1 00:00:05,800 --> 00:00:10,240 WELCOME TO EVERYONE. 2 00:00:10,240 --> 00:00:13,480 AND THANK YOU FOR JOINING THE 3 00:00:13,480 --> 00:00:16,960 ACHIEVEMENTS OF MARJORIE 4 00:00:16,960 --> 00:00:19,000 ROBERT-GUROFF WHOM WE'RE HERE TO 5 00:00:19,000 --> 00:00:21,240 HONOR TODAY. 6 00:00:21,240 --> 00:00:24,000 I FIRST MET MARJORIE NOT AS A 7 00:00:24,000 --> 00:00:29,760 FELLOW SCIENTIST BUT AS A FELLOW 8 00:00:29,760 --> 00:00:32,480 PARENT WHEN MARJORIE'S DAUGHTER 9 00:00:32,480 --> 00:00:36,480 SARAH AND MY SON ALEX WERE 10 00:00:36,480 --> 00:00:38,680 CLASSMATES AT WINGATE ELEMENTARY 11 00:00:38,680 --> 00:00:38,920 SCHOOL. 12 00:00:38,920 --> 00:00:41,160 THAT WAS LONG BEFORE WE KNEW 13 00:00:41,160 --> 00:00:42,920 EACH OTHER IN SCIENTIFIC REALMS. 14 00:00:42,920 --> 00:00:48,040 I'VE WORKED WITH MARJORIE NOW 15 00:00:48,040 --> 00:00:52,680 FOR NEARLY 18 YEARS SINCE THE 16 00:00:52,680 --> 00:00:55,000 FORMATION OF THE VACCINE BRANCH 17 00:00:55,000 --> 00:01:01,280 AND MARJORIE'S BEEN A GREAT 18 00:01:01,280 --> 00:01:06,600 CONTRIBUTOR OVER THAT TIME. 19 00:01:06,600 --> 00:01:08,760 YOU'LL HEAR FROM OTHER SPEAKERS 20 00:01:08,760 --> 00:01:10,720 ABOUT HER ACCOMPLISHMENTS OVER 21 00:01:10,720 --> 00:01:12,000 THE YEARS. 22 00:01:12,000 --> 00:01:15,600 ONE MAJOR THEME SINCE I'VE KNOWN 23 00:01:15,600 --> 00:01:19,080 MARJORIE HAS BOTH THE PIONEERING 24 00:01:19,080 --> 00:01:23,080 USE OF REPLICATION ADENOVIRUSES 25 00:01:23,080 --> 00:01:24,760 AS VACCINE VECTORS. 26 00:01:24,760 --> 00:01:26,480 YOU'LL HEAR MORE FROM A NUMBER 27 00:01:26,480 --> 00:01:30,920 OF SPEAKERS. 28 00:01:30,920 --> 00:01:34,880 THEN IN RECENT YEARS I WANT TO 29 00:01:34,880 --> 00:01:38,160 MENTION TWO I THINK VERY 30 00:01:38,160 --> 00:01:39,680 IMPORTANT DISCOVERIES SORT OF 31 00:01:39,680 --> 00:01:41,200 AHEAD OF THE FIELD MARJORIE'S 32 00:01:41,200 --> 00:01:41,560 MADE. 33 00:01:41,560 --> 00:01:44,840 ONE IS THE IMPORTANCE OF 34 00:01:44,840 --> 00:01:46,960 NON-NEUTRALIZING ANTIBODIES IN 35 00:01:46,960 --> 00:01:50,360 PROTECTION AGAINST VIRUS 36 00:01:50,360 --> 00:01:53,160 INFECTIONS IN PARTICULAR SIV AND 37 00:01:53,160 --> 00:01:55,720 HIV MARJORIE MADE IN HER MACAQUE 38 00:01:55,720 --> 00:01:58,280 STUDIES, IF MY MEMORY IS CORRECT 39 00:01:58,280 --> 00:02:02,520 PRECEDE THE OBSERVATION OF SUCH 40 00:02:02,520 --> 00:02:07,560 THINGS IN HUMAN TRIALS IN THE 41 00:02:07,560 --> 00:02:09,960 PHASE 3 TRIAL. 42 00:02:09,960 --> 00:02:12,000 THAT WAS PRESCIENT AND THE 43 00:02:12,000 --> 00:02:15,880 SECOND WAS THE ROLE OF GENDER OR 44 00:02:15,880 --> 00:02:16,600 SEX DIFFERENCES IN IMMUNE 45 00:02:16,600 --> 00:02:18,280 RESPONSE TO VACCINES. 46 00:02:18,280 --> 00:02:20,000 AND WE'VE BEEN SEEING MORE AND 47 00:02:20,000 --> 00:02:22,280 MORE EXAMPLES OF THAT. 48 00:02:22,280 --> 00:02:27,920 IT'S TRUE WITH COVID AND WITH A 49 00:02:27,920 --> 00:02:34,680 LOT OF THINGS AS WELL. 50 00:02:34,680 --> 00:02:39,760 YOU'LL HEAR MORE FROM MANY 51 00:02:39,760 --> 00:02:43,080 SPEAKERS WHO WORKED WITH 52 00:02:43,080 --> 00:02:44,040 MARJORIE THOUGH WE'VE BEEN 53 00:02:44,040 --> 00:02:45,880 TOGETHER IN THE VACCINE BRANCH 54 00:02:45,880 --> 00:02:47,480 I'VE NEVER HAD THE PLEASURE OF 55 00:02:47,480 --> 00:02:49,080 BEING IN HER LAB. 56 00:02:49,080 --> 00:02:50,760 I'LL LEAVE IT TO THE OTHER 57 00:02:50,760 --> 00:02:51,960 SPEAKERS WHO WORKED MORE 58 00:02:51,960 --> 00:02:53,920 CLOSELY. 59 00:02:53,920 --> 00:02:57,240 I WANT TO INTRODUCE OUR KEY NOTE 60 00:02:57,240 --> 00:02:58,880 SPEAKER BOB GALLO WHO I THINK 61 00:02:58,880 --> 00:03:01,680 NEEDS NO INTRODUCTION TO THE 62 00:03:01,680 --> 00:03:02,720 AUDIENCE BUT NEVERTHELESS I'LL 63 00:03:02,720 --> 00:03:03,680 GIVE A BRIEF INTRODUCTION. 64 00:03:03,680 --> 00:03:05,920 HE'S THE FOUNDER AND DIRECTOR OF 65 00:03:05,920 --> 00:03:07,880 THE INSTITUTE OF HUMAN VIROLOGY 66 00:03:07,880 --> 00:03:13,360 AT THE UNIVERSITY OF MARYLAND 67 00:03:13,360 --> 00:03:18,800 BALTIMORE BUT ALSO ALUMNUS OF 68 00:03:18,800 --> 00:03:23,960 THE NATIONAL CANCER INSTITUTE. 69 00:03:23,960 --> 00:03:25,120 WHERE A LOT OF DISCOVERIES WERE 70 00:03:25,120 --> 00:03:31,360 MADE AND ALSO THE FOUNDER OF THE 71 00:03:31,360 --> 00:03:34,160 GLOBAL VACCINE NETWORK AND I 72 00:03:34,160 --> 00:03:39,600 WANT TO MENTION AT LEAST THREE 73 00:03:39,600 --> 00:03:44,600 THINGS, ANY OF WHICH WOULD BE A 74 00:03:44,600 --> 00:03:47,120 LIFE TIME ACHIEVEMENT ONE OF THE 75 00:03:47,120 --> 00:03:52,120 DISCOVERY OF INTERLEUKIN 2 THAT 76 00:03:52,120 --> 00:03:56,880 LOU THE GROWTH OF T LYMPHOCYTES 77 00:03:56,880 --> 00:03:59,080 THAT'S OPENED UP THE WORLD OF 78 00:03:59,080 --> 00:04:01,280 THE IMMUNOLOGY AND THE DISCOVERY 79 00:04:01,280 --> 00:04:05,160 OF THE HTLV-1 WE'LL TALK ABOUT 80 00:04:05,160 --> 00:04:14,840 TODAY AND ADULT T CELL LEUKEMIA 81 00:04:14,840 --> 00:04:18,480 AND THE OTHER IS THE DISCOVERY 82 00:04:18,480 --> 00:04:21,400 OF THE AIDS VIRUS NOW KNOWN AS 83 00:04:21,400 --> 00:04:25,080 HIV AND WE'LL BE HEARING MORE 84 00:04:25,080 --> 00:04:27,320 ABOUT THAT AS WELL. 85 00:04:27,320 --> 00:04:28,880 SO IT'S INCREDIBLE FOR ANYONE TO 86 00:04:28,880 --> 00:04:30,480 MAKE SO MANY LANDMARK 87 00:04:30,480 --> 00:04:33,640 DISCOVERIES IN ONE LIFE TIME AND 88 00:04:33,640 --> 00:04:35,880 IT'S A GREAT PRIVILEGE TO HAVE 89 00:04:35,880 --> 00:04:44,000 BOB HERE AND HE'LL TELL US ABOUT 90 00:04:44,000 --> 00:04:45,440 MARJORIE'S CONTRIBUTIONS IN THE 91 00:04:45,440 --> 00:04:47,160 EARLY DAYS. 92 00:04:47,160 --> 00:04:48,640 BOB, THANK YOU. 93 00:04:48,640 --> 00:04:54,520 >> I WANT TO SAY THEY SAW ME 94 00:04:54,520 --> 00:04:57,120 LIMPING AND I SAID I HAD KNEE 95 00:04:57,120 --> 00:05:03,240 SURGERY. 96 00:05:03,240 --> 00:05:04,280 THIS IS A MARJORIE TALK SO THERE 97 00:05:04,280 --> 00:05:09,440 WERE CLINICAL ASSOCIATES AND IN 98 00:05:09,440 --> 00:05:12,360 1971 PEOPLE THINK WE HAD A LOT 99 00:05:12,360 --> 00:05:15,040 OF HELP I CAN TELL YOU IT DIDN'T 100 00:05:15,040 --> 00:05:19,440 START THAT WAY. 101 00:05:19,440 --> 00:05:24,200 I HAD ZERO -- I CAME IN '65 AND 102 00:05:24,200 --> 00:05:25,720 PERSONALLY WAS SUPPOSED TO WORK 103 00:05:25,720 --> 00:05:28,520 WITH WENDELL ROSS AND WENT TO 104 00:05:28,520 --> 00:05:31,840 WORK AND IN NIH'S WISDOM THEY 105 00:05:31,840 --> 00:05:33,840 SENT ME TO THE CHILDHOOD 106 00:05:33,840 --> 00:05:34,920 LEUKEMIA WARD AND I WENT TO THE 107 00:05:34,920 --> 00:05:38,960 LAB AND WAS ALONE FOR YEARS AND 108 00:05:38,960 --> 00:05:41,920 BE THE WE CONVERTED AMY GRIMES 109 00:05:41,920 --> 00:05:44,440 AN EDUCATOR AT THE FOURTH GRADE 110 00:05:44,440 --> 00:05:47,200 AND BECAME MY TECHNICIAN. 111 00:05:47,200 --> 00:05:48,920 THERE WERE MANY LONELY YEARS BUT 112 00:05:48,920 --> 00:05:54,360 THIS IS THE BEGINNING OF HAVING 113 00:05:54,360 --> 00:05:58,240 SOME HELP. 114 00:05:58,240 --> 00:06:04,600 AND MY MAIN INTEREST WAS 115 00:06:04,600 --> 00:06:10,600 LEUKEMIA AND IN ANIMAL THERE'S A 116 00:06:10,600 --> 00:06:13,080 COMMON CAUSE AND THERE WERE RNA 117 00:06:13,080 --> 00:06:28,560 TUMOR VIRUSES SO I THOUGHT AND 118 00:06:28,560 --> 00:06:30,280 THEN THE PROVIRUS THEORY WAS 119 00:06:30,280 --> 00:06:32,000 THOUGHT TO BE CORRECT AND THERE 120 00:06:32,000 --> 00:06:36,400 WAS A DISCOVERY BY KEVIN IN 121 00:06:36,400 --> 00:06:41,880 BALTIMORE FOR REVERSE TRANSCRIPT 122 00:06:41,880 --> 00:06:45,080 TRANSCRIPTASE I WAS COMPARING 123 00:06:45,080 --> 00:06:49,840 THEM WORKING ON PHA STIMULATED 124 00:06:49,840 --> 00:06:53,760 LYMPH SITES. 125 00:06:53,760 --> 00:06:55,880 WE DIDN'T KNOW -- LYMPHOCYTES 126 00:06:55,880 --> 00:06:57,040 AND THEY WERE BEING DESCRIBED IN 127 00:06:57,040 --> 00:07:01,840 THE BEGINNING AND THEY DESCRIBED 128 00:07:01,840 --> 00:07:05,840 THIS PLANT PROTEIN COULD MAKE 129 00:07:05,840 --> 00:07:07,160 LYMPHOCYTES. 130 00:07:07,160 --> 00:07:11,400 WE DIDN'T KNOW WHICH ONES BECAME 131 00:07:11,400 --> 00:07:19,320 CELLS AND THEY LOOKED LIKE ACUTE 132 00:07:19,320 --> 00:07:21,080 LYMPHOCYTIC CELLS. 133 00:07:21,080 --> 00:07:25,040 ONE OF THOSE WAS DNA POLYMERASE 134 00:07:25,040 --> 00:07:28,280 AND WITH BALTIMORE AND OTHERS WE 135 00:07:28,280 --> 00:07:29,880 PUBLISHED IN SCIENCE WE KNEW 136 00:07:29,880 --> 00:07:33,080 THREE AND CALLED THEM ALPHA, 137 00:07:33,080 --> 00:07:35,320 BETA, GAMMA. 138 00:07:35,320 --> 00:07:36,960 MARJORIE WAS ALREADY TRAINED IN 139 00:07:36,960 --> 00:07:55,080 BIOCHEMISTRY. 140 00:07:55,080 --> 00:07:57,040 SO MARJORIE HAD HISTORY AND THE 141 00:07:57,040 --> 00:08:01,080 STAGE WAS SET AND CURTAIN BOWS 142 00:08:01,080 --> 00:08:01,880 WERE RATHER FAR AWAY. 143 00:08:01,880 --> 00:08:05,880 THE TIMING WAS BAD FOR ALL OF 144 00:08:05,880 --> 00:08:19,200 US. 145 00:08:19,200 --> 00:08:21,280 THIS IS NOW THE 1970. 146 00:08:21,280 --> 00:08:25,920 AND WE MOVE FROM THE '60s TO THE 147 00:08:25,920 --> 00:08:27,120 '70s. 148 00:08:27,120 --> 00:08:29,680 AND THERE WAS A HEALTHY RESPECT 149 00:08:29,680 --> 00:08:33,000 FOR PANDEMICS BUT IN THE '70s IT 150 00:08:33,000 --> 00:08:35,760 WAS THOUGHT TO BE A WASTE AND 151 00:08:35,760 --> 00:08:39,040 THE CANCER CENTER WAS SHUT DOWN 152 00:08:39,040 --> 00:08:41,600 AND THERE WAS A MEETING AND 153 00:08:41,600 --> 00:08:45,040 THERE'S NO EVIDENCE FOR ANY 154 00:08:45,040 --> 00:08:46,000 INFECTIOUS INVOLVEMENT OF HUMAN 155 00:08:46,000 --> 00:08:50,200 CANCER IT WAS ALL CHEMICALS AT 156 00:08:50,200 --> 00:08:53,360 THE TIME THOUGHT VERY WRONGLY 157 00:08:53,360 --> 00:08:55,200 AND THE DEPARTMENTS AND SOME 158 00:08:55,200 --> 00:08:56,880 MEDICAL SCHOOLS WERE TERMINATED. 159 00:08:56,880 --> 00:08:58,560 HARD TO BELIEVE. 160 00:08:58,560 --> 00:09:03,680 THIS IS AROUND THE MID 1970s. 161 00:09:03,680 --> 00:09:07,800 RETROVIRUSES DON'T INFECT HUMANS 162 00:09:07,800 --> 00:09:09,080 AND THEY THOUGHT YOU DON'T NEED 163 00:09:09,080 --> 00:09:09,720 TO FUND IT. 164 00:09:09,720 --> 00:09:11,560 THE ARGUMENT WELL OF WAS ALL 165 00:09:11,560 --> 00:09:16,280 MONEY SHOULD GO TO DEGENERATIVE 166 00:09:16,280 --> 00:09:17,600 DISEASES AND MOLECULAR BIOLOGY 167 00:09:17,600 --> 00:09:19,080 AND GENETICS AND SOME OF THOSE 168 00:09:19,080 --> 00:09:21,760 DISEASES WERE INVOLVING VIRUSES. 169 00:09:21,760 --> 00:09:23,080 SO I SAID THE LAST ONE NO 170 00:09:23,080 --> 00:09:26,520 VIRUSES WERE INVOLVED IN HUMAN 171 00:09:26,520 --> 00:09:26,960 CANCER. 172 00:09:26,960 --> 00:09:29,120 THESE BIASES WERE FINISHED BY 173 00:09:29,120 --> 00:09:32,360 THE BEGINNING OF THE 1980s AND 174 00:09:32,360 --> 00:09:33,720 WERE SHOWN TO BE INVOLVED IN THE 175 00:09:33,720 --> 00:09:38,960 CAUSE OF ABOUT 20% HUMAN CANCERS 176 00:09:38,960 --> 00:09:40,560 AND THERE DOESN'T SEEM TO BE 177 00:09:40,560 --> 00:09:41,960 ANYTHING ELSE REQUIRED SO THE 178 00:09:41,960 --> 00:09:45,120 RETROVIRUSES WERE FOUND IN 179 00:09:45,120 --> 00:09:49,880 HUMANS AND FOUND FATAL 180 00:09:49,880 --> 00:09:55,360 NEUROLOGIC DISEASE AND EVEN SOME 181 00:09:55,360 --> 00:09:55,720 AUTOIMMUNITY. 182 00:09:55,720 --> 00:10:01,640 AND WE LOOKED AT HOW THE 183 00:10:01,640 --> 00:10:08,840 DEVELOPMENTS OCCURRED. 184 00:10:08,840 --> 00:10:11,440 SO OUR APPROACH WAS METHODS 185 00:10:11,440 --> 00:10:12,080 USING GROWTH FACTORS. 186 00:10:12,080 --> 00:10:15,080 I FELT WE HAD TO HAVE PRIMARY 187 00:10:15,080 --> 00:10:16,920 CELLS AND WE NEEDED GROWTH 188 00:10:16,920 --> 00:10:17,160 FACTORS. 189 00:10:17,160 --> 00:10:22,200 THEY WERE JUST DISCOVERED. 190 00:10:22,200 --> 00:10:30,000 THEY WERE DISCOVERED BY 191 00:10:30,000 --> 00:10:32,520 VANDERBILT WITH AN EPITHELIAL 192 00:10:32,520 --> 00:10:33,800 GROWTH FACTOR. 193 00:10:33,800 --> 00:10:38,160 THEY WERE NOT LIKE CYTOKINES. 194 00:10:38,160 --> 00:10:41,560 IT WAS AUTOCRINE AND THE CONCEPT 195 00:10:41,560 --> 00:10:43,320 HAD NOT YET BEEN DEVELOPED AND 196 00:10:43,320 --> 00:10:49,080 WE THOUGHT WE NEEDED SPECIFIC 197 00:10:49,080 --> 00:10:51,360 ASSAYS FOR FINDING A RETROVIRUS. 198 00:10:51,360 --> 00:10:54,760 WE KNOW THERE'S A MECHANISM FOR 199 00:10:54,760 --> 00:10:56,760 THE PROVIRUS AND A TOOL THAT 200 00:10:56,760 --> 00:10:58,760 IMPACTED MOLECULAR BIOLOGY. 201 00:10:58,760 --> 00:11:02,760 IT WAS 1,000 TIMES MORE 202 00:11:02,760 --> 00:11:04,760 SENSITIVE THAN MICROSCOPY AND IT 203 00:11:04,760 --> 00:11:08,560 BECAME A SURROGATE MARK AND 204 00:11:08,560 --> 00:11:09,880 ALLOWS FOR FREQUENT SAMPLING 205 00:11:09,880 --> 00:11:11,400 IMPORTANT FOR VIRUSES INVOLVED 206 00:11:11,400 --> 00:11:13,520 IN PERIODIC BURST. 207 00:11:13,520 --> 00:11:16,840 I CAN'T EMPHASIZE THE FIRST A IS 208 00:11:16,840 --> 00:11:21,080 OFFICE BUT B MAY BE MORE 209 00:11:21,080 --> 00:11:21,840 IMPORTANT. 210 00:11:21,840 --> 00:11:24,880 HTLV-1 I CAN'T SAY ABOUT HTLV-2 211 00:11:24,880 --> 00:11:26,560 SO MUCH BUT IN HIV TEND TO COME 212 00:11:26,560 --> 00:11:29,120 OUT IN PERIODIC BURSTS 213 00:11:29,120 --> 00:11:30,600 ESPECIALLY WITH HTLV-1. 214 00:11:30,600 --> 00:11:33,840 NO WAY YOU'LL FIND THE VIRUS BY 215 00:11:33,840 --> 00:11:36,200 ELECTRON MICROSCOPY EASILY 216 00:11:36,200 --> 00:11:38,160 BECAUSE YOU CAN'T SAMPLE EVERY 217 00:11:38,160 --> 00:11:39,800 15 MINUTES OR STIMULATE A 218 00:11:39,800 --> 00:11:41,560 CULTURE REGULARLY ALL THE TIME 219 00:11:41,560 --> 00:11:43,760 BUT YOU CAN WITH THE REVERSE 220 00:11:43,760 --> 00:11:44,720 TRANSCRIPTASE ASSAY. 221 00:11:44,720 --> 00:11:46,960 IT'S NOT A HISTORY THAT'S REALLY 222 00:11:46,960 --> 00:11:48,160 BEEN DESCRIBED. 223 00:11:48,160 --> 00:11:50,160 THERE'S NO PLACE WE EVER KIND OF 224 00:11:50,160 --> 00:11:51,160 GATHERED THIS TOGETHER AND SAID 225 00:11:51,160 --> 00:11:52,760 THIS IS HOW IT HAPPENED. 226 00:11:52,760 --> 00:11:54,560 WE TALK ABOUT IT BUT IT'S NOT 227 00:11:54,560 --> 00:11:56,360 REALLY WRITTEN. 228 00:11:56,360 --> 00:11:58,880 THERE WERE STRONG VIEWS AGAINST 229 00:11:58,880 --> 00:12:03,040 THE POSSIBILITY OF HUMAN ANTI 230 00:12:03,040 --> 00:12:05,800 ANTIVIEANT 231 00:12:05,800 --> 00:12:10,440 ANTIVIRUSES AND ANIMAL MODELS 232 00:12:10,440 --> 00:12:14,280 WERE SELECTED FOR WHICH ARE 233 00:12:14,280 --> 00:12:16,360 OBVIOUS AND THE SAME WITH MOUSE 234 00:12:16,360 --> 00:12:17,240 LEUKEMIA VIRUS. 235 00:12:17,240 --> 00:12:19,200 THE ONES REALLY KNOWN AT THE 236 00:12:19,200 --> 00:12:22,880 TIME. 237 00:12:22,880 --> 00:12:24,120 THERE WAS LITTLE EVIDENCE 238 00:12:24,120 --> 00:12:26,960 CAUSING AIDS UNTIL THE '70s 239 00:12:26,960 --> 00:12:29,200 SHOWN BY A GROUP AT DAVIS 240 00:12:29,200 --> 00:12:31,600 CALIFORNIA AND THEY ONLY TESTED 241 00:12:31,600 --> 00:12:34,000 SMALL ANIMAL RETROVIRUSES. 242 00:12:34,000 --> 00:12:36,520 AND HUMANS WERE PROTECTED AND 243 00:12:36,520 --> 00:12:37,600 LASTLY AND WHAT YOU WON'T 244 00:12:37,600 --> 00:12:38,920 APPRECIATE IN TODAY'S WORLD IF 245 00:12:38,920 --> 00:12:41,120 YOU'RE YOUNG, HUMAN RESEARCH WAS 246 00:12:41,120 --> 00:12:41,920 NOT APPRECIATED. 247 00:12:41,920 --> 00:12:43,760 CANCER IS CATCHING LIKE AN 248 00:12:43,760 --> 00:12:45,400 INFECTION SEEMED TO BE A 249 00:12:45,400 --> 00:12:46,360 PRIMITIVE VIRUS AND SLOW VIRUS 250 00:12:46,360 --> 00:12:48,960 NOT REALLY THOUGHT ABOUT AND 251 00:12:48,960 --> 00:12:51,000 THOUGHT HUMAN RESEARCH WAS, IF 252 00:12:51,000 --> 00:12:53,240 YOU PARDON ME THE PITS. 253 00:12:53,240 --> 00:12:55,160 THE LAST SOPHISTICATED. 254 00:12:55,160 --> 00:12:56,960 IT WAS A POORMAN'S WAY OF DOING 255 00:12:56,960 --> 00:12:59,800 RESEARCH. 256 00:12:59,800 --> 00:13:01,960 A FEW MAJOR KEY PAPERS IN THAT 257 00:13:01,960 --> 00:13:09,800 PERIOD FROM OUR GROUP. 258 00:13:09,800 --> 00:13:18,000 MARJORIE ET AL AND JACK GABRIEL 259 00:13:18,000 --> 00:13:24,760 WITH MARJORIE AND OTHERS AND 260 00:13:24,760 --> 00:13:30,000 POLYMERASES AND POLYMERASES TO 261 00:13:30,000 --> 00:13:34,000 DEPOLYMERASE GAMMA AND OUR 262 00:13:34,000 --> 00:13:38,000 FRIEND, NEOPLASTIC CELLS AFTER 263 00:13:38,000 --> 00:13:39,760 THOROUGH REVIEW. 264 00:13:39,760 --> 00:13:43,280 MARJORIE ET AL. 265 00:13:43,280 --> 00:13:48,000 GAMMA IS CONFUSED WITH 266 00:13:48,000 --> 00:13:51,400 TRANSCRIPTASE AND LYMPHO BLASTS. 267 00:13:51,400 --> 00:13:53,960 AND THERE WERE TALKS ON HUMAN 268 00:13:53,960 --> 00:13:55,720 BLOOD CELLS. 269 00:13:55,720 --> 00:13:58,760 SHE DIDN'T WORK IN BLOOD CELL 270 00:13:58,760 --> 00:14:00,720 STORIES. 271 00:14:00,720 --> 00:14:02,040 WE CULTURED HUMAN MYELOID CELLS 272 00:14:02,040 --> 00:14:05,800 AND WE HAD AN EMBRYONIC GROWTH 273 00:14:05,800 --> 00:14:09,680 FACTOR AND ONE BECAME THE FIRST 274 00:14:09,680 --> 00:14:13,440 MYELOID CELL LINE HH60 WHICH 275 00:14:13,440 --> 00:14:20,280 BECAME THE THERAPY FOR 276 00:14:20,280 --> 00:14:21,800 PROMILOCYTIC LEUKEMIA WON A 277 00:14:21,800 --> 00:14:30,840 PRIZE FOR CLINICAL USE OF RETINO 278 00:14:30,840 --> 00:14:34,000 RETINOACID AND SOME CALLED IT 279 00:14:34,000 --> 00:14:36,880 THE FIRST RECOGNIZED CYTOKINE. 280 00:14:36,880 --> 00:14:40,080 WE CULTURED HUMAN T CELLS IN 281 00:14:40,080 --> 00:14:41,960 1967 THEN THIS POINTED US 282 00:14:41,960 --> 00:14:43,200 TOWARDS T CELLS BY NECESSITY. 283 00:14:43,200 --> 00:14:47,760 WE HAD THE ABILITY TO GROW HUMAN 284 00:14:47,760 --> 00:14:50,000 T CELLS AND COULD SHOW T CELLS 285 00:14:50,000 --> 00:14:53,120 COULD BE GROWN BEYOND A SINGLE 286 00:14:53,120 --> 00:14:53,360 MITOSIS. 287 00:14:53,360 --> 00:15:01,360 IN 1978 WE ISOLATED A STRAIN OF 288 00:15:01,360 --> 00:15:04,200 LEUKEMIA VIRUS AND CAUSED 289 00:15:04,200 --> 00:15:07,560 CHRONIC MYELOID LEUKEMIA AND 290 00:15:07,560 --> 00:15:10,320 FOUND WHAT HAD T CELL LEUKEMIA 291 00:15:10,320 --> 00:15:14,040 AND THESE TWO THINGS PUSHED US 292 00:15:14,040 --> 00:15:16,160 TOWARDS T CELL MALIGNANCIES. 293 00:15:16,160 --> 00:15:20,200 THIS IS THE FIRST COLLECTED 294 00:15:20,200 --> 00:15:21,400 ELECTRON MICROGRAPH THE THIRST 295 00:15:21,400 --> 00:15:38,000 HUMAN RETROVIRUS AND THAT'S THE 296 00:15:38,000 --> 00:15:40,240 LEUKEMIC PAERPZ 297 00:15:44,360 --> 00:15:48,560 PAPERS WE ISOLATED BIOPSIES OF 298 00:15:48,560 --> 00:15:51,480 THE LESIONS THAT WERE 299 00:15:51,480 --> 00:15:54,360 INFILTRATED WITH MAG IG NANT 300 00:15:54,360 --> 00:15:55,360 CELLS AND AN AGGRESSIVE DISEASE 301 00:15:55,360 --> 00:15:56,600 AND RECOGNIZED IN JAPAN. 302 00:15:56,600 --> 00:15:58,800 IN JAPAN THEY KNEW THE DISEASE 303 00:15:58,800 --> 00:16:01,040 BUT DIDN'T FOE THE VIRUS FIRST. 304 00:16:01,040 --> 00:16:03,880 WE FOUND IT IN SPORADIC CASES. 305 00:16:03,880 --> 00:16:05,960 ONE WONDERS IF WE WERE LIVING IN 306 00:16:05,960 --> 00:16:08,640 JAPAN IF IT WOULD HAVE OCCURRED 307 00:16:08,640 --> 00:16:10,880 EARLIER BECAUSE IT WAS DESCRIBED 308 00:16:10,880 --> 00:16:16,360 AS AN EPIDEMIC IN SOUTHWEST 309 00:16:16,360 --> 00:16:18,160 JAPAN AND THROUGHOUT BUT LESION 310 00:16:18,160 --> 00:16:21,600 IS CHARACTERIZED BY THE 311 00:16:21,600 --> 00:16:24,720 INFILTRATED LEUKEMIC CELLS AND 312 00:16:24,720 --> 00:16:27,800 ABOUT 20% IS CALLED SMOLDERING 313 00:16:27,800 --> 00:16:29,760 OR CHRONIC THOSE ARE MORE MILDER 314 00:16:29,760 --> 00:16:32,560 DISEASES BUT WERE RAPIDLY FATAL 315 00:16:32,560 --> 00:16:35,320 WHICH HAPPENED IN THIS YOUNG MAN 316 00:16:35,320 --> 00:16:37,360 WITH NO PAST HISTORY, PERSONAL, 317 00:16:37,360 --> 00:16:38,840 SEXUAL, NOTHING. 318 00:16:38,840 --> 00:16:39,560 WE FOUND ANTIBODIES AND 319 00:16:39,560 --> 00:16:41,360 DEVELOPED ASSAYS BY MARJORIE, I 320 00:16:41,360 --> 00:16:45,880 CAN'T RECALL AND SOME FAMILY 321 00:16:45,880 --> 00:16:46,120 MEMBERS. 322 00:16:46,120 --> 00:16:49,120 WIN TIME IT BECAME CLEAR IT WAS 323 00:16:49,120 --> 00:16:51,240 NOT TRANSMITTED BY VIRUS BUT 324 00:16:51,240 --> 00:16:52,120 INFECTED CELLS. 325 00:16:52,120 --> 00:16:55,360 THE PROVIRUS IS WHAT IS 326 00:16:55,360 --> 00:16:57,360 INFECTIOUS WHICH WAS AMAZING AND 327 00:16:57,360 --> 00:17:04,680 THAT WAS DIFFERENT IN RETRO 328 00:17:04,680 --> 00:17:06,720 VIROLOGY AND ENCODED IN GENES 329 00:17:06,720 --> 00:17:08,480 FOR THESE REGULATORY PROTEINS. 330 00:17:08,480 --> 00:17:10,960 THIS WOULD PREDICT ALL THE 331 00:17:10,960 --> 00:17:15,960 THINGS THAT HAPPENED WITH HIV, 332 00:17:15,960 --> 00:17:18,040 CD4 TROPISM AND SMALLER CORE 333 00:17:18,040 --> 00:17:20,920 PROTEIN P34 INSTEAD OF P30. 334 00:17:20,920 --> 00:17:22,360 THOUGH THE GENES ARE NOT SIMILAR 335 00:17:22,360 --> 00:17:24,160 BY SEQUENCE IS ALMOST LIKE A 336 00:17:24,160 --> 00:17:28,640 CONVERGENT BETWEEN THE TWO 337 00:17:28,640 --> 00:17:32,600 FAMILIES OF HUMAN RETROVIRUSES. 338 00:17:32,600 --> 00:17:41,160 AND LOOK AT NUMBER 3, IT'S IT'S 339 00:17:41,160 --> 00:17:44,000 LIKELY THE MOST ONCOGENIC KNOWN 340 00:17:44,000 --> 00:17:48,960 AGENT AND IT'S THE ONLY LEUKEMIA 341 00:17:48,960 --> 00:18:01,520 VIRUS THE FIRST RETROVIRUS AND 342 00:18:01,520 --> 00:18:03,440 LINKED AND IF YOU USE THE 343 00:18:03,440 --> 00:18:05,400 PROVIRUS OR CERTAIN GENES FROM 344 00:18:05,400 --> 00:18:10,240 IT YOU CAN CREATE ADULT T CELL 345 00:18:10,240 --> 00:18:12,360 LEUKEMIA IN MOUSE MODELS. 346 00:18:12,360 --> 00:18:14,400 IT'S AN IMMORTALIZING 347 00:18:14,400 --> 00:18:17,800 TRANSFORMING VIRUS AND LINKED 348 00:18:17,800 --> 00:18:20,160 EPIDEMIOLOGICALLY TO ALL THE IN 349 00:18:20,160 --> 00:18:21,840 VITRO RESULTS YOU HAVE ARGUE 350 00:18:21,840 --> 00:18:27,080 FORCEFULLY IT'S A DIRECT CAUSE 351 00:18:27,080 --> 00:18:34,000 OF THIS CANCER. 352 00:18:34,000 --> 00:18:41,160 AND WE PUBLISHED THIS PAPER 353 00:18:41,160 --> 00:18:46,840 TOGETHER AND WE CAME TO THE 354 00:18:46,840 --> 00:18:48,720 CONCLUSION THAT HTLV-1 IS THE 355 00:18:48,720 --> 00:18:53,960 MOST ONCOGENIC AND IT'S 356 00:18:53,960 --> 00:18:55,920 PARTICULARLY TRUE IF YOU LOOK AT 357 00:18:55,920 --> 00:19:00,920 THE PEOPLE THAT WERE INFECTED AT 358 00:19:00,920 --> 00:19:01,560 BIRTH. 359 00:19:01,560 --> 00:19:04,760 IT WAS REPORTED AROUND 20% TO 360 00:19:04,760 --> 00:19:07,360 25% OF CHILDREN BORN WITH 361 00:19:07,360 --> 00:19:08,960 HTLV-1, NOT BORN WITH IT BUT 362 00:19:08,960 --> 00:19:11,160 INFECTED SOON AFTER IN INFANCY 363 00:19:11,160 --> 00:19:12,960 WILL DEVELOP T CELL LEUKEMIA. 364 00:19:12,960 --> 00:19:14,880 THAT'S A VERY HIGH RATE. 365 00:19:14,880 --> 00:19:17,040 FORTUNATELY, IT'S SO POORLY 366 00:19:17,040 --> 00:19:18,400 INFECTIOUS SO IT BECOMES PUBLIC 367 00:19:18,400 --> 00:19:20,720 HEALTH WISE NOT THAT IMPORTANT 368 00:19:20,720 --> 00:19:23,280 THAT WHO VIRTUALLY FORGOT ABOUT 369 00:19:23,280 --> 00:19:26,000 IT UNTIL THERE WAS PROTEST IN 370 00:19:26,000 --> 00:19:29,360 AUSTRALIA WHERE HALF THE 371 00:19:29,360 --> 00:19:33,400 ABORIGINAL NATIVE PEOPLE 372 00:19:33,400 --> 00:19:37,960 DEVELOPED A SEVERE DISEASE FROM 373 00:19:37,960 --> 00:19:42,280 HTLV AND THEY'RE FOLLOWING IT 374 00:19:42,280 --> 00:19:44,400 MUCH CLOSER AND I HOPE THERE'LL 375 00:19:44,400 --> 00:19:53,960 BE SOMETHING SAID ABOUT IT. 376 00:19:53,960 --> 00:19:57,480 MARJORIE'S PLAYS A KEY ROLE IN 377 00:19:57,480 --> 00:19:58,840 THE ROLE OF HTLV TO LEUKEMIA. 378 00:19:58,840 --> 00:20:00,920 I DON'T KNOW IF I NEED TO SAY 379 00:20:00,920 --> 00:20:04,000 THEM ALL. 380 00:20:04,000 --> 00:20:10,000 IF YOU LOOK YOU'LL SEE 381 00:20:10,000 --> 00:20:14,040 IMMUNOLOGICAL LINKAGE. 382 00:20:14,040 --> 00:20:16,120 AND ESTABLISHING THE LINK WAS 383 00:20:16,120 --> 00:20:18,120 HER MORE THAN ANYBODY ON EARTH. 384 00:20:18,120 --> 00:20:21,000 AND JAPAN PICKED IT UP STRONGLY 385 00:20:21,000 --> 00:20:23,280 TOO BECAUSE THEY HAD MANY MORE 386 00:20:23,280 --> 00:20:25,880 PATIENTS AND THIS IS THE 387 00:20:25,880 --> 00:20:28,360 EARLIEST AND STRONGEST OF THIGHS 388 00:20:28,360 --> 00:20:31,160 KINDS OF PAPERS. 389 00:20:31,160 --> 00:20:34,360 SO IN MANY MANY MORE PAPERS 390 00:20:34,360 --> 00:20:37,200 LINKING HTLV-1 TO VARIOUS 391 00:20:37,200 --> 00:20:37,440 REGIONS. 392 00:20:37,440 --> 00:20:38,920 MARJORIE, I DIDN'T GO THROUGH 393 00:20:38,920 --> 00:20:40,760 EVERYWHERE PAPER YOU PUBLISHED. 394 00:20:40,760 --> 00:20:41,960 THERE'S MORE THAN I'M LISTING IN 395 00:20:41,960 --> 00:20:42,800 THE SLIDE. 396 00:20:42,800 --> 00:20:47,760 THE DISCOVERY AND SOME FEATURES 397 00:20:47,760 --> 00:20:49,120 OF THE HUMAN RETROVIRUS IS 398 00:20:49,120 --> 00:20:49,360 HTLV-2. 399 00:20:49,360 --> 00:20:52,080 THE PAPER IS COMING AROUND IN A 400 00:20:52,080 --> 00:20:53,080 POST-DOC WORKING TOGETHER WITH 401 00:20:53,080 --> 00:20:53,760 US. 402 00:20:53,760 --> 00:20:57,360 IT'S A NEW SUBTYPE WHICH I CAN 403 00:20:57,360 --> 00:21:01,680 SAY I PREDICTED IT WOULD BE A 404 00:21:01,680 --> 00:21:04,360 NEW RETROVIRUS RELATED TO HTLV-1 405 00:21:04,360 --> 00:21:06,720 AND CAME FROM T CELL LEUKEMIA 406 00:21:06,720 --> 00:21:08,120 PUBLISHED IN SCIENCE IN 1982. 407 00:21:08,120 --> 00:21:10,320 A RARE DISEASE LIKELY SOMETIMES 408 00:21:10,320 --> 00:21:12,560 CALLED BY HTLV-2. 409 00:21:12,560 --> 00:21:14,360 IT'S UNIQUE TO THE PATIENT. 410 00:21:14,360 --> 00:21:17,440 IT WAS A YOUNG WHITE MALE BUT 411 00:21:17,440 --> 00:21:20,280 HAD A GIRLFRIEND THAT HE WAS 412 00:21:20,280 --> 00:21:24,160 INFECTED BY A NATIVE ALASKAN 413 00:21:24,160 --> 00:21:29,160 NATIVE AND IT IMMORTALIZED THE 414 00:21:29,160 --> 00:21:31,920 STARTER CELLS LIKE HTLV-1 BUT 415 00:21:31,920 --> 00:21:34,800 STUDIES SHOW IT'S A RARE VIRUS 416 00:21:34,800 --> 00:21:37,960 AND DISEASE AND HELPFUL IN 417 00:21:37,960 --> 00:21:41,960 REASONING ABOUT THE MOLECULAR 418 00:21:41,960 --> 00:21:44,320 PATHOGENESIS OF HTLV-1. 419 00:21:44,320 --> 00:21:46,760 AND IT'S IMPORTANT TO WHAT COMES 420 00:21:46,760 --> 00:21:47,360 NEXT, HIV. 421 00:21:47,360 --> 00:21:49,360 WHY'S IT IMPORTANT FOR HIV? 422 00:21:49,360 --> 00:21:51,840 THERE'S ONE AND TWO AND THERE'LL 423 00:21:51,840 --> 00:21:52,480 BE MORE. 424 00:21:52,480 --> 00:21:54,520 WE CERTAINLY MADE THE FRUITFUL 425 00:21:54,520 --> 00:21:57,360 SUGGESTION THAT IT WOULD BE 426 00:21:57,360 --> 00:22:00,760 HUMAN RESOURCE BECAUSE IT'S 427 00:22:00,760 --> 00:22:04,240 TARGETING THE T CELLS BUT WAS 428 00:22:04,240 --> 00:22:09,920 NOT EXPECTED OUTSIDE THE 429 00:22:09,920 --> 00:22:11,960 EXOGENOUS INFECTIOUS FAMILY 430 00:22:11,960 --> 00:22:13,200 MEMBERS. 431 00:22:13,200 --> 00:22:16,520 NOT TRUE WITH MACAQUE, RAT, 432 00:22:16,520 --> 00:22:21,120 MOUSE, CHICKEN, COW. 433 00:22:21,120 --> 00:22:22,760 MARJORIE PLAYED A KEY ROLE IN 434 00:22:22,760 --> 00:22:24,200 THE PAPER OF HTLV-2 DISCOVERY 435 00:22:24,200 --> 00:22:25,840 AND COULD HAVE BEEN THE FIRST 436 00:22:25,840 --> 00:22:26,520 AUTHOR. 437 00:22:26,520 --> 00:22:32,280 WE SAID, WELL, SINCE IN THE 438 00:22:32,280 --> 00:22:38,080 IMMUNOLOGICAL PAPER MAYBE REMMIN 439 00:22:38,080 --> 00:22:40,960 SHOULD BE THE FIRST AUTHOR AND 440 00:22:40,960 --> 00:22:44,840 IT'S A MORE QUOTED PAPER. 441 00:22:44,840 --> 00:22:46,080 THE FIRST HUMAN RETROVIRUS LED 442 00:22:46,080 --> 00:22:47,680 TO THE DISCOVERY OF HIV. 443 00:22:47,680 --> 00:22:49,800 I WANT TO BE PROVOCATIVE SO FOR 444 00:22:49,800 --> 00:22:51,200 THOSE WHO DON'T KNOW OR BELIEVE 445 00:22:51,200 --> 00:22:53,600 IT, HOW WOULD YOU THINK OF THAT? 446 00:22:53,600 --> 00:22:55,680 WHAT WAS OUR THINKING? 447 00:22:55,680 --> 00:23:00,320 WHAT WE WERE TOLD ABOUT AIDS. 448 00:23:00,320 --> 00:23:03,880 THE CLINICIANS TOLD US IT WAS A 449 00:23:03,880 --> 00:23:05,120 CD4 T CELL DISEASE. 450 00:23:05,120 --> 00:23:06,920 THEY WERE DECLINING. 451 00:23:06,920 --> 00:23:12,120 WHAT DOES HTLV-1 AND HTLV-2 DO? 452 00:23:12,120 --> 00:23:15,120 TARGET CD4 T CELLS AND BLOOD SEX 453 00:23:15,120 --> 00:23:17,960 TO MOTHER AND INFANT SOUNDED 454 00:23:17,960 --> 00:23:19,840 LIKE HTLV-1. 455 00:23:19,840 --> 00:23:21,760 THE LONG LATENCY DISEASE OBVIOUS 456 00:23:21,760 --> 00:23:23,960 FROM THE HISTORY OF AIDS 457 00:23:23,960 --> 00:23:26,760 PATIENTS AND WE KNEW IT WAS TRUE 458 00:23:26,760 --> 00:23:29,080 WITH HUMAN RETROVIRUSES AND 459 00:23:29,080 --> 00:23:29,960 IMPAIRMENTS. 460 00:23:29,960 --> 00:23:32,120 WE KNOW HTLV-1 CAUSED LEUKEMIA 461 00:23:32,120 --> 00:23:33,000 AND IMPAIRMENT. 462 00:23:33,000 --> 00:23:35,200 THEY SHOWED THAT IN PEOPLE WHO 463 00:23:35,200 --> 00:23:37,960 DIDN'T HAVE MALIGNANCY AND 464 00:23:37,960 --> 00:23:40,200 PREVALENCE IN HAITI AND AFRICA. 465 00:23:40,200 --> 00:23:41,960 WHAT WE WERE LEARNING ABOUT 466 00:23:41,960 --> 00:23:42,160 HAITI? 467 00:23:42,160 --> 00:23:44,040 IT HAD A LOT OF AIDS. 468 00:23:44,040 --> 00:23:45,960 WHAT DID WE THINK OF AFRICA? 469 00:23:45,960 --> 00:23:47,120 PEOPLE WERE THINKING THE 470 00:23:47,120 --> 00:23:49,440 EARLIEST CASES THIS WAS AN OLD 471 00:23:49,440 --> 00:23:51,560 VIRUS IN THE RAIN FOREST. 472 00:23:51,560 --> 00:23:54,320 SO THAT SEEMED TO FIT AS WELL. 473 00:23:54,320 --> 00:23:55,360 TECHNICALLY, METHODS FOR GROWTH 474 00:23:55,360 --> 00:23:57,920 AND CULTURE OF HUMAN T CELLS 475 00:23:57,920 --> 00:24:01,040 BASED ON THE 1976 STUDIES 476 00:24:01,040 --> 00:24:03,760 APPLIED TO HTLV-1 AND 2 AND 477 00:24:03,760 --> 00:24:05,920 TESTS FOR RETROVIRUSES BASED ON 478 00:24:05,920 --> 00:24:12,320 REVERSE TRANSCRIPTASE IN THE 479 00:24:12,320 --> 00:24:15,960 '70s AND FELT IT WAS HELPFUL. 480 00:24:15,960 --> 00:24:22,400 IN 1982 THERE WAS MORE FROM THE 481 00:24:22,400 --> 00:24:40,760 FDA AND HUMAN PHILIACS IN WERE 482 00:24:40,760 --> 00:24:41,960 NOT INVOLVED AND THERE WAS 483 00:24:41,960 --> 00:24:43,680 DISCUSSED AS THE MOST LIKELY 484 00:24:43,680 --> 00:24:45,960 THEORY AND YET THINK ABOUT IT 485 00:24:45,960 --> 00:24:46,160 AGAIN. 486 00:24:46,160 --> 00:24:50,080 WHAT ABOUT HEMOPHILICS AND 487 00:24:50,080 --> 00:24:52,280 TRANSFUSED PEOPLE. 488 00:24:52,280 --> 00:24:55,960 THE IDEA WAS YOU GET INFECTION 489 00:24:55,960 --> 00:24:57,920 FROM ROUGH SEX YOU THINK DIDN'T 490 00:24:57,920 --> 00:24:59,760 WOMEN GET EXPOSED TO ROUGH SEX 491 00:24:59,760 --> 00:25:03,160 EARLIER THAN AIDS AND WHAT ABOUT 492 00:25:03,160 --> 00:25:04,280 BABIES AND WHAT ABOUT THIS. 493 00:25:04,280 --> 00:25:07,920 IT WASN'T A GOOD IDEA AND THERE 494 00:25:07,920 --> 00:25:11,760 WAS INFECTIOUS CAUSES AND 495 00:25:11,760 --> 00:25:13,560 ADENOVIRUSES FROM ALBERT 496 00:25:13,560 --> 00:25:15,720 EINSTEIN THERE WAS A UNIQUE TYPE 497 00:25:15,720 --> 00:25:21,160 BUT IT WAS IN GAY MEN AND THERE 498 00:25:21,160 --> 00:25:30,760 ARE IDEAS OF HERPES RELATED 499 00:25:30,760 --> 00:25:35,520 CAUSES AND AN UNNECESSARY 500 00:25:35,520 --> 00:25:40,200 CO-FACTOR AND THEN WE POSTULATED 501 00:25:40,200 --> 00:25:44,200 A NEW T LYMPHOTROPIC RETROVIRUS. 502 00:25:44,200 --> 00:25:45,240 IF YOU KNEW ABOUT THE HISTORY OF 503 00:25:45,240 --> 00:25:48,040 THE FIELD AND YOU KNEW THIS, YOU 504 00:25:48,040 --> 00:25:51,960 CERTAINLY COME TO THAT. 505 00:25:51,960 --> 00:25:57,160 THEN ONE WAS CREATED BY THE 506 00:25:57,160 --> 00:25:59,960 UNITED STATES THE RUSSIAN KGB 507 00:25:59,960 --> 00:26:01,200 THROUGH EASTERN GERMANY. 508 00:26:01,200 --> 00:26:04,280 WE WON'T HAVE TIME TO GO THROUGH 509 00:26:04,280 --> 00:26:08,080 THESE THINGS BUT IT WAS 510 00:26:08,080 --> 00:26:09,360 INTERESTING BEING ATTACKED BY 511 00:26:09,360 --> 00:26:10,560 ALL THESE THINGS THAT YOU EITHER 512 00:26:10,560 --> 00:26:13,560 MADE IT IN THE LAB OR MADE IT UP 513 00:26:13,560 --> 00:26:16,160 AND AIDS PRESENTED UNIQUE 514 00:26:16,160 --> 00:26:16,440 CHALLENGES. 515 00:26:16,440 --> 00:26:18,320 THIS IS A SLIDE SHOWN 516 00:26:18,320 --> 00:26:18,920 REPEATEDLY. 517 00:26:18,920 --> 00:26:22,520 THE CLINICAL LATENCY OF SEVEN 518 00:26:22,520 --> 00:26:22,960 YEARS. 519 00:26:22,960 --> 00:26:24,440 YOU DON'T ASK WHAT THEY DID 520 00:26:24,440 --> 00:26:25,960 SEVEN YEARS AGO BUT WHAT THEY 521 00:26:25,960 --> 00:26:28,120 DID LAST YEAR OR LAST MONTH AND 522 00:26:28,120 --> 00:26:32,120 THE MICROBIAL INFECTIONS THAT A 523 00:26:32,120 --> 00:26:33,640 PERSON WITH AIDS HAD NONE WERE 524 00:26:33,640 --> 00:26:36,120 THE EVIDENT CAUSE AND THAT 525 00:26:36,120 --> 00:26:37,960 CREATED A LOT OF PROBLEMS. 526 00:26:37,960 --> 00:26:40,320 WE HAD HELP FROM CLINICAL 527 00:26:40,320 --> 00:26:40,600 COLLEAGUES. 528 00:26:40,600 --> 00:26:42,000 THEY'RE ALL LISTED HERE AND WELL 529 00:26:42,000 --> 00:26:44,120 KNOWN PEOPLE IN THE FIELD AND 530 00:26:44,120 --> 00:26:45,800 HELP WITH DISCUSSIONS AND HELP 531 00:26:45,800 --> 00:26:49,440 PROVIDING TOO MANY SAMPLES. 532 00:26:49,440 --> 00:26:50,040 WE WERE OVERWHELMED IN THE 533 00:26:50,040 --> 00:26:51,560 LABORATORY AS THOSE WHO WERE 534 00:26:51,560 --> 00:26:54,160 THERE AT THE TIME CAN CERTAINLY 535 00:26:54,160 --> 00:26:54,400 TESTIFY. 536 00:26:54,400 --> 00:26:56,480 WE HAD CULTURES COMING OUT OF 537 00:26:56,480 --> 00:26:58,280 OUR EARS. 538 00:26:58,280 --> 00:27:02,960 NOW, THIS IS AN INTERESTING 539 00:27:02,960 --> 00:27:03,160 SLIDE. 540 00:27:03,160 --> 00:27:05,360 AND WE NEVER PUBLISHED THIS. 541 00:27:05,360 --> 00:27:09,520 THIS HELPED AND SET ME BACK FOR 542 00:27:09,520 --> 00:27:10,000 MONTHS. 543 00:27:10,000 --> 00:27:11,880 I WAS THINKING THINGS AS WE'RE 544 00:27:11,880 --> 00:27:16,800 PREDICTING THINGS ARE COMING 545 00:27:16,800 --> 00:27:16,960 OUT. 546 00:27:16,960 --> 00:27:18,760 WE'RE GETTING MORE IN RETROSPECT 547 00:27:18,760 --> 00:27:21,240 THERE'S HUMAN LESSONS IN THIS 548 00:27:21,240 --> 00:27:22,520 AND WE'RE CONFIDENT WE'RE RIGHT 549 00:27:22,520 --> 00:27:24,400 ABOUT IT SEEMS ALL OF IT. 550 00:27:24,400 --> 00:27:24,760 WHY? 551 00:27:24,760 --> 00:27:26,760 LOOK AT THE SLIDE CAREFULLY AND 552 00:27:26,760 --> 00:27:29,960 YOU SEE IT'S LABELLING HIV AND 553 00:27:29,960 --> 00:27:32,680 HTLV-1 IN THE SAME CELL AND 554 00:27:32,680 --> 00:27:32,960 INDIVIDUAL. 555 00:27:32,960 --> 00:27:35,960 UNFORTUNATELY HERE IN RETRO 556 00:27:35,960 --> 00:27:37,960 VIROLOGY YOU SAY THERE'S VARIETY 557 00:27:37,960 --> 00:27:39,360 INTERFERENCE AND DISMISS THIS AS 558 00:27:39,360 --> 00:27:42,560 THE INTERPRETATION AND PEOPLE 559 00:27:42,560 --> 00:27:44,720 WOULDN'T BE DOUBLY INFECTED AND 560 00:27:44,720 --> 00:27:50,280 IF THEY WERE THERE WOULDN'T BE 561 00:27:50,280 --> 00:27:53,920 IN THE SAME CELL SO THIS WAS A 562 00:27:53,920 --> 00:27:59,160 SAMPLE GIVEN TO US FROM A YOUNG 563 00:27:59,160 --> 00:28:07,360 MAN AND THIS CAME FROM A MAN WHO 564 00:28:07,360 --> 00:28:10,000 WAS ON HONEYMOON IN HAITI AND 565 00:28:10,000 --> 00:28:11,720 HAD AN ACCIDENT AND GOT INFUSED 566 00:28:11,720 --> 00:28:15,240 AND DIED OF AIDS PRETTY RAPIDLY. 567 00:28:15,240 --> 00:28:18,760 THIS IS AN IMMORTALIZED T CELL 568 00:28:18,760 --> 00:28:21,160 BUT HIV IS KILLING THOSE CELLS. 569 00:28:21,160 --> 00:28:27,160 WE SAY IT'S GOT DIFFERENT 570 00:28:27,160 --> 00:28:34,400 MORPHOLOGY AND MOREOVER WITH 571 00:28:34,400 --> 00:28:35,800 MARJORIE'S MONTANA 572 00:28:39,960 --> 00:28:41,160 MONOCLONAL THOUGHT THE CELLS 573 00:28:41,160 --> 00:28:41,960 WERE STILL GROWING AND 574 00:28:41,960 --> 00:28:43,280 EVERYTHING IS GOING THE WAY 575 00:28:43,280 --> 00:28:45,040 PREDICTED AHEAD OF TIME. 576 00:28:45,040 --> 00:28:47,080 I'M THINKING DOWN THE LINE IT'S 577 00:28:47,080 --> 00:28:53,320 GOING TO BE AN ENVELOPE VARIANT 578 00:28:53,320 --> 00:28:54,120 OF HTLV-1 AND 2. 579 00:28:54,120 --> 00:28:56,600 A FEW OF US DISCUSSED IT. 580 00:28:56,600 --> 00:28:59,120 THEN CAME MARJORIE WITH SEROLOGY 581 00:28:59,120 --> 00:29:01,560 ASSAYS AND FORGOT THIS ONCE WHEN 582 00:29:01,560 --> 00:29:04,960 I SAID IT, SHE KNOWS THE DATA 583 00:29:04,960 --> 00:29:06,800 BUT DIDN'T REMEMBER WHAT IT 584 00:29:06,800 --> 00:29:09,320 INFLUENCED IT SO MUCH. 585 00:29:09,320 --> 00:29:11,600 HER SEROLOGY DATA WAS SHOWING WE 586 00:29:11,600 --> 00:29:13,200 DON'T SEE THIS REACTION VERY 587 00:29:13,200 --> 00:29:17,920 OFTEN IT'S RARE. 588 00:29:17,920 --> 00:29:23,080 IN 95%, 96%, 98% WE SEE 589 00:29:23,080 --> 00:29:25,560 PARTICLES ACTING LIKE A VIRUS 590 00:29:25,560 --> 00:29:27,160 EVEN WITHOUT GROWING THEM 591 00:29:27,160 --> 00:29:28,880 SUBSTANTIALLY THEY'RE NOT 592 00:29:28,880 --> 00:29:31,040 REACTING WITH THE HTLV-1 593 00:29:31,040 --> 00:29:32,400 REAGENTS THEY MUST BE DOUBLE 594 00:29:32,400 --> 00:29:34,720 INFECTIONS IS WHAT SHE SAID AND 595 00:29:34,720 --> 00:29:38,600 MAYBE THERE'S MORE DRUG ADDICTS 596 00:29:38,600 --> 00:29:40,040 WE WERE SEEING POSITIVE AND WE 597 00:29:40,040 --> 00:29:42,880 WERE SEEING POSITIVE, NEGATIVE, 598 00:29:42,880 --> 00:29:45,520 NEGATIVE AND POSITIVE-NEGATIVE 599 00:29:45,520 --> 00:29:47,560 AND HOW ARE WE GOING PUBLISH 600 00:29:47,560 --> 00:29:47,760 THIS? 601 00:29:47,760 --> 00:29:52,760 WE DIDN'T KNOW WHAT WAS GOING ON 602 00:29:52,760 --> 00:29:55,760 THEN IT BECAME CLEAR THEY WERE 603 00:29:55,760 --> 00:29:57,440 TWO VIRUSES AND OUR GROUP WAS 604 00:29:57,440 --> 00:30:00,000 ABLE TO SEPARATE THE TWO OUT. 605 00:30:00,000 --> 00:30:01,840 THIS IS BEFORE WE HAD POWER OF 606 00:30:01,840 --> 00:30:03,920 CLONING AND ALL THIS STUFF. 607 00:30:03,920 --> 00:30:07,040 WE HAD TO GO BACK IN TIME AND 608 00:30:07,040 --> 00:30:08,560 SEPARATING THE VIRUS AND THINGS 609 00:30:08,560 --> 00:30:09,920 BECAME OBVIOUS AND WE SAID OH, 610 00:30:09,920 --> 00:30:12,360 MY GOD, WE'VE BEEN WASTING 611 00:30:12,360 --> 00:30:12,560 MOONS. 612 00:30:12,560 --> 00:30:15,560 SO WE LOST A LOT OF TIME AND WE 613 00:30:15,560 --> 00:30:19,760 DIDN'T PUBLISH JUST ON FINDING 614 00:30:19,760 --> 00:30:21,080 VIRUS BECAUSE WHEN I WE 615 00:30:21,080 --> 00:30:22,760 PUBLISHED WE FELT WE HAD TO SHOW 616 00:30:22,760 --> 00:30:25,560 THE CAUSE AND CAN'T GROW IT VERY 617 00:30:25,560 --> 00:30:28,360 WELL AND CHARACTERIZE IT AND I 618 00:30:28,360 --> 00:30:29,960 DESCRIBED A FRENCH PAPER AND 619 00:30:29,960 --> 00:30:30,520 THAT WAS IT. 620 00:30:30,520 --> 00:30:33,080 WE WEREN'T IN A POSITION TO DO 621 00:30:33,080 --> 00:30:33,440 THAT. 622 00:30:33,440 --> 00:30:34,640 WE HAD TO SHOW IT WAS SOMETHING 623 00:30:34,640 --> 00:30:35,760 IMPORTANT OR NOT. 624 00:30:35,760 --> 00:30:41,760 THAT WAS WHERE THINGS WERE. 625 00:30:41,760 --> 00:30:44,760 THIS IS MARJORIE'S CONTRIBUTION. 626 00:30:44,760 --> 00:30:47,240 THE EXCITING FEBRUARY '83 LED US 627 00:30:47,240 --> 00:30:49,960 TO PROVE THIS WAS A DOUBLE 628 00:30:49,960 --> 00:30:52,400 INFECTION SAME CELL AND NOT 629 00:30:52,400 --> 00:30:55,160 ANTICIPATED AND MARJORIE'S 630 00:30:55,160 --> 00:30:56,600 VIROLOGY SHOWED IT WAS RARE AND 631 00:30:56,600 --> 00:30:57,560 I GAVE YOU THAT HISTORY BEFORE. 632 00:30:57,560 --> 00:31:00,440 IT WAS PART OF OUR DECISION TO 633 00:31:00,440 --> 00:31:01,240 PUBLISH WITH OTHER COLLEAGUES 634 00:31:01,240 --> 00:31:04,040 FIVE PAPERS SHOWING THE CAUSE OF 635 00:31:04,040 --> 00:31:05,240 AIDS. 636 00:31:05,240 --> 00:31:06,560 FOUR IN SCIENCE IN THE SAME 637 00:31:06,560 --> 00:31:09,720 ISSUE MAY 4 AND ONE IN LANCET IN 638 00:31:09,720 --> 00:31:12,400 JUNE AND THINGS BECAME CLEAR. 639 00:31:12,400 --> 00:31:16,320 MARJORIE PUBLISHED HTLV-1 640 00:31:16,320 --> 00:31:21,200 ANTIBODIES AND OTHERS IN LANCET 641 00:31:21,200 --> 00:31:23,160 IN '84 SHOWING WHAT I JUST SAID 642 00:31:23,160 --> 00:31:25,480 THE CONTRIBUTION AND NOT WHEN 643 00:31:25,480 --> 00:31:27,160 YOU IDENTIFIED SHOWING THE CAUSE 644 00:31:27,160 --> 00:31:28,560 OF AIDS OR ONE ANYONE TALKED 645 00:31:28,560 --> 00:31:29,880 ABOUT BUT BEFORE THERE WAS 646 00:31:29,880 --> 00:31:31,360 CLARITY AND THIS IS HOW CLARITY 647 00:31:31,360 --> 00:31:34,280 BEGAN TO OCCUR, SLOWLY, STEADILY 648 00:31:34,280 --> 00:31:36,360 AND DEFINITIVELY. 649 00:31:36,360 --> 00:31:39,280 SO IN THE FREQUENCY DETECTION OR 650 00:31:39,280 --> 00:31:41,920 ISOLATION OF OUR VIRUS BY OUR 651 00:31:41,920 --> 00:31:46,960 GROUP BETWEEN '83 AND '84. 652 00:31:46,960 --> 00:31:52,280 IF YOU LOOK AT THE PAPER IT HAS 653 00:31:52,280 --> 00:31:54,440 MY NAME FIRST AND THERE'S 48 654 00:31:54,440 --> 00:31:55,360 DIFFERENT SAMPLES AND 48 655 00:31:55,360 --> 00:31:56,240 DIFFERENT PATIENTS. 656 00:31:56,240 --> 00:31:58,360 THAT WAS OUR FIRST PUBLICATION 657 00:31:58,360 --> 00:32:09,840 AND IN JANUARY OF '85, 105 658 00:32:09,840 --> 00:32:12,120 ISOLETS AND IN OUR COUNTRY AND 659 00:32:12,120 --> 00:32:14,080 MOST TODAY YOU NEED TO BE 660 00:32:14,080 --> 00:32:14,360 VERIFIED. 661 00:32:14,360 --> 00:32:16,160 WOULD ANYBODY ELSE BE ISOLATING 662 00:32:16,160 --> 00:32:16,880 THE VIRUS? 663 00:32:16,880 --> 00:32:21,760 HOW MANY LABS IN VIROLOGY CAN 664 00:32:21,760 --> 00:32:24,520 USE IL2 AND GROW T CELLS? 665 00:32:24,520 --> 00:32:27,960 NOT MANY AND WE WERE GETTING 666 00:32:27,960 --> 00:32:30,120 BLOOD NOT LYMPH NODES. 