OF THE AREA FROM THE 5265 04:17:13,661 --> 04:17:15,029 HOST GENOME. 5266 04:17:15,029 --> 04:17:16,965 AND THEN DELIVERY WE USED FOR 5267 04:17:16,965 --> 04:17:20,001 THAT WAS AAV9. 5268 04:17:20,001 --> 04:17:23,237 AND THEN WE REALIZED IT'S 5269 04:17:23,237 --> 04:17:24,072 BROADLY DISTRIBUTED TO ALMOST 5270 04:17:24,072 --> 04:17:27,642 EVERY CELLS AND THE RESULT OF 5271 04:17:27,642 --> 04:17:35,116 THE DISTRIBUTION WAS EXCISION 5272 04:17:35,116 --> 04:17:37,685 FROM THE GENE IN THE DNA AND 5273 04:17:37,685 --> 04:17:40,888 THIS OBSERVATION FOR WHY THE 5274 04:17:40,888 --> 04:17:46,494 CONVINCING EVIDENCE FOR THE 5275 04:17:46,494 --> 04:17:47,662 CRISPR EXCISION BY THERAPEUTIC 5276 04:17:47,662 --> 04:17:53,267 TEAM TO GO TO NIH AND GET FDA 5277 04:17:53,267 --> 04:17:57,338 APPROVAL AND THE CLINICAL 5278 04:17:57,338 --> 04:17:57,572 TRIALS. 5279 04:17:57,572 --> 04:17:58,740 WE'RE NOT GOING TO TALK ABOUT 5280 04:17:58,740 --> 04:18:01,075 THE OUTCOME OF THAT STUDY 5281 04:18:01,075 --> 04:18:03,378 BECAUSE IT'S OUT OF THE SCOPE OF 5282 04:18:03,378 --> 04:18:08,216 THE MARTIN DELANEY. 5283 04:18:08,216 --> 04:18:12,954 SO WE WHAT YOU'LL HEAR ARE 5284 04:18:12,954 --> 04:18:14,422 STUDIES USED IN THE NONHUMAN 5285 04:18:14,422 --> 04:18:19,927 PRIMATE FOR THE EDITING OF THE 5286 04:18:19,927 --> 04:18:24,465 VIRAL GENOME SO THEN AT THAT 5287 04:18:24,465 --> 04:18:26,234 POINT WE ALSO FORMED A TEAM. 5288 04:18:26,234 --> 04:18:27,869 A TEAM THAT INCLUDED OTHER SMALL 5289 04:18:27,869 --> 04:18:31,172 GROUP AS YOU PROBABLY NOTICED 5290 04:18:31,172 --> 04:18:38,046 COMPARED TO OTHER DELANEYS AND 5291 04:18:38,046 --> 04:18:43,351 THEN AND CASE WESTERN UNIVERSITY 5292 04:18:43,351 --> 04:18:49,657 AND UCLA AND EXCISION WAS OUR 5293 04:18:49,657 --> 04:18:51,526 CORPORATE PARTNER AND A TEAM 5294 04:18:51,526 --> 04:18:55,530 MOVED TO RUTGERS AND INITIATED 5295 04:18:55,530 --> 04:18:58,433 THE PROGRAM AT THE RUTGERS 5296 04:18:58,433 --> 04:19:01,202 INSTITUTE OF TRANSLATIONAL 5297 04:19:01,202 --> 04:19:07,475 RESEARCH AND THE BIO QUAL WHICH 5298 04:19:07,475 --> 04:19:13,214 IS BASICALLY A FACILITY FOR 5299 04:19:13,214 --> 04:19:14,782 NONHUMAN PRIMATE STUDIES CLOSE 5300 04:19:14,782 --> 04:19:15,883 TO HERE AND ALSO WASHINGTON 5301 04:19:15,883 --> 04:19:17,452 UNIVERSITY SCHOOL OF MEDICINE 5302 04:19:17,452 --> 04:19:20,822 ST. LOUIS. 5303 04:19:20,822 --> 04:19:23,157 SO AS YOU SEE IT'S VERY FOCUSSED 5304 04:19:23,157 --> 04:19:25,660 BEFORE PEOPLE GOT TOGETHER AND 5305 04:19:25,660 --> 04:19:28,529 CARRIED ON THE STUDIES WITH THE 5306 04:19:28,529 --> 04:19:31,399 CENTRAL THEME AND THE GOAL IS 5307 04:19:31,399 --> 04:19:33,701 ERADICATION OF THE INTEGRATED 5308 04:19:33,701 --> 04:19:39,674 COPY OF THE VIRUS. 5309 04:19:39,674 --> 04:19:43,945 THE PROGRAM IS COMPRISED OF OF 5310 04:19:43,945 --> 04:19:48,015 THE RESEARCH FOCUS AND WE HAVE 5311 04:19:48,015 --> 04:19:52,754 AN RF1 FOCUSSING ON THE 5312 04:19:52,754 --> 04:19:58,726 UTILIZING BAR CODE SIB KINDLY 5313 04:19:58,726 --> 04:20:06,968 PROVIDED AND FOR THE STUDIES AND 5314 04:20:06,968 --> 04:20:09,537 USING ROLLOVER EPIGENETIC IN THE 5315 04:20:09,537 --> 04:20:19,046 CHRIS PER -- CRISPR EDITING 5316 04:20:19,046 --> 04:20:20,414 APPROACH AND THE LATENT TISSUE 5317 04:20:20,414 --> 04:20:25,253 RESERVOIR AND IMAGING ANALYSIS 5318 04:20:25,253 --> 04:20:31,759 AND THEN LOOKING AT THE VIRUS 5319 04:20:31,759 --> 04:20:33,861 AND BASIC SCIENCE AT THE CORE OF 5320 04:20:33,861 --> 04:20:35,396 OUR GROUP AND RF2 IS INVOLVING 5321 04:20:35,396 --> 04:20:37,832 THE LOOKING AT THE NUMBER OF 5322 04:20:37,832 --> 04:20:41,102 AREAS WHICH CAN HELP TO 5323 04:20:41,102 --> 04:20:42,436 UNDERSTAND THE VIRUS HOST 5324 04:20:42,436 --> 04:20:43,437 INTERACTION AND POTENTIAL EFFECT 5325 04:20:43,437 --> 04:20:52,480 OF THE VIRUS IN ELIMINATION OF 5326 04:20:52,480 --> 04:20:53,681 THE VIRUS AND THE AREA OF FROM 5327 04:20:53,681 --> 04:20:54,882 FOR OUR TEAM. 5328 04:20:54,882 --> 04:21:00,054 ON ONE HAND WE USED THE 5329 04:21:00,054 --> 04:21:05,426 INFLAMMASOME CONTROLLING SIV 5330 04:21:05,426 --> 04:21:08,996 DISEASE PROGRESSION AND CRISPR 5331 04:21:08,996 --> 04:21:10,898 MODIFICATION IN MONKEY MODEL AND 5332 04:21:10,898 --> 04:21:18,139 ALSO IMMUNOMODULATION AND THE 5333 04:21:18,139 --> 04:21:21,309 EXPANDING OR ACTIVATING NK CELLS 5334 04:21:21,309 --> 04:21:27,215 AND FINALLY THE CRISPR EDITING 5335 04:21:27,215 --> 04:21:29,150 IN THE NONHUMAN PRIMATE AND WE 5336 04:21:29,150 --> 04:21:31,152 HAVE DONE THAT PREVIOUSLY IN THE 5337 04:21:31,152 --> 04:21:33,688 MICE BUT TRYING TO SEE WHAT 5338 04:21:33,688 --> 04:21:37,425 RESPONSE WE GET IF WE CAN PAIR 5339 04:21:37,425 --> 04:21:39,260 THE ELIMINATION OF THE 5340 04:21:39,260 --> 04:21:44,866 ACTIVATION OF SIV IN CONTEXT OF 5341 04:21:44,866 --> 04:21:46,767 THE VIRUS. 5342 04:21:46,767 --> 04:21:50,404 AND THE RF3 IS BASICALLY 5343 04:21:50,404 --> 04:21:55,943 TECHNICAL ASPECT OF THE CRISPR 5344 04:21:55,943 --> 04:21:57,311 WHICH INCLUDES THE TOOLS 5345 04:21:57,311 --> 04:21:59,947 CREATING FOR THE GENETIC 5346 04:21:59,947 --> 04:22:02,884 ANALYSIS AND THEN LOOKING AT THE 5347 04:22:02,884 --> 04:22:06,921 OFF TARGET, ON TARGET SEQUENCE 5348 04:22:06,921 --> 04:22:10,691 AND THE FOCUS IS TO CREATE THE 5349 04:22:10,691 --> 04:22:16,264 BEST AND EFFICIENT PRODUCTS. 5350 04:22:16,264 --> 04:22:18,966 THE PRODUCTS IS THE CAS 9 RNAs. 5351 04:22:18,966 --> 04:22:21,736 THE TOOL FOR THE DELIVERY WE 5352 04:22:21,736 --> 04:22:27,675 USED WAS AT THAT STAGE WAS AAV9 5353 04:22:27,675 --> 04:22:30,411 AND THEN OBVIOUSLY MODIFYING 5354 04:22:30,411 --> 04:22:33,681 THAT DELIVERY SYSTEM AS WE MOVE 5355 04:22:33,681 --> 04:22:35,716 ALONG. 5356 04:22:35,716 --> 04:22:37,285 SO THIS IS JUST AN EXAMPLE OF 5357 04:22:37,285 --> 04:22:39,954 THE FEW PUBLICATION THAT WE HAD 5358 04:22:39,954 --> 04:22:43,157 OVER THE LAST YEAR OR TWO. 5359 04:22:43,157 --> 04:22:45,660 AND THEN AS YOU SEE NOTICE IT'S 5360 04:22:45,660 --> 04:22:47,428 COMING FROM THE DIFFERENT 5361 04:22:47,428 --> 04:22:48,963 LABORATORIES PARTICIPATING IN 5362 04:22:48,963 --> 04:22:53,534 THIS GROUP FROM RF1, RF2 AND 5363 04:22:53,534 --> 04:22:54,402 RF3. 5364 04:22:54,402 --> 04:23:01,676 SO, WITH THAT NOTE I'M GOING TO 5365 04:23:01,676 --> 04:23:06,047 START BASICALLY TALKING ABOUT 5366 04:23:06,047 --> 04:23:08,182 SOME OF THE OBSERVATION WE HAD 5367 04:23:08,182 --> 04:23:10,885 IN THE RF3 FOCUSSING ON THE 5368 04:23:10,885 --> 04:23:15,156 CREATION OF THE CRISPR GUIDE RNA 5369 04:23:15,156 --> 04:23:17,425 FOR THE VIRUS IN THE NONHUMAN 5370 04:23:17,425 --> 04:23:17,658 PRIMATE. 5371 04:23:17,658 --> 04:23:20,828 THE VIRUS THAT WE USED WAS 5372 04:23:20,828 --> 04:23:24,131 BASICALLY A BAR CODED AS I 5373 04:23:24,131 --> 04:23:29,136 MENTIONED PROVIDED TO US BY OUR 5374 04:23:29,136 --> 04:23:32,940 COLLEAGUE HERE AND THEN THIS 5375 04:23:32,940 --> 04:23:35,409 LOOKS AT BASICALLY FOR THE 5376 04:23:35,409 --> 04:23:37,812 INCORPORATION OF THE BAR CODED 5377 04:23:37,812 --> 04:23:41,515 SEQUENCE AND THEN AFTER THE 5378 04:23:41,515 --> 04:23:43,584 SERIES OF THE ASSAYS THEY ARE 5379 04:23:43,584 --> 04:23:44,585 DEVELOPED SOME IN THE LABORATORY 5380 04:23:44,585 --> 04:23:50,291 WE IDENTIFIED THE REGIONS WITHIN 5381 04:23:50,291 --> 04:23:52,226 THE OUTSIDE OF THE BAR CODED 5382 04:23:52,226 --> 04:23:55,363 SEQUENCE WHICH CAN BE USED FOR 5383 04:23:55,363 --> 04:23:56,297 INACTIVATION OF THE VIRUS. 5384 04:23:56,297 --> 04:23:58,199 OBVIOUSLY WE DIDN'T WANT TO USE 5385 04:23:58,199 --> 04:23:59,834 THE AREA IN THIS PART OF THE 5386 04:23:59,834 --> 04:24:02,269 GENE YOU HAVE TO FOCUS ON THE 5387 04:24:02,269 --> 04:24:09,677 PART AWAY FROM THE BAR CODED 5388 04:24:09,677 --> 04:24:09,944 SEQUENCE. 5389 04:24:09,944 --> 04:24:14,181 SO THE RESULT FROM THE ANALYSIS 5390 04:24:14,181 --> 04:24:16,517 USING THE SINGLE RNA FIRST TO 5391 04:24:16,517 --> 04:24:17,685 IDENTIFY THE REGION WHICH CAN 5392 04:24:17,685 --> 04:24:23,357 SERVE FOR DEVELOPMENT OF THE 5393 04:24:23,357 --> 04:24:30,765 GUIDE RNA FOR ELIMB FLATION --' 5394 04:24:30,765 --> 04:24:32,733 ELIMINATION AND DIDN'T RESULT 5395 04:24:32,733 --> 04:24:37,271 THE ENTIRE ELIMINATION AND 5396 04:24:37,271 --> 04:24:38,906 REMOVED THE SEQUENCE AND 5397 04:24:38,906 --> 04:24:42,777 IDENTIFIED THE REGION OF THE 5398 04:24:42,777 --> 04:24:48,249 VIRUS AS YOU SEE HERE . 