667 00:32:30,120 --> 00:32:35,560 THINK OF AIDS PATIENTS, SEVERE 668 00:32:35,560 --> 00:32:36,640 AIDS HOW MANY T CELLS DO THEY 669 00:32:36,640 --> 00:32:41,000 HAVE SO THE NEGATIVES ARE 670 00:32:41,000 --> 00:32:41,920 OBVIOUS. 671 00:32:41,920 --> 00:32:45,160 WE COULDN'T DETECT ANYTHING. 672 00:32:45,160 --> 00:32:47,640 SO WE FELT THAT EVEN WITH 673 00:32:47,640 --> 00:32:48,920 ISOLATES IT WOULD BE INEFFICIENT 674 00:32:48,920 --> 00:32:52,560 TO GO OUT ON A LIMB AND -- 675 00:32:52,560 --> 00:32:55,120 INSUFFICIENT AND GO OUT ON A 676 00:32:55,120 --> 00:32:56,320 LIMB AND SAY THIS IS THE CAUSE 677 00:32:56,320 --> 00:33:00,440 OF AIDS AND THE SPECIMENS WERE 678 00:33:00,440 --> 00:33:02,600 LIMITED AND NOT EVEN ALLOWED IN 679 00:33:02,600 --> 00:33:05,680 SOME INSTITUTES AND AIDS HAD TO 680 00:33:05,680 --> 00:33:07,200 BE CLINICALLY RELEVANT AND THE 681 00:33:07,200 --> 00:33:07,840 CONSEQUENCE WAS HARDLY ANYBODY 682 00:33:07,840 --> 00:33:16,960 WAS INVOLVED. 683 00:33:16,960 --> 00:33:19,840 AND IN THE FALL OF '83 THE 684 00:33:19,840 --> 00:33:21,880 CONTINUANCE CELL LINE CULTURE 685 00:33:21,880 --> 00:33:25,360 AND A TOTAL OF 6 AND IT MADE 686 00:33:25,360 --> 00:33:29,240 SEVERAL THINGS POSSIBLE THE 687 00:33:29,240 --> 00:33:32,240 BLOOD TREST AND DRUG SCREEN AND 688 00:33:32,240 --> 00:33:33,880 PROTEINS AND THE KEY COLLEAGUE 689 00:33:33,880 --> 00:33:36,960 WORKS HERE IN NCI AS ONE OF THE 690 00:33:36,960 --> 00:33:38,720 PROJECT OFFICERS WHOSE HUSBAND 691 00:33:38,720 --> 00:33:41,320 AT THE TIME DIED OF AIDS FROM A 692 00:33:41,320 --> 00:33:46,280 BLOOD TRANSFUSION AND THESE WERE 693 00:33:46,280 --> 00:33:52,240 MY TECHNICIANS AND THIS LED TO 694 00:33:52,240 --> 00:33:54,840 THE BLOOD TEST AND IT WAS SAFE, 695 00:33:54,840 --> 00:33:56,760 SENSITIVE, ACCURATE AND 696 00:33:56,760 --> 00:33:59,800 VERIFICATION BECAME ALMOST 697 00:33:59,800 --> 00:34:01,720 INSTANT AND IT REMOVED DOUBTS 698 00:34:01,720 --> 00:34:04,280 FOR US TO PUBLIC AND WE PILED UP 699 00:34:04,280 --> 00:34:05,400 PAPER AND PUN ESTABLISHED. 700 00:34:05,400 --> 00:34:07,360 IT WAS A KEY ADVANCE NOT ONLY 701 00:34:07,360 --> 00:34:09,800 BECAUSE OF PUBLIC HEALTH REASONS 702 00:34:09,800 --> 00:34:11,160 FOR PROTECTING THE BLOOD SUPPLY 703 00:34:11,160 --> 00:34:13,000 BUT ALSO ALLOWED THE EPIDEMIC TO 704 00:34:13,000 --> 00:34:14,560 BE RESOLVED AND ALLOWED THE 705 00:34:14,560 --> 00:34:16,120 FIRST SCREENING FOR HIV DRUGS 706 00:34:16,120 --> 00:34:17,920 AND WHEN THERAPY BECAME 707 00:34:17,920 --> 00:34:20,440 AVAILABLE WE COULD DETERMINE WHO 708 00:34:20,440 --> 00:34:21,920 TO TREAT AS WELL AS BLOCKING 709 00:34:21,920 --> 00:34:25,000 TRANSMISSION AND CRITICALLY FOR 710 00:34:25,000 --> 00:34:28,800 US VERIFIED HIV AS THE CAUSE OF 711 00:34:28,800 --> 00:34:29,000 AIDS. 712 00:34:29,000 --> 00:34:30,440 I'M MENTIONING ONLY WHAT WAS 713 00:34:30,440 --> 00:34:33,840 DONE WITH DIRECTLY IN OUR GROUP 714 00:34:33,840 --> 00:34:37,880 WITH MARJORIE OR IMPACTED OUR 715 00:34:37,880 --> 00:34:40,080 WORK AT HIV IN BALTIMORE. 716 00:34:40,080 --> 00:34:45,880 OF COURSE NOT ALL MARJORIE'S HIV 717 00:34:45,880 --> 00:34:49,880 WORK IS NOTED AND MARJORIE 718 00:34:49,880 --> 00:34:53,680 DEVELOPED THE ASSAY AND MOST THE 719 00:34:53,680 --> 00:34:55,680 IHD RESEARCH AND YOU SEE 720 00:34:55,680 --> 00:34:56,760 GEORGE'S REPORT LATER IN THE 721 00:34:56,760 --> 00:35:00,000 MEETING WHERE EEL GO INTO THAT 722 00:35:00,000 --> 00:35:01,840 AND THOUGH WE HAVEN'T DISCUSSED 723 00:35:01,840 --> 00:35:03,960 IT IN MUCH MORE DETAIL. 724 00:35:03,960 --> 00:35:05,120 I'LL CONCLUDE BY SAYING I HOPE 725 00:35:05,120 --> 00:35:06,440 YOU FEEL THE PRESENTATION IN 726 00:35:06,440 --> 00:35:08,320 SOME WAYS IS MY PERSONAL TRIBUTE 727 00:35:08,320 --> 00:35:09,200 TO YOU. 728 00:35:09,200 --> 00:35:10,360 TO MAKE IT CERTAIN YOU DO WISH 729 00:35:10,360 --> 00:35:12,320 TO END THE TALK WITH THIS, 730 00:35:12,320 --> 00:35:16,120 YOU'VE BEEN ONE OF THE MOST 731 00:35:16,120 --> 00:35:18,000 INTELLIGENT, DEDICATED HUMBLE 732 00:35:18,000 --> 00:35:19,720 COLLEAGUES ANYONE COULD WISH 733 00:35:19,720 --> 00:35:20,120 FOR. 734 00:35:20,120 --> 00:35:22,840 AMONG THE FEW OF A LARGE 735 00:35:22,840 --> 00:35:24,240 TALENTED GROUP WITHOUT WHICH I 736 00:35:24,240 --> 00:35:26,160 WOULD NOT HAVE SURVIVED AND I 737 00:35:26,160 --> 00:35:28,320 KNOW THAT WELL. 738 00:35:28,320 --> 00:35:31,240 I CONSIDER YOU ONE OF THE MOST 739 00:35:31,240 --> 00:35:33,400 VALUABLE PERSONS I'VE EVER 740 00:35:33,400 --> 00:35:35,000 ASSOCIATED WITH LIKE ALL OTHERS 741 00:35:35,000 --> 00:35:37,080 HERE WE WISH YOU SAFETY, HEALTH 742 00:35:37,080 --> 00:35:38,760 AND MUCH DESERVED HAPPINESS. 743 00:35:38,760 --> 00:35:41,000 THANK YOU FOR EVERYTHING YOU DID 744 00:35:41,000 --> 00:35:43,880 FOR US IN THE OLD LABORATORY OF 745 00:35:43,880 --> 00:35:45,040 TUMOR CELL BIOLOGY AND FOR ME 746 00:35:45,040 --> 00:35:45,760 PERSONALLY. 747 00:35:45,760 --> 00:35:46,360 CONGRATULATIONS ON A GREAT 748 00:35:46,360 --> 00:36:13,920 CAREER. 749 00:36:13,920 --> 00:36:23,240 >> THANK YOU VERY MUCH. 750 00:36:23,240 --> 00:36:24,240 >> THANK YOU. 751 00:36:24,240 --> 00:36:25,760 I FEEL LIKE YOU'VE MADE ME 752 00:36:25,760 --> 00:36:26,040 EMOTIONAL. 753 00:36:26,040 --> 00:36:31,680 I APOLOGIZE FOR THAT. 754 00:36:31,680 --> 00:36:34,320 YOU'VE BEEN A GREAT MENTOR. 755 00:36:34,320 --> 00:36:37,880 TOOK A CHANCE ON SOMEONE WHO HAD 756 00:36:37,880 --> 00:36:45,040 NO KNOWLEDGE OF VIROLOGY THE 757 00:36:45,040 --> 00:36:47,680 WORK I DID WAS STUDYING 758 00:36:47,680 --> 00:36:49,200 ADAPTATION TO COLD TEMPERATURES 759 00:36:49,200 --> 00:36:49,880 MAYBE SHOULD BE WARM 760 00:36:49,880 --> 00:36:51,160 TEMPERATURES GIVEN WHAT WE KNOW 761 00:36:51,160 --> 00:36:53,840 TODAY BUT YOU PUT KNOW WORK ON 762 00:36:53,840 --> 00:36:56,400 REVERSE TRANSCRIPTASE AND HAD TO 763 00:36:56,400 --> 00:36:59,600 COMPARE TO POLYMERASE GAMMA. 764 00:36:59,600 --> 00:37:01,640 IT WAS VERY DIFFICULT. 765 00:37:01,640 --> 00:37:03,160 IMMUNE OWE LOGICALLY IT WAS 766 00:37:03,160 --> 00:37:03,440 EASIER. 767 00:37:03,440 --> 00:37:08,440 YOU PROVIDED ME THE RESOURCES TO 768 00:37:08,440 --> 00:37:11,520 DO THAT AND SENT ME TO LEARN HOW 769 00:37:11,520 --> 00:37:16,400 TO MAKE HYBRID ILLNESS AND HOW 770 00:37:16,400 --> 00:37:20,000 TO MAKE MONOCLONAL ANTIBODIES 771 00:37:20,000 --> 00:37:20,680 AND CONTACTED RESEARCHERS 772 00:37:20,680 --> 00:37:22,080 WORLDWIDE TO LOOK AT SEROLOGY 773 00:37:22,080 --> 00:37:25,360 AND LOOK AT CELLS FOR THE 774 00:37:25,360 --> 00:37:28,360 PRESENCE OF HTLV AND ULTIMATELY 775 00:37:28,360 --> 00:37:40,320 HLV. 776 00:37:40,320 --> 00:37:41,720 YOU GAVE ME EXPOSURE TO THE 777 00:37:41,720 --> 00:37:43,840 WORLD OF SCIENCE AND ONE OF THE 778 00:37:43,840 --> 00:37:49,360 LAST THINGS YOU DID BEFORE YOU 779 00:37:49,360 --> 00:37:56,040 LEFT WAS TO START THE WORK WITH 780 00:37:56,040 --> 00:37:57,120 ADENOVIRUS VACCINE. 781 00:37:57,120 --> 00:38:02,000 I GUESS I WOULD CONCLUDE BY 782 00:38:02,000 --> 00:38:03,560 SAYING MUCH OF WHAT I'VE 783 00:38:03,560 --> 00:38:04,400 ACCOMPLISHED IS DUE TO YOUR 784 00:38:04,400 --> 00:38:07,840 MENTORSHIP. 785 00:38:07,840 --> 00:38:08,720 SOW I THANK YOU AND THANK YOU 786 00:38:08,720 --> 00:38:09,600 FOR BEING HERE AND THANK YOU FOR 787 00:38:09,600 --> 00:38:24,920 YOUR KIND REMARKS. 788 00:38:24,920 --> 00:38:28,360 >> IT'S A GREAT PLEASURE TO 789 00:38:28,360 --> 00:38:32,600 INTRODUCE THE NEXT SPEAKER THIS 790 00:38:32,600 --> 00:38:34,600 MORNING JOINING YOU FROM THE 791 00:38:34,600 --> 00:38:39,360 UNIVERSITY OF LOUISIANA AND AS 792 00:38:39,360 --> 00:38:41,360 HIGH AS GOING TO TALK ABOUT SOME 793 00:38:41,360 --> 00:38:41,960 OF HER WORK WITH MARJORIE. 794 00:38:41,960 --> 00:38:57,240 PLEASE. 795 00:38:57,240 --> 00:38:58,320 >> THANK YOU FOR YOUR KIND 796 00:38:58,320 --> 00:39:01,480 INTRODUCTION AND MARJORIE FOR 797 00:39:01,480 --> 00:39:02,520 ALL THE COLLABORATIONS OVER THE 798 00:39:02,520 --> 00:39:28,360 YEARS. 799 00:39:28,360 --> 00:39:29,920 I WANTED TO GIVE YOU A FOLLOW-UP 800 00:39:29,920 --> 00:39:31,480 WITH THE COLLABORATIONS. 801 00:39:31,480 --> 00:39:32,680 SOME WERE CLIFF HANGERS AT THE 802 00:39:32,680 --> 00:39:33,560 TIME WE PUBLISHED THEM. 803 00:39:33,560 --> 00:39:39,880 HERE'S THE FIRST ONE. 804 00:39:39,880 --> 00:39:45,360 CLASSIC IMMUNIZATION OF MACAQUE 805 00:40:00,320 --> 00:40:00,760 S. 806 00:40:00,760 --> 00:40:04,120 THE INITIAL PLAN WAS SIMPLE WHAT 807 00:40:04,120 --> 00:40:13,960 TITE PREPARED -- PREVENTS MUSE 808 00:40:13,960 --> 00:40:17,480 -- MUCOSAL SHIFT. 809 00:40:17,480 --> 00:40:20,760 WE PLANNED TO DO MUCOSAL 810 00:40:20,760 --> 00:40:22,400 CHALLENGES WITH A SHIFT TO 811 00:40:22,400 --> 00:40:28,880 REFLECT ACUTELY TRANSMITTED 812 00:40:28,880 --> 00:40:34,360 STRAINS IN HUMANS AND WE WERE 813 00:40:34,360 --> 00:40:35,840 GOING TO GIVE IT EVERY TWO 814 00:40:35,840 --> 00:40:36,560 WEEKS. 815 00:40:36,560 --> 00:40:38,080 THE IDEA WAS TO USE THE IGG FROM 816 00:40:38,080 --> 00:40:45,920 THE SAME SPECIES. 817 00:40:45,920 --> 00:40:56,920 WE ISOLATED IT FROM RHESUS 818 00:40:56,920 --> 00:41:02,400 MONKEYS AND RELATED TO THE 819 00:41:02,400 --> 00:41:05,560 PANELS THE CLADS WE MADE. 820 00:41:05,560 --> 00:41:08,760 WE SCREENED FOR IN VITRO 821 00:41:08,760 --> 00:41:10,840 NEUTRALIZATION WITH A SHIFT C 822 00:41:10,840 --> 00:41:12,440 THE STRAIN NAME THAT. 823 00:41:12,440 --> 00:41:14,960 THAT WAS THE INTENT. 824 00:41:14,960 --> 00:41:19,240 WE KNOW PEOPLE WHO GET 825 00:41:19,240 --> 00:41:21,200 VACCINATED AGAINST HIV HAVE A 826 00:41:21,200 --> 00:41:24,000 SNOWFLAKE'S CHANCE IN LOUISIANA 827 00:41:24,000 --> 00:41:26,240 TO EVER MAKE AN EXACTLY MATCHED 828 00:41:26,240 --> 00:41:26,480 STRAIN. 829 00:41:26,480 --> 00:41:33,200 SO WE WANTED TO HAVE UP FRONT 830 00:41:33,200 --> 00:41:42,040 HETE 831 00:41:42,040 --> 00:41:44,880 HETE 832 00:41:44,880 --> 00:41:47,400 HETEROLOGOUS CHANCES AND WE 833 00:41:47,400 --> 00:42:10,280 WANTED TO TEST DIFFERENT DOSES. 834 00:42:10,280 --> 00:42:13,680 DO TITERS PREDICT IN VIVO 835 00:42:13,680 --> 00:42:14,040 PROTECTION? 836 00:42:14,040 --> 00:42:14,560 COMPLICATED ANSWER. 837 00:42:14,560 --> 00:42:16,520 I TOOK IT FROM THE ABSTRACT AND 838 00:42:16,520 --> 00:42:27,360 YOU CAN START READING HERE. 839 00:42:27,360 --> 00:42:29,800 THIS PREPARATION FAILED TO 840 00:42:29,800 --> 00:42:33,840 PREVENT ACQUISITION OF THE 841 00:42:33,840 --> 00:42:37,720 REPEATED CHALLENGES BUT THE DOSE 842 00:42:37,720 --> 00:42:43,360 OF 400MGs LOWERED THIS AND WE 843 00:42:43,360 --> 00:42:45,840 WERE IN FOR THE SURPRISE. 844 00:42:45,840 --> 00:42:47,200 UNEXPECTEDLY SINGLE GENOME 845 00:42:47,200 --> 00:42:49,560 ANALYSIS REVEALED A HIGHER 846 00:42:49,560 --> 00:42:53,800 NUMBER OF TRANSMITTED VARIANTS 847 00:42:53,800 --> 00:42:57,200 AT THE LOW DOSE IMPLYING 848 00:42:57,200 --> 00:43:02,080 INCREASED ACQUISITION OF VIRUS 849 00:43:02,080 --> 00:43:16,360 AT LOW SHIVIG LEVELS AT 850 00:43:16,360 --> 00:43:19,160 CONCENTRATIONS OBSERVED IN 851 00:43:19,160 --> 00:43:21,840 RHESUS MONKEYS TREATED. 852 00:43:21,840 --> 00:43:25,480 THE CONCLUSION WAS THAT MAYBE 853 00:43:25,480 --> 00:43:28,360 IGG IS TWO PHASED AND DEPENDING 854 00:43:28,360 --> 00:43:30,560 ON THE PLASMA LEVELS IT ADDED 855 00:43:30,560 --> 00:43:31,560 PARTIAL PROTECTION OR POSSIBLY 856 00:43:31,560 --> 00:43:35,160 ENHANCEMENT. 857 00:43:35,160 --> 00:43:37,240 AND IMPORTANT QUESTION THAT 858 00:43:37,240 --> 00:43:37,680 REQUIRES AN ANSWER. 859 00:43:37,680 --> 00:43:39,560 AND WE PUBLISHED THE ANSWER IN 860 00:43:39,560 --> 00:43:48,200 DECEMBER OF LAST YEAR. 861 00:43:48,200 --> 00:43:49,920 THIS IS THE SUMMARY OF THE 862 00:43:49,920 --> 00:43:51,920 SINGLE GENOME ANALYSIS. 863 00:43:51,920 --> 00:43:53,080 THE LOW DOSE CLEARLY HIGHER THAN 864 00:43:53,080 --> 00:43:57,480 THE UNTREATED CONTROLS AND AT 865 00:43:57,480 --> 00:44:00,520 THE HIGHEST DOSE OF 675 866 00:44:00,520 --> 00:44:03,360 MILLIGRAMS PER KILOGRAM ONLY ONE 867 00:44:03,360 --> 00:44:06,640 WAS TRANSMITTED. 868 00:44:06,640 --> 00:44:09,280 HERE ARE THE IN VITRO ASSAYS FOR 869 00:44:09,280 --> 00:44:11,560 C PRIME ADE. 870 00:44:11,560 --> 00:44:15,640 YOUR LOOKING AT NEGATIVE 871 00:44:15,640 --> 00:44:17,200 NEUTRALIZATION IN THE RED CURVE 872 00:44:17,200 --> 00:44:20,040 AND SOMETIMES IN MINUS 300% WITH 873 00:44:20,040 --> 00:44:22,920 THE ONE TEST VIRUS AND IN THE 874 00:44:22,920 --> 00:44:27,280 OTHER CASE TO MINUS ROUGHLY 875 00:44:27,280 --> 00:44:30,320 1600% NEGATIVE NEUTRALIZATION IV 876 00:44:30,320 --> 00:44:31,840 ENHANCE MANY. 877 00:44:31,840 --> 00:44:36,920 THE ENHANCEMENT GOES AWAY IF YOU 878 00:44:36,920 --> 00:44:44,560 HEAT INACTIVATE THE COMPLIMENT 879 00:44:44,560 --> 00:44:49,760 AND SO OBVIOUSLY THIS BEGS THE 880 00:44:49,760 --> 00:44:56,520 QUESTION IS THIS REAL AND THE 881 00:44:56,520 --> 00:44:59,360 SHIVIG NO PREVENTION OF 882 00:44:59,360 --> 00:45:04,960 ACQUISITION IN ANIMALS AFTER 883 00:45:04,960 --> 00:45:07,040 REPEATED DOSE CHALLENGES. 884 00:45:07,040 --> 00:45:13,920 400 MILLIGRAM PER KILOGRAM CLOSE 885 00:45:13,920 --> 00:45:16,400 IS SIGNIFICANTLY LOWER AND THERE 886 00:45:16,400 --> 00:45:19,120 COULD BE ENHANCEMENT. 887 00:45:19,120 --> 00:45:27,880 AND THE ENHANCEMENT WAS LINKED 888 00:45:27,880 --> 00:45:32,360 IN VITRO SO THE CONCLUSION OF 889 00:45:32,360 --> 00:45:35,880 THE PAPER WAS POLY CLONAL SHIVIG 890 00:45:35,880 --> 00:45:37,880 DEPEND ON LEVELS OF THE VIRUS 891 00:45:37,880 --> 00:45:41,760 AND OBVIOUSLY IF YOU VACCINATE 892 00:45:41,760 --> 00:45:43,320 AGAINST HIV THE ANTIBODY LEVELS 893 00:45:43,320 --> 00:45:45,440 DON'T STAY STEADY. 894 00:45:45,440 --> 00:45:47,040 THEY DECLINE AND THE QUESTION IS 895 00:45:47,040 --> 00:45:49,880 WOULD YOU ACTUALLY GET INTO A 896 00:45:49,880 --> 00:45:58,120 DANGER ZONE. 897 00:45:58,120 --> 00:45:59,080 IN OTHER WORDS, THUMBS UP OR 898 00:45:59,080 --> 00:46:13,920 THUMBS DOWN FOR IGG. 899 00:46:13,920 --> 00:46:18,840 AND THE REAL WAS IN VIVO. 900 00:46:18,840 --> 00:46:21,600 IN VITRO YOU CAN GET DIFFERENT 901 00:46:21,600 --> 00:46:23,960 PHENOMENA AND THE IDEA WAS TO 902 00:46:23,960 --> 00:46:27,640 GIVE POLY CLONAL IGG THE BEST 903 00:46:27,640 --> 00:46:29,200 CHANCE TO SCORE IN VIVO AND TO 904 00:46:29,200 --> 00:46:32,160 SETTLE THE QUESTION ONCE AND FOR 905 00:46:32,160 --> 00:46:34,520 ALL IT ENHANCES TO THE BEST OF 906 00:46:34,520 --> 00:46:37,880 CIRCUMSTANCES TO DO IT OR IT 907 00:46:37,880 --> 00:46:43,160 DOESN'T AND THEN QUESTIONS. 908 00:46:43,160 --> 00:46:48,800 AND OPPOSITE OF WHAT WE DID TO 909 00:46:48,800 --> 00:46:52,760 ACTUATE SHIV IG. 910 00:46:52,760 --> 00:47:00,560 HERE WE LOOKED AT ENHANCING IGG. 911 00:47:00,560 --> 00:47:03,320 AND WE SCREENED WHAT I JUST 912 00:47:03,320 --> 00:47:05,840 SHOWED YOU FOR NEGATIVE 913 00:47:05,840 --> 00:47:06,200 NEUTRALIZATION. 914 00:47:06,200 --> 00:47:09,360 WE PULLED ANIMALS WHO HAVE THE 915 00:47:09,360 --> 00:47:16,360 MOST NEGATIVE NEUTRALIZATION AND 916 00:47:16,360 --> 00:47:19,160 MADE THE SHIVIG. 917 00:47:19,160 --> 00:47:22,560 THIS TIME IT WAS AN INFECTIOUS 918 00:47:22,560 --> 00:47:25,880 MOLECULAR CLONE. 919 00:47:25,880 --> 00:47:28,400 THE INFECTIOUS MOLECULAR CLONE 920 00:47:28,400 --> 00:47:33,760 IS HETEROLOGOUS TO THE SHIVIG 921 00:47:33,760 --> 00:47:38,200 DONORS AND THIS YIELDS A UNIFORM 922 00:47:38,200 --> 00:47:41,920 CHALLENGE FOR IN VIVO TESTING AN 923 00:47:41,920 --> 00:47:45,880 R5 VIRUS AND IT'S A DIFFERENT 924 00:47:45,880 --> 00:47:48,360 STRAIN FROM THE VIRUS HARVEST 925 00:47:48,360 --> 00:47:49,280 THE DONOR ANIMALS. 926 00:47:49,280 --> 00:47:52,040 THAT WAS THE SYSTEM WE USED TO 927 00:47:52,040 --> 00:47:55,600 ADDRESS THE KEY QUESTION. 928 00:47:55,600 --> 00:47:58,320 DOES PRE-TREATMENT OF SHIVIG 929 00:47:58,320 --> 00:48:00,560 LOWER THE VIRUS DOSE NEEDED TO 930 00:48:00,560 --> 00:48:01,840 ACHIEVE SYSTEMIC INFECTION. 931 00:48:01,840 --> 00:48:05,960 THIS IS A PARAMETER WE HAVE USED 932 00:48:05,960 --> 00:48:07,680 THROUGHOUT TO NOT GET FOOLED BY 933 00:48:07,680 --> 00:48:09,720 LOW LEVELS OF INFECTION. 934 00:48:09,720 --> 00:48:13,160 THE ANIMALS NEEDED TO HAVE 935 00:48:13,160 --> 00:48:15,080 PERSISTENT SYSTEMIC INFECTION WE 936 00:48:15,080 --> 00:48:17,760 DEFINED AS A VIRAL LOAD 937 00:48:17,760 --> 00:48:21,680 EXCEEDING 10,000 COPIES PER ML 938 00:48:21,680 --> 00:48:26,040 AND I'M NOT GOING TO SHOW YOU 939 00:48:26,040 --> 00:48:28,400 THE DATA. 940 00:48:28,400 --> 00:48:35,400 HERE AND HERE'S IS IN VITRO AND 941 00:48:35,400 --> 00:48:45,280 THE BEST AND THE IGG ISOLATE 942 00:48:45,280 --> 00:48:49,040 FROM THE VARIOUS TIME POINTS 943 00:48:49,040 --> 00:48:49,960 POSTINOCULATION AND I'M SHOWING 944 00:48:49,960 --> 00:48:51,160 THE DOTTED ARROW. 945 00:48:51,160 --> 00:48:55,160 WHEN WE DID THE CONTROL THE HEAT 946 00:48:55,160 --> 00:48:56,280 INACTIVATING SYSTEM THE 947 00:48:56,280 --> 00:48:56,960 ENHANCEMENT WENT AWAY AND THAT 948 00:48:56,960 --> 00:49:08,000 IS SHOWN HERE. 949 00:49:08,000 --> 00:49:10,040 AND WE DID EXPERIMENTS BLOCKING 950 00:49:10,040 --> 00:49:13,960 THE COMPLIMENT RECEPTOR 2 AND 951 00:49:13,960 --> 00:49:16,480 ALSO KNOWN AS CD21 AND BLOCKING 952 00:49:16,480 --> 00:49:20,440 THE RECEPTOR ABOLISHED C PROGRAM 953 00:49:20,440 --> 00:49:21,280 80E. 954 00:49:21,280 --> 00:49:26,880 WE MADE THE SHIVIG POOL AND THEN 955 00:49:26,880 --> 00:49:28,440 WE ASKED END POINT IN VIVO VIRUS 956 00:49:28,440 --> 00:49:32,280 TITRATION WITH THE INFECTIOUS 957 00:49:32,280 --> 00:49:34,440 MOLECULAR CLONE WHETHER OR NOT 958 00:49:34,440 --> 00:49:39,520 WE WOULD SEE A DIFFERENCE IN THE 959 00:49:39,520 --> 00:49:41,400 REQUIREMENT OF VIRUS FOR 960 00:49:41,400 --> 00:49:45,920 OBTAINING A PERSISTENT SYSTEMIC 961 00:49:45,920 --> 00:49:48,800 INFECTION OF CHALLENGE ONE TIME 962 00:49:48,800 --> 00:49:51,200 COMPARING NAIVE UNTREATED 963 00:49:51,200 --> 00:49:52,520 ANIMALS SHOWN AT THE TOP OF THE 964 00:49:52,520 --> 00:49:56,160 TIME LINE VERSUS ANIMALS GIVING 965 00:49:56,160 --> 00:49:57,920 THE SHIVIG 24 HOURS BEFORE THE 966 00:49:57,920 --> 00:49:58,440 VIRUS EXPOSURE. 967 00:49:58,440 --> 00:50:07,400 SO WHAT WE DID WAS WE TOOK A 968 00:50:07,400 --> 00:50:09,320 1:10 DILUTION AND WANTED TO MAKE 969 00:50:09,320 --> 00:50:13,960 SURE THEY WERE SYSTEMIC POSITIVE 970 00:50:13,960 --> 00:50:19,400 AND ONCE WE KNEW THE NEGATIVE 971 00:50:19,400 --> 00:50:21,520 DILUTION WE DID INTERMEDIATE 972 00:50:21,520 --> 00:50:22,760 DILUTIONS SOMETIMES TWO ANIMALS 973 00:50:22,760 --> 00:50:27,280 AT THE SAME TIME AND ANIMALS 974 00:50:27,280 --> 00:50:29,320 THAT WERE CLEARLY NEGATIVE AFTER 975 00:50:29,320 --> 00:50:31,280 THE VIRUS EXPOSURE WERE RECYCLED 976 00:50:31,280 --> 00:50:36,400 AND GIVEN A HIGH DOSE OF THE 977 00:50:36,400 --> 00:50:37,720 VIRUS. 978 00:50:37,720 --> 00:50:41,960 TO GET SOME ADDITIONAL 979 00:50:41,960 --> 00:50:44,920 EXPERIMENT. 980 00:50:44,920 --> 00:50:49,920 AND THEN WE STARTED TO DO THE 981 00:50:49,920 --> 00:50:52,720 SAME DILUTION WITH THE ENSHIVIG 982 00:50:52,720 --> 00:50:56,600 PRETREATED ANIMALS. 983 00:50:56,600 --> 00:50:59,600 WE ALREADY KNEW A 1:1,000 984 00:50:59,600 --> 00:51:01,800 SOLUTION WAS BORDERLINE SO TO 985 00:51:01,800 --> 00:51:04,400 SAVE ANIMALS WE STARTED WITH 986 00:51:04,400 --> 00:51:06,160 1,000 AND WENT ON TO USE FURTHER 987 00:51:06,160 --> 00:51:09,880 DILUTIONS. 988 00:51:09,880 --> 00:51:14,360 HERE'S THE SUMMARY. 989 00:51:14,360 --> 00:51:16,920 WE USED THE CALCULATION TO 990 00:51:16,920 --> 00:51:21,880 ESTIMATE TO EXTRAPOLATE I SHOULD 991 00:51:21,880 --> 00:51:27,160 SAY THE AID50 AND IT TURNED OUT 992 00:51:27,160 --> 00:51:30,680 THAT THE ENSHIVIG PRETREATED 993 00:51:30,680 --> 00:51:33,400 ANIMALS REQUIRED A STATISTICALLY 994 00:51:33,400 --> 00:51:35,560 SIGNIFICANTLY LOWER AMOUNT OF 995 00:51:35,560 --> 00:51:35,760 VIRUS. 996 00:51:35,760 --> 00:51:37,840 SO ROUGHLY THREEFOLD LOWER. 997 00:51:37,840 --> 00:51:41,880 THAT WAS PUBLISHED AS A SAID IN 998 00:51:41,880 --> 00:51:50,040 DECEMBER LAST YEAR. 999 00:51:50,040 --> 00:51:53,120 SO THAT WAS OBVIOUSLY A DONOR 1000 00:51:53,120 --> 00:51:54,640 AND SOMETIMES WHEN YOU -- AFTER 1001 00:51:54,640 --> 00:51:57,280 DECADES OF TRYING YOU DON'T HAVE 1002 00:51:57,280 --> 00:51:59,080 AN AIDS VACCINE YOU NEED TO LOOK 1003 00:51:59,080 --> 00:52:00,840 AT THE ELEPHANT IN THE ROOM. 1004 00:52:00,840 --> 00:52:04,360 I THINK THE FACT THAT ENHANCING 1005 00:52:04,360 --> 00:52:05,920 ANTIBODIES ARE REAL IS AN 1006 00:52:05,920 --> 00:52:07,840 IMPORTANT ASPECT OF AIDS VACCINE 1007 00:52:07,840 --> 00:52:09,240 DEVELOPMENT TO BE TAKEN INTO 1008 00:52:09,240 --> 00:52:09,800 ACCOUNT FOR FURTHER 1009 00:52:09,800 --> 00:52:14,440 CONSIDERATION. 1010 00:52:14,440 --> 00:52:15,480 I'M JUST SAYING IT RIGHT NOW BUT 1011 00:52:15,480 --> 00:52:19,160 YOU DON'T LIKE TO END IT WITH 1012 00:52:19,160 --> 00:52:20,840 THAT SO THE OTHER PAPER MARJORIE 1013 00:52:20,840 --> 00:52:22,960 CONTRIBUTED AGAIN HER EXPERTISE 1014 00:52:22,960 --> 00:52:28,400 IN ANTIBODY IGG EFFECTIVE 1015 00:52:28,400 --> 00:52:31,000 FUNCTION INCLUDES AN INTERESTING 1016 00:52:31,000 --> 00:52:36,720 CASE AND THIS ANIMAL WAS 1017 00:52:36,720 --> 00:52:39,720 VACCINAT 1018 00:52:39,720 --> 00:52:40,360 VACCINAT 1019 00:52:40,360 --> 00:52:41,360 VACCINAT 1020 00:52:41,360 --> 00:52:50,080 VACCINATED 2003 AND REMAINED 1021 00:52:50,080 --> 00:52:54,080 VIREMIC AND HERE IS THIS ANIMAL 1022 00:52:54,080 --> 00:52:58,840 VACCINATED IN 2003 WITH PROTEIN 1023 00:52:58,840 --> 00:53:03,480 RECOMBINANT PARTICLES GP160 OF 1024 00:53:03,480 --> 00:53:08,680 OTHER HIV STRAIN AGAINST 1025 00:53:08,680 --> 00:53:11,360 HETEROLOGOUS AND IT WAS A TRIMER 1026 00:53:11,360 --> 00:53:13,800 AND HIV TRACT. 1027 00:53:13,800 --> 00:53:19,680 THE FIRST CHALLENGE WAS A VIRUS. 1028 00:53:19,680 --> 00:53:21,880 NO VIREMIA BUT RESPONSE AND WE 1029 00:53:21,880 --> 00:53:25,840 SID ALREADY, THE ANIMAL MADE 1030 00:53:25,840 --> 00:53:26,720 NEUTRALIZING ANTIBODIES AGAINST 1031 00:53:26,720 --> 00:53:29,600 THIS TIER 1 VIRUS. 1032 00:53:29,600 --> 00:53:34,000 LET'S TAKE THE TIER 2 VERSION 1033 00:53:34,000 --> 00:53:36,040 WHERE NO NEUTRALIZING ANTIBODY 1034 00:53:36,040 --> 00:53:40,400 MADE AND SAME OUTCOME AND THE 1035 00:53:40,400 --> 00:53:42,840 ANIMAL REMAINED FLAT LINE AS FAR 1036 00:53:42,840 --> 00:53:45,120 AS VIREMIA GOES FOR YEARS. 1037 00:53:45,120 --> 00:53:48,240 THIS ANIMAL STARTED TO MAKE SOME 1038 00:53:48,240 --> 00:53:49,960 MEDIATED IMMUNE RESPONSES 1039 00:53:49,960 --> 00:53:53,880 AGAINST VIRAL TARGETS NOT 1040 00:53:53,880 --> 00:53:57,960 PRESENT IN THE INITIAL VACCINE 1041 00:53:57,960 --> 00:54:02,240 AND NOT PRESENT IN PUBLISHED 1042 00:54:02,240 --> 00:54:06,120 DATA WITH ME FOR YEARS AGAIN AND 1043 00:54:06,120 --> 00:54:08,760 THIS WE DID A CASE REPORT IN 1044 00:54:08,760 --> 00:54:09,360 '22. 1045 00:54:09,360 --> 00:54:11,120 THE CONCLUSION IS THE ANIMAL IS 1046 00:54:11,120 --> 00:54:12,960 THE FIRST EXAMPLE OF A 1047 00:54:12,960 --> 00:54:16,240 VIRUS-EXPOSED PERSISTENTLY 1048 00:54:16,240 --> 00:54:17,680 AVIREMIC ANIMAL THAT HAS MADE 1049 00:54:17,680 --> 00:54:21,160 LONG-TERM HIGH-LEVEL CELLULAR 1050 00:54:21,160 --> 00:54:23,720 ANTIVIRAL IMMUNITY IN THE 1051 00:54:23,720 --> 00:54:25,520 ABSENCE OF AN IDENTIFIABLE 1052 00:54:25,520 --> 00:54:28,960 CRYPTIC RESERVOIR THAT WAS 1053 00:54:28,960 --> 00:54:30,800 PUBLISHED IN 2012. 1054 00:54:30,800 --> 00:54:32,560 AS YOU KNOW I HAVE MOVED AND NOW 1055 00:54:32,560 --> 00:54:34,560 THE RESERVOIR IS NO LONGER 1056 00:54:34,560 --> 00:54:41,920 CRYPTIC AS YOU WILL SEE. 1057 00:54:41,920 --> 00:54:44,320 THIS WAS SUCH A PROVOCATIVE 1058 00:54:44,320 --> 00:54:47,840 FINDING THAT AFTER ALL THE YEARS 1059 00:54:47,840 --> 00:54:50,720 THE STUDIES WERE MAINTAINED AND 1060 00:54:50,720 --> 00:54:53,840 HOW LONG DOES AIDS VACCINE 1061 00:54:53,840 --> 00:54:55,520 PROTECTION LAST WITHOUT BOOSTS? 1062 00:54:55,520 --> 00:54:58,400 THIS ANIMAL WAS NEVER BOOSTED. 1063 00:54:58,400 --> 00:55:04,000 JUST HAD THE VACCINE IN 2003. 1064 00:55:04,000 --> 00:55:06,760 WE RECRUITED OTHER ANIMALS WHEN 1065 00:55:06,760 --> 00:55:09,720 MARJORIE WORKED WITH US AND WE 1066 00:55:09,720 --> 00:55:13,600 DECIDED TO DO A TIER 2R5 SHIFT 1067 00:55:13,600 --> 00:55:16,000 AND CHALLENGE MORE THAN 10 YEARS 1068 00:55:16,000 --> 00:55:17,360 AFTER THE INITIAL VACCINE 1069 00:55:17,360 --> 00:55:17,760 PROTECTION. 1070 00:55:17,760 --> 00:55:21,560 SO THIS WAS A TWO-PART 1071 00:55:21,560 --> 00:55:25,800 EXPERIMENT AND HERE, MARJORIE, 1072 00:55:25,800 --> 00:55:26,840 THANK YOU AGAIN THIS WAS 1073 00:55:26,840 --> 00:55:29,440 COLLABORATION WHERE WE TRIED 1074 00:55:29,440 --> 00:55:33,680 DIFFERENT WAYS OF INDUCING 1075 00:55:33,680 --> 00:55:34,400 SIMULTANEOUS ANTIBODY RESPONSES 1076 00:55:34,400 --> 00:55:36,480 AND CELL-MEDIATED RESPONSE. 1077 00:55:36,480 --> 00:55:38,560 I HAVE BEEN A BELIEVER FROM THE 1078 00:55:38,560 --> 00:55:40,560 GET GO THAT HIV IS SUCH A TOUGH 1079 00:55:40,560 --> 00:55:43,760 ENEMY YOU HAVE TO ATTACK IT WITH 1080 00:55:43,760 --> 00:55:45,880 MULTIPLE BRANCHES OF THE 1081 00:55:45,880 --> 00:55:46,360 MILITARY. 1082 00:55:46,360 --> 00:55:47,800 YOU CAN'T JUST HAVE ONE 1083 00:55:47,800 --> 00:55:48,360 MODALITY. 1084 00:55:48,360 --> 00:55:51,160 WE CALL THIS DEFENSE IN DEPTH. 1085 00:55:51,160 --> 00:55:53,880 WE ALWAYS USED THAN ONE 1086 00:55:53,880 --> 00:55:54,760 APPROACH. 1087 00:55:54,760 --> 00:55:56,800 HERE'S AGAIN ONE OF THOSE 1088 00:55:56,800 --> 00:55:59,560 APPROACHES AND WE HAD ANIMALS, 1089 00:55:59,560 --> 00:56:00,480 FOUR ADDITIONAL ANIMALS THAT 1090 00:56:00,480 --> 00:56:04,160 WERE PROTECTED. 1091 00:56:04,160 --> 00:56:05,840 SOME I'M SHOWING HERE. 1092 00:56:05,840 --> 00:56:09,840 SOME OF THEM HAD NO VIREMIA 1093 00:56:09,840 --> 00:56:11,520 EVER. 1094 00:56:11,520 --> 00:56:14,720 THIS ONE INTEROPT 12 AND SOME 1095 00:56:14,720 --> 00:56:20,360 HAD LOW LEVELS OF VIREMIA 1096 00:56:20,360 --> 00:56:24,760 BEGINNING OR HAVE INTERMITTENT 1097 00:56:24,760 --> 00:56:28,160 BUT NEVER REACHING PSI 1098 00:56:28,160 --> 00:56:28,480 POSITIVITY. 1099 00:56:28,480 --> 00:56:31,280 AND NOW THAT I'VE TOLD YOU ABOUT 1100 00:56:31,280 --> 00:56:32,800 THE IMMUNOGENS ARE LISTED HERE 1101 00:56:32,800 --> 00:56:35,920 AS I SAID THEY ALL GOT PROTEIN 1102 00:56:35,920 --> 00:56:39,080 AND VARIOUS APPROACHES THAT WE 1103 00:56:39,080 --> 00:56:41,800 TRIED OUT WITH OVERLAPPING 1104 00:56:41,800 --> 00:56:43,960 SYNTHETIC PEPTIDES AGAINST 1105 00:56:43,960 --> 00:56:45,080 VARIOUS TARGETS THAT COULD 1106 00:56:45,080 --> 00:56:46,440 INDUCE CMI. 1107 00:56:46,440 --> 00:56:47,560 THAT'S NOT IMPORTANT. 1108 00:56:47,560 --> 00:56:51,440 WHAT IS IMPORTANT IS THE TIME 1109 00:56:51,440 --> 00:56:51,640 LINE. 1110 00:56:51,640 --> 00:56:54,360 THE TWO ANIMALS IN GREEN AND 1111 00:56:54,360 --> 00:56:57,360 THAT WERE FLAT LINERS. 1112 00:56:57,360 --> 00:57:00,680 NO VIREMIA WE DISCOUNTED THAT SO 1113 00:57:00,680 --> 00:57:01,040 MUCH LATER. 1114 00:57:01,040 --> 00:57:04,400 THE EXPERIMENTS STARTED IN 2011 1115 00:57:04,400 --> 00:57:06,720 AND THEN ONE WAS FLIPPING IN THE 1116 00:57:06,720 --> 00:57:10,160 BEGINNING DIDN'T REACH THE 1117 00:57:10,160 --> 00:57:12,640 10,000 LEVEL AND THE PURPLE 1118 00:57:12,640 --> 00:57:16,480 ANIMAL WAS LOW-LEVEL 1119 00:57:16,480 --> 00:57:21,920 OCCASIONALLY BUT NEVER HIGH 1120 00:57:21,920 --> 00:57:25,880 ENOUGH. 1121 00:57:25,880 --> 00:57:28,960 I MOVED TO THE RESEARCH CENTER 1122 00:57:28,960 --> 00:57:33,880 WHERE WE ESTABLISHED PET CT 1123 00:57:33,880 --> 00:57:35,560 SCANNING. 1124 00:57:35,560 --> 00:57:40,440 WE WERE ABLE TO LABEL THIS VIRUS 1125 00:57:40,440 --> 00:57:45,280 PRODUCING CELLS FROM THE PG2121 1126 00:57:45,280 --> 00:57:48,040 AND WAS LABELLED WITH RADIO 1127 00:57:48,040 --> 00:57:50,200 ACTIVE COPPER AND THE ANIMAL WAS 1128 00:57:50,200 --> 00:57:52,440 SCANNED OVER TIME TO SEE UPTAKE. 1129 00:57:52,440 --> 00:58:01,840 AND UPTAKE WE SAW. 1130 00:58:01,840 --> 00:58:06,080 AND THERE'S SEVERAL OTHER SPOTS 1131 00:58:06,080 --> 00:58:07,320 THAT WERE NOT EXPIRATION OF THE 1132 00:58:07,320 --> 00:58:09,840 RADIO ACTIVE LABEL. 1133 00:58:09,840 --> 00:58:16,480 IN FACT THIS ONE LYMPH NODE WAS 1134 00:58:16,480 --> 00:58:17,120 ACCESSIBLE. 1135 00:58:17,120 --> 00:58:23,360 AND WE EXCISED AND SENT THE 1136 00:58:23,360 --> 00:58:36,120 LYMPH NODE DA DNA TO UCLA TO 1137 00:58:36,120 --> 00:58:46,480 IDENTIFY VARL SEQUEN-- VIRAL SEQUENCES 1138 00:58:46,480 --> 00:58:49,920 AND NOW WE HAVE PROOF THE ANIMAL 1139 00:58:49,920 --> 00:58:51,520 HAS INDEED A TISSUE RESERVOIR 1140 00:58:51,520 --> 00:58:53,240 AND THE DISTRIBUTION OF THE 1141 00:58:53,240 --> 00:58:55,120 LABEL IS DIFFERENT FROM ANIMALS 1142 00:58:55,120 --> 00:58:58,720 THAT ARE VIREMIC AND HAVE VIRE 1143 00:58:58,720 --> 00:59:00,240 SPREAD OF THE SYSTEMIC 1144 00:59:00,240 --> 00:59:00,560 CIRCULATION. 1145 00:59:00,560 --> 00:59:02,480 THIS IS WHAT I JUST TOLD YOU AND 1146 00:59:02,480 --> 00:59:09,080 LET ME GO ON. 1147 00:59:09,080 --> 00:59:12,280 WE HAVE TO DO IT IN TWO SESSIONS 1148 00:59:12,280 --> 00:59:13,760 FOR LOGISTICAL REASONS. 1149 00:59:13,760 --> 00:59:15,960 WE HAVE TWO SETS OF CONTROL. 1150 00:59:15,960 --> 00:59:17,320 ONE EXPERIMENT INVOLVED FOUR 1151 00:59:17,320 --> 00:59:19,280 INTERACTIVE CHALLENGES AND THE 1152 00:59:19,280 --> 00:59:20,960 OTHER ONE THREE AND THOSE ARE 1153 00:59:20,960 --> 00:59:23,760 SHOWN HERE WITH THE ARROWS PLUS 1154 00:59:23,760 --> 00:59:26,360 OR MINUS THE GRAY. 1155 00:59:26,360 --> 00:59:29,480 THE BOTTOM LINE IS ALL OF THESE 1156 00:59:29,480 --> 00:59:31,240 CONTROLS BECAME VEREMIC. 1157 00:59:31,240 --> 00:59:34,360 THE CONTROLS WERE ALSO ANIMALS 1158 00:59:34,360 --> 00:59:35,960 THAT HAD SEEN LIVE VIRUS UNDER 1159 00:59:35,960 --> 00:59:40,560 THE PROTECTION OF PASSIVELY 1160 00:59:40,560 --> 00:59:43,200 ADMINISTERED ANTIBODIES CLASS 1161 00:59:43,200 --> 00:59:46,520 AND THEY BECAME CLEARLY VIREMIC 1162 00:59:46,520 --> 00:59:52,120 AND NO PROBLEM THERE. 1163 00:59:52,120 --> 00:59:55,640 SO RAT 9 RESISTED LATE 1164 00:59:55,640 --> 00:59:57,120 RECHALLENGE SOMETHING LIKE 18 1165 00:59:57,120 --> 00:59:58,920 YEARS AFTER THE INITIAL 1166 00:59:58,920 --> 00:59:59,200 VACCINATION. 1167 00:59:59,200 --> 01:00:01,120 NO VIREMIA. 1168 01:00:01,120 --> 01:00:05,880 THE VIRUS WAS THE TIER 2 1169 01:00:05,880 --> 01:00:13,560 INFECTIOUS MOLECULAR CLONE. 1170 01:00:13,560 --> 01:00:15,040 THE EXTRA ANIMALS HAD AN 1171 01:00:15,040 --> 01:00:20,200 INTERESTING AND PROVOCATIVE 1172 01:00:20,200 --> 01:00:21,120 OUTCOME. 1173 01:00:21,120 --> 01:00:23,000 TWO HAD HIGH PEAK VIREMIA AND 1174 01:00:23,000 --> 01:00:25,800 THEY WERE PROTECTED IN THE 1175 01:00:25,800 --> 01:00:27,920 BEGINNING. 1176 01:00:27,920 --> 01:00:33,000 THEY HAD STERILIZATION IMMUNITY 1177 01:00:33,000 --> 01:00:36,800 AND DID NOT EXTEND TO THE 1178 01:00:36,800 --> 01:00:45,920 CHALLENGE AND THE OTHERS WERE 1179 01:00:45,920 --> 01:00:51,000 ALSO REMAINED FLAT LINED. 1180 01:00:51,000 --> 01:00:53,360 THE RED ANIMAL THAT WAS FLAT 1181 01:00:53,360 --> 01:00:56,720 LINED AFTER THE INITIAL ACUTE 1182 01:00:56,720 --> 01:00:59,280 VIREMIA AND THEY KEPT DOING THE 1183 01:00:59,280 --> 01:01:02,400 SAME THING THERE WERE LITTLE 1184 01:01:02,400 --> 01:01:05,880 BLIPS BUT NOT MAKING COPIES SO 1185 01:01:05,880 --> 01:01:11,160 THE BOTTOM LINE HERE IS THAT AND 1186 01:01:11,160 --> 01:01:16,960 ONLY RHESUS MONKEYS WITH 1187 01:01:16,960 --> 01:01:21,760 PROTECTION EXISTED LATE AND 1188 01:01:21,760 --> 01:01:22,480 THOSE STERILIZING IMMUNITY 1189 01:01:22,480 --> 01:01:24,600 BECAME VEREMIC AND THE 1190 01:01:24,600 --> 01:01:28,360 CONCLUSION IS AND THIS IS AN 1191 01:01:28,360 --> 01:01:29,840 IMPORTANT MESSAGE FOR VACCINE 1192 01:01:29,840 --> 01:01:33,840 DEVELOPMENT AND ANTIGEN 1193 01:01:33,840 --> 01:01:35,120 PERSISTENCE MAY BE NEEDED FOR 1194 01:01:35,120 --> 01:01:37,360 LONG-TERM PROTECTION BUT DOING 1195 01:01:37,360 --> 01:01:39,400 IT ONE TIME AND THEN ACHIEVING 1196 01:01:39,400 --> 01:01:51,680 PROTECTION IS ANOTHER THING. 1197 01:01:51,680 --> 01:01:54,520 AND WE COINED THIS A TERM TO 1198 01:01:54,520 --> 01:01:57,160 MAKE IT CLEAR THAT WE NEED 1199 01:01:57,160 --> 01:02:00,360 ANTIBODY DEPENDENT ENHANCEMENT 1200 01:02:00,360 --> 01:02:01,080 OF VIRUS ACQUISITION. 1201 01:02:01,080 --> 01:02:04,400 THE INITIAL ENCOUNTER WAS TO 1202 01:02:04,400 --> 01:02:05,800 HAVE NOT CHANGE DISEASE PATTERN 1203 01:02:05,800 --> 01:02:19,120 OR ANYTHING. 1204 01:02:19,120 --> 01:02:23,880 AND THERE'S COLLABORATION FROM 1205 01:02:23,880 --> 01:02:27,360 THE PAPER PAPER AND I THINK WE 1206 01:02:27,360 --> 01:02:28,320 NAILED IT. 1207 01:02:28,320 --> 01:02:35,040 THIS IS REAL AND IS PASSIVE 1208 01:02:35,040 --> 01:02:36,120 IMMUNIZATION. 1209 01:02:36,120 --> 01:02:37,680 PASSIVE IMMUNIZATION EXPERIMENT 1210 01:02:37,680 --> 01:02:41,560 CAUSE AND EFFECT AND AGAIN THE 1211 01:02:41,560 --> 01:02:42,560 TROUBLING OBSERVATION OVER TIME 1212 01:02:42,560 --> 01:02:48,800 THERE'S INDIRECT EVIDENCE IN 1213 01:02:48,800 --> 01:02:55,520 HUMAN VACCINEES GIVEN THE 1214 01:02:55,520 --> 01:03:00,000 MONOMER THIS MAY ALSO MAY BE 1215 01:03:00,000 --> 01:03:03,400 TRUE AND IN SUMMARY NUMBER 2, 1216 01:03:03,400 --> 01:03:08,720 THE LONG-TERM PROTECTION I'VE 1217 01:03:08,720 --> 01:03:13,640 SHOWN YOU THE STORY OF RAT 9 AND 1218 01:03:13,640 --> 01:03:17,080 THE BOTTOM LINE IS THE ANIMAL IS 1219 01:03:17,080 --> 01:03:20,000 A CASE OF ARREST OF VIRUS 1220 01:03:20,000 --> 01:03:21,080 DISSEMINATION OVER MANY YEARS 1221 01:03:21,080 --> 01:03:23,680 AND ABILITY TO RESIST LATE 1222 01:03:23,680 --> 01:03:24,960 RECHALLENGE MORE THAN 15 YEARS 1223 01:03:24,960 --> 01:03:28,880 AFTER THE LAST VIRUS EXPOSURE. 1224 01:03:28,880 --> 01:03:31,880 THE ADDITIONAL FOUR ANIMALS 1225 01:03:31,880 --> 01:03:34,560 SHOWED THAT ANTIGEN PERSISTENCE 1226 01:03:34,560 --> 01:03:36,840 OR ANTIGEN BOOSTING IS REQUIRED 1227 01:03:36,840 --> 01:03:40,200 FOR LONG-TERM PROTECTION. 1228 01:03:40,200 --> 01:03:43,360 YOU DON'T GET IT IF YOU JUST 1229 01:03:43,360 --> 01:03:43,960 VACCINATE AND THIS IS WHAT A 1230 01:03:43,960 --> 01:03:50,080 JUST SAID. 1231 01:03:50,080 --> 01:03:55,520 AND I'D LIKE TO THANK THE 1232 01:03:55,520 --> 01:03:57,840 COLLABORATORS THAT MADE THE 1233 01:03:57,840 --> 01:03:58,520 INTERDISCIPLINARY WORK POSSIBLE 1234 01:03:58,520 --> 01:03:59,960 AND FIRST AND FOREMOST I'D LIKE 1235 01:03:59,960 --> 01:04:01,920 TO THANK MARJORIE AND HER LAB 1236 01:04:01,920 --> 01:04:04,480 MEMBERS WHO HAVE CONTRIBUTED AND 1237 01:04:04,480 --> 01:04:07,760 ACTUALLY STIMULATED THESE 1238 01:04:07,760 --> 01:04:09,840 QUESTIONS FOR THE FOLLOW-UP 1239 01:04:09,840 --> 01:04:10,480 STUDIES. 1240 01:04:10,480 --> 01:04:17,920 MARJORIE, MANY MANY THANKS. 1241 01:04:17,920 --> 01:04:22,680 [APPLAUSE] 1242 01:04:22,680 --> 01:04:24,600 THE QUESTION WAS WHETHER OR NOT 1243 01:04:24,600 --> 01:04:27,120 WE KNOW WHICH REGIONS OF THE 1244 01:04:27,120 --> 01:04:29,960 ANIMAL ARE INVOLVED IN THE 1245 01:04:29,960 --> 01:04:31,320 ENHANCEMENT, CORRECT? 1246 01:04:31,320 --> 01:04:36,720 WE DID MAPPING AND COMPARED THE 1247 01:04:36,720 --> 01:04:38,280 SHIVIG WITH CROSS-NEUTRALIZING 1248 01:04:38,280 --> 01:04:41,040 ANTIBODIES AND THE SHIVIG WAS 1249 01:04:41,040 --> 01:04:43,640 ISOLATED IN THE LATE STAGE OF 1250 01:04:43,640 --> 01:04:46,680 SHIV INFECTION OF RHESUS MONKEYS 1251 01:04:46,680 --> 01:04:53,000 AND THE END SHIVIG WAS ISOLATED 1252 01:04:53,000 --> 01:05:00,680 EARLY BEFORE THE ANIMALS MADE 1253 01:05:00,680 --> 01:05:01,640 NEUTRALIZING ANTIBODIES. 1254 01:05:01,640 --> 01:05:04,440 WE DID CROSS-COMPARE PEPTIDE 1255 01:05:04,440 --> 01:05:07,000 MAPPING BETWEEN SHIVIG AND END 1256 01:05:07,000 --> 01:05:07,240 SHIVIG. 1257 01:05:07,240 --> 01:05:12,600 THE SHIVIG, AS EXPECTED, HAD 1258 01:05:12,600 --> 01:05:15,680 GOOD REACTIVITY AND THE END 1259 01:05:15,680 --> 01:05:19,480 SHIVIG WAS MOSTLY AGAINST GP41 1260 01:05:19,480 --> 01:05:20,720 PRACTICALLY NOTHING AGAINST THE 1261 01:05:20,720 --> 01:05:21,160 V3 LOOP. 1262 01:05:21,160 --> 01:05:24,040 WE ACTUALLY IN THE PAPER WE 1263 01:05:24,040 --> 01:05:30,560 DEPLETED THE END SHIVIG OF THE 1264 01:05:30,560 --> 01:05:32,560 REACTIVITY AND THERE WAS NO 1265 01:05:32,560 --> 01:05:32,880 DIFFERENCE. 1266 01:05:32,880 --> 01:05:37,720 SO THE IMPLICATION WAS IN THE 1267 01:05:37,720 --> 01:05:41,800 END SHIVIG THE EPITOPE 1268 01:05:41,800 --> 01:05:46,840 SPECIFICITY WAS LIKELY SHIVIG 41 1269 01:05:46,840 --> 01:05:50,040 BUT THE ANIMALS THAT HAD DUAL 1270 01:05:50,040 --> 01:05:55,320 OUTWITH THE SHIVIG, THEY HAD 1271 01:05:55,320 --> 01:05:56,680 REACTIVITY AGAINST GP120. 1272 01:05:56,680 --> 01:06:03,320 AND THERE IS A PAPER OUT IN PNS. 1273 01:06:03,320 --> 01:06:04,920 WE WILL TALK WITH YOU LATER 1274 01:06:04,920 --> 01:06:07,280 ABOUT IT WHERE WE SHOWED 1275 01:06:07,280 --> 01:06:09,520 ENHANCEMENT WITH MONOCLONAL 1276 01:06:09,520 --> 01:06:11,240 ANTIBODIES AGAINST GP120. 1277 01:06:11,240 --> 01:06:15,880 SO IT'S NOT ONLY THAT GP41 IS A 1278 01:06:15,880 --> 01:06:16,080 SUSPECT. 1279 01:06:16,080 --> 01:06:20,800 THE ENTIRE ENVELOPE CAN BE 1280 01:06:20,800 --> 01:06:29,480 CAUSING ENHANCEMENT. 1281 01:06:29,480 --> 01:06:30,240 >> OKAY. 1282 01:06:30,240 --> 01:06:31,880 IF THERE ARE NO FURTHER 1283 01:06:31,880 --> 01:06:33,960 QUESTIONS, THANK YOU VERY MUCH, 1284 01:06:33,960 --> 01:06:34,200 RUTH. 1285 01:06:34,200 --> 01:06:35,440 THIS WAS A FANTASTIC 1286 01:06:35,440 --> 01:06:37,040 PRESENTATION AND WITH THIS WE 1287 01:06:37,040 --> 01:06:43,520 HAVE A LITTLE BREAK 1288 01:06:43,520 --> 01:06:45,240 >> I WANT TO TALK ABOUT OUR WORK 1289 01:06:45,240 --> 01:06:48,320 ON THE IMPACT OF IMMUNOGEN 1290 01:06:48,320 --> 01:06:51,440 DESIGN AND REPLICATION ON 1291 01:06:51,440 --> 01:06:52,600 PRECLINICAL AND CLINICAL 1292 01:06:52,600 --> 01:06:56,200 IMMUNO-GENESIMMUNO 1293 01:06:56,200 --> 01:07:00,000 GENESSE -- IMMUNOGENICITY. 1294 01:07:00,000 --> 01:07:01,520 MARJORIE HAS MADE TREMENDOUS 1295 01:07:01,520 --> 01:07:03,520 CONTRIBUTIONS NOT ONLY SPECIFIC 1296 01:07:03,520 --> 01:07:07,520 TO HIV BUT ALSO IN THE VACCINE 1297 01:07:07,520 --> 01:07:14,000 AND ADENOVIRUS RECOMBINANT AND 1298 01:07:14,000 --> 01:07:17,880 THEY WERE ISOLATED HERE AT NIH 1299 01:07:17,880 --> 01:07:21,280 IN THE EARLY '50s AND THEN 1300 01:07:21,280 --> 01:07:26,720 THROUGH SOME WORK WITH BOB 1301 01:07:26,720 --> 01:07:28,040 CHANNIC'S LAB VIRUSES WERE 1302 01:07:28,040 --> 01:07:31,600 LICENSED IN 1980 AND THEN IN 1303 01:07:31,600 --> 01:07:35,480 1997, MARJORIE ALONG WITH A 1304 01:07:35,480 --> 01:07:43,440 GROUP AT YF PUBLISHED -- THIS 1305 01:07:43,440 --> 01:07:51,760 PAPER LUBEK ET AL. AND 1306 01:07:51,760 --> 01:07:54,920 DISCOVERED CHIMPANZEES WERE 1307 01:07:54,920 --> 01:07:59,120 PROTECTED AGAINST A VIRUS. 1308 01:07:59,120 --> 01:08:03,200 IN THE LATE '90s I WAS ASKED TO 1309 01:08:03,200 --> 01:08:07,440 COLLABORATE WITH MARJORIE AND I 1310 01:08:07,440 --> 01:08:11,400 WORKED WITH ADENOVIRUS 1311 01:08:11,400 --> 01:08:21,000 RECOMBINANTS AND SHE HAD 1312 01:08:21,000 --> 01:08:22,560 RECLINARECLIN 1313 01:08:22,560 --> 01:08:24,320 RECOMBINANTS AND IF YOU DON'T 1314 01:08:24,320 --> 01:08:25,000 HAVE A CORPORATE PARTNER IT'S 1315 01:08:25,000 --> 01:08:27,760 TOUGH SLEDDING AT THAT TIME AND 1316 01:08:27,760 --> 01:08:32,240 DURING THAT PHASE MARJORIE HAD 1317 01:08:32,240 --> 01:08:36,440 PUBLISHED MORE THAN 60 PAPERS ON 1318 01:08:36,440 --> 01:08:43,440 AD RECOMBINANTS AND 1319 01:08:43,440 --> 01:08:44,120 EXTRAORDINARY CONTRIBUTIONS THAT 1320 01:08:44,120 --> 01:08:46,920 HIGHLIGHT LEAD IT ASPECTS OF THE 1321 01:08:46,920 --> 01:08:48,000 ADVANTAGES OF REPLICATION 1322 01:08:48,000 --> 01:08:50,120 CONFIDENT ADENOVIRUS AND THE 1323 01:08:50,120 --> 01:08:51,240 REPLICATION OF THE VIRUS HAD 1324 01:08:51,240 --> 01:08:53,560 ADVANTAGES IN TERMS OF THE 1325 01:08:53,560 --> 01:08:54,680 MAGNITUDE OF THE IMMUNE RESPONSE 1326 01:08:54,680 --> 01:08:58,560 AND SOME EXTENT THE DURABILITY. 1327 01:08:58,560 --> 01:09:01,520 IN ADDITION, THERE WAS INDUCTION 1328 01:09:01,520 --> 01:09:02,600 OF MUCOSAL IMMUNITY AND THE 1329 01:09:02,600 --> 01:09:04,160 IMPORTANCE OF A PROTEIN BOOST 1330 01:09:04,160 --> 01:09:07,400 AND GETTING THAT RESPONSE TO THE 1331 01:09:07,400 --> 01:09:07,680 NEXT LEVEL. 1332 01:09:07,680 --> 01:09:10,760 AND SO WE INITIATED PHASE 1 OF 1333 01:09:10,760 --> 01:09:13,600 HIV RECOMBINANTS IN 2011 AND A 1334 01:09:13,600 --> 01:09:17,320 COUPLE YEARS BEFORE US OF H5 1335 01:09:17,320 --> 01:09:18,880 RECOMBINANTS IN HUMANS THAT 1336 01:09:18,880 --> 01:09:21,520 PAVED THE WAY TO STUDY DIFFERENT 1337 01:09:21,520 --> 01:09:26,480 ASPECTS OF USING THE VIRUS IN 1338 01:09:26,480 --> 01:09:26,920 HUMANS. 1339 01:09:26,920 --> 01:09:27,520 TREMENDOUS CONTRIBUTIONS FROM 1340 01:09:27,520 --> 01:09:29,000 MARJORIE THAT LAID THE 1341 01:09:29,000 --> 01:09:30,680 FOUNDATION FOR A LOT OF THE WORK 1342 01:09:30,680 --> 01:09:31,480 I'LL DESCRIBE TODAY. 1343 01:09:31,480 --> 01:09:34,920 THERE IS A REALLY IMPORTANT 1344 01:09:34,920 --> 01:09:39,160 IMPACT OF VACCINE PLATFORM ON 1345 01:09:39,160 --> 01:09:39,520 IMMUNOGENICITY. 1346 01:09:39,520 --> 01:09:42,480 A LOT OF THESE HAVE VARYING 1347 01:09:42,480 --> 01:09:44,080 AMOUNTS OF ATTENTION OVER THE 1348 01:09:44,080 --> 01:09:50,240 YEARS FROM THE HIV FIELD BUT 1349 01:09:50,240 --> 01:09:55,080 THEY CONTRIBUTE TO THE RESPONSE, 1350 01:09:55,080 --> 01:09:55,960 MAGNITUDE AND VARIABILITY. 1351 01:09:55,960 --> 01:09:58,920 IT'S NOT A SIMPLE STICKING IN A 1352 01:09:58,920 --> 01:09:59,680 120 PROTEIN. 1353 01:09:59,680 --> 01:10:00,920 THERE ARE ALL THESE OTHER FACTOR 1354 01:10:00,920 --> 01:10:04,360 GO INTO OUR RESPONSE TO VIRUSES 1355 01:10:04,360 --> 01:10:07,400 AND THOSE INCLUDE ENVELOPE 1356 01:10:07,400 --> 01:10:15,360 CONFIRMATION THE VALENCY AND THE 1357 01:10:15,360 --> 01:10:16,360 LOW AFFINITY INTERACTION, THE 1358 01:10:16,360 --> 01:10:23,480 REPLICATION OF THE VIRUS THEY 1359 01:10:23,480 --> 01:10:28,160 COME TOGETHER TO GIVE US A 1360 01:10:28,160 --> 01:10:31,960 DURABLE RESPONSE THAT IS OF HIGH 1361 01:10:31,960 --> 01:10:32,240 MAGNITUDE. 1362 01:10:32,240 --> 01:10:35,560 WE HAVE BEGUN STUDYING THESE 1363 01:10:35,560 --> 01:10:37,960 FACTORS IN SOME ISOLATION 1364 01:10:37,960 --> 01:10:41,480 THROUGH THE USE OF VIRUS-LIKE 1365 01:10:41,480 --> 01:10:41,720 PARTICLES. 1366 01:10:41,720 --> 01:10:44,040 THIS IS THE WORK OF OUR LAB IN 1367 01:10:44,040 --> 01:10:46,880 WHICH HE IS STUDIES THE IMPACT 1368 01:10:46,880 --> 01:10:50,040 OF VALENCIES AND THE SPIKE AND 1369 01:10:50,040 --> 01:10:52,320 DOSE REPLICATION IN SMALL 1370 01:10:52,320 --> 01:10:58,560 ANIMALS AND RABBITS AND 1371 01:10:58,560 --> 01:11:00,080 ANTOGENIC AND WE'RE ABLE TO 1372 01:11:00,080 --> 01:11:01,400 MODULATE THE DIFFERENT FACTORS 1373 01:11:01,400 --> 01:11:02,200 IN ISOLATION AND TRY TO 1374 01:11:02,200 --> 01:11:05,320 UNDERSTAND BETTER WHAT ARE THE 1375 01:11:05,320 --> 01:11:11,080 MOST IMPORTANT FACTORS FOR 1376 01:11:11,080 --> 01:11:16,680 VACCINE IMMUNOGENICITY IN HIV 1377 01:11:16,680 --> 01:11:19,120 AND TWO HAVE GOTTEN ATTENTION 1378 01:11:19,120 --> 01:11:25,120 THE ANTIGENICITY AND MAINTAINING 1379 01:11:25,120 --> 01:11:26,560 THE SPIKE AND THOSE ARE 1380 01:11:26,560 --> 01:11:29,600 CONSERVES HAVE BEEN RESOLVED BY 1381 01:11:29,600 --> 01:11:38,160 THE WORK OF JOHN MOORE AND 1382 01:11:38,160 --> 01:11:41,400 STABLIZING HIV SPIKE AND WE VA 1383 01:11:41,400 --> 01:11:44,040 HIGH VALENCY PART KALTZ AND 1384 01:11:44,040 --> 01:11:46,040 THESE ARE PARTICLES WHERE WE'RE 1385 01:11:46,040 --> 01:11:47,040 ABLE TO MAKE BEAUTIFUL PRIMERS 1386 01:11:47,040 --> 01:11:50,280 THAT COAT THE SURFACE SO HIGH 1387 01:11:50,280 --> 01:11:54,320 VALENCY, ANTIGENICALLY THEY LOOK 1388 01:11:54,320 --> 01:11:56,680 FANTASTIC BY PROBING WITH 1389 01:11:56,680 --> 01:11:58,520 MONOCLONAL ANTIBODIES OR BY EM 1390 01:11:58,520 --> 01:12:01,320 AND MAKE THE STRUCTURAL 1391 01:12:01,320 --> 01:12:04,440 BIOLOGISTS JEALOUS AND YOU WOULD 1392 01:12:04,440 --> 01:12:10,080 ANTICIPATE IF VALENCY WERE THE 1393 01:12:10,080 --> 01:12:14,240 ONLY CRITICAL FACTORS THIS WOULD 1394 01:12:14,240 --> 01:12:17,040 BE AN APPROACH AND HIV IS NOT AN 1395 01:12:17,040 --> 01:12:18,400 EASY TARGET. 1396 01:12:18,400 --> 01:12:24,520 IF YOU DO THE EXPERIMENT WITH 1397 01:12:24,520 --> 01:12:32,360 VLP THAT HAS IT FROM BIRD FLU 1398 01:12:32,360 --> 01:12:33,600 AND IF YOU DO THE SAME 1399 01:12:33,600 --> 01:12:40,760 EXPERIMENT WITH VLP WITH THE 1400 01:12:40,760 --> 01:12:41,160 PRI 1401 01:12:41,160 --> 01:12:43,160 TRIMERS I HEAD TO YOU DO NOT SEE 1402 01:12:43,160 --> 01:12:44,680 A RESPONSE AND THERE'S AN 1403 01:12:44,680 --> 01:12:46,680 INHERENT LACK OF IMMUNOGENICITY 1404 01:12:46,680 --> 01:12:48,520 THAT HAS OTHER FACTORS TO 1405 01:12:48,520 --> 01:12:49,400 GENERATE AN IMMUNE RESPONSE. 1406 01:12:49,400 --> 01:12:52,520 SO VERY TOUGH TARGET. 1407 01:12:52,520 --> 01:12:54,400 AND IT WILL BE IMPORTANT FOR THE 1408 01:12:54,400 --> 01:12:57,200 NEXT GENERATION OF VACCINES TO 1409 01:12:57,200 --> 01:12:59,800 INCORPORATE MANY OF THE 1410 01:12:59,800 --> 01:13:01,120 ADVANTAGES OR THE WAYS I SHOWED 1411 01:13:01,120 --> 01:13:03,440 YOU IN THE SECOND SLIDE HOW WE 1412 01:13:03,440 --> 01:13:06,960 SENSED VIRUSES INTO THE VACCINE 1413 01:13:06,960 --> 01:13:08,520 AND TAKE ADVANTAGE OF 1414 01:13:08,520 --> 01:13:10,600 REPLICATING VECTORS, FOR 1415 01:13:10,600 --> 01:13:13,120 EXAMPLE, THAT HAVE A LOT OF 1416 01:13:13,120 --> 01:13:13,760 THOSE ATTRIBUTES. 1417 01:13:13,760 --> 01:13:19,240 THERE'S A KNOWN HIERARCHY OF 1418 01:13:19,240 --> 01:13:23,440 IMMUNOGENICITY FOR ANY GIVEN 1419 01:13:23,440 --> 01:13:26,240 TARGET ANTIGEN AND THAT IS BY 1420 01:13:26,240 --> 01:13:31,080 THERE'S ATTENUATED 1421 01:13:33,920 --> 01:13:35,080 AND REPLICATING VECTORS HAVE A 1422 01:13:35,080 --> 01:13:37,040 NUMBER OF ADVANTAGES YOU CAN SEE 1423 01:13:37,040 --> 01:13:40,160 AND THAT IS THAT THEY MAINTAIN 1424 01:13:40,160 --> 01:13:42,280 THE APPROPRIATE CONFIRMATION 1425 01:13:42,280 --> 01:13:47,400 BECAUSE THEY'RE PRODUCING EN 1426 01:13:47,400 --> 01:13:50,600 ENVELOPE IN VIVO AND CONTINUE TO 1427 01:13:50,600 --> 01:13:51,920 REPLICATE IN THE HOST UNTIL THE 1428 01:13:51,920 --> 01:13:53,840 IMMUNE SYSTEM SAYS STOP. 1429 01:13:53,840 --> 01:14:01,800 THEY HAVE TLR AGONISTS AND SIGHT 1430 01:14:01,800 --> 01:14:04,880 CYTOKINES AND FOR ALL THESE 1431 01:14:04,880 --> 01:14:08,040 REASONS WE HAVE FOCUSSED ON 1432 01:14:08,040 --> 01:14:08,800 REPLICATING VECTORS IN OUR 1433 01:14:08,800 --> 01:14:15,360 ANIMAL AND HUMAN WORK. 1434 01:14:15,360 --> 01:14:17,760 AND THERE'S EXPRESSION OF GLYCO 1435 01:14:17,760 --> 01:14:20,920 GLYCOPROTEINS AND THIS WAS A 1436 01:14:20,920 --> 01:14:22,440 NATURAL VIRUS TO START THE WORK 1437 01:14:22,440 --> 01:14:25,000 WITH BECAUSE IT'S BEEN GIVEN TO 1438 01:14:25,000 --> 01:14:25,920 MORE THAN 10 MILLION PEOPLE IN 1439 01:14:25,920 --> 01:14:29,000 THE MILITARY WITH A 99.3% 1440 01:14:29,000 --> 01:14:29,840 EFFICACY RATE AND EXTRAORDINARY 1441 01:14:29,840 --> 01:14:30,680 SAFETY RECORD. 1442 01:14:30,680 --> 01:14:33,440 IT'S NOT ASSOCIATED WITH 1443 01:14:33,440 --> 01:14:34,120 INCREASED ACQUISITION RISK AND 1444 01:14:34,120 --> 01:14:38,000 WE'VE NOW EITHER STARTED OR 1445 01:14:38,000 --> 01:14:39,120 COMPLETED MULTIPLE CLINICAL 1446 01:14:39,120 --> 01:14:42,440 TRIALS TO EVALUATE THE SAFETY, 1447 01:14:42,440 --> 01:14:47,480 DOSE, ROOT IMMUNOGENICITY AND 1448 01:14:47,480 --> 01:14:50,120 STARTED WITH WORK TO ESTABLISH A 1449 01:14:50,120 --> 01:14:52,120 DOSE AT ROOT AND I'LL SHOW A 1450 01:14:52,120 --> 01:14:54,720 LITTLE BIT OF THAT WORK TODAY. 1451 01:14:54,720 --> 01:14:57,240 WE THEN ALONG WITH MARJORIE 1452 01:14:57,240 --> 01:15:01,160 STARTED THIS EARLY TRIAL OF AD 4 1453 01:15:01,160 --> 01:15:05,960 WITH GAG OR A C150 A 1086 1454 01:15:05,960 --> 01:15:07,920 ISOLATE THERE AND WE'RE IN THE 1455 01:15:07,920 --> 01:15:09,920 MIDDLE OF THE TRIAL THE AD 4 1456 01:15:09,920 --> 01:15:15,680 THAT ENCODES THE 1086 1457 01:15:15,680 --> 01:15:19,360 CONFIRMATIONALLY NATIVE LIKE OR 1458 01:15:19,360 --> 01:15:27,240 A STABILIZED NFL FROM RICH WYATT 1459 01:15:27,240 --> 01:15:29,200 IN CLINIC. 1460 01:15:29,200 --> 01:15:31,920 THE EARLY WORK SHOWED IT TO BE A 1461 01:15:31,920 --> 01:15:32,680 PROMISING PLATFORM PUBLISHED 1462 01:15:32,680 --> 01:15:34,560 FROM OUR GROUP IN 2019 AND 2021. 1463 01:15:34,560 --> 01:15:37,400 WE EITHER GAVE IT BY AN ORAL 1464 01:15:37,400 --> 01:15:39,400 CAPSULE SIMILAR TO THE MILITARY 1465 01:15:39,400 --> 01:15:44,040 OR PAINTED IT ON THE TONSILS OF 1466 01:15:44,040 --> 01:15:47,080 PARTICIPANTS AND BY AN 1467 01:15:47,080 --> 01:15:47,960 INTRANASAL SPRAY AND THERE'S TWO 1468 01:15:47,960 --> 01:15:50,200 FORMS OF ATTENUATION. 1469 01:15:50,200 --> 01:15:51,960 ONE IS ON THE G.I. TRACT AND THE 1470 01:15:51,960 --> 01:15:53,480 SECOND IS AN INSERT THAT TURNS 1471 01:15:53,480 --> 01:15:55,840 OUT TO BE OVERLY ATTENUATED. 1472 01:15:55,840 --> 01:15:58,240 YOU GET A NICE BUMP EARLY BUT 1473 01:15:58,240 --> 01:16:00,880 YOU DON'T GET THE DURABILITY IF 1474 01:16:00,880 --> 01:16:02,560 YOU HAVE MORE LONG-LASTING 1475 01:16:02,560 --> 01:16:05,920 DURABILITY AND YOU PUT IT ON THE 1476 01:16:05,920 --> 01:16:07,080 TONSILS AND HAVE BETTER 1477 01:16:07,080 --> 01:16:08,680 REPLICATION AND GOT DURABLE 1478 01:16:08,680 --> 01:16:08,960 RESPONSES. 1479 01:16:08,960 --> 01:16:10,120 THIS IS AT SIX MONTHS. 1480 01:16:10,120 --> 01:16:11,360 NO DIFFERENT FROM THE RESPONSE 1481 01:16:11,360 --> 01:16:18,120 OF 28 DAYS. 1482 01:16:18,120 --> 01:16:21,960 WE ALSO SAW THIS NICE INCREASE 1483 01:16:21,960 --> 01:16:23,480 IN THE MEMORY COMPARTMENT OF 1484 01:16:23,480 --> 01:16:26,120 MONOCLONAL ANTIBODIES WE 1485 01:16:26,120 --> 01:16:27,480 DERIVED. 1486 01:16:27,480 --> 01:16:31,160 A SINGLE IMMUNIZATION DROVE SIX 1487 01:16:31,160 --> 01:16:34,120 MONTHS TO A YEAR OF SOMATIC 1488 01:16:34,120 --> 01:16:36,120 MUTATION AND THEY BECOME MORE 1489 01:16:36,120 --> 01:16:38,040 POTENT AND THERE'S B CELL 1490 01:16:38,040 --> 01:16:38,840 EXPANSIONS THAT PARALLEL THIS 1491 01:16:38,840 --> 01:16:44,280 OVER A LONG PERIOD OF TIME. 1492 01:16:44,280 --> 01:16:45,800 PARTICIPANTS IN THE TRIAL WOULD 1493 01:16:45,800 --> 01:16:50,840 SHED NUCLEIC ACID AND INFECTIOUS 1494 01:16:50,840 --> 01:16:52,680 VIRUS WAS SHED 4 TO 7 DAYS AND 1495 01:16:52,680 --> 01:16:54,760 THE MEDIAN DURATION OF SHEDDING 1496 01:16:54,760 --> 01:16:57,520 WAS ONE DAY WHEN YOU LOOK AT THE 1497 01:16:57,520 --> 01:16:57,920 INDIVIDUAL LEVEL. 1498 01:16:57,920 --> 01:16:59,440 VERY PROMISING DATA. 1499 01:16:59,440 --> 01:17:02,000 WE HAD NO TRANSMISSION BETWEEN 1500 01:17:02,000 --> 01:17:03,920 PARTICIPANTS AND INTIMATE 1501 01:17:03,920 --> 01:17:05,320 CONTACTS AND THIS LOOKED LIKE 1502 01:17:05,320 --> 01:17:11,400 QUITE A GOOD IMMUNOGENIC. 1503 01:17:11,400 --> 01:17:18,680 WE DID NOT SET OUT THIS APPROACH 1504 01:17:18,680 --> 01:17:20,160 FOR SARS COV2 IN MARCH OF 2020 1505 01:17:20,160 --> 01:17:21,960 WHEN I LOOKED AT THE LIST OF 1506 01:17:21,960 --> 01:17:25,960 VACCINES AND SAW THERE WERE NOT 1507 01:17:25,960 --> 01:17:31,480 ONLY REVIEW COMPETENT APPROACHES 1508 01:17:31,480 --> 01:17:35,960 AND NO MUCOSAL APPROACH AND THIS 1509 01:17:35,960 --> 01:17:37,960 WAS OUR FOURTH TRIAL AND KNEW IT 1510 01:17:37,960 --> 01:17:39,360 WAS AN IMMUNOGENIC PLATFORM. 1511 01:17:39,360 --> 01:17:40,960 WE DEVELOPED A PARTNERSHIP WITH 1512 01:17:40,960 --> 01:17:47,800 A COMPANY IN BELGIUM AND THEY 1513 01:17:47,800 --> 01:17:57,520 ARE VERY GOOD FIT FOR US AND THE 1514 01:17:57,520 --> 01:17:59,440 SMALLER MACHINES CAN FUNCTION AS 1515 01:17:59,440 --> 01:18:10,440 A FACTORY FOR VACCINES AND WE'RE 1516 01:18:10,440 --> 01:18:13,000 PARTNERED WITH OTHERS AT DRUMMER 1517 01:18:13,000 --> 01:18:14,280 HITCHCOCK AND THEY'RE REMARKABLY 1518 01:18:14,280 --> 01:18:19,120 ONE OF THE FEW CENTERS THAT HAVE 1519 01:18:19,120 --> 01:18:21,040 DEVELOPED AN EXTRAORDINARY TOOLS 1520 01:18:21,040 --> 01:18:23,280 FOR MEASURING MUCOSAL IMMUNITY. 1521 01:18:23,280 --> 01:18:25,720 IT'S QUITE SOMETHING YOU HAVE A 1522 01:18:25,720 --> 01:18:27,040 VIRUS LIKE SARS COV2 AND FEW 1523 01:18:27,040 --> 01:18:28,840 PEOPLE ARE FOCUSSED ON MUCOSAL 1524 01:18:28,840 --> 01:18:30,840 IMMUNITY BUT THAT GROUP HAS A 1525 01:18:30,840 --> 01:18:32,320 GREAT SUITE OF TOOLS. 1526 01:18:32,320 --> 01:18:33,800 IT'S A NICE COLLABORATION 1527 01:18:33,800 --> 01:18:34,600 BETWEEN THE GROUPS. 1528 01:18:34,600 --> 01:18:43,440 SO I'M GOING TO GO QUICKLY 1529 01:18:43,440 --> 01:18:44,320 THROUGH GO THROUGH THE 1530 01:18:44,320 --> 01:18:45,840 DURABILITY OF RESPONSE TO 1531 01:18:45,840 --> 01:18:48,320 VACCINE AND PRE-CLINICAL RESULTS 1532 01:18:48,320 --> 01:18:50,800 AND OUR PLANS FOR PHASE 1 AND 2. 1533 01:18:50,800 --> 01:18:56,120 FIRST INDUCTION OF MUCOSAL 1534 01:18:56,120 --> 01:19:05,080 IMMUNITY. 1535 01:19:05,080 --> 01:19:06,120 AND THERE'S NO BETTER EXAMPLE 1536 01:19:06,120 --> 01:19:08,080 THAN POLIO AND IT'S BEEN DONE 1537 01:19:08,080 --> 01:19:11,000 MANY WAYS, MANY TIMES. 1538 01:19:11,000 --> 01:19:14,080 IF YOU HAVE EXPERIENCE WITH TYPE 1539 01:19:14,080 --> 01:19:17,840 1 AND TYPE 3 POLIO BY AN ORAL 1540 01:19:17,840 --> 01:19:20,720 ROUTE SO THIS IS A TYPE 2 1541 01:19:20,720 --> 01:19:23,000 CHALLENGE OR YOU GOT TYPE 1, 1542 01:19:23,000 --> 01:19:28,480 TYPE 3 ORALLY AND GOT TYPE 2 BY 1543 01:19:28,480 --> 01:19:30,920 IPV INTRAMUSCULARLY YOU 1544 01:19:30,920 --> 01:19:32,560 REPRESENTED IT FULLY BUT IF YOU 1545 01:19:32,560 --> 01:19:34,080 HAVE AN ORAL POLIO VACCINE THAT 1546 01:19:34,080 --> 01:19:35,840 INCLUDE THE TYPE 2, THEN THE 1547 01:19:35,840 --> 01:19:39,080 TYPE 2 CHALLENGE IS RESTRICTED 1548 01:19:39,080 --> 01:19:39,920 IN THESE PEOPLE. 1549 01:19:39,920 --> 01:19:42,320 AN INTRAMUSCULAR VACCINE DOES 1550 01:19:42,320 --> 01:19:44,120 NOT INFER THE ABILITY TO 1551 01:19:44,120 --> 01:19:45,120 INTERRUPT TRANSMISSION. 1552 01:19:45,120 --> 01:19:46,000 IT'S A VERY IMPORTANT LESSON IN 1553 01:19:46,000 --> 01:19:51,080 POLIO. 1554 01:19:51,080 --> 01:19:56,720 AND THE IDEA FOR SARS COV2 IS A 1555 01:19:56,720 --> 01:19:59,440 MUCOSAL RESPONSE WOULD CURTAIL 1556 01:19:59,440 --> 01:20:01,360 VIRUS SHEDDING. 1557 01:20:01,360 --> 01:20:03,320 IT'S A HIGHLY INFECTIOUS VIRUS. 1558 01:20:03,320 --> 01:20:05,520 IT MAY BE WE'RE UNABLE TO 1559 01:20:05,520 --> 01:20:06,480 COMPLETELY PROTECT AGAINST 1560 01:20:06,480 --> 01:20:06,840 INFECTION. 1561 01:20:06,840 --> 01:20:08,920 YOU MAY RAISE THE BAR SOMEWHAT 1562 01:20:08,920 --> 01:20:12,120 BUT AT A MINIMUM YOU WOULD LIMIT 1563 01:20:12,120 --> 01:20:14,280 THE ABILITY AND THE REASON IS IF 1564 01:20:14,280 --> 01:20:18,720 YOU GIVE AN INTRAMUSCULAR 1565 01:20:18,720 --> 01:20:22,800 VACCINATION IT MAY LEAK AND GET 1566 01:20:22,800 --> 01:20:24,520 A LOWER RESPIRATORY TRACT 1567 01:20:24,520 --> 01:20:26,280 PROTECTION BUT HAVE LIMITED 1568 01:20:26,280 --> 01:20:28,520 ABILITY TO STOP THE SHEDDING OF 1569 01:20:28,520 --> 01:20:29,920 THE VIRUS. 1570 01:20:29,920 --> 01:20:32,800 IF YOU GET A LOCAL MUCOSAL 1571 01:20:32,800 --> 01:20:35,440 INFECTION YOU GET B CELLS AND 1572 01:20:35,440 --> 01:20:43,200 THEY PRODUCE DIME ERIC IGA AND 1573 01:20:43,200 --> 01:20:44,440 CAN CAPTURE VIRUS AT THE EARLY 1574 01:20:44,440 --> 01:20:46,400 STAGE AND PRESENTS TO THE IMMUNE 1575 01:20:46,400 --> 01:20:48,360 SYSTEM OR STOPS INFECTION AND SO 1576 01:20:48,360 --> 01:20:52,920 THIS IS A VERY POTENT ABILITY TO 1577 01:20:52,920 --> 01:20:56,320 BLOCK TRANSMISSION POTENTIALLY. 1578 01:20:56,320 --> 01:20:59,360 AND THIS IS ACTUALLY QUITE 1579 01:20:59,360 --> 01:21:00,560 APPLICABLE TO RESPIRATORY 1580 01:21:00,560 --> 01:21:03,440 VIRUSES NOT JUST A POLIO 1581 01:21:03,440 --> 01:21:05,440 PHENOMENON SHOWN IN THE PAST FOR 1582 01:21:05,440 --> 01:21:07,520 INFLUENZA VIRUS CHALLENGE 1583 01:21:07,520 --> 01:21:11,120 STUDIES BY BRIAN MURPHY FOR 1584 01:21:11,120 --> 01:21:14,280 USING FLUMIST. 1585 01:21:14,280 --> 01:21:17,160 THERE ARE PROTECTIONS FROM 1586 01:21:17,160 --> 01:21:18,280 SEASONAL CORONAVIRUS THAT 1587 01:21:18,280 --> 01:21:20,040 CORRELATES WITH MUCOSAL IGA 1588 01:21:20,040 --> 01:21:23,000 SHOWN IN THE '80s AND NOW 1589 01:21:23,000 --> 01:21:24,480 THERE'S PROBABLY MORE THAN 20 1590 01:21:24,480 --> 01:21:26,320 PAPERS IN THE LITERATURE SHOWING 1591 01:21:26,320 --> 01:21:30,000 THIS PHENOMENON IN EXPERIMENTAL 1592 01:21:30,000 --> 01:21:31,720 ANIMALS IF YOU GIVE AN TRA NASAL 1593 01:21:31,720 --> 01:21:36,280 VACCINATION YOU'RE ABLE TO 1594 01:21:36,280 --> 01:21:37,520 RESTRICT THE CHALLENGE VIRUS AND 1595 01:21:37,520 --> 01:21:42,920 YOU SEE LIMIT THE AMOUNTS 1596 01:21:42,920 --> 01:21:47,120 CHAIRED TO SHAM IMMUNIZATION OR 1597 01:21:47,120 --> 01:21:47,920 INTRAMUSCULAR VACCINE WITH THE 1598 01:21:47,920 --> 01:21:51,520 SAME VECTORER SHOWN IN BLUE. 1599 01:21:51,520 --> 01:21:54,080 THIS HAS BEEN SHOWN IN HIGH 1600 01:21:54,080 --> 01:21:55,320 SUSCEPTIBLE ANIMAL MODELS AND 1601 01:21:55,320 --> 01:21:56,920 LOTS OF VACCINES. 1602 01:21:56,920 --> 01:22:01,480 IT'S QUITE A ROBUST PHENOMENON 1603 01:22:01,480 --> 01:22:02,920 THAT INTRANASAL VACCINE CAN 1604 01:22:02,920 --> 01:22:06,680 LIMIT THE ABILITY TO INFECT A 1605 01:22:06,680 --> 01:22:07,320 HIGHLY SUSCEPTIBLE ANIMAL AND 1606 01:22:07,320 --> 01:22:09,080 LIMIT THE ABILITY TO TRANSMIT. 1607 01:22:09,080 --> 01:22:11,480 SECONDLY THE DURABILITY OF THE 1608 01:22:11,480 --> 01:22:13,640 RESPONSE TO VACCINE. 1609 01:22:13,640 --> 01:22:15,480 IT'S BEEN WELL TELEGRAPHED AND 1610 01:22:15,480 --> 01:22:19,320 MOST PEOPLE IN THE ROOM ARE 1611 01:22:19,320 --> 01:22:21,080 SIMILAR TO THE ISSUE WITH mRNA 1612 01:22:21,080 --> 01:22:24,320 VACCINES THE DURABILITY IS QUITE 1613 01:22:24,320 --> 01:22:25,720 PURE BUT IT'S NOT NEW OR 1614 01:22:25,720 --> 01:22:27,520 SPECIFIC TO SARS COV2. 1615 01:22:27,520 --> 01:22:30,520 IN THE PAST THE MODERNA H7 1616 01:22:30,520 --> 01:22:36,320 VACCINES WHEN GIVEN YOU HAD HIGH 1617 01:22:36,320 --> 01:22:39,240 LEVELS OF NEUTRALIZING 1618 01:22:39,240 --> 01:22:41,000 ANTIBODIES AFTER 28 DAYS OF THE 1619 01:22:41,000 --> 01:22:43,160 IMMUNIZATION AND BY DAY 200 YOU 1620 01:22:43,160 --> 01:22:46,240 WERE BARELY ABOVE GMT OF 10. 1621 01:22:46,240 --> 01:22:48,360 NOT DURABLE. 1622 01:22:48,360 --> 01:22:50,920 SIMILAR RESULTS WITH RABIES 1623 01:22:50,920 --> 01:22:53,120 VACCINE USING mRNA. 1624 01:22:53,120 --> 01:22:56,880 ON THE RIGHT IS IF YOU SPLIT THE 1625 01:22:56,880 --> 01:22:58,720 H5 VACCINE IN WHICH IF YOU GIVE 1626 01:22:58,720 --> 01:23:02,000 THE VACCINE AND YOU CAN AD ASO1 1627 01:23:02,000 --> 01:23:07,360 OR 3 AND JACK UP THE TITERS 200 1628 01:23:07,360 --> 01:23:09,520 TO 300 BUT BY 12 MONTHS YOU CAN 1629 01:23:09,520 --> 01:23:11,400 BARELY TELL THE PERSON HAS BEEN 1630 01:23:11,400 --> 01:23:11,720 VACCINATED. 1631 01:23:11,720 --> 01:23:14,320 SO THIS IS A VERY DIFFERENT 1632 01:23:14,320 --> 01:23:15,440 PHENOMENON FROM WHAT I'LL SHOW 1633 01:23:15,440 --> 01:23:18,520 IN THE NEXT COUPLE SLIDES AND 1634 01:23:18,520 --> 01:23:22,000 YOU GIVE A LOT OF VIRUS 1635 01:23:22,000 --> 01:23:22,880 INFECTION. 1636 01:23:22,880 --> 01:23:26,400 IT'S KNOWN THE HALF LIFE OF IGG 1637 01:23:26,400 --> 01:23:31,320 WILD TYPE INFECTION FOR EXAMPLE 1638 01:23:31,320 --> 01:23:33,680 WITH MEASLES OR A VACCINIA OR 1639 01:23:33,680 --> 01:23:36,480 THE HALF LIFE OF THE IGG IN THE 1640 01:23:36,480 --> 01:23:38,200 PERIPHERAL BLOOD IS IN THE ORDER 1641 01:23:38,200 --> 01:23:40,640 OF HUNDREDS TO THOUSANDS OF 1642 01:23:40,640 --> 01:23:42,000 YEARS ESSENTIALLY MEANING FLAT 1643 01:23:42,000 --> 01:23:46,080 BUT IF YOU GIVE A PROTEIN LIKE 1644 01:23:46,080 --> 01:23:50,280 DIPHTHERIA, TETANUS, OTHER 1645 01:23:50,280 --> 01:23:51,040 APPROACHES, THE ANTIBODY 1646 01:23:51,040 --> 01:23:54,200 RESPONSE EVENTUALLY WANES AND 1647 01:23:54,200 --> 01:23:55,400 REQUIRES BOOSTING. 1648 01:23:55,400 --> 01:23:58,080 THESE ARE THE RESPONSES IN A 1649 01:23:58,080 --> 01:24:00,520 COHORT IN THE MILITARY TO 1650 01:24:00,520 --> 01:24:02,360 REPLICATION COMPETENT AT 4 THE 1651 01:24:02,360 --> 01:24:05,080 MILITARY VACCINE THAT'S GIVEN ON 1652 01:24:05,080 --> 01:24:06,040 THE G.I. TRACT. 1653 01:24:06,040 --> 01:24:08,160 SO IF YOU'RE NEGATIVE AT THE 1654 01:24:08,160 --> 01:24:10,360 OUTSET YOU THEN DEVELOP A 1655 01:24:10,360 --> 01:24:11,680 RESPONSE AND THEN BRING THE 1656 01:24:11,680 --> 01:24:13,160 PEOPLE BACK FIVE TO SIX YEARS 1657 01:24:13,160 --> 01:24:15,720 AND THERE'S NO CHANGE FROM THE 1658 01:24:15,720 --> 01:24:18,240 PEAK OF OTHER SPOTS. 1659 01:24:18,240 --> 01:24:21,920 IF YOU'RE ZERO POSITIVE 1660 01:24:21,920 --> 01:24:23,000 PRE-VACCINATION YOU'RE ABLE TO 1661 01:24:23,000 --> 01:24:27,440 BE REINFECTED BECAUSE IT'S A 1662 01:24:27,440 --> 01:24:28,160 MUCOSAL INFECTION AND IF YOU 1663 01:24:28,160 --> 01:24:29,560 BRING PEOPLE BACK FIVE TO SIX 1664 01:24:29,560 --> 01:24:35,000 YEARS LATER THERE'S NO CHANGE IN 1665 01:24:35,000 --> 01:24:35,440 NEW TITER. 1666 01:24:35,440 --> 01:24:37,720 QUITE DURABLE RESPONSES TO THE 1667 01:24:37,720 --> 01:24:39,320 VACCINE GIVEN ORALLY IN THE 1668 01:24:39,320 --> 01:24:39,560 MILITARY. 1669 01:24:39,560 --> 01:24:42,560 WE SAW A SIMILAR PHENOMENON IN 1670 01:24:42,560 --> 01:24:44,320 OUR STUDIES WITH H5 WHEN WE 1671 01:24:44,320 --> 01:24:45,520 BROUGHT PEOPLE BACK THREE TO 1672 01:24:45,520 --> 01:24:46,320 FIVE YEARS LATER. 1673 01:24:46,320 --> 01:24:49,400 THERE WAS NO CHANGE REALLY IN 1674 01:24:49,400 --> 01:24:52,600 THEIR H5 TITERS AND AT THREE TO 1675 01:24:52,600 --> 01:24:56,160 FIVE YEARS SO DURABLE ANTIBODY 1676 01:24:56,160 --> 01:24:59,400 RESPONSES TO THIS VACCINE. 1677 01:24:59,400 --> 01:25:01,840 JUST BRIEFLY I OFTEN GET ASKED 1678 01:25:01,840 --> 01:25:03,760 ABOUT PRE-EXISTING IMMUNITY. 1679 01:25:03,760 --> 01:25:05,720 IT'S NOT A BINARY EVENT. 1680 01:25:05,720 --> 01:25:10,680 IF YOU'RE GIVING IT ON A MUCOSAL 1681 01:25:10,680 --> 01:25:12,840 SURFACE IT'S NOT THEY'RE ROUTINE 1682 01:25:12,840 --> 01:25:15,360 PROTECTED AGAINST VACCINATION. 1683 01:25:15,360 --> 01:25:17,520 PEOPLE ZERO POSITIVE CURTAIL 1684 01:25:17,520 --> 01:25:21,400 THEIR DAYS OF SHEDDING SHOWN IN 1685 01:25:21,400 --> 01:25:23,360 THE LOWER RIGHT BUT TO LESS THAN 1686 01:25:23,360 --> 01:25:25,560 SEVEN DAYS BUT THERE'S ONLY SIX 1687 01:25:25,560 --> 01:25:26,960 PEOPLE IN THE ENTIRE TRIAL WE 1688 01:25:26,960 --> 01:25:31,560 DID NOT INFECT WITH THAT OR THE 1689 01:25:31,560 --> 01:25:33,120 RESPONSE ALSO DEPENDS -- THE 1690 01:25:33,120 --> 01:25:35,160 ABILITY TO INFECT DEPENDS ON 1691 01:25:35,160 --> 01:25:36,920 YOUR PRE-EXISTING TITER WHICH IS 1692 01:25:36,920 --> 01:25:38,720 NOT BINARY. 1693 01:25:38,720 --> 01:25:40,520 IT'S A CONTINUUM SHOWN IN THE 1694 01:25:40,520 --> 01:25:41,440 UPPER RIGHT. 1695 01:25:41,440 --> 01:25:43,160 THERE ARE SOME PEOPLE WITH 1696 01:25:43,160 --> 01:25:44,880 EXTRAORDINARY HIGH TITERS BUT 1697 01:25:44,880 --> 01:25:46,840 PEOPLE HAVE QUITE MODEST TITERS 1698 01:25:46,840 --> 01:25:49,280 AND ALSO TWO OTHER FACTORS AND 1699 01:25:49,280 --> 01:25:52,320 THAT'S AN EFFECT OF THE 1700 01:25:52,320 --> 01:25:53,880 IMMUNOGENICITY OF THE TRANS GENE 1701 01:25:53,880 --> 01:25:54,920 PRODUCT. 1702 01:25:54,920 --> 01:25:58,920 PEOPLE WE WOULD BE IMMUNIZING 1703 01:25:58,920 --> 01:26:01,600 WITH AD 4 AND SARS 2 NOT ONLY 1704 01:26:01,600 --> 01:26:04,200 IMMUNIZED WITH AN IMMUNOGENIC 1705 01:26:04,200 --> 01:26:05,120 TRANS GENE WHICH WOULD SHIFT 1706 01:26:05,120 --> 01:26:06,920 THIS OUT FURTHER BUT HAVE A 1707 01:26:06,920 --> 01:26:08,360 MEMORY RESPONSE PREEXIST FROM 1708 01:26:08,360 --> 01:26:09,920 PRIOR VACCINATION OR INFECTION. 1709 01:26:09,920 --> 01:26:11,360 THIS WOULD BE IN MOST PEOPLE 1710 01:26:11,360 --> 01:26:15,120 WOULD BE BOOST. 1711 01:26:15,120 --> 01:26:20,080 THEN THE MUCOSAL INFECTION ROUTE 1712 01:26:20,080 --> 01:26:22,600 IS KNOWN THAT YOU CAN BYPASS 1713 01:26:22,600 --> 01:26:26,320 MOST THE SYSTEMIC RESPONSE BY 1714 01:26:26,320 --> 01:26:31,360 MUCOSAL INFECTION. 1715 01:26:31,360 --> 01:26:37,480 S THE REACTOGENICITY IS SHOWN 1716 01:26:37,480 --> 01:26:39,480 HERE AGAINST THE DATA FOR THE 1717 01:26:39,480 --> 01:26:41,280 PFIZER AND MODERNA mRNA 1718 01:26:41,280 --> 01:26:47,480 VACCINES AS PART OF THEIR EUA. 1719 01:26:47,480 --> 01:26:51,520 AND WE HAVE A CATEGORY EXCEPT 1720 01:26:51,520 --> 01:26:54,560 FOR PEOPLE WITH A SORE AND 1721 01:26:54,560 --> 01:26:56,360 SCRATCHY THROAT OR COUGH BUT NO 1722 01:26:56,360 --> 01:26:57,760 GRADE 3 OR GRADE 4 REACTIONS. 1723 01:26:57,760 --> 01:26:59,560 WE HAVE NOT SEEN THAT IN ANY OF 1724 01:26:59,560 --> 01:27:01,760 OUR CLINICAL TRIALS AND HALF THE 1725 01:27:01,760 --> 01:27:04,720 PEOPLE ARE COMPLETELY 1726 01:27:04,720 --> 01:27:07,240 ASYMPTOMATIC TO THIS VIRUS. 1727 01:27:07,240 --> 01:27:08,280 SO JUST A LITTLE BIT OF 1728 01:27:08,280 --> 01:27:10,760 PRE-CLINICAL RESULTS. 1729 01:27:10,760 --> 01:27:15,120 WE'VE NOW BUILT VIRUSES THAT CAN 1730 01:27:15,120 --> 01:27:17,120 EXPRESS A NUMBER OF DIFFERENT 1731 01:27:17,120 --> 01:27:18,000 VARIANTS OF CONCERN. 1732 01:27:18,000 --> 01:27:20,520 WE'RE DOWN TO NOW OMICRON. 1733 01:27:20,520 --> 01:27:23,480 THESE ARE ALL STABILIZED SPIKES 1734 01:27:23,480 --> 01:27:25,920 THAT WILL HAVE HAMSTER DATA NEXT 1735 01:27:25,920 --> 01:27:27,240 WEEK AND WE'RE PLANNING A 1736 01:27:27,240 --> 01:27:29,720 CHALLENGE STUDY OF THE BEST TWO 1737 01:27:29,720 --> 01:27:31,040 CANDIDATES WE'VE ALREADY PUT 1738 01:27:31,040 --> 01:27:32,680 INTO HAMSTERS. 1739 01:27:32,680 --> 01:27:38,360 WE DO QUITE WELL WITH REGARD TO 1740 01:27:38,360 --> 01:27:47,440 NEUTRALIZING ANTIBODIES. 1741 01:27:47,440 --> 01:27:50,520 IF EITHER IF YOU GIVE THE SARS 1742 01:27:50,520 --> 01:27:53,520 COV2 WUHAN OR DELTA SHOWN AS 1743 01:27:53,520 --> 01:27:56,880 INDIA IN THE UPPER LEFT, WE GET 1744 01:27:56,880 --> 01:27:59,920 NEUTRALIZING ANTIBODY RESPONSES 1745 01:27:59,920 --> 01:28:02,360 CLOSE TO 1,000 AND IF YOU 1746 01:28:02,360 --> 01:28:06,920 IMMUNIZE THEM WITH J&J 1747 01:28:06,920 --> 01:28:08,000 INTRAMUSCULARLY AND RESPONSES 1748 01:28:08,000 --> 01:28:11,560 ARE SOMEWHAT LOWER TO DELTA AND 1749 01:28:11,560 --> 01:28:15,400 EVEN LOWER TO OMICRON. 1750 01:28:15,400 --> 01:28:17,680 VERY IMPORTANTLY WE ALSO INDUCE 1751 01:28:17,680 --> 01:28:20,120 A MUCOSAL RESPONSE. 1752 01:28:20,120 --> 01:28:23,280 THIS IS WORK FROM PETER AND 1753 01:28:23,280 --> 01:28:27,320 MARJORIE ACKERMAN'S LAB AND RUTH 1754 01:28:27,320 --> 01:28:28,480 CONNOR SHOWING BINDING 1755 01:28:28,480 --> 01:28:30,800 ANTIBODIES IN THE UPPER 1756 01:28:30,800 --> 01:28:31,520 RESPIRATORY TRACT OF HAMSTERS 1757 01:28:31,520 --> 01:28:34,320 AFTER VACCINATION AND YOU CAN 1758 01:28:34,320 --> 01:28:36,800 SEE WE INDUCE NASAL IGA AND IGG 1759 01:28:36,800 --> 01:28:40,080 AND IGM. 1760 01:28:40,080 --> 01:28:47,440 YOU DON'T SEE THIS USING J&J AT 1761 01:28:47,440 --> 01:28:49,240 26IM AND THAT VACCINE LOOKS 1762 01:28:49,240 --> 01:28:53,440 BARELY ABOVE THAT OF SHAM OR FLU 1763 01:28:53,440 --> 01:28:53,680 VACCINE. 1764 01:28:53,680 --> 01:28:56,480 THESE DO INDUCE ANTIBODIES IN 1765 01:28:56,480 --> 01:28:59,120 THE UPPER RESPIRATORY TRACT TO A 1766 01:28:59,120 --> 01:28:59,720 VARIETY OF DIFFERENT PROTEINS 1767 01:28:59,720 --> 01:29:04,880 SHOWN HERE. 1768 01:29:04,880 --> 01:29:07,440 LASTLY THE PHASE 1 TO 2 PLANS. 1769 01:29:07,440 --> 01:29:09,720 THIS IS THE DESIGN OF THE 1770 01:29:09,720 --> 01:29:14,360 CLINICAL TRIAL WE BEGIN THIS 1771 01:29:14,360 --> 01:29:14,760 SUMMER. 1772 01:29:14,760 --> 01:29:18,680 PEOPLE WILL RECEIVE AD 4 SARS 1773 01:29:18,680 --> 01:29:20,720 COV2 INTRANASALLY BY OTHER 1774 01:29:20,720 --> 01:29:22,960 PROCESSES AND THEY'RE SIMILAR 1775 01:29:22,960 --> 01:29:26,400 BUT THE FDA WANTS BOTH PROCESSES 1776 01:29:26,400 --> 01:29:27,480 TESTED. 1777 01:29:27,480 --> 01:29:29,560 THEN WE'RE HOPING TO GET 1778 01:29:29,560 --> 01:29:30,520 INTERNATIONAL PARTNERSHIP TO TRY 1779 01:29:30,520 --> 01:29:32,720 TO GET SOME INDIVIDUALS WOULD 1780 01:29:32,720 --> 01:29:35,120 ARE SARS COV2 NAIVE. 1781 01:29:35,120 --> 01:29:35,920 THAT'S BECOME INCREASINGLY 1782 01:29:35,920 --> 01:29:44,400 DIFFICULT TO OBTAIN. 1783 01:29:44,400 --> 01:29:46,600 AND IN USING THIS TO A VACCINE 1784 01:29:46,600 --> 01:29:49,560 PRODUCT AND HERE I'M SHOWING IT 1785 01:29:49,560 --> 01:29:57,120 AGAINST mRNA BUT COULD BE ANY 1786 01:29:57,120 --> 01:29:58,880 OTHER VACCINE AND PROTECTION 1787 01:29:58,880 --> 01:30:03,280 COULD BE LIFE LONG. 1788 01:30:03,280 --> 01:30:06,720 AND THIS IS NOT A CONCERN FOR 1789 01:30:06,720 --> 01:30:07,440 MRNA. 1790 01:30:07,440 --> 01:30:11,400 PRODUCTION CAPACITY CONSTRAINTS 1791 01:30:11,400 --> 01:30:12,360 ARE REALLY NONE. 1792 01:30:12,360 --> 01:30:14,040 THERE ARE A LOT OF CAPACITY 1793 01:30:14,040 --> 01:30:17,520 CONSTRAINTS FOR mRNA. 1794 01:30:17,520 --> 01:30:20,160 THIS IS VERY INEXPENSIVE ABOUT A 1795 01:30:20,160 --> 01:30:30,160 PENNY PER DOSE AND HAS MINIMAL 1796 01:30:30,160 --> 01:30:32,400 COLD CHAIN REQUIREMENTS AND A 1797 01:30:32,400 --> 01:30:34,920 SCALEX MUCH PRODUCE 500 MILLION 1798 01:30:34,920 --> 01:30:36,600 DOSES IN FIVE DAYS. 1799 01:30:36,600 --> 01:30:38,360 REALLY, YOU CAN PRODUCE HUNDREDS 1800 01:30:38,360 --> 01:30:41,280 OF MILLIONS AND BILLIONS OF 1801 01:30:41,280 --> 01:30:58,120 DOSES QUITE RAPIDLY WITH THIS. 1802 01:30:58,120 --> 01:31:02,880 AND EMMA AND ELEANOR AND BEN 1803 01:31:02,880 --> 01:31:06,920 LEECH AND NIAID PERSONNEL AND 1804 01:31:06,920 --> 01:31:11,240 INVESTIGATORS AT THE VRC, FRED 1805 01:31:11,240 --> 01:31:15,240 HUTCH AND FLORYN KRAMER AND 1806 01:31:15,240 --> 01:31:18,520 MARJORIE AND DIVISION OF AIDS 1807 01:31:18,520 --> 01:31:19,120 HAVE SUPPORTED A LOT OF WORK AND 1808 01:31:19,120 --> 01:31:23,000 PARTICIPANTS. 1809 01:31:23,000 --> 01:31:23,640 I'LL STOP THERE AND TAKE 1810 01:31:23,640 --> 01:31:49,080 QUESTIONS. 1811 01:31:49,080 --> 01:31:51,320 >> VERY NICE STUDY. 1812 01:31:51,320 --> 01:31:57,840 I WANTED TO REINFORCE YOUR IDEA 1813 01:31:57,840 --> 01:32:00,120 OF INTRANASAL MUCOSAL VACCINE. 1814 01:32:00,120 --> 01:32:02,040 WE HAVEN'T USED THE REPLICATING 1815 01:32:02,040 --> 01:32:04,840 VIRUS BUT THERE'S BEEN DEVELOPED 1816 01:32:04,840 --> 01:32:09,440 A MUCOSAL NANO PARTICLE S1 BASED 1817 01:32:09,440 --> 01:32:15,440 PROTEIN VACCINE WITH TLR LIGAND 1818 01:32:15,440 --> 01:32:19,520 AND CYTOKINE AGINENTS AND WE 1819 01:32:19,520 --> 01:32:26,360 TESTED THIS IN RHESUS MACAQUES 1820 01:32:26,360 --> 01:32:29,240 AND WERE ABLE TO GET MORE 1821 01:32:29,240 --> 01:32:33,520 CLEARANCE IN THE NOSE AND NASAL 1822 01:32:33,520 --> 01:32:37,160 PHARYNX COMPARED TO INTRAMUSS 1823 01:32:37,160 --> 01:32:41,520 INTRAMUSCULARLY AND THINK IT'S 1824 01:32:41,520 --> 01:32:43,520 IMPORTANT NOT ONLY TO NIP THE 1825 01:32:43,520 --> 01:32:46,680 INFECTION IN THE BUD BEFORE IT 1826 01:32:46,680 --> 01:32:50,440 BECOMES SYSTEMIC BECAUSE ONCE 1827 01:32:50,440 --> 01:32:55,480 IT'S SYSTEMIC IT CAN CAUSE CAN 1828 01:32:55,480 --> 01:33:02,440 CAUSE BLOOD CLOTTING AND CAUSE 1829 01:33:02,440 --> 01:33:08,320 PROBLEMS AND IF YOU CAN CLEAR IT 1830 01:33:08,320 --> 01:33:15,640 YOU MAY REDUCE AND WE'RE SEEING 1831 01:33:15,640 --> 01:33:17,120 THESE IN HAMSTERS. 1832 01:33:17,120 --> 01:33:23,440 >> HAMSTERS IS A MORE 1833 01:33:23,440 --> 01:33:47,160 SUSCEPTIBLE MODEL. 1834 01:33:47,160 --> 01:33:50,200 >> WE USED IT IN ALUM AND NOW 1835 01:33:50,200 --> 01:33:51,280 REVIEWERS ARE SAYING WHY DIDN'T 1836 01:33:51,280 --> 01:33:56,480 YOU PRIME WITH ONE OF THE 1837 01:33:56,480 --> 01:34:08,400 EXISTING VACCINE VACCINES -- 1838 01:34:08,400 --> 01:34:24,680 [OFF MIC] 1839 01:34:24,680 --> 01:34:28,680 >> IT MAY HAVE TO GO TO THE 1840 01:34:28,680 --> 01:34:32,400 TOTAL DOSE TO ME WAS AN IN 1841 01:34:32,400 --> 01:34:34,040 EXPECTED ANSWER. 1842 01:34:34,040 --> 01:34:36,720 IT'S NOT THAT SIMPLE. 1843 01:34:36,720 --> 01:34:39,240 IF YOU'RE TALKING ABOUT JUST THE 1844 01:34:39,240 --> 01:34:40,720 B CELL RESPONSE AND THE HSN, YOU 1845 01:34:40,720 --> 01:34:44,120 CAN GET THAT WITH A 1846 01:34:44,120 --> 01:34:45,400 NON-REPLICATING VECTOR. 1847 01:34:45,400 --> 01:34:48,560 SO THAT HAS BEEN SHOWN FOR FLU 1848 01:34:48,560 --> 01:34:50,640 AND ALSO FOR SARS COV2 AND LOOK 1849 01:34:50,640 --> 01:34:53,640 AT THE PAPER THE HSM AND THE 1850 01:34:53,640 --> 01:34:55,400 MEMORY B CELL COMPARTMENT FOR 1851 01:34:55,400 --> 01:35:00,440 PEOPLE WHO GOT mRNA ISN'T 1852 01:35:00,440 --> 01:35:02,480 DIFFERENT BUT FOR mRNA THEY'RE 1853 01:35:02,480 --> 01:35:04,040 NOT BEING PUSHED IN THE LONG 1854 01:35:04,040 --> 01:35:07,400 LIVED PLASMA CELL POOL. 1855 01:35:07,400 --> 01:35:09,640 SO THERE'S A CLEAR DIFFERENCE IN 1856 01:35:09,640 --> 01:35:13,120 THE BREADTH AND DURABLE OF YOUR 1857 01:35:13,120 --> 01:35:14,760 SERUM RESPONSE BETWEEN mRNA 1858 01:35:14,760 --> 01:35:15,320 VERSUS INFECTION. 1859 01:35:15,320 --> 01:35:17,680 SO THAT I THINK IS THE 1860 01:35:17,680 --> 01:35:19,360 IMPORTANCE OF THE REPLICATION 1861 01:35:19,360 --> 01:35:21,280 THAT GIVES YOU THAT PUSH THAT 1862 01:35:21,280 --> 01:35:24,200 GETS THEM OUT OF THE MEMORY B 1863 01:35:24,200 --> 01:35:27,440 CELL AND INTO THE BONE MARROW 1864 01:35:27,440 --> 01:35:31,040 AND PRODUCING A LONG LIVED 1865 01:35:31,040 --> 01:35:31,400 RESPONSE. 1866 01:35:31,400 --> 01:35:36,560 BUT IN RABBITS FOR HIV THE 1867 01:35:36,560 --> 01:35:37,240 IMMUNE RESPONSE KEEPS GOING FOR 1868 01:35:37,240 --> 01:35:39,600 SIX MONTHS TO A YEAR. 1869 01:35:39,600 --> 01:35:43,400 [OFF MIC] 1870 01:35:43,400 --> 01:35:47,400 >> YES. 1871 01:35:47,400 --> 01:35:50,960 >> 1872 01:35:50,960 --> 01:35:52,240 [OFF MIC] 1873 01:35:52,240 --> 01:35:54,680 >> I'M HOPING SOMETHING THAT CAN 1874 01:35:54,680 --> 01:35:55,840 GET CLOSER TO TAKING ADVANTAGE 1875 01:35:55,840 --> 01:36:00,480 OF ALL THOSE PARAMETERS THAT A 1876 01:36:00,480 --> 01:36:01,960 LIVE VIRUS DOES FOR YOUR IMMUNE 1877 01:36:01,960 --> 01:36:04,120 RESPONSE BUT WE'LL HAVE TO SEE. 1878 01:36:04,120 --> 01:36:07,640 ALMOST NO ONE PUBLISHES 1879 01:36:07,640 --> 01:36:09,480 DURABILITY DATA AND LIKE SARS 1880 01:36:09,480 --> 01:36:11,360 COV2 IN 28 DAYS OF SUBMITTING 1881 01:36:11,360 --> 01:36:13,760 YOUR PAPER AND THE 1882 01:36:13,760 --> 01:36:14,920 SELF-REPLICATING mRNA I HAVEN'T 1883 01:36:14,920 --> 01:36:16,400 SEEN DURABILITY. 1884 01:36:16,400 --> 01:36:20,920 >> ON THE DOSE I THINK DO YOU 1885 01:36:20,920 --> 01:36:23,360 KNOW WHAT IS THE DOSE -- YOU 1886 01:36:23,360 --> 01:36:25,080 MUST KNOW THE DOSE COMPARED TO 1887 01:36:25,080 --> 01:36:30,160 THE ADENO 4 VACCINE THAT HAS 1888 01:36:30,160 --> 01:36:30,520 BEEN GIVEN? 1889 01:36:30,520 --> 01:36:35,800 >> YEAH, BUT IT'S MUCH MUCH 1890 01:36:35,800 --> 01:36:37,640 LOWER FOR INTRANASAL I THINK 1891 01:36:37,640 --> 01:36:42,840 IT'S 10 TO THE 9. 1892 01:36:42,840 --> 01:36:45,640 WHEN WE PUT IT ON THE NOSE THE 1893 01:36:45,640 --> 01:36:48,080 DOSE AT WHICH YOU START TO GET 1894 01:36:48,080 --> 01:36:49,920 INFECTION IS BELOW 10 SIMILAR TO 1895 01:36:49,920 --> 01:36:51,280 SARS COV2. 1896 01:36:51,280 --> 01:36:52,760 IMPORTANTLY, IT DOESN'T MATTER 1897 01:36:52,760 --> 01:36:54,320 WHAT DOSE YOU GIVE AS LONG AS 1898 01:36:54,320 --> 01:36:56,480 YOU GET AN INFECTION. 1899 01:36:56,480 --> 01:36:59,080 WE WENT UP FROM 10 TO THE 8 AND 1900 01:36:59,080 --> 01:37:02,920 YOU SEE ONCE A PERSON'S INFECTED 1901 01:37:02,920 --> 01:37:04,680 YOU SEE NO DIFFERENCE FROM 1902 01:37:04,680 --> 01:37:06,200 SOMEBODY WHO GOT 10 TO THE 8 1903 01:37:06,200 --> 01:37:07,040 VERSUS 10 TO THE 2. 1904 01:37:07,040 --> 01:37:08,920 >> DO YOU EXPECT THE RESISTANCE 1905 01:37:08,920 --> 01:37:21,320 IN TERMS OF THE FDA FOR 1906 01:37:21,320 --> 01:37:23,160 INTRANASAL ADMINISTRATION. 1907 01:37:23,160 --> 01:37:24,720 >> THE INTRANASAL PART WE WORKED 1908 01:37:24,720 --> 01:37:26,480 THROUGH WITH THE FDA OVER MANY 1909 01:37:26,480 --> 01:37:27,200 YEARS. 1910 01:37:27,200 --> 01:37:30,240 WE HAVEN'T HAD TO DO ANY TOX 1911 01:37:30,240 --> 01:37:32,480 SINCE THE FIRST TRIAL. 1912 01:37:32,480 --> 01:37:35,560 THEY'RE COMPLETELY COMFORTABLE 1913 01:37:35,560 --> 01:37:40,920 WITH INTRANASAL. 1914 01:37:40,920 --> 01:37:41,640 INITIALLY THERE WERE CONCERNS 1915 01:37:41,640 --> 01:37:43,240 SPIKE WAS GOING THROUGH THE 1916 01:37:43,240 --> 01:37:45,240 RECEPTOR BUT NO ONE HAS SEEN 1917 01:37:45,240 --> 01:37:48,120 THAT AND THERE'S ABOUT A DOZEN 1918 01:37:48,120 --> 01:37:48,760 INTRANASAL VACCINES BEING TESTED 1919 01:37:48,760 --> 01:37:51,360 IN PHASE 1 NOW. 1920 01:37:51,360 --> 01:37:53,000 NO ONE HAS OBSERVED THAT. 1921 01:37:53,000 --> 01:37:57,000 I THINK THOSE TWO ISSUES ARE NOT 1922 01:37:57,000 --> 01:37:59,440 GREAT ISSUES. 1923 01:37:59,440 --> 01:38:02,960 THE ONE LAST ONE TTS WE HAVE TO 1924 01:38:02,960 --> 01:38:04,680 WATCH FOR BUT THERE'S NOT GREAT 1925 01:38:04,680 --> 01:38:06,520 DATA THAT SAYS IT'S ALL 1926 01:38:06,520 --> 01:38:07,000 ADENOVIRUSES. 1927 01:38:07,000 --> 01:38:11,440 SO YOU DON'T SEE TTS OR 1928 01:38:11,440 --> 01:38:14,120 THROMBOTIC COMPLICATIONS WITH 1929 01:38:14,120 --> 01:38:16,280 THE ORAL AND IN THE AD 4 IN THE 1930 01:38:16,280 --> 01:38:18,080 MILITARY YOU DON'T SEE WAVES OF 1931 01:38:18,080 --> 01:38:19,640 INTRANASAL INFECTION. 1932 01:38:19,640 --> 01:38:23,200 IT'S PROBABLY SOMETHING TO DO 1933 01:38:23,200 --> 01:38:26,960 WITH 10:11 IM AND WHERE IT'S 1934 01:38:26,960 --> 01:38:28,840 EXPRESSING PROTEIN THAT PROBABLY 1935 01:38:28,840 --> 01:38:29,880 HAS TO DO -- 1936 01:38:29,880 --> 01:38:34,560 >> ON THE TTS SPECIFICALLY, CAN 1937 01:38:34,560 --> 01:38:39,440 ONE USE THE OLD DATA THE ADENO 4 1938 01:38:39,440 --> 01:38:43,440 VACCINE DATA IN THE MILITARY TO 1939 01:38:43,440 --> 01:38:44,080 SUPPORT SAFETY CONSIDERATIONS 1940 01:38:44,080 --> 01:38:45,520 BECAUSE -- 1941 01:38:45,520 --> 01:38:48,960 >> IT WILL BE MENTIONED. 1942 01:38:48,960 --> 01:38:49,640 THAT WILL WILL BE AN IMPORTANT 1943 01:38:49,640 --> 01:38:53,000 ISSUE WITH OTHER ADENOS. 1944 01:38:53,000 --> 01:38:56,840 WE KNOW THEY HAVE A PROBLEM WITH 1945 01:38:56,840 --> 01:39:00,960 THROMBOSIS BUT WE SAW THAT IN A 1946 01:39:00,960 --> 01:39:02,040 MILLION VACCINATIONS. 1947 01:39:02,040 --> 01:39:04,840 THE ARGUMENT IS CAN WE LOOK BACK 1948 01:39:04,840 --> 01:39:08,680 AT THE MILLION VACCINATIONS WITH 1949 01:39:08,680 --> 01:39:09,760 ADENO 4 VACCINE AND BECAUSE I 1950 01:39:09,760 --> 01:39:13,600 DON'T KNOW HOW GOOD THE DATA IS 1951 01:39:13,600 --> 01:39:18,040 FOR THESE RECRUITS, THE MILITARY 1952 01:39:18,040 --> 01:39:18,560 RECRUITS. 1953 01:39:18,560 --> 01:39:19,880 >> WITH MORE THAN 10 MILLION 1954 01:39:19,880 --> 01:39:20,960 PEOPLE AND YOU WOULD HAVE 1955 01:39:20,960 --> 01:39:23,080 EXPECTED MORE THAN THAT NOW YOU 1956 01:39:23,080 --> 01:39:25,120 WOULD EXPECT MORE THAN 50 CASES 1957 01:39:25,120 --> 01:39:26,480 OF STRONG THROMBOSIS BUT IT'S 1958 01:39:26,480 --> 01:39:28,160 NOT BEEN REPORTED. 1959 01:39:28,160 --> 01:39:29,760 SOME CRITICS WOULD SAY WELL, 1960 01:39:29,760 --> 01:39:31,360 THEY WEREN'T REALLY LOOKING FOR 1961 01:39:31,360 --> 01:39:32,720 IT SO MAYBE IN THE MILITARY 1962 01:39:32,720 --> 01:39:34,120 YOU'RE DOING ALL KINDS OF CRAZY 1963 01:39:34,120 --> 01:39:36,880 THINGS YOU MAY BE DEHYDRATED AND 1964 01:39:36,880 --> 01:39:39,080 MAYBE YOU HAD THROMBOSIS AND IT 1965 01:39:39,080 --> 01:39:40,200 WAS MISSED. 1966 01:39:40,200 --> 01:39:41,360 WHO KNOWS. 1967 01:39:41,360 --> 01:39:42,600 BUT IT WILL BE RAISED THAT THERE 1968 01:39:42,600 --> 01:39:43,440 ARE THOSE DATA. 1969 01:39:43,440 --> 01:39:44,280 WHETHER THE FDA WILL PAY 1970 01:39:44,280 --> 01:39:45,720 ATTENTION I DON'T KNOW. 1971 01:39:45,720 --> 01:39:47,560 I THINK PROBABLY THEY'LL REQUIRE 1972 01:39:47,560 --> 01:39:50,520 IT TO BE SCREENED FOR OVER A 1973 01:39:50,520 --> 01:39:52,160 LONGER PERIOD OF TIME AND MAYBE 1974 01:39:52,160 --> 01:39:53,480 BY THE TIME THAT COMES AROUND, 1975 01:39:53,480 --> 01:39:54,880 THERE'LL BE MORE INFORMATION 1976 01:39:54,880 --> 01:39:59,520 ABOUT THE ACTUAL MECHANISM OF 1977 01:39:59,520 --> 01:40:02,360 WHAT IS INDUCING PEOPLE 1978 01:40:02,360 --> 01:40:03,320 POSTULATING CONTAMINANT AND A 1979 01:40:03,320 --> 01:40:05,240 VARIETY OF OTHER ISSUES ON WHAT 1980 01:40:05,240 --> 01:40:05,600 INDUCES THAT. 1981 01:40:05,600 --> 01:40:09,120 IT'S JUST GOING TO TAKE TIME. 1982 01:40:09,120 --> 01:40:11,440 >> FINAL QUESTION, SINCE WE HAVE 1983 01:40:11,440 --> 01:40:15,400 YOU HEAR AN OPPORTUNITY TO 1984 01:40:15,400 --> 01:40:16,920 LEARN. 