5399 04:24:48,249 --> 04:24:55,456 ALSO NEXT TO THAT WAS THESE 5400 04:24:55,456 --> 04:24:59,660 REGIONS AND THESE TWO BASED ON 5401 04:24:59,660 --> 04:25:00,895 THE ANALYSIS SHOWED INEFFICIENCY 5402 04:25:00,895 --> 04:25:06,567 FOR THE EDITING OF THE GENE. 5403 04:25:06,567 --> 04:25:09,870 AND HERE YOU CAN SEE EVEN IN THE 5404 04:25:09,870 --> 04:25:12,540 PAIR WHEN WE PAIRED THEM THESE 5405 04:25:12,540 --> 04:25:17,711 TWO YOU SEE GOOD EFFICIENCY OF 5406 04:25:17,711 --> 04:25:20,214 T 5407 04:25:20,214 --> 04:25:21,282 THE REMOVAL OF THE DNA. 5408 04:25:21,282 --> 04:25:31,826 SO WE MOVE ON WITH THE TARGETS 5409 04:25:32,059 --> 04:25:32,393 IN THE STUDIES. 5410 04:25:32,393 --> 04:25:39,266 SO THIS SHOWS SOME OF THE 5411 04:25:39,266 --> 04:25:41,869 RESULTS IN TERMS OF THE RESULT 5412 04:25:41,869 --> 04:25:47,374 FROM THE LOSS OF SIGNAL DDPCR 5413 04:25:47,374 --> 04:25:52,680 SHOWED 31% OF THE EXCISION OF 5414 04:25:52,680 --> 04:25:58,152 THE REMOVAL AND USED ANOTHER 5415 04:25:58,152 --> 04:25:59,420 CANDIDATE AND THE NUMBER WAS 5416 04:25:59,420 --> 04:26:03,424 MUCH LESS THAN THAT SO WE'LL 5417 04:26:03,424 --> 04:26:05,392 MOVE FORWARD. 5418 04:26:05,392 --> 04:26:08,696 AND THEN THE NEXT ONE WAS 5419 04:26:08,696 --> 04:26:11,432 FOCUSSING ON THE VIRAL VECTOR. 5420 04:26:11,432 --> 04:26:16,537 FOR VIRAL VECTOR AS WE NOTED THE 5421 04:26:16,537 --> 04:26:17,738 SMALLER IS BETTER TO USE AS 5422 04:26:17,738 --> 04:26:19,740 SMALL AS YOU COULD BECAUSE OF 5423 04:26:19,740 --> 04:26:21,976 THE PACKAGE INEFFICIENCIES. 5424 04:26:21,976 --> 04:26:26,380 SO FOR THAT WE IDENTIFIED THE 5425 04:26:26,380 --> 04:26:30,284 ELONGATION AND ONE ALPHA 5426 04:26:30,284 --> 04:26:31,886 PROMOTER WHICH BASICALLY SHOWS 5427 04:26:31,886 --> 04:26:34,455 GOOD EFFICIENCY FOR THE 5428 04:26:34,455 --> 04:26:35,723 EXPLANATION OF THE CAS 9. 5429 04:26:35,723 --> 04:26:38,626 THIS WAS CREATED AND YOU SEE ON 5430 04:26:38,626 --> 04:26:42,062 THE RIGHT AND THEN VALIDATED IN 5431 04:26:42,062 --> 04:26:47,501 THE CELLS FOR THE EXPIRATION OF 5432 04:26:47,501 --> 04:26:58,045 THE CAS 9 RNA AND THE VIRAL DNA. 5433 04:26:59,613 --> 04:27:01,549 THERE'S NO SIGNIFICANT 5434 04:27:01,549 --> 04:27:03,817 DIFFERENCE IN THE PRODUCTION OF 5435 04:27:03,817 --> 04:27:08,489 THE CAS 9 ELONGATION ONE ALPHA 5436 04:27:08,489 --> 04:27:10,791 PROMOTER VERSUS GENETIC PROMOTER 5437 04:27:10,791 --> 04:27:14,361 WE USUALLY USE OR BEING USED BY 5438 04:27:14,361 --> 04:27:18,065 MANY OTHER PEOPLE. 5439 04:27:18,065 --> 04:27:25,673 AND THEN WE SHOWED BY SEQUENCING 5440 04:27:25,673 --> 04:27:32,346 THE EX CISION OF THE SEGMENTS. 5441 04:27:32,346 --> 04:27:36,684 THIS CONSTRUCT WAS PACKAGED IN 5442 04:27:36,684 --> 04:27:39,587 THE NORTH CAROLINA VECTOR 5443 04:27:39,587 --> 04:27:40,521 LABORATORIES. 5444 04:27:40,521 --> 04:27:43,424 AND THEN WE BASICALLY START THE 5445 04:27:43,424 --> 04:27:46,093 EXPERIMENT IN THE MONKEY 5446 04:27:46,093 --> 04:27:48,362 INJECTION DONE IN THE FACILITY 5447 04:27:48,362 --> 04:27:51,999 AND FACILITY WHICH IS EXISTING 5448 04:27:51,999 --> 04:27:54,969 HERE AND THEN SOME DETAILS ARE 5449 04:27:54,969 --> 04:27:55,536 SHOWING HERE. 5450 04:27:55,536 --> 04:27:58,872 SO WHAT I'M GOING TO DO IS SHOW 5451 04:27:58,872 --> 04:28:02,610 YOU THE BRIEF SUMMARY OF THE 5452 04:28:02,610 --> 04:28:05,012 VAST NUMBER OF THE DATA THAT WE 5453 04:28:05,012 --> 04:28:05,613 OBTAINED. 5454 04:28:05,613 --> 04:28:11,418 I WON'T GO THROUGH THAT BUT SHOW 5455 04:28:11,418 --> 04:28:18,392 YOU ONE OF THEM IS THE LYMPH 5456 04:28:18,392 --> 04:28:22,563 NODE AND IF YOU LOOK HERE YOU 5457 04:28:22,563 --> 04:28:28,469 SEE THE CRISPR AND ATI AND NE 5458 04:28:28,469 --> 04:28:31,472 NECROPSY IS HIGH. 5459 04:28:31,472 --> 04:28:34,675 IT SHOWED THE REBOUND HAPPENED. 5460 04:28:34,675 --> 04:28:43,617 BUT THE THING HERE IS WE WERE 5461 04:28:43,617 --> 04:28:45,419 HOPING WE DIDN'T SEE BUT WE DID 5462 04:28:45,419 --> 04:28:49,123 SEE THE REBOUND AND WE NOTICED 5463 04:28:49,123 --> 04:28:53,427 WHEN WE LOOK AT THE EXPIRATION 5464 04:28:53,427 --> 04:28:56,664 OF THE CAS 9 IT WAS EXPERIENCING 5465 04:28:56,664 --> 04:28:58,732 BECAUSE THAT WAS A CONTROL. 5466 04:28:58,732 --> 04:29:01,302 THERE WAS AN EXPERIMENTAL SET 5467 04:29:01,302 --> 04:29:03,304 DID NOT GET GUIDE RNAs WHICH IS 5468 04:29:03,304 --> 04:29:03,537 BLINDED. 5469 04:29:03,537 --> 04:29:09,877 YOU DON'T SEE THAT ONE. 5470 04:29:09,877 --> 04:29:13,981 WE ALSO FOUND IN THE SUMMARY IN 5471 04:29:13,981 --> 04:29:19,253 THE LIVE LYMPH NODE NINE COPIES 5472 04:29:19,253 --> 04:29:24,258 OF THE DAP SEQUENCE DETECTED IN 5473 04:29:24,258 --> 04:29:26,093 10,000 CELLS. 5474 04:29:26,093 --> 04:29:29,630 AND IN THE SPLEEN THIS WAS THREE 5475 04:29:29,630 --> 04:29:35,302 COPIES PER 10,000 CELLS AND WE 5476 04:29:35,302 --> 04:29:36,770 DIDN'T TAKE ANYTHING AND IN THE 5477 04:29:36,770 --> 04:29:38,505 BRAIN ALSO UNDETECTABLE. 5478 04:29:38,505 --> 04:29:41,642 AND WHEN YOU LOOKING AT THE AAV 5479 04:29:41,642 --> 04:29:47,414 THE NUMBER SHOWS THE AAV WAS 5480 04:29:47,414 --> 04:29:52,019 BROADLY DISTRIBUTED ALMOST IN 5481 04:29:52,019 --> 04:29:57,224 THE LIVER AND THEN ALSO TO A 5482 04:29:57,224 --> 04:29:59,426 LESSER DEGREE IN THE SPLEEN AND 5483 04:29:59,426 --> 04:30:01,295 IN THE LYMPH NODE AND MORE IN 5484 04:30:01,295 --> 04:30:05,199 THE BRAIN. 5485 04:30:05,199 --> 04:30:09,470 AND THEN WHEN YOU THE ASSAY IT 5486 04:30:09,470 --> 04:30:10,437 SHOWED THE RESULT SHOWS 5487 04:30:10,437 --> 04:30:15,776 DETECTION OF THE FRAGMENTS 5488 04:30:15,776 --> 04:30:17,277 ACROSS THE BOARD ESPECIALLY IN 5489 04:30:17,277 --> 04:30:20,948 ONE OF THE ANIMALS WE USED. 5490 04:30:20,948 --> 04:30:23,417 IN THE BRAIN AND SPLEEN AND 5491 04:30:23,417 --> 04:30:29,390 LIVER SHOWS DETECTION OF THE 5492 04:30:29,390 --> 04:30:30,991 FRAGMENTS OF THE VIRUS. 5493 04:30:30,991 --> 04:30:35,896 THIS SLIDE ILLUSTRATES THE GUIDE 5494 04:30:35,896 --> 04:30:42,569 RNA EXCISION HERE AND HERE AND 5495 04:30:42,569 --> 04:30:44,138 AS YOU SEE IN THE NUMBER OF ONE 5496 04:30:44,138 --> 04:30:49,676 OF THE ANIMALS YOU SEE THEIR 5497 04:30:49,676 --> 04:30:55,149 EXCISION IN THE BRAIN AND SPLEEN 5498 04:30:55,149 --> 04:30:59,420 IN SOME WASN'T COMPLETE EXCISION 5499 04:30:59,420 --> 04:31:04,358 BASICALLY IN THE MUTATIONS. 5500 04:31:04,358 --> 04:31:07,561 INTERESTINGLY WE SAW PRECISE 5501 04:31:07,561 --> 04:31:08,829 EXCISION OF THE VIRAL DNA YOU 5502 04:31:08,829 --> 04:31:09,897 SEE IN THE CASE AND IN THIS 5503 04:31:09,897 --> 04:31:20,007 CASE. 5504 04:31:20,974 --> 04:31:24,745 SO THIS EXPERIMENT DEMONSTRATED 5505 04:31:24,745 --> 04:31:26,847 THE VIRAL DNA CAN BE EXCISED 5506 04:31:26,847 --> 04:31:29,416 FROM THE BROAD RANGE OF TISSUE 5507 04:31:29,416 --> 04:31:32,119 THAT SERVES AS THE VIRAL 5508 04:31:32,119 --> 04:31:33,554 RESERVOIR BUT THE PROBLEM WAS 5509 04:31:33,554 --> 04:31:35,989 DELIVERY WHICH I THINK DELIVERY 5510 04:31:35,989 --> 04:31:37,324 WAS NOT AS STRONG. 5511 04:31:37,324 --> 04:31:40,260 WE DECIDED TO CHANGE THE 5512 04:31:40,260 --> 04:31:41,361 DELIVERY SYSTEM AND THAT'S AN 5513 04:31:41,361 --> 04:31:42,162 EXPERIMENT IN PROCESS. 5514 04:31:42,162 --> 04:31:45,232 SO I DON'T HAVE A CLEAR UPDATE 5515 04:31:45,232 --> 04:31:47,034 FOR YOU TO SHOW IN THE MONKEYS. 5516 04:31:47,034 --> 04:31:52,773 BUT I'M GOING TO JUST SHOW YOU 5517 04:31:52,773 --> 04:31:57,778 THE DELIVERY SYSTEM WAS BASED ON 5518 04:31:57,778 --> 04:32:00,113 SOMETHING PUBLISHED RECENTLY AND 5519 04:32:00,113 --> 04:32:02,716 THAT IS A PSEUDO LENTI VIRUS 5520 04:32:02,716 --> 04:32:08,889 WHICH BASICALLY CARRIES THE 5521 04:32:08,889 --> 04:32:12,960 GUIDE RNAs AND CAS 9 PROTEINS 5522 04:32:12,960 --> 04:32:15,496 AND ALSO WE CAN EXPRESS THE GFP 5523 04:32:15,496 --> 04:32:17,264 IN THAT AND THE DETECTION THEN 5524 04:32:17,264 --> 04:32:20,901 WE INTRODUCED THE CONSTRUCT IN 5525 04:32:20,901 --> 04:32:23,437 THE CD4 AND CD 8 POSITIVE AND 5526 04:32:23,437 --> 04:32:26,473 NEGATIVE AND SHOWED IT CLEARLY 5527 04:32:26,473 --> 04:32:28,742 SHOWS YOU CAN INCREASE THE 5528 04:32:28,742 --> 04:32:33,480 NUMBER OF THE CD4 POSITIVE 5529 04:32:33,480 --> 04:32:35,315 RECEIVED AND THAT THE DELIVERY 5530 04:32:35,315 --> 04:32:35,549 SYSTEM. 5531 04:32:35,549 --> 04:32:36,550 SO PERHAPS THIS IS SOMETHING 5532 04:32:36,550 --> 04:32:41,822 THAT WE HAVE TO MOVE FORWARD. 5533 04:32:41,822 --> 04:32:45,359 WE UNDERSTAND THAT WE SHOWED 5534 04:32:45,359 --> 04:32:49,663 THAT THE BRAIN AND LYMPH NODE IN 5535 04:32:49,663 --> 04:32:50,631 PARTICULAR RECEIVE THE GUIDE RNA 5536 04:32:50,631 --> 04:32:52,633 AND VIRAL GENOME BUT WE NEED TO 5537 04:32:52,633 --> 04:32:54,334 GET THE DELIVERY SYSTEM AND HERE 5538 04:32:54,334 --> 04:32:56,169 WE HAVE PROBABLY SOMETHING THAT 5539 04:32:56,169 --> 04:32:58,472 WE HAVE TO MOVE FORWARD ON AND 5540 04:32:58,472 --> 04:32:59,139 WORK ON IT. 5541 04:32:59,139 --> 04:33:09,683 I THINK I'LL STOP AT THIS STAGE. 5542 04:33:18,392 --> 04:33:20,360 >> I'M TRISH BURDO ONE OF THE 5543 04:33:20,360 --> 04:33:24,331 CORE LEADERS AND INVESTIGATOR 5544 04:33:24,331 --> 04:33:26,567 AND TALKING ABOUT THE WORK IN 5545 04:33:26,567 --> 04:33:27,234 THE NONHUMAN PRIMATES AND TRYING 5546 04:33:27,234 --> 04:33:30,337 TO GIVE A FEEL NOR ASSAYS WE DO 5547 04:33:30,337 --> 04:33:37,010 FOR RF1 AND OTHER THINGS IN RF2. 5548 04:33:37,010 --> 04:33:39,980 THIS IS OUR PLAIN LANGUAGE 5549 04:33:39,980 --> 04:33:40,881 SUMMARY. 5550 04:33:40,881 --> 04:33:42,482 AFTER USING CRISPR TARGETING DNA 5551 04:33:42,482 --> 04:33:45,652 IN MONKEYS WHEN WE STOP 5552 04:33:45,652 --> 04:33:46,320 ANTIRETROVIRAL? 5553 04:33:46,320 --> 04:33:50,090 AND HOW DO WE MEASURE THE 5554 04:33:50,090 --> 04:33:51,658 RESERVOIR WITH CUTTING EDGE 5555 04:33:51,658 --> 04:33:53,827 METHODS ADAPTED TO SIV. 5556 04:33:53,827 --> 04:33:56,363 KEY FINDINGS AND TAKEAWAY 5557 04:33:56,363 --> 04:33:56,630 MESSAGES. 5558 04:33:56,630 --> 04:33:58,966 SO CRISPR WAS DELIVERED TO THE 5559 04:33:58,966 --> 04:34:04,204 SIV INFECT ED MONKEYS AND SHOW 5560 04:34:04,204 --> 04:34:05,572 DATA FROM STUDIES WE'VE SHOWN 5561 04:34:05,572 --> 04:34:08,475 THERE WAS NO SIDE EFFECTS AND 5562 04:34:08,475 --> 04:34:10,844 STUDIES ARE UNDERWAY TO 5563 04:34:10,844 --> 04:34:13,680 DETERMINE IF CRISPR AFFECTED THE 5564 04:34:13,680 --> 04:34:19,920 VIRAL RESERVOIR AND METHODS 5565 04:34:19,920 --> 04:34:20,921 ADAPTED FOR SIV. 5566 04:34:20,921 --> 04:34:22,422 WE'RE TRYING TO DETERMINE HOW IT 5567 04:34:22,422 --> 04:34:26,560 WORKS AND IF IT'S SUCCESSFUL IN 5568 04:34:26,560 --> 04:34:27,427 REDUCING VIRAL COURSE. 5569 04:34:27,427 --> 04:34:30,297 WHY SHOULD WE BE EXCITED? 5570 04:34:30,297 --> 04:34:33,033 IF WE CAN SHOW CRISPR CAN REDUCE 5571 04:34:33,033 --> 04:34:36,403 SIV IN MONKEYS IT COULD 5572 04:34:36,403 --> 04:34:37,537 POTENTIALLY DO THE SAME IN 5573 04:34:37,537 --> 04:34:38,305 PEOPLE. 5574 04:34:38,305 --> 04:34:40,207 OVER ALL THE MORE WE UNDERSTAND 5575 04:34:40,207 --> 04:34:43,377 ABOUT HOW TREATMENTS AFFECT THE 5576 04:34:43,377 --> 04:34:44,611 VIRAL RESERVOIR THE BETTER WE 5577 04:34:44,611 --> 04:34:45,212 CAN DESIGN AND TARGET FUTURE 5578 04:34:45,212 --> 04:34:52,853 STRATEGIES. 5579 04:34:52,853 --> 04:34:58,225 RF1 IN OUR LABORATORY RAN BY 5580 04:34:58,225 --> 04:34:58,959 DR. ZACH. 5581 04:34:58,959 --> 04:35:01,662 NEITHER COULD BE HERE BUT WE 5582 04:35:01,662 --> 04:35:04,097 HAVE JOCELYN KIM DESCRIBING HER 5583 04:35:04,097 --> 04:35:05,565 WORK IN RF1. 5584 04:35:05,565 --> 04:35:09,670 SO ONE OF THE MAIN AIMS OF RF1 5585 04:35:09,670 --> 04:35:11,405 IS TO USE BAR CODED VIRUS TO 5586 04:35:11,405 --> 04:35:17,911 LOOK AT THE SOURCES OF VIRAL 5587 04:35:17,911 --> 04:35:20,213 REBOUND AND THE MECHANISMS OF 5588 04:35:20,213 --> 04:35:21,481 VIRAL PERSISTENCE. 5589 04:35:21,481 --> 04:35:25,285 WE'RE USING TWO MODELS IN OUR 5590 04:35:25,285 --> 04:35:25,619 COLLABORATORY. 5591 04:35:25,619 --> 04:35:27,688 THE HUMANIZED MOUSE MODEL AND 5592 04:35:27,688 --> 04:35:29,589 THE NONHUMAN PRIMATES AND WE'LL 5593 04:35:29,589 --> 04:35:31,792 BE TALKING TODAY MOSTLY ABOUT 5594 04:35:31,792 --> 04:35:34,261 THE NONHUMAN PRIMATE WORK. 5595 04:35:34,261 --> 04:35:42,602 SO AS KAMALL MENTIONED WE'RE 5596 04:35:42,602 --> 04:35:45,672 USING THE BAR CODED VIRUS AND 5597 04:35:45,672 --> 04:35:53,046 THERE IS THE BAR CODE HAS THREE 5598 04:35:53,046 --> 04:35:57,651 34 NUCLEOTIDE BANDWIDTH AND 10 5599 04:35:57,651 --> 04:35:59,653 RANDOM NUCLEOTIDES AND WHAT 5600 04:35:59,653 --> 04:36:01,621 WE'RE USING THIS FOR IN THE 5601 04:36:01,621 --> 04:36:04,057 STUDIES IS TO DEEP SEQUENCE THE 5602 04:36:04,057 --> 04:36:06,626 RESERVOIR TO LOOK AT PLASMA 5603 04:36:06,626 --> 04:36:09,963 VIRUS TISSUE RNA AND DNA AND 5604 04:36:09,963 --> 04:36:12,132 ANALYSIS OF OUR HIV THAT 5605 04:36:12,132 --> 04:36:12,632 REBOUNDS. 5606 04:36:12,632 --> 04:36:18,205 SO WE'RE USING THIS ASSAY TO SEE 5607 04:36:18,205 --> 04:36:23,343 CRISPR IS SUCCESSFULLY 5608 04:36:23,343 --> 04:36:27,981 DECREASING THE RF2. 5609 04:36:27,981 --> 04:36:33,053 AND THEY ARE HAVE BEEN DESIGN 5610 04:36:33,053 --> 04:36:38,158 ING THE RNA BAR CODE ASSAYS THAT 5611 04:36:38,158 --> 04:36:39,593 WORK IN SIV. 5612 04:36:39,593 --> 04:36:41,962 BRIEFLY THEY USED A UMI THAT IS 5613 04:36:41,962 --> 04:36:50,837 ATTACHED TO A VIRAL BAR CODE 5614 04:36:50,837 --> 04:36:53,507 THAT ENABLES THEM TO LOOK AT THE 5615 04:36:53,507 --> 04:36:55,041 NUCLEOTIDE AT EACH POSITION AND 5616 04:36:55,041 --> 04:36:57,611 SEQUENCE AND GET RID OF PCR OR 5617 04:36:57,611 --> 04:36:59,412 DEEP SEQUENCING. 5618 04:36:59,412 --> 04:37:09,956 SO THEY'RE USING THE TECHNOLOGY. 5619 04:37:17,130 --> 04:37:19,866 >> A/V GUIDES WE JUST NEED THE 5620 04:37:19,866 --> 04:37:20,867 SLIDES. 5621 04:37:20,867 --> 04:37:21,601 NOT THE SPEAKER. 5622 04:37:21,601 --> 04:37:23,436 >> SCARY, EVERYONE SEES ME. 5623 04:37:23,436 --> 04:37:33,613 THANK YOU. 5624 04:37:49,229 --> 04:37:54,334 THE WORK WORKS WITH BRANDON 5625 04:37:54,334 --> 04:37:55,569 KEEL'S GROUP LOOKING AT THE 5626 04:37:55,569 --> 04:37:59,406 ASSAYS AND DID A COMPARISON 5627 04:37:59,406 --> 04:38:01,641 ACROSS THE LABS AND THE OTHER 5628 04:38:01,641 --> 04:38:04,945 METHOD WAS FROM DR. KIM'S LAB 5629 04:38:04,945 --> 04:38:06,446 AND SHOWED THERE'S A STRONG 5630 04:38:06,446 --> 04:38:07,414 CORRELATION IN THE RESULTS. 5631 04:38:07,414 --> 04:38:09,449 SO THE NUMBER OF BAR CODES, THE 5632 04:38:09,449 --> 04:38:11,785 DIVERSITY OF THE BAR CODE AND 5633 04:38:11,785 --> 04:38:13,620 ABUNDANCE OF THE BAR CODE WAS 5634 04:38:13,620 --> 04:38:16,890 ALL VERY CORRELATIVE AND SO WE 5635 04:38:16,890 --> 04:38:18,758 BELIEVE THIS SHOWED THE ASSAY IS 5636 04:38:18,758 --> 04:38:22,028 ROBUST AND SO WE'RE GOING TO 5637 04:38:22,028 --> 04:38:23,697 UTILIZE THE VIRUS TECHNOLOGY IN 5638 04:38:23,697 --> 04:38:28,268 OUR STUDIES. 5639 04:38:28,268 --> 04:38:29,903 TO GIVE AN EXAMPLE OF THIS. 5640 04:38:29,903 --> 04:38:34,708 ON THE LEFT SIDE WE HAVE AN 5641 04:38:34,708 --> 04:38:37,510 MRALZ AND ACUTE INFECTION DAY 14 5642 04:38:37,510 --> 04:38:40,847 AFTER INFECTION AND SEE A NUMBER 5643 04:38:40,847 --> 04:38:41,781 OF BAR CODES. 5644 04:38:41,781 --> 04:38:44,985 ON THE LEFT-HAND SIDE IS THE 5645 04:38:44,985 --> 04:38:45,252 FREQUENCY. 5646 04:38:45,252 --> 04:38:47,754 YOU SEE A LOT OF ABUNDANT BAR 5647 04:38:47,754 --> 04:38:51,224 CODE AND VARIANTS ATHET BOTTOM 5648 04:38:51,224 --> 04:38:52,492 OF THE FREQUENCY AND MINOR 5649 04:38:52,492 --> 04:38:54,027 VARIANCES AND SAMPLE ON THE 5650 04:38:54,027 --> 04:38:55,762 RIGHT SIDE ARE THE ART SAMPLE SO 5651 04:38:55,762 --> 04:38:57,797 THIS IS ONE WEEK AFTER ART. 5652 04:38:57,797 --> 04:39:01,101 AND YOU SEE A DECREASE IN THE 5653 04:39:01,101 --> 04:39:04,638 BAR CODES AND THEN YOU ALSO SEE 5654 04:39:04,638 --> 04:39:07,274 A DROP OUT OF THE MINOR BAR CODE 5655 04:39:07,274 --> 04:39:10,777 AND SO REALLY THAT'S BECAUSE 5656 04:39:10,777 --> 04:39:11,544 ONCE YOU START ANTIRETROVIRAL IN 5657 04:39:11,544 --> 04:39:13,647 THE CIRCULATION THOSE ARE THE 5658 04:39:13,647 --> 04:39:17,150 ONES THAT ARE MOST EASILY 5659 04:39:17,150 --> 04:39:17,417 EXPELLED. 5660 04:39:17,417 --> 04:39:19,252 WE'RE USING THIS ASSAY THROUGH 5661 04:39:19,252 --> 04:39:20,654 OUR STUDY AND WILL BE USING IT 5662 04:39:20,654 --> 04:39:21,721 TO LOOK AT DIVERSITY IN CHRIS 5663 04:39:21,721 --> 04:39:25,625 PER. 5664 04:39:25,625 --> 04:39:26,159 -- CRISPR. 5665 04:39:26,159 --> 04:39:30,730 THIS BRINGS US TO OUR DESIGN AND 5666 04:39:30,730 --> 04:39:35,402 BRIEFLY WE USED SAB MAC 239M AND 5667 04:39:35,402 --> 04:39:38,338 14 DAYS LATER STARTED 5668 04:39:38,338 --> 04:39:39,839 ANTIRETROVIRAL AND MONITORED THE 5669 04:39:39,839 --> 04:39:41,074 ANIMALS DRAWING BLOOD AND 5670 04:39:41,074 --> 04:39:42,609 LOOKING AT VIRAL LOADS AND SO 5671 04:39:42,609 --> 04:39:44,377 YOU CAN SEE VIRAL LOADS WERE 5672 04:39:44,377 --> 04:39:46,046 INCREASED AND AS SOON AS WE PUT 5673 04:39:46,046 --> 04:39:47,614 THE ANIMALS WE STARTED TO 5674 04:39:47,614 --> 04:39:49,649 DECREASE AND WE DIDN'T DO OUR 5675 04:39:49,649 --> 04:39:51,484 CRISPR STUDIES UNTIL ALL THE 5676 04:39:51,484 --> 04:39:56,823 ANIMALS IN THE STUDY WERE WELL 5677 04:39:56,823 --> 04:39:57,123 SUPPRESSED. 5678 04:39:57,123 --> 04:39:59,859 IN THIS EXPERIMENTAL SET UP WE 5679 04:39:59,859 --> 04:40:01,528 HAVE 10 ANIMALS. 