1985 01:40:16,920 --> 01:40:19,240 WHY DO YOU THINK THE MUCOSAL 1986 01:40:19,240 --> 01:40:20,440 ESPECIALLY ADENO VECTOR WHICH IS 1987 01:40:20,440 --> 01:40:24,120 A UNIQUE OPPORTUNITY, WHY DIDN'T 1988 01:40:24,120 --> 01:40:26,600 IT PROGRESS FASTER THAN THE TWO 1989 01:40:26,600 --> 01:40:28,240 YEARS AND A HALF WE ARE NOW? 1990 01:40:28,240 --> 01:40:33,240 >> WELL, THAT'S EASY. 1991 01:40:33,240 --> 01:40:36,720 SO IT WAS MORE IF YOU TALK TO 1992 01:40:36,720 --> 01:40:38,480 PEOPLE THERE'S TWO FACTORS. 1993 01:40:38,480 --> 01:40:41,200 ONE IS A LOGISTIC ONE AND 1994 01:40:41,200 --> 01:40:42,560 ASPECTS GOT BOUGHT BY EMERGENT 1995 01:40:42,560 --> 01:40:45,640 AND IT WAS A CONTRACT 1996 01:40:45,640 --> 01:40:47,720 MANUFACTURER FOR OTHER VACCINES 1997 01:40:47,720 --> 01:40:53,080 PART OF OPERATION WARP SPEED. 1998 01:40:53,080 --> 01:40:55,440 THEY PUT THAT AND WE HAVE A NEW 1999 01:40:55,440 --> 01:40:57,120 CORPORATE PARTNER AND THAT FIXED 2000 01:40:57,120 --> 01:41:01,120 THAT BUT IF YOU TALK TO PETER 2001 01:41:01,120 --> 01:41:02,880 POLASI OR OTHERS PRODUCING 2002 01:41:02,880 --> 01:41:05,800 VACCINES, IF YOU WEREN'T PART OF 2003 01:41:05,800 --> 01:41:07,320 THAT INITIAL SELECTED VACCINE 2004 01:41:07,320 --> 01:41:09,440 YOU GOT SHOVED TO THE SIDE AND I 2005 01:41:09,440 --> 01:41:11,520 WAS HARD TO GET FUNDING AND GET 2006 01:41:11,520 --> 01:41:12,920 A CONTRACT MANUFACTURER EVEN IF 2007 01:41:12,920 --> 01:41:17,320 YOU GOT THE MONEY FROM A FUNDER. 2008 01:41:17,320 --> 01:41:18,520 >> CLINICAL TRIALS? 2009 01:41:18,520 --> 01:41:24,520 >> FOR US IT'S NOT AN ISSUE. 2010 01:41:24,520 --> 01:41:28,840 BUT YES, IT WAS A BRUTAL YEAR TO 2011 01:41:28,840 --> 01:41:29,800 GET THIS TOGETHER. 2012 01:41:29,800 --> 01:41:31,480 >> ONE MORE QUICK QUESTION, I 2013 01:41:31,480 --> 01:41:38,520 DON'T WANT TO RUN OVER TIME. 2014 01:41:38,520 --> 01:41:40,520 ONE POTENTIAL CONCERN HAS BEEN 2015 01:41:40,520 --> 01:41:46,840 RAISED ABOUT INTRANASAL VACCINES 2016 01:41:46,840 --> 01:41:49,360 WAS RAISED RECENTLY BY SOMEONE 2017 01:41:49,360 --> 01:41:54,280 AT YALE WITH AN INTRANASAL SPIKE 2018 01:41:54,280 --> 01:41:55,520 PROTEIN BEING USED WITHOUT 2019 01:41:55,520 --> 01:41:56,760 ADJUVENTS AND HER CONCERN IS 2020 01:41:56,760 --> 01:41:57,960 THINGS CAN YOU PUT THROUGH THE 2021 01:41:57,960 --> 01:42:00,120 NOSE CAN GO THROUGH THE 2022 01:42:00,120 --> 01:42:02,400 OLFACTORY SYSTEM TO THE BRAIN 2023 01:42:02,400 --> 01:42:05,760 AND CAUSE POTENTIAL PROBLEMS. 2024 01:42:05,760 --> 01:42:10,880 I'M WONDERING IF YOU'VE RAN INTO 2025 01:42:10,880 --> 01:42:14,840 THAT CONCERN ADJUVANT VIRUSES IF 2026 01:42:14,840 --> 01:42:18,360 THERE EVIDENCE THEY ARE CAN GO 2027 01:42:18,360 --> 01:42:26,520 TO THE BRAIN AND IF SO WHAT'S 2028 01:42:26,520 --> 01:42:28,640 RESULT. 2029 01:42:28,640 --> 01:42:31,360 >> WAS CAUSE IT GOT TO THE 2030 01:42:31,360 --> 01:42:32,720 OLFACTORY BULK AND THE DATA FOR 2031 01:42:32,720 --> 01:42:33,960 SPREADING TO THE BRAIN WAS 2032 01:42:33,960 --> 01:42:35,520 WEAKER IF YOU LOOK AT THE 2033 01:42:35,520 --> 01:42:36,120 DETECTION SYSTEM USED IN THE 2034 01:42:36,120 --> 01:42:58,840 SLIDES WE WERE ASKED TO DO THE 2035 01:42:58,840 --> 01:43:00,200 SAME STUDY AND THERE WAS NO 2036 01:43:00,200 --> 01:43:09,120 SPREAD TO THE BRAIN. 2037 01:43:09,120 --> 01:43:11,840 WE'VE INTRANASALLY IMMUNIZED 2038 01:43:11,840 --> 01:43:13,080 PEOPLE AT THE CLINICAL CENTER 2039 01:43:13,080 --> 01:43:17,040 AND I'VE BEEN TOLD SIMILAR DATA 2040 01:43:17,040 --> 01:43:18,640 WERE OBTAINED FOR FLUMIST THAT 2041 01:43:18,640 --> 01:43:20,600 THIS IS GETTING TO THE OLFACTORY 2042 01:43:20,600 --> 01:43:23,160 BULB IS SOMETHING THAT HAPPENS 2043 01:43:23,160 --> 01:43:26,120 NOT JUST WITH VIRUS BUT OTHER 2044 01:43:26,120 --> 01:43:26,400 PROTEINS. 2045 01:43:26,400 --> 01:43:27,840 BUT REALLY SPREAD TO THE BRAIN 2046 01:43:27,840 --> 01:43:28,800 IS THE KEY THING. 2047 01:43:28,800 --> 01:43:34,520 SO WE HAVE NO EVIDENCE OF ANY 2048 01:43:34,520 --> 01:43:34,720 ISSUE. 2049 01:43:34,720 --> 01:43:37,280 >> THERE'S OLD LITERATURE THAT 2050 01:43:37,280 --> 01:43:38,560 SAYS IF YOU PUT GOLD 2051 01:43:38,560 --> 01:43:39,960 MICROPARTICLES IN THE NOSE YOU 2052 01:43:39,960 --> 01:43:41,760 CAN SEE THEM IN THE BRAIN BY EM. 2053 01:43:41,760 --> 01:43:43,400 >> I DIDN'T KNOW ABOUT THE 2054 01:43:43,400 --> 01:43:44,280 BRAIN. 2055 01:43:44,280 --> 01:43:46,040 I KNOW THERE ARE SIMILAR DATA 2056 01:43:46,040 --> 01:43:51,080 ABOUT THE OLFACTORY BULB. 2057 01:43:51,080 --> 01:43:52,640 >> THANK YOU. 2058 01:43:52,640 --> 01:43:53,720 FASCINATING. 2059 01:43:53,720 --> 01:43:58,720 THANK YOU SO MUCH FOR THAT. 2060 01:43:58,720 --> 01:44:04,440 AND I MUST SAY THAT I DON'T KNOW 2061 01:44:04,440 --> 01:44:07,400 IF ANYBODY WILL HAVE THE CHANCE 2062 01:44:07,400 --> 01:44:10,200 TO MENTION THAT WITH THE ADENO 2063 01:44:10,200 --> 01:44:11,400 4. 2064 01:44:11,400 --> 01:44:17,760 IT STARTED A LONG TIME AGO WITH 2065 01:44:17,760 --> 01:44:23,160 BOB AND WITH WYATT AND THEN WHEN 2066 01:44:23,160 --> 01:44:25,160 WYATT DECIDED TO ELIMINATE THE 2067 01:44:25,160 --> 01:44:29,120 WHOLE ADENOVIRUS DEPARTMENT, I 2068 01:44:29,120 --> 01:44:31,120 WAS THEN THE CONSULTANT FOR 2069 01:44:31,120 --> 01:44:36,960 WYATT SO I REMEMBER AND MARJORIE 2070 01:44:36,960 --> 01:44:53,920 INSIST 2071 01:44:53,920 --> 01:44:54,800 INSISTED AND THAT SAYS SOMETHING 2072 01:44:54,800 --> 01:45:00,160 ABOUT STAMINA AND GOOD THINGS 2073 01:45:00,160 --> 01:45:06,120 ABOUT NIH AND NCI THAT WE WERE 2074 01:45:06,120 --> 01:45:10,200 ABLE TO WE HAD POPULAR PROJECTS 2075 01:45:10,200 --> 01:45:12,520 AT TIMES. 2076 01:45:12,520 --> 01:45:19,120 ANYWAY, THE NEXT SPEAKER WILL BE 2077 01:45:19,120 --> 01:45:19,640 MICHAEL THOMAS OF HOWARD 2078 01:45:19,640 --> 01:45:22,720 UNIVERSITY. 2079 01:45:22,720 --> 01:45:25,480 I BELIEVE THAT HE LEFT 2080 01:45:25,480 --> 01:45:29,520 MARJORIE'S GROUP RECENTLY AND IS 2081 01:45:29,520 --> 01:45:31,440 NOW AT HOWARD UNIVERSITY AND HIS 2082 01:45:31,440 --> 01:45:33,800 TITLE IS ROELDZ AND FUNCTIONS OF 2083 01:45:33,800 --> 01:45:35,360 THE ADENOVIRUS EARLY GENES IN 2084 01:45:35,360 --> 01:45:35,880 VACCINE-INDUCED IMMUNE 2085 01:45:35,880 --> 01:45:47,400 RESPONSES. 2086 01:45:47,400 --> 01:45:48,560 >> THANK YOU. 2087 01:45:48,560 --> 01:45:50,320 I FEEL HONORED TO SHARE THE 2088 01:45:50,320 --> 01:45:51,280 PODIUM WITH YOU GUYS. 2089 01:45:51,280 --> 01:45:54,760 I TELL SOME PEOPLE THE STORY 2090 01:45:54,760 --> 01:45:57,560 HERE THEY DON'T SEE A WOW FACTOR 2091 01:45:57,560 --> 01:46:02,280 IN IT BUT IN 2007, PART OF MY 2092 01:46:02,280 --> 01:46:08,920 F31 WHY WE HAD A TRAVEL AWARD SO 2093 01:46:08,920 --> 01:46:11,400 I WENT TO CANADA WHERE THEY WERE 2094 01:46:11,400 --> 01:46:13,920 HAVING A HIV MEETING AND ONE OF 2095 01:46:13,920 --> 01:46:16,760 THE SPEAKERS THERE WAS 2096 01:46:16,760 --> 01:46:21,320 DR. MARJORIE GUROFF AND TALKING 2097 01:46:21,320 --> 01:46:23,360 ABOUT REPLICATING THE ADENOVIRUS 2098 01:46:23,360 --> 01:46:26,520 AND I WAS DOING WORK WITH 2099 01:46:26,520 --> 01:46:27,280 REPLICATING ADENOVIRUS. 2100 01:46:27,280 --> 01:46:32,720 I WENT TO HER AFTER HER TALK AND 2101 01:46:32,720 --> 01:46:35,960 I WENT TO HER AFTER THE TALK AND 2102 01:46:35,960 --> 01:46:38,520 I TOLD HER I WAS ABOUT TO 2103 01:46:38,520 --> 01:46:41,040 GRADUATE AND WAS INTERESTED IN A 2104 01:46:41,040 --> 01:46:42,160 POST-DOC POSITION IN HER LAB. 2105 01:46:42,160 --> 01:46:43,480 AT THAT POINT SHE DIDN'T HAVE 2106 01:46:43,480 --> 01:46:45,520 ANY POSITIONS BUT TOLD ME KEEP 2107 01:46:45,520 --> 01:46:48,200 IN CONTACT AND IF SOMETHING 2108 01:46:48,200 --> 01:46:51,920 COMES UP AND WE'LL SEE AND 2109 01:46:51,920 --> 01:46:55,520 SOMETHING CAME UP BUT SHE 2110 01:46:55,520 --> 01:47:17,320 DOESN'T REMEMBER THAT. 2111 01:47:17,320 --> 01:47:18,360 AND WE LOOKED TO BETTER 2112 01:47:18,360 --> 01:47:20,480 UNDERSTAND THE ROLE AND FUNCTION 2113 01:47:20,480 --> 01:47:27,480 OF THE ADENOVIRUS EARLY GENES. 2114 01:47:27,480 --> 01:47:30,640 OF COURSE YOU KNOW THAT 2115 01:47:30,640 --> 01:47:31,480 ADENOVIRUS HAS BEEN DEVELOPED 2116 01:47:31,480 --> 01:47:35,480 FOR A WIDE VARIETY OF DIFFERENT 2117 01:47:35,480 --> 01:47:40,960 INFECTIOUS DISEASES AND WE'RE 2118 01:47:40,960 --> 01:47:42,360 FOCUSSING ON HIV. 2119 01:47:42,360 --> 01:47:48,280 AND MOST RECENTLY OUT OF THE 2120 01:47:48,280 --> 01:47:54,720 AIDS VACCINES FOR COVID THAT YOU 2121 01:47:54,720 --> 01:47:59,120 FIND A ROLE WORLDWIDE OR IN THE 2122 01:47:59,120 --> 01:48:01,040 CLINICAL DEVELOPMENT AIDS, SIX 2123 01:48:01,040 --> 01:48:07,120 ARE BASED ON ADENOVIRUS. 2124 01:48:07,120 --> 01:48:09,200 SO OUR GOAL IS TO DEVELOP A 2125 01:48:09,200 --> 01:48:11,160 BETTER UNDERSTANDING OF THE 2126 01:48:11,160 --> 01:48:14,120 VIRAL AND CELLULAR FACTORS THAT 2127 01:48:14,120 --> 01:48:16,520 INFLUENCE THE IMMUNE RESPONSES 2128 01:48:16,520 --> 01:48:19,400 TO IMMUNOGENS EXPRESSED WITHIN 2129 01:48:19,400 --> 01:48:20,720 THE ADENOVIRUS. 2130 01:48:20,720 --> 01:48:26,080 SO ADENOVIRUS IS A DNA 2131 01:48:26,080 --> 01:48:27,480 CONTAINING VIRUS THAT WAS 2132 01:48:27,480 --> 01:48:33,840 DISCOVERED IN THE 1950s AND IN 2133 01:48:33,840 --> 01:48:35,480 HEALTHY INDIVIDUALS YOU GET MILD 2134 01:48:35,480 --> 01:48:37,920 UPPER RESPIRATORY TRACT 2135 01:48:37,920 --> 01:48:38,520 DISEASES. 2136 01:48:38,520 --> 01:48:42,000 BUT ADENOVIRUS CAN KILL AND WE 2137 01:48:42,000 --> 01:48:47,040 HAVE SEEN EVIDENCE OF THAT NOT 2138 01:48:47,040 --> 01:48:53,120 TOO LONG AGO IN UNIVERSITY OF 2139 01:48:53,120 --> 01:48:53,360 MARYLAND. 2140 01:48:53,360 --> 01:48:59,440 IT INFECTS CELLS BY BINDING TO 2141 01:48:59,440 --> 01:49:06,040 THE CAR RECEPTOR AND IT'S 2142 01:49:06,040 --> 01:49:08,520 INFECTED AND TRAVELED TO THE 2143 01:49:08,520 --> 01:49:10,560 LATE ENDOSOME WHERE THE VIRAL 2144 01:49:10,560 --> 01:49:13,680 PARTICLE IS DESTABILIZED. 2145 01:49:13,680 --> 01:49:15,040 THE PARTICLE TRAVELS TO THE 2146 01:49:15,040 --> 01:49:15,280 NUCLEUS. 2147 01:49:15,280 --> 01:49:20,080 WE'VE KNOWN FOR A LONG TIME THAT 2148 01:49:20,080 --> 01:49:24,800 ADENOVIRUS STRUCTURED GENES THE 2149 01:49:24,800 --> 01:49:38,520 LATE AND STRUCTURAL GENES FIBER 2150 01:49:38,520 --> 01:49:43,160 AND THOSE PROTEINS ACT LIKE THIS 2151 01:49:43,160 --> 01:49:45,880 AND EVERYONE USING ADENOVIRUS 2152 01:49:45,880 --> 01:49:47,320 FOR VACCINE STUDIES ARE 2153 01:49:47,320 --> 01:49:54,840 UTILIZING THIS THE ADENOVIRUS 2154 01:49:54,840 --> 01:50:03,760 STRUCTURAL PROTEINS WILL AS AN 2155 01:50:03,760 --> 01:50:18,440 ADJUVANT AND WE THEY'D EARLY 2156 01:50:18,440 --> 01:50:19,840 GENE E1A. 2157 01:50:19,840 --> 01:50:22,480 SO MANY VIRUSES YOU SEE IN THE 2158 01:50:22,480 --> 01:50:23,560 CLINIC NOW DON'T HAVE THIS GENE 2159 01:50:23,560 --> 01:50:31,320 AND I'LL TALK TO YOU ABOUT THAT. 2160 01:50:31,320 --> 01:50:33,280 ANYHOW THE E1A IS IMPORTANT 2161 01:50:33,280 --> 01:50:39,480 BECAUSE IT TRANSACTS ALL THE 2162 01:50:39,480 --> 01:50:45,520 OTHER ADENOVIRUS GENES AND THEY 2163 01:50:45,520 --> 01:50:49,440 ARE EXPRESSED BEFORE VIRAL DNA 2164 01:50:49,440 --> 01:50:52,600 SYNTHESIS AND THOSE LABELLED L 2165 01:50:52,600 --> 01:51:02,520 ARE EXPRESSED AFTER ADENOVIRUS 2166 01:51:02,520 --> 01:51:12,760 GENO SYNTHESIS. 2167 01:51:12,760 --> 01:51:14,520 AND THESE OTHER GENES IN 2168 01:51:14,520 --> 01:51:15,520 ADENOVIRUS AND WE HAVE MORE 2169 01:51:15,520 --> 01:51:17,120 WE'LL SHOW YOU LATER. 2170 01:51:17,120 --> 01:51:19,160 WHAT ABOUT THOSE GENES AND DO 2171 01:51:19,160 --> 01:51:20,120 THEY CONTRIBUTE TO THE VACCINE 2172 01:51:20,120 --> 01:51:29,120 INDUCED IMMUNE RESPONSES WE SEE? 2173 01:51:29,120 --> 01:51:34,240 PEOPLE ASKED THE QUESTION BEFORE 2174 01:51:34,240 --> 01:51:50,000 US AND WE WANTED TO LOOK AT IT 2175 01:51:50,000 --> 01:51:50,720 DIFFERENT 2176 01:51:50,720 --> 01:51:52,080 DIFFERENTLY AND HOW DO THEY 2177 01:51:52,080 --> 01:51:53,320 FUNCTION IN IMMUNE RESPONSES? 2178 01:51:53,320 --> 01:51:58,720 ONE OF THE THINGS WE NOTICED WAS 2179 01:51:58,720 --> 01:52:25,720 THAT AND HERE WHAT WE'RE DOING 2180 01:52:25,720 --> 01:52:31,520 IS USING THIS IODINE FOR DNA AND 2181 01:52:31,520 --> 01:52:48,520 WE'RE LOOKING AT THE DNA AND 2182 01:52:48,520 --> 01:52:51,520 THERE ARE CELLS IN TISSUE 2183 01:52:51,520 --> 01:52:56,560 CULTURE AND OTHERS GOING THROUGH 2184 01:52:56,560 --> 01:53:04,000 THE CELL CYCLE AND IN CANCER 2185 01:53:04,000 --> 01:53:06,640 CELLS YOU CAN FIND DNA CONTENT 2186 01:53:06,640 --> 01:53:08,560 BETTER THAN D2M. 2187 01:53:08,560 --> 01:53:14,880 SO HERE WE INFECTED BRAIN CANCER 2188 01:53:14,880 --> 01:53:17,560 CELLS AND 48 HOURS AFTER WE ARE 2189 01:53:17,560 --> 01:53:19,720 LOOKING AT THE DNA CELL CYCLE 2190 01:53:19,720 --> 01:53:22,360 PROFILE WHERE WE QUANTIFY THEM 2191 01:53:22,360 --> 01:53:24,040 AND WE CAN SEE THAT THERE'S 2192 01:53:24,040 --> 01:53:26,200 ENHANCED OR INCREASED LEVEL OF 2193 01:53:26,200 --> 01:53:30,000 CELLS WITH DNA CONTENT GREATER 2194 01:53:30,000 --> 01:53:31,520 THAN D2M. 2195 01:53:31,520 --> 01:53:34,800 THIS IS 48 HOURS. 2196 01:53:34,800 --> 01:53:36,920 120 HOURS YOU SEE THE INCREASE 2197 01:53:36,920 --> 01:53:39,280 AND WE OVERLAID TO SLOW YOU IT 2198 01:53:39,280 --> 01:53:46,000 BETTER. 2199 01:53:46,000 --> 01:53:47,680 SO TO UNDERSTAND THIS THING I'VE 2200 01:53:47,680 --> 01:53:50,840 BEEN TALKING ABOUT THIS DNA 2201 01:53:50,840 --> 01:53:52,920 GREATER THAN 4N AND HOW IT 2202 01:53:52,920 --> 01:53:54,720 BECOMES RELEVANT, SO THIS IS 2203 01:53:54,720 --> 01:53:57,040 YOUR NORMAL CELL CYCLE. 2204 01:53:57,040 --> 01:54:03,000 SO CELLS GO FROM G1 TO S, G2 TO 2205 01:54:03,000 --> 01:54:05,200 M AND DAUGHTER CELLS AND GO BACK 2206 01:54:05,200 --> 01:54:06,160 TO G1. 2207 01:54:06,160 --> 01:54:09,400 BUT THERE'S THIS ALTERNATE CELL 2208 01:54:09,400 --> 01:54:12,040 CYCLE IN WHICH CELLS GO FROM G1 2209 01:54:12,040 --> 01:54:18,120 TO S, G2, THEY SKIP M ALTOGETHER 2210 01:54:18,120 --> 01:54:20,520 AND REENTER THE CELL CYCLE. 2211 01:54:20,520 --> 01:54:25,480 THE PROBLEM WITH THIS IS THAT IT 2212 01:54:25,480 --> 01:54:27,440 IS PART THIS VICIOUS CYCLE WHERE 2213 01:54:27,440 --> 01:54:30,520 YOU HAVE DNA DAMAGE, DNA DAMAGE 2214 01:54:30,520 --> 01:54:34,000 SEEMS TO LEAD TO THIS THING I'M 2215 01:54:34,000 --> 01:54:38,560 TELLING YOU ABOUT, THE DNA 2216 01:54:38,560 --> 01:54:41,080 GREATER THAN 4N AND SEEMS TO 2217 01:54:41,080 --> 01:54:43,320 MAKE CELLS MORE TOLERANT TO DNA 2218 01:54:43,320 --> 01:54:46,720 DAMAGE AND THAT SEEMED TO LEAD 2219 01:54:46,720 --> 01:54:50,440 TO GENOME INSTABILITY AND MORE 2220 01:54:50,440 --> 01:54:52,280 GENOME INSTABILITY ENHANCES DNA 2221 01:54:52,280 --> 01:54:55,760 DAMAGE WHICH ENHANCES THIS, 2222 01:54:55,760 --> 01:55:02,520 ENHANCES THAT AND GETS CONFUSED 2223 01:55:02,520 --> 01:55:05,520 LIKE THAT. 2224 01:55:05,520 --> 01:55:10,720 SO DNA DAMAGE RESPONSE IS A VIEW 2225 01:55:10,720 --> 01:55:14,280 BUT YOU CAN HAVE DAMAGE FROM 2226 01:55:14,280 --> 01:55:17,280 DIFFERENT CHEMICAL, DIFFERENT 2227 01:55:17,280 --> 01:55:17,760 AGENTS. 2228 01:55:17,760 --> 01:55:20,440 SO IN RESPONSE TO DOUBLE STRAND 2229 01:55:20,440 --> 01:55:25,720 BREAKS YOU HAVE THE MAJOR KINASE 2230 01:55:25,720 --> 01:55:29,560 ATM RECRUITED TO DOUBLE STRAND 2231 01:55:29,560 --> 01:55:32,560 BREAK AND WHILE THERE IT 2232 01:55:32,560 --> 01:55:34,920 PHOSPHORYLATED DOWN STREAM 2233 01:55:34,920 --> 01:55:37,240 MEDIATORS AND EFFECTERS THAT CAN 2234 01:55:37,240 --> 01:55:39,720 STOP THE CELL IN THE CELL CYCLE 2235 01:55:39,720 --> 01:55:41,760 AND IF IT WAS SINGLE STRAND 2236 01:55:41,760 --> 01:55:43,520 BREAK THAN ATR WOULD DO THE SAME 2237 01:55:43,520 --> 01:55:44,600 THING AND STOP THE CELL IN THE 2238 01:55:44,600 --> 01:55:48,760 CELL CYCLE. 2239 01:55:48,760 --> 01:55:51,640 SO WE'VE WANTED TO KNOW THEN 2240 01:55:51,640 --> 01:55:54,920 WHETHER THIS WAS POSSIBLY AN 2241 01:55:54,920 --> 01:55:56,520 ADENOVIRUS INFECTED CELLS 2242 01:55:56,520 --> 01:55:59,400 BECAUSE WE SAW A LOT OF EVIDENCE 2243 01:55:59,400 --> 01:56:02,080 THAT SUGGESTS THE DNA DAMAGED 2244 01:56:02,080 --> 01:56:03,520 AGENT OR DAMAGE ITSELF CAN 2245 01:56:03,520 --> 01:56:09,280 STIMULATE THE IMMUNE RESPONSE. 2246 01:56:09,280 --> 01:56:11,400 SO ONE OF THE FIRST THINGS WE 2247 01:56:11,400 --> 01:56:13,760 DID WAS INFECT CELLS WITH WILD 2248 01:56:13,760 --> 01:56:16,480 TYPE ADENOVIRUS AND THE VIRUS IN 2249 01:56:16,480 --> 01:56:20,120 WHICH WE DELETED THE E1B55K GENE 2250 01:56:20,120 --> 01:56:24,800 THE GENE ITSELF IS PROBABLY 2251 01:56:24,800 --> 01:56:26,480 IMPORTANT AND THE IMPORTANCE OF 2252 01:56:26,480 --> 01:56:29,000 THIS VIRUS HERE IS IT'S BEEN 2253 01:56:29,000 --> 01:56:30,240 USED IN CLINICAL TRIALS IN THE 2254 01:56:30,240 --> 01:56:34,280 U.S. AND IS ACTUALLY BEING USED 2255 01:56:34,280 --> 01:56:38,560 TO TREAT HEAD AND NECK CANCER IN 2256 01:56:38,560 --> 01:56:40,520 CHINA. 2257 01:56:40,520 --> 01:56:43,520 YOU CAN SEE WHEN WE INFECT CELLS 2258 01:56:43,520 --> 01:56:49,520 WITH THE WILD TYPE VIRUS THIS 2259 01:56:49,520 --> 01:56:52,440 STAYS IN THE NUCLEUS AND THIS IS 2260 01:56:52,440 --> 01:56:53,920 THE SAME PHOSPHORYLATION YOU'D 2261 01:56:53,920 --> 01:56:57,800 FIND IN RESPONSE TO DNA DAMAGE 2262 01:56:57,800 --> 01:57:00,800 AND THE SAME YOU FIND ON ATM IN 2263 01:57:00,800 --> 01:57:02,240 RESPONSE TO DNA DAMAGE AND YOU 2264 01:57:02,240 --> 01:57:08,560 CAN SEE HERE THAT THE WILD TYPE 2265 01:57:08,560 --> 01:57:10,120 ADENOVIRUS INDUCED HIGHER LEVELS 2266 01:57:10,120 --> 01:57:14,560 OF THE PHOSPHORYLATED PROTEIN OF 2267 01:57:14,560 --> 01:57:17,760 THE DNA PHOSPHORYLATED DAMAGED 2268 01:57:17,760 --> 01:57:20,800 PROTEIN AND HERE I MEASURED AND 2269 01:57:20,800 --> 01:57:23,480 QUANTIFIED BY FLOW. 2270 01:57:23,480 --> 01:57:24,840 THESE PROTEINS HERE THIS IS JUST 2271 01:57:24,840 --> 01:57:28,040 SHOWING YOU THE RESPONSE TO DNA 2272 01:57:28,040 --> 01:57:35,480 DAMAGE, THE MRN COMPLEX IS 2273 01:57:35,480 --> 01:57:37,600 RECRUITED TO THE BREAK AND THERE 2274 01:57:37,600 --> 01:57:42,960 THEY RECRUIT ATM, ATM 2275 01:57:42,960 --> 01:57:47,480 PHOSPHORYLATED H2X AND ATM CAN 2276 01:57:47,480 --> 01:57:50,480 ALSO PHOSPHORYLATE DOWN STREAM 2277 01:57:50,480 --> 01:57:52,160 MEDIATORS THAT CAN STOP THE CELL 2278 01:57:52,160 --> 01:57:56,280 THAT CAN INDUCE DEATH OR THAT 2279 01:57:56,280 --> 01:57:59,440 CAN CAUSE REPAIR FOR WHATEVER 2280 01:57:59,440 --> 01:58:00,800 THE DAMAGE IS. 2281 01:58:00,800 --> 01:58:04,000 SO THESE TWO VIRUSES THEN WE 2282 01:58:04,000 --> 01:58:09,320 KNOW THAT IT INDUCES DNA DAMAGE 2283 01:58:09,320 --> 01:58:14,200 SIGNALS AND COMPARED THEM AS FAR 2284 01:58:14,200 --> 01:58:18,120 AS THEIR ABILITY TO WHEN THEY 2285 01:58:18,120 --> 01:58:20,360 INFECT CELLS TO INDUCE INNATE 2286 01:58:20,360 --> 01:58:21,960 IMMUNE RESPONSE AND HERE WHAT 2287 01:58:21,960 --> 01:58:26,480 WE'RE DOING IS MEASURING 2288 01:58:26,480 --> 01:58:29,920 CYTOKINES PRODUCED IN A54 THE 2289 01:58:29,920 --> 01:58:33,040 CELLS AND IN HELA CELLS. 2290 01:58:33,040 --> 01:58:36,000 IN EACH CASE THE VIRUS WHERE WE 2291 01:58:36,000 --> 01:58:39,160 DELETE THE E1G GENE PRODUCED 2292 01:58:39,160 --> 01:58:42,920 MORE CYTOKINES OR IT ALLOWED 2293 01:58:42,920 --> 01:58:46,040 CELLS TO PRODUCE MORE CYTOKINES 2294 01:58:46,040 --> 01:58:48,680 THAN THE WILD TYPE VIRUS. 2295 01:58:48,680 --> 01:59:01,360 NOW, WITH THE HELA CELL AND THE 2296 01:59:01,360 --> 01:59:06,720 GENES ARE DIFFERENT AND ALLOWED 2297 01:59:06,720 --> 01:59:12,120 THEM DIFFERENT AND THEY DON'T 2298 01:59:12,120 --> 01:59:14,800 ALL HAVE THE SAME GENES OR THE 2299 01:59:14,800 --> 01:59:16,360 SAME SPLICED VARIANTS OF THE 2300 01:59:16,360 --> 01:59:19,400 GENES AND THE TUMOR CELLS ARE 2301 01:59:19,400 --> 01:59:21,360 WHAT CAUSED THEM TO BECOME TUMOR 2302 01:59:21,360 --> 01:59:23,480 CELLS, THAT ITSELF IS DIFFERENT 2303 01:59:23,480 --> 01:59:26,480 BECAUSE OF THAT YOU CAN HAVE 2304 01:59:26,480 --> 01:59:28,280 DIFFERENT CYTOKINES PRODUCED IN 2305 01:59:28,280 --> 01:59:30,120 THE DIFFERENT CELLS. 2306 01:59:30,120 --> 01:59:35,480 ANYHOW, WE LOOKED AT A DIFFERENT 2307 01:59:35,480 --> 01:59:35,880 FACTOR. 2308 01:59:35,880 --> 01:59:44,720 THIS IS LOOKING AT AND THE 2309 01:59:44,720 --> 01:59:47,480 LIGAND THIS IS AN ACTIVATING 2310 01:59:47,480 --> 01:59:56,600 MARKER YOU FIND IN NKT CELLS AND 2311 01:59:56,600 --> 02:00:02,320 GANA DELTA CELLS AND TUMOR 2312 02:00:02,320 --> 02:00:03,920 CELLS TEND TO HAVE HIGHER LEVELS 2313 02:00:03,920 --> 02:00:06,120 AND YOU SEE THIS BLACK LINE. 2314 02:00:06,120 --> 02:00:07,440 THIS IS THE LEVELS ON THE HELA 2315 02:00:07,440 --> 02:00:11,440 CELL. 2316 02:00:11,440 --> 02:00:12,640 I INFECTED THEM WITH THE WILD 2317 02:00:12,640 --> 02:00:13,640 TYPE VIRUS WITH THE DELETION IN 2318 02:00:13,640 --> 02:00:16,160 THE E1B AND YOU CAN THEN LOOK 2319 02:00:16,160 --> 02:00:22,480 OVER TIME AND YOU CAN SEE OVER 2320 02:00:22,480 --> 02:00:31,160 TIME THE LEVELS OF THE INCREASE 2321 02:00:31,160 --> 02:00:34,280 WAS IN THE DELETED FILES. 2322 02:00:34,280 --> 02:00:37,080 THIS AND WHAT I SHOWED YOU 2323 02:00:37,080 --> 02:00:38,320 BEFORE HAVE BEEN INFORMING US 2324 02:00:38,320 --> 02:00:42,800 ABOUT E1B55K AND THE POTENTIAL 2325 02:00:42,800 --> 02:00:57,760 ROLE IN INFECTED CELLS. 2326 02:00:57,760 --> 02:01:00,280 WE WANTED TO EVALUATE THE IDEA 2327 02:01:00,280 --> 02:01:02,400 THAT VIRUSES ARE ABLE TO INDUCE 2328 02:01:02,400 --> 02:01:05,400 THIS GREATER THAN 4N ARE MORE 2329 02:01:05,400 --> 02:01:06,800 IMMUNOGENIC THAN THE VIRUSES 2330 02:01:06,800 --> 02:01:09,320 THAT DON'T PRODUCE AS MUCH. 2331 02:01:09,320 --> 02:01:11,680 THAT WAS KIND OF REALLY 2332 02:01:11,680 --> 02:01:13,560 SIMPLISTIC AND NOW THAT WE THINK 2333 02:01:13,560 --> 02:01:16,800 ABOUT IT, IT'S KIND OF LIKE 2334 02:01:16,800 --> 02:01:20,240 SILLY BUT IT WAS SOMETHING TO GO 2335 02:01:20,240 --> 02:01:24,080 ON BECAUSE WE COULD MEASURE IT 2336 02:01:24,080 --> 02:01:26,920 AND THEN WE COULD SEE WHETHER IT 2337 02:01:26,920 --> 02:01:27,240 CORRELATES. 2338 02:01:27,240 --> 02:01:30,720 SO WHAT WE DID IS FIRST MADE 2339 02:01:30,720 --> 02:01:31,120 VIRUSES. 2340 02:01:31,120 --> 02:01:32,640 THIS IS SHOWING AGAIN THE 2341 02:01:32,640 --> 02:01:38,440 ADENOVIRUS GENOME AND HERE'S 2342 02:01:38,440 --> 02:01:40,520 THERE'S MORE BUT THESE ARE THE 2343 02:01:40,520 --> 02:01:43,320 TWO MAIN ONES AND HERE IN THE E4 2344 02:01:43,320 --> 02:01:47,120 REGION THERE'S SEVERAL OTHER 2345 02:01:47,120 --> 02:01:47,400 PRODUCTS. 2346 02:01:47,400 --> 02:01:49,760 SO WE MADE VIRUSES IN WHICH WE 2347 02:01:49,760 --> 02:01:56,080 DELETED THE E1B GENE AND WE 2348 02:01:56,080 --> 02:01:58,120 EXCHANGED THE E3. 2349 02:01:58,120 --> 02:02:02,400 AND THE E3 AND ADENOVIRUS IS NOT 2350 02:02:02,400 --> 02:02:03,760 NECESSARY FOR OPTIMAL VIRUS 2351 02:02:03,760 --> 02:02:04,080 REPLICATION. 2352 02:02:04,080 --> 02:02:08,080 IN FACT, WE DON'T REALLY WANT TO 2353 02:02:08,080 --> 02:02:14,720 KNOW BECAUSE WHAT IT DOES IS IT 2354 02:02:14,720 --> 02:02:18,400 DOWN REGULATES THE MOLECULES. 2355 02:02:18,400 --> 02:02:23,920 WE CAN'T HAVE THAT SO WE GOT RID 2356 02:02:23,920 --> 02:02:24,920 OF THIS. 2357 02:02:24,920 --> 02:02:28,440 AND THIS YOU'VE HEARD OF BEFORE. 2358 02:02:28,440 --> 02:02:32,680 THIS IS JUST FULL AND SINGLE 2359 02:02:32,680 --> 02:02:36,120 CHAIN HIV LINKED TO THE D1, D2 2360 02:02:36,120 --> 02:02:38,480 DOMAIN OF CD4. 2361 02:02:38,480 --> 02:02:41,120 THIS IS FIRST DESCRIBED EARLIER 2362 02:02:41,120 --> 02:02:43,480 AND WAS SHOWN THAT IT CORRELATED 2363 02:02:43,480 --> 02:02:46,400 WITH PROTECTION AND WE SHOWED 2364 02:02:46,400 --> 02:02:51,680 THAT WHEN WE MADE A VACCINE IT 2365 02:02:51,680 --> 02:02:58,000 CAN GENERATE HIGH NEUTRALIZING 2366 02:02:58,000 --> 02:03:00,000 ANTIBODY AND BOOST AGAINST THE 2367 02:03:00,000 --> 02:03:00,320 PEPTIDES. 2368 02:03:00,320 --> 02:03:03,480 SO WE MADE THE VIRUS, DELETED 2369 02:03:03,480 --> 02:03:07,040 E1B AND VERIFIED THAT IT 2370 02:03:07,040 --> 02:03:08,120 PRODUCED A TRANS GENE. 2371 02:03:08,120 --> 02:03:14,640 AND THIS IS WHAT IS MADE IN THE 2372 02:03:14,640 --> 02:03:17,480 CELL SO WE JUST LOOKED IF THE 2373 02:03:17,480 --> 02:03:18,960 PROTEIN IS IN THERE YES OR NO 2374 02:03:18,960 --> 02:03:19,920 AND THERE'S NOT A LOT IN THE 2375 02:03:19,920 --> 02:03:24,720 CELL BUT WHEN YOU LOOK AT IN THE 2376 02:03:24,720 --> 02:03:26,120 MEDIUM THIS MAJORITY OF THE 2377 02:03:26,120 --> 02:03:29,240 PROTEIN IS SECRETED. 2378 02:03:29,240 --> 02:03:31,320 AND RELATIVE TO THE VIRUS WE 2379 02:03:31,320 --> 02:03:36,120 DELETED THE E1B, THEN THIS WILD 2380 02:03:36,120 --> 02:03:38,640 TYPE VIRUS PRODUCED MORE OF THE 2381 02:03:38,640 --> 02:03:40,040 TRANS GENE. 2382 02:03:40,040 --> 02:03:42,280 SO WE JUST GOING IN THINK WOW, 2383 02:03:42,280 --> 02:03:45,240 IF THE TRANS GENE IS ANYTHING TO 2384 02:03:45,240 --> 02:03:54,120 SAY THAT THIS VARIOUS IS AT A 2385 02:03:54,120 --> 02:03:54,480 DISADVANTAGE. 2386 02:03:54,480 --> 02:03:55,000 KNOWLEDGES WE DECIDED TO 2387 02:03:55,000 --> 02:04:02,960 IMMUNIZE MICE. 2388 02:04:02,960 --> 02:04:06,800 AND WE COLLECTED BLOOD AND I'M 2389 02:04:06,800 --> 02:04:10,320 SHOWING YOU ONE FOR THE SAKE OF 2390 02:04:10,320 --> 02:04:10,520 TIME. 2391 02:04:10,520 --> 02:04:13,320 WE LOOKED AT LEVELS OF BINDING 2392 02:04:13,320 --> 02:04:14,560 ANTIBODIES AGAINST THE VIRUS, 2393 02:04:14,560 --> 02:04:18,240 AGAINST THE ADENOVIRUS. 2394 02:04:18,240 --> 02:04:20,440 THE LEVELS OF ANTIBODY MADE THE 2395 02:04:20,440 --> 02:04:22,240 SAME AND DIDN'T SEE ANY 2396 02:04:22,240 --> 02:04:23,360 DIFFERENCE AS FAR AS AGAINST THE 2397 02:04:23,360 --> 02:04:26,640 TRANS GENE IN EITHER OF THE 2398 02:04:26,640 --> 02:04:38,640 FORMS. 2399 02:04:38,640 --> 02:04:41,360 AND THE VIRUSES THAT MAKE 2400 02:04:41,360 --> 02:04:45,520 GREATER THAN 4N SHOULD BE MORE 2401 02:04:45,520 --> 02:04:47,400 IMMUNOGENIC BUT FOR THE I WAS 2402 02:04:47,400 --> 02:04:49,280 EXCITED BECAUSE BECAUSE ONE OF 2403 02:04:49,280 --> 02:04:51,480 THE FIRST THINGS WE DID WAS 2404 02:04:51,480 --> 02:04:53,920 SHOWED THIS VIRUS THAT IS IN THE 2405 02:04:53,920 --> 02:04:55,600 CLINIC BEING USED TO TREAT 2406 02:04:55,600 --> 02:04:58,840 CANCER IN CHINA, MADE IT TO 2407 02:04:58,840 --> 02:05:00,360 PHASE 3 CLINICAL TRIALS IN THE 2408 02:05:00,360 --> 02:05:02,280 U.S., I SHOWED THIS VIRUS CAN 2409 02:05:02,280 --> 02:05:03,400 INDUCE IMMUNE RESPONSES SIMILAR 2410 02:05:03,400 --> 02:05:06,480 TO VIRUSES BEING USED FOR 2411 02:05:06,480 --> 02:05:07,120 PRECLINICAL TRIALS SO I WAS 2412 02:05:07,120 --> 02:05:08,520 EXCITED ABOUT THAT. 2413 02:05:08,520 --> 02:05:10,920 I WAS ALSO EXCITED ABOUT THIS 2414 02:05:10,920 --> 02:05:12,640 BECAUSE I KNOW THIS VIRUS AND 2415 02:05:12,640 --> 02:05:14,600 NOW I KNOW HOW I CAN IMPROVE ON 2416 02:05:14,600 --> 02:05:19,360 THIS. 2417 02:05:19,360 --> 02:05:25,880 THE ADENOVIRUS E1B GENE PRODUCT 2418 02:05:25,880 --> 02:05:28,760 CONTROLS LEVELS OF SURFACE OF 2419 02:05:28,760 --> 02:05:31,440 INFECTED CELLS AND PROTEINS AND 2420 02:05:31,440 --> 02:05:34,720 TRANS GENE AND IT CONTROLS 2421 02:05:34,720 --> 02:05:37,760 LEVELS AND TYPES OF CYTOKINES. 2422 02:05:37,760 --> 02:05:40,680 SO THAT'S THE E1B. 2423 02:05:40,680 --> 02:05:41,320 THERE'S STILL A LOT OF GENES 2424 02:05:41,320 --> 02:05:45,160 THAT ARE ADENOVIRUS. 2425 02:05:45,160 --> 02:05:49,840 SO WE'VE FOCUSSED ON THE E4 2426 02:05:49,840 --> 02:05:50,800 GENES AND WE DID THIS BECAUSE IF 2427 02:05:50,800 --> 02:05:53,720 YOU LOOK HERE AT THE ADENOVIRUS, 2428 02:05:53,720 --> 02:05:57,240 IT CAN ONLY CARRY THIS WILD TYPE 2429 02:05:57,240 --> 02:06:02,000 AND CARRY A TRANS GENE ABOUT 2430 02:06:02,000 --> 02:06:02,240 2.5KB. 2431 02:06:02,240 --> 02:06:06,520 SO YOU COULDN'T REALLY PUT IN A 2432 02:06:06,520 --> 02:06:08,280 HUGE CANCER GENE AND YOU 2433 02:06:08,280 --> 02:06:09,720 COULDN'T INVERT MULTIPLE GENES 2434 02:06:09,720 --> 02:06:14,080 IN THERE BUT IF WE DELETED THE 2435 02:06:14,080 --> 02:06:17,840 E1B WE GET ABOUT 1,000 BASE 2436 02:06:17,840 --> 02:06:22,520 PAIRS OF SPACE AND PUT IN 1 TO 4 2437 02:06:22,520 --> 02:06:23,800 AND WE GET ANOTHER 1,000 BASE 2438 02:06:23,800 --> 02:06:26,920 AND CARRY CAPACITY. 2439 02:06:26,920 --> 02:06:30,400 NOT ONLY THAT, WE LEARNED THAT 2440 02:06:30,400 --> 02:06:32,680 THESE GENES, SOME OF THESE GENE 2441 02:06:32,680 --> 02:06:35,240 PRODUCTS, WELL OTHERS HAD SHOWN 2442 02:06:35,240 --> 02:06:52,080 THAT THESE PRODUCTS INHIBIT AND 2443 02:06:52,080 --> 02:06:53,960 HERE WE'RE SHOWING WE 2444 02:06:53,960 --> 02:06:56,200 CHARACTERIZED THE VIRUS JUST AS 2445 02:06:56,200 --> 02:06:58,960 FAR AS HOW MUCH PROGENY IS MADE 2446 02:06:58,960 --> 02:07:03,960 AND THIS IS LOOKING AT THE DNA 2447 02:07:03,960 --> 02:07:05,160 OF VIRUSES. 2448 02:07:05,160 --> 02:07:07,440 THIS IS LOOKING AT THE LATE 2449 02:07:07,440 --> 02:07:09,280 VIRAL PROTEINS BY WESTERN BLOCK 2450 02:07:09,280 --> 02:07:10,200 AND THIS IS THE TRANS GENE. 2451 02:07:10,200 --> 02:07:13,560 THIS IS LOOKING AT A TRANS GENE 2452 02:07:13,560 --> 02:07:15,440 PRODUCED BY WESTERN BLOCK. 2453 02:07:15,440 --> 02:07:20,280 SO HERE THIS VIRUS WE CREATED BY 2454 02:07:20,280 --> 02:07:29,200 DELETING E1B AND E4 HAVE MUCH 2455 02:07:29,200 --> 02:07:31,480 EFFECT ON THE DNA. 2456 02:07:31,480 --> 02:07:33,200 WE HAVE DONE THIS AND WE DON'T 2457 02:07:33,200 --> 02:07:34,640 ALWAYS GET THIS HERE. 2458 02:07:34,640 --> 02:07:38,720 THIS IS JUST THIS TIME. 2459 02:07:38,720 --> 02:07:45,160 AND THE LATE VIRAL PROTEIN MAKES 2460 02:07:45,160 --> 02:07:47,480 QUITE A BIT BUT IT MAKES THE 2461 02:07:47,480 --> 02:07:49,080 TRANS GENE WHICH IS THE 2462 02:07:49,080 --> 02:07:52,360 IMPORTANT THING. 2463 02:07:52,360 --> 02:07:55,160 SO WE FIRST THEN INFECTED CELLS 2464 02:07:55,160 --> 02:07:59,440 AND AGAIN WE WANTED TO SEE HOW 2465 02:07:59,440 --> 02:08:07,160 THESE VIRUSES, HOW THEY WHETHER 2466 02:08:07,160 --> 02:08:12,240 THEY CONTROL THE CYTOKINES IN 2467 02:08:12,240 --> 02:08:15,520 THE CELL AND WE RANSOM PCR AND 2468 02:08:15,520 --> 02:08:20,680 THIS IS A549 CELLS AND DID 2469 02:08:20,680 --> 02:08:22,320 EXPERIMENTS ALSO AND WE NOTED 2470 02:08:22,320 --> 02:08:25,960 THAT THE VIRUS WHERE WE DELETED 2471 02:08:25,960 --> 02:08:29,520 E1B AND E14, THEY SEEM TO BE A 2472 02:08:29,520 --> 02:08:36,560 LOT MORE RED ON THE SIDE THAT IS 2473 02:08:36,560 --> 02:08:36,920 ENHANCED. 2474 02:08:36,920 --> 02:08:41,880 THIS IS A FOLD COPY AND IN SIDE 2475 02:08:41,880 --> 02:08:44,000 THERE'S MORE RED AND NOT ONLY 2476 02:08:44,000 --> 02:08:47,280 MORE RED SOME ARE SIGNIFICANTLY 2477 02:08:47,280 --> 02:08:47,960 HIGHER THAN BLACK. 2478 02:08:47,960 --> 02:08:51,400 WE LOOKED IN GENERAL ALL OF THEM 2479 02:08:51,400 --> 02:08:55,440 AND THAT PATTERN REMAINED AND 2480 02:08:55,440 --> 02:08:58,920 ALL THOSE ABOVE ZERO ABOVE THE 2481 02:08:58,920 --> 02:09:02,200 MARK THIS WAS ALSO SIGNIFICANTLY 2482 02:09:02,200 --> 02:09:02,800 HIGHER THAN IN THE WILD TYPE 2483 02:09:02,800 --> 02:09:10,920 VIRUS. 2484 02:09:10,920 --> 02:09:17,120 WE THEN WENT TO MICE AND 2485 02:09:17,120 --> 02:09:19,120 IMMUNIZED MICE AND LOOKED AT THE 2486 02:09:19,120 --> 02:09:21,280 IMMUNE RESPONSE. 2487 02:09:21,280 --> 02:09:24,000 SO HERE I'M SHOWING YOU BIND 2488 02:09:24,000 --> 02:09:31,280 BEING ANTIBODIES AGAINST THE 2489 02:09:31,280 --> 02:09:35,480 ADENOVIRUS AND THIS THE LEVELS 2490 02:09:35,480 --> 02:09:37,240 OF BINDING IG IS THE SAME 2491 02:09:37,240 --> 02:09:40,280 AGAINST IT THE ADENOVIRUS THE 2492 02:09:40,280 --> 02:09:43,480 MUTATIONS MADE IN THE VIRUS THEY 2493 02:09:43,480 --> 02:09:45,360 DON'T AFFECT THIS. 2494 02:09:45,360 --> 02:09:47,480 WELL, THAT'S TELLING ME THAT 2495 02:09:47,480 --> 02:09:53,880 THIS, THIS IS AGAINST THAT THING 2496 02:09:53,880 --> 02:09:56,320 THAT'S OUTSIDE THE VIRUS AND 2497 02:09:56,320 --> 02:10:02,640 THAT'S A RESPONSE AGAINST THIS. 2498 02:10:02,640 --> 02:10:08,160 THAT'S SO THEY'RE THE SAME. 2499 02:10:08,160 --> 02:10:11,920 BUT NOW WHEN WE LOOK AT THE 2500 02:10:11,920 --> 02:10:14,760 GP120 WE NOTE THE VIRUS THAT WE 2501 02:10:14,760 --> 02:10:16,120 CREATED CAN INDUCE HIGHER LEVELS 2502 02:10:16,120 --> 02:10:20,680 OF BINDING ANTIBODY IN THE CASE 2503 02:10:20,680 --> 02:10:22,200 BY SIGNIFICANTLY HIGHER LEVELS 2504 02:10:22,200 --> 02:10:26,720 OF BINDING ANTIBODIES. 2505 02:10:26,720 --> 02:10:28,280 BINDING ANTIBODIES ON THE WHOLE 2506 02:10:28,280 --> 02:10:31,720 ARE NOT THE SAME SO IN HUMAN THE 2507 02:10:31,720 --> 02:10:33,000 IG1 IS THE MOST FUNCTION. 2508 02:10:33,000 --> 02:10:35,520 IT HAS THE MOST FUNCTION. 2509 02:10:35,520 --> 02:10:37,400 AND IT'S EQUIVALENT IN MOUSE IS 2510 02:10:37,400 --> 02:10:43,360 THE IG2A. 2511 02:10:43,360 --> 02:10:47,320 SO IG2A IS PREDOMINANTLY MADE 2512 02:10:47,320 --> 02:10:48,920 AGAINST VIRAL PATHOGENS. 2513 02:10:48,920 --> 02:10:51,520 WE LOOKED AT IG2A AND SEE THERE 2514 02:10:51,520 --> 02:10:54,840 AGAINST THE ADENOVIRUS THE 2515 02:10:54,840 --> 02:10:57,680 LEVELS OF ANTIBODIES MADE ARE 2516 02:10:57,680 --> 02:10:59,440 THE SAME. 2517 02:10:59,440 --> 02:11:01,960 HOWEVER, AGAINST THE TRANS GENE 2518 02:11:01,960 --> 02:11:04,280 THE LEVEL OF ANTIBODIES MADE IN 2519 02:11:04,280 --> 02:11:10,920 THE VIRUS THAT WE CREATED AS 2520 02:11:10,920 --> 02:11:12,200 THIS ENHANCE. 2521 02:11:12,200 --> 02:11:13,840 SO WE REMEMBER I SHOWED YOU 2522 02:11:13,840 --> 02:11:16,160 THIS, WHEN WE JUST DELETED E1B 2523 02:11:16,160 --> 02:11:19,400 AND THERE WAS NO DIFFERENCE. 2524 02:11:19,400 --> 02:11:23,000 BUT IN THESE, WHERE I DELETED IN 2525 02:11:23,000 --> 02:11:27,480 ADDITION E41 TO 4, NOW YOU CAN 2526 02:11:27,480 --> 02:11:28,840 SEE MARK DIFFERENCES. 2527 02:11:28,840 --> 02:11:32,200 SO THIS ALLOWS US TO CONCLUDE 2528 02:11:32,200 --> 02:11:37,720 THE E4, 1 TO 4 IT IMPACTED 2529 02:11:37,720 --> 02:11:40,960 ANTIBODY THAT ARE REPORTED TO 2530 02:11:40,960 --> 02:11:43,400 PLAY A VIRAL PATHOGEN AND THE 2531 02:11:43,400 --> 02:11:44,760 VIRUS MADE THIS VACCINE 2532 02:11:44,760 --> 02:11:47,440 CANDIDATE INDUCED HIGHER LEVELS 2533 02:11:47,440 --> 02:11:53,240 OF RESPONSE THAN THE WILD TYPE. 2534 02:11:53,240 --> 02:11:58,800 WE THEN WENT TO NON-HUMAN 2535 02:11:58,800 --> 02:12:04,720 PRIMATES AND WE IMMUNIZED ORAL 2536 02:12:04,720 --> 02:12:06,240 INTRANASAL TWICE AND BOOSTED FOR 2537 02:12:06,240 --> 02:12:07,040 THE C. 2538 02:12:07,040 --> 02:12:08,720 THESE ARE THE NUMBERS OF 2539 02:12:08,720 --> 02:12:16,360 NON-HUMAN PRIMATES WE HAD AND WE 2540 02:12:16,360 --> 02:12:17,680 COLLECTED BLOOD AND CELLS. 2541 02:12:17,680 --> 02:12:21,520 WE FIRST LOOKED AT THE MUCOSAL T 2542 02:12:21,520 --> 02:12:31,320 CELLS AND IN LOOKING AT THE 2543 02:12:31,320 --> 02:12:32,440 MUCOSAL T CELLS WE NOTE THE 2544 02:12:32,440 --> 02:12:38,000 VIRUS WE CREATED INDUCED 2545 02:12:38,000 --> 02:12:43,440 SIGNIFICANT LEVELS OF CENTRAL 2546 02:12:43,440 --> 02:12:45,120 MEMORY CELLS RELATIVE TO THE 2547 02:12:45,120 --> 02:12:47,480 PRELEVELS AND SO DID THE DELETED 2548 02:12:47,480 --> 02:12:50,040 VIRUS AND THE VIRUS WE CREATED, 2549 02:12:50,040 --> 02:12:55,480 THE LEVELS WERE HIGHER THAN THAN 2550 02:12:55,480 --> 02:13:08,400 THE WILD TYPE VIRUS. 2551 02:13:08,400 --> 02:13:12,960 WE THEN LOOK AT DIFFERENT 2552 02:13:12,960 --> 02:13:15,960 ANTIBODIES AND LOOKED AT IG1 AND 2553 02:13:15,960 --> 02:13:22,960 THAT'S THE MOST FUNCTIONAL 2554 02:13:22,960 --> 02:13:25,080 ANTIBODY IN NON-HUMAN PRIMATES 2555 02:13:25,080 --> 02:13:27,880 AND THIS IS THE AREA UNDER THE 2556 02:13:27,880 --> 02:13:31,280 CURVE AND THE VIRUS WHERE WE 2557 02:13:31,280 --> 02:13:34,520 DELETE AND YOU CAN SEE THE LINES 2558 02:13:34,520 --> 02:13:40,560 IN BOTH CASES ARE HIGHER THAN 2559 02:13:40,560 --> 02:13:44,360 THIS LINE WHICH IS THE WILD TYPE 2560 02:13:44,360 --> 02:13:46,560 AND THE E1B. 2561 02:13:46,560 --> 02:13:47,440 THIS JUST SHOWING THE 2562 02:13:47,440 --> 02:13:48,720 QUANTIFICATION OVER TIME AND 2563 02:13:48,720 --> 02:13:53,800 WHAT YOU'LL NOTE IS THE LEVELS 2564 02:13:53,800 --> 02:13:59,920 DROP OFF FOR THE OTHER VIRUSES 2565 02:13:59,920 --> 02:14:03,720 RAPIDLY BUT MAINTAINED FOR THE 2566 02:14:03,720 --> 02:14:07,400 A4 DELETED VIRUS WE CREATED. 2567 02:14:07,400 --> 02:14:31,320 THIS IS SHOWING FROM THE GP120. 2568 02:14:31,320 --> 02:14:36,600 AND THE CYTOKINES PRODUCED IN 2569 02:14:36,600 --> 02:14:38,080 NON-HUMAN PRIMATES AND THE 2570 02:14:38,080 --> 02:14:39,720 DURATION AND THE VIRUS WE'VE 2571 02:14:39,720 --> 02:14:41,720 CREATED, WELL, IT CAN PRODUCE 2572 02:14:41,720 --> 02:14:43,440 HIGHER LEVELS OF ANTIBODIES FOR 2573 02:14:43,440 --> 02:14:48,240 A LONGER DURATION THAN THE 2574 02:14:48,240 --> 02:14:48,880 PARENT VIRUS AND THE WILD TYPE 2575 02:14:48,880 --> 02:14:56,520 VIRUS. 2576 02:14:56,520 --> 02:15:00,520 AND WE DELETE THE GENES AND JUST 2577 02:15:00,520 --> 02:15:02,160 DELETING THESE GENES CHANGED THE 2578 02:15:02,160 --> 02:15:17,400 RATIO OF ANTIBODIES OR THE 2579 02:15:17,400 --> 02:15:19,360 ANTIBODIES MADE. 2580 02:15:19,360 --> 02:15:20,560 AND STARTED TO EVALUATE HOW OR 2581 02:15:20,560 --> 02:15:22,120 WHERE THE VIRUSES WORK. 2582 02:15:22,120 --> 02:15:26,440 >> WE NEED TO SPEED UP A LITTLE 2583 02:15:26,440 --> 02:15:26,720 BIT. 2584 02:15:26,720 --> 02:15:27,800 WE NEED TO HEAR OUR LAST 2585 02:15:27,800 --> 02:15:31,440 SPEAKER. 2586 02:15:31,440 --> 02:15:36,520 >> RIGHT, RIGHT. 2587 02:15:36,520 --> 02:15:38,000 >> WHAT WE LEARNED FROM THIS THE 2588 02:15:38,000 --> 02:15:40,920 IDEA WE START OUT JUST LOOKING 2589 02:15:40,920 --> 02:15:45,440 AT THE DNA CONTENT AND RELATIVE 2590 02:15:45,440 --> 02:15:49,120 TO OTHERS AND SAYING OH, YOU 2591 02:15:49,120 --> 02:15:50,720 HAVE HIGHER LEVELS IT SHOULD BE 2592 02:15:50,720 --> 02:15:52,280 MORE IMMUNOGENIC BUT IT'S MORE 2593 02:15:52,280 --> 02:15:54,920 THAN THAT AND THEY CONTROL DNA 2594 02:15:54,920 --> 02:15:55,480 DAMAGE RESPONSES. 2595 02:15:55,480 --> 02:15:57,480 SO WHAT WE END UP THINKING OR 2596 02:15:57,480 --> 02:16:02,720 LOOKING AT IS THE IDEA THAT IF 2597 02:16:02,720 --> 02:16:05,640 THE VIRUS CANNOT CONTROL DNA 2598 02:16:05,640 --> 02:16:08,120 DAMAGE RESPONSE THEN THEY ARE 2599 02:16:08,120 --> 02:16:08,440 IMMUNOGENIC. 2600 02:16:08,440 --> 02:16:13,080 THESE VIRUSES HERE THEY CAN'T 2601 02:16:13,080 --> 02:16:13,720 CONTROL THE RESPONSE THE DNA 2602 02:16:13,720 --> 02:16:28,560 DAMAGE RESPONSE. 2603 02:16:28,560 --> 02:16:33,520 AND THIS WAS IMPORTANT FOR THE 2604 02:16:33,520 --> 02:16:36,840 VIRUSES AND CAN INHIBIT THIS AND 2605 02:16:36,840 --> 02:16:38,720 LOSE THIS. 2606 02:16:38,720 --> 02:16:41,960 AND WHAT WE DISCOVERED WAS THE 2607 02:16:41,960 --> 02:16:45,320 SIGNALLING PATHWAY THAT OCCURS 2608 02:16:45,320 --> 02:16:48,080 IN THESE INFECTED CELLS SUCH AS 2609 02:16:48,080 --> 02:16:54,920 THE SIGNAL TO THE KINASE THAT 2610 02:16:54,920 --> 02:16:59,320 STIMULATES THE MF KAPPA B AND 2611 02:16:59,320 --> 02:17:02,920 E43 INHIBITS PML AND ALLOWS ATM 2612 02:17:02,920 --> 02:17:07,480 TO AGAIN ACT ON NF KAPPA B. 2613 02:17:07,480 --> 02:17:14,720 WORK TOGETHER THEY REPROGRAM NF 2614 02:17:14,720 --> 02:17:18,560 KAPPA B AND HAVE YOU MORE CELL 2615 02:17:18,560 --> 02:17:20,320 SURVIVAL AND IT'S MORE ON 2616 02:17:20,320 --> 02:17:22,360 SURVIVAL AND LESS ON IMMUNE 2617 02:17:22,360 --> 02:17:26,800 RESPONSE AND HERE LESS SURVIVAL 2618 02:17:26,800 --> 02:17:32,320 AND MORE IMMUNE RESPONSE. 2619 02:17:32,320 --> 02:17:35,200 WE TESTED THE IDEA THAT IF WE 2620 02:17:35,200 --> 02:17:37,000 DELETE THE SIGNAL HERE THEN WE 2621 02:17:37,000 --> 02:17:38,760 SHOULD GET MORE IMMUNE RESPONSES 2622 02:17:38,760 --> 02:17:42,440 AND SO WE DELETED E41 SHOWING 2623 02:17:42,440 --> 02:17:45,240 THE DELETION AND IT CHANGED TO 2624 02:17:45,240 --> 02:17:47,480 SOME LEVEL OF CYTOKINES AND THAT 2625 02:17:47,480 --> 02:17:49,600 WAS ENOUGH TO SAY LET'S GO ON TO 2626 02:17:49,600 --> 02:17:52,000 THE NON-HUMAN PRIMATES. 2627 02:17:52,000 --> 02:17:54,240 WE IMMUNIZED NON-HUMAN PRIMATES 2628 02:17:54,240 --> 02:17:56,720 AND WHEN WE LOOKED AT THE 2629 02:17:56,720 --> 02:18:00,960 MUCOSAL MEMORY CELLS, CD4, CD8 2630 02:18:00,960 --> 02:18:08,400 IT INDUCED HIGHER LEVELS OF 2631 02:18:08,400 --> 02:18:08,920 CYTOKI 2632 02:18:08,920 --> 02:18:09,200 CYTOKINES. 2633 02:18:09,200 --> 02:18:11,400 WE LOOKED AT ANTIBODIES, THIS IS 2634 02:18:11,400 --> 02:18:12,520 IG, THERE'S NOT MUCH DIFFERENCE 2635 02:18:12,520 --> 02:18:16,280 BUT WHEN WE LOOK AT IG1 THE 2636 02:18:16,280 --> 02:18:25,720 RELEVANT IG1 ANTIBODY OR IGA -- 2637 02:18:25,720 --> 02:18:26,160 >> 2638 02:18:26,160 --> 02:18:27,360 [OFF MIC] 2639 02:18:27,360 --> 02:18:29,720 >> AND THE LAST SLIDE WAS WE 2640 02:18:29,720 --> 02:18:32,000 SHOWED YOU ADENOVIRUS HAS THE 2641 02:18:32,000 --> 02:18:38,240 SAME SURFACE PROTEIN WE CAN 2642 02:18:38,240 --> 02:18:42,080 CHANGE THE GENES AND WE CAN TEST 2643 02:18:42,080 --> 02:18:44,240 THEM IN MICE AND INFORM US FOR 2644 02:18:44,240 --> 02:18:45,720 WHAT WE SHOULD SEE IN MICE AND 2645 02:18:45,720 --> 02:18:47,440 THAT INFORMS US FOR WHAT WE 2646 02:18:47,440 --> 02:18:50,400 SHOULD SEE IN NON-HUMAN PRIMATES 2647 02:18:50,400 --> 02:18:53,320 AND DATA SUGGESTS SO FAR IS 2648 02:18:53,320 --> 02:18:55,440 ADENOVIRUS EARLY GENES CONTROL 2649 02:18:55,440 --> 02:18:57,680 INNATE MUCOSAL AND SYSTEMIC 2650 02:18:57,680 --> 02:19:02,040 VACCINE INDUCED IMMUNE RESPONSES 2651 02:19:02,040 --> 02:19:07,280 AND THEY DID MOST THE WORK WITH 2652 02:19:07,280 --> 02:19:16,560 THE VACCINE AND A LOT OF THIS 2653 02:19:16,560 --> 02:19:23,280 STARTED THAT ALLOWED ME AND ITS 2654 02:19:23,280 --> 02:19:24,720 WAS FUN FOR ME AND THIS IS WHAT 2655 02:19:24,720 --> 02:19:36,600 WE HAVE DONE SINCE THEN. 2656 02:19:36,600 --> 02:19:37,120 >> THANK YOUVIC. 2657 02:19:37,120 --> 02:19:38,800 A LOT OF WORK AND IF THERE'S NO 2658 02:19:38,800 --> 02:19:41,720 PRESSING QUESTIONS I THINK WE 2659 02:19:41,720 --> 02:19:56,520 SHOULD GO STRAIGHT TO LAST L LASTLY 2660 02:19:56,520 --> 02:19:59,040 ABIMIKU WAS THE FIRST POST-DOC 2661 02:19:59,040 --> 02:20:00,000 OF MARJORIE AND GOING TO 2662 02:20:00,000 --> 02:20:02,760 BETHESDA TO WORK WITH BOB AND 2663 02:20:02,760 --> 02:20:05,200 THEN THERE WAS A BRILLIANT IDEA 2664 02:20:05,200 --> 02:20:08,720 TO WORK WITH MARJORIE AND THE 2665 02:20:08,720 --> 02:20:09,120 REST IS HISTORY. 2666 02:20:09,120 --> 02:20:11,600 THANK YOU FOR COMING. 2667 02:20:11,600 --> 02:20:16,640 >> THANK YOU FOR HAVING ME. 2668 02:20:16,640 --> 02:20:18,200 THOUGH I'M AN IN UNCOMFORTABLE 2669 02:20:18,200 --> 02:20:19,640 POSITION BECAUSE I'M STANDING 2670 02:20:19,640 --> 02:20:21,360 BETWEEN YOU AND LUNCH AND EARLY 2671 02:20:21,360 --> 02:20:22,840 LUNCH IT WAS SUPPOSED TO BE BUT 2672 02:20:22,840 --> 02:20:24,280 I HAVE MARJORIE STILL TO PROTECT 2673 02:20:24,280 --> 02:20:32,120 ME AGAINST BOB. 2674 02:20:32,120 --> 02:20:35,440 AND TODAY I THOUGHT IT SHOULD BE 2675 02:20:35,440 --> 02:20:39,480 IT'S APPROPRIATE TO SHARE WITH 2676 02:20:39,480 --> 02:20:42,840 THE AUDIENCE HOW MUCH MARJORIE'S 2677 02:20:42,840 --> 02:20:44,320 IMPACTING WHAT WE DO GLOBALLY AS 2678 02:20:44,320 --> 02:20:47,480 WELL IN TERMS OF WHAT SHE'S DONE 2679 02:20:47,480 --> 02:20:54,360 IN RESEARCH. 2680 02:20:54,360 --> 02:20:56,160 AND WE HAVE THE NORTH SIDE 2681 02:20:56,160 --> 02:20:57,520 COLLABORATION STARTING WITH THE 2682 02:20:57,520 --> 02:21:08,080 POST-DOC IN MARJORIE'S LOB. 2683 02:21:08,080 --> 02:21:09,480 AND THERE'S AN GLOBAL 2684 02:21:09,480 --> 02:21:12,400 INTERNATIONAL PROGRAM AND 2685 02:21:12,400 --> 02:21:15,800 CURRENTLY WE'RE IN EIGHT AFRICAN 2686 02:21:15,800 --> 02:21:20,880 COUNTRIES DOING LARGELY WORK IN 2687 02:21:20,880 --> 02:21:27,960 HIV AND TB. 2688 02:21:27,960 --> 02:21:31,480 OUR PROGRAM INCORPORATES A LOT 2689 02:21:31,480 --> 02:21:33,880 OF ACTIVITY AND THE PEP FAR 2690 02:21:33,880 --> 02:21:37,120 PROGRAM WHICH HAS PROVIDED 2691 02:21:37,120 --> 02:21:38,800 TREATMENT FOR INDIVIDUALS THAT 2692 02:21:38,800 --> 02:21:43,440 ARE INFECTED WITH HIV. 2693 02:21:43,440 --> 02:21:45,960 WE HAVE A LOT OF WE'VE DONE AND 2694 02:21:45,960 --> 02:21:49,640 WE HAVE HEALTH SYSTEMS TO ENSURE 2695 02:21:49,640 --> 02:21:55,400 THE DATA BEING PRODUCED IS 2696 02:21:55,400 --> 02:21:59,640 APPROPRIATE BY SECURITY AND ONE 2697 02:21:59,640 --> 02:22:02,280 AREA THAT WE HAVE ALSO BUILT IN 2698 02:22:02,280 --> 02:22:04,120 MORE RECENT YEARS AND AS A 2699 02:22:04,120 --> 02:22:05,320 RESULT OF OUR COLLABORATION IS 2700 02:22:05,320 --> 02:22:11,480 THE AREA OF RESEARCH. 2701 02:22:11,480 --> 02:22:13,120 THIS IS MOST DEVELOPED IN 2702 02:22:13,120 --> 02:22:14,800 NIGERIA WHERE I'M FROM. 2703 02:22:14,800 --> 02:22:17,680 IN NIGERIA, WHAT WE'VE DONE IS 2704 02:22:17,680 --> 02:22:20,880 THAT WE BUILT A PROGRAM THAT IS 2705 02:22:20,880 --> 02:22:24,960 BASED ON TREATMENT OF HIV 2706 02:22:24,960 --> 02:22:27,200 INFECTED INDIVIDUALS MOST 2707 02:22:27,200 --> 02:22:29,480 CO-INFECTED WITH TB BUT ALSO 2708 02:22:29,480 --> 02:22:31,520 HAVE A GLOBAL FUND PROGRAM THAT 2709 02:22:31,520 --> 02:22:35,520 FOCUSSED ON TB. 2710 02:22:35,520 --> 02:22:37,520 DUE TO THE COLLABORATION WITH 2711 02:22:37,520 --> 02:22:41,200 THE NORTH, IT WAS IMPORTANT THAT 2712 02:22:41,200 --> 02:22:44,480 WE OVERLAID SOME OF THE 2713 02:22:44,480 --> 02:22:46,200 ACTIVITIES THAT WE'RE DOING FOR 2714 02:22:46,200 --> 02:22:47,760 SERVICE PROGRAM USING THE 2715 02:22:47,760 --> 02:22:48,480 INFRASTRUCTURE THAT WE'VE BUILT 2716 02:22:48,480 --> 02:22:50,800 TO ALSO PROMOTE RESEARCH. 2717 02:22:50,800 --> 02:22:55,480 BUT IN TERMS OF RESEARCH AND 2718 02:22:55,480 --> 02:23:03,920 THIS IS PART OF MY FOCUS IN 2016 2719 02:23:03,920 --> 02:23:06,320 AND THE INSTITUTE OF HUMAN 2720 02:23:06,320 --> 02:23:10,120 VIROLOGY IN NIGERIA WAS SET UP 2721 02:23:10,120 --> 02:23:11,120 IN 2004. 2722 02:23:11,120 --> 02:23:14,680 OVERLAYING A LOT OF WORK WE'VE 2723 02:23:14,680 --> 02:23:15,960 DONE WITH RESEARCH WAS MY FOCUS 2724 02:23:15,960 --> 02:23:18,840 IN 2016 THAT WE ESTABLISHED THE 2725 02:23:18,840 --> 02:23:19,480 INTERNATIONAL RESEARCH CENTER OF 2726 02:23:19,480 --> 02:23:26,520 EXCELLENCE. 2727 02:23:26,520 --> 02:23:27,520 AND ONE THING IN TERMS OF THE 2728 02:23:27,520 --> 02:23:29,880 RESEARCH AREA IS TO FOCUS ON 2729 02:23:29,880 --> 02:23:32,120 CLINICAL TRIAL COHORT STUDIES 2730 02:23:32,120 --> 02:23:33,880 AND MOLECULAR IMMUNOLOGY AND 2731 02:23:33,880 --> 02:23:36,920 FOCUSSING ON HIV AND TB. 2732 02:23:36,920 --> 02:23:39,480 AND THEN WE PARTNERED WITH 2733 02:23:39,480 --> 02:23:40,000 INTERNATIONAL RESEARCH 2734 02:23:40,000 --> 02:23:41,880 INDIVIDUAL AND MORE IMPORTANTLY 2735 02:23:41,880 --> 02:23:48,920 ALSO WITH ACADEMIC FACULTY 2736 02:23:48,920 --> 02:23:50,760 WITHIN THE COUNTRY. 2737 02:23:50,760 --> 02:23:54,640 THE PURPOSE OF SETTING UP THIS 2738 02:23:54,640 --> 02:23:58,960 IS TO ENSURE RESEARCH IS 2739 02:23:58,960 --> 02:24:00,680 PROMOTED AND MAINLY FOCUSSING 2740 02:24:00,680 --> 02:24:02,880 WITH THE INSTITUTE OF HUMAN 2741 02:24:02,880 --> 02:24:08,320 VIROLOGY AND THE UNIVERSITY OF 2742 02:24:08,320 --> 02:24:12,680 MARYLAND WITH HIV NIGERIA 2743 02:24:12,680 --> 02:24:18,000 PROVIDING ONE-CLASS PLATFORM TO 2744 02:24:18,000 --> 02:24:20,360 MAKE SURE IT'S USING 2745 02:24:20,360 --> 02:24:21,720 INTERNATIONAL SCIENTIFICAL AND 2746 02:24:21,720 --> 02:24:22,520 ETHICAL NORMS AND RESPECTING THE 2747 02:24:22,520 --> 02:24:25,920 NORMS WITHIN THE COUNTRIES. 2748 02:24:25,920 --> 02:24:26,800 IT WAS MAINLY TO FIRST 2749 02:24:26,800 --> 02:24:32,800 COLLABORATE BETWEEN THE NORTH 2750 02:24:32,800 --> 02:24:35,440 AND SOUTH BUT ALSO WITHIN THE 2751 02:24:35,440 --> 02:24:37,800 NIGERIA AREA RESEARCHERS AND 2752 02:24:37,800 --> 02:24:38,800 LIKE I SAID INTERNATIONAL 2753 02:24:38,800 --> 02:24:40,920 RESEARCH INSTITUTES. 2754 02:24:40,920 --> 02:24:43,080 BUT YOU KNOW, WE DIDN'T START 2755 02:24:43,080 --> 02:24:51,800 WITH SUCH ELABORATE RESEARCH 2756 02:24:51,800 --> 02:24:52,720 CAPACITY. 2757 02:24:52,720 --> 02:24:55,320 OUR INTERACTION AND SETTING UP 2758 02:24:55,320 --> 02:24:55,880 THE COLLABORATIONS AND 2759 02:24:55,880 --> 02:24:59,200 INFRASTRUCTURE IN NIGERIA 2760 02:24:59,200 --> 02:25:01,600 STARTED REALLY IN 1991 WHEN I 2761 02:25:01,600 --> 02:25:07,400 CAME TO THE LTCB LABORATORY FOR 2762 02:25:07,400 --> 02:25:08,960 MY POST-DOC. 2763 02:25:08,960 --> 02:25:11,560 THE USUAL NUMBER WAS THAT IT 2764 02:25:11,560 --> 02:25:13,360 WOULD ALLOW TO YOU CIRCLE 2765 02:25:13,360 --> 02:25:17,520 THROUGH THE LABORATORIES AND HIS 2766 02:25:17,520 --> 02:25:19,280 SENIOR SCIENTISTS AND THEN YOU 2767 02:25:19,280 --> 02:25:20,760 HAD A MEETING WITH HIM AT THE 2768 02:25:20,760 --> 02:25:24,920 END OF IT TO KIND OF INFORM HIM 2769 02:25:24,920 --> 02:25:26,840 OF THE LABORATORY YOU'VE DECIDED 2770 02:25:26,840 --> 02:25:29,640 TO WORK IN. 2771 02:25:29,640 --> 02:25:32,120 AND I REMEMBER CERTAINLY THROUGH 2772 02:25:32,120 --> 02:25:33,720 AND HAVING AN EXTENDED 2773 02:25:33,720 --> 02:25:36,120 DISCUSSION WITH MARJORIE, I WAS 2774 02:25:36,120 --> 02:25:38,600 CERTAINLY INTERESTED IN 2775 02:25:38,600 --> 02:25:41,520 IMMUNOLOGY BECAUSE THAT WAS PART 2776 02:25:41,520 --> 02:25:43,680 OF MY TRAINING AS MASTER'S 2777 02:25:43,680 --> 02:25:46,960 BEFORE I DID MY Ph.D. BUT THE 2778 02:25:46,960 --> 02:25:50,520 OTHER ASPECT I WAS REALLY 2779 02:25:50,520 --> 02:25:51,520 INTERESTED IN WAS SETTING UP AN 2780 02:25:51,520 --> 02:25:53,200 INFRASTRUCTURE IN MY HOME 2781 02:25:53,200 --> 02:25:55,400 COUNTRY TO ALLOW ME TO CONTINUE 2782 02:25:55,400 --> 02:25:57,200 TO DO RESEARCH. 2783 02:25:57,200 --> 02:26:00,040 AND THAT WASN'T THE KIND OF 2784 02:26:00,040 --> 02:26:01,760 THING YOU DISCUSS WITH BOB GALLO 2785 02:26:01,760 --> 02:26:07,000 WHEN COUPLE TO HIS LAB BECAUSE 2786 02:26:07,000 --> 02:26:10,600 IT'S A VERY RENOWN LABORATORY ON 2787 02:26:10,600 --> 02:26:11,400 MAINLY RESEARCH. 2788 02:26:11,400 --> 02:26:13,080 CAPACITY BUILDING AT SOME STAGE 2789 02:26:13,080 --> 02:26:14,480 BUT YOU KNOW EVENTUALLY BUT THE 2790 02:26:14,480 --> 02:26:18,560 FIRST FOCUS HAS TO BE RESEARCH. 2791 02:26:18,560 --> 02:26:20,880 IT WAS WONDERFUL TO HAVE 2792 02:26:20,880 --> 02:26:23,960 MARJORIE THAT WANTED TO SUPPORT 2793 02:26:23,960 --> 02:26:26,880 ME AND WITH ME TREMBLING AT THE 2794 02:26:26,880 --> 02:26:28,600 KNEES AS SHE WAS ABLE TO 2795 02:26:28,600 --> 02:26:31,440 CONVINCE BOB THAT I COULD DO 2796 02:26:31,440 --> 02:26:35,360 BOTH. 2797 02:26:35,360 --> 02:26:37,920 AND SO I GOT SUPPORT FROM BOTH. 2798 02:26:37,920 --> 02:26:39,440 THAT BUFFER STILL WORK TODAY. 2799 02:26:39,440 --> 02:26:40,880 AND JUST TO MENTION THAT 2800 02:26:40,880 --> 02:26:43,320 ACTUALLY OUR FIRST ENTRY INTO 2801 02:26:43,320 --> 02:26:45,680 NIGERIA WAS CONVINCING THE 2802 02:26:45,680 --> 02:26:47,400 GOVERNMENT THEN THAT THERE WAS 2803 02:26:47,400 --> 02:26:48,080 HIV. 2804 02:26:48,080 --> 02:26:50,000 THIS WAS REALLY AS A RESULT OF 2805 02:26:50,000 --> 02:26:53,200 THE WOULD BLOOD TEST THAT WAS 2806 02:26:53,200 --> 02:26:54,520 DEVELOPED IN BOB'S SLIDE AND WE 2807 02:26:54,520 --> 02:26:56,040 STARTED WITH A ROOM AND TWO 2808 02:26:56,040 --> 02:26:58,920 DOORS AND TWO ROOMS I REMEMBER 2809 02:26:58,920 --> 02:27:00,080 HAVING THE NATIONAL TELEVISION 2810 02:27:00,080 --> 02:27:03,360 COME IN AS I DRAW BLOOD AND TEST 2811 02:27:03,360 --> 02:27:06,360 INDIVIDUALS TO CONVINCE THE 2812 02:27:06,360 --> 02:27:09,160 COUNTRY THEN THAT THERE WAS HIV. 2813 02:27:09,160 --> 02:27:10,880 WE'VE MOVED SINCE THEN. 2814 02:27:10,880 --> 02:27:16,520 WE HAVE A TWO-STORY RESEARCH 2815 02:27:16,520 --> 02:27:20,040 FACILITY IN 2001 AND IT PROBABLY 2816 02:27:20,040 --> 02:27:22,320 WAS THE MAIN RESEARCH FACILITY 2817 02:27:22,320 --> 02:27:25,520 THAT WAS DOING HIV TESTING AND 2818 02:27:25,520 --> 02:27:26,160 CONFIRMATION FOR MOST OF THE 2819 02:27:26,160 --> 02:27:32,880 NORTHERN PART OF THE COUNTRY. 2820 02:27:32,880 --> 02:27:34,560 SUBSEQUENTLY NOW WE HAVE TWO 2821 02:27:34,560 --> 02:27:36,920 TWIN TOWER BUILDINGS, EIGHT 2822 02:27:36,920 --> 02:27:38,880 FLOORS EACH, WHICH IS ON BOARD 2823 02:27:38,880 --> 02:27:43,520 AND WE'VE CONTINUED TO BUILD THE 2824 02:27:43,520 --> 02:27:45,680 RESEARCH PROGRAM. 2825 02:27:45,680 --> 02:27:47,960 BUT HOW DID MY POST-DOC IN 2826 02:27:47,960 --> 02:27:50,280 MARJORIE'S LAB TRAIN ME FOR SOME 2827 02:27:50,280 --> 02:27:52,160 OF THE THINGS I WAS THEN ABLE TO 2828 02:27:52,160 --> 02:27:52,320 DO? 2829 02:27:52,320 --> 02:27:54,520 LIKE I MENTIONED EARLIER, ONE OF 2830 02:27:54,520 --> 02:27:56,800 MY INTERESTS WAS REALLY BUILDING 2831 02:27:56,800 --> 02:27:58,000 CAPACITY AND INFORMATION THE 2832 02:27:58,000 --> 02:27:59,720 EPIDEMIC IN MY HOME COUNTRY AS 2833 02:27:59,720 --> 02:28:03,720 WELL. 2834 02:28:03,720 --> 02:28:09,800 AND THIS PAPER IS ONE THAT WAS 2835 02:28:09,800 --> 02:28:13,080 PUBLISHED THE FIRST SUBTYPES IN 2836 02:28:13,080 --> 02:28:17,160 NIGERIA SHOWING VERY CLEARLY 2837 02:28:17,160 --> 02:28:21,000 THAT IT WAS A SUBTYPE GROUP GENE 2838 02:28:21,000 --> 02:28:27,480 AND LATER ON IT IS A STANDARD TO 2839 02:28:27,480 --> 02:28:30,520 AG RECOMBINANT BUT THIS G SUB 2840 02:28:30,520 --> 02:28:32,800 TYPE HAS CONTINUOUSLY REMAINED 2841 02:28:32,800 --> 02:28:35,160 AS THE PREDOMINANT STRAIN AND 2842 02:28:35,160 --> 02:28:37,280 ONE OF THE THINGS THAT MARJORIE 2843 02:28:37,280 --> 02:28:38,960 DID WAS REALLY TO LINK ME UP 2844 02:28:38,960 --> 02:28:42,840 WITH OTHER MEMBERS OF THE TEAM 2845 02:28:42,840 --> 02:28:45,720 AND I LEARNED A LOT OF MOLECULAR 2846 02:28:45,720 --> 02:28:49,120 VIROLOGY IN THE LAB AS WELL. 2847 02:28:49,120 --> 02:28:52,520 WE WENT ON SUBSEQUENTLY TO 2848 02:28:52,520 --> 02:28:55,440 ESTABLISH AND DID AGAIN THE 2849 02:28:55,440 --> 02:28:57,960 COLLABORATIONS THAT REALLY WAS 2850 02:28:57,960 --> 02:28:59,680 BROUGHT TOGETHER AS A RESULT OF 2851 02:28:59,680 --> 02:29:00,560 MARJORIE. 2852 02:29:00,560 --> 02:29:03,840 BUT ALSO IN WORKING WITH THE 2853 02:29:03,840 --> 02:29:06,640 RHESUS MACAQUE GIVES ME AN 2854 02:29:06,640 --> 02:29:08,720 OPPORTUNITY TO LEARN A LOT OF 2855 02:29:08,720 --> 02:29:10,880 CELL MEDIATED IMMUNITY THAT 2856 02:29:10,880 --> 02:29:13,520 LATER ON DESCRIBED FROM THE 2857 02:29:13,520 --> 02:29:14,200 FOUNDATION OF WHAT WE'VE 2858 02:29:14,200 --> 02:29:15,320 ESTABLISHED IN NIGERIA. 2859 02:29:15,320 --> 02:29:20,840 SO WHAT DO WE HAVE NOW? 2860 02:29:20,840 --> 02:29:24,040 WE HAVE A GROUP OF FACULTY AND 2861 02:29:24,040 --> 02:29:25,960 WE'VE CONTINUED TO COLLABORATE 2862 02:29:25,960 --> 02:29:26,920 IN INTERNATIONAL RESEARCH. 2863 02:29:26,920 --> 02:29:28,400 WHAT ARE THE AREAS THAT WE'RE 2864 02:29:28,400 --> 02:29:33,720 FOCUSSING ON AS I MENTIONED 2865 02:29:33,720 --> 02:29:37,720 EARLIER OUR FOCUS IS ON HIV AND 2866 02:29:37,720 --> 02:29:42,200 WHAT YOU SEE HERE THAT IS 2867 02:29:42,200 --> 02:29:43,560 STARRED AND NIH FUNDED GRANTS 2868 02:29:43,560 --> 02:29:46,760 WE'VE BEEN ABLE TO GET AND WHAT 2869 02:29:46,760 --> 02:29:49,200 I'M SHOWING HERE IN RED IS SOME 2870 02:29:49,200 --> 02:29:50,360 OF THE FUNDING WE'VE GOTTEN 2871 02:29:50,360 --> 02:29:54,400 THROUGH NIH TO BUILD THE 2872 02:29:54,400 --> 02:29:55,480 CAPACITY FOR TRAINING AND 2873 02:29:55,480 --> 02:29:59,480 RAISING UP POST-DOC AT 2874 02:29:59,480 --> 02:30:04,600 INDEPENDENT RESEARCHERS. 2875 02:30:04,600 --> 02:30:11,120 OUR FUNDING HAS CONTINUED TO 2876 02:30:11,120 --> 02:30:11,360 EXPAND. 2877 02:30:11,360 --> 02:30:15,560 IN 2016 THE FUNDING WE HAS WAS 2878 02:30:15,560 --> 02:30:17,840 AS A RESULT OF COLLABORATION 2879 02:30:17,840 --> 02:30:21,480 WITH A NUMBER OF THE FUNDED AS 2880 02:30:21,480 --> 02:30:24,120 NIH BUT SINCE IT'S A LOW AND 2881 02:30:24,120 --> 02:30:25,200 MIDDLE INCOME COUNTRIES THERE'S 2882 02:30:25,200 --> 02:30:27,000 OTHER FUNDING MECHANISMS IN 2883 02:30:27,000 --> 02:30:29,000 EUROPE AVAILABLE TO FACULTY IN 2884 02:30:29,000 --> 02:30:30,040 NIGERIA NOT NECESSARILY 2885 02:30:30,040 --> 02:30:35,120 AVAILABLE TO OUR COLLEAGUES HERE 2886 02:30:35,120 --> 02:30:37,080 AT IHV. 2887 02:30:37,080 --> 02:30:38,560 WE'VE BEEN ABLE TO EXPAND AND 2888 02:30:38,560 --> 02:30:41,320 SOME IS INITIATED FROM OUR 2889 02:30:41,320 --> 02:30:47,280 RESEARCH CENTER IN NIGERIA. 2890 02:30:47,280 --> 02:30:48,840 SOME OF ANY NEXT SLIDES WILL 2891 02:30:48,840 --> 02:30:50,880 POINT TO SOME OF THE THINGS THAT 2892 02:30:50,880 --> 02:30:56,880 HAVE REALLY MADE AS OUR ABILITY 2893 02:30:56,880 --> 02:31:00,920 TO CONDUCT RESEARCH AT AN 2894 02:31:00,920 --> 02:31:02,360 INTERNATIONAL LEVEL WITHIN 2895 02:31:02,360 --> 02:31:04,240 RESOURCE LIMITED COUNTRY. 2896 02:31:04,240 --> 02:31:06,640 SOME OF THEM HERE PEOPLE TAKE IT 2897 02:31:06,640 --> 02:31:11,440 FOR GRANTED BECAUSE HAVE YOU 2898 02:31:11,440 --> 02:31:22,600 POWER ALL THE TIME AND SOME HAVE 2899 02:31:22,600 --> 02:31:24,440 HAD FOUR POWER BACKUPS TO MAKE 2900 02:31:24,440 --> 02:31:25,360 SURE WE HAVE POWER ALL THE TIME 2901 02:31:25,360 --> 02:31:29,160 AND ON TOP OF THAT WE HAVE A 2902 02:31:29,160 --> 02:31:33,520 LICK ID NITROGEN PLANT JUST IN 2903 02:31:33,520 --> 02:31:38,520 CASE AND THE VSL3 FACILITY WAS A 2904 02:31:38,520 --> 02:31:39,080 CONTINUIZED LABORATORY PUT 2905 02:31:39,080 --> 02:31:40,440 TOGETHER HERE IN FLORIDA AND 2906 02:31:40,440 --> 02:31:44,920 SHIPPED AND ASSEMBLED AND WE'RE 2907 02:31:44,920 --> 02:31:50,920 ABLE TO DO SEQUENCE IN THE 2908 02:31:50,920 --> 02:31:59,320 FUNDED LAB. 2909 02:31:59,320 --> 02:32:03,400 THE WORK WE DO INCLUDES -- OKAY. 2910 02:32:03,400 --> 02:32:07,240 A SHARED FACILITIES ESPECIALLY 2911 02:32:07,240 --> 02:32:08,880 ENSURING THE DATA IS OF HIGH 2912 02:32:08,880 --> 02:32:10,840 QUALITY. 2913 02:32:10,840 --> 02:32:13,360 WE REALLY HAVE TAKEN ADVANTAGE 2914 02:32:13,360 --> 02:32:14,480 OF OUR INTERNATIONAL PARTNERS 2915 02:32:14,480 --> 02:32:17,320 AND COVID HAS TAUGHT US HOW TO 2916 02:32:17,320 --> 02:32:18,800 DO A LOT OF THINGS VIRTUALLY. 2917 02:32:18,800 --> 02:32:20,920 SO THERE'S A LOT OF TRAINING 2918 02:32:20,920 --> 02:32:28,120 ESPECIALLY IN DATA THAT HAPPENS 2919 02:32:28,120 --> 02:32:31,520 VIRTUALLY AND HERE WHAT I'M 2920 02:32:31,520 --> 02:32:33,160 SHOWING IS A LOT OF THE 2921 02:32:33,160 --> 02:32:37,320 TRAININGS THAT WE DO ALSO. 2922 02:32:37,320 --> 02:32:42,080 SO THE LAST FEW SLIDES I WOULD 2923 02:32:42,080 --> 02:32:44,320 LIKE TO JUST UNDER SCORE HOW 2924 02:32:44,320 --> 02:32:46,880 MUCH WE HAVE BUILT CAPACITY 2925 02:32:46,880 --> 02:32:48,520 ESPECIALLY RESEARCH CAPACITY 2926 02:32:48,520 --> 02:32:49,840 THROUGH THE FOGARTY PROGRAM. 2927 02:32:49,840 --> 02:32:54,120 THIS REALLY STARTED WITH BILL 2928 02:32:54,120 --> 02:32:57,040 BLATNER THE CO-FOUNDER WITH BOB 2929 02:32:57,040 --> 02:33:03,520 AND HAD ABOUT 15 YEARS WHERE A 2930 02:33:03,520 --> 02:33:06,880 NUMBER OF MASTERS AND Ph.D. 2931 02:33:06,880 --> 02:33:08,360 INDIVIDUALS WERE TRAINED. 2932 02:33:08,360 --> 02:33:09,520 A LOT OF THE COURSES ARE 2933 02:33:09,520 --> 02:33:11,480 RELEVANT TO THE KIND OF RESEARCH 2934 02:33:11,480 --> 02:33:14,160 THAT WE DO TODAY. 2935 02:33:14,160 --> 02:33:19,440 BUT WHAT IS INTERESTING IS WE'VE 2936 02:33:19,440 --> 02:33:23,080 CONTINUED TO BUILD ON BILL'S 2937 02:33:23,080 --> 02:33:26,280 FOUNDATION AND WE'RE ABLE TO 2938 02:33:26,280 --> 02:33:31,440 ALSO CONTINUE THIS TO TRAIN 2939 02:33:31,440 --> 02:33:33,520 ADDITIONAL MASTER'S IN Ph.D. AND 2940 02:33:33,520 --> 02:33:37,480 WE HAVE THOSE MASTER'S IN Ph.D. 2941 02:33:37,480 --> 02:33:43,000 STATIONED OR ABSORBED INTO OUR 2942 02:33:43,000 --> 02:33:45,360 RESEARCH CENTER AT HIV IN 2943 02:33:45,360 --> 02:33:45,800 NIGERIA. 2944 02:33:45,800 --> 02:33:47,880 THAT WAY WE DO NOT HAVE THEM ALL 2945 02:33:47,880 --> 02:33:50,560 SCATTERED AROUND AND WE BEGIN TO 2946 02:33:50,560 --> 02:33:53,320 BUILD ON THAT POOL. 2947 02:33:53,320 --> 02:33:56,560 AND MORE RECENTLY IN FACT IT WAS 2948 02:33:56,560 --> 02:34:02,880 FEBRUARY THIS YEAR, NADIA AND I, 2949 02:34:02,880 --> 02:34:11,120 BY THE WAY NADIA -- AND USED TO 2950 02:34:11,120 --> 02:34:13,720 CALL ME THE AFRICAN WOMAN WHEN I 2951 02:34:13,720 --> 02:34:16,040 JOINED HIS LAB BUT NADIA AND I 2952 02:34:16,040 --> 02:34:21,120 GOT ANOTHER FOGARTY PROGRAM 2953 02:34:21,120 --> 02:34:21,960 FOCUSSING ON IMPLEMENTING 2954 02:34:21,960 --> 02:34:25,360 SCIENCE AND THE PLAN IS TO 2955 02:34:25,360 --> 02:34:27,240 CONTINUE DEVELOP THE LONG-TERM 2956 02:34:27,240 --> 02:34:28,000 POST-DOCTORAL GETTING TO THE 2957 02:34:28,000 --> 02:34:29,920 CORE OF INDIVIDUALS THAT WOULD 2958 02:34:29,920 --> 02:34:31,800 THEN NEED TO USE THE CORE 2959 02:34:31,800 --> 02:34:32,920 INFRASTRUCTURE THAT WAS SET UP 2960 02:34:32,920 --> 02:34:35,240 IN THIS RESEARCH BUILDING TO 2961 02:34:35,240 --> 02:34:37,520 CONTINUE TO ALSO COMPETE FOR 2962 02:34:37,520 --> 02:34:40,920 THIS VARIOUS RESEARCH 2963 02:34:40,920 --> 02:34:41,240 ACTIVITIES. 2964 02:34:41,240 --> 02:34:44,520 AND LASTLY WE -- THIS JUST SHOWS 2965 02:34:44,520 --> 02:34:47,440 IN THIS RECENT ONE SOME OF THE 2966 02:34:47,440 --> 02:34:49,440 MODELS WE'LL BE FOCUSSING ON ONE 2967 02:34:49,440 --> 02:34:50,520 CERTAINLY ON IMPLEMENTATION 2968 02:34:50,520 --> 02:34:52,680 SCIENCE AND WE ALSO WANT TO 2969 02:34:52,680 --> 02:34:54,800 FOCUS ON GRANT WRITING AND 2970 02:34:54,800 --> 02:34:59,400 MOVING THE INDIVIDUALS TO 2971 02:34:59,400 --> 02:35:00,920 INDEPENDENT RESEARCH. 2972 02:35:00,920 --> 02:35:04,720 THAT'S LEARNING FROM SOME OF THE 2973 02:35:04,720 --> 02:35:05,960 EXPERIENCES I'VE GONE THROUGH. 2974 02:35:05,960 --> 02:35:07,400 LASTLY, WE DID COMPETE FOR THE 2975 02:35:07,400 --> 02:35:11,040 DATA SCIENCE IN AFRICA AND WE'RE 2976 02:35:11,040 --> 02:35:12,880 VERY PROUD OF THIS. 2977 02:35:12,880 --> 02:35:15,400 LIKE I SAID, THESE ARE THE BIG 2978 02:35:15,400 --> 02:35:15,760 5. 2979 02:35:15,760 --> 02:35:17,360 I DON'T KNOW HOW MANY IN THE 2980 02:35:17,360 --> 02:35:26,920 AUDIENCE CAN IDENTIFY THE 2981 02:35:26,920 --> 02:35:34,920 ELEPHANT BUFFALO LIONESSE AND 2982 02:35:34,920 --> 02:35:37,040 WE'RE PROUD OF THIS AND WE JUST 2983 02:35:37,040 --> 02:35:44,840 GOT FUNDED IN OCTOBER. 2984 02:35:44,840 --> 02:35:47,440 AND WE'LL ESTABLISH THE 2985 02:35:47,440 --> 02:35:50,880 MULTI-LAYER INTERACTIONS BETWEEN 2986 02:35:50,880 --> 02:35:58,200 COVID AND SOCIAL INTERACTIONS 2987 02:35:58,200 --> 02:35:59,320 AND WE'RE USING TOOLS AND 2988 02:35:59,320 --> 02:36:01,800 MOBILITY DATA TO SEE HOW WE CAN 2989 02:36:01,800 --> 02:36:03,400 OVERLAY THE TRANSMISSION AND THE 2990 02:36:03,400 --> 02:36:06,240 SPREAD AND THE HOT SPOT OF COVID 2991 02:36:06,240 --> 02:36:11,840 WITH THE DATA THAT HAS BEEN 2992 02:36:11,840 --> 02:36:14,120 ACCUMULATE 2993 02:36:14,120 --> 02:36:15,320 ACCUMULATED AND OVERLAY THE HIV 2994 02:36:15,320 --> 02:36:18,200 AND SEE THE IMPACT OF AN 2995 02:36:18,200 --> 02:36:20,840 EXISTENT PANDEMIC ON ONE COMING 2996 02:36:20,840 --> 02:36:22,120 IN. 2997 02:36:22,120 --> 02:36:23,760 THIS IS INFORM AFRICA. 2998 02:36:23,760 --> 02:36:25,400 WE HAVE FIVE YEARS OF DOING DATA 2999 02:36:25,400 --> 02:36:26,920 SCIENCE WHICH IS VERY EXCITING 3000 02:36:26,920 --> 02:36:32,480 FOR US. 3001 02:36:32,480 --> 02:36:34,280 SO I'LL JUST END BY THANKING 3002 02:36:34,280 --> 02:36:37,120 YOU, MARJORIE, FOR EVERYTHING 3003 02:36:37,120 --> 02:36:37,840 YOU'VE DONE. 3004 02:36:37,840 --> 02:36:41,400 ONE THING I LEARNED DURING THE 3005 02:36:41,400 --> 02:36:44,520 POST-DOC IN YOUR LAB IS THE 3006 02:36:44,520 --> 02:36:46,560 IMPORTANCE OF EXCELLENCE AND THE 3007 02:36:46,560 --> 02:36:48,160 IMPORTANCE OF BUILDING OTHER 3008 02:36:48,160 --> 02:36:49,000 PEOPLE UP. 3009 02:36:49,000 --> 02:36:51,920 I KNOW YOU TRIED TO TEACH ME 3010 02:36:51,920 --> 02:36:53,520 PATIENCE BUT I STILL YELL AT 3011 02:36:53,520 --> 02:36:55,680 PEOPLE SO I STILL HAVE SOME WORK 3012 02:36:55,680 --> 02:36:58,720 TO DO BUT JUST TO SHOW THAT WHAT 3013 02:36:58,720 --> 02:37:02,880 YOU HAVE INVESTED IN ME IS 3014 02:37:02,880 --> 02:37:05,200 REALLY HAVING AN IMPACT GLOBALLY 3015 02:37:05,200 --> 02:37:06,360 SO WE WANT TO THANK YOU FOR THAT 3016 02:37:06,360 --> 02:37:07,400 AGAIN. 3017 02:37:07,400 --> 02:37:07,680 THANK YOU. 3018 02:37:07,680 --> 02:37:23,520 [APPLAUSE] 3019 02:37:23,520 --> 02:37:27,720 >> SO I THINK WE SHOULD TAKE 3020 02:37:27,720 --> 02:37:28,920 ADVANTAGE OF YOUR PRESENCE HERE 3021 02:37:28,920 --> 02:37:30,120 TO LEARN MORE ABOUT AFRICA AND 3022 02:37:30,120 --> 02:37:32,640 THE BEAUTIFUL WORK THAT IS 3023 02:37:32,640 --> 02:37:35,480 HAPPENING THERE. 3024 02:37:35,480 --> 02:37:37,080 IT'S AN EXTREMELY IMPORTANT 3025 02:37:37,080 --> 02:37:39,840 PROJECT LONG TERM AND WE SEE HOW 3026 02:37:39,840 --> 02:37:41,720 IMPORTANT IT IS NOW WITH ALSO 3027 02:37:41,720 --> 02:37:45,840 ADDRESSING AS YOU JUST MENTIONED 3028 02:37:45,840 --> 02:37:49,480 IN PASSING, COVID IN AFRICA. 3029 02:37:49,480 --> 02:37:52,360 PERSONALLY, I WOULD LOVE TO KNOW 3030 02:37:52,360 --> 02:37:55,120 A LITTLE BIT MORE ABOUT WHAT IS 3031 02:37:55,120 --> 02:37:58,480 HAPPENING IN AFRICA IN COVID. 3032 02:37:58,480 --> 02:38:02,920 WE HEAR A LOT OF DIFFERENT 3033 02:38:02,920 --> 02:38:07,240 THINGS AND IT WOULD BE GREAT IF 3034 02:38:07,240 --> 02:38:10,200 YOU CAN TELL US MORE SINCE YOU 3035 02:38:10,200 --> 02:38:11,360 WERE SO MUCH BELOW YOUR ASSIGNED 3036 02:38:11,360 --> 02:38:15,160 TIME YOU'RE NOT FREE TO GO YET. 3037 02:38:15,160 --> 02:38:17,680 >> I WAS TERRIFIED OF DELAYING 3038 02:38:17,680 --> 02:38:18,400 LUNCH. 3039 02:38:18,400 --> 02:38:22,680 I'M GLAD I DID SAVE US SOME 3040 02:38:22,680 --> 02:38:23,040 TIME. 3041 02:38:23,040 --> 02:38:26,720 I THINK THE WORLD REALLY KNOWS 3042 02:38:26,720 --> 02:38:28,640 WHAT IS HAPPENING IN SOUTH 3043 02:38:28,640 --> 02:38:30,440 AFRICA BECAUSE THERE'S GOOD DATA 3044 02:38:30,440 --> 02:38:33,920 AND GOOD INFRASTRUCTURE THAT'S 3045 02:38:33,920 --> 02:38:34,200 COME -- 3046 02:38:34,200 --> 02:38:37,840 >> THERE ARE OTHER PLACES. 3047 02:38:37,840 --> 02:38:44,920 >> PLACES LIKE NIGERIA OF 200 3048 02:38:44,920 --> 02:38:50,920 MILLION THAT WE DO NOT SEE A 3049 02:38:50,920 --> 02:38:53,160 SIGNIFICANT AMOUNT OF 3050 02:38:53,160 --> 02:38:53,640 SYMPTOMATIC COVID. 3051 02:38:53,640 --> 02:38:55,880 I KNOW THERE IS UNDER REPORTING. 3052 02:38:55,880 --> 02:38:58,720 I KNOW THERE'S UNDER TESTING BUT 3053 02:38:58,720 --> 02:39:01,320 YOU CANNOT ARGUE WITH THE FACT 3054 02:39:01,320 --> 02:39:04,200 THAT THE HOSPITALS AT SOME STAGE 3055 02:39:04,200 --> 02:39:06,560 WHEN COVID STARTED WERE ALL 3056 02:39:06,560 --> 02:39:07,440 PACKED WITH INDIVIDUALS THAT 3057 02:39:07,440 --> 02:39:10,880 WERE REALLY SICK AND DYING OF 3058 02:39:10,880 --> 02:39:14,080 COVID AND THOSE ISOLATION UNITS 3059 02:39:14,080 --> 02:39:16,640 ARE PRETTY MUCH EMPTY NOW. 3060 02:39:16,640 --> 02:39:19,120 VACCINATION LEVEL IS VERY LOW. 3061 02:39:19,120 --> 02:39:22,040 IT'S 8% TO 10% OF INDIVIDUALS 3062 02:39:22,040 --> 02:39:23,520 THAT ARE VACCINATED. 3063 02:39:23,520 --> 02:39:26,840 WE KNOW FOR A FACT THAT THE 3064 02:39:26,840 --> 02:39:28,840 RURAL AREAS BECAUSE MOST OF THE 3065 02:39:28,840 --> 02:39:30,440 TIME EVERYBODY'S OUTDOOR IN THE 3066 02:39:30,440 --> 02:39:32,520 PONDS AND EVERYTHING HARDLY USE 3067 02:39:32,520 --> 02:39:33,520 ANY MASK. 3068 02:39:33,520 --> 02:39:34,640 VERY LITTLE COMING FROM RURAL 3069 02:39:34,640 --> 02:39:35,040 AREAS. 3070 02:39:35,040 --> 02:39:38,960 MOST THE INFECTIONS ARE WITHIN 3071 02:39:38,960 --> 02:39:42,720 THE CITIES AS YOU WOULD EXPECT 3072 02:39:42,720 --> 02:39:44,920 BUT REALLY NOT AS MUCH 3073 02:39:44,920 --> 02:39:48,320 DEVASTATION THAT WAS PREDICTED. 3074 02:39:48,320 --> 02:39:50,720 >> BUT HOW MUCH OF THAT DO YOU 3075 02:39:50,720 --> 02:39:53,520 THINK IS CAUSED BY THE YOUNG 3076 02:39:53,520 --> 02:39:56,920 POPULATION WHICH IS TOTALLY 3077 02:39:56,920 --> 02:39:58,560 DIFFERENT THAN EUROPEAN 3078 02:39:58,560 --> 02:40:05,000 ETCETERA, CHINESE SOCIETIES. 3079 02:40:05,000 --> 02:40:06,720 >> I THINK AT THE BEGINNING OF 3080 02:40:06,720 --> 02:40:09,520 THE PANDEMIC THAT WAS THE 3081 02:40:09,520 --> 02:40:12,800 BIGGEST IMPACT UNTIL THE VARIOUS 3082 02:40:12,800 --> 02:40:18,040 MUTANTS STARTED INFECTING THE 3083 02:40:18,040 --> 02:40:21,560 YOUNGER POPULATION AND I KNOW 3084 02:40:21,560 --> 02:40:23,720 THERE'S SOME NERVOUSNESS IN 3085 02:40:23,720 --> 02:40:25,440 TERMS OF THE LOW VACCINE 3086 02:40:25,440 --> 02:40:26,960 COVERAGE AND THERE'S A STRONG 3087 02:40:26,960 --> 02:40:30,280 PUSH TO IMPROVE ON THAT. 3088 02:40:30,280 --> 02:40:34,920 BUT I THINK A LOT OF THE OUTDOOR 3089 02:40:34,920 --> 02:40:37,360 KINDS OF INTERACTIONS WOULD HAVE 3090 02:40:37,360 --> 02:40:54,240 HELPED A LOT. 3091 02:40:54,240 --> 02:40:56,080 >> HOLD ON. 3092 02:40:56,080 --> 02:40:58,320 NOT EVERYONE IS IN THE TREES IN 3093 02:40:58,320 --> 02:40:58,920 NIGERIA. 3094 02:40:58,920 --> 02:41:00,200 >> IF YOU GO TO THE RURAL AREAS 3095 02:41:00,200 --> 02:41:02,160 HARDLY ANY MASK AT ALL AND YET 3096 02:41:02,160 --> 02:41:04,640 IT'S VERY LOW. 3097 02:41:04,640 --> 02:41:10,160 MOST THE RURAL AREAS ARE -- I GO 3098 02:41:10,160 --> 02:41:12,520 WITH MY MOM AND EVERYBODY'S IN 3099 02:41:12,520 --> 02:41:13,120 THE CORRIDOR BECAUSE IT'S SO 3100 02:41:13,120 --> 02:41:21,120 WARM. 3101 02:41:21,120 --> 02:41:22,840 >> WHAT IS HAPPENING WITH 3102 02:41:22,840 --> 02:41:24,480 VACCINATION IN AFRICA? 3103 02:41:24,480 --> 02:41:27,560 A YEAR AGO IT WAS THE MOST 3104 02:41:27,560 --> 02:41:29,560 URGENT THING IN THE WORLD AND 3105 02:41:29,560 --> 02:41:33,320 SOME ARE SAYING HOLD ON TO THE 3106 02:41:33,320 --> 02:41:34,320 VACCINES UNTIL WE BUILD 3107 02:41:34,320 --> 02:41:34,680 INFRASTRUCTURE. 3108 02:41:34,680 --> 02:41:39,240 WHAT DO YOU THINK IS THE ROLE IN 3109 02:41:39,240 --> 02:41:39,520 P 3110 02:41:39,520 --> 02:41:41,040 PEPFAR OR HOW MUCH HELP IS 3111 02:41:41,040 --> 02:41:44,320 NEEDED AND WHAT'S HAPPENING WITH 3112 02:41:44,320 --> 02:41:45,800 THE NEW VARIANTS? 3113 02:41:45,800 --> 02:41:49,320 AS YOU SAID THE NEW VARIANTS ARE 3114 02:41:49,320 --> 02:41:50,480 DOING A TOTALLY DIFFERENT JOB 3115 02:41:50,480 --> 02:41:51,880 THAN INITIALLY. 3116 02:41:51,880 --> 02:41:53,040 >> ABSOLUTELY. 3117 02:41:53,040 --> 02:41:56,000 THESE ARE ALL VERY GOOD POINTS. 3118 02:41:56,000 --> 02:41:58,080 ONE THING PEPFAR HAS DONE REALLY 3119 02:41:58,080 --> 02:42:00,200 WELL IS TO MOVE AND USE THE 3120 02:42:00,200 --> 02:42:02,920 INFRASTRUCTURE FOR ALL THE PCR 3121 02:42:02,920 --> 02:42:03,120 TESTING. 3122 02:42:03,120 --> 02:42:06,120 FOR INSTANCE, ALL OF OUR 3123 02:42:06,120 --> 02:42:08,400 LABORATORIES THAT WERE FOR VIRAL 3124 02:42:08,400 --> 02:42:11,440 LOADING AND EARLY DIAGNOSIS WERE 3125 02:42:11,440 --> 02:42:13,240 ALL CONVERTED TO TESTING FOR 3126 02:42:13,240 --> 02:42:13,440 COVID. 3127 02:42:13,440 --> 02:42:16,480 NOW WE HAVE THE ANTIGEN-BASED 3128 02:42:16,480 --> 02:42:17,720 TEST THAT IS HAPPENING. 3129 02:42:17,720 --> 02:42:20,560 I THINK THE NEGATIVE PART OF THE 3130 02:42:20,560 --> 02:42:23,320 HARM THAT WAS DONE IN TERMS OF 3131 02:42:23,320 --> 02:42:28,920 VACCINE UPTAKE IS SOCIAL MEDIA. 3132 02:42:28,920 --> 02:42:31,400 AND ALL OF THE -- THERE ARE SO 3133 02:42:31,400 --> 02:42:33,880 MANY RELIGIOUS COUNTRIES. 3134 02:42:33,880 --> 02:42:35,520 NIGERIA IS DEFINITELY RELIGIOUS 3135 02:42:35,520 --> 02:42:38,600 AND WHEN YOU HAVE PASTORS AND 3136 02:42:38,600 --> 02:42:39,760 INDIVIDUALS SAYING THIS IS NOT 3137 02:42:39,760 --> 02:42:41,840 GOOD FOR YOU THEN IT REALLY 3138 02:42:41,840 --> 02:42:42,080 IMPACTS. 3139 02:42:42,080 --> 02:42:43,440 SO ONE OF THE THINGS THEY'RE 3140 02:42:43,440 --> 02:42:47,560 DOING THAT IS REALLY TRYING TO 3141 02:42:47,560 --> 02:42:47,960 EDUCATE. 3142 02:42:47,960 --> 02:42:49,040 IN TERMS OF CAPACITY IT'S LIKE 3143 02:42:49,040 --> 02:42:51,840 YOU MENTIONED THE FREEZERS AND 3144 02:42:51,840 --> 02:42:53,240 EVERYTHING THAT HAS BEEN PUMPED 3145 02:42:53,240 --> 02:42:55,520 INTO A LOT OF THE COUNTRIES 3146 02:42:55,520 --> 02:43:00,680 THROUGH PEPFAR HAVE BEEN 3147 02:43:00,680 --> 02:43:02,520 SUPPORTED. 3148 02:43:02,520 --> 02:43:04,440 >> DO YOU THINK THAT THERE WILL 3149 02:43:04,440 --> 02:43:08,160 BE MORE THAN USUAL RESISTANCE TO 3150 02:43:08,160 --> 02:43:09,320 VACCINATION BECAUSE OF SOME OF 3151 02:43:09,320 --> 02:43:12,360 THE REASONS THAT YOU MENTIONED? 3152 02:43:12,360 --> 02:43:14,960 >> I THINK THERE'S STILL A LOT 3153 02:43:14,960 --> 02:43:15,960 OF RESISTANCE. 3154 02:43:15,960 --> 02:43:16,720 THERE'S A LOT OF EDUCATION THAT 3155 02:43:16,720 --> 02:43:19,480 HAS TO GO IN AND MORE AND MORE 3156 02:43:19,480 --> 02:43:22,280 PEOPLE -- IT'S REALLY SAD 3157 02:43:22,280 --> 02:43:24,760 BECAUSE YOU WONDER IF WE HAVE 3158 02:43:24,760 --> 02:43:26,960 HAD A WORSE IMPACT MAYBE PEOPLE 3159 02:43:26,960 --> 02:43:29,480 WOULD HAVE TAKEN VACCINATION 3160 02:43:29,480 --> 02:43:31,440 MORE SERIOUSLY. 3161 02:43:31,440 --> 02:43:34,800 YOU DON'T WISH THAT FOR ANYBODY 3162 02:43:34,800 --> 02:43:35,920 SO IT HAS TO BE A LOT OF 3163 02:43:35,920 --> 02:43:38,240 EDUCATION AND YOU'VE GOT TO 3164 02:43:38,240 --> 02:43:41,960 BRING ALL THE OPINION LEADERS 3165 02:43:41,960 --> 02:43:44,040 AND THEY MUST PENETRATE -- WE 3166 02:43:44,040 --> 02:43:46,320 MUST PENETRATE THE CHURCHES AND 3167 02:43:46,320 --> 02:43:48,680 THE MOSQUES OTHERWISE WE'RE NOT 3168 02:43:48,680 --> 02:43:49,920 GOING GET THE VACCINATION. 3169 02:43:49,920 --> 02:43:52,040 >> OKAY. 3170 02:43:52,040 --> 02:43:52,720 ANY OTHER QUESTIONS? 3171 02:43:52,720 --> 02:44:00,680 BOB IS HUNGRY. 3172 02:44:00,680 --> 02:44:00,920 OKAY. 3173 02:44:00,920 --> 02:44:08,680 THANK YOU SO MUCH. 3174 02:44:08,680 --> 02:44:13,800 >> LET ME INTRODUCE THE SPEAKER, 3175 02:44:13,800 --> 02:44:18,400 FROM THE COALITION OF ACADEMIC 3176 02:44:18,400 --> 02:44:19,640 PREPAREDNESS FROM NORWAY WHO 3177 02:44:19,640 --> 02:44:23,960 WILL TELL US ABOUT NON-UTILIZING 3178 02:44:23,960 --> 02:44:25,520 ANTIBODIES FOR EPIDEMIC 3179 02:44:25,520 --> 02:44:26,000 PREPAREDNESS. 3180 02:44:26,000 --> 02:44:28,800 THANK YOU. 3181 02:44:28,800 --> 02:44:31,360 >> GOOD AFTERNOON, EVERYONE. 3182 02:44:31,360 --> 02:44:34,440 WHAT A CHALLENGE TO BE THE FIRST 3183 02:44:34,440 --> 02:44:34,960 SPEAKER AFTER LUNCH. 3184 02:44:34,960 --> 02:44:38,440 I WILL TRY TO KEEP US ALL AWAKE. 3185 02:44:38,440 --> 02:44:39,760 FIRST THANK YOU TO THE 3186 02:44:39,760 --> 02:44:41,760 ORGANIZERS FOR INVITING ME TO 3187 02:44:41,760 --> 02:44:43,880 PARTICIPATE IN THIS SYMPOSIUM. 3188 02:44:43,880 --> 02:44:46,280 I HOPE THAT IT'S -- I ADD TO 3189 02:44:46,280 --> 02:44:48,160 CELEBRATION OF MARJORIE'S CAREER 3190 02:44:48,160 --> 02:44:51,120 AND I WILL TRY TO BE BRIEF IN 3191 02:44:51,120 --> 02:44:53,640 THE PRESENTATION OF WHAT 3192 02:44:53,640 --> 02:44:56,720 REGARDING ADCC PRIMARILY, ADCC 3193 02:44:56,720 --> 02:44:58,360 AND HOPEFULLY SHED REFLECTIONS 3194 02:44:58,360 --> 02:45:01,000 ON ADCC AND EPIDEMIC 3195 02:45:01,000 --> 02:45:05,000 PREPAREDNESS INNOVATIONS. 3196 02:45:05,000 --> 02:45:07,400 THIS IS THE OVERVIEW OF MY TALK, 3197 02:45:07,400 --> 02:45:11,000 I WILL TALK PRIMARILY ABOUT 3198 02:45:11,000 --> 02:45:13,120 ADCC, HISTORY OF ADCC IN 3199 02:45:13,120 --> 02:45:14,600 MARJORIE'S LAB AND BRIEFLY 3200 02:45:14,600 --> 02:45:15,840 MENTION OTHER FC MEDIATED 3201 02:45:15,840 --> 02:45:18,040 MECHANISMS OF PROTECTION. 3202 02:45:18,040 --> 02:45:42,560 I WILL END ONSO I THINK 3203 02:45:42,560 --> 02:45:44,000 AS A BRIEF INTRODUCTION OF WHAT 3204 02:45:44,000 --> 02:45:45,560 WE WILL TALK ABOUT HERE I WANT 3205 02:45:45,560 --> 02:45:49,920 -- I RAN A QUICK SEARCH JUST 3206 02:45:49,920 --> 02:45:55,200 PUTTING IN THE WORDS HIV AND 3207 02:45:55,200 --> 02:45:59,800 HDCC ON PUBMED, YOU GET ROUGHRY 3208 02:45:59,800 --> 02:46:02,000 150 PUBLICATIONS BETWEEN 1985 3209 02:46:02,000 --> 02:46:04,240 AND RECENTLY. 3210 02:46:04,240 --> 02:46:09,600 FROM THIS GRAPH THEY PRETTY MUCH 3211 02:46:09,600 --> 02:46:11,120 LIE WITHIN THREE PERIODS OF 3212 02:46:11,120 --> 02:46:11,320 TIME. 3213 02:46:11,320 --> 02:46:12,720 THE FIRST PERIOD OF TIME WAS 3214 02:46:12,720 --> 02:46:13,840 SHORTLY AFTER THE VIRUS WAS 3215 02:46:13,840 --> 02:46:16,400 DISCOVERED AND FOR THE FIRST 15 3216 02:46:16,400 --> 02:46:18,160 YEARS YOU SEE PUBLICATIONS FROM 3217 02:46:18,160 --> 02:46:18,560 SWEDEN. 3218 02:46:18,560 --> 02:46:22,760 THERE'S A LOT OF OBLIGATIONS 3219 02:46:22,760 --> 02:46:24,200 FROM (INAUDIBLE) LAB, SEVERAL 3220 02:46:24,200 --> 02:46:25,520 PUBLICATIONS FROM U.S. FOLKS AND 3221 02:46:25,520 --> 02:46:27,960 COUPLE OF PUBLICATIONS FROM 3222 02:46:27,960 --> 02:46:28,360 CANADIAN FOLKS. 3223 02:46:28,360 --> 02:46:30,000 THIS IS THE FIRST 15 YEARS OR 3224 02:46:30,000 --> 02:46:30,600 SO. 3225 02:46:30,600 --> 02:46:31,920 THEN YOU CAN SEE THAT THERE WAS 3226 02:46:31,920 --> 02:46:34,600 A PERIOD OF TIME WHEN 3227 02:46:34,600 --> 02:46:36,360 PUBLICATION, I WOULDN'T SAY THEY 3228 02:46:36,360 --> 02:46:37,960 SUBSIDE BUD THEY WERE LOWER. 3229 02:46:37,960 --> 02:46:38,880 BUT NOT LESS IMPORTANT. 3230 02:46:38,880 --> 02:46:40,640 OF COURSE, THIS IS ACTUALLY A 3231 02:46:40,640 --> 02:46:42,120 PERIOD OF TIME WHEN MARJORIE 3232 02:46:42,120 --> 02:46:43,800 STARTED PUBLISHING ON THIS, YOU 3233 02:46:43,800 --> 02:46:45,200 ALSO HAVE SEVERAL OTHER NAMES 3234 02:46:45,200 --> 02:46:49,240 FROM THE US. DAVID MONTEFURI, 3235 02:46:49,240 --> 02:46:51,240 DENISE BURTON AND YOU CONTINUE 3236 02:46:51,240 --> 02:46:52,240 TO HAVE CANADIAN FOLKS, YOU 3237 02:46:52,240 --> 02:46:55,320 BEGIN TO HAVE AUSTRALIAN FOLKS, 3238 02:46:55,320 --> 02:46:57,400 SOME IN SWITZERLAND BUT MOST 3239 02:46:57,400 --> 02:46:59,000 IMPORTANTLY GETTING INITIAL DATA 3240 02:46:59,000 --> 02:47:01,080 ON MULTI-CENTER TRIALS WHICH IS 3241 02:47:01,080 --> 02:47:01,680 QUITE IMPORTANT. 3242 02:47:01,680 --> 02:47:03,800 THEY START EXAMINING THE ROLE OF 3243 02:47:03,800 --> 02:47:08,360 ADCC IN CONTEXT OF HIV AIDS AND 3244 02:47:08,360 --> 02:47:11,360 HIV VACCINE TRIALS. 3245 02:47:11,360 --> 02:47:13,240 THEN YOU HAVE I WOULDN'T CALL 3246 02:47:13,240 --> 02:47:15,760 EXPLOSION BUT A LARGER SET OF 3247 02:47:15,760 --> 02:47:17,080 PUBLICATIONS HERE AND THIS IS 3248 02:47:17,080 --> 02:47:20,000 WHERE YOU ENTER A -- THE BROADER 3249 02:47:20,000 --> 02:47:21,280 INTERNATIONAL SCENE I WOULD SAY 3250 02:47:21,280 --> 02:47:23,000 BEYOND JUST THE U.S. AND EUROPE 3251 02:47:23,000 --> 02:47:25,320 YOU START SEEING A LOT OF 3252 02:47:25,320 --> 02:47:26,000 PUBLICATIONS FROM CHINA FOR 3253 02:47:26,000 --> 02:47:28,600 EXAMPLE, YOU SEE A LOT OF GROUPS 3254 02:47:28,600 --> 02:47:30,120 PUBLISHING IN SYSTEMS IMMUNOLOGY 3255 02:47:30,120 --> 02:47:31,800 APPROACHES AND WE WILL HEAR THAT 3256 02:47:31,800 --> 02:47:33,520 FROM OTHER SPEAKERS. 3257 02:47:33,520 --> 02:47:36,800 BUT AGAIN JUST TO SAY THAT 3258 02:47:36,800 --> 02:47:37,600 NON-NEUTRALIZING ANTIBODY 3259 02:47:37,600 --> 02:47:39,720 RESPONSES OF COURSE GO BEYOND 3260 02:47:39,720 --> 02:47:40,400 ADCC. 3261 02:47:40,400 --> 02:47:43,640 THIS IS PERHAPS THE THIRD PERIOD 3262 02:47:43,640 --> 02:47:46,000 OF TIME SHED LIGHT ON ADDITIONAL 3263 02:47:46,000 --> 02:47:46,840 MECHANISMS OF POTENTIAL 3264 02:47:46,840 --> 02:47:50,280 PROTECTION. 3265 02:47:50,280 --> 02:47:53,760 SO I WAS VERY HONORED TO BE IN 3266 02:47:53,760 --> 02:47:57,720 MARJORIE'S LAB IN -- TRYING TO 3267 02:47:57,720 --> 02:48:13,320 SEE THE POINTER HERE. 3268 02:48:13,320 --> 02:48:17,800 I WAS IN MARJORIE'S LAB HERE. 3269 02:48:17,800 --> 02:48:22,200 IN THIS PERIOD, MORE OR LESS 3270 02:48:22,200 --> 02:48:23,600 BETWEEN 2001 AND 2005 BUT 3271 02:48:23,600 --> 02:48:25,400 SEVERAL PUBLICATIONS OF THE WORK 3272 02:48:25,400 --> 02:48:29,440 THAT WE DID TOGETHER HAPPENED 3273 02:48:29,440 --> 02:48:30,880 MUCH LATER THAN THAT, THEY 3274 02:48:30,880 --> 02:48:32,120 CONTINUE HAPPENING AND I WAS 3275 02:48:32,120 --> 02:48:33,800 VERY HAPPY AND HONORED TO BE 3276 02:48:33,800 --> 02:48:34,680 PART OF THE LAB DURING THAT 3277 02:48:34,680 --> 02:48:36,600 TIME. 3278 02:48:36,600 --> 02:48:39,560 I THINK ONE OF THE ITEMS THAT I 3279 02:48:39,560 --> 02:48:41,120 WANTED TO GET ACROSS HERE WAS 3280 02:48:41,120 --> 02:48:43,080 WHEN I ARRIVED INTO MARJORIE'S 3281 02:48:43,080 --> 02:48:45,520 LAB I DID ASK -- I REMEMBER 3282 02:48:45,520 --> 02:48:46,520 ASKING MARJORIE IS ANYONE 3283 02:48:46,520 --> 02:48:48,160 LOOKING AT ADCC? 3284 02:48:48,160 --> 02:48:52,160 SHE SAID WE HAVE LOOKED AT IT 3285 02:48:52,160 --> 02:48:54,520 BUBO PRETTY MESSY ASSAYS THEY 3286 02:48:54,520 --> 02:48:55,640 REQUIRE CHROMIUM RELEASE, I 3287 02:48:55,640 --> 02:48:57,960 DIDN'T WANT TO WORK WITH 3288 02:48:57,960 --> 02:48:58,880 CHROMIUM RELEASE ASSAYS. 