5680 04:40:01,528 --> 04:40:08,768 FIVE RECEIVED THE AAV9 THAT 5681 04:40:08,768 --> 04:40:10,036 INCLUDE THE PSI AND GAG. 5682 04:40:10,036 --> 04:40:12,372 WE DID THIS BECAUSE WE WANTED TO 5683 04:40:12,372 --> 04:40:14,341 KEEP THE BAR CODE AND OTHER 5684 04:40:14,341 --> 04:40:18,445 STRATEGIES IN THE PAST HAVE BEEN 5685 04:40:18,445 --> 04:40:22,615 LTR AND GAG AND WE THOUGHT IT 5686 04:40:22,615 --> 04:40:27,487 WILL ONLY BE RETRAINED IN ONE 5687 04:40:27,487 --> 04:40:31,925 AND WANTED TO DO SOMETHING S 5688 04:40:31,925 --> 04:40:34,160 SIMPLE AND RETAIN THE BAR CODE 5689 04:40:34,160 --> 04:40:38,598 AND THE OTHERS RETAINED PLASMA 5690 04:40:38,598 --> 04:40:41,001 AND IT'S A CONTROL AND WHAT 5691 04:40:41,001 --> 04:40:42,902 HAPPENS AFTER CRISPR TREATMENT 5692 04:40:42,902 --> 04:40:45,271 DURING THE ATI? 5693 04:40:45,271 --> 04:40:47,674 CAN CRISPR DECREASE THE VIRAL 5694 04:40:47,674 --> 04:40:48,775 DIVERSITY OR BAR CODE? 5695 04:40:48,775 --> 04:40:51,444 DOES IT MAKE AN IMPACT ON THE 5696 04:40:51,444 --> 04:40:51,778 RESERVOIR. 5697 04:40:51,778 --> 04:40:55,382 IS THERE A DELAY IN REBOUNDS AND 5698 04:40:55,382 --> 04:40:59,252 CRISPR MAKE AN IMPACT ON THE 5699 04:40:59,252 --> 04:40:59,753 CRISPR RESERVOIR. 5700 04:40:59,753 --> 04:41:03,556 WE GAVE THE INFUSION AND ONE 5701 04:41:03,556 --> 04:41:05,425 WEEK LATER WE REMOVED ART AND 5702 04:41:05,425 --> 04:41:08,695 THEN WE MONITORED THE ANIMALS 5703 04:41:08,695 --> 04:41:11,431 EVERY THREE DAYS OR RETURN OF 5704 04:41:11,431 --> 04:41:14,734 VIRAL LOAD AND DID THIS WITH THE 5705 04:41:14,734 --> 04:41:16,770 GROUP AT NCI FREDERICK. 5706 04:41:16,770 --> 04:41:19,305 SO THANKS FOR THAT. 5707 04:41:19,305 --> 04:41:21,608 ONCE THE VIRAL LOAD RETURNED WE 5708 04:41:21,608 --> 04:41:26,012 DID AN EXTENSIVE NECROPSY. 5709 04:41:26,012 --> 04:41:30,116 THE SLIDE IS BUSY BUT SHOWS THE 5710 04:41:30,116 --> 04:41:31,918 PROCESS ONCE WE HAVE THE ANIMALS 5711 04:41:31,918 --> 04:41:34,587 BECAUSE OTHER LABS ARE DOING 5712 04:41:34,587 --> 04:41:36,356 DOWN STREAM ASSAYS. 5713 04:41:36,356 --> 04:41:37,757 MY LAB AT RUTGERS IS IN CHARGE 5714 04:41:37,757 --> 04:41:40,160 OF THE PROCESSING AND WE RUN THE 5715 04:41:40,160 --> 04:41:42,896 STUDIES ANALYZING THE VIRAL 5716 04:41:42,896 --> 04:41:46,199 LOADS CHEMISTRIES AND BIO 5717 04:41:46,199 --> 04:41:48,001 DISTRIBUTION AND THIS SHOWS THE 5718 04:41:48,001 --> 04:41:49,102 INTERACTION WITH THE LARGER 5719 04:41:49,102 --> 04:41:51,704 GROUP FOR DOWN STREAMS INCLUDING 5720 04:41:51,704 --> 04:41:54,474 CASE WESTERN AND UCLA FOR THE 5721 04:41:54,474 --> 04:42:04,217 BAR CODES AND TEMPLE FOR THE 5722 04:42:04,217 --> 04:42:04,484 EXCISION. 5723 04:42:04,484 --> 04:42:07,153 WE LOOKED AT THE CHEMISTRIES AND 5724 04:42:07,153 --> 04:42:11,157 SEE DIFFERENCE AFTER CRISPR FOR 5725 04:42:11,157 --> 04:42:12,292 THE GROUPS. 5726 04:42:12,292 --> 04:42:16,963 WE ALSO SAW SOMETHING SIMILAR 5727 04:42:16,963 --> 04:42:19,365 WITH THE CDC COUNTS AND DIDN'T 5728 04:42:19,365 --> 04:42:21,000 SEE SIGNIFICANT CHANGES IN THE 5729 04:42:21,000 --> 04:42:21,501 GROUPS. 5730 04:42:21,501 --> 04:42:24,204 AND LAST WE LOOKED AT FLOW 5731 04:42:24,204 --> 04:42:26,306 ANALYSIS TO LOOK AT CD4, CD 8 5732 04:42:26,306 --> 04:42:29,676 AND MONOCYTES AND DIDN'T SEE 5733 04:42:29,676 --> 04:42:31,878 SIGNIFICANT DIFFERENCE BETWEEN 5734 04:42:31,878 --> 04:42:38,151 THE CONTROL AND CRISPR GROUPS. 5735 04:42:38,151 --> 04:42:40,820 OUR LAB PERFORMED CAS 9 DNA AND 5736 04:42:40,820 --> 04:42:45,859 RNA FOR DISTRIBUTION AT 5737 04:42:45,859 --> 04:42:46,126 NECROPSY. 5738 04:42:46,126 --> 04:42:48,928 WE ADD AN EXTENSIVE AMOUNT OF 5739 04:42:48,928 --> 04:42:50,730 ORGANS AND TISSUES AND SHOWED IN 5740 04:42:50,730 --> 04:42:53,399 BOTH THE CRISPR TREATED AND 5741 04:42:53,399 --> 04:42:54,534 CONTROLS WE HAD GOOD 5742 04:42:54,534 --> 04:42:55,635 DISTRIBUTION OF THE VECTOR AND 5743 04:42:55,635 --> 04:43:02,842 THE CONTROL HAS CAS 9. 5744 04:43:02,842 --> 04:43:06,746 AND KAMALSHOWED THE COMMISSION 5745 04:43:06,746 --> 04:43:07,280 DATA. 5746 04:43:07,280 --> 04:43:13,653 IT'S BY DISTRIBUTION AND SHOWED 5747 04:43:13,653 --> 04:43:15,421 IT EXCISES TISSUE AND WHAT WE 5748 04:43:15,421 --> 04:43:17,457 ARE INTERESTED IN IS WHAT 5749 04:43:17,457 --> 04:43:20,093 HAPPENS ONCE WE REMOVE ART. 5750 04:43:20,093 --> 04:43:22,629 YOU'LL SEE FROM THE GRAPH ONCE 5751 04:43:22,629 --> 04:43:25,431 WE REMOVED ART VIRAL LOAD CAME 5752 04:43:25,431 --> 04:43:26,199 BACK QUICKLY. 5753 04:43:26,199 --> 04:43:27,867 IN ALL THE ANIMALS. 5754 04:43:27,867 --> 04:43:31,070 THE CRISPR AN CONTROL ANIMALS. 5755 04:43:31,070 --> 04:43:34,307 BUT IF WE MADE AN IMPACT ON THE 5756 04:43:34,307 --> 04:43:36,376 TIME TO REBOUND THAT WOULD HAVE 5757 04:43:36,376 --> 04:43:37,477 BEEN THE HOME RUN. 5758 04:43:37,477 --> 04:43:39,112 SO WE DIDN'T GET THE HOME RUN 5759 04:43:39,112 --> 04:43:41,714 BUT NOW WE'RE LOOKING AT THE 5760 04:43:41,714 --> 04:43:44,284 TISSUE DIVERSITY, VIRAL LOADS 5761 04:43:44,284 --> 04:43:47,020 AND RESERVOIRS AND SO WE REALLY 5762 04:43:47,020 --> 04:43:48,788 THINK THAT'S WHERE WE'LL GAIN A 5763 04:43:48,788 --> 04:43:49,422 LOT OF INFORMATION AND THERE'S 5764 04:43:49,422 --> 04:43:50,823 ALWAYS WAYS TO IMPROVE. 5765 04:43:50,823 --> 04:43:51,424 THAT'S WHAT WE'RE WORKING ON 5766 04:43:51,424 --> 04:43:54,627 NOW. 5767 04:43:54,627 --> 04:43:56,829 AND SO ONE OF THE ASSAYS WE'RE 5768 04:43:56,829 --> 04:44:00,366 LOOKING AT IS THE IPDA ASSAY. 5769 04:44:00,366 --> 04:44:06,005 SO JOHN CARN'S LAB AND BEN 5770 04:44:06,005 --> 04:44:07,273 DEVELOPED TWO ASSAYS. 5771 04:44:07,273 --> 04:44:12,745 THE TOP ASSAY IS THE IPGA 5772 04:44:12,745 --> 04:44:18,384 SLIGHTLY MODIFIED FROM THE LAB 5773 04:44:18,384 --> 04:44:22,822 AND THE PRIMER WAS MODIFIED AND 5774 04:44:22,822 --> 04:44:25,124 DEVELOPED A FOUR-COLOR DDPCR 5775 04:44:25,124 --> 04:44:28,228 ASSAY THAT DETECT THE INTACT PRO 5776 04:44:28,228 --> 04:44:32,332 VIRUS AND THE BAR CODED REGION 5777 04:44:32,332 --> 04:44:35,435 BETWEEN BPX AND BPR AND THE 5778 04:44:35,435 --> 04:44:37,337 CLEAVED REGION. 5779 04:44:37,337 --> 04:44:39,973 IT'S BETWEEN PSI AND GAG SO ONCE 5780 04:44:39,973 --> 04:44:41,541 IT'S CLEAVED YOU CAN GET 5781 04:44:41,541 --> 04:44:42,575 INFORMATION OWN THAT AS WELL. 5782 04:44:42,575 --> 04:44:45,345 THIS IS THE ASSAY WE'RE USING. 5783 04:44:45,345 --> 04:44:48,081 AND EVERYONE KNOWS WHAT THE IPDA 5784 04:44:48,081 --> 04:44:50,617 ASSAY IS BUT JUST TO KNOW IN THE 5785 04:44:50,617 --> 04:44:55,555 GREEN THOSE ARE INTACT VIRUSES 5786 04:44:55,555 --> 04:44:59,025 AND SIV WE HAVE INTACT PROVIRAL 5787 04:44:59,025 --> 04:44:59,459 DNA. 5788 04:44:59,459 --> 04:45:03,663 AND DETECTION OF THE FOUR SIV 5789 04:45:03,663 --> 04:45:04,097 TARGETS. 5790 04:45:04,097 --> 04:45:07,667 THE TOP SHOWS THE TRADITIONAL 5791 04:45:07,667 --> 04:45:10,169 IPDA WHICH WE SHOWED THE INTACT 5792 04:45:10,169 --> 04:45:10,370 VIRUS. 5793 04:45:10,370 --> 04:45:13,539 THE BOTTOM SHOWS WE CAN DETECT 5794 04:45:13,539 --> 04:45:14,974 IN THE INTACT VIRUS WE CAN 5795 04:45:14,974 --> 04:45:18,177 DETECT THE BAR CODES AND DETECT 5796 04:45:18,177 --> 04:45:28,721 THE PSI TO GIVE THE SKWIGS -- 5797 04:45:35,495 --> 04:45:36,529 EXCISION ANIMALS AND MOST THE 5798 04:45:36,529 --> 04:45:39,565 VIRUS IS INTACT AND THE INTACT 5799 04:45:39,565 --> 04:45:43,436 VIRUS, 95% FROM THE BAR CODE AND 5800 04:45:43,436 --> 04:45:45,672 ALSO 90% OF THE BAR CODED ARE 5801 04:45:45,672 --> 04:45:47,974 ALSO INTACT. 5802 04:45:47,974 --> 04:45:52,312 SO THIS IS GOING TO GIVE US GOOD 5803 04:45:52,312 --> 04:45:54,447 POWER TO LOOK AT THE CODE AND 5804 04:45:54,447 --> 04:45:55,682 THE DNA BAR CODE. 5805 04:45:55,682 --> 04:45:58,117 THE STUFF WE WERE TALKING ABOUT 5806 04:45:58,117 --> 04:45:59,919 BEFORE WAS DNA AND SEQUENCE THE 5807 04:45:59,919 --> 04:46:03,056 DNA BAR CODE IN THE STUDIES. 5808 04:46:03,056 --> 04:46:05,391 AND THE CONCLUSIONS ARE THAT WE 5809 04:46:05,391 --> 04:46:06,125 USED THIS. 5810 04:46:06,125 --> 04:46:07,327 IT WAS SAFE. 5811 04:46:07,327 --> 04:46:10,163 WE DEVELOPED A NUMBER OF ASSAYS 5812 04:46:10,163 --> 04:46:11,998 FOR SIV BUT NOW WE NEED TO GET 5813 04:46:11,998 --> 04:46:13,533 INTO THE MEAT OF IT. 5814 04:46:13,533 --> 04:46:16,903 SO WE HAVE A LOT OF ONGOING WORK 5815 04:46:16,903 --> 04:46:18,571 SO THIS IS A LOT OF PROCESS TO 5816 04:46:18,571 --> 04:46:19,906 GET UP TO THIS POINT BUT WE INTO 5817 04:46:19,906 --> 04:46:23,076 HE HAD TO MEASURE THE INTACT DNA 5818 04:46:23,076 --> 04:46:25,211 AND LOOK AT THE DIVERSITY AND 5819 04:46:25,211 --> 04:46:29,882 THESE ARE ALL ONGOING AS WE 5820 04:46:29,882 --> 04:46:30,283 SPEAK. 5821 04:46:30,283 --> 04:46:34,954 THEN WE ARE ALWAYS LOOKING AT 5822 04:46:34,954 --> 04:46:35,488 MESSENGER RAN. 5823 04:46:35,488 --> 04:46:39,726 I HAVE TWO OR THREE MORE SLIDES. 5824 04:46:39,726 --> 04:46:42,595 THE VISION OF OUR APPROACH. 