3289 02:48:58,880 --> 02:49:00,000 I WANTED TO AVOID THEM. 3290 02:49:00,000 --> 02:49:01,240 SO SHE SAID WHY DON'T YOU COME 3291 02:49:01,240 --> 02:49:02,800 UP WITH WHAT AN ASSAY, VERY 3292 02:49:02,800 --> 02:49:04,000 SUPPORTIVE OF THIS PROCESS 3293 02:49:04,000 --> 02:49:06,080 COMING UP WITH SAY ASSAY AND 3294 02:49:06,080 --> 02:49:09,800 WHAT WE STARTED TO DOING IS 3295 02:49:09,800 --> 02:49:12,160 ADAPTING ASSAY AND REBRANDED FOR 3296 02:49:12,160 --> 02:49:16,800 ADCC AND WE NAMED IT RAPID FLOUR 3297 02:49:16,800 --> 02:49:19,000 METRIC ADCC ASSAY. 3298 02:49:19,000 --> 02:49:22,040 IT WAS SIMPLE, LOOKS RUDIMENTARY 3299 02:49:22,040 --> 02:49:23,040 COMPARED TO WHAT OTHERS ARE 3300 02:49:23,040 --> 02:49:25,720 DOING BUT AT THE TIME WE DID 3301 02:49:25,720 --> 02:49:27,880 BASICALLY LABELING DOUBLE 3302 02:49:27,880 --> 02:49:31,120 LABELING TARGET CELLS, THESE ARE 3303 02:49:31,120 --> 02:49:33,680 TARGET CELLS WE WERE DOUBLE 3304 02:49:33,680 --> 02:49:35,440 LABELING WITH MEMBRANE BODY 3305 02:49:35,440 --> 02:49:38,400 WHICH IS PKH 26. 3306 02:49:38,400 --> 02:49:41,320 PERMEABILITY WHICH IS CFSC. 3307 02:49:41,320 --> 02:49:43,520 WHAT YOU WOULD SEE BY LABELING 3308 02:49:43,520 --> 02:49:45,400 THE EFFECTOR CELLS YOU SEE IN 3309 02:49:45,400 --> 02:49:47,840 THIS QUADRANT AND THEY ARE UNDER 3310 02:49:47,840 --> 02:49:50,720 TWO FLOW CYTOMETRY ASSAY. 3311 02:49:50,720 --> 02:49:53,040 IN THE PRESENCE OF ADCC ANTIBODY 3312 02:49:53,040 --> 02:49:54,280 YOU SEE KILLING AND BY GATING 3313 02:49:54,280 --> 02:49:55,760 YOU WOULD BE ABLE TO CALCULATE 3314 02:49:55,760 --> 02:49:57,360 THE PERCENTAGE OF KILLING. 3315 02:49:57,360 --> 02:50:03,920 AND YOU WOULD HAVE CONTROLS IGG 3316 02:50:03,920 --> 02:50:05,800 1 CONTROL WHICH WHICH WE THOUGHT 3317 02:50:05,800 --> 02:50:06,760 WAS APPROPRIATE BECAUSE IT 3318 02:50:06,760 --> 02:50:07,880 ALLOWED US NOT TO WORK WITH 3319 02:50:07,880 --> 02:50:11,320 RADIO ACTIVITY WHICH I DID NOT 3320 02:50:11,320 --> 02:50:13,000 WANT TO DO AND IT WAS SIMPLE FOR 3321 02:50:13,000 --> 02:50:15,640 THE TIME, ALSO SEEMED RELATIVELY 3322 02:50:15,640 --> 02:50:16,960 HIGH THROUGH PUT AND ENABLED US 3323 02:50:16,960 --> 02:50:18,360 TO START ANSWERING SOME OF THE 3324 02:50:18,360 --> 02:50:19,200 QUESTIONS THAT WE WANTED TO 3325 02:50:19,200 --> 02:50:21,000 ADDRESS. 3326 02:50:21,000 --> 02:50:24,120 SO THE FIRST PUBLICATION THAT WE 3327 02:50:24,120 --> 02:50:26,720 GOT OUT USING THIS ASSAY, THIS 3328 02:50:26,720 --> 02:50:30,240 IS THE PUBLICATION FROM JOURNAL 3329 02:50:30,240 --> 02:50:31,400 IMMUNOLOGY IN 2006. 3330 02:50:31,400 --> 02:50:34,680 WE WENT BACK AND LOOKED AT SERUM 3331 02:50:34,680 --> 02:50:37,200 SAMPLES FROM COLLEAGUES PRIMED 3332 02:50:37,200 --> 02:50:39,920 AND BOOSTED, PRIME WITH VARIOUS 3333 02:50:39,920 --> 02:50:41,040 ADENOVIRUSES, VACCINES AND 3334 02:50:41,040 --> 02:50:43,160 BOOSTED WITH PROTEIN AND WE SAW 3335 02:50:43,160 --> 02:50:44,600 IF THEY TESTED THE SAMPLES USING 3336 02:50:44,600 --> 02:50:46,840 THIS ASSAY YOU CAN SEE VERY HIGH 3337 02:50:46,840 --> 02:50:49,000 LEVELS OF ADCC ACTIVITY, 3338 02:50:49,000 --> 02:50:50,640 ACTIVITY ACTUALLY TITRATES ALL 3339 02:50:50,640 --> 02:50:53,320 THE WAY -- YOU CAN DETECT SOME 3340 02:50:53,320 --> 02:50:55,360 ACTIVITY AT ONE TO 100,000 3341 02:50:55,360 --> 02:50:56,640 DILUTION BUT THE LINEAR RANGE I 3342 02:50:56,640 --> 02:50:59,560 WOULD SAY WOULD BE AROUND AT THE 3343 02:50:59,560 --> 02:51:02,560 TIME AROUND 10 -- 1 IN 10,000. 3344 02:51:02,560 --> 02:51:06,720 WE SAW THAT THIS ACTIVITY IN -- 3345 02:51:06,720 --> 02:51:08,040 WAS PRESENT IN THE -- PRIME 3346 02:51:08,040 --> 02:51:10,200 BOOSTED WITH VARIOUS VACCINES, 3347 02:51:10,200 --> 02:51:12,080 THIS WAS DISTINGUISHABLE FROM 3348 02:51:12,080 --> 02:51:14,720 THE CONTROL ANIMALS WHICH WERE 3349 02:51:14,720 --> 02:51:21,000 JUST PRIME BOOSTED WITH 3350 02:51:21,000 --> 02:51:24,680 NON-ADENOVIRUS VACCINE, EMPTY 3351 02:51:24,680 --> 02:51:26,200 VECTOR VACCINE AND NOT BOOSTED 3352 02:51:26,200 --> 02:51:26,600 WITH PROTEIN. 3353 02:51:26,600 --> 02:51:30,120 YOU CAN SEE SOME LEVEL OF 3354 02:51:30,120 --> 02:51:32,600 ACTIVITIES IN COWS PRIME WITH 3355 02:51:32,600 --> 02:51:35,600 ADENOVIRUS SIV AND VACCINE BUT 3356 02:51:35,600 --> 02:51:37,040 BOOSTED ONLY WITH VECTOR. 3357 02:51:37,040 --> 02:51:39,080 SO THIS WAS THE INITIAL 3358 02:51:39,080 --> 02:51:40,200 UNDERSECURITIZATION WE SAW SOME 3359 02:51:40,200 --> 02:51:42,280 ACTIVITY. 3360 02:51:42,280 --> 02:51:45,080 BUT THE IMPETUS FOR LOOKING AT 3361 02:51:45,080 --> 02:51:46,520 THIS THAT MACAQUES WERE LOOKED 3362 02:51:46,520 --> 02:51:49,680 AT PREVIOUSLY UNDER OTHER 3363 02:51:49,680 --> 02:51:50,840 PUBLICATIONS AND THAT YES KNEW 3364 02:51:50,840 --> 02:51:53,360 THERE WAS PROTECTION -- WE KNEW 3365 02:51:53,360 --> 02:51:54,880 THERE WAS PROTECTION DURING 3366 02:51:54,880 --> 02:51:57,120 ACUTE VIEW REAMIA, IT WAS 3367 02:51:57,120 --> 02:51:58,040 IMPORTANT ADENOVIRUS VACCINES AT 3368 02:51:58,040 --> 02:52:00,240 LEVEL OF PROTECTION, BUT THIS 3369 02:52:00,240 --> 02:52:02,560 COULDN'T BE EXPLAINED BY 3370 02:52:02,560 --> 02:52:04,840 NEUTRALIZING ANTIBODIES BECAUSE 3371 02:52:04,840 --> 02:52:08,640 SIV IS EXTREMELY DIFFICULT TO 3372 02:52:08,640 --> 02:52:09,160 NEUTRALIZE, NEUTRALIZING 3373 02:52:09,160 --> 02:52:10,160 ACTIVITY WAS MEASURED BUT NOT 3374 02:52:10,160 --> 02:52:11,200 PRESENT. 3375 02:52:11,200 --> 02:52:12,680 SO THE IMPETUS, I WANT TO 3376 02:52:12,680 --> 02:52:15,000 EMPHASIZE THAT HERE, THE IMPETUS 3377 02:52:15,000 --> 02:52:18,200 WAS TRYING TO FIND SOME LEVEL OF 3378 02:52:18,200 --> 02:52:21,040 ASSOCIATION OR CORRELATE OF 3379 02:52:21,040 --> 02:52:26,320 PROTECTION AGAINST SIVMAC 251 IN 3380 02:52:26,320 --> 02:52:27,920 THIS MODEL. 3381 02:52:27,920 --> 02:52:29,480 WHAT WE DID TOGETHER DAVID'S 3382 02:52:29,480 --> 02:52:31,880 GROUP BY STATISTICS WE STARTED 3383 02:52:31,880 --> 02:52:33,560 DRAWING CORRELATIONS AND SAW 3384 02:52:33,560 --> 02:52:37,440 THAT ADCC ACTIVITY CORRELATED 3385 02:52:37,440 --> 02:52:40,240 WITH LOWER ACUTE VIRAL LOADS. 3386 02:52:40,240 --> 02:52:42,680 THIS IS -- THIS WAS TESTED 3387 02:52:42,680 --> 02:52:53,360 AGAINST S SIVMAC 251 H 9 CELLS AND 3388 02:52:53,360 --> 02:52:55,800 CORRELATED WITH GTB ANTIBODY 3389 02:52:55,800 --> 02:52:59,080 BINDING -- GP 120 ANTIBODY 3390 02:52:59,080 --> 02:53:00,480 BINDING TITRATES. 3391 02:53:00,480 --> 02:53:02,160 SO THIS WAS VERY GOOD FINDING 3392 02:53:02,160 --> 02:53:06,000 FOR US, WE CONTINUED TO BE 3393 02:53:06,000 --> 02:53:07,200 INTERESTED ON THIS, MARJORIE 3394 02:53:07,200 --> 02:53:08,080 CONTINUED TO BE SUPPORTIVE OF 3395 02:53:08,080 --> 02:53:09,960 LOOKING AT ADDITIONAL 3396 02:53:09,960 --> 02:53:10,840 EXPERIMENTS AND I BELIEVE IN THE 3397 02:53:10,840 --> 02:53:12,960 LAB THAT THAT KEPT HAPPENING 3398 02:53:12,960 --> 02:53:16,400 QUITE SOME TIME. 3399 02:53:16,400 --> 02:53:17,800 ADDRESSING TWO OTHER POSITIONS 3400 02:53:17,800 --> 02:53:19,120 LATER BE U STILL ABLE TO 3401 02:53:19,120 --> 02:53:20,960 FOLLOW-UP ON SOME EXPERIMENTS, 3402 02:53:20,960 --> 02:53:22,520 AND ONE OF THE POINTS I WANTED 3403 02:53:22,520 --> 02:53:26,440 TO GET ACROSS WITH THIS SLIDE IS 3404 02:53:26,440 --> 02:53:29,000 KINETICS YOU CAN ACTUALLY SEE 3405 02:53:29,000 --> 02:53:30,880 SOME MEASURABLE ADCC ACTIVITY, 3406 02:53:30,880 --> 02:53:33,000 NOT VERY HIGH BUT YOU SEE SOME 3407 02:53:33,000 --> 02:53:35,120 MEASURABLE ADCC ACTIVITY RIGHT 3408 02:53:35,120 --> 02:53:39,400 AFTER PRIMING WITH THE VECTOR. 3409 02:53:39,400 --> 02:53:41,760 OF COURSE YOU SEE THE ACTIVITY 3410 02:53:41,760 --> 02:53:44,080 GOING UP BEING HIGHER AFTER YOU 3411 02:53:44,080 --> 02:53:47,160 BOOST AND ESPECIALLY RESPONSE TO 3412 02:53:47,160 --> 02:53:47,800 CHALLENGE. 3413 02:53:47,800 --> 02:53:52,040 THIS WAS REPLICATED IN HIV AND 3414 02:53:52,040 --> 02:53:53,720 ADENOVIRUS HIV RECOMBINANT 3415 02:53:53,720 --> 02:53:58,000 VACCINE MODEL USING THE 3416 02:53:58,000 --> 02:53:58,600 CHIMPANZEE MODEL. 3417 02:53:58,600 --> 02:53:59,920 YOU CAN SEE COMPARISON HERE 3418 02:53:59,920 --> 02:54:01,560 WHERE YOU SEE AFTER PRIMING WITH 3419 02:54:01,560 --> 02:54:05,520 THE ADENOVIRUS HIV RECOMBINANT 3420 02:54:05,520 --> 02:54:08,480 VACCINE YOU SEE AGAIN SOME LEVEL 3421 02:54:08,480 --> 02:54:10,440 OF ADCC ACTIVITY, NOT HIGH BUT 3422 02:54:10,440 --> 02:54:12,680 YOU SEE IT AND THEN YOU SEE THAT 3423 02:54:12,680 --> 02:54:16,200 GOING HIGHER AFTER BOOSTING WITH 3424 02:54:16,200 --> 02:54:18,240 GP 140 PROTEIN WHICH IN THIS 3425 02:54:18,240 --> 02:54:21,280 CASE WAS GIVEN IN I BELIEVE IN 3426 02:54:21,280 --> 02:54:22,080 59 ADJUVANT. 3427 02:54:22,080 --> 02:54:23,400 YOU CAN SEE CERTAIN DIFFERENCES 3428 02:54:23,400 --> 02:54:24,760 BETWEEN REPLICATION COMPETENT 3429 02:54:24,760 --> 02:54:28,040 AND REPLICATION DEFECTIVE HIV. 3430 02:54:28,040 --> 02:54:28,360 HIV 3431 02:54:28,360 --> 02:54:29,280 VACCINES. 3432 02:54:29,280 --> 02:54:32,720 SO THAT IS INITIAL PART THAT I 3433 02:54:32,720 --> 02:54:34,920 WOULD SAY WOULD SUMMARIZE THE 3434 02:54:34,920 --> 02:54:38,800 INITIAL EXPERIMENTS IN TERMS OF 3435 02:54:38,800 --> 02:54:42,840 ADCC AND THAT WERE DONE IN 3436 02:54:42,840 --> 02:54:43,680 MARJORIE'S LAB. 3437 02:54:43,680 --> 02:54:45,680 FAST FORWARD IN TIME AGAIN LIKE 3438 02:54:45,680 --> 02:54:48,320 I SAID, THERE ARE SEVERAL OTHER 3439 02:54:48,320 --> 02:54:49,880 HC MEDIATED MECHANISMS OF 3440 02:54:49,880 --> 02:54:51,600 PROTECTION. 3441 02:54:51,600 --> 02:54:52,800 ADCC'S ONLY PART OF THE PICTURE. 3442 02:54:52,800 --> 02:54:54,000 WE SEE IT HERE. 3443 02:54:54,000 --> 02:54:55,320 SEVERAL OTHER GROUPS HAVE 3444 02:54:55,320 --> 02:54:57,000 DESCRIBED MANY, MANY OTHER WAYS 3445 02:54:57,000 --> 02:55:00,440 OF POTENTIAL PROTECTION FROM -- 3446 02:55:00,440 --> 02:55:03,120 WITH FC MEDIATED FUNCTIONS. 3447 02:55:03,120 --> 02:55:06,200 WE ARE INVOLVING FC MEDIATED 3448 02:55:06,200 --> 02:55:06,760 FUNCTION. 3449 02:55:06,760 --> 02:55:09,600 SO HOW DOES THAT FIT IN TO WHAT 3450 02:55:09,600 --> 02:55:11,120 IS HAPPENING NOW? 3451 02:55:11,120 --> 02:55:13,320 WHEN I WAS INVITED TO GIVE THIS 3452 02:55:13,320 --> 02:55:14,200 TALK IT WAS MORE THAN TWO YEARS 3453 02:55:14,200 --> 02:55:15,880 AGO. 3454 02:55:15,880 --> 02:55:17,720 AND THIS WAS BEFORE COVID-19 SO 3455 02:55:17,720 --> 02:55:19,800 MY TALK WOULD HAVE BEEN VERY 3456 02:55:19,800 --> 02:55:21,000 DIFFERENT FROM WHAT I'M 3457 02:55:21,000 --> 02:55:22,200 PRESENTING TODAY BUT I DID WANT 3458 02:55:22,200 --> 02:55:24,200 TO PUT THIS IN THE CONTEXT OF 3459 02:55:24,200 --> 02:55:28,840 HOW THE WORLD IS NOW. 3460 02:55:28,840 --> 02:55:32,040 AND WHERE WE ARE POTENTIALLY 3461 02:55:32,040 --> 02:55:32,440 GOING. 3462 02:55:32,440 --> 02:55:34,120 SO COALITION FOR THE COALITION 3463 02:55:34,120 --> 02:55:35,640 FOR EPIDEMIC PREPAREDNESS 3464 02:55:35,640 --> 02:55:38,200 INNOVATIONS AND WE ARE TRYING TO 3465 02:55:38,200 --> 02:55:39,640 INNOVATE IN THAT SENSE. 3466 02:55:39,640 --> 02:55:42,720 ONE OF THE QUESTIONS REGARDING 3467 02:55:42,720 --> 02:55:44,840 INNOVATION WOULD BE NEUTRALIZING 3468 02:55:44,840 --> 02:55:46,720 ANTIBODIES IMPORTANT IN THE 3469 02:55:46,720 --> 02:55:48,920 CONTEXT OF EPIDEMIC PREPAREDNESS 3470 02:55:48,920 --> 02:55:50,240 PARTICULARLY PATHOGENS WITH ANY 3471 02:55:50,240 --> 02:55:54,680 PANDEMIC POTENTIAL. 3472 02:55:54,680 --> 02:55:56,360 MY RESPONSE WOULD BE YES AND I 3473 02:55:56,360 --> 02:55:58,880 WILL PRESENT SOME EVIDENCE THAT 3474 02:55:58,880 --> 02:56:01,400 IS NOT MINE, I REVIEWED IT 3475 02:56:01,400 --> 02:56:02,400 BEFORE COMING TO THE MEETING SO 3476 02:56:02,400 --> 02:56:04,960 BEAR WITH ME IF I'M NOT AN 3477 02:56:04,960 --> 02:56:05,600 EXPERT BUT THOUGHT IT 3478 02:56:05,600 --> 02:56:06,320 APPROPRIATE TO RAISE THIS. 3479 02:56:06,320 --> 02:56:08,800 SO THIS IS EVIDENCE FOR EBOLA 3480 02:56:08,800 --> 02:56:13,400 AND MARBURG AND THIS IS REVIEWD 3481 02:56:13,400 --> 02:56:14,480 BY (INAUDIBLE) AND ERICA 3482 02:56:14,480 --> 02:56:15,000 SAPPHIRE. 3483 02:56:15,000 --> 02:56:15,800 PUT THE REFERENCE THERE. 3484 02:56:15,800 --> 02:56:18,360 BUT IN THE EBOLA MODEL BASICALLY 3485 02:56:18,360 --> 02:56:21,560 WHAT THEY HAVE SEEN IS THAT IF 3486 02:56:21,560 --> 02:56:24,000 YOU -- THERE HAVE BEEN 3487 02:56:24,000 --> 02:56:25,600 ANTIBODIES NEUTRALIZING IN 3488 02:56:25,600 --> 02:56:25,880 VITRO. 3489 02:56:25,880 --> 02:56:27,880 THEY HAVE VERY POTENT 3490 02:56:27,880 --> 02:56:29,960 NEUTRALIZING ANTIBODY IN VITRO 3491 02:56:29,960 --> 02:56:30,920 AND THOUGHT THESE ANTIBODIES 3492 02:56:30,920 --> 02:56:32,920 WOULD HAVE SOME LEVEL OF 3493 02:56:32,920 --> 02:56:33,680 PROTECTION AGAINST EXBOW LA. 3494 02:56:33,680 --> 02:56:34,960 THEY DIDN'T. 3495 02:56:34,960 --> 02:56:37,400 WHEN THEY TESTED THEM IN EBOLA 3496 02:56:37,400 --> 02:56:38,120 MODEL THEY DIDN'T. 3497 02:56:38,120 --> 02:56:40,560 WHEN THEY STARTED TESTING 3498 02:56:40,560 --> 02:56:44,400 COMBINATIONS OF NEUTRALIZING AND 3499 02:56:44,400 --> 02:56:46,840 NON-NEUTRALIZING ANTIBODIES OR 3500 02:56:46,840 --> 02:56:48,360 ANTIBODIES POORLY NEUTRALIZING 3501 02:56:48,360 --> 02:56:51,080 THEY WERE PROTECTED IN THE EBOLA 3502 02:56:51,080 --> 02:56:57,080 MODEL SO THIS IS PIECE OF 3503 02:56:57,080 --> 02:56:58,160 SHOWING PANDEMIC POTENTIAL YOU 3504 02:56:58,160 --> 02:57:00,160 SEE A ROLE FOR NON-NEUTRALIZING 3505 02:57:00,160 --> 02:57:01,280 ANTIBODIES TO HAVE PROTECTION 3506 02:57:01,280 --> 02:57:01,800 HERE. 3507 02:57:01,800 --> 02:57:05,000 THESE OTHER ANTIBODIES SHOWN IN 3508 02:57:05,000 --> 02:57:06,920 THE BOTTOM SHOW THREE PRODUCTS 3509 02:57:06,920 --> 02:57:10,080 THAT HAVE BEEN APPROVED BY WHO 3510 02:57:10,080 --> 02:57:12,840 FOR EPIDEMIC RESPONSE DURING 3511 02:57:12,840 --> 02:57:14,640 EBOLA AND ALL THESE HAVE BEEN 3512 02:57:14,640 --> 02:57:17,080 VERY WELL CHARACTERIZED IN TERMS 3513 02:57:17,080 --> 02:57:19,440 OF NEUTRALIZING AND 3514 02:57:19,440 --> 02:57:22,120 NON-NEUTRALIZING CAPACITY. 3515 02:57:22,120 --> 02:57:23,840 WHAT THE AUTHORS CONCLUDE HERE 3516 02:57:23,840 --> 02:57:26,120 IS THAT IF YOU LOOK AT THE 3517 02:57:26,120 --> 02:57:27,880 GLYCOPROTEIN AT EBOLA 3518 02:57:27,880 --> 02:57:29,000 GLYCOPROTEIN YOU CAN DIVIDE INTO 3519 02:57:29,000 --> 02:57:30,640 THREE TIERS. 3520 02:57:30,640 --> 02:57:33,040 AND THEN THE ANTIBODIES THAT 3521 02:57:33,040 --> 02:57:36,800 MEDIATE FC MEDIATED PROTECTION, 3522 02:57:36,800 --> 02:57:39,560 PRESUMABLY BIND TO TIER 1 OR 3523 02:57:39,560 --> 02:57:41,000 VERY TOP GLYCOPROTEINS AND THE 3524 02:57:41,000 --> 02:57:42,400 OTHER ANTIBODIES THAT ARE 3525 02:57:42,400 --> 02:57:45,280 NEUTRALIZING AND MAY NOT BE AS 3526 02:57:45,280 --> 02:57:47,480 PROTECTIVE OR THAT MAYBE 3527 02:57:47,480 --> 02:57:48,800 RECOMMENDATION PROTECTIVE AND 3528 02:57:48,800 --> 02:57:49,920 NON-PROTECTIVE BINDING MORE TO 3529 02:57:49,920 --> 02:57:51,680 THE BOTTOM PART OF THIS TALK OF 3530 02:57:51,680 --> 02:57:54,000 THE GLYCOPROTEIN TALK SO I'M NOT 3531 02:57:54,000 --> 02:57:56,200 EXPERT ON THIS, NOT MY DATA BUT 3532 02:57:56,200 --> 02:57:58,000 PUTTING THAT REFERENCE THERE FOR 3533 02:57:58,000 --> 02:58:00,480 THE INTEREST OF THIS AUDIENCE. 3534 02:58:00,480 --> 02:58:03,920 THE CONCLUSION WAS THE 3535 02:58:03,920 --> 02:58:05,600 NEUTRALIZATION ALONE WAS 3536 02:58:05,600 --> 02:58:07,480 INCOMPLETE PREDICTOR OF IN VIVO 3537 02:58:07,480 --> 02:58:08,920 SUCCESS WHICH FOR US IN THE HIV 3538 02:58:08,920 --> 02:58:14,400 VACCINE FIELD IS NOT NECESSARILY 3539 02:58:14,400 --> 02:58:15,320 SURPRISE. 3540 02:58:15,320 --> 02:58:17,400 WHAT ABOUT LASA? 3541 02:58:17,400 --> 02:58:19,200 THERE IS ONE PIECE OF EVIDENCE 3542 02:58:19,200 --> 02:58:20,960 THAT THIS IS AN ARTICLE 3543 02:58:20,960 --> 02:58:23,400 PUBLISHED RELATIVELY RECENTLY. 3544 02:58:23,400 --> 02:58:26,560 AGAIN, NOT MY DATA, BUT THIS IS 3545 02:58:26,560 --> 02:58:28,920 A MODEL OF RABIES VECTOR 3546 02:58:28,920 --> 02:58:30,240 VACCINE, IT IS A RABIES VEHICLER 3547 02:58:30,240 --> 02:58:33,000 TO OF LASSA VACCINE. 3548 02:58:33,000 --> 02:58:35,520 YOU CAN SEE IN THIS SWISS 3549 02:58:35,520 --> 02:58:36,840 WEBSTER PUB MODEL THERE'S 3550 02:58:36,840 --> 02:58:38,280 VARIOUS LEVELS OF PROTECTION. 3551 02:58:38,280 --> 02:58:39,920 WHEN THEY EXAMINE THE 3552 02:58:39,920 --> 02:58:41,280 NEUTRALIZING ANTIBODY ACTIVITY 3553 02:58:41,280 --> 02:58:44,920 WHICH IS SHOWN HERE, THERE IS 3554 02:58:44,920 --> 02:58:48,520 NOT ANY LASSA VIRUS NEUTRALIZING 3555 02:58:48,520 --> 02:58:50,600 ANTIBODY ACTIVITY BUT THEN WHEN 3556 02:58:50,600 --> 02:58:52,280 THEY TAKE THESE SERA AND THEY 3557 02:58:52,280 --> 02:58:54,520 HAVE VARIOUS LEVELS OF NK CELLS 3558 02:58:54,520 --> 02:58:59,480 YOU SEE KILLING OF LASSA VIRUS 3559 02:58:59,480 --> 02:59:00,720 INFECTED CELLINGS SO THERE IS 3560 02:59:00,720 --> 02:59:02,400 ANOTHER PIECE OF EVIDENCE FOR 3561 02:59:02,400 --> 02:59:04,400 LASSA, WHICH IS ANOTHER PATHOGEN 3562 02:59:04,400 --> 02:59:06,960 OF EPIDEMIC OR PANDEMIC 3563 02:59:06,960 --> 02:59:08,680 POTENTIAL NON-NEUTRALIZING 3564 02:59:08,680 --> 02:59:10,040 ANTIBODIES COULD BE IMPORTANT. 3565 02:59:10,040 --> 02:59:12,400 I DON'T HAVE TO GO OVER THIS, 3566 02:59:12,400 --> 02:59:13,880 GIVE YOU -- YOU HAVE PROBABLY 3567 02:59:13,880 --> 02:59:16,320 SEEN MANY PIECES OF EVIDENCE ON 3568 02:59:16,320 --> 02:59:18,400 HOW NON-NEUTRALIZING ANTIBODIES 3569 02:59:18,400 --> 02:59:20,120 HAVE BEEN INVOLVED IN PROTECTION 3570 02:59:20,120 --> 02:59:22,000 AGAINST COVID-19. 3571 02:59:22,000 --> 02:59:24,560 THIS IS DATA FROM (INAUDIBLE) 3572 02:59:24,560 --> 02:59:26,080 LAB AND THERE IS DATA FROM A 3573 02:59:26,080 --> 02:59:27,800 GROUP IN CHINA WHICH THEY LOOK 3574 02:59:27,800 --> 02:59:31,760 AT LONGITUDINAL ADCC RESPONSES 3575 02:59:31,760 --> 02:59:34,400 AND YOU SEE SEVERAL KINETICS 3576 02:59:34,400 --> 02:59:36,440 HAPPENING DURING THE FIRST 21 3577 02:59:36,440 --> 02:59:38,000 DAYS OF INFECTION YOU SEE 3578 02:59:38,000 --> 02:59:40,120 DIFFERENCES BETWEEN THE PATIENTS 3579 02:59:40,120 --> 02:59:41,040 WHO DO BETTER THAN OTHERS. 3580 02:59:41,040 --> 02:59:43,120 SO THERE IS A -- SOME 3581 02:59:43,120 --> 02:59:44,800 ASSOCIATION BETWEEN ADCC 3582 02:59:44,800 --> 02:59:49,000 RESPONSES AND PROGNOSIS. 3583 02:59:49,000 --> 02:59:56,800 WHETHER INFECTION IS MILD OR NOT 3584 02:59:56,800 --> 02:59:58,960 AS MILD, ALSO SAW EVIDENCE FOR 3585 02:59:58,960 --> 03:00:03,320 NEPA VIRUS, HEARSA THIS IS ONE OF MY 3586 03:00:03,320 --> 03:00:06,200 FAVORITE VIRUS, THEY ARE NOXIOUS 3587 03:00:06,200 --> 03:00:08,080 TO BATS BUT TO US THEY ARE 3588 03:00:08,080 --> 03:00:08,640 LETHAL. 3589 03:00:08,640 --> 03:00:12,680 THESE ARE THE RANGE -- THIS IS A 3590 03:00:12,680 --> 03:00:18,400 FLYING RANGE OF BATS, BUT AREAS 3591 03:00:18,400 --> 03:00:20,320 SEQUENCES FOUND IN THE WORLD SO 3592 03:00:20,320 --> 03:00:22,120 MANY THINK THE NEXT PANDEMIC 3593 03:00:22,120 --> 03:00:25,280 COULD BE BY A NIPAH VIRUS OR 3594 03:00:25,280 --> 03:00:28,040 NIPAH VIRUS LIKE VIRUS. 3595 03:00:28,040 --> 03:00:29,840 SO THERE HAS NOT BEEN ANY 3596 03:00:29,840 --> 03:00:34,000 REPORTS OF ADCC AGAINST NIPAH 3597 03:00:34,000 --> 03:00:35,920 VIRUS OR HENDRA VIRUS BUT MAYBE 3598 03:00:35,920 --> 03:00:37,840 IMPORTANT TO ADDRESS A QUESTION 3599 03:00:37,840 --> 03:00:40,280 OF COULD ADCC PLAY A ROLE IN 3600 03:00:40,280 --> 03:00:42,920 ACHIEVING A RAPID RESPONSE OR 3601 03:00:42,920 --> 03:00:44,720 RAPID IMMUNE RESPONSE TO VIRUS? 3602 03:00:44,720 --> 03:00:46,240 AND THE REASON I ASK THIS 3603 03:00:46,240 --> 03:00:47,600 QUESTION IS BECAUSE IF YOU LOOK 3604 03:00:47,600 --> 03:00:51,160 AT THE WHO TARGET PRODUCT 3605 03:00:51,160 --> 03:00:52,960 PROFILE FOR THESE VACCINE, THEY 3606 03:00:52,960 --> 03:00:58,000 WANT YOU TO HAVE AN EFFICACY OF 3607 03:00:58,000 --> 03:00:58,920 90%, PREVENTING DISEASE AND TO 3608 03:00:58,920 --> 03:01:01,560 HAVE A RAPID ONSET OF PROTECTION 3609 03:01:01,560 --> 03:01:03,800 PREFERABLY WITHIN A FEW WEEKS 3610 03:01:03,800 --> 03:01:05,480 AFTER ADMINISTRATION. 3611 03:01:05,480 --> 03:01:07,040 SO THAT IS A QUESTION THAT I'M 3612 03:01:07,040 --> 03:01:11,000 ASKING, WOULD IT BE POSSIBLE 3613 03:01:11,000 --> 03:01:12,800 NON-NEUTRALIZING ANTIBODY 3614 03:01:12,800 --> 03:01:13,640 RESPONSE COULD CONTRIBUTE TO 3615 03:01:13,640 --> 03:01:16,080 PANDEMIC PREPAREDNESS OR 3616 03:01:16,080 --> 03:01:17,360 EPIDEMIC PREPAREDNESS AGAINST 3617 03:01:17,360 --> 03:01:21,360 THIS VIRUS. 3618 03:01:21,360 --> 03:01:24,960 ALSO IN TERMS OF SEPPE, PLEASE 3619 03:01:24,960 --> 03:01:26,480 REMIND IF I'M CROSSING MY TIME 3620 03:01:26,480 --> 03:01:28,520 BUT IN TERMS OF CEPI MISSION AS 3621 03:01:28,520 --> 03:01:30,320 YOU MIGHT HAVE HEARD, CEPI IS 3622 03:01:30,320 --> 03:01:32,760 CURRENTLY PREPARING TO -- 3623 03:01:32,760 --> 03:01:36,600 ACTUALLY CHANGED STRATEGIC PLAN. 3624 03:01:36,600 --> 03:01:38,160 AND IT HAS IT WILL BE TRYING TO 3625 03:01:38,160 --> 03:01:40,800 ACHIEVE A GOAL TO DEVELOP 3626 03:01:40,800 --> 03:01:43,080 VACCINE WITHIN 100 DAYS SO THIS 3627 03:01:43,080 --> 03:01:46,440 IS SOMETHING THAT IS RATHER 3628 03:01:46,440 --> 03:01:47,960 CONTROVERSIAL BUT HAS BEEN 3629 03:01:47,960 --> 03:01:52,600 APPROVED BY BOARD AND SECRETARY 3630 03:01:52,600 --> 03:01:55,960 AND ON THIS FIGURE HERE, WHAT 3631 03:01:55,960 --> 03:01:59,920 CEPI IS TRYING TO SHOW IS FOR 3632 03:01:59,920 --> 03:02:01,680 COVID 326 DAYS TRANSPIRED 3633 03:02:01,680 --> 03:02:03,640 BETWEEN IDENTIFICATION OF 3634 03:02:03,640 --> 03:02:06,280 SEQUENCE AND DEVELOPMENT AND 3635 03:02:06,280 --> 03:02:07,520 APPROVAL, REGISTRATION OR 3636 03:02:07,520 --> 03:02:10,160 APPROVAL FOR EMERGENCY APPROVAL 3637 03:02:10,160 --> 03:02:12,760 FOR VACCINE SO TRIERING TO BRING 3638 03:02:12,760 --> 03:02:15,600 THE TIME TO 100 DAYS. 3639 03:02:15,600 --> 03:02:17,240 IS THIS ACHIEVABLE, WE DON'T 3640 03:02:17,240 --> 03:02:18,200 KNOW BUT WE CAN TRY AND THE 3641 03:02:18,200 --> 03:02:20,240 CONCEPT TO DO THIS WOULD BE TO 3642 03:02:20,240 --> 03:02:22,600 FOCUS ON 25 VIRUS FAMILIES AND 3643 03:02:22,600 --> 03:02:25,120 TO TRY TO HAVE VACCINES OR 3644 03:02:25,120 --> 03:02:28,320 VACCINE LIBRARIES AGAINST 25 3645 03:02:28,320 --> 03:02:29,440 PROTOTYPIC VIRUS FAMILIES SO YOU 3646 03:02:29,440 --> 03:02:33,000 CAN POTENTIALLY HAVE PREPARED SO 3647 03:02:33,000 --> 03:02:36,280 TO SPEAK AND PULL THEM UP TO THE 3648 03:02:36,280 --> 03:02:42,000 SHELF IN TERMS IN CASE EPIDEMIC 3649 03:02:42,000 --> 03:02:44,640 HAPPENED AND CONTINUE WITH 3650 03:02:44,640 --> 03:02:45,200 RESEARCH AND PRODUCTION BUT 3651 03:02:45,200 --> 03:02:45,760 BASIC CONCEPT IS THERE. 3652 03:02:45,760 --> 03:02:47,000 THE QUESTION TO BE ADDRESSED 3653 03:02:47,000 --> 03:02:49,880 HERE COULD ADCC AND OTHER 3654 03:02:49,880 --> 03:02:51,880 NON-NEUTRALIZING ANTIBODIES 3655 03:02:51,880 --> 03:02:53,280 EFFECTOR FUNCTION PLAY A ROLE IN 3656 03:02:53,280 --> 03:02:54,840 ACHIEVING THESE 100 DAY MISSION. 3657 03:02:54,840 --> 03:02:56,480 I THINK THEY WOULD -- THEY 3658 03:02:56,480 --> 03:02:59,800 SHOULD BE LOOKED AT BECAUSE 3659 03:02:59,800 --> 03:03:01,720 AGAIN, IT IS NOT ALL ABOUT 3660 03:03:01,720 --> 03:03:02,920 NEUTRALIZING ANTIBODIES. 3661 03:03:02,920 --> 03:03:05,600 I THINK THE HISTORY OF MANY 3662 03:03:05,600 --> 03:03:08,120 DISEASES HAS SHOWN US THAT MAYBE 3663 03:03:08,120 --> 03:03:11,640 THE CASE. 3664 03:03:11,640 --> 03:03:13,320 I WANT TO END WITH REFLECTIONS 3665 03:03:13,320 --> 03:03:13,720 HERE. 3666 03:03:13,720 --> 03:03:16,560 I DON'T KNOW HOW MANY PEOPLE IN 3667 03:03:16,560 --> 03:03:17,400 THE AUDIENCE READ THIS BOOK BUT 3668 03:03:17,400 --> 03:03:21,720 I HIGH LIE RECOMMEND IT. 3669 03:03:21,720 --> 03:03:23,280 THIS IS A BOOK BY ALEX 3670 03:03:23,280 --> 03:03:26,080 (INAUDIBLE) AND HE'S THE 3671 03:03:26,080 --> 03:03:30,040 PRESIDENT OF WORLD PEACE 3672 03:03:30,040 --> 03:03:31,120 FOUNDATION ACTIVITIES 3673 03:03:31,120 --> 03:03:32,920 UNIVERSITY, NEW PANDEMICS OR 3674 03:03:32,920 --> 03:03:33,480 POLITICS. 3675 03:03:33,480 --> 03:03:35,840 IT IS RELEVANT IN THE CONTEXT OF 3676 03:03:35,840 --> 03:03:40,520 THIS AUDIENCE BECAUSE SEVERAL -- 3677 03:03:40,520 --> 03:03:42,400 I WON'T SPOIL THE BOOK BUT 3678 03:03:42,400 --> 03:03:43,640 SEVERAL KEY POINTS ADDRESSED IN 3679 03:03:43,640 --> 03:03:46,840 THIS BOOK AND ONE IS WHENEVER WE 3680 03:03:46,840 --> 03:03:51,000 TRY TO FIGHT EPIDEMIC USING A 3681 03:03:51,000 --> 03:03:53,080 MARSHALL SCRIPT LIKE WAR DISEASE 3682 03:03:53,080 --> 03:03:54,200 SCRIPT THAT GENERALLY FAILS AND 3683 03:03:54,200 --> 03:03:55,640 THE AUTHOR SHOWS YOU MANY 3684 03:03:55,640 --> 03:03:56,800 EXAMPLES OF THAT. 3685 03:03:56,800 --> 03:03:58,600 BUT WHAT I REALLY LIKE ABOUT 3686 03:03:58,600 --> 03:04:00,000 THIS BOOK AND THINK IT IS 3687 03:04:00,000 --> 03:04:01,440 PARTICULARLY IMPORTANT IN THE 3688 03:04:01,440 --> 03:04:05,560 CONTEXT OF THIS GROUP, HE ARGUES 3689 03:04:05,560 --> 03:04:08,200 E MANS PATORY APPROACH USED IN 3690 03:04:08,200 --> 03:04:10,360 HIV AIDS MITIGATION ALLOWED US 3691 03:04:10,360 --> 03:04:11,960 TO LIVE WITH HIV WITH DISEASE 3692 03:04:11,960 --> 03:04:13,240 FOR MORE THAN 40 YEARS. 3693 03:04:13,240 --> 03:04:15,120 AND MANY OF THESE HAVE ALSO 3694 03:04:15,120 --> 03:04:16,480 ALLOWED US TO COME UP WITH 3695 03:04:16,480 --> 03:04:19,160 COUNTER MEASURES AGAINST THE 3696 03:04:19,160 --> 03:04:20,080 VIRUS. 3697 03:04:20,080 --> 03:04:22,320 BUT THIS EMANCIPATION APPROACHES 3698 03:04:22,320 --> 03:04:28,320 INVOLVE COMMUNITY ACTIVISM 3699 03:04:28,320 --> 03:04:29,560 EMANCIPATION SCIENCE AND 3700 03:04:29,560 --> 03:04:30,560 POLITICS, DIVERSITY INCLUSION 3701 03:04:30,560 --> 03:04:32,160 AND THIS WILL LEAD TO ACCESS TO 3702 03:04:32,160 --> 03:04:33,280 PREVENTION AND TREATMENT. 3703 03:04:33,280 --> 03:04:34,920 AND I THINK THAT IS QUITE 3704 03:04:34,920 --> 03:04:37,520 RELEVANT BECAUSE IT IS SOMETHING 3705 03:04:37,520 --> 03:04:40,760 THAT WE CAN LEARN FROM HIV AIDS 3706 03:04:40,760 --> 03:04:42,760 THAT IS SOMETHING PANDEMIC 3707 03:04:42,760 --> 03:04:43,840 PREPAREDNESS CAN BENEFIT FROM IN 3708 03:04:43,840 --> 03:04:48,720 LOOKING AT EXAMPLES OF HIV AIDS. 3709 03:04:48,720 --> 03:04:50,400 JUST TO FINISH MY TALK CLOSING 3710 03:04:50,400 --> 03:04:52,200 REMARKS, THERE IS A WEALTH OF 3711 03:04:52,200 --> 03:04:53,840 KNOWLEDGE ON THE ROLE OF ADCC 3712 03:04:53,840 --> 03:04:57,160 AND NON-NEUTRALIZING ANN BODIES 3713 03:04:57,160 --> 03:04:59,960 AGAINST HIV AIDS. 3714 03:04:59,960 --> 03:05:01,600 MARJORIE'S LAB WAS KEY. 3715 03:05:01,600 --> 03:05:03,480 IN GENERATING SCIENTIFIC 3716 03:05:03,480 --> 03:05:07,320 EVIDENCE ABOUT THIS. 3717 03:05:07,320 --> 03:05:08,560 THERE IS CLEAR EVIDENCE OF ROLE 3718 03:05:08,560 --> 03:05:12,480 OF ADCC NON-NEUTRALIZING 3719 03:05:12,480 --> 03:05:14,360 EFFECTOR MECHANISMS AGAINST 3720 03:05:14,360 --> 03:05:16,600 DISEASES OF PANDEMIC AND 3721 03:05:16,600 --> 03:05:18,120 EPIDEMIC POTENTIAL, IT IS NOT 3722 03:05:18,120 --> 03:05:19,360 ALL ABOUT NEUTRALIZING 3723 03:05:19,360 --> 03:05:20,600 ANTIBODIES AND THERE IS AN 3724 03:05:20,600 --> 03:05:22,000 OPPORTUNITY FOR ADCC TO PLAY A 3725 03:05:22,000 --> 03:05:23,440 ROLE IN HOW WE ARE 3726 03:05:23,440 --> 03:05:25,120 CONCEPTUALIZING THE UNIVERSE OF 3727 03:05:25,120 --> 03:05:26,120 EPIDEMIC PREPAREDNESS AND 3728 03:05:26,120 --> 03:05:28,400 RESPONSE. 3729 03:05:28,400 --> 03:05:31,360 LAST BUT NOT LEAST LIKE IN HIV 3730 03:05:31,360 --> 03:05:34,200 AIDS, COMMUNITY ACTIVISM 3731 03:05:34,200 --> 03:05:35,480 EMANCIPATION POLITICS, SHOULD BE 3732 03:05:35,480 --> 03:05:38,200 A PART OF PREPAREDNESS AND 3733 03:05:38,200 --> 03:05:40,640 RESPONSE AND IN THIS SENSE 3734 03:05:40,640 --> 03:05:43,000 DIVERSITY IN THE SCIENCE 3735 03:05:43,000 --> 03:05:47,480 ACTIVISM SHOULD PLAY A ROLE IN 3736 03:05:47,480 --> 03:05:48,080 GENERATING A -- I PERSONALLY 3737 03:05:48,080 --> 03:05:49,960 BELIEVE YOU CANNOT HAVE ACCESS 3738 03:05:49,960 --> 03:05:51,080 IF YOU DON'T INVOLVE ALL THE 3739 03:05:51,080 --> 03:05:53,040 COMMUNITIES THAT WILL ULTIMATELY 3740 03:05:53,040 --> 03:05:54,840 BENEFIT FROM THE DEVELOPMENT OF 3741 03:05:54,840 --> 03:05:56,320 THESE COUNTER MEASURES. 3742 03:05:56,320 --> 03:05:58,320 IN THIS REGARD I DO WANT TO SAY 3743 03:05:58,320 --> 03:06:01,400 THANK YOU, MARJORIE BECAUSE THE 3744 03:06:01,400 --> 03:06:03,800 LABORATORY WHERE YOUR LABORATORY 3745 03:06:03,800 --> 03:06:05,800 WAS PROBABLY IS NOT THE MOST WAS 3746 03:06:05,800 --> 03:06:08,920 PROBABLY ONE OF THE MOST DIVERSE 3747 03:06:08,920 --> 03:06:12,800 LABORATORIES WHERE OPINIONS FROM 3748 03:06:12,800 --> 03:06:14,640 EVERYONE WHERE VALUABLE I HAVE 3749 03:06:14,640 --> 03:06:16,840 FOND MEMORIES OF MANY PEOPLE 3750 03:06:16,840 --> 03:06:17,600 FROM MANY DIFFERENT 3751 03:06:17,600 --> 03:06:18,840 NATIONALITIES SITTING AT THE 3752 03:06:18,840 --> 03:06:22,000 SAME TABLE WITH YOU DISCUSSING 3753 03:06:22,000 --> 03:06:24,600 SCIENCE SOMETIMES POLITICS OR 3754 03:06:24,600 --> 03:06:26,800 SCIENCE BUT EVERYONE WAS HURT IN 3755 03:06:26,800 --> 03:06:30,000 YOUR LAB AND YOU CREATE AD VERY 3756 03:06:30,000 --> 03:06:32,200 HIGH BAR FOR ME AS I MOVE ON IN 3757 03:06:32,200 --> 03:06:34,200 OTHER CAREERS BECAUSE I WAS 3758 03:06:34,200 --> 03:06:35,880 ACTUALLY QUITE SPOILED BY YOU. 3759 03:06:35,880 --> 03:06:38,560 IN TERMS OF BEING ABLE TO HAVE 3760 03:06:38,560 --> 03:06:41,880 VERY EQUITABLE ACCESS TO GETTING 3761 03:06:41,880 --> 03:06:43,400 AN OPINION AND BE RESPECTED FOR 3762 03:06:43,400 --> 03:06:47,080 THE OPINIONS SO THEY HAVE -- SO 3763 03:06:47,080 --> 03:06:49,160 THANK YOU VERY MUCH AND I WISH 3764 03:06:49,160 --> 03:06:50,280 YOU VERY GOOD LUCK IN THE 3765 03:06:50,280 --> 03:06:52,400 JOURNEY AHEAD. 3766 03:06:52,400 --> 03:07:06,360 [APPLAUSE] 3767 03:07:06,360 --> 03:07:09,320 >> COULD YOU GO INTO MORE 3768 03:07:09,320 --> 03:07:11,680 DETAIL, REGARDING THE HUNDRED 3769 03:07:11,680 --> 03:07:12,480 DAYS? 3770 03:07:12,480 --> 03:07:15,680 WHAT IS THE BOARD THINKING THAT 3771 03:07:15,680 --> 03:07:16,920 WOULD -- WHAT SORTS OF THINGS 3772 03:07:16,920 --> 03:07:19,800 FROM THE STANDARD OR EVEN 3773 03:07:19,800 --> 03:07:23,080 ACCELERATED VACCINE DEVELOPMENT 3774 03:07:23,080 --> 03:07:25,080 WOULD THEY MODIFY TO ENABLE YOU 3775 03:07:25,080 --> 03:07:26,120 TO GET THERE? 3776 03:07:26,120 --> 03:07:28,640 IF IT TOOK 60 DAYS FOR mRNA TO 3777 03:07:28,640 --> 03:07:31,040 GET INTO CLINIC, THAT'S TINY 3778 03:07:31,040 --> 03:07:32,600 PART OF A YEAR AND ALL THE REST 3779 03:07:32,600 --> 03:07:35,480 WAS ACCRUAL OF PHASE 1, 2, 3 3780 03:07:35,480 --> 03:07:37,960 DATA AND THEN FINALLY APPROVAL. 3781 03:07:37,960 --> 03:07:40,800 SO WHAT THINGS WOULD THEY HAVE, 3782 03:07:40,800 --> 03:07:43,760 WOULD THEY BE ABLE TO GO -- HAVE 3783 03:07:43,760 --> 03:07:45,280 ALREADY PROTOTYPE PLATFORMS FOR 3784 03:07:45,280 --> 03:07:46,680 EXAMPLE THAT WOULD GO STRAIGHT 3785 03:07:46,680 --> 03:07:47,960 TO PHASE 2? 3786 03:07:47,960 --> 03:07:49,600 OR WHAT ARE THEY THINKING ABOUT? 3787 03:07:49,600 --> 03:07:52,400 >> IT IS A COMBINATION AND IT IS 3788 03:07:52,400 --> 03:07:54,240 PROBABLY WON'T BE A ONE SIZE 3789 03:07:54,240 --> 03:07:55,240 FITS ALL TO BE HONEST. 3790 03:07:55,240 --> 03:07:57,000 I THINK IT DEPENDS ON THE 3791 03:07:57,000 --> 03:07:57,560 PATHOGEN. 3792 03:07:57,560 --> 03:08:01,000 FOR EXAMPLE, IF WE PREFERRED TO 3793 03:08:01,000 --> 03:08:02,800 BETA CORONA VIRUS, WE KNOW WE 3794 03:08:02,800 --> 03:08:04,760 HAVE SUPPORTED VACCINES 3795 03:08:04,760 --> 03:08:09,160 DEVELOPMENT OF VACCINES AGAINST 3796 03:08:09,160 --> 03:08:11,880 VIRUS, WE HAVE VIRUS COVE 1 AND 3797 03:08:11,880 --> 03:08:13,600 SOME VACCINES COULD BE FAST 3798 03:08:13,600 --> 03:08:15,400 FORWARD THAT IN THAT REGARD AND 3799 03:08:15,400 --> 03:08:17,800 THEN WE HAVE SARS COV-2 VACCINE 3800 03:08:17,800 --> 03:08:20,400 AND VARIANTS. 3801 03:08:20,400 --> 03:08:24,560 FROM THAT PARTICULAR BETA CORONA 3802 03:08:24,560 --> 03:08:25,960 VIRUS FAMILY THE APPROACH COULD 3803 03:08:25,960 --> 03:08:27,600 BE SOMEWHAT DIFFERENTLY THAN 3804 03:08:27,600 --> 03:08:29,520 FROM NEPA VIRUS VACCINE APPROACH 3805 03:08:29,520 --> 03:08:31,520 WHERE YOU ARE NOT ABLE TO RUN 3806 03:08:31,520 --> 03:08:33,200 PHASE 3 TRIALS. 3807 03:08:33,200 --> 03:08:33,600 FOR EXAMPLE. 3808 03:08:33,600 --> 03:08:35,600 FOR NEPA VACCINES YOU NEED TO 3809 03:08:35,600 --> 03:08:38,280 RUN A PHASE 1 PHASE 2 AND THEN 3810 03:08:38,280 --> 03:08:42,440 HAVE IT READY IN CASE THE RNA 3811 03:08:42,440 --> 03:08:44,880 CHANGE TYPE OF 1 TO TEST IN THE 3812 03:08:44,880 --> 03:08:46,440 POPULATION BUT OR PURSUE OTHER 3813 03:08:46,440 --> 03:08:47,840 MECHANISMS OF REGULATORY 3814 03:08:47,840 --> 03:08:48,200 APPROVAL. 3815 03:08:48,200 --> 03:08:49,880 SO I THINK IT IS NOT A ONE SIZE 3816 03:08:49,880 --> 03:08:51,400 FITS ALL, DEPENDS ON THE 3817 03:08:51,400 --> 03:08:54,000 PARTICULAR VIRUS FAMILIES. 3818 03:08:54,000 --> 03:08:55,880 IT WOULD BE A COMBINATION OF 3819 03:08:55,880 --> 03:08:59,600 SEVERAL PROCESSES. 3820 03:08:59,600 --> 03:09:02,800 >> OKAY. 3821 03:09:02,800 --> 03:09:05,320 NO MORE QUESTIONS THEN THANK YOU 3822 03:09:05,320 --> 03:09:05,800 VERY MUCH. 3823 03:09:05,800 --> 03:09:07,600 VERY NICE PRESENTATION. 3824 03:09:07,600 --> 03:09:11,000 GEORGE, SO NOW WE ARE GO GEORGE 3825 03:09:11,000 --> 03:09:15,200 LEWIS WHO WILL TALK ABOUT 3826 03:09:15,200 --> 03:09:16,640 (INAUDIBLE) THAT WILL TELL US 3827 03:09:16,640 --> 03:09:18,080 ABOUT OBSERVATIONAL STRUCTURE 3828 03:09:18,080 --> 03:09:21,600 AND FUNCTION OF FC MEDIATED 3829 03:09:21,600 --> 03:09:22,560 EFFECTER FUNCTION WITH SPECIAL 3830 03:09:22,560 --> 03:09:33,520 THANKS TO MARJORIE. 3831 03:09:33,520 --> 03:09:34,840 >> OKAY. 3832 03:09:34,840 --> 03:09:36,840 THANKS FOR THE OPPORTUNITY TO 3833 03:09:36,840 --> 03:09:39,120 SPEAK AT THE SYMPOSIUM TODAY. 3834 03:09:39,120 --> 03:09:42,600 WHAT I'M GOING TO DO IS AS BETH 3835 03:09:42,600 --> 03:09:45,240 SAID TELL YOU ABOUT SOME SORT OF 3836 03:09:45,240 --> 03:09:46,440 NEW OBSERVATION, SOME VERY NEW 3837 03:09:46,440 --> 03:09:49,200 WE HAVE COME UP WITH IN THE 3838 03:09:49,200 --> 03:09:51,840 INSTITUTE AND WITH COLLABORATORS 3839 03:09:51,840 --> 03:09:57,000 ON STRUCTURE AND FUNCTION FC -- 3840 03:09:57,000 --> 03:09:59,320 WHAT IS GOING ON WITH FC 3841 03:09:59,320 --> 03:10:01,760 MEDIATED EFFECTOR FUNCTION. 3842 03:10:01,760 --> 03:10:05,160 I WILL FOCUS ON TROGO CYTOSIS OF 3843 03:10:05,160 --> 03:10:07,920 ALL THINGS YOU WILL SEE WHY IN A 3844 03:10:07,920 --> 03:10:08,160 MINUTE. 3845 03:10:08,160 --> 03:10:12,400 I WANT TO BEGIN BY TALKING ABOUT 3846 03:10:12,400 --> 03:10:16,240 SPECIAL THANKS TO MARJORIE, I 3847 03:10:16,240 --> 03:10:17,960 WAS AROUND BACK IN THE EARLY 3848 03:10:17,960 --> 03:10:19,600 DAYS OF HIV, I WASN'T WORKING ON 3849 03:10:19,600 --> 03:10:21,400 IT BUT I WAS GETTING READY TO 3850 03:10:21,400 --> 03:10:25,880 GET INTO IT AND I WAS TRAINED AS 3851 03:10:25,880 --> 03:10:27,680 A QUASI STRUCTURAL CELLULAR 3852 03:10:27,680 --> 03:10:30,000 IMMUNOLOGIST CHEMIST AT HEART. 3853 03:10:30,000 --> 03:10:31,800 AND ONE OF THE THINGS THAT YOU 3854 03:10:31,800 --> 03:10:33,520 FIRST START LOOKING FOR IS 3855 03:10:33,520 --> 03:10:35,800 SOMETHING LIKE THIS AT LEAST I 3856 03:10:35,800 --> 03:10:36,760 DO, NEUTRALIZING ANTIBODIES. 3857 03:10:36,760 --> 03:10:38,600 THINKING ABOUT IT. 3858 03:10:38,600 --> 03:10:42,880 AS BOB POINTED OUT TODAY, 3859 03:10:42,880 --> 03:10:44,240 EARLIER, THAT THERE ARE PAPE -- 3860 03:10:44,240 --> 03:10:46,600 HAIR PAPER WAS THE FIRST 3861 03:10:46,600 --> 03:10:47,400 DEMONSTRATION, CLEAR 3862 03:10:47,400 --> 03:10:49,960 DEMONSTRATION OF NEUTRALIZING 3863 03:10:49,960 --> 03:10:52,040 ANTIBODIES IN AIDS AND AIDS 3864 03:10:52,040 --> 03:10:54,400 RELATED COMPLEX, VERY IMPORTANT 3865 03:10:54,400 --> 03:10:54,600 PAPER. 3866 03:10:54,600 --> 03:10:59,720 BUT I THINK ALSO EQUALLY 3867 03:10:59,720 --> 03:11:02,440 IMPORTANT, IS THE FOLLOW-ON 3868 03:11:02,440 --> 03:11:04,600 PAPER WHERE THEY SHOWED 3869 03:11:04,600 --> 03:11:07,440 DEMONSTRATED NEUTRALIZATION 3870 03:11:07,440 --> 03:11:08,040 ESCAPE. 3871 03:11:08,040 --> 03:11:12,800 THIS IS SOMETHING THAT I KNEW 3872 03:11:12,800 --> 03:11:15,080 ABOUT YEARS AGO BECAUSE WE USED 3873 03:11:15,080 --> 03:11:17,520 TO USE HAPPEN CONJUGATED 3874 03:11:17,520 --> 03:11:20,240 BACTERIA PHAGOS, SENSITIVE ASSAY 3875 03:11:20,240 --> 03:11:24,000 FOR MEASURING ANTIBODIES AND I 3876 03:11:24,000 --> 03:11:26,080 KNEW ABOU ABOUT PHAGE NEUTRALIZATION 3877 03:11:26,080 --> 03:11:26,800 FROM THEN. 3878 03:11:26,800 --> 03:11:28,160 THIS WAS IMPORTANT, THERE'S 3879 03:11:28,160 --> 03:11:30,200 STILL SOME INFORMATION IN THE 3880 03:11:30,200 --> 03:11:33,640 PAPERS, THERE IS A FOLLOW ON 3881 03:11:33,640 --> 03:11:36,400 PAPER FROM MARJORIE AND MARV, 3882 03:11:36,400 --> 03:11:39,280 THE FIRST AUTHOR ON IT, WHERE 3883 03:11:39,280 --> 03:11:42,120 THEY MAP THE POINT MUTATION THAT 3884 03:11:42,120 --> 03:11:43,800 CONTROL NEUTRALIZATION 3885 03:11:43,800 --> 03:11:44,760 SENSITIVITY GLOBALLY TO THE 3886 03:11:44,760 --> 03:11:45,440 VIRUS. 3887 03:11:45,440 --> 03:11:47,640 NOW, WHEN I SAW THIS, I THOUGHT 3888 03:11:47,640 --> 03:11:50,600 GREAT, THIS IS TELLING YOU ABOUT 3889 03:11:50,600 --> 03:11:53,320 THE STRUCTURE BECAUSE APPARENTLY 3890 03:11:53,320 --> 03:11:55,360 IT WAS IN THE NEUTRALIZATION 3891 03:11:55,360 --> 03:11:56,400 SITE SO THERE'S SOMETHING ABOUT 3892 03:11:56,400 --> 03:11:58,840 THE ENVELOPE STRUCTURE THAT WAS 3893 03:11:58,840 --> 03:11:59,240 INTERESTING. 3894 03:11:59,240 --> 03:12:01,960 YOU WERE SEEING EPISTATIC 3895 03:12:01,960 --> 03:12:03,360 EFFECTS WITH NEUTRALIZATION. 3896 03:12:03,360 --> 03:12:05,760 SURE ENOUGH NOW THAT WE HAVE 3897 03:12:05,760 --> 03:12:09,040 GOTTEN STRUCTURE, YOU CAN SEE 3898 03:12:09,040 --> 03:12:11,200 WHERE THE MUTATION MAPS. 3899 03:12:11,200 --> 03:12:15,040 THIS IS A CRYOEM STRUCTURE FROM 3900 03:12:15,040 --> 03:12:18,840 STEVE HARRISON, MEMBRANE 3901 03:12:18,840 --> 03:12:19,800 REMEMBER FROM HIV AND IF YOU 3902 03:12:19,800 --> 03:12:24,320 LOOK THERE WHERE THE YELLOW 3903 03:12:24,320 --> 03:12:26,400 ARROWS POINT THAT IS POINT 3904 03:12:26,400 --> 03:12:29,520 MUTATION IN -- THE PAPER, IT'S 3905 03:12:29,520 --> 03:12:33,000 IN -- THE A IN THE AVERY 3906 03:12:33,000 --> 03:12:34,360 SEQUENCE IN THE THING, THIS IS 3907 03:12:34,360 --> 03:12:35,400 DEEP IN THE INTERIOR OF THE 3908 03:12:35,400 --> 03:12:38,000 MOLECULE. 3909 03:12:38,000 --> 03:12:40,000 SO SOMEHOW OR ANOTHER THOSE 3910 03:12:40,000 --> 03:12:43,280 RESIDUES POINTS MUTATION ARE 3911 03:12:43,280 --> 03:12:44,560 GLOBALLY CHANGING THINGS WHEN 3912 03:12:44,560 --> 03:12:47,800 AND I WENT AND LOOKED, WORK A 3913 03:12:47,800 --> 03:12:52,240 BIT ON NEUTRALIZATION, ALSO 3914 03:12:52,240 --> 03:12:53,600 PARTICULARLY (INAUDIBLE) THE 3915 03:12:53,600 --> 03:12:55,920 LEAD PROFESSOR THAT WORK US WITH 3916 03:12:55,920 --> 03:12:58,120 US AND I COULDN'T FIND ANYTHING 3917 03:12:58,120 --> 03:12:59,160 WHERE ANYTHING HAS TRIED TO 3918 03:12:59,160 --> 03:13:00,520 FIGURE OUT WHAT THIS DOES NOW 3919 03:13:00,520 --> 03:13:01,760 THAT WE HAVE GOOD PANELS OF 3920 03:13:01,760 --> 03:13:03,680 BROADLY NEUTRALIZING ANTIBODIES, 3921 03:13:03,680 --> 03:13:06,400 ET CETERA SO SOMETHING WORTH 3922 03:13:06,400 --> 03:13:07,960 LOOKING INTO AFTER ALL THESE 3923 03:13:07,960 --> 03:13:09,000 YEARS. 3924 03:13:09,000 --> 03:13:10,480 INFORMATION GENERATED CLOSE TO 3925 03:13:10,480 --> 03:13:13,320 40 YEARS AGO NOW, REALLY 3926 03:13:13,320 --> 03:13:15,160 VALUABLE. 