5825 04:46:42,595 --> 04:46:44,364 WE THINK NOW THAT COMBINING 5826 04:46:44,364 --> 04:46:47,633 IMMUNE MODULATION WHICH IS WHAT 5827 04:46:47,633 --> 04:46:49,669 RF2 IS AND PROVIRAL EXTENSION IS 5828 04:46:49,669 --> 04:46:50,737 SOMETHING THAT'S GOING TO 5829 04:46:50,737 --> 04:46:50,970 HAPPEN. 5830 04:46:50,970 --> 04:46:52,372 WE DON'T THINK IT'S GOING TO 5831 04:46:52,372 --> 04:46:53,539 HAPPEN ALONE. 5832 04:46:53,539 --> 04:46:54,640 I THINK I'VE HEARD THAT A LOT 5833 04:46:54,640 --> 04:46:56,442 THIS WEEK THAT IT'S GOING TO TO 5834 04:46:56,442 --> 04:46:57,844 BE SOME COMBINATION. 5835 04:46:57,844 --> 04:47:00,747 SO OUR FIRST STUDY TO DO THIS IS 5836 04:47:00,747 --> 04:47:03,616 GOING TO USE EXPANDED NK CELLS 5837 04:47:03,616 --> 04:47:05,418 ALONE OR IN COMBINATION WITH 5838 04:47:05,418 --> 04:47:07,220 CRISPR EDITING AND THEN WE'RE 5839 04:47:07,220 --> 04:47:08,454 GOING TO USE THE NOVEL ASSAYS WE 5840 04:47:08,454 --> 04:47:11,357 DEVELOPED TO LOOK AT THE IMPACT 5841 04:47:11,357 --> 04:47:16,929 OF THE VIRAL RESERVOIR. 5842 04:47:16,929 --> 04:47:20,166 SO VERY BRIEFLY THERE'S 5843 04:47:20,166 --> 04:47:30,610 ESTABLISHED METHODS TO CULTURE N 5844 04:47:30,610 --> 04:47:32,712 ENK CELLS AND THEY ARE GAVE 5845 04:47:32,712 --> 04:47:34,714 THREE DIFFERENT INOCULATIONS OF 5846 04:47:34,714 --> 04:47:36,249 THESE EXPANDED NK CELLS AND THEN 5847 04:47:36,249 --> 04:47:39,852 LOOKED AT HOW IT AFFECTED A FEW 5848 04:47:39,852 --> 04:47:44,090 VUREMIA AND SHOWED THERE WAS A 5849 04:47:44,090 --> 04:47:49,462 .76 LOG DECREASE IN THE VIREMIA 5850 04:47:49,462 --> 04:47:51,931 IN THE NK STUDY WE TOOK THE DATA 5851 04:47:51,931 --> 04:47:54,400 AND THOUGHT WE WANT TO DO THIS 5852 04:47:54,400 --> 04:47:57,670 BUT WE'LL DO THIS IN ANIMALS 5853 04:47:57,670 --> 04:47:59,439 THAT ARE HIGHLY SUPPRESSED 5854 04:47:59,439 --> 04:48:04,610 ALREADY IN ART AND COMBINE THIS 5855 04:48:04,610 --> 04:48:08,614 WITH CRISPR AND USE AUTOLOGOUS 5856 04:48:08,614 --> 04:48:11,150 INFUSION AND COMBINE THAT WITH 5857 04:48:11,150 --> 04:48:13,219 THE CRISPR TARGET THERAPY IN THE 5858 04:48:13,219 --> 04:48:21,928 SIMILAR MANNER. 5859 04:48:21,928 --> 04:48:24,096 WE'RE GOING TO LOOK AT NK CELLS 5860 04:48:24,096 --> 04:48:25,465 AND MODIFY THEM. 5861 04:48:25,465 --> 04:48:28,301 NK CELLS WHEN YOU INFUSE THEM 5862 04:48:28,301 --> 04:48:32,638 INTO A MOUSE AND THIS IS DATA 5863 04:48:32,638 --> 04:48:36,876 FROM UNPUBLISHED IN A MOUSE AND 5864 04:48:36,876 --> 04:48:39,378 TOOK NK CELLS IN THE MOUSE AND 5865 04:48:39,378 --> 04:48:43,349 GOES TO THE LIVER, LUNG AND 5866 04:48:43,349 --> 04:48:43,583 SPLEEN. 5867 04:48:43,583 --> 04:48:45,351 WE NEED TO GET MORE SO WE ARE 5868 04:48:45,351 --> 04:48:48,721 GOING TO RETARGET THE NATURAL 5869 04:48:48,721 --> 04:48:53,759 KILLER CELLS AWAY FROM THE LIVER 5870 04:48:53,759 --> 04:49:04,270 BY KNOCKING OUT THESE AND WE 5871 04:49:05,071 --> 04:49:10,276 HAVE A VERY NICE ANIMAL MODEL 5872 04:49:10,276 --> 04:49:13,713 USING THE MISTRG-615 AND SEE 5873 04:49:13,713 --> 04:49:18,317 WHAT WORKS AND PROBABLY RECREATE 5874 04:49:18,317 --> 04:49:19,785 THAT IN THE MONKEYS. 5875 04:49:19,785 --> 04:49:23,890 WITH WANT TO TRY TO IMPROVE 5876 04:49:23,890 --> 04:49:26,092 PERSISTENCE AND ENHANCE ACTIVITY 5877 04:49:26,092 --> 04:49:31,731 AND DO NOVEL WORK ON KNOCKING 5878 04:49:31,731 --> 04:49:37,203 OUT FISH THE ONES WE'VE HEARD 5879 04:49:37,203 --> 04:49:38,538 ABOUT ALREADY TODAY. 5880 04:49:38,538 --> 04:49:38,971 I'LL END THERE WITH 5881 04:49:38,971 --> 04:49:49,282 ACKNOWLEDGEMENTS. 5882 04:49:54,220 --> 04:50:00,626 >> NOW I'LL TALK TO EDIT BEING 5883 04:50:00,626 --> 04:50:03,129 HIV-1 PROVIRAL. 5884 04:50:03,129 --> 04:50:05,064 AND WE HAVE FOUR STEPS. 5885 04:50:05,064 --> 04:50:11,270 WE START WITH IN SILICO 5886 04:50:11,270 --> 04:50:13,940 SCREENING AND MOVING TO IN VIVO 5887 04:50:13,940 --> 04:50:20,046 AND THE HUMANIZED MOUSE AND I'LL 5888 04:50:20,046 --> 04:50:23,215 GO THROUGH THIS ROAD MAP. 5889 04:50:23,215 --> 04:50:29,722 AND TO FIND THE BEST GUIDE RNA 5890 04:50:29,722 --> 04:50:39,465 WE SCREENED AND USED THE NNGRRT 5891 04:50:39,465 --> 04:50:43,035 AND LOOKING THE AND INITIAL 5892 04:50:43,035 --> 04:50:47,974 SCREENING INVOLVED IN SILICO 5893 04:50:47,974 --> 04:50:52,311 LOOKING INTO THE TOOLS WE USE 5894 04:50:52,311 --> 04:50:57,650 FOR OFF TARGETING AND DIFFERENT 5895 04:50:57,650 --> 04:51:01,621 DATABASES FOR INSTANCE. 5896 04:51:01,621 --> 04:51:03,155 WHEN WE DO THESE TYPES OF 5897 04:51:03,155 --> 04:51:08,694 SCREENING WE LOOK AT THE BROAD 5898 04:51:08,694 --> 04:51:11,430 SPECTRUM AND INITIAL SCREEN IS 5899 04:51:11,430 --> 04:51:13,666 IDENTIFIED 14 GUIDE RNAs WITH 5900 04:51:13,666 --> 04:51:14,500 HIGH CONSERVATION. 5901 04:51:14,500 --> 04:51:19,205 FROM THERE, WE MOVE INTO IN 5902 04:51:19,205 --> 04:51:23,409 VITRO CELL LINE SYSTEMS WHERE WE 5903 04:51:23,409 --> 04:51:25,244 HAVE MYELOID CELLS LATENTLY 5904 04:51:25,244 --> 04:51:27,213 INFECTED VIRUS AND LOOK AT 5905 04:51:27,213 --> 04:51:28,047 VARIOUS ASSAYS. 5906 04:51:28,047 --> 04:51:30,850 ONE IS THE EDIT ACTIVITY IN 5907 04:51:30,850 --> 04:51:41,093 SINGLE GUIDE RNA ACTIVITY OR 5908 04:51:41,093 --> 04:51:43,829 INTERFERENCE AND HAVE GUIDE RNAs 5909 04:51:43,829 --> 04:51:49,435 WITH ACTIVITY. 5910 04:51:49,435 --> 04:51:52,638 THEN WE MOVED FOR FURTHER 5911 04:51:52,638 --> 04:51:52,938 VALIDATION. 5912 04:51:52,938 --> 04:51:56,909 THESE ARE THE BEST SO FAR 5913 04:51:56,909 --> 04:52:01,847 IDENTIFIED FOR GUIDE RNAs OVER 5914 04:52:01,847 --> 04:52:11,323 THE 500 GUIDE RNAs WE SCREENED. 5915 04:52:11,323 --> 04:52:13,225 WE HAVE COLLABORATION BETWEEN 5916 04:52:13,225 --> 04:52:15,227 TEMPLE AND DREXEL UNIVERSITY. 5917 04:52:15,227 --> 04:52:17,430 THE BLOOD IS COLLECTED FROM THE 5918 04:52:17,430 --> 04:52:27,807 DONORS AT DREXEL AND PBMCs OR 5919 04:52:27,807 --> 04:52:29,875 FLESH BLOOD FOR CD4 ISOLATION 5920 04:52:29,875 --> 04:52:32,545 AND AT TEMPLE WE FIRST SCREEN 5921 04:52:32,545 --> 04:52:37,216 FOR ON TARGET ADDITIVE WHICH IS 5922 04:52:37,216 --> 04:52:40,820 INVOLVING SINGLE GUIDE RNA 5923 04:52:40,820 --> 04:52:42,321 ANALYSIS AND DUAL GUIDE RNA 5924 04:52:42,321 --> 04:52:46,859 COMBINATION IN VARIOUS 5925 04:52:46,859 --> 04:52:47,827 COMBINATIONS AND DOING THE 5926 04:52:47,827 --> 04:52:50,029 EXCISION ASSAY AND ALL THE 5927 04:52:50,029 --> 04:52:52,231 SAMPLES WE COLLECT FROM THE 5928 04:52:52,231 --> 04:52:58,137 CELLS GETS TO THE DREXEL FOR 5929 04:52:58,137 --> 04:53:00,272 FURTHER ANALYSIS FOR SEQUENCE 5930 04:53:00,272 --> 04:53:03,008 AND MOVING INTO THE 5931 04:53:03,008 --> 04:53:10,316 COMPUTATIONAL ANALYSIS FOR 5932 04:53:10,316 --> 04:53:14,253 QUANTITATIVE ANALYSIS. 5933 04:53:14,253 --> 04:53:20,526 THIS IS AN EXAMPLE OF THE ICE 5934 04:53:20,526 --> 04:53:22,962 ANALYSIS AND WE HAVE VARIOUS 5935 04:53:22,962 --> 04:53:26,832 DONORS AND AMPLIFY THE REGION WE 5936 04:53:26,832 --> 04:53:30,836 TARGET AND YOU END UP WITH A 5937 04:53:30,836 --> 04:53:36,942 SCORE FROM BETWEEN 0% AND 98% 5938 04:53:36,942 --> 04:53:37,176 ROUGHLY. 5939 04:53:37,176 --> 04:53:38,677 THAT'S THE RANGE DETECTED FROM 5940 04:53:38,677 --> 04:53:39,044 VARIOUS OWNERS. 5941 04:53:39,044 --> 04:53:42,515 AND THIS IS AN EXAMPLE OF THE 5942 04:53:42,515 --> 04:53:43,883 COMMISSION ASSAY WHERE YOU 5943 04:53:43,883 --> 04:53:45,451 COMBINE THEM IN VARIOUS 5944 04:53:45,451 --> 04:53:48,154 COMBINATIONS AND YOU SEE 5945 04:53:48,154 --> 04:53:51,590 EXAMPLES HERE FOR PSI GAG AND 5946 04:53:51,590 --> 04:53:54,660 THE OTHERS AND REPRESENTS THE 5947 04:53:54,660 --> 04:53:57,396 TRUNCATED REGION BETWEEN THE 5948 04:53:57,396 --> 04:54:07,907 SITES AND YOU VERIFY FOR THE 5949 04:54:08,274 --> 04:54:12,144 EXCISION WE ALSO MOVED TO THE 5950 04:54:12,144 --> 04:54:13,512 FUNCTIONAL ASSAYS WHERE IN OUR 5951 04:54:13,512 --> 04:54:17,583 INITIAL COHORT WE HAD CONTROL 5952 04:54:17,583 --> 04:54:20,119 SAMPLES AND ASSESSED FOR SEVEN 5953 04:54:20,119 --> 04:54:23,189 DAYS BUT A COUPLE DONORS WE 5954 04:54:23,189 --> 04:54:25,591 TESTED SHOWED REBOUNDS FROM THE 5955 04:54:25,591 --> 04:54:28,928 BEGINNING AND WE WERE ABLE TO 5956 04:54:28,928 --> 04:54:33,766 CHECK THE ATI ASSAY WHERE WE HAD 5957 04:54:33,766 --> 04:54:35,801 THE VIRAL REBOUNDS AND WE PUT 5958 04:54:35,801 --> 04:54:46,345 THE CELLS ON THE ART AND CHECKED 5959 04:54:49,215 --> 04:54:52,318 THE VIRAL LOAD. 5960 04:54:52,318 --> 04:54:52,818 INTERESTINGLY ALL THE 5961 04:54:52,818 --> 04:54:57,623 COMBINATION SHOWED STRONG 5962 04:54:57,623 --> 04:55:05,431 SUPPRESSION IN THE EX VIVO 5963 04:55:05,431 --> 04:55:08,767 SETTINGS FOR HIV AND IN 5964 04:55:08,767 --> 04:55:10,669 COLLABORATION WITH DREXEL GROUP 5965 04:55:10,669 --> 04:55:14,139 AND CAN DETERMINE ON AND OFF 5966 04:55:14,139 --> 04:55:17,543 TARGET ASSESSMENT OF THE EACH 5967 04:55:17,543 --> 04:55:18,010 INDIVIDUAL GUIDE RNA. 5968 04:55:18,010 --> 04:55:21,680 IN SUMMARY FOR EX VIVO WE 5969 04:55:21,680 --> 04:55:25,618 PERFORMED STUDIES ON SINGLE 5970 04:55:25,618 --> 04:55:28,254 GUIDE ANALYSIS TO EXCISION 5971 04:55:28,254 --> 04:55:32,358 ASSAYS AND COMPATIBILITY ASSAY 5972 04:55:32,358 --> 04:55:33,792 AND QUANTITATIVE ASSAYS AND 5973 04:55:33,792 --> 04:55:35,594 TARGET ANALYSIS AND I DON'T HAVE 5974 04:55:35,594 --> 04:55:37,663 TIME TO GO OVER ALL THE RESULTS 5975 04:55:37,663 --> 04:55:41,901 BUT SO FAR WE COMPLETED 5976 04:55:41,901 --> 04:55:45,337 SCREENING FOR THE FOUR CANDIDATE 5977 04:55:45,337 --> 04:55:48,374 GUIDE RNAs IN CD4 T CELLS FROM 5978 04:55:48,374 --> 04:55:55,247 16 DONORS AND FINALLY CAME TO A 5979 04:55:55,247 --> 04:55:56,515 CONCLUSION OUR COMBINATION 5980 04:55:56,515 --> 04:55:57,783 WORKED BEST AMONG THE OTHER 5981 04:55:57,783 --> 04:56:02,855 COMBINATIONS SO FAR. 5982 04:56:02,855 --> 04:56:07,259 THESE ARE THE GUIDE RNAs. 5983 04:56:07,259 --> 04:56:13,666 I'D LIKE TO HIGHLIGHT QUICKLY WE 5984 04:56:13,666 --> 04:56:18,237 INITIATED STUDIES INTO THE 5985 04:56:18,237 --> 04:56:20,506 CRISPR GENE EDITING AND DREXEL 5986 04:56:20,506 --> 04:56:22,074 AND CASE WESTERN RESERVE. 5987 04:56:22,074 --> 04:56:26,679 WE LOOK IN OUR INITIAL STUDIES 5988 04:56:26,679 --> 04:56:32,551 WE LOOKED INTO THE INHIBITORS 5989 04:56:32,551 --> 04:56:36,422 AND USED DIFFERENT ONES IN CD4 5990 04:56:36,422 --> 04:56:38,991 PLUS T MEMORY CELLS. 5991 04:56:38,991 --> 04:56:41,093 THESE ARE PRELIMINARY AND WE'RE 5992 04:56:41,093 --> 04:56:44,063 EXPANDING OUR DONORS AND SAMPLES 5993 04:56:44,063 --> 04:56:46,231 BUT INTERESTINGLY THE TAKE HOME 5994 04:56:46,231 --> 04:56:49,335 MESSAGE IS WITH THE EPZ WE SEE 5995 04:56:49,335 --> 04:56:51,537 LIKE INCREASED ADDED ACTIVITY 5996 04:56:51,537 --> 04:56:56,141 COMPARED TO THE UNTREATED CELLS 5997 04:56:56,141 --> 04:56:57,743 THOUGH WE SAW VERY HIGH EXCISION 5998 04:56:57,743 --> 04:56:59,845 ACTIVITY WITH THE UNC. 5999 04:56:59,845 --> 04:57:03,215 WE ARE STILL ANALYZING THE DATA 6000 04:57:03,215 --> 04:57:07,586 AND IT'S QUITE EXCITING THAT 6001 04:57:07,586 --> 04:57:08,754 EPIGENETICS IN THE CELLS WHERE 6002 04:57:08,754 --> 04:57:11,523 VIRUS ARE LATENT AND EPIGENETIC 6003 04:57:11,523 --> 04:57:17,529 CONTROL IS IMPORTANT. 6004 04:57:17,529 --> 04:57:23,268 SO IN SUMMARY WE STUDIED IN 6005 04:57:23,268 --> 04:57:27,439 SILICO AND COMPLETED EX VIVO 6006 04:57:27,439 --> 04:57:29,942 STUDIES AND NOW CURRENTLY WE ARE 6007 04:57:29,942 --> 04:57:31,310 WORKING ON THE VECTOR SYSTEMS IN 6008 04:57:31,310 --> 04:57:34,380 ADDITION TO AAV. 6009 04:57:34,380 --> 04:57:40,352 WE'RE WORKING ON A NEW LENTI 6010 04:57:40,352 --> 04:57:41,653 VIRAL VIRUS WITH SPECIFIC 6011 04:57:41,653 --> 04:57:44,123 DELIVERY IN OUR HUMANIZED MOUSE 6012 04:57:44,123 --> 04:57:45,491 MODEL IN THE UPCOMING YEAR. 6013 04:57:45,491 --> 04:57:46,759 WITH THIS I WOULD LIKE TO STOP. 6014 04:57:46,759 --> 04:57:56,935 THANK YOU. 6015 04:57:58,370 --> 04:58:03,609 GOOD AFTERNOON I'M ZACHARY P 6016 04:58:03,609 --> 04:58:11,483 PIE -- PIERRE AND I WON'T COVER 6017 04:58:11,483 --> 04:58:12,851 THE OTHER STUDIES BEYOND THANK 6018 04:58:12,851 --> 04:58:14,386 YOU FOR INVITING US. 6019 04:58:14,386 --> 04:58:16,722 WE APPRECIATE IT. 6020 04:58:16,722 --> 04:58:18,424 WHAT ARE HIGHLIGHTS? 6021 04:58:18,424 --> 04:58:20,325 AS THE PROGRAM MANAGER I MEET 6022 04:58:20,325 --> 04:58:22,227 REGULARLY WITH THE COMMUNITY 6023 04:58:22,227 --> 04:58:23,429 ENGAGEMENT TEAM USUALLY 6024 04:58:23,429 --> 04:58:23,896 BIWEEKLY. 6025 04:58:23,896 --> 04:58:25,764 MY BACKGROUND IS IN SOCIAL 6026 04:58:25,764 --> 04:58:27,366 SCIENCES I'M MORE OF A PUBLIC 6027 04:58:27,366 --> 04:58:29,034 HEALTH PERSON NOT A BENCH 6028 04:58:29,034 --> 04:58:30,436 SCIENTIST SO IT'S A NICE 6029 04:58:30,436 --> 04:58:31,637 PIPELINE BETWEEN OUR COMMUNITY 6030 04:58:31,637 --> 04:58:33,105 ENGAGEMENT EFFORTS AND THE 6031 04:58:33,105 --> 04:58:35,107 MANAGEMENT OF THE GROUP. 6032 04:58:35,107 --> 04:58:38,010 WE CONTINUE TO HAVE REGULAR 6033 04:58:38,010 --> 04:58:38,277 MEETINGS. 6034 04:58:38,277 --> 04:58:41,413 ANYONE EXPERIENCED IN RUNNING 6035 04:58:41,413 --> 04:58:42,815 CABS KNOWS JUST HOLDING THE 6036 04:58:42,815 --> 04:58:45,117 MEETING IS HALF THE BATTLE AND 6037 04:58:45,117 --> 04:58:46,085 HAVE CONSISTENT CAB MEMBERS 6038 04:58:46,085 --> 04:58:47,553 SHOWING UP AND GIVING INPUT AND 6039 04:58:47,553 --> 04:58:48,821 THOUGHTS AND I APPRECIATE THAT. 6040 04:58:48,821 --> 04:58:51,690 ONE THING WE DID THIS YEAR WHICH 6041 04:58:51,690 --> 04:58:54,860 WAS INTERESTING AND GAVE US 6042 04:58:54,860 --> 04:58:56,695 VALUABLE INFORMATION WE SET TIME 6043 04:58:56,695 --> 04:58:59,865 ASIDE FOR OUR CAB TO MEET 6044 04:58:59,865 --> 04:59:03,068 PRIVATELY WITH THE SAB ADVISORS 6045 04:59:03,068 --> 04:59:05,504 AND NIH ADVISORS AND IT SEEMS 6046 04:59:05,504 --> 04:59:06,672 LIKE THAT WAS A FRUITFUL 6047 04:59:06,672 --> 04:59:07,005 CONVERSATION. 6048 04:59:07,005 --> 04:59:09,441 WE LOOK FORWARD TO DOING THAT 6049 04:59:09,441 --> 04:59:10,409 AGAIN IN THE FUTURE. 6050 04:59:10,409 --> 04:59:12,010 AND SO A MAJOR PROJECT WE'VE 6051 04:59:12,010 --> 04:59:17,182 BEEN WORKING ON IS THE CREATION 6052 04:59:17,182 --> 04:59:20,018 OF THE COFFEE WITH CRISPR FOR 6053 04:59:20,018 --> 04:59:21,153 CURE EDUCATION VIDEO. 6054 04:59:21,153 --> 04:59:23,455 THIS AGED ME AND THIS WAS A 6055 04:59:23,455 --> 04:59:23,689 PROCESS. 6056 04:59:23,689 --> 04:59:25,457 WE MET WEEKLY FOR A LONG TIME TO 6057 04:59:25,457 --> 04:59:26,358 DISCUSS WHAT WERE THE NEEDS OF 6058 04:59:26,358 --> 04:59:31,964 THE VIDEO AND WHAT THEY NEED TO 6059 04:59:31,964 --> 04:59:42,508 LOOK LIKE AND REFLECT WHAT ARE 6060 04:59:43,742 --> 04:59:45,711 YOU CONCERNED ABOUT HIV AND CURE 6061 04:59:45,711 --> 04:59:48,714 RESEARCH AND KNOWLEDGE ABOUT 6062 04:59:48,714 --> 04:59:50,916 CRISPR AND WHAT ARE YOU HOPING 6063 04:59:50,916 --> 04:59:53,185 TO SEE FROM OUR RESEARCH. 6064 04:59:53,185 --> 04:59:59,024 WE FEATURED THIS AS THE MAY 6065 04:59:59,024 --> 04:59:59,958 COMMUNITY MEETING AND GOT GREAT 6066 04:59:59,958 --> 05:00:01,493 FEEDBACK AND IF YOU WERE ON THE 6067 05:00:01,493 --> 05:00:02,461 CALL AND GAVE YOUR THOUGHTS 6068 05:00:02,461 --> 05:00:03,295 THANK YOU SO MUCH AND WE 6069 05:00:03,295 --> 05:00:04,596 APPRECIATE IT AND HOPE YOU SEE 6070 05:00:04,596 --> 05:00:05,497 YOUR FEEDBACK INTEGRATED IN THE 6071 05:00:05,497 --> 05:00:08,400 VIDEO. 6072 05:00:08,400 --> 05:00:10,736 IF YOU WANT TO SEE THE VIDEO AND 6073 05:00:10,736 --> 05:00:12,905 I RECOMMEND IT WE SPENT A LOT OF 6074 05:00:12,905 --> 05:00:15,474 TIME ON THIS IT'S CRISPR FOR 6075 05:00:15,474 --> 05:00:17,009 CURE.org AND YOU CAN WATCH THIS 6076 05:00:17,009 --> 05:00:17,242 VIDEO. 6077 05:00:17,242 --> 05:00:19,044 HERE'S A SCREEN SHOT OF WHAT IT 6078 05:00:19,044 --> 05:00:19,344 LOOKS LIKE. 6079 05:00:19,344 --> 05:00:22,481 WE HAVE RESEARCHERS ON THE LEFT 6080 05:00:22,481 --> 05:00:24,316 AND CAB MEMBERS ON THE RIGHT AND 6081 05:00:24,316 --> 05:00:26,051 IF YOU'RE INTERESTED IN BEING 6082 05:00:26,051 --> 05:00:28,487 INVOLVED REACH OUT TO OUR 6083 05:00:28,487 --> 05:00:29,388 COMMUNITY ENGAGEMENT 6084 05:00:29,388 --> 05:00:29,855 COORDINATOR. 6085 05:00:29,855 --> 05:00:31,056 AGAIN, PLEASE WATCH THE VIDEO 6086 05:00:31,056 --> 05:00:31,890 AND REACH OUT TO KATE IF YOU'RE 6087 05:00:31,890 --> 05:00:35,661 INTERESTED. 6088 05:00:35,661 --> 05:00:37,129 WE'VE DONE A NUMBER OF 6089 05:00:37,129 --> 05:00:38,096 EDUCATIONAL OUTREACH IN THE PAST 6090 05:00:38,096 --> 05:00:38,297 YEAR. 6091 05:00:38,297 --> 05:00:41,200 OUR FAVORITE WAS PROBABLY A 6092 05:00:41,200 --> 05:00:42,734 JOINT EVENT WITH BEAT HIV. 6093 05:00:42,734 --> 05:00:45,103 IN TIME FOR PRIDE MONTH IN JUNE 6094 05:00:45,103 --> 05:00:47,539 WE TOOK SPACE IN THE WILLIAM 6095 05:00:47,539 --> 05:00:48,840 WHITE COMMUNITY CENTER AND 6096 05:00:48,840 --> 05:00:51,143 SCREENED A SHORT DOCUMENTARY BY 6097 05:00:51,143 --> 05:00:53,712 A LOCAL HIV ACTIVIST AND HAD A 6098 05:00:53,712 --> 05:00:55,047 SHORT DISCUSSION WITH HER AND 6099 05:00:55,047 --> 05:00:58,283 HER EXPERIENCE AND THEN INVITED 6100 05:00:58,283 --> 05:00:59,785 RESEARCHERS FROM CRISPR AND BEAT 6101 05:00:59,785 --> 05:01:02,521 TO ENGAGE IN A SPEED DATING TYPE 6102 05:01:02,521 --> 05:01:03,655 OF EVENT. 