3927 03:13:15,160 --> 03:13:19,280 THE OTHERWISE I WANT TO THANK IS 3928 03:13:19,280 --> 03:13:21,600 FOR THE CONTRIBUTIONS FC 3929 03:13:21,600 --> 03:13:23,240 MEDIATOR FUNCTION, AND 3930 03:13:23,240 --> 03:13:27,000 PROTECTION AGAINST SIV AND SHIF. 3931 03:13:27,000 --> 03:13:31,440 WE TALKED ABOUT IT A MINUTE AGO. 3932 03:13:31,440 --> 03:13:33,240 SO BY THE TIME THESE PAPERS CAME 3933 03:13:33,240 --> 03:13:35,360 OUT, I FIGURED ALREADY STARTED 3934 03:13:35,360 --> 03:13:38,600 IN WORKING WITH TONY AND BOB GAL 3935 03:13:38,600 --> 03:13:40,600 LOW AND OTHERS TRYING TO COME UP 3936 03:13:40,600 --> 03:13:42,920 WITH VACCINE CONCEPT. 3937 03:13:42,920 --> 03:13:45,320 WE HAD ONE THAT CAME OUT OF 3938 03:13:45,320 --> 03:13:45,800 TONY'S GROUP. 3939 03:13:45,800 --> 03:13:50,080 BUT THE PAPER APPEARED ON 3940 03:13:50,080 --> 03:13:53,400 VACCINE ELICITED OR MEDIATE ADCC 3941 03:13:53,400 --> 03:13:56,320 THAT CORRELATE WITH PROTECTION. 3942 03:13:56,320 --> 03:13:58,480 VIREMIA AND RHESUS MACAQUES. 3943 03:13:58,480 --> 03:14:01,520 AND IT WAS USING THE ASSESS THAT 3944 03:14:01,520 --> 03:14:04,760 WE TALKED ABOUT RFADC ASSAY, I 3945 03:14:04,760 --> 03:14:06,320 THINK IT IS A TERRIFIC ASSAY, WE 3946 03:14:06,320 --> 03:14:07,840 USE IT EVERY DAY, WE MODIFY IT 3947 03:14:07,840 --> 03:14:08,840 AND WE CAN DO PRETTY MUCH 3948 03:14:08,840 --> 03:14:10,080 ANYTHING WE WANT TO DO WITH IT 3949 03:14:10,080 --> 03:14:10,480 RIGHT NOW. 3950 03:14:10,480 --> 03:14:12,880 AND I SEE NO REASON TO CHANGE 3951 03:14:12,880 --> 03:14:13,920 WITH IT. 3952 03:14:13,920 --> 03:14:15,320 JUST EXTREMELY QUANTITATIVE AND 3953 03:14:15,320 --> 03:14:16,680 I WILL COME BACK TO THIS IN A 3954 03:14:16,680 --> 03:14:20,520 MINUTE. 3955 03:14:20,520 --> 03:14:23,040 SO THIS IS A MAJOR TOOL WE USE 3956 03:14:23,040 --> 03:14:25,000 FOR LOOKING EFFECTOR FUNCTION, 3957 03:14:25,000 --> 03:14:27,160 THE ONLY THING WE HAVE DONE TO 3958 03:14:27,160 --> 03:14:28,600 IT IS TRICKED OUT THE TARGET 3959 03:14:28,600 --> 03:14:31,880 CELL LINE A LITTLE BIT SO WE NO 3960 03:14:31,880 --> 03:14:33,960 LONGER HAVE TO LABEL WITH 3961 03:14:33,960 --> 03:14:36,600 CYTOPLASMIC DYE OR MEMBRANE DYE, 3962 03:14:36,600 --> 03:14:38,800 WHAT WE HAVE IS SAME TARGET CELL 3963 03:14:38,800 --> 03:14:40,880 EXPRESSING GFP INTERNALLY, CELL 3964 03:14:40,880 --> 03:14:43,440 LYSIS RELEASES GFP. 3965 03:14:43,440 --> 03:14:46,200 WE PUT A COMMERCIALLY AVAILABLE 3966 03:14:46,200 --> 03:14:51,800 CCR 5 SNAP TAG DYE, SNAP TAG IS 3967 03:14:51,800 --> 03:14:53,680 A BINDING PROTEIN YOU BELIEVE 3968 03:14:53,680 --> 03:14:59,440 LABEL PUT A DIMER IN EASILY. 3969 03:14:59,440 --> 03:15:01,960 CCR 5 IS ALSO FUNCTIONAL. 3970 03:15:01,960 --> 03:15:05,840 WE DEVELOPED THE ASSAY OUR GROUP 3971 03:15:05,840 --> 03:15:08,720 DID, SO THIS OBVIATES STEPS OF 3972 03:15:08,720 --> 03:15:12,800 HAVING TO LABEL THE CELLS. 3973 03:15:12,800 --> 03:15:14,240 AND IT IS ALSO HIGH THROUGH PUT 3974 03:15:14,240 --> 03:15:16,400 AND WE SET THINGS UP VERY FAST 3975 03:15:16,400 --> 03:15:18,200 BUT SOMETHING CAME OUT OF THIS 3976 03:15:18,200 --> 03:15:19,560 UNSUSPECTED TO US, WE FIRST 3977 03:15:19,560 --> 03:15:21,600 STARTED DOING THIS WE WERE 3978 03:15:21,600 --> 03:15:23,480 READING JUST LIKE IN THE 3979 03:15:23,480 --> 03:15:26,560 ORIGINAL PAPER. 3980 03:15:26,560 --> 03:15:28,200 AND WHAT WE DIDN'T KNOW AT TIME 3981 03:15:28,200 --> 03:15:34,160 WAS THAT THIS ASSAY REALLY 3982 03:15:34,160 --> 03:15:35,920 SIMULTANEOUSLY PICK UP TWO 3983 03:15:35,920 --> 03:15:37,440 EFFECTOR MECHANISM, ONE PICKS UP 3984 03:15:37,440 --> 03:15:39,560 TRUE KILLING AND THAT'S MEDIATED 3985 03:15:39,560 --> 03:15:45,040 BY NK CELLS, IN THE PREPARATION 3986 03:15:45,040 --> 03:15:47,240 USING PDMC AS EFFECTERS. 3987 03:15:47,240 --> 03:15:49,240 WE FOOLED WITH A LOT OF CELL 3988 03:15:49,240 --> 03:15:50,400 LINES NK LINES OR WHAT NOT 3989 03:15:50,400 --> 03:15:53,240 TRYING TO GET THOSE TO WORK AS 3990 03:15:53,240 --> 03:15:54,600 EFFECTORS AND THEY ARE AT LEAST 3991 03:15:54,600 --> 03:15:56,440 IN OUR HANDS TRICKY, WHEREAS 3992 03:15:56,440 --> 03:15:58,160 THIS ALWAYS WORKS. 3993 03:15:58,160 --> 03:16:02,840 BUT THE OTHER THING THAT HAPPENS 3994 03:16:02,840 --> 03:16:09,040 IS THERE ARE MONOCYTES IN THERE, 3995 03:16:09,040 --> 03:16:10,600 OFF THE EFFECTOR -- TARGET CELL 3996 03:16:10,600 --> 03:16:14,600 SURFACE ON TO THE EFFECTOR 3997 03:16:14,600 --> 03:16:14,800 CELLS. 3998 03:16:14,800 --> 03:16:16,720 WHY WE DO THE ASSAY TURNS OUT WE 3999 03:16:16,720 --> 03:16:21,560 DIDN'T KNOW THIS FOR A LONG TIME 4000 03:16:21,560 --> 03:16:26,000 BUT USING A FLOW SIGH TOM TRY WE 4001 03:16:26,000 --> 03:16:28,640 FOUND OUT WITH (INAUDIBLE) DOWN 4002 03:16:28,640 --> 03:16:31,800 AT DUKE BY AREA SCALING YOU CAN 4003 03:16:31,800 --> 03:16:34,800 DISCRIMINATE BETWEEN NK EFFECTS 4004 03:16:34,800 --> 03:16:36,080 AND MONOCYTE EFFECTS IN THE SAME 4005 03:16:36,080 --> 03:16:38,200 PREPARATION OF PBMCs. 4006 03:16:38,200 --> 03:16:40,760 TURNS OUT THAT THE MONOCYTES 4007 03:16:40,760 --> 03:16:41,320 MAKE TIGHT CELL JUNCTIONS. 4008 03:16:41,320 --> 03:16:43,920 THAT ACTUALLY SURVIVE FIXATION 4009 03:16:43,920 --> 03:16:45,400 THROUGH FLOW. 4010 03:16:45,400 --> 03:16:49,280 SO LOOK FOR DOUBLEETTES THOSE 4011 03:16:49,280 --> 03:16:53,280 MONOCYTE, THOSE CELLS ARETROPE 4012 03:16:53,280 --> 03:16:55,720 CYTOING WHEREAS WITH NK KILLING 4013 03:16:55,720 --> 03:16:57,000 YOU WILL SEE DEAD CELLS. 4014 03:16:57,000 --> 03:16:59,920 THE OTHER WAY IT IS SET UP IS 4015 03:16:59,920 --> 03:17:01,000 GFP IN CYTOPLASM. 4016 03:17:01,000 --> 03:17:03,160 WHAT WE NOTICED WAS WHEN WE 4017 03:17:03,160 --> 03:17:04,960 CLEANED UP ASSAY AND STARTED 4018 03:17:04,960 --> 03:17:07,080 DOING WITH PURIFIED MONOCYTES WE 4019 03:17:07,080 --> 03:17:09,400 WEREN'T SEEING KILLING. 4020 03:17:09,400 --> 03:17:13,000 THE GFP STAYED IN CYTOPLASM. 4021 03:17:13,000 --> 03:17:18,320 WE SAW TRANSFER OF MEMBRANE TO 4022 03:17:18,320 --> 03:17:20,400 THE EFFECTOR CELL MONOSITE. 4023 03:17:20,400 --> 03:17:22,160 MORE DATA ON THAT IN A MINUTE 4024 03:17:22,160 --> 03:17:23,560 BUT HOW IMPORTANT THIS HAS BEEN 4025 03:17:23,560 --> 03:17:25,000 FOR US. THESE ARE ALL STUDIES 4026 03:17:25,000 --> 03:17:27,520 DONE IN RHESUS MACAQUES GOING 4027 03:17:27,520 --> 03:17:33,320 BACK TO THE FIRST ONE, THAT WE 4028 03:17:33,320 --> 03:17:36,400 REPORTED IN 2007 WHERE WE TOOK 4029 03:17:36,400 --> 03:17:38,080 VACCINE I WILL TELL YOU ABOUT IN 4030 03:17:38,080 --> 03:17:40,800 A MINUTE, MICHAEL HAS SAID A 4031 03:17:40,800 --> 03:17:46,200 LITTLE BIT ABOUT IT WE IMMUNIZED 4032 03:17:46,200 --> 03:17:49,200 MACAQUES AND GOT PROTECTION 4033 03:17:49,200 --> 03:17:51,400 AGAINST HIGH DOSE CHALLENGE 4034 03:17:51,400 --> 03:17:53,400 EXEMPLIFIED BY POST INFECTION 4035 03:17:53,400 --> 03:17:55,600 CONTROL, EXACTLY WHAT YOU SAW 4036 03:17:55,600 --> 03:17:57,560 WITH MARJORIE, WHAT ALSO THIS IS 4037 03:17:57,560 --> 03:18:01,800 WHAT THE SHIV 162P 3 CHALLENGE. 4038 03:18:01,800 --> 03:18:05,640 THAT'S HARD TO NEUTRALIZE VIRUS. 4039 03:18:05,640 --> 03:18:07,560 WE GET NEUTRALIZING ANTIBODIES 4040 03:18:07,560 --> 03:18:09,120 THAT NEUTRALIZE WHAT WE WERE 4041 03:18:09,120 --> 03:18:13,720 TALKING ABOUT AT THE TIME BEING 4042 03:18:13,720 --> 03:18:16,480 A NOT LAB ADAPTED VIRUS BUT 4043 03:18:16,480 --> 03:18:17,680 PRIMARY VIRUS, NO TIERED 4044 03:18:17,680 --> 03:18:19,160 ANYTHING AT THE TIME. 4045 03:18:19,160 --> 03:18:22,800 THAT'S WHY TONY WE PUSH THE 4046 03:18:22,800 --> 03:18:24,200 STUDY, BUT TURNS OUT THERE ARE 4047 03:18:24,200 --> 03:18:26,000 NO NEUTRALIZING ANTIBODIES 4048 03:18:26,000 --> 03:18:27,240 AGAINST CHALLENGE VIRUS BUT YET 4049 03:18:27,240 --> 03:18:29,560 THERE WAS PROTECTION. 4050 03:18:29,560 --> 03:18:31,400 THAT PROTECTION CORRELATED WITH 4051 03:18:31,400 --> 03:18:35,480 SPECIFICITY AGAINST CD4 INDUCED 4052 03:18:35,480 --> 03:18:35,840 EPITOPES. 4053 03:18:35,840 --> 03:18:37,960 WE DIDN'T DO ADCC FIRST, WE DID 4054 03:18:37,960 --> 03:18:39,600 IT LATER BUT WE WENT BACK AND 4055 03:18:39,600 --> 03:18:41,480 LOOKED AT IT AND IT CONFIRMED 4056 03:18:41,480 --> 03:18:43,160 EVERYTHING WE HAVE SEEN LATER. 4057 03:18:43,160 --> 03:18:45,000 ONCE WE GOT THE APHASIA GOING OR 4058 03:18:45,000 --> 03:18:45,440 WHAT NOT. 4059 03:18:45,440 --> 03:18:48,160 SO THERE'S A WHOLE SERIES OF 4060 03:18:48,160 --> 03:18:49,880 STUDIES ONE HERE AND MANY FOLKS 4061 03:18:49,880 --> 03:18:53,320 IN THE ROOM CO-AUTHORS ON, 4062 03:18:53,320 --> 03:18:55,400 PAPERS ONE HERE WITH A NUMBER OF 4063 03:18:55,400 --> 03:18:58,800 -- I THINK THREE OR FOUR PRIMATE 4064 03:18:58,800 --> 03:19:02,600 STUDIES ONE SIV AND THE REST 4065 03:19:02,600 --> 03:19:03,000 SHIV. 4066 03:19:03,000 --> 03:19:06,120 OVER TIME WE HAVE DONE A LOT OF 4067 03:19:06,120 --> 03:19:08,880 THINGS WITH COLLABORATORS ON 4068 03:19:08,880 --> 03:19:10,240 THIS. 4069 03:19:10,240 --> 03:19:14,000 LOOKING AT THINGS FOR EXAMPLE 4070 03:19:14,000 --> 03:19:20,600 LIKE ONE WITH MARGE ACKERMAN AND 4071 03:19:20,600 --> 03:19:22,680 CHRIS KELLOGG LOOKING AT SYSTEMS 4072 03:19:22,680 --> 03:19:24,440 IMMUNOLOGY AND THEY FOUND 4073 03:19:24,440 --> 03:19:27,000 ANTIBODY FC FUNCTIONS IN THIS 4074 03:19:27,000 --> 03:19:29,600 VACCINE STUDY SIV CORRELATED 4075 03:19:29,600 --> 03:19:31,040 WITH BETTER PROTECTION THAN JUST 4076 03:19:31,040 --> 03:19:33,800 ABOUT ANYTHING ELSE AND ALSO 4077 03:19:33,800 --> 03:19:39,200 WITH YUNG SU AND JAY AND TONY 4078 03:19:39,200 --> 03:19:44,240 AND BOB AND OTHERS WHERE WE 4079 03:19:44,240 --> 03:19:47,080 FOUND TRAINED IMMUNITY EFFECT. 4080 03:19:47,080 --> 03:19:49,600 WHICH MAKES A LOT OF SENSE. 4081 03:19:49,600 --> 03:19:52,800 SO THAT'S VERY IMPORTANT FOR US. 4082 03:19:52,800 --> 03:20:00,040 THE RFA -- OUR RDADACC ASSAYS. 4083 03:20:00,040 --> 03:20:01,400 NOW DONE STUDIES IN IN HUMANS. 4084 03:20:01,400 --> 03:20:03,080 THE FIRST THING WHERE WE TRY TO 4085 03:20:03,080 --> 03:20:04,520 USE IT IN FACT IT WAS APPROVED 4086 03:20:04,520 --> 03:20:06,760 TO BE USED, IT WAS IN THE 4087 03:20:06,760 --> 03:20:09,240 CORRELATE STUDY FOR RV 144, 4088 03:20:09,240 --> 03:20:12,440 THERE WAS A INITIAL VETTING OF 4089 03:20:12,440 --> 03:20:14,040 METHODS IN THAT THING WHERE THEY 4090 03:20:14,040 --> 03:20:16,040 SENT OUT SPECIMENS AND WE WERE 4091 03:20:16,040 --> 03:20:19,560 PART OF THE EVALUATION TEAM THAT 4092 03:20:19,560 --> 03:20:22,520 HAD THAT HAPPEN, THE RFADCC 4093 03:20:22,520 --> 03:20:24,960 ASSAY SCORED BEAUTIFULLY, THE 4094 03:20:24,960 --> 03:20:26,880 BEST IN CLASS FOR ADCC ASSAYS. 4095 03:20:26,880 --> 03:20:28,400 WE WOUND OUT NOT GOING AHEAD AND 4096 03:20:28,400 --> 03:20:30,880 DOING THOSE IN THE RV 144 TRIAL 4097 03:20:30,880 --> 03:20:32,680 BECAUSE WE DIDN'T HAVE THE BAND 4098 03:20:32,680 --> 03:20:33,240 WITHAND THERE WERE NO OTHER 4099 03:20:33,240 --> 03:20:35,920 PEOPLE LOOKING AT CD 4I 4100 03:20:35,920 --> 03:20:37,040 ANTIBODIES IN THAT TRIAL. 4101 03:20:37,040 --> 03:20:39,080 TONY'S GROUP LOOK AT A 32 LIKE 4102 03:20:39,080 --> 03:20:40,720 ANTIBODIES AND WE LOOK AT 4103 03:20:40,720 --> 03:20:42,400 CORECEPTOR BINDING ANTIBODIES. 4104 03:20:42,400 --> 03:20:45,600 YOU GOT TWO OTHER ADCC ASSAYS 4105 03:20:45,600 --> 03:20:46,080 THERE. 4106 03:20:46,080 --> 03:20:47,320 EPITHAT WOULD BE THE STORY. 4107 03:20:47,320 --> 03:20:51,120 SORRY NOW WE DIDN'T LOOK. 4108 03:20:51,120 --> 03:20:54,680 THEN COME ON DOWN, COMPARATIVE 4109 03:20:54,680 --> 03:20:55,640 STUDY, THE ONLY ONE OUT THERE 4110 03:20:55,640 --> 03:20:58,720 THAT I KNOW OF, STILL MORE 4111 03:20:58,720 --> 03:21:02,440 RECENT ONE, THAT WAS DONE WITH 4112 03:21:02,440 --> 03:21:05,000 YUNG HUNG AND MARGIE ACKERMAN'S 4113 03:21:05,000 --> 03:21:10,280 TEAM WHERE WE LOOK AT DIFFERENT 4114 03:21:10,280 --> 03:21:13,600 ASSAYS AND THE ASSAY SHOOK OUT 4115 03:21:13,600 --> 03:21:17,320 THERE AND CORRELATED CLOSE WITH 4116 03:21:17,320 --> 03:21:19,600 FERRARI TYPE ASSAY BUT NOT 4117 03:21:19,600 --> 03:21:22,080 OTHERS. 4118 03:21:22,080 --> 03:21:23,680 THE OTHERS THING WE USE THIS 4119 03:21:23,680 --> 03:21:27,920 ASSAY FOR, WE GOT PASSKEYS GROUP 4120 03:21:27,920 --> 03:21:29,560 WHEN HE WAS HAVE US AT MARYLAND 4121 03:21:29,560 --> 03:21:31,200 NOW UNIFORM SERVICES, GOT A 4122 03:21:31,200 --> 03:21:36,320 BUNCH OF MONOCLONALS OUT OF RV 4123 03:21:36,320 --> 03:21:40,280 144, 306 STUDY AND SAW CRYSTAL 4124 03:21:40,280 --> 03:21:43,600 STRUCTURE ANTIBODY LIGAND. 4125 03:21:43,600 --> 03:21:45,400 TURNS OUT THAT THESE ANTIBODIES 4126 03:21:45,400 --> 03:21:49,240 THAT COME UP IN RV 144 LOOK LIKE 4127 03:21:49,240 --> 03:21:51,160 THE ONES WE HAVE WITH VACCINES 4128 03:21:51,160 --> 03:21:52,600 IN MACAQUES AND WITH PEOPLE. 4129 03:21:52,600 --> 03:21:53,600 AND THOSE STRUCTURE OF THESE 4130 03:21:53,600 --> 03:21:56,840 THINGS I WILL TELL YOU IN A 4131 03:21:56,840 --> 03:21:57,080 MINUTE. 4132 03:21:57,080 --> 03:22:00,320 SO THEN FINALLY, THIS YEAR WE 4133 03:22:00,320 --> 03:22:02,880 COMPLETED THE FIRST PHASE 1 4134 03:22:02,880 --> 03:22:05,000 TRIAL FOR OUR VACCINE. 4135 03:22:05,000 --> 03:22:07,440 SUCCESSFULLY DONE, DONE ENTIRELY 4136 03:22:07,440 --> 03:22:10,440 INSIDE THE IHV AT THIS POINT. 4137 03:22:10,440 --> 03:22:12,200 GOT RESPONSES LIKE WHAT WE SEE 4138 03:22:12,200 --> 03:22:14,560 IN RHESUS MACAQUES. 4139 03:22:14,560 --> 03:22:18,760 AND THE VACCINE IS NOW BEING 4140 03:22:18,760 --> 03:22:21,640 EVALUATED FOLLOW ON STUDY BY 4141 03:22:21,640 --> 03:22:24,320 MHRP IN THAILAND. 4142 03:22:24,320 --> 03:22:28,000 PHASE 1B STUDY, COME BACK TO 4143 03:22:28,000 --> 03:22:30,880 THAT SO WE DID ONE MOUSE STUDY 4144 03:22:30,880 --> 03:22:39,440 THAT'S FORGETTABLE, AND SO BUT 4145 03:22:39,440 --> 03:22:41,400 WHAT WE HAVE ALSO DONE, WE HAVE 4146 03:22:41,400 --> 03:22:42,960 DONE STRUCTURE FUNCTION STUDIES 4147 03:22:42,960 --> 03:22:45,280 THIS IS ALWAYS NEAR ANNEDIDAE TO 4148 03:22:45,280 --> 03:22:48,040 MY HEART BECAUSE IT DOSE -- NEAR 4149 03:22:48,040 --> 03:22:49,760 AND DEAR TO MY HEART BECAUSE IT 4150 03:22:49,760 --> 03:22:51,320 GOES BACK TO BEGINNINGS OF MY 4151 03:22:51,320 --> 03:22:52,200 CAREER, WHAT I WAS SORT OF 4152 03:22:52,200 --> 03:22:53,560 TRAINED TO DO. 4153 03:22:53,560 --> 03:22:57,280 FIRST THING, WE PUBLISHED A 4154 03:22:57,280 --> 03:23:00,400 STUDY IN 2013 WHEREBY THIS TIME 4155 03:23:00,400 --> 03:23:04,520 WE WERE GOING AFTER CD4 INDUCE 4156 03:23:04,520 --> 03:23:05,960 ANTIBODIES ISOLATING MONOCLONALS 4157 03:23:05,960 --> 03:23:07,840 WE WORKED OUT PROCEDURE WHEN IT 4158 03:23:07,840 --> 03:23:09,560 WAS HARD TO DO THEM. 4159 03:23:09,560 --> 03:23:12,200 AND CAME UP WITH A LOT OF 4160 03:23:12,200 --> 03:23:14,800 ANTIBODIES OUT OF LEAD CONTROL, 4161 03:23:14,800 --> 03:23:15,280 (INAUDIBLE) GROUP HAS. 4162 03:23:15,280 --> 03:23:18,800 AND THIS IS WHERE WE IDENTIFIED 4163 03:23:18,800 --> 03:23:21,120 A COMPETITION GROUP OF 4164 03:23:21,120 --> 03:23:22,600 ANTIBODIES THAT COMPETED WITH 4165 03:23:22,600 --> 03:23:25,360 SOME OF JANE'S ROBINSON'S 4166 03:23:25,360 --> 03:23:27,560 EARLIER ANN BODIES, WE CALL IT 4167 03:23:27,560 --> 03:23:29,000 EPITOPE CLUSTER A IN THIS 4168 03:23:29,000 --> 03:23:30,640 PARTICULAR STUDY AND THAT IS 4169 03:23:30,640 --> 03:23:34,360 BECOME WIDELY USED NOW. 4170 03:23:34,360 --> 03:23:37,400 WE KNOW A LOT ABOUT STRUCTURE OF 4171 03:23:37,400 --> 03:23:37,800 THESE ANTIBODIES. 4172 03:23:37,800 --> 03:23:39,920 THAT WAS THE FIRST PAPER. 4173 03:23:39,920 --> 03:23:42,600 AND THEN ANOTHER PAPER WAS ONE 4174 03:23:42,600 --> 03:23:45,200 WE STARTED LOOKING AT THE ASSAY, 4175 03:23:45,200 --> 03:23:46,640 THERE WAS SOME INTERESTING 4176 03:23:46,640 --> 03:23:48,800 THINGS ABOUT THE DOSE RESPONSE 4177 03:23:48,800 --> 03:23:52,360 CURVES THAT WOULD JUST LIKE AN 4178 03:23:52,360 --> 03:23:55,560 IGE BASOPHIL DOSE RESPONSE CURVE 4179 03:23:55,560 --> 03:23:57,320 IF YOU DOSE THOSE ASSAYS AND 4180 03:23:57,320 --> 03:23:58,600 FAMILIAR WITH THOSE FROM THE OLD 4181 03:23:58,600 --> 03:23:59,600 DAYS. 4182 03:23:59,600 --> 03:24:02,240 AGAIN WE PUBLISHED A NUMBER OF 4183 03:24:02,240 --> 03:24:04,000 STRUCTURE ALL AT THESE POINT 4184 03:24:04,000 --> 03:24:06,320 WITH MARZANA. 4185 03:24:06,320 --> 03:24:08,200 WE HAVE NEW PERSON IN OUR GROUP 4186 03:24:08,200 --> 03:24:11,240 WHERE DOING CRYOEM STRUCTURE ON 4187 03:24:11,240 --> 03:24:12,320 THE VACCINE ANTIGEN GETTING 4188 03:24:12,320 --> 03:24:14,200 CLOSE WITH THAT. 4189 03:24:14,200 --> 03:24:17,200 BUT STUFF ALL WITH THEIR GROUP. 4190 03:24:17,200 --> 03:24:20,080 SO THESE -- THIS WAS ALL USED 4191 03:24:20,080 --> 03:24:23,200 FOR THESE STUDIES. 4192 03:24:23,200 --> 03:24:26,800 AND THERE IS ANOTHER FOLLOW-ON 4193 03:24:26,800 --> 03:24:31,760 STUDY AGAIN WITH MARJORIE -- 4194 03:24:31,760 --> 03:24:33,200 MARGIE ACKERMAN'S GROUP LOOKING 4195 03:24:33,200 --> 03:24:35,160 AT EFFECTOR ACTIVITIES PREDICTED 4196 03:24:35,160 --> 03:24:36,600 BY PHYSICAL PROPERTIES AND THE 4197 03:24:36,600 --> 03:24:38,200 ASSAY SHOOK OUT IN THAT GAVE US 4198 03:24:38,200 --> 03:24:39,280 INTERESTING INFORMATION. 4199 03:24:39,280 --> 03:24:41,240 THERE'S OTHER PAPERS UNDER 4200 03:24:41,240 --> 03:24:43,800 SUBMISSION RIGHT NOW, FOLLOWING 4201 03:24:43,800 --> 03:24:44,880 ON FOR THESE. 4202 03:24:44,880 --> 03:24:50,120 SO WHAT I'M GOING TO POINT OUT 4203 03:24:50,120 --> 03:24:53,080 ALSO, GLAD THIS WAS MENTIONED. 4204 03:24:53,080 --> 03:24:54,640 WE HAVE A GUY IN OUR GROUP WHO 4205 03:24:54,640 --> 03:24:57,400 IS A LONG TERM FRIEND FROM FIRST 4206 03:24:57,400 --> 03:25:00,800 DAYS WHEN, A GUY NAMED ALLEN 4207 03:25:00,800 --> 03:25:02,040 SMALLJOHN. 4208 03:25:02,040 --> 03:25:03,600 IF YOU KNOW ABOUT EBOLA OR 4209 03:25:03,600 --> 03:25:06,640 MARKBURG, ALAN WAS IN T MILITARY 4210 03:25:06,640 --> 03:25:07,840 USAMRID FOR YEARS BUT HE WAS IN 4211 03:25:07,840 --> 03:25:08,800 MARYLAND WHEN I FIRST CAME. 4212 03:25:08,800 --> 03:25:11,000 HE PUBLISHED THE FIRST CLEAR CUT 4213 03:25:11,000 --> 03:25:13,200 DEFINITIVE STUDY SHOWING THAT 4214 03:25:13,200 --> 03:25:14,200 NON-NEUTRALIZING ANTIBODIES 4215 03:25:14,200 --> 03:25:14,840 COULD PROTECT. 4216 03:25:14,840 --> 03:25:17,640 PUBLISHED IN NATURE IN 1982. 4217 03:25:17,640 --> 03:25:19,400 AND IS WHEN PEOPLE WERE FIRST 4218 03:25:19,400 --> 03:25:21,720 STARTED MAKING MONOCLONAL 4219 03:25:21,720 --> 03:25:23,200 ANTIBODIES. EVERYBODY THOUGHT 4220 03:25:23,200 --> 03:25:25,840 NEUTRALIZATION HAD TO BE IT. 4221 03:25:25,840 --> 03:25:28,400 HE WAS WITH JERRY COLE AT 4222 03:25:28,400 --> 03:25:29,000 HOPKINS. 4223 03:25:29,000 --> 03:25:30,120 JERRY CAME TO MARYLAND JUST 4224 03:25:30,120 --> 03:25:31,600 BEFORE I DID. 4225 03:25:31,600 --> 03:25:36,200 ANDEN ALLEN MAKES MONOCLONALS 4226 03:25:36,200 --> 03:25:37,760 FOR THE VIRUS, NEUROTROPIC VIRUS 4227 03:25:37,760 --> 03:25:40,200 AND SHOWED CLEARLY THAT HE COULD 4228 03:25:40,200 --> 03:25:42,960 GET PROTECTION, BEST PROTECTIVE 4229 03:25:42,960 --> 03:25:44,320 ANTIBODY, DIDN'T NEUTRALIZE. 4230 03:25:44,320 --> 03:25:46,000 DIDN'T KNOW WHAT IT DID. 4231 03:25:46,000 --> 03:25:47,600 HE LOOKED INTO IT LATER AND 4232 03:25:47,600 --> 03:25:49,440 TRIED TO FIGURE IT OUT BUT GO 4233 03:25:49,440 --> 03:25:51,120 LOOK IN THE LITERATURE HE WAS A 4234 03:25:51,120 --> 03:25:53,160 PERSON WHO ISOLATED ONE ANTIBODY 4235 03:25:53,160 --> 03:25:56,880 IN COCKTAIL IN THE EBOLA. 4236 03:25:56,880 --> 03:25:59,480 C 13 C 6, TO THIS DAY SO WE SET 4237 03:25:59,480 --> 03:26:02,360 UP THE SYSTEM BECAUSE ALLEN WENT 4238 03:26:02,360 --> 03:26:04,400 INTO RETIREMENT BUT CAME BACK 4239 03:26:04,400 --> 03:26:07,240 OUT AND WITH US AT THE INSTITUTE 4240 03:26:07,240 --> 03:26:12,680 AND SO WE SET UP MODIFIED RFACD 4241 03:26:12,680 --> 03:26:14,880 ASSAY, WE PUT GP ON THE SURFACE 4242 03:26:14,880 --> 03:26:16,640 SO THAT LED TO A NUMBER OF 4243 03:26:16,640 --> 03:26:17,960 STUDIES, ALL COLLABORATIVE 4244 03:26:17,960 --> 03:26:19,800 STUDIES AT THIS POINT. 4245 03:26:19,800 --> 03:26:22,000 ONE WAS THE FIRST WITH 4246 03:26:22,000 --> 03:26:24,280 HAIRIOTROBINSON WITH HER EBOLA 4247 03:26:24,280 --> 03:26:27,000 VACCINE ENCODES VIRUS LIKE 4248 03:26:27,000 --> 03:26:29,120 PARTICLE IN MVA AND SHE GETS 4249 03:26:29,120 --> 03:26:32,000 PROTECTION AGAINST EBOLA. 4250 03:26:32,000 --> 03:26:34,080 IN THAT MODEL IN MONKEYS. TURNS 4251 03:26:34,080 --> 03:26:37,600 OUT WE RAN THE ADCC, IT 4252 03:26:37,600 --> 03:26:38,320 CORRELATES WITHOUT, AND I 4253 03:26:38,320 --> 03:26:43,160 HAVEN'T ANYTHING PUBLISHED BUT 4254 03:26:43,160 --> 03:26:44,400 (INAUDIBLE) WAS PART OF THE 4255 03:26:44,400 --> 03:26:45,840 STUFF FUNDED BY MILITARY FOR 4256 03:26:45,840 --> 03:26:48,640 DOING THINGS WITH THE VACCINES 4257 03:26:48,640 --> 03:26:52,600 FROM THE VSV VACCINE THAT MERCK 4258 03:26:52,600 --> 03:26:53,280 HAS. 4259 03:26:53,280 --> 03:26:55,600 AND FALLS OUT FOR THAT. 4260 03:26:55,600 --> 03:27:00,440 THEN WITH JIM CROW, AT 4261 03:27:00,440 --> 03:27:01,480 VANDERBILT PUBLISHED SEVERAL 4262 03:27:01,480 --> 03:27:03,200 STUDIES WHERE WE HAVE DONE THE 4263 03:27:03,200 --> 03:27:06,400 ADCC ASSAY ON THE INTERESTING 4264 03:27:06,400 --> 03:27:08,880 ANTIBODIES THAT JIM AND GROUP 4265 03:27:08,880 --> 03:27:10,880 HAS ISOLATED. 4266 03:27:10,880 --> 03:27:13,680 AND IT TURNS OUT THAT IT 4267 03:27:13,680 --> 03:27:15,000 CORRELATES PRETTY WELL IN MANY 4268 03:27:15,000 --> 03:27:18,720 WAYS WITH THESE THINGS. 4269 03:27:18,720 --> 03:27:22,440 NOW WE HAVE A REALLY NICE 4270 03:27:22,440 --> 03:27:25,640 COLLABORATION WITH DANIEL 4271 03:27:25,640 --> 03:27:27,320 (INAUDIBLE) AT SCRIPS FORMER 4272 03:27:27,320 --> 03:27:29,800 STUDENT OF ERICA SAPPHIRE AND HE 4273 03:27:29,800 --> 03:27:31,920 IS THERE POST DOC WITH ANDREW 4274 03:27:31,920 --> 03:27:32,120 WARD. 4275 03:27:32,120 --> 03:27:34,200 SO THAT'S HOW WE ARE CONTINUING 4276 03:27:34,200 --> 03:27:36,200 THE EBOLA WORKS SO WHAT I WILL 4277 03:27:36,200 --> 03:27:37,920 SHOW YOU NOW FOR HIV WE HAVE 4278 03:27:37,920 --> 03:27:41,280 ALSO SEEN FOR EBOLA. 4279 03:27:41,280 --> 03:27:43,280 THAT IS OUR SITE SO TO SPEAK. 4280 03:27:43,280 --> 03:27:46,480 HERE IS VACCINE, TALKING ABOUT 4281 03:27:46,480 --> 03:27:48,800 BEFORE, SINGLE CHAIN WE CALL IT 4282 03:27:48,800 --> 03:27:51,560 CONFIRMATIONALLY CONSTRAINED GP 4283 03:27:51,560 --> 03:27:51,880 120. 4284 03:27:51,880 --> 03:27:55,720 FIRST DESCRIPTION OF THAT WAS IN 4285 03:27:55,720 --> 03:27:58,600 2000 WHEN TONY DESIGNED IT BUNCH 4286 03:27:58,600 --> 03:27:59,800 OF US ALL WORKING TOGETHER 4287 03:27:59,800 --> 03:28:01,040 LOOKING AT DIFFERENT VACCINE 4288 03:28:01,040 --> 03:28:02,680 CONCEPTS WITH THE INSTITUTE WAS 4289 03:28:02,680 --> 03:28:04,240 FIRST STARTED. 4290 03:28:04,240 --> 03:28:08,360 CAME UP WITH THIS CONCEPT, AND 4291 03:28:08,360 --> 03:28:09,800 WHEN WE WENT THROUGH VETTING 4292 03:28:09,800 --> 03:28:11,720 PROCESS, ALL THE THINGS WE LOOK 4293 03:28:11,720 --> 03:28:13,080 AT FELL BY THE WAYSIDE. 4294 03:28:13,080 --> 03:28:14,960 THIS WAS CHOSEN AS THE PRIMARY 4295 03:28:14,960 --> 03:28:16,440 CANDIDATE. 4296 03:28:16,440 --> 03:28:19,880 SO THE FIRST STUDY I MENTION WAS 4297 03:28:19,880 --> 03:28:21,200 PUBLISHED IN 2007. 4298 03:28:21,200 --> 03:28:23,400 WHERE ANTIBODIES AGAINST CD4 4299 03:28:23,400 --> 03:28:26,800 INDUCE SITES AND GP 120 CONTROL 4300 03:28:26,800 --> 03:28:28,280 SHIV CHALLENGE. 4301 03:28:28,280 --> 03:28:31,320 I HAVE NO RELIGION ABOUT 4302 03:28:31,320 --> 03:28:32,080 NEUTRALIZATION, 4303 03:28:32,080 --> 03:28:32,520 NON-NEUTRALIZATION. 4304 03:28:32,520 --> 03:28:34,560 THIS IS SIMPLE OBSERVATION. 4305 03:28:34,560 --> 03:28:38,360 WE SET UP THIS STUDY, WHEN WE 4306 03:28:38,360 --> 03:28:41,760 GOT IT GOING, SOLE GOAL IS WE 4307 03:28:41,760 --> 03:28:43,400 GOT PROTECTION WE WORK WITH -- 4308 03:28:43,400 --> 03:28:44,720 WE DO SOME MORE WITH IT WE 4309 03:28:44,720 --> 03:28:46,280 DIDN'T GET PROTECTION IN MONKEY 4310 03:28:46,280 --> 03:28:47,080 MODEL WE WOULDN'T. 4311 03:28:47,080 --> 03:28:52,280 SO THIS IS A SHIV 16 P 3, SO 4312 03:28:52,280 --> 03:28:54,160 PASSES AT THE TIME, POST 4313 03:28:54,160 --> 03:28:56,480 INFECTION CONTROL OF VIREMIA, WE 4314 03:28:56,480 --> 03:28:57,360 WONDERED HOW THESE THINGS 4315 03:28:57,360 --> 03:28:57,880 WORKED. 4316 03:28:57,880 --> 03:29:00,240 THERE WAS A LITTLE REVIEW HERE 4317 03:29:00,240 --> 03:29:01,600 IN CURRENT HIV RESEARCH WHERE 4318 03:29:01,600 --> 03:29:04,400 TONY POINTED THIS OUT. 4319 03:29:04,400 --> 03:29:06,240 THAT THE NEUTRALIZATION PROBABLY 4320 03:29:06,240 --> 03:29:07,600 WAS AND SOMETHING LIKE ADCC WAS 4321 03:29:07,600 --> 03:29:09,320 PROBABLY GOING ON. 4322 03:29:09,320 --> 03:29:12,240 AND THAT IS WHY WHEN THE ASSAY 4323 03:29:12,240 --> 03:29:13,640 CAME OUT WE JUMPED ON IT. 4324 03:29:13,640 --> 03:29:16,800 AND STARTED USING IT. 4325 03:29:16,800 --> 03:29:19,840 AND I AM COMFORTABLE WORKING 4326 03:29:19,840 --> 03:29:21,920 WITH CHROMIUM, THAT STUFF BUT 4327 03:29:21,920 --> 03:29:24,400 HAVEN'T DONE CTL ASSAYS FOR 4328 03:29:24,400 --> 03:29:26,920 SEVERAL YEARS, I SAID OH HELL 4329 03:29:26,920 --> 03:29:29,720 NO, THEY ARE A MESS. 4330 03:29:29,720 --> 03:29:31,560 I WAS CO-AUTHOR ON ONE OF THE 4331 03:29:31,560 --> 03:29:33,480 FIRST ADCC PAPERS THAT WAS 4332 03:29:33,480 --> 03:29:37,400 PUBLISHED IN 1982 THAT WAS DONE 4333 03:29:37,400 --> 03:29:39,320 WITH CHROMIUM RELEASE, US 4334 03:29:39,320 --> 03:29:40,440 THOUGHT IT WAS THE MOST BORING 4335 03:29:40,440 --> 03:29:41,560 THING THAT I WAS PART OF AT THE 4336 03:29:41,560 --> 03:29:42,880 TIME, DIDN'T DO ANYTHING WITH IT 4337 03:29:42,880 --> 03:29:45,320 FOR YEARS. 4338 03:29:45,320 --> 03:29:46,600 YOU GET WISER AS YOU GET OLDER. 4339 03:29:46,600 --> 03:29:52,160 SO ANYHOW, FULL ON SINGLE 4340 03:29:52,160 --> 03:29:54,560 CHAINS, THIS EXPOSES THE MOST 4341 03:29:54,560 --> 03:29:56,920 CONSERVED PARTS OF GP 120. 4342 03:29:56,920 --> 03:29:59,200 AND THAT INCLUDES CORECEPTOR 4343 03:29:59,200 --> 03:30:00,680 BINDING SITE BUT ALSO INCLUDES 4344 03:30:00,680 --> 03:30:02,880 THIS REGION DOWN THERE WE DEFINE 4345 03:30:02,880 --> 03:30:05,320 AS EPITOPE CLUSTER A, EPITOPE 4346 03:30:05,320 --> 03:30:07,840 CLUSTER A IN NATIVE TRIMER IS 4347 03:30:07,840 --> 03:30:12,400 THE INTERNAL DOCKING SITE FOR GP 4348 03:30:12,400 --> 03:30:12,920 41. 4349 03:30:12,920 --> 03:30:16,280 SO WHEN GETS TRIGGEREDDED YOU 4350 03:30:16,280 --> 03:30:18,480 WIND UP TWO EPITOPE REGIONS COME 4351 03:30:18,480 --> 03:30:19,280 TOGETHER. 4352 03:30:19,280 --> 03:30:22,480 FIRST THE 32 SIDE OF IT, AGAIN 4353 03:30:22,480 --> 03:30:26,760 ONE OF JAMES ROBINSON'S ANTIBODY 4354 03:30:26,760 --> 03:30:28,000 AND SECOND IS C 11. 4355 03:30:28,000 --> 03:30:29,560 WE KNEW IT STRUCTURALLY BUT AT 4356 03:30:29,560 --> 03:30:31,480 THE TIME OF PUBLISH WE KNEW IT 4357 03:30:31,480 --> 03:30:33,200 CORRELATE WITH PROTECTION. 4358 03:30:33,200 --> 03:30:34,880 THAT'S WHAT WE KEPT ZYSEING. 4359 03:30:34,880 --> 03:30:36,520 I MENTION THIS, WE JUST 4360 03:30:36,520 --> 03:30:39,400 PUBLISHED THE FIRST VACCINE 4361 03:30:39,400 --> 03:30:41,280 TRIAL WHERE WE GOT THESE 4362 03:30:41,280 --> 03:30:42,800 RESPONSES, CORECEPTOR BINDING 4363 03:30:42,800 --> 03:30:44,600 SITE ANTIBODIES AS WELL AS 4364 03:30:44,600 --> 03:30:46,200 CLUSTER A ANN BODIES AND WE 4365 03:30:46,200 --> 03:30:47,680 HAVEN'T DONE CRYSTAL STRUCTURES 4366 03:30:47,680 --> 03:30:50,360 OR CRYOEMs ON THE ANTIBODIES 4367 03:30:50,360 --> 03:30:51,920 OUTS OF THESE PEOPLE BUT BY 4368 03:30:51,920 --> 03:30:53,920 COMPETITION ANALYSES WHICH TURN 4369 03:30:53,920 --> 03:30:54,400 OUT TO BE GOOD. 4370 03:30:54,400 --> 03:30:56,520 THESE LOOK LIKE THE ONES THAT 4371 03:30:56,520 --> 03:30:58,840 CAME UP IN RV 144 THAT CAME UP 4372 03:30:58,840 --> 03:31:03,640 IN MONKEY STUDIES. 4373 03:31:03,640 --> 03:31:06,360 SO THIS IS PART OF THE TRIAL 46 4374 03:31:06,360 --> 03:31:08,080 I MENTION WHERE IT IS A LATE 4375 03:31:08,080 --> 03:31:15,000 BOOST OF RV 306, BOOST OF RV 144 4376 03:31:15,000 --> 03:31:17,400 VOLUNTEERS, COLLABORATION WITH 4377 03:31:17,400 --> 03:31:19,840 MMRP AND DUKE WITH BART HAYNES 4378 03:31:19,840 --> 03:31:23,200 TEAM AT DUKE AND (INAUDIBLE) ET 4379 03:31:23,200 --> 03:31:23,400 AL. 4380 03:31:23,400 --> 03:31:26,200 SO THAT IS ONGOING, JUST STARTED 4381 03:31:26,200 --> 03:31:30,360 ENROLLING AND IMMUNIZING ABOUT 4382 03:31:30,360 --> 03:31:33,000 THREE MONTHS ACHE, IN IS GOING 4383 03:31:33,000 --> 03:31:33,600 ON IN THAILAND. 4384 03:31:33,600 --> 03:31:35,200 SO THAT'S GOING -- WE ARE 4385 03:31:35,200 --> 03:31:38,000 MANAGING THE DRUG PRODUCT, ET 4386 03:31:38,000 --> 03:31:38,920 CETERA, AND SPENT TIME DOING 4387 03:31:38,920 --> 03:31:41,160 THAT. 4388 03:31:41,160 --> 03:31:43,520 BUT HERE IS WHERE I AM HEADED. 4389 03:31:43,520 --> 03:31:45,640 WE SAW THESE KINDS OF DATA FOR 4390 03:31:45,640 --> 03:31:50,600 EXAMPLE, THIS PAPER PUBLISHED 4391 03:31:50,600 --> 03:31:53,440 WITH TIM PHOTS LEAD AUTHOR A LOT 4392 03:31:53,440 --> 03:31:55,120 OF FOLKS CO-AUTHORS. 4393 03:31:55,120 --> 03:31:56,280 WE FOUND IN OUR PROTECTION 4394 03:31:56,280 --> 03:32:00,000 STUDIES THAT WE SEE A SWEET 4395 03:32:00,000 --> 03:32:02,200 SPOT, THAT THERE WAS -- IF YOU 4396 03:32:02,200 --> 03:32:03,840 HAD ENOUGH ANIMALS, ENOUGH 4397 03:32:03,840 --> 03:32:05,040 INDEPENDENT TYPES OF STUDIES YOU 4398 03:32:05,040 --> 03:32:09,800 CAN SEE A SITUATION WHERE IF YOU 4399 03:32:09,800 --> 03:32:12,960 PLOT NUMBER OF CHALLENGES, LOW 4400 03:32:12,960 --> 03:32:16,200 DOSE CHALLENGES OF SHIV 1623P OR 4401 03:32:16,200 --> 03:32:18,200 SIV THERE IS A SWEET SPOT FOR 4402 03:32:18,200 --> 03:32:18,800 PROTECTION. 4403 03:32:18,800 --> 03:32:22,920 WHERE THE ADCC RESPONSE TO THE 4404 03:32:22,920 --> 03:32:24,640 CD4I EPITOPES IS HIGH ENOUGH, 4405 03:32:24,640 --> 03:32:30,120 BUT YOU DON'T HAVE TOO HIGH OF 4406 03:32:30,120 --> 03:32:30,520 T-CELL RESPONSE. 4407 03:32:30,520 --> 03:32:32,320 WE DON'T KNOW ABOUT T-CELL 4408 03:32:32,320 --> 03:32:33,880 PHENOTYPE THERE BUT WE HAVE SOME 4409 03:32:33,880 --> 03:32:35,040 INDICATION WHAT IT IS NOW AND IT 4410 03:32:35,040 --> 03:32:36,120 IS WHAT YOU WOULD EXPECT IT TO 4411 03:32:36,120 --> 03:32:36,520 BE. 4412 03:32:36,520 --> 03:32:40,200 SORT OF LIKE WHAT YOU SAW WITH 4413 03:32:40,200 --> 03:32:42,400 THE QUOTE UNQUOTE RV 144 REPEAT 4414 03:32:42,400 --> 03:32:45,200 THAT DIDN'T REPEAT. 4415 03:32:45,200 --> 03:32:51,560 ANYHOW SO WE HAD THAT, SO WE HAD 4416 03:32:51,560 --> 03:32:53,040 THE ABILITY AND INTEREST TO DO 4417 03:32:53,040 --> 03:32:57,200 ALL THE CRYSTALLOGRAPHY, ET 4418 03:32:57,200 --> 03:32:58,160 CETERA, MONOCLONALS PULLED OUT 4419 03:32:58,160 --> 03:33:02,320 OF PEOPLE AND NOW MACAQUES TO GO 4420 03:33:02,320 --> 03:33:03,880 PICK APART WHAT THESE EPITOPE 4421 03:33:03,880 --> 03:33:05,160 REGIONS LOOK LIKE AND NOTHING 4422 03:33:05,160 --> 03:33:08,800 WAS KNOWN ABOUT THEM UNTIL WE 4423 03:33:08,800 --> 03:33:09,680 STARTED THIS EXCEPT POINT 4424 03:33:09,680 --> 03:33:12,400 MUTATIONS. THE POINT MUTATIONS 4425 03:33:12,400 --> 03:33:14,600 ARE SHOWING REGIONS WE KNOW ARE 4426 03:33:14,600 --> 03:33:15,840 OUTSIDE THE EPITOPE FOOTPRINT. 4427 03:33:15,840 --> 03:33:20,040 WHAT THIS IS, IS THIS IS GP 120, 4428 03:33:20,040 --> 03:33:22,400 ACTUAL STRUCTURE, FOR CORECEPTOR 4429 03:33:22,400 --> 03:33:25,480 BINDING SITE ANTIBODIES IN 12I 2 4430 03:33:25,480 --> 03:33:26,880 THAT WORKS ON PASSIVE 4431 03:33:26,880 --> 03:33:29,440 IMMUNIZATION STUDY FOR POST 4432 03:33:29,440 --> 03:33:31,560 INFECTION CONTROL, DOESN'T 4433 03:33:31,560 --> 03:33:32,840 NEUTRALIZE THE VIRUS. 4434 03:33:32,840 --> 03:33:34,280 EPITOPE CLUSTER A THERE WAS 4435 03:33:34,280 --> 03:33:38,000 COMPETITION DATA THAT SAID THAT 4436 03:33:38,000 --> 03:33:42,200 THE ANTIBODIES A 32 AND C 11 4437 03:33:42,200 --> 03:33:44,880 WOULD CROSS COMPETE BUT 4438 03:33:44,880 --> 03:33:45,800 NON-RECIPROCAL FASHION. 4439 03:33:45,800 --> 03:33:49,080 SO THERE WAS EPITOPE OVERLAP OR 4440 03:33:49,080 --> 03:33:50,880 THESE TWO EPITOPES WERE 4441 03:33:50,880 --> 03:33:53,120 PHYSICALLY CLOSE ENOUGH TO ONE 4442 03:33:53,120 --> 03:33:55,320 ANOTHER WITH FULL LENGTH 4443 03:33:55,320 --> 03:33:56,560 ANTIBODY, IF ONE BOUND THE OTHER 4444 03:33:56,560 --> 03:33:59,600 TRY TO COME IN, THERE'S 4445 03:33:59,600 --> 03:34:01,120 CANDIDATES REDUCE, BY CRYSTAL 4446 03:34:01,120 --> 03:34:03,600 STRUCTURE WE SHOW THESE THINGS 4447 03:34:03,600 --> 03:34:05,480 RECOGNIZE ADJACENT EPITOPES, IN 4448 03:34:05,480 --> 03:34:09,000 THIS REGION THAT FORMS ON GP 120 4449 03:34:09,000 --> 03:34:13,960 AFTER LETS GO GP 41 DURING VIRAL 4450 03:34:13,960 --> 03:34:16,880 ENTRY OR DURING EXIT IF COMPELS 4451 03:34:16,880 --> 03:34:18,920 HAVE CD4 ON IT. 4452 03:34:18,920 --> 03:34:20,840 WHAT I AM NOT SHOWING YOU IS WE 4453 03:34:20,840 --> 03:34:22,680 HAVE MONKEY MONOCLONAL, ONE OF 4454 03:34:22,680 --> 03:34:24,120 JAMES,NA RECOGNIZES THE HYBRID 4455 03:34:24,120 --> 03:34:27,000 REGION IN HERE, A LOT OF THESE 4456 03:34:27,000 --> 03:34:29,080 ANTIBODIES COMING OUT OF ONE 4457 03:34:29,080 --> 03:34:33,160 FROM RV 144 RECOGNIZE FOOTPRINT 4458 03:34:33,160 --> 03:34:34,360 THAT OVERLAPS THESE. 4459 03:34:34,360 --> 03:34:35,760 SO WE HAVE THESE STRUCTURE, WE 4460 03:34:35,760 --> 03:34:39,320 HAVE BINDING ANGLES WE HAVE 4461 03:34:39,320 --> 03:34:41,120 PHYSICAL CHEMICAL INFORMATION 4462 03:34:41,120 --> 03:34:46,200 PLUS WE HAVE A ROBUST ASSAY THAT 4463 03:34:46,200 --> 03:34:47,640 IS QUANTITATIVE SO ALLOWED US TO 4464 03:34:47,640 --> 03:34:48,320 HAVE FUN WITH THERE'S THINGS. 4465 03:34:48,320 --> 03:35:04,400 THIS IS WHERE I GO OFF OF HIV. 4466 03:35:04,400 --> 03:35:07,040 WHICH TAKE PRIME MARE HUMAN 4467 03:35:07,040 --> 03:35:09,560 MONOCYTES, -- PRIMARY HUMAN 4468 03:35:09,560 --> 03:35:11,560 MONOCYTES AND WE WILL PUT THEM 4469 03:35:11,560 --> 03:35:14,520 TOGETHER AND DO THE TROGO 4470 03:35:14,520 --> 03:35:16,680 CYTOSIS BUSINESS AND LOOK IT IN. 4471 03:35:16,680 --> 03:35:18,640 SO WE DO WE ARE ABLE LOOK IN 4472 03:35:18,640 --> 03:35:20,320 TISSUE NOW AND THICK TISSUE 4473 03:35:20,320 --> 03:35:24,880 SECTION, ABLE TO DO THIS BY LIVE 4474 03:35:24,880 --> 03:35:27,080 IMAGING LIVE CELL IMAGING, DO IT 4475 03:35:27,080 --> 03:35:31,560 BY STANDARD CONFOCAL AND SUPER 4476 03:35:31,560 --> 03:35:32,720 RESOLUTION CONFOCAL MICROSCOPY 4477 03:35:32,720 --> 03:35:33,800 SO I WILL SHOW YOU DATA FROM 4478 03:35:33,800 --> 03:35:34,240 THIS. 4479 03:35:34,240 --> 03:35:36,880 AND WHAT IS GOING ON WITH THIS, 4480 03:35:36,880 --> 03:35:39,400 IS TROGO CYTOSIS PROCESS, YOU 4481 03:35:39,400 --> 03:35:41,000 GET MEMBRANE FRAGMENTS FROM 4482 03:35:41,000 --> 03:35:42,960 TARGET CELL TRANSFERRED OVER ON 4483 03:35:42,960 --> 03:35:45,080 TO THE EFFECTOR CELL BUT YOU 4484 03:35:45,080 --> 03:35:46,280 ALSO GET ANTIGEN ANTIBODY 4485 03:35:46,280 --> 03:35:49,200 COMPLEXES GOING OVER AS WELL. 4486 03:35:49,200 --> 03:35:50,720 NO ANTIBODY IN THERE OR ANTIGEN 4487 03:35:50,720 --> 03:35:53,760 IN THERE, YOU DON'T GET TROGO 4488 03:35:53,760 --> 03:35:54,560 CYTOSIS. 4489 03:35:54,560 --> 03:35:55,680 WHAT IT MEANS, I DON'T KNOW. 4490 03:35:55,680 --> 03:35:59,320 IT CORRELATES IN OUR STUDIES. 4491 03:35:59,320 --> 03:36:01,080 IT'S CLEARLY THE PHENOMENON 4492 03:36:01,080 --> 03:36:02,000 ITSELF CLEARLY IMPORTANT FOR 4493 03:36:02,000 --> 03:36:03,640 BOTH POSITIVE AND NEGATIVE 4494 03:36:03,640 --> 03:36:05,960 OUTCOMES FROM CANCER ANTIBODY 4495 03:36:05,960 --> 03:36:06,480 TRIALS. 4496 03:36:06,480 --> 03:36:10,960 ALSO THERE IS A PROBLEM IN NK -- 4497 03:36:10,960 --> 03:36:14,000 CAR T-CELL MEDIATED KILLING, 4498 03:36:14,000 --> 03:36:19,040 ITSELETCETERA. 4499 03:36:19,040 --> 03:36:20,520 THERE'S LIKE 10,000 GRANTS THAT 4500 03:36:20,520 --> 03:36:23,800 HAVE PHAGOCYTOSIS OR ADCC IN IT, 4501 03:36:23,800 --> 03:36:25,840 EIGHT HAVE TROGO CYTOSIS. 4502 03:36:25,840 --> 03:36:29,040 AND THEY ARE ALL ON MAINTENANCE 4503 03:36:29,040 --> 03:36:30,600 WHICH IS WHERE THE PHENOMENON 4504 03:36:30,600 --> 03:36:31,840 WAS DISCOVER SOD IT HAS THAT 4505 03:36:31,840 --> 03:36:32,640 ATTRACTION. 4506 03:36:32,640 --> 03:36:35,840 SO THINKING NOW, BACK FROM A 4507 03:36:35,840 --> 03:36:37,200 FUNCTIONAL BASIS WHICH 4508 03:36:37,200 --> 03:36:38,320 STRUCTURAL BASIS, I ALWAYS TRY 4509 03:36:38,320 --> 03:36:41,000 TO DO THIS BUT PLOTTED HERE, WE 4510 03:36:41,000 --> 03:36:43,640 SET THE SYSTEM SO THAT WE CAN 4511 03:36:43,640 --> 03:36:47,720 VET IN A SINGLE ASSAY ANTIBODIES 4512 03:36:47,720 --> 03:36:51,200 AGAINST ALL PARTS OF ENVELOPE, 4513 03:36:51,200 --> 03:36:51,920 ON THE TARGET. 4514 03:36:51,920 --> 03:36:56,120 WE DID THIS BY SPINNING 4515 03:36:56,120 --> 03:36:57,040 (INAUDIBLE) ON TOP OF TARGET 4516 03:36:57,040 --> 03:36:59,280 CELLS SO WE CAN PICK UP CD4 1, 4517 03:36:59,280 --> 03:37:03,520 ET CETERA, AND MADE THESE 4518 03:37:03,520 --> 03:37:05,640 ANTIBODIES AND EXPRESSED IN SAME 4519 03:37:05,640 --> 03:37:06,960 SYSTEM, PURIFIED THE SAME WAY ET 4520 03:37:06,960 --> 03:37:07,240 CETERA. 4521 03:37:07,240 --> 03:37:09,440 AND WHEN WE WENT TO LOOK TO SEE 4522 03:37:09,440 --> 03:37:11,600 WHAT ROLE SPECIFICITY PLAYED IN 4523 03:37:11,600 --> 03:37:13,920 EFFECTOR FUNCTION IN THIS ASSAY, 4524 03:37:13,920 --> 03:37:14,800 BELIEVE OR NOT THIS WAS THE 4525 03:37:14,800 --> 03:37:16,760 FIRST STUDY I COULD FIND WHERE 4526 03:37:16,760 --> 03:37:18,200 ANYBODY COMPREHENSIVELY LOOKED 4527 03:37:18,200 --> 03:37:21,200 AT ANY ANTIBODIES IN TERMS OF 4528 03:37:21,200 --> 03:37:22,440 SPECIFICITY OF STANDARD SYSTEM. 4529 03:37:22,440 --> 03:37:23,360 TO DO THAT. 4530 03:37:23,360 --> 03:37:26,400 SO HERE IS WHAT WE CAME UP WITH. 4531 03:37:26,400 --> 03:37:27,800 FIRST, THINKING ABOUT IT, UP 4532 03:37:27,800 --> 03:37:30,880 HERE, AT THE TOP IS INTRINSIC 4533 03:37:30,880 --> 03:37:33,000 AFFINITY RANGE OF FC GAMMA 4534 03:37:33,000 --> 03:37:36,520 RECEPTORS BINDING TO PURIFIED 4535 03:37:36,520 --> 03:37:41,240 HUMAN IGG 1 WE ARE TALKING ABOUT 4536 03:37:41,240 --> 03:37:41,760 HERE. 4537 03:37:41,760 --> 03:37:45,760 AND SO IT IS ALL UP IN THE HIGH 4538 03:37:45,760 --> 03:37:47,640 -- LOW MICROMOLAR RANGE, ALL THE 4539 03:37:47,640 --> 03:37:49,280 WAY UP TO ESSENTIALLY THE 4540 03:37:49,280 --> 03:37:50,520 MILLIMOLAR RANGE DEPENDING WHICH 4541 03:37:50,520 --> 03:37:52,520 PAPERS YOU LOOK AT AND SO THAT 4542 03:37:52,520 --> 03:37:56,000 IS UNLIGANDED FREE ANTIBODY, IT 4543 03:37:56,000 --> 03:37:59,120 BINDS. IF YOU LOOK HERE, THERE 4544 03:37:59,120 --> 03:38:04,800 WAS A BIG DIFFERENCE BIG SPREAD 4545 03:38:04,800 --> 03:38:06,880 CYTOTOXICITY VERSUS EC 50, HALF 4546 03:38:06,880 --> 03:38:08,680 MAX VALUE FOR DIFFERENT ANTIBODY 4547 03:38:08,680 --> 03:38:10,800 CLASS SPECIFICITY CLASSES. 4548 03:38:10,800 --> 03:38:12,760 TURNED OUT THEST ONES IN THIS 4549 03:38:12,760 --> 03:38:16,000 ASSAY FORMAT, TURNED OUT TO BE 4550 03:38:16,000 --> 03:38:17,520 CONSISTENTLY CLUSTER A 4551 03:38:17,520 --> 03:38:18,040 ANTIBODIES. 4552 03:38:18,040 --> 03:38:20,560 THESE WERE ONES WE ISOLATED PLUS 4553 03:38:20,560 --> 03:38:21,880 JAMES ANTIBODIES THERE WAS A 4554 03:38:21,880 --> 03:38:23,960 BUNCH WE PULLED OUT. 4555 03:38:23,960 --> 03:38:25,720 THE NEXT BEST WERE CO-RECEPTOR 4556 03:38:25,720 --> 03:38:27,400 BINDING SITE ANTIBODIES IN THIS 4557 03:38:27,400 --> 03:38:28,320 PARTICULAR ASSAY. 4558 03:38:28,320 --> 03:38:31,080 WE CAN GET THINGS, THIS WOULD 4559 03:38:31,080 --> 03:38:33,400 PICK UP SOME ANTIBODIES AGAINST 4560 03:38:33,400 --> 03:38:34,960 CD4 BINDING SITES WHICH ARE 4561 03:38:34,960 --> 03:38:38,920 INTERMEDIATE IN GP 481 ANTIBODY 4562 03:38:38,920 --> 03:38:40,200 ARE NOT GOOD FOR THIS AND MANY 4563 03:38:40,200 --> 03:38:41,600 WAYS NOT PARTICULARLY GOOD IN A 4564 03:38:41,600 --> 03:38:43,720 LOT OF DIFFERENT TYPES OF 4565 03:38:43,720 --> 03:38:45,240 EFFECTOR ACTIVITIES SO THIS IS 4566 03:38:45,240 --> 03:38:45,840 WHAT INTERESTED ME. 4567 03:38:45,840 --> 03:38:47,080 WHAT IS GOING ON HERE? 4568 03:38:47,080 --> 03:38:50,080 THESE ARE MUTANT COMPLEXES, 4569 03:38:50,080 --> 03:38:52,880 GIVING YOU A BIOLOGICAL GAME FAR 4570 03:38:52,880 --> 03:38:54,560 AND ABOVE INTRINSIC BINDING 4571 03:38:54,560 --> 03:38:56,560 CONSTANT IS FOR FREE IGG. 4572 03:38:56,560 --> 03:38:57,840 THAT MAKES SENSE, YOU ARE 4573 03:38:57,840 --> 03:39:00,000 SWIMMING IN FREE IGG. 4574 03:39:00,000 --> 03:39:06,600 SO THERE IS A TONIC BINDING BUT 4575 03:39:06,600 --> 03:39:08,240 IT'S LOW AFFINITY SO WILL IS A 4576 03:39:08,240 --> 03:39:09,600 AFFINITY COMPONENT TO THIS BUT 4577 03:39:09,600 --> 03:39:11,200 OTHER STUFF GOING ON AS WELL, WE 4578 03:39:11,200 --> 03:39:12,920 WANT TO KNOW WHAT THIS IS. 4579 03:39:12,920 --> 03:39:15,120 FIRST WE GOT STRUCTURALLY 4580 03:39:15,120 --> 03:39:16,880 DEFINED MOLECULES THAT ARE DOING 4581 03:39:16,880 --> 03:39:17,400 THIS. 4582 03:39:17,400 --> 03:39:19,480 WHAT ARE THE IMMUNE COMPLEXES 4583 03:39:19,480 --> 03:39:19,920 LOOK LIKE? 4584 03:39:19,920 --> 03:39:21,400 THAT DO THIS? 4585 03:39:21,400 --> 03:39:22,720 THIS IS WHAT WE HAVE BEEN 4586 03:39:22,720 --> 03:39:24,000 WORKING, THIS SHOWS YOU IF YOU 4587 03:39:24,000 --> 03:39:28,000 LOOK AT EC 50 OF THE CLUSTER A 4588 03:39:28,000 --> 03:39:31,200 ANTIBODIES, THERE IN BLUE, IT IS 4589 03:39:31,200 --> 03:39:34,480 10,000 FOLD DIFFERENCE FROM WHAT 4590 03:39:34,480 --> 03:39:38,560 YOU SEE BY INTRINSIC -- 4591 03:39:38,560 --> 03:39:40,880 DIFFERENT FC RECEPTORS FROM 4592 03:39:40,880 --> 03:39:42,720 HUMAN IGG 1. 