6103 05:01:03,655 --> 05:01:05,824 YOU SEE DR. ALBERTO AND 6104 05:01:05,824 --> 05:01:07,059 COMMUNITY MEMBERS AT DIFFERENT 6105 05:01:07,059 --> 05:01:08,393 TABLES AND I THINK WE WERE GIVEN 6106 05:01:08,393 --> 05:01:10,529 FIVE MINUTES AND AT THE END 6107 05:01:10,529 --> 05:01:13,098 SCIENTISTS ROTATED AROUND AND 6108 05:01:13,098 --> 05:01:15,934 ENGAGED IN ORGANIC CONVERSATIONS 6109 05:01:15,934 --> 05:01:18,537 WITH COMMUNITY MEMBERS ON WHAT 6110 05:01:18,537 --> 05:01:19,738 YOU'RE WORK BEING ON AND WHAT 6111 05:01:19,738 --> 05:01:21,873 ARE YOU HOPING FOR FROM THE 6112 05:01:21,873 --> 05:01:23,308 FIELD AND WHAT HAVE YOU SEEN 6113 05:01:23,308 --> 05:01:24,576 PREVIOUSLY YOU DON'T THINK IS 6114 05:01:24,576 --> 05:01:25,544 WORTH INVESTIGATING. 6115 05:01:25,544 --> 05:01:27,246 IT WAS AN ORGANIC CONVERSATION. 6116 05:01:27,246 --> 05:01:28,480 COMMUNITY MEMBERS HAD GOOD 6117 05:01:28,480 --> 05:01:30,182 THINGS AND RESEARCHERS HAD GREAT 6118 05:01:30,182 --> 05:01:32,684 THINGS TO SAY AND NOT JUST 6119 05:01:32,684 --> 05:01:33,719 BECAUSE WE PROVIDED A LOT OF 6120 05:01:33,719 --> 05:01:33,986 FOOD. 6121 05:01:33,986 --> 05:01:36,388 AND AT THE END WE HAD A 6122 05:01:36,388 --> 05:01:39,825 COLLECTION OF NICE ART ON LOAN 6123 05:01:39,825 --> 05:01:42,728 TO US AND THIS ADDRESS CREATED 6124 05:01:42,728 --> 05:01:47,899 BY STUDENTS AND ARTWORK FOR 6125 05:01:47,899 --> 05:01:50,769 COLORS AND MY CO-CHAIR AND WE 6126 05:01:50,769 --> 05:01:53,505 WERE INVITED TO PRESENT AS A 6127 05:01:53,505 --> 05:01:54,640 PANEL DISCUSSION ON HIV CURE 6128 05:01:54,640 --> 05:02:00,512 RESEARCH AT THE PHILADELPHIA 6129 05:02:00,512 --> 05:02:03,548 PREVENTION SUMMIT. 6130 05:02:03,548 --> 05:02:06,418 AND DIRECTOR OF COLORS HOSTED A 6131 05:02:06,418 --> 05:02:08,353 COMMUNITY EVENT WITH A PATIENT 6132 05:02:08,353 --> 05:02:11,223 AND IT WAS A COMMUNITY 6133 05:02:11,223 --> 05:02:12,324 CONVERSATION BETWEEN ADAM AND 6134 05:02:12,324 --> 05:02:15,594 OTHERS ABOUT HIV AND WHAT HIS 6135 05:02:15,594 --> 05:02:16,495 EXPERIENCE HAS BEEN. 6136 05:02:16,495 --> 05:02:17,696 WE WERE GRACIOUSLY INVITED TO 6137 05:02:17,696 --> 05:02:19,798 PARTICIPATE AND I WAS ABLE TO GO 6138 05:02:19,798 --> 05:02:21,266 AND MEET WITH COMMUNITY MEMBERS 6139 05:02:21,266 --> 05:02:25,037 AND HEAR THEIR FEEDBACK AND TALK 6140 05:02:25,037 --> 05:02:28,407 ABOUT OUR RESEARCH AND IT WAS A 6141 05:02:28,407 --> 05:02:33,645 VALUABLE EXPERIENCE AND THANK 6142 05:02:33,645 --> 05:02:34,713 YOU FOR INCLUDING US. 6143 05:02:34,713 --> 05:02:38,150 THE WORLD OF CRISPR IS MOVING AT 6144 05:02:38,150 --> 05:02:41,186 A BREAK NECK SPEED AND THERE'S A 6145 05:02:41,186 --> 05:02:42,621 LOT OF INFORMATION AND WRONG 6146 05:02:42,621 --> 05:02:44,790 INFORMATION OUT THERE. 6147 05:02:44,790 --> 05:02:46,758 WE WERE SPEARHEADED AT DREXEL 6148 05:02:46,758 --> 05:02:49,161 UNIVERSITY AND WE PUT TOGETHER A 6149 05:02:49,161 --> 05:02:51,730 SURVEY ASSESSING KNOWLEDGE, 6150 05:02:51,730 --> 05:02:52,497 ATTITUDES AND BELIEFS IN HIV 6151 05:02:52,497 --> 05:02:54,733 CURE AND CRISPR. 6152 05:02:54,733 --> 05:02:56,435 THE GOAL IS TO ROLE THIS OUT AT 6153 05:02:56,435 --> 05:02:57,869 STAFF MEETINGS OF OUR PARTNER 6154 05:02:57,869 --> 05:02:59,604 ORGANIZATIONS AND SIMILAR 6155 05:02:59,604 --> 05:03:00,772 ORGANIZATIONS THAT SERVE 6156 05:03:00,772 --> 05:03:02,808 INDIVIDUALS LIVING WITH HIV. 6157 05:03:02,808 --> 05:03:04,409 AND WE KNOW WHERE PEOPLE RECEIVE 6158 05:03:04,409 --> 05:03:08,814 CARE IMPACTS THEIR ATTITUDES AND 6159 05:03:08,814 --> 05:03:12,918 WE ALSO SAW EARLIER THAT 6160 05:03:12,918 --> 05:03:14,119 PROVIDERS HAVE A RANGE OF 6161 05:03:14,119 --> 05:03:18,123 RESEARCH AND SO THE HOPE IS WE 6162 05:03:18,123 --> 05:03:21,593 CAN GET GOOD INPUT HOW OUR 6163 05:03:21,593 --> 05:03:22,494 MEDICAL PROVIDERS ARE FEELING 6164 05:03:22,494 --> 05:03:25,697 ABOUT HIV, HIV CURE AND CRISPR. 6165 05:03:25,697 --> 05:03:27,733 WE WANT TO INCLUDE ALL LEVELS 6166 05:03:27,733 --> 05:03:29,835 BECAUSE IT'S NOT JUST DOCTORS OR 6167 05:03:29,835 --> 05:03:32,537 NURSE PRACTITIONERS BUT YOUR 6168 05:03:32,537 --> 05:03:35,574 PHLEBOTOMISTS AND THE PEER 6169 05:03:35,574 --> 05:03:37,642 NAVIGATOR AND ALL THESE 6170 05:03:37,642 --> 05:03:39,878 INDIVIDUALS IN THE CARE TEAM 6171 05:03:39,878 --> 05:03:40,846 IMPACT HOW PEOPLE RECEIVE HEALTH 6172 05:03:40,846 --> 05:03:42,481 INFORMATION AND IMPACT WHAT 6173 05:03:42,481 --> 05:03:46,017 THEY'RE ABLE TO OR WILLING TO 6174 05:03:46,017 --> 05:03:46,785 ENGAGE WITH. 6175 05:03:46,785 --> 05:03:49,654 OF COURSE IF YOU'RE INVOLVED IN 6176 05:03:49,654 --> 05:03:51,857 CABS RECRUITMENT IS AN ONGOING 6177 05:03:51,857 --> 05:03:53,625 CONCERN AND HOPING TO ROLL THIS 6178 05:03:53,625 --> 05:03:56,328 OUT AND USE IT AS A RECRUITMENT 6179 05:03:56,328 --> 05:03:59,531 TOOL TO RECRUIT NEW CAB MEMBERS. 6180 05:03:59,531 --> 05:04:01,700 THAT'S THE END OF MY 6181 05:04:01,700 --> 05:04:02,033 PRESENTATION. 6182 05:04:02,033 --> 05:04:07,506 THANK YOU. 6183 05:04:07,506 --> 05:04:09,408 >> I KNOW WE'RE KEEPING YOU FROM 6184 05:04:09,408 --> 05:04:11,176 YOUR DINNER BUT IF ANYONE HAS A 6185 05:04:11,176 --> 05:04:13,245 QUESTION FOR THE CRISPR FOR CURE 6186 05:04:13,245 --> 05:04:13,712 PLEASE COME UP TO THE 6187 05:04:13,712 --> 05:04:17,048 MICROPHONE. 6188 05:04:17,048 --> 05:04:20,819 >> HELLO. 6189 05:04:20,819 --> 05:04:23,021 SO IF I UNDERSTOOD YOUR MACAQUE 6190 05:04:23,021 --> 05:04:26,124 DATA YOU HAD 10 ANIMALS ON ART 6191 05:04:26,124 --> 05:04:28,260 FOR TWO YEARS AND THE CRISPR 6192 05:04:28,260 --> 05:04:33,432 TREATMENT I THINK YOU USED 10 TO 6193 05:04:33,432 --> 05:04:38,537 THE 13 PER KIG A TYPICAL DOSE IN 6194 05:04:38,537 --> 05:04:41,039 SYSTEMIC AAV GENE THERAPIES AND 6195 05:04:41,039 --> 05:04:46,778 USED ATI AND SAW NO EFFECT AND 6196 05:04:46,778 --> 05:04:49,314 THAT MATCHES FROM THE DATA FROM 6197 05:04:49,314 --> 05:04:52,584 THE IN HUMAN TRIALS I BELIEVE 6198 05:04:52,584 --> 05:04:57,155 THREE PATIENTS UNDERWENT ATI AND 6199 05:04:57,155 --> 05:04:58,190 ALL REBOUNDED. 6200 05:04:58,190 --> 05:05:00,225 >> THAT'S TRUE BUT ONE HAD A 6201 05:05:00,225 --> 05:05:01,993 DELAYED REBOUND. 6202 05:05:01,993 --> 05:05:05,464 I'M NOT SURE THE EXACT DATA. 6203 05:05:05,464 --> 05:05:08,467 SIX MONTHS, 16 WEEKS. 6204 05:05:08,467 --> 05:05:11,236 >> I'M WONDERING WHAT THE 6205 05:05:11,236 --> 05:05:18,276 COMPELLING EVIDENCE IS FROM YOUR 6206 05:05:18,276 --> 05:05:19,211 MACAQUE STUDIES. 6207 05:05:19,211 --> 05:05:21,680 IT MAKES YOU WANT TO GO INTO 6208 05:05:21,680 --> 05:05:21,947 HUMANS. 6209 05:05:21,947 --> 05:05:22,881 I'M NOT SEEING IT. 6210 05:05:22,881 --> 05:05:24,783 >> LIKE I SAID IN THE TALK WE 6211 05:05:24,783 --> 05:05:28,086 HAVE A LOT OF WORK TO DO. 6212 05:05:28,086 --> 05:05:29,254 I THINK -- 6213 05:05:29,254 --> 05:05:33,658 >> WITH RESPECT YOU WENT INTO 6214 05:05:33,658 --> 05:05:36,194 HUMANS PRESUMABLY WITH A LOT OF 6215 05:05:36,194 --> 05:05:38,330 WORK SO WONDERING WHAT THE 6216 05:05:38,330 --> 05:05:39,064 COMPELLING EVIDENCE WAS AND NOT 6217 05:05:39,064 --> 05:05:40,665 YOU PERSONALLY BUT THE RELATED 6218 05:05:40,665 --> 05:05:43,101 STUDIES THAT WENT INTO HUMANS. 6219 05:05:43,101 --> 05:05:50,275 >> I DON'T KNOW IF KAMAL WANTS 6220 05:05:50,275 --> 05:05:50,876 TO COMMENT. 6221 05:05:50,876 --> 05:05:53,411 >> MAYBE I CAN ASK IT A 6222 05:05:53,411 --> 05:05:55,313 DIFFERENT WAY SLIGHTLY LESS 6223 05:05:55,313 --> 05:05:57,215 AGGRESSIVE, MAYBE I CAN 6224 05:05:57,215 --> 05:05:57,516 APOLOGIZE. 6225 05:05:57,516 --> 05:05:59,584 MAYBE YOU CAN EXPLAIN TO ME WHAT 6226 05:05:59,584 --> 05:06:00,886 YOU WERE HOPING TO SEE THAT 6227 05:06:00,886 --> 05:06:03,154 WOULD BE CONVINCING ENOUGH FOR 6228 05:06:03,154 --> 05:06:04,789 YOU THAT IT SHOULD HAVE ANOTHER 6229 05:06:04,789 --> 05:06:06,224 ROUND IN HUMANS? 6230 05:06:06,224 --> 05:06:08,126 >> I CAN ANSWER THAT ONE. 6231 05:06:08,126 --> 05:06:11,897 >> WE WOULD LIKE TO SEE WHEN YOU 6232 05:06:11,897 --> 05:06:13,665 STOP ART THE VIRUS DOESN'T COME 6233 05:06:13,665 --> 05:06:15,834 BACK. 6234 05:06:15,834 --> 05:06:17,769 >> WELL, YOU'VE DONE THAT 6235 05:06:17,769 --> 05:06:21,706 EXPERIMENT TWICE IN HUMANS. 6236 05:06:21,706 --> 05:06:24,910 >> WHAT I SAID IN MY TALK AND 6237 05:06:24,910 --> 05:06:26,344 HOPEFULLY I'M SORRY I RUSHED 6238 05:06:26,344 --> 05:06:27,312 THROUGH A LITTLE BIT WE'RE 6239 05:06:27,312 --> 05:06:30,682 HOPING TO SEE A DECREASE IN THE 6240 05:06:30,682 --> 05:06:33,018 VIRAL DIVERSITY IN THE TISSUE 6241 05:06:33,018 --> 05:06:35,053 RESERVOIR RATE BECAUSE IF YOU 6242 05:06:35,053 --> 05:06:36,288 HAVE IN THE CIRCULATION IF YOU 6243 05:06:36,288 --> 05:06:38,156 HAVE ONE VIRUS THAT GETS OUT 6244 05:06:38,156 --> 05:06:39,891 THERE AND REBOUND'S GOING TO GO 6245 05:06:39,891 --> 05:06:40,158 UP. 6246 05:06:40,158 --> 05:06:44,563 DID WE MAKE AN IMPACT ON THE 6247 05:06:44,563 --> 05:06:47,832 TISSUE RESERVOIR, RIGHT. 6248 05:06:47,832 --> 05:06:49,434 THAT'S ONE THING WE HAVEN'T 6249 05:06:49,434 --> 05:06:52,137 EXAMINED FULLY TO SEE IF THAT IS 6250 05:06:52,137 --> 05:06:54,906 IF WE HAVE DONE THAT. 6251 05:06:54,906 --> 05:06:56,374 THAT'S WHAT I SAID. 6252 05:06:56,374 --> 05:07:00,278 I THINK VIRAL REBOUND AND 6253 05:07:00,278 --> 05:07:03,381 ESPECIALLY IN AN SAB 239 MACAQUE 6254 05:07:03,381 --> 05:07:06,351 MODEL TO HAVE VIRAL REBOUND AS 6255 05:07:06,351 --> 05:07:08,053 YOUR GOAL IS LIKE TO STOP VIRAL 6256 05:07:08,053 --> 05:07:08,920 REBOUND IS LIKE UP HERE. 6257 05:07:08,920 --> 05:07:12,457 SO I THINK WE HAVE TO MAKE THOSE 6258 05:07:12,457 --> 05:07:16,394 STEPS THAT SHOW DOES IT AFFECT 6259 05:07:16,394 --> 05:07:17,162 DIVERSITY OF THE RESERVOIR 6260 05:07:17,162 --> 05:07:19,230 BEFORE WE CAN GET UP THERE. 6261 05:07:19,230 --> 05:07:26,037 AND THEN HONESTLY WE USE AAV9 6262 05:07:26,037 --> 05:07:29,574 AND EVERYONE IN THE FIELD KNOWS 6263 05:07:29,574 --> 05:07:32,344 THAT'S NOT PROBABLY THE BEST 6264 05:07:32,344 --> 05:07:33,678 DELIVERY BUT IT'S THE BEST 6265 05:07:33,678 --> 05:07:34,879 DELIVERY WE HAVE AT THE MOMENT. 6266 05:07:34,879 --> 05:07:38,917 SO IT'S A GOOD START. 6267 05:07:38,917 --> 05:07:44,789 I THINK BETTER DELIVERY. 6268 05:07:44,789 --> 05:07:47,592 IF WE DO SEE THE VIRAL LOAD IN 6269 05:07:47,592 --> 05:07:48,793 TISSUES IS DECREASED A COUPLE 6270 05:07:48,793 --> 05:07:49,594 LOGS TO ME THAT WOULD BE 6271 05:07:49,594 --> 05:07:52,230 INTERESTING. 6272 05:07:52,230 --> 05:07:59,904 >> OKAY, GOOD LUCK. 6273 05:07:59,904 --> 05:08:03,975 >> ARE THERE ANY OTHER 6274 05:08:03,975 --> 05:08:04,242 QUESTIONS? 6275 05:08:04,242 --> 05:08:07,579 EITHER IN THE ROOM OR ONLINE? 6276 05:08:07,579 --> 05:08:13,985 OKAY. 6277 05:08:13,985 --> 05:08:15,854 >> OVER ALL THE PROBLEM OF 6278 05:08:15,854 --> 05:08:17,222 EXERTION IS A DIFFICULT ONE BUT 6279 05:08:17,222 --> 05:08:21,726 MY QUESTION WAS MORE WHAT ARE 6280 05:08:21,726 --> 05:08:25,330 YOU DOING TO ADDRESS THAT? 6281 05:08:25,330 --> 05:08:27,399 AT WHAT STEP IS THE DISCONNECT 6282 05:08:27,399 --> 05:08:29,167 BETWEEN YOUR TREATMENT AND THE 6283 05:08:29,167 --> 05:08:29,334 ATI? 6284 05:08:29,334 --> 05:08:31,536 I THINK YOU CAN PROBABLY LEARN A 6285 05:08:31,536 --> 05:08:34,139 LOT FROM THESE STUDY. 6286 05:08:34,139 --> 05:08:36,841 I WOULDN'T EXPECT LIKE A 100% 6287 05:08:36,841 --> 05:08:37,242 CURE. 6288 05:08:37,242 --> 05:08:39,177 IT'S A DIFFICULT PROCESS. 6289 05:08:39,177 --> 05:08:43,481 I WOULD LIKE TO SEE THE STEPS IN 6290 05:08:43,481 --> 05:08:45,483 BETWEEN ADDRESSED AND WHAT COULD 6291 05:08:45,483 --> 05:08:46,685 BE IMPROVED. 6292 05:08:46,685 --> 05:08:49,421 >> THAT WAS THE FIRST TIME THAT 6293 05:08:49,421 --> 05:08:52,590 WE DID THE EXPERIMENT AND 6294 05:08:52,590 --> 05:08:53,425 THERE'S A LOT OF COLLABORATION 6295 05:08:53,425 --> 05:08:54,526 THAT NEED TO BE DONE. 6296 05:08:54,526 --> 05:08:56,861 ONE IS THE DELIVERY SYSTEM AND 6297 05:08:56,861 --> 05:08:59,397 THOSE OF THE DELIVERY SYSTEM 6298 05:08:59,397 --> 05:09:01,499 WE'RE USING AND MORE THE DESIGN 6299 05:09:01,499 --> 05:09:05,670 OF THE EXPERIMENTS. 6300 05:09:05,670 --> 05:09:07,405 FOR EXAMPLE HERE WE DIDN'T 6301 05:09:07,405 --> 05:09:09,908 PROVIDE ENOUGH TIME FOR CRISPR 6302 05:09:09,908 --> 05:09:11,376 TO CIRCULATE IN THE BODY. 6303 05:09:11,376 --> 05:09:12,610 ONLY SEVEN DAYS. 6304 05:09:12,610 --> 05:09:17,015 MAYBE YOU SHOULD DO IT LONGER. 6305 05:09:17,015 --> 05:09:18,550 IT'S A START OF THE JOURNEY THAT 6306 05:09:18,550 --> 05:09:20,218 I THINK IS GOING TO TAKE US TO 6307 05:09:20,218 --> 05:09:23,054 THE PLACE THAT WE WOULD LIKE TO 6308 05:09:23,054 --> 05:09:23,855 BE. 6309 05:09:23,855 --> 05:09:26,458 BUT IT'S A FIRST TIME 6310 05:09:26,458 --> 05:09:28,626 EXPERIMENT. 6311 05:09:28,626 --> 05:09:31,596 FIRST TIME YOU'RE SHOWING IN THE 6312 05:09:31,596 --> 05:09:33,665 LYMPH NODE YOU CAN EXCISE PART 6313 05:09:33,665 --> 05:09:36,134 OF DNA BY A LOUSY DELIVERY 6314 05:09:36,134 --> 05:09:39,270 SYSTEM SUCH AS AAV9 AND IF YOU 6315 05:09:39,270 --> 05:09:44,075 IMPROVE IT INCREASES THE 6316 05:09:44,075 --> 05:09:47,712 EFFICIENCY OF THE EXCISION OR 6317 05:09:47,712 --> 05:09:48,780 EDITING. 6318 05:09:48,780 --> 05:09:53,585 EVEN IN THE BRAIN WE SHOWED THE 6319 05:09:53,585 --> 05:09:56,688 VIRAL DNA IN PLACE AND WE HAVE 6320 05:09:56,688 --> 05:10:00,625 TO WAIT A LITTLE BIT ON THE 6321 05:10:00,625 --> 05:10:11,069 OTHER DATA COMES AND FROM 6322 05:10:12,537 --> 05:10:14,105 INFECTED ANIMALS. 6323 05:10:14,105 --> 05:10:17,075 >> WE WANTED THE CRISPR TO BE 6324 05:10:17,075 --> 05:10:20,378 THERE WHEN WE CATCH THE VIRUS 6325 05:10:20,378 --> 05:10:22,914 REBOUND AND THIS SIV IS AN 6326 05:10:22,914 --> 05:10:30,455 EXTREMELY AGGRESSIVE VIRUS. 6327 05:10:30,455 --> 05:10:33,525 >> THERE'S A SINGLE APPROACH 6328 05:10:33,525 --> 05:10:33,958 THAT'S CHALLENGING. 6329 05:10:33,958 --> 05:10:37,595 WE SHOW PLENTY OF DATA AND 6330 05:10:37,595 --> 05:10:40,498 CRISPR SYSTEM CAN EXCISE AND 6331 05:10:40,498 --> 05:10:42,433 DEACTIVATE HIV BUT DELIVERY IS 6332 05:10:42,433 --> 05:10:43,468 ONE KEY. 6333 05:10:43,468 --> 05:10:45,303 THAT'S WHY WE'RE INTEGRATING 6334 05:10:45,303 --> 05:10:46,805 INTO THE SYSTEM WITH CD4 6335 05:10:46,805 --> 05:10:48,206 SPECIFIC DELIVERY. 6336 05:10:48,206 --> 05:10:50,241 AND ALSO WE WORK ON AN VECTOR 6337 05:10:50,241 --> 05:10:53,945 WHICH IS GOING TO ONLY GO TO CD4 6338 05:10:53,945 --> 05:10:55,113 CELLS. 6339 05:10:55,113 --> 05:10:57,282 I THINK DELIVERY VECTOR 6340 05:10:57,282 --> 05:10:59,584 IMPROVEMENT WILL CHANGE THE 6341 05:10:59,584 --> 05:10:59,818 OUTCOME. 6342 05:10:59,818 --> 05:11:03,521 AND ALSO WE ARE WORKING ON 6343 05:11:03,521 --> 05:11:05,590 STRATEGIES TO COMBINE IN 6344 05:11:05,590 --> 05:11:07,292 MULTIPLE APPROACHES LIKE 6345 05:11:07,292 --> 05:11:10,662 TARGETING NK CELLS OR NK 6346 05:11:10,662 --> 05:11:15,133 MEDIATED THERAPY COMBINED WITH 6347 05:11:15,133 --> 05:11:19,404 CRISPR AND MAYBE THE CELLS WILL 6348 05:11:19,404 --> 05:11:21,706 TAKE THAT OUT AND THOSE ARE 6349 05:11:21,706 --> 05:11:23,608 APPROACHES WE BELIEVE WILL 6350 05:11:23,608 --> 05:11:24,242 IMPROVE SIGNIFICANTLY. 6351 05:11:24,242 --> 05:11:26,411 >> YOU WILL USE THE ANIMALS THAT 6352 05:11:26,411 --> 05:11:29,113 REBOUNDED AND PUT CRISPR ON THEM 6353 05:11:29,113 --> 05:11:29,314 AGAIN. 6354 05:11:29,314 --> 05:11:32,116 TREAT THEM OVER AND OVER. 6355 05:11:32,116 --> 05:11:34,319 >> WE CANNOT DO IT WITH THE 6356 05:11:34,319 --> 05:11:40,258 CURRENT DELIVERY SYSTEM BECAUSE 6357 05:11:40,258 --> 05:11:41,926 BUT WITH THE NEW DELIVERY SYSTEM 6358 05:11:41,926 --> 05:11:43,194 WE'RE DEVELOPING WE MIGHT BE 6359 05:11:43,194 --> 05:11:44,128 ABLE TO DO THAT. 6360 05:11:44,128 --> 05:11:45,663 >> SORRY, WE'RE A LITTLE BIT OUT 6361 05:11:45,663 --> 05:11:48,199 OF TIME AND I SEE SHARON YOU GET 6362 05:11:48,199 --> 05:11:50,068 THE LAST QUESTION AND THEN THE 6363 05:11:50,068 --> 05:11:51,569 BREAK. 6364 05:11:51,569 --> 05:11:53,972 >> ACTUALLY I WAS GOING TO ASK 6365 05:11:53,972 --> 05:11:56,975 ABOUT THE ROLE OF REPEATED 6366 05:11:56,975 --> 05:11:58,042 DOSING INFECTION. 6367 05:11:58,042 --> 05:12:04,549 DO YOU WORK WITH DELIVERY IN 6368 05:12:04,549 --> 05:12:09,954 mRNA OPPOSED TO THE ARB SYSTEM. 6369 05:12:09,954 --> 05:12:13,424 >> AND WE'RE CONTAINING THE 6370 05:12:13,424 --> 05:12:15,093 COMBINATION AS WELL AS WE CAN 6371 05:12:15,093 --> 05:12:19,564 PACKAGE IN OTHER PARTICLES AND 6372 05:12:19,564 --> 05:12:21,733 WHERE HE ARE WORKING ON THE 6373 05:12:21,733 --> 05:12:23,568 MODELS AND GREAT POSTERS OUT 6374 05:12:23,568 --> 05:12:25,470 THERE FROM OTHER GROUPS 6375 05:12:25,470 --> 05:12:27,805 DEVELOPING SIMILAR SYSTEMS AND 6376 05:12:27,805 --> 05:12:29,574 WE'RE ADOPTING THOSE. 6377 05:12:29,574 --> 05:12:31,376 >> THANK YOU AND CONTINUE THE 6378 05:12:31,376 --> 05:12:34,178 CONVERSATION OVER DINNER. 6379 05:12:34,178 --> 05:12:35,613 SO LET'S THANK CRISPR FOR CURE. 6380 05:12:35,613 --> 05:12:43,321 THANK YOU. 6381 05:12:43,321 --> 05:12:45,290 >> I HAVE AN ACKNOWLEDGEMENT 6382 05:12:45,290 --> 05:12:47,592 THERE'S A PROGRAM THIS EVENING 6383 05:12:47,592 --> 05:12:50,461 IF YOU'RE INTERESTED UP HERE ON 6384 05:12:50,461 --> 05:12:51,129 THE SCREEN. 6385 05:12:51,129 --> 05:12:53,798 IT'S AN ORGANIZED COLLABORATION 6386 05:12:53,798 --> 05:12:58,202 BETWEEN THE CENTER FOR AIDS 6387 05:12:58,202 --> 05:13:00,538 RESEARCH AND OTHERS. 6388 05:13:00,538 --> 05:13:02,707 PLEASE FEEL FREE TO GO TO THIS 6389 05:13:02,707 --> 05:13:04,876 EVENT AND FOR TOMORROW WE START 6390 05:13:04,876 --> 05:13:14,876 THE SESSION AT 8:30 EXACTLY.