4593 03:39:42,720 --> 03:39:45,600 WE USE THIS ASSAY, WHAT WE 4594 03:39:45,600 --> 03:39:47,320 DECIDED TO DO WE STARTED IMAGING 4595 03:39:47,320 --> 03:39:50,960 WHAT'S GOING ON, REALLY GET A 4596 03:39:50,960 --> 03:39:52,200 PICTURE OF THE KINETICS OF THE 4597 03:39:52,200 --> 03:39:54,000 ASSAY, WHO IS DOING WHAT. 4598 03:39:54,000 --> 03:39:55,960 BEAUTY OF IT IS, WE GET 4599 03:39:55,960 --> 03:39:58,480 INTERESTING BIOLOGY WITH ONE 4600 03:39:58,480 --> 03:39:59,920 ANTIBODY, ONE ANTIGEN, TWO 4601 03:39:59,920 --> 03:40:01,520 CELLS. 4602 03:40:01,520 --> 03:40:04,720 AND YOU ONLY SEE PART IN FLOW 4603 03:40:04,720 --> 03:40:06,440 CYTOMETRY, LOOK IN CULTURE A LOT 4604 03:40:06,440 --> 03:40:14,240 OF STUFF GOING ON FLO ON IN THE FLOW 4605 03:40:14,240 --> 03:40:16,120 SIGH TOM TEAR IF YOU DON'T DO IT 4606 03:40:16,120 --> 03:40:16,520 RIGHT. 4607 03:40:16,520 --> 03:40:19,400 A FEW MONTHS IN TOM'S LAB AS 4608 03:40:19,400 --> 03:40:23,720 PARTS OF GATES FOUNDATION THING, 4609 03:40:23,720 --> 03:40:25,400 AND SO YOU CAN SEE THE CLASSIC 4610 03:40:25,400 --> 03:40:28,320 SORT OF SYNAPSE FORMATION, OVER 4611 03:40:28,320 --> 03:40:30,480 TIME AND THEN YOU CAN SEE 4612 03:40:30,480 --> 03:40:32,160 TRANSFER OF THE MEMBRANE 4613 03:40:32,160 --> 03:40:34,000 FRAGMENT WHICH IS CCR 5, IN THIS 4614 03:40:34,000 --> 03:40:36,800 CASE JUST LOOKING AT GP 120 HERE 4615 03:40:36,800 --> 03:40:38,400 AS IT COMES ACROSS. 4616 03:40:38,400 --> 03:40:40,000 SO YOU CAN DEFINE THESE 4617 03:40:40,000 --> 03:40:41,520 DIFFERENT STEPS, YOU ALSO SEE 4618 03:40:41,520 --> 03:40:43,600 THIS HAPPENING IN LIVE CELL 4619 03:40:43,600 --> 03:40:44,880 CULTURE. 4620 03:40:44,880 --> 03:40:46,760 AND YOU CAN ALSO DO GREATER 4621 03:40:46,760 --> 03:40:48,840 IMAGING ON THIS, AND FOLLOW 4622 03:40:48,840 --> 03:40:50,840 THESE EVENTS DURING FLOW 4623 03:40:50,840 --> 03:40:51,200 CYTOMETRY. 4624 03:40:51,200 --> 03:40:53,520 SO WE ARE CALLING THIS ANTIBODY 4625 03:40:53,520 --> 03:40:56,760 MEDIATED TROG CYTOSIS. 4626 03:40:56,760 --> 03:41:00,000 THIS IS THE CLUSTER A. 4627 03:41:00,000 --> 03:41:01,560 AND ONE OF THE THINGS WE NOTICE 4628 03:41:01,560 --> 03:41:05,000 IN THESE ASSAYS IS THEY SHOW PRO 4629 03:41:05,000 --> 03:41:08,040 ZONES YOU DON'T ALWAYS SEE A PRO 4630 03:41:08,040 --> 03:41:10,520 ZONE ASSAY IN ADCC ASSAY BUT 4631 03:41:10,520 --> 03:41:12,800 OFTEN YOU DO, WE ARE STARTING TO 4632 03:41:12,800 --> 03:41:14,920 UNDERSTAND WHY YOU SEE IT NOT 4633 03:41:14,920 --> 03:41:16,720 OTHERS BUT THESE ANTIBODIES DO 4634 03:41:16,720 --> 03:41:18,160 IT AND PRO ZONES IN THE DOSE 4635 03:41:18,160 --> 03:41:19,600 RESPONSE CURVE TO ME THAT LOOKED 4636 03:41:19,600 --> 03:41:22,160 LIKE A BASE FILL ACTIVATION BY 4637 03:41:22,160 --> 03:41:25,560 IGE AND CROSS LINKING IGE 4638 03:41:25,560 --> 03:41:26,880 ANTIBODY, THERE'S LITERATURE ON 4639 03:41:26,880 --> 03:41:27,400 THAT. 4640 03:41:27,400 --> 03:41:29,720 SO THIS PAPER POSITION PIECE PUB 4641 03:41:29,720 --> 03:41:30,920 ESTABLISHED ON IT WHAT IS GOING 4642 03:41:30,920 --> 03:41:35,880 ON HERE, WE THINK THIS LOOKED 4643 03:41:35,880 --> 03:41:40,840 LIKE JAY AND I HAD A PRECIPITOUS 4644 03:41:40,840 --> 03:41:41,960 REACTION AND SOMETHING AROUND 4645 03:41:41,960 --> 03:41:45,440 FOR OVER A HUNDRED YEARS, 4646 03:41:45,440 --> 03:41:46,360 SOMETHING SIMILAR TO THIS GOING 4647 03:41:46,360 --> 03:41:47,960 ON YOU WILL SEE IN A SECOND. 4648 03:41:47,960 --> 03:41:49,360 SO WHAT HAPPENS IN THE SWEET 4649 03:41:49,360 --> 03:41:52,440 SPOT WHERE YOU GET BIOLOGY IS 4650 03:41:52,440 --> 03:41:54,000 ASCENDING PART OF THE CURVE, EC 4651 03:41:54,000 --> 03:41:56,120 50 UP TO PLATEAU CYTOTOXICITY, 4652 03:41:56,120 --> 03:41:58,480 WHATEVER THAT IS. 4653 03:41:58,480 --> 03:42:01,440 SO HERE THIS IS EQUIVALENT 4654 03:42:01,440 --> 03:42:03,160 PREDICTION WISE EQUIVALENT TO 4655 03:42:03,160 --> 03:42:05,800 ZONE OF EPITOPE ACCESS OR 4656 03:42:05,800 --> 03:42:07,160 ANTIGEN EXCESS PRECIPITOUS 4657 03:42:07,160 --> 03:42:09,800 REACTION SO THE ANTIBODIES 4658 03:42:09,800 --> 03:42:10,960 COMING IN ARE (INAUDIBLE) BUT 4659 03:42:10,960 --> 03:42:12,760 THEY HAVE TO DO SOMETHING WITH 4660 03:42:12,760 --> 03:42:17,600 IT TO MAKE THE RIGHT COMPLEX. 4661 03:42:17,600 --> 03:42:19,200 THEN THINGS GET -- YOU HAVE SOME 4662 03:42:19,200 --> 03:42:22,000 OPTIMAL PRESENTATION OF THE 4663 03:42:22,000 --> 03:42:22,440 IMMUNE COMPLEX. 4664 03:42:22,440 --> 03:42:28,200 AS YOU ADD MORE ANTIBODY IN, THE 4665 03:42:28,200 --> 03:42:30,840 COMPLEXES BECOME INCREASINGLY 4666 03:42:30,840 --> 03:42:33,120 VALENT AND LESS EFFECTIVE 4667 03:42:33,120 --> 03:42:34,600 BIOLOGICALLY SO YOU SEE PRO ZONE 4668 03:42:34,600 --> 03:42:35,800 GOING DOWN. 4669 03:42:35,800 --> 03:42:37,440 WITH HE IS DIFFERENT ANTI-DO 4670 03:42:37,440 --> 03:42:38,800 BODIES YOU SEE DIFFERENT PRO 4671 03:42:38,800 --> 03:42:40,440 ZONES WITH IT. 4672 03:42:40,440 --> 03:42:43,000 LOOK AT THE EC 50s OR DOWN 4673 03:42:43,000 --> 03:42:44,680 INTO THE EXTREMELY POTENT WITH 4674 03:42:44,680 --> 03:42:46,760 THESE ANTIBODIES ADCC WE ARE 4675 03:42:46,760 --> 03:42:51,240 DOWN IN THE -- ALMOST INTO THE 4676 03:42:51,240 --> 03:42:52,320 LOW PICA MOLAR RANGE WHICH IS 4677 03:42:52,320 --> 03:42:55,200 WAY BELOW WHAT YOU SEE WITH ANY 4678 03:42:55,200 --> 03:42:56,640 NEUTRALIZATION ASSAY. 4679 03:42:56,640 --> 03:42:59,200 SO WHAT WE HAVE DONE THEN, SHOW 4680 03:42:59,200 --> 03:43:04,080 YOU THE NEXT SLIDE HERE. 4681 03:43:04,080 --> 03:43:05,640 SO WHAT WE HAVE DONE WE HAVE 4682 03:43:05,640 --> 03:43:07,400 LABELED ANTIGEN, LABELED 4683 03:43:07,400 --> 03:43:09,840 ANTIBODY AND LABELED MEMBRANE. 4684 03:43:09,840 --> 03:43:13,200 SO WE HAVE -- LOOK AT TROGO 4685 03:43:13,200 --> 03:43:14,400 CYTOSIS EFFECT AND SO THAT'S 4686 03:43:14,400 --> 03:43:16,480 SHOWN IN RED THERE IN THE CURVE 4687 03:43:16,480 --> 03:43:18,400 AND YOU SEE IT IS A BELL SHAPED 4688 03:43:18,400 --> 03:43:19,920 CURVE JUST WHAT WE SEE, IF WE 4689 03:43:19,920 --> 03:43:23,320 ARE READING FLOW CYTOMETRY,TROGO 4690 03:43:23,320 --> 03:43:23,960 CYTOSIS ASSAY. 4691 03:43:23,960 --> 03:43:26,920 THAT'S WHAT IT LOOKS LIKE FOR C 4692 03:43:26,920 --> 03:43:28,760 11 ANTIBODY, MOST POTENT. 4693 03:43:28,760 --> 03:43:30,640 AND THAT IS INTERESTING, IF YOU 4694 03:43:30,640 --> 03:43:32,880 LOOK AT ANTIGEN ON THE EFFECTOR 4695 03:43:32,880 --> 03:43:34,760 CELL THIS IS ALL EFFECTOR CELL 4696 03:43:34,760 --> 03:43:36,200 NOT TARGET CELL, LOOK AT AMOUNT 4697 03:43:36,200 --> 03:43:38,200 OF ANTIGEN ON EFFECTOR CELL IT 4698 03:43:38,200 --> 03:43:39,080 ROUGHLY CORRELATES. 4699 03:43:39,080 --> 03:43:41,760 YOU SEE THE SAME BELL SHAPED 4700 03:43:41,760 --> 03:43:43,080 CURVE WHICH MAKES SENSE, WITH 4701 03:43:43,080 --> 03:43:44,240 THIS. 4702 03:43:44,240 --> 03:43:46,800 BUT WHEN WE WENT AND LOOKED AT 4703 03:43:46,800 --> 03:43:50,680 TRACK ANTIBODY IN THE SAME CELLS 4704 03:43:50,680 --> 03:43:52,920 SAME TIME, WE SAW MORE ANTIBODY 4705 03:43:52,920 --> 03:43:55,880 WE PUT IN, THE MORE ANTIBODY 4706 03:43:55,880 --> 03:43:58,000 AFTER POINT WE FOUND ON THE 4707 03:43:58,000 --> 03:44:01,400 EFFECTOR CELL BUT AT SOME POINT 4708 03:44:01,400 --> 03:44:02,320 LESS ANTIGEN. 4709 03:44:02,320 --> 03:44:04,320 SO THAT SAID LET'S LOOK AT RATIO 4710 03:44:04,320 --> 03:44:08,080 OF ANTIGEN AND ANTIBODY SO I 4711 03:44:08,080 --> 03:44:08,720 NORMALIZED EVERYTHING, WHEN WE 4712 03:44:08,720 --> 03:44:10,440 GET TO STUDY WE DIDN'T CALIBRATE 4713 03:44:10,440 --> 03:44:11,920 INSTRUMENT TO GET NUMBERS OF 4714 03:44:11,920 --> 03:44:13,000 MOLECULES PER CELL BUT IN THE 4715 03:44:13,000 --> 03:44:14,520 PROCESS OF DOING THAT. 4716 03:44:14,520 --> 03:44:16,200 SO THIS EMERGED TO BE VERY 4717 03:44:16,200 --> 03:44:17,560 INTERESTING TO US. 4718 03:44:17,560 --> 03:44:19,000 SO THOSE ARE THE CURVES TOGETHER 4719 03:44:19,000 --> 03:44:20,920 SO IF YOU LOOK UP IN PURPLE 4720 03:44:20,920 --> 03:44:22,800 THAT'S THE RATIO CURVE OF 4721 03:44:22,800 --> 03:44:24,880 ANTIGEN TO ANTIBODY OR ANTIBODY 4722 03:44:24,880 --> 03:44:30,120 TO ANTIGEN ON THE EFFECTOR CELL. 4723 03:44:30,120 --> 03:44:32,400 THAT'S WHAT'S COME OVER TROGO 4724 03:44:32,400 --> 03:44:32,840 CYTOSIS. 4725 03:44:32,840 --> 03:44:35,680 SO DOWN HERE IN THE LINEAR 4726 03:44:35,680 --> 03:44:38,320 ASCENDING OR EXPONENTIAL 4727 03:44:38,320 --> 03:44:40,720 ASCENDING RANGE OF DOSE RESPONSE 4728 03:44:40,720 --> 03:44:42,000 CURVE WHAT YOU SEE IS COMPLEXES 4729 03:44:42,000 --> 03:44:44,200 COMING ON TO EFFECTOR CELL ARE 4730 03:44:44,200 --> 03:44:46,720 ROUGHLY ONE TO ONE FOR ANTIBODY 4731 03:44:46,720 --> 03:44:47,120 ANTIGEN. 4732 03:44:47,120 --> 03:44:50,880 THAT DOESN'T MEAN IT'S MOLAR 1 4733 03:44:50,880 --> 03:44:55,120 TO 1 JUST SORRY .1, THAT DOESN'T 4734 03:44:55,120 --> 03:44:57,680 MEAN WE DON'T KNOW WHAT THE TRUE 4735 03:44:57,680 --> 03:44:58,800 STOICHIOMETRY IS BUT POINT IS 4736 03:44:58,800 --> 03:45:00,360 THAT REGION INCREASING 4737 03:45:00,360 --> 03:45:02,560 BIOLOGICAL ACTIVITY PUTTING MORE 4738 03:45:02,560 --> 03:45:04,120 ANTIBODY, THAT RATIO OF ANTIGEN 4739 03:45:04,120 --> 03:45:06,320 TO ANTIBODY IS COMINGEN EFFECTOR 4740 03:45:06,320 --> 03:45:09,280 CELL IS CONSTANT. 4741 03:45:09,280 --> 03:45:12,120 THEN YOU GET OUT TO MAXIMUM 4742 03:45:12,120 --> 03:45:14,640 TROGO CYTOSIS EFFECT AND WHAT 4743 03:45:14,640 --> 03:45:16,200 YOU GET PAST MAXIMUM THAT RATIO 4744 03:45:16,200 --> 03:45:17,440 STARTS TO GO DOWN. 4745 03:45:17,440 --> 03:45:19,800 SO YOU START GETTING MORE 4746 03:45:19,800 --> 03:45:22,640 ANTIBODY AND LESS ANTIGEN ON THE 4747 03:45:22,640 --> 03:45:24,960 TARGET CELL. 4748 03:45:24,960 --> 03:45:26,400 SO THIS IS VERY INTERESTING 4749 03:45:26,400 --> 03:45:28,840 BECAUSE THIS IS EXACTLY WHAT YOU 4750 03:45:28,840 --> 03:45:32,040 PREDICT FROM A LITERATURE 4751 03:45:32,040 --> 03:45:33,280 EXACTLY WHAT THOUGHT IN THE 4752 03:45:33,280 --> 03:45:34,440 PAPER. 4753 03:45:34,440 --> 03:45:36,120 MADE US START WONDERING WHAT IS 4754 03:45:36,120 --> 03:45:39,760 GOING ON NOW ON THE TARGET CELL 4755 03:45:39,760 --> 03:45:42,080 SIDE AND ON THE EFFECTOR CELL 4756 03:45:42,080 --> 03:45:43,200 SIDE WE HAVE THE TOOLS TO LOOK 4757 03:45:43,200 --> 03:45:43,640 AT THIS. 4758 03:45:43,640 --> 03:45:45,200 THIS IS AN EARLIER PAPER ALL OUR 4759 03:45:45,200 --> 03:45:47,480 COMPLEXES ARE MADE WITH GP 120 4760 03:45:47,480 --> 03:45:49,600 BINDING TO CD4 IN THIS 4761 03:45:49,600 --> 03:45:53,840 PARTICULAR MODEL. 4762 03:45:53,840 --> 03:45:58,200 SO WHERE IS -- HOW CD4 ARRANGED 4763 03:45:58,200 --> 03:46:02,440 ON CD4 POSITIVE T-CELL SURFACE? 4764 03:46:02,440 --> 03:46:07,960 TURNS OUT THAT THE -- IN 4765 03:46:07,960 --> 03:46:10,680 UNINFECTED CELLS FOR EXAMPLE, 4766 03:46:10,680 --> 03:46:14,520 THEY RANGE IN NANOCLUSTERS THAT 4767 03:46:14,520 --> 03:46:16,520 ARE ROUGHLY 50 NANOMETERS ACROSS 4768 03:46:16,520 --> 03:46:19,200 AND USUALLY HAVE TYPICALLY FOUR 4769 03:46:19,200 --> 03:46:21,320 CD4 MOLECULES OF NANOCLUSTER. 4770 03:46:21,320 --> 03:46:23,320 PUT HIV ON THEM, OVER THERE THE 4771 03:46:23,320 --> 03:46:27,320 GREEN PUT HIV ON THEM, THEN THE 4772 03:46:27,320 --> 03:46:28,800 NANOCLUSTERS GET TO BE 200 4773 03:46:28,800 --> 03:46:34,240 MICRONS AND YOU WIND UP WITH 16 4774 03:46:34,240 --> 03:46:38,960 COMPLEXES IN THE CLUSTER. 4775 03:46:38,960 --> 03:46:40,520 SO BECAUSE WE DO STRUCTURAL 4776 03:46:40,520 --> 03:46:44,000 STUFF WE BUILT MODELS, BUILT -- 4777 03:46:44,000 --> 03:46:46,960 THERE IS NO CREE OWE EM OF 4778 03:46:46,960 --> 03:46:49,800 ANYTHING IN CD4 BUT USE STITCHED 4779 03:46:49,800 --> 03:46:52,000 TOGETHER THE BEST -- CRYOEM OF 4780 03:46:52,000 --> 03:46:53,360 ANYTHING IN CD4. 4781 03:46:53,360 --> 03:46:57,120 THAT CD4 IN RED IN THE CIRCLE 4782 03:46:57,120 --> 03:46:59,360 THERE IS THE CELL MEMBRANE, 4783 03:46:59,360 --> 03:47:00,800 MICRODOMAIN, IF YOU WILL, THE 4784 03:47:00,800 --> 03:47:02,040 GREEN IS GP 120 BINDING. 4785 03:47:02,040 --> 03:47:06,000 WHAT WE WILL DO IS DOCK ON OUR 4786 03:47:06,000 --> 03:47:06,640 ANTIBODIES AGAINST CLUSTER A WE 4787 03:47:06,640 --> 03:47:07,840 HAVE THE STRUCTURE FOR. 4788 03:47:07,840 --> 03:47:09,520 SO THERE IT IS. 4789 03:47:09,520 --> 03:47:14,560 THAT IS THE 7SN ANTIBODY TAKEN 4790 03:47:14,560 --> 03:47:17,160 FROM STRUCTURE THAT IS ONE OF 4791 03:47:17,160 --> 03:47:18,200 THE STRUCTURE THAT WAS FROM 4792 03:47:18,200 --> 03:47:21,280 SMALL ANGLE X-RAY SCATTERING 4793 03:47:21,280 --> 03:47:24,080 STUDY DONE BY PERKINS THAT'S FC 4794 03:47:24,080 --> 03:47:25,920 RECEPTOR COMPETENT FOR BINDING. 4795 03:47:25,920 --> 03:47:27,480 SO YOU IT BINDING THERE AND THEN 4796 03:47:27,480 --> 03:47:30,680 WHAT WE DID HERE, THE PURPLE WE 4797 03:47:30,680 --> 03:47:32,920 HAVE DOCKED IN AN FC RECEPTOR. 4798 03:47:32,920 --> 03:47:37,040 AND THE C TERMINUS OF THE FC 4799 03:47:37,040 --> 03:47:39,880 RECEPTOR TOWARD EFFECTOR CELL IS 4800 03:47:39,880 --> 03:47:41,080 ORIENTED DISTAL TO THE TARGET 4801 03:47:41,080 --> 03:47:44,080 CELL MEMBRANE. 4802 03:47:44,080 --> 03:47:46,200 WE HAVE OTHER ANTIBODIES WITH 4803 03:47:46,200 --> 03:47:48,040 DIFFERENT BINDING ANGLING. 4804 03:47:48,040 --> 03:47:49,760 WE PUBLISHED A COUPLE OF PAPERS 4805 03:47:49,760 --> 03:47:52,600 ON THESE AND WE FIND THE FORMER 4806 03:47:52,600 --> 03:47:54,160 A-- FARTHER AWAY FROM TARGET 4807 03:47:54,160 --> 03:47:56,280 CELL THAT FC DOCKING SITE IS, 4808 03:47:56,280 --> 03:47:59,000 THAT CORRELATES WITH ACTIVITY. 4809 03:47:59,000 --> 03:48:01,560 RIGHT NOW WE ARE BUILDING A 4810 03:48:01,560 --> 03:48:02,880 VECTOR SPACE MODEL SO THAT WE 4811 03:48:02,880 --> 03:48:04,840 CAN ACTUALLY QUANTIFY THAT WITH 4812 03:48:04,840 --> 03:48:08,400 SOME PRECISION. 4813 03:48:08,400 --> 03:48:09,840 SO MADE US WONDER WHAT IS GOING 4814 03:48:09,840 --> 03:48:12,280 ON IN MICRODOMAINS SO BASED ON 4815 03:48:12,280 --> 03:48:13,000 THE INFORMATION FROM OUR 4816 03:48:13,000 --> 03:48:16,080 MODELING STUDIES WE KNOW ROUGHLY 4817 03:48:16,080 --> 03:48:18,000 THE SIZE OF -- THIS IS A TWO 4818 03:48:18,000 --> 03:48:20,520 DIMENSIONAL ARRAY, OF THE 4819 03:48:20,520 --> 03:48:22,560 CLUSTERS THERE ABOUT 20 MICRONS, 4820 03:48:22,560 --> 03:48:24,200 20 NANOMETERS IN SIZE. 4821 03:48:24,200 --> 03:48:26,120 SO WHAT I'M SHOWING HERE IS WHAT 4822 03:48:26,120 --> 03:48:28,360 A MICRODOMAIN LOOKS LIKE, IF YOU 4823 03:48:28,360 --> 03:48:30,800 GOT 16 MOLECULES OR 15 MOLECULES 4824 03:48:30,800 --> 03:48:32,240 CD4 AND YOU HAVE THESE THINGS 4825 03:48:32,240 --> 03:48:33,160 DOCKING ON THERE. 4826 03:48:33,160 --> 03:48:36,360 SO THIS IS A RELATIVELY SPARSE 4827 03:48:36,360 --> 03:48:37,320 BASE. 4828 03:48:37,320 --> 03:48:40,040 BUT THESE THINGS ACTIVATE FC 4829 03:48:40,040 --> 03:48:43,000 RECEPTOR THERE HAS TO BE CROSS 4830 03:48:43,000 --> 03:48:43,720 LINKING. 4831 03:48:43,720 --> 03:48:46,680 BUT WHAT WE FOUND FROM ALL THIS 4832 03:48:46,680 --> 03:48:49,240 IS THAT WE UNCOVERED AN 4833 03:48:49,240 --> 03:48:50,800 ALLOSTERIC EFFECT THAT FAVORS 4834 03:48:50,800 --> 03:48:52,880 CROSS LINKING UNDER SPARSE 4835 03:48:52,880 --> 03:48:53,440 CONDITIONS. 4836 03:48:53,440 --> 03:48:55,240 WE FOUND THIS FROM THIS KIND OF 4837 03:48:55,240 --> 03:49:01,040 STUDY, THIS IS DONE BY 4838 03:49:01,040 --> 03:49:03,040 (INAUDIBLE) RAY A BIOPHYSICIST 4839 03:49:03,040 --> 03:49:08,840 IN OUR GROUP AND TIARA, WE TOOK 4840 03:49:08,840 --> 03:49:10,200 MONOMERIC ANTIBODY WITH AND 4841 03:49:10,200 --> 03:49:13,520 WITHOUT ANTIGEN AND ASKED TO 4842 03:49:13,520 --> 03:49:16,560 BIND TO FC RECEPTORS ON A 4843 03:49:16,560 --> 03:49:18,960 JERKETTE CELL YOU PUT FC 4844 03:49:18,960 --> 03:49:20,800 RECEPTORS ON SO BINDING WE KNOW 4845 03:49:20,800 --> 03:49:22,400 ANTIBODY IS MONOMERIC BECAUSE OF 4846 03:49:22,400 --> 03:49:23,840 SEVERAL THINGS. 4847 03:49:23,840 --> 03:49:27,280 WE DO CORRELATION SPECTROSCOPY 4848 03:49:27,280 --> 03:49:29,000 THAT GIVES YOU DIFFUSION 4849 03:49:29,000 --> 03:49:30,560 COEFFICIENT SO MONOMERIC 4850 03:49:30,560 --> 03:49:31,800 ANTIBODY, WHEN IT BINDS ANTIGEN, 4851 03:49:31,800 --> 03:49:36,320 IT IS NOT MAKING HIGHER ORDER 4852 03:49:36,320 --> 03:49:38,200 POLYMERS, MOST BINDING TO 4853 03:49:38,200 --> 03:49:39,040 INDEPENDENT ANTIGEN MOLECULES 4854 03:49:39,040 --> 03:49:40,400 AND ONE ANTIBODY BUT MOSTLY ONE 4855 03:49:40,400 --> 03:49:41,200 TO ONE. 4856 03:49:41,200 --> 03:49:46,360 WE HAVE NOW GOTTEN EQUIVALENT TO 4857 03:49:46,360 --> 03:49:48,960 DO SIZE EXCLUSION CHROMING TOTY 4858 03:49:48,960 --> 03:49:50,400 LIGHT ANGLE LIGHT SCATTERING 4859 03:49:50,400 --> 03:49:50,800 ANALYSES. 4860 03:49:50,800 --> 03:49:52,760 IT SAYS THE SAME THING. 4861 03:49:52,760 --> 03:49:54,280 MAKING THESE COMPLEXES WE ARE 4862 03:49:54,280 --> 03:49:55,400 MAKING ACTUALLY SOME OF THE 4863 03:49:55,400 --> 03:49:58,280 CLINICAL MATERIAL THAT WENT INTO 4864 03:49:58,280 --> 03:50:01,200 THE PRACTICE RUN THAT WENT INTO 4865 03:50:01,200 --> 03:50:01,840 CLINICAL TRIALS. 4866 03:50:01,840 --> 03:50:04,000 WHAT WE ARE SHOWING HERE IS 4867 03:50:04,000 --> 03:50:08,560 SIMPLY C 11 FLUORESCENT C 11 4868 03:50:08,560 --> 03:50:09,200 BIENSTOCK JERKETTE CELLS ON THE 4869 03:50:09,200 --> 03:50:11,000 LEFT WITHOUT ANTIGEN AND THEN 4870 03:50:11,000 --> 03:50:12,760 WHERE WE SIMPLY GIVEN ONE 4871 03:50:12,760 --> 03:50:16,880 MOLECULE OR TWO MOLECULES OF 4872 03:50:16,880 --> 03:50:18,640 FULL LENGTH SINGLE CHAIN WHERE 4873 03:50:18,640 --> 03:50:20,760 IT IS NOT CROSSING, YOU SEE A 4874 03:50:20,760 --> 03:50:22,560 BIG DIFFERENCE BY FLUORESCENCE 4875 03:50:22,560 --> 03:50:23,000 INTENSITY. 4876 03:50:23,000 --> 03:50:24,440 THAT COMPLEX EVEN UNDER THESE 4877 03:50:24,440 --> 03:50:25,480 CONDITIONS YOU GET SOME BINDING 4878 03:50:25,480 --> 03:50:28,880 OF FREE ANTIBODY, YOU GET 4879 03:50:28,880 --> 03:50:30,800 BINDING INCREASE BINDING THERE. 4880 03:50:30,800 --> 03:50:34,160 YOU CAN ALSO SEE BY ELISA, 4881 03:50:34,160 --> 03:50:38,200 MARGIE ACKERMAN'S GROUP ALSO GOT 4882 03:50:38,200 --> 03:50:42,120 THIS OBSERVATION WITH SPR DATA. 4883 03:50:42,120 --> 03:50:43,800 ANYHOW, SO THAT TELLS ME 4884 03:50:43,800 --> 03:50:44,360 SOMETHING INTERESTING RIGHT 4885 03:50:44,360 --> 03:50:47,000 THERE BUT THE OTHER THING YOU 4886 03:50:47,000 --> 03:50:49,360 CAN DO IS YOU CAN DO LIFETIME 4887 03:50:49,360 --> 03:50:50,080 FLUORESCENCE. 4888 03:50:50,080 --> 03:50:51,560 WHICH MEASURES THE LIFETIME OF 4889 03:50:51,560 --> 03:50:53,520 THE DECAY SIGNAL. 4890 03:50:53,520 --> 03:50:55,320 AND TURNS OUT THAT INTENSITY 4891 03:50:55,320 --> 03:50:56,720 FLUORESCENCE IS INDEPENDENT OF 4892 03:50:56,720 --> 03:51:00,200 THE ENVIRONMENT. 4893 03:51:00,200 --> 03:51:02,160 WHEREAS LIFETIME IS AFFECTED BY 4894 03:51:02,160 --> 03:51:02,600 LOCAL ENVIRONMENT. 4895 03:51:02,600 --> 03:51:04,600 SO WHAT IT IS REALLY GOOD AT, IF 4896 03:51:04,600 --> 03:51:07,240 YOU SEE LIFETIME SIGNAL SAYING 4897 03:51:07,240 --> 03:51:07,800 CONFIRMATIONAL CHANGE. 4898 03:51:07,800 --> 03:51:09,600 IN THE MOLECULES THAT -- WHERE 4899 03:51:09,600 --> 03:51:12,000 YOU GOT YOUR DYE. 4900 03:51:12,000 --> 03:51:14,720 SO YOU LOOK HERE, WE HAVE GOT A 4901 03:51:14,720 --> 03:51:16,600 REALLY FLOOD FLUORESCENT 4902 03:51:16,600 --> 03:51:18,360 LIFETIME SIGNAL THERE. IS A 4903 03:51:18,360 --> 03:51:20,920 CONFIRMATIONAL CHANGE AND THAT 4904 03:51:20,920 --> 03:51:22,160 COMPLEX OF SOME SORT THAT'S 4905 03:51:22,160 --> 03:51:23,320 ASSOCIATED WITH THE BINDING TO 4906 03:51:23,320 --> 03:51:25,000 THE FC RECEPTOR. 4907 03:51:25,000 --> 03:51:26,440 AGAIN, NO ROSALYNING HERE AT 4908 03:51:26,440 --> 03:51:26,800 THIS POINT. 4909 03:51:26,800 --> 03:51:32,120 NO CROSS LINKING. 4910 03:51:32,120 --> 03:51:35,520 SO BY USING SUPER RESOLUTION 4911 03:51:35,520 --> 03:51:37,560 MICROSCOPY, (INAUDIBLE) WHO DID 4912 03:51:37,560 --> 03:51:39,880 THIS, WE FED THESE SAME CELLS 4913 03:51:39,880 --> 03:51:42,880 NOW TWO DIFFERENT CLUSTER A 4914 03:51:42,880 --> 03:51:46,760 ANTIBODIES N 5 I 5 A 32 LIKE AND 4915 03:51:46,760 --> 03:51:49,600 WE LOOK FOR THE CO-LOCALIZATION 4916 03:51:49,600 --> 03:51:52,920 OF THESE TWO OVER SEPARATE 4917 03:51:52,920 --> 03:51:55,120 DISPOSITION OF THESE TWO ON THE 4918 03:51:55,120 --> 03:51:57,680 CELLS AND IF YOU JUST SEE RED OR 4919 03:51:57,680 --> 03:52:03,160 GREEN BY ITSELF, THAT MEANS 4920 03:52:03,160 --> 03:52:05,800 COMPLEXES BIND INDEPENDENT LET 4921 03:52:05,800 --> 03:52:07,440 AND NOT COLOCALLIZING. 4922 03:52:07,440 --> 03:52:09,640 THAT DOESN'T MEAN THE SAME 4923 03:52:09,640 --> 03:52:10,280 COMPLEX JUST CLOSE TO ONE 4924 03:52:10,280 --> 03:52:11,160 ANOTHER. 4925 03:52:11,160 --> 03:52:14,200 WE DON'T KNOW YET WHAT'S GOING 4926 03:52:14,200 --> 03:52:15,600 ON THERE THEY COULD BE IN THE 4927 03:52:15,600 --> 03:52:16,800 SAME COMPLEX BECAUSE THESE CAN 4928 03:52:16,800 --> 03:52:20,400 BIND SIMULTANEOUSLY TO THE FULL 4929 03:52:20,400 --> 03:52:22,800 ON SINGLE CHAIN BUT THIS SHOWS 4930 03:52:22,800 --> 03:52:24,280 YOU BINDING TO MICRODOMAIN 4931 03:52:24,280 --> 03:52:26,600 ROUGHLY THE SIZE WHAT YOU WOULD 4932 03:52:26,600 --> 03:52:30,920 BE TO SEE FOR CD4 ON TARGET CELL 4933 03:52:30,920 --> 03:52:34,520 AND SAME THING GOES ON IN THE 4934 03:52:34,520 --> 03:52:35,800 EFFECTOR CELL. 4935 03:52:35,800 --> 03:52:38,560 SO WITH THIS, WHEN WE GOT THIS 4936 03:52:38,560 --> 03:52:39,640 OBSERVATION, BECAUSE I REMEMBER 4937 03:52:39,640 --> 03:52:42,080 ALL THE OLD TIMES HIKING ABOUT 4938 03:52:42,080 --> 03:52:44,280 THIS STUFF, MAYBE THERE IS AN AL 4939 03:52:44,280 --> 03:52:48,600 LORALLOSTERIC CHAIN. 4940 03:52:48,600 --> 03:52:50,240 LET ME QUICKLY SAY WHAT WE DID 4941 03:52:50,240 --> 03:52:52,800 IS WE PUBLISHED, WE FOUND AN 4942 03:52:52,800 --> 03:52:54,840 ALLOSTERIC CHAIN BY HYDROGEN 4943 03:52:54,840 --> 03:52:58,520 EXCHANGE AND OTHER METHODS, 4944 03:52:58,520 --> 03:53:00,200 SHOWING THAT THE BINDK ANTIBODY 4945 03:53:00,200 --> 03:53:03,800 TO ANTIGEN, THOUGH MONOMERIC 4946 03:53:03,800 --> 03:53:06,120 MAKES FC RECEPTOR ASSUME 4947 03:53:06,120 --> 03:53:08,640 CONFIRMATION MORE FAVORABLE TO 4948 03:53:08,640 --> 03:53:11,080 ANTIBODY, SO IT'S SIMULATING THE 4949 03:53:11,080 --> 03:53:14,240 LOCAL MICRODOMAIN SO ANYHOW, 4950 03:53:14,240 --> 03:53:15,600 JUST SKIP PAST THIS AND TELL YOU 4951 03:53:15,600 --> 03:53:18,920 THE IMPORTANT PART. 4952 03:53:18,920 --> 03:53:22,000 THE END OF IT YEAH. 4953 03:53:22,000 --> 03:53:25,000 THANK YOU, MARJORIE. 4954 03:53:25,000 --> 03:53:26,200 [APPLAUSE] 4955 03:53:26,200 --> 03:53:43,160 SORRY FOR RUNNING OVER. 4956 03:53:43,160 --> 03:53:45,400 >> THE LAST SPEAKER BEFORE THE 4957 03:53:45,400 --> 03:53:50,160 BREAK IS MARGIE ACKERMAN, AND 4958 03:53:50,160 --> 03:53:51,480 SHE IS (INAUDIBLE) GOING TO TELL 4959 03:53:51,480 --> 03:53:57,520 US COMPLIMENTS TO MARJORIE AND 4960 03:53:57,520 --> 03:53:57,920 (INAUDIBLE). 4961 03:53:57,920 --> 03:54:00,400 >> THANK YOU. 4962 03:54:00,400 --> 03:54:01,800 SO I'M GRATEFUL FOR THE 4963 03:54:01,800 --> 03:54:03,600 OPPORTUNITY TO TO PARTICIPATE IN 4964 03:54:03,600 --> 03:54:04,920 THIS CELEBRATION OF MARJORIE'S 4965 03:54:04,920 --> 03:54:07,600 CAREER. 4966 03:54:07,600 --> 03:54:09,320 WHICH I THINK I HAVE SUB 4967 03:54:09,320 --> 03:54:11,000 CONSCIOUSLY EMULATED A LITTLE 4968 03:54:11,000 --> 03:54:12,360 BIT, OR AT LEAST ASPIRE TO NOW 4969 03:54:12,360 --> 03:54:14,800 THAT I'M AWARE OF IT. 4970 03:54:14,800 --> 03:54:16,240 HAVING DONE MY Ph.D. WORK IN 4971 03:54:16,240 --> 03:54:18,000 THE SETTING OF CANCER AND 4972 03:54:18,000 --> 03:54:21,080 TRANSITIONED INTO ANTIBODIES AND 4973 03:54:21,080 --> 03:54:24,720 FROM THERE TO EXTRA NEUTRALIZING 4974 03:54:24,720 --> 03:54:25,840 ACTIVITIES OF ANTIBODIES. 4975 03:54:25,840 --> 03:54:27,840 I DIDN'T TRAIN WITH MARJORIE, 4976 03:54:27,840 --> 03:54:32,640 BUT I CAME INTO THE FIELD OF HIV 4977 03:54:32,640 --> 03:54:34,080 RESEARCH AT MAYBE THE SECOND 4978 03:54:34,080 --> 03:54:36,200 PEAK, THE BEGINNING OF SECOND 4979 03:54:36,200 --> 03:54:38,160 UPSWING OF INTEREST IN 4980 03:54:38,160 --> 03:54:39,680 NON-NEUTRALIZING ANTIBODY 4981 03:54:39,680 --> 03:54:40,800 FUNCTIONS THAT WE TALKED ABOUT 4982 03:54:40,800 --> 03:54:43,800 AND LOOKING BACK AT WHO WAS IN 4983 03:54:43,800 --> 03:54:46,000 THAT SPACE BEFORE THAT BOOM. 4984 03:54:46,000 --> 03:54:48,720 IT WAS MARJORIE. 4985 03:54:48,720 --> 03:54:51,120 SO THE -- FOR BETTER OR WORSE 4986 03:54:51,120 --> 03:54:52,360 THE FIRST GRANT EVER GOT WAS A 4987 03:54:52,360 --> 03:54:55,000 BIG ONE AND IT HAD AN SAB. 4988 03:54:55,000 --> 03:54:56,920 SO MARJORIE WAS THE PERSON WE 4989 03:54:56,920 --> 03:54:58,720 ASKED TO ADVISE US IN THAT 4990 03:54:58,720 --> 03:54:59,800 EFFORT. 4991 03:54:59,800 --> 03:55:03,480 I QUICKLY CAME TO RECOGNIZE HER 4992 03:55:03,480 --> 03:55:05,560 AS A PERSON WHO DIDN'T HAVE THE 4993 03:55:05,560 --> 03:55:07,400 LOUDEST VOICE IN THE ROOM BUT 4994 03:55:07,400 --> 03:55:09,040 HAD THINGS THAT I WANTED TO HEAR 4995 03:55:09,040 --> 03:55:12,600 AND WANTED TO THINK ABOUT. 4996 03:55:12,600 --> 03:55:17,000 SO DESPITE BEING AT DISTANCE, I 4997 03:55:17,000 --> 03:55:18,560 REPRESENT MANY, MANY, MANY 4998 03:55:18,560 --> 03:55:21,280 DOZENS IF NOT HUNDREDS OF JUNIOR 4999 03:55:21,280 --> 03:55:22,800 SCIENTISTS WHO HAVE FELT 5000 03:55:22,800 --> 03:55:25,200 POSITIVE EFFECTS OF YOUR CAREER 5001 03:55:25,200 --> 03:55:27,520 IN LESS DIRECT WAYS THAN 5002 03:55:27,520 --> 03:55:34,200 TRAINEES DESCRIBED TODAY. 5003 03:55:34,200 --> 03:55:35,400 SO WE HAVE ALREADY HEARD ABOUT 5004 03:55:35,400 --> 03:55:37,480 TODAY A NUMBER OF NON-HUMAN 5005 03:55:37,480 --> 03:55:39,560 PRIMATE AND HUMAN IMMUNIZATION 5006 03:55:39,560 --> 03:55:41,240 STUDIES IN WHICH QUALITATIVE 5007 03:55:41,240 --> 03:55:43,320 ASPECTS OF THE IMMUNE RESPONSE 5008 03:55:43,320 --> 03:55:45,840 RATHER THAN NEUTRALIZATION HAVE 5009 03:55:45,840 --> 03:55:46,800 RELATED TO PROTECTION FROM 5010 03:55:46,800 --> 03:55:48,560 INFECTION. 5011 03:55:48,560 --> 03:55:50,760 SO MY GROUP HAS BEEN USING BIG 5012 03:55:50,760 --> 03:55:52,200 DATA AND MACHINE LEARNING 5013 03:55:52,200 --> 03:55:55,880 APPROACHES TO TRY TO INTEGRATE 5014 03:55:55,880 --> 03:55:56,840 UNDERSTANDING ABOUT FEATURES OF 5015 03:55:56,840 --> 03:55:58,520 THE ANTIBODY RESPONSE AND 5016 03:55:58,520 --> 03:56:02,120 FUNCTIONS OF ANTIBODIES, ACROSS 5017 03:56:02,120 --> 03:56:04,320 DIVERSE INDIVIDUALS TO REALLY 5018 03:56:04,320 --> 03:56:07,240 UNDERSTAND WHAT MAKES FOR AN 5019 03:56:07,240 --> 03:56:08,040 EFFECTIVE HUMORAL IMMUNE 5020 03:56:08,040 --> 03:56:10,000 RESPONSE. 5021 03:56:10,000 --> 03:56:13,040 BY DOING SO, WE REALLY HOPE TO 5022 03:56:13,040 --> 03:56:18,000 USE DATA DRIVEN DISCOVERY TO 5023 03:56:18,000 --> 03:56:18,800 FIND ROBUST CORRELATES OF 5024 03:56:18,800 --> 03:56:20,400 PROTECTION TO ADVANCE VACCINES 5025 03:56:20,400 --> 03:56:23,720 AS WELL AS PROVIDE INSIGHT HOW 5026 03:56:23,720 --> 03:56:25,600 MONOCLONAL ANTIBODY BASED 5027 03:56:25,600 --> 03:56:29,200 INTERVENTIONS MIGHT BE IMPROVED. 5028 03:56:29,200 --> 03:56:31,600 SO THE WORK I WILL TALK ABOUT 5029 03:56:31,600 --> 03:56:33,440 TODAY STARTS WITH A STORY YOU 5030 03:56:33,440 --> 03:56:38,320 HAVE ALREADY HEARD ABOUT DNA 5031 03:56:38,320 --> 03:56:39,520 PRIME VACCINE BASED STUDY 5032 03:56:39,520 --> 03:56:43,160 CONDUCTED BY FOLKS AT IHV AND 5033 03:56:43,160 --> 03:56:44,800 PROSPECTUS BIOSCIENCES DNA 5034 03:56:44,800 --> 03:56:46,520 ENCODED ADJUVANTS WERE COMPARED. 5035 03:56:46,520 --> 03:56:48,800 ONE ARM OF THE STUDY THE ONE 5036 03:56:48,800 --> 03:56:51,120 WITH ADJUVANTED WITH IL 12 WAS 5037 03:56:51,120 --> 03:56:53,240 ASSOCIATED WITH REDUCED RISK OF 5038 03:56:53,240 --> 03:56:55,600 INFECTION AFTER REPEATED LOW 5039 03:56:55,600 --> 03:56:58,920 DOSE INTRARECTAL CHALLENGE. 5040 03:56:58,920 --> 03:57:01,000 WHAT WAS REPORTED IN THE 5041 03:57:01,000 --> 03:57:05,520 ORIGINAL STUDY WAS ANIMALS WITH 5042 03:57:05,520 --> 03:57:07,800 HIGH ADCC BUT LOW INTERFERON 5043 03:57:07,800 --> 03:57:09,200 GAMMA EXPRESSION THOSE SHOWN IN 5044 03:57:09,200 --> 03:57:11,600 RED WERE BETTER PROTECTED THAN 5045 03:57:11,600 --> 03:57:15,280 THOSE WITH ADCC BUT HIGH 5046 03:57:15,280 --> 03:57:18,280 INTERFERON GAMMA EXPRESS SHOWN 5047 03:57:18,280 --> 03:57:21,320 IN GREEN OR NO ADCC ACTIVITY AT 5048 03:57:21,320 --> 03:57:23,080 ALL IN BLUE SO THE CONCLUSION 5049 03:57:23,080 --> 03:57:26,160 WAS YOU NEEDED BALANCE BETWEEN 5050 03:57:26,160 --> 03:57:27,920 ARMS ADAPTIVE IMMUNE SYSTEM. 5051 03:57:27,920 --> 03:57:30,120 SO THIS FELT LIKE MAYBE AN IDEAL 5052 03:57:30,120 --> 03:57:32,520 SETTING IN WHICH TO USE THESE 5053 03:57:32,520 --> 03:57:33,960 MULTI-VARIANT ANALYTICAL 5054 03:57:33,960 --> 03:57:36,480 TECHNIQUES TO TRY TO UNDERSTAND 5055 03:57:36,480 --> 03:57:38,160 HOW ASPECTS OF THE ANTIBODY 5056 03:57:38,160 --> 03:57:39,400 RESPONSE RELATE TO EACH OTHER 5057 03:57:39,400 --> 03:57:42,480 AND RELATE TO OUTCOMES. 5058 03:57:42,480 --> 03:57:46,160 I THINK THAT OBSERVATION 5059 03:57:46,160 --> 03:57:47,280 RESULTED FROM SOMEWHAT AD HOC 5060 03:57:47,280 --> 03:57:48,040 ANALYSIS. 5061 03:57:48,040 --> 03:57:49,400 WHEN YOU READ THROUGH YOUR PILE 5062 03:57:49,400 --> 03:57:52,240 OF DATA AND TRY TO DISCOVER WHAT 5063 03:57:52,240 --> 03:57:54,400 ON EARTH RELATES TO OUTCOME 5064 03:57:54,400 --> 03:57:57,280 OBSERVED SO WE WANTED TO DEPLOY 5065 03:57:57,280 --> 03:57:59,400 ASSAYS AND ANALYSIS MORE 5066 03:57:59,400 --> 03:58:01,800 SYSTEMATICALLY AND BROADLY. 5067 03:58:01,800 --> 03:58:03,040 BUT AT THE SAME TIME DO IT IN 5068 03:58:03,040 --> 03:58:05,160 STATISTICALLY PRINCIPLED WAY 5069 03:58:05,160 --> 03:58:07,400 WHICH GETS TRICKIER THE MORE 5070 03:58:07,400 --> 03:58:09,000 MEASUREMENTS YOU HAVE SO FOR 5071 03:58:09,000 --> 03:58:10,560 THAT WE TURN TO SYSTEMS SEROLOGY 5072 03:58:10,560 --> 03:58:12,200 TOOLS THAT AIM TO ENABLE US TO 5073 03:58:12,200 --> 03:58:13,640 CAST THAT BROAD NET ACROSS 5074 03:58:13,640 --> 03:58:15,640 ANTIBODY PHENOTYPES AND ANTIBODY 5075 03:58:15,640 --> 03:58:17,520 FUNCTION AND THEN USE RIGOROUSLY 5076 03:58:17,520 --> 03:58:20,480 CONTROLLED MACHINE LEARNING 5077 03:58:20,480 --> 03:58:21,200 TECHNIQUES TO UNDERSTAND 5078 03:58:21,200 --> 03:58:23,280 RELATIONSHIPS. 5079 03:58:23,280 --> 03:58:25,280 SO WE USED CROSS VALIDATED 5080 03:58:25,280 --> 03:58:26,720 MACHINE LEARNING APPROACHES TO 5081 03:58:26,720 --> 03:58:29,240 PREDICT RISK OF INFECTION. 5082 03:58:29,240 --> 03:58:30,840 HOW THIS WORKS IS THAT WE TAKE A 5083 03:58:30,840 --> 03:58:33,680 SUBSET OF THE ANIMALS IN THE 5084 03:58:33,680 --> 03:58:35,600 STUDY AND WE IDENTIFY FEATURES 5085 03:58:35,600 --> 03:58:38,600 AND COEFFICIENT WEIGHTS FOR 5086 03:58:38,600 --> 03:58:39,920 THOSE FEATURES THAT PREDICT 5087 03:58:39,920 --> 03:58:41,800 INFECTION RISK AND WE TEST THEIR 5088 03:58:41,800 --> 03:58:43,440 ACCURACY ON THE ANIMALS THAT 5089 03:58:43,440 --> 03:58:44,800 WERE HELD OUT FROM THE MODELING. 5090 03:58:44,800 --> 03:58:46,600 SO IT IS NOT A DATA FITTING 5091 03:58:46,600 --> 03:58:52,000 EXERCISE, TRULY A PREDICTIVE 5092 03:58:52,000 --> 03:58:53,360 EXERCISE, SACRIFICING SOME OF 5093 03:58:53,360 --> 03:58:56,440 THE DATA LEARNING RULES AND 5094 03:58:56,440 --> 03:58:58,080 PREDICTIVE MODEL AND APPLYING TO 5095 03:58:58,080 --> 03:58:59,360 EXAMPLE ANIMALS THAT WERE HELD 5096 03:58:59,360 --> 03:58:59,720 OUT. 5097 03:58:59,720 --> 03:59:00,760 SO YOU CAN DO THIS AGAIN AND 5098 03:59:00,760 --> 03:59:02,600 AGAIN AND AGAIN WITH DIFFERENT 5099 03:59:02,600 --> 03:59:03,960 COMBINATIONS OF ANIMALS, 5100 03:59:03,960 --> 03:59:04,920 DIFFERENT COMBINATIONS OF 5101 03:59:04,920 --> 03:59:08,720 FEATURES AND SEE WHAT HAPPENS. 5102 03:59:08,720 --> 03:59:10,360 SO WHEN WE DID THAT WITH 5103 03:59:10,360 --> 03:59:12,360 RESPONSE MAGNITUDE OR TITER 5104 03:59:12,360 --> 03:59:14,600 ALONE, THERE WAS REALLY NO 5105 03:59:14,600 --> 03:59:17,520 ABILITY TO PREDICT RISK OF 5106 03:59:17,520 --> 03:59:18,560 INFECTION. 5107 03:59:18,560 --> 03:59:20,320 O SHOWN HERE PREDICTIVE RISK 5108 03:59:20,320 --> 03:59:21,880 VERSUS CHALLENGE OUTCOME ACROSS 5109 03:59:21,880 --> 03:59:23,400 THE DIFFERENT IMMUNIZATION 5110 03:59:23,400 --> 03:59:26,840 GROUPS IN THIS STUDY AND THERE'S 5111 03:59:26,840 --> 03:59:29,840 NO WISHFUL THINKING, THERE'S A 5112 03:59:29,840 --> 03:59:31,320 RELATIONSHIP HERE OR NOT. 5113 03:59:31,320 --> 03:59:36,640 AND THERE WAS ALSO NO ABILITY TO 5114 03:59:36,640 --> 03:59:37,240 RECAPITULATE WHAT WAS OBSERVED 5115 03:59:37,240 --> 03:59:39,080 THIS TRIAL, REDUCED RISK OF 5116 03:59:39,080 --> 03:59:41,120 INFECTION OBSERVED IN IL 12 5117 03:59:41,120 --> 03:59:42,760 ADJUVANTED GROUP SO USING 5118 03:59:42,760 --> 03:59:44,240 ANTIBODY TITTEDDER MEASUREMENTS 5119 03:59:44,240 --> 03:59:46,960 THAT AMOUNT OF IGG SPECIFIC TO 5120 03:59:46,960 --> 03:59:50,000 HIV ANTIGENS, IN THIS STUDY 5121 03:59:50,000 --> 03:59:51,000 DIDN'T GIVE ANY ABILITY TO 5122 03:59:51,000 --> 03:59:55,920 PREDICT THE OUTCOME. 5123 03:59:55,920 --> 03:59:57,800 IN CONTRAST IF WE INCLUDE THE 5124 03:59:57,800 --> 03:59:59,120 QUALITATIVE FEATURES OF 5125 03:59:59,120 --> 04:00:00,640 ANTIBODIES THAT WERE RAISED AND 5126 04:00:00,640 --> 04:00:03,200 FUNCTIONS OF THOSE ANTIBODIES 5127 04:00:03,200 --> 04:00:05,080 MEASURED IN CELL BASED ASSAYS, 5128 04:00:05,080 --> 04:00:07,400 WE NOT ONLY SAW GOOD CORRELATION 5129 04:00:07,400 --> 04:00:08,600 BETWEEN PREDICTIVE RISK AND 5130 04:00:08,600 --> 04:00:10,720 NUMBER OF CHALLENGES REQUIRED TO 5131 04:00:10,720 --> 04:00:12,960 ESTABLISH INFECTION AT LEVEL OF 5132 04:00:12,960 --> 04:00:14,200 INDIVIDUAL ANIMALS WHICH IS 5133 04:00:14,200 --> 04:00:15,840 SHOWN AT THE LEFT, PREDICTED 5134 04:00:15,840 --> 04:00:18,040 RISK THOSE ANIMALS EACH DOT IS 5135 04:00:18,040 --> 04:00:20,080 AN INDIVIDUAL ANIMAL. 5136 04:00:20,080 --> 04:00:22,840 THOSE WITH RELATIVELY HIGH RISK 5137 04:00:22,840 --> 04:00:25,720 WERE INFECTED EARLIER IN SERIES, 5138 04:00:25,720 --> 04:00:27,280 THOSE WITH PREDICTED LOWER RISK 5139 04:00:27,280 --> 04:00:30,240 WERE INFECTED LATER WE CAN 5140 04:00:30,240 --> 04:00:31,600 RECAPITULATE OBSERVATION THE IL 5141 04:00:31,600 --> 04:00:33,760 12 ADJUVANTED GROUP HAD A LOWER 5142 04:00:33,760 --> 04:00:36,080 RISK OF INFECTION. 5143 04:00:36,080 --> 04:00:39,320 SO THIS WAS PRETTY EXCITING. 5144 04:00:39,320 --> 04:00:41,560 THEN WE LOOKED UNDER THE HOOD OF 5145 04:00:41,560 --> 04:00:42,960 THE MODEL AND FOUND FEATURES 5146 04:00:42,960 --> 04:00:46,640 ASSOCIATED WITH REDUCE RISK OF 5147 04:00:46,640 --> 04:00:48,960 INFECTION THOSE HIGH AND SHOWN 5148 04:00:48,960 --> 04:00:51,480 IN RED, AMONG INFECTION 5149 04:00:51,480 --> 04:00:53,360 RESISTANT ANIMALS SHOWN IN 5150 04:00:53,360 --> 04:00:56,000 BRIGHT GREEN, THOSE WERE 5151 04:00:56,000 --> 04:00:58,040 UNINFECTED OR DARK GRAY, WERE 5152 04:00:58,040 --> 04:01:00,920 ASSOCIATED WITH THE C 1Q BINDING 5153 04:01:00,920 --> 04:01:02,040 ABILITY OF HIV SPECIFIC 5154 04:01:02,040 --> 04:01:02,640 ANTIBODIES. 5155 04:01:02,640 --> 04:01:06,400 SO THIS ANALYSIS REALLY 5156 04:01:06,400 --> 04:01:08,280 IMPLICATED A ROLE OF THE 5157 04:01:08,280 --> 04:01:11,000 COMPLIMENT SYSTEM YOU ALREADY 5158 04:01:11,000 --> 04:01:12,840 HEARD ABOUT TODAY IN PROTECTION 5159 04:01:12,840 --> 04:01:16,320 MEDIATED BY THIS VACCINE. 5160 04:01:16,320 --> 04:01:19,720 A LOT THESE NON-HUMAN PRIMATE 5161 04:01:19,720 --> 04:01:23,880 VACCINATION STUDIES HAVE RAISED 5162 04:01:23,880 --> 04:01:26,120 QUESTIONS ABOUT WHETHER THESE 5163 04:01:26,120 --> 04:01:27,120 RELATIONSHIPS ARE INTERESTING 5164 04:01:27,120 --> 04:01:28,360 ASSOCIATIONS OR MECHANISTICALLY 5165 04:01:28,360 --> 04:01:30,760 RELEVANT. 5166 04:01:30,760 --> 04:01:32,600 EVEN AS THESE OBSERVATIONS PILE 5167 04:01:32,600 --> 04:01:34,440 UP FROM DIFFERENT STUDIES, THEY 5168 04:01:34,440 --> 04:01:36,640 STILL DON'T ENABLE YOU TO 5169 04:01:36,640 --> 04:01:39,600 DIRECTLY CONCLUDE WHAT ACTIVITY 5170 04:01:39,600 --> 04:01:44,400 WAS RESPONSIBLE FOR PROTECTION. 5171 04:01:44,400 --> 04:01:48,120 ASSOCIATIVE EVIDENCE. 5172 04:01:48,120 --> 04:01:49,400 SINCE THIS WAS THE FIRST BUT NOT 5173 04:01:49,400 --> 04:01:51,000 THE ONLY TIME WE HAVE SEEN 5174 04:01:51,000 --> 04:01:52,320 COMPLIMENT RELATED SIGNATURE WE 5175 04:01:52,320 --> 04:01:54,320 WANTED TO ASK WHAT DO WE KNOW 5176 04:01:54,320 --> 04:01:56,560 ABOUT COMPLIMENT IN VACCINE OR 5177 04:01:56,560 --> 04:02:00,240 ANTIBODY MEDIATED PROTECTION 5178 04:02:00,240 --> 04:02:01,400 FROM HIV INFECTION OR ANY OTHER 5179 04:02:01,400 --> 04:02:03,600 INFECTION. 5180 04:02:03,600 --> 04:02:05,720 THE ANSWER IS, IT IS 5181 04:02:05,720 --> 04:02:07,880 COMPLICATED, THIS IS THE 5182 04:02:07,880 --> 04:02:08,600 SIMPLEST DIAGRAM, CLEANEST I 5183 04:02:08,600 --> 04:02:09,520 HAVE SEEN IN THE COMPLIMENT 5184 04:02:09,520 --> 04:02:10,760 CASCADE. 5185 04:02:10,760 --> 04:02:17,720 IT IS TRULY A HUMONGOUS MESS. 5186 04:02:17,720 --> 04:02:18,760 AND UNPREDICTABLE. 5187 04:02:18,760 --> 04:02:21,840 IT IS AFTER LUNCH SOME OF US ARE 5188 04:02:21,840 --> 04:02:23,600 SHIELDING OUR EYES FOR 5189 04:02:23,600 --> 04:02:25,200 SLEEPINESS REASONS BUT I HAVE 5190 04:02:25,200 --> 04:02:26,200 GIVEN YOU ANOTHER ONE. 5191 04:02:26,200 --> 04:02:27,640 LOTS OF WAYS TO ACTIVATE 5192 04:02:27,640 --> 04:02:30,080 COMPLIMENT, SOME MEDIATED BY 5193 04:02:30,080 --> 04:02:30,600 ANTIBODIES, MANY IMMEDIATE 5194 04:02:30,600 --> 04:02:32,520 YATESED BY OTHER FACTORS, MANY 5195 04:02:32,520 --> 04:02:34,520 WAYS TO INTERRUPT AND 5196 04:02:34,520 --> 04:02:37,080 PREMATURELY TERMINATE COMPLIMENT 5197 04:02:37,080 --> 04:02:38,920 CASCADE BEFORE IT RESULTS IN 5198 04:02:38,920 --> 04:02:42,520 LYSIS OR CLEARANCE OF A TARGET 5199 04:02:42,520 --> 04:02:43,040 PARTICLE. 5200 04:02:43,040 --> 04:02:44,880 AND ALSO WAYS COMPLIMENT 5201 04:02:44,880 --> 04:02:46,600 PROTEINS INFLUENCE EACH OTHER 5202 04:02:46,600 --> 04:02:49,160 AND INFLUENCE OTHER EFFECTOR 5203 04:02:49,160 --> 04:02:51,800 CELLS PHENOTYPES. 5204 04:02:51,800 --> 04:02:54,120 NORBERT AND FOR WORSE. 5205 04:02:54,120 --> 04:02:55,360 FOR BETTER AND FOR WORSE. 5206 04:02:55,360 --> 04:02:56,640 THIS IS A COMPLICATED SYSTEM 5207 04:02:56,640 --> 04:02:59,400 THAT'S BEEN TRICKY FOR US TO TRY 5208 04:02:59,400 --> 04:03:01,360 TO PARSE OUT IN VITRO. 5209 04:03:01,360 --> 04:03:02,840 I WILL SPEND A LITTLE BIT OF 5210 04:03:02,840 --> 04:03:04,200 TIME TALKING ABOUT THAT. 5211 04:03:04,200 --> 04:03:06,320 BUT SINCE IT IS COMPLICATED, IT 5212 04:03:06,320 --> 04:03:08,320 IS ALSO INTERESTING AND SO 5213 04:03:08,320 --> 04:03:11,400 MARJORIE HAS WORKED ON IT AND SO 5214 04:03:11,400 --> 04:03:13,480 HERE IS MAYBE ONE STUDY THAT 5215 04:03:13,480 --> 04:03:18,280 HASN'T BEEN MENTIONED YET TODAY, 5216 04:03:18,280 --> 04:03:20,400 MILLION WHICH A MODEST 5217 04:03:20,400 --> 04:03:24,400 CORRELATION OF VIRAL LYSIS WAS 5218 04:03:24,400 --> 04:03:25,480 ASSOCIATED WITH REDUCED 5219 04:03:25,480 --> 04:03:27,400 INFECTION RATE IN A SEX 5220 04:03:27,400 --> 04:03:28,080 DEPENDENT FASHION. 5221 04:03:28,080 --> 04:03:31,320 SO THAT'S THE GRAPH SHOWN AT THE 5222 04:03:31,320 --> 04:03:33,600 LEFT YOU SEE VIRION LYSIS 5223 04:03:33,600 --> 04:03:34,960 MEDIATED BY ANTIBODIES IN 5224 04:03:34,960 --> 04:03:36,200 COMPLIMENT, ON THE Y AXIS AND 5225 04:03:36,200 --> 04:03:38,600 THE NUMBER OF CHALLENGES TO 5226 04:03:38,600 --> 04:03:42,000 ESTABLISH INFECTION ON THE X. 5227 04:03:42,000 --> 04:03:45,200 ALSO SOME EVIDENCE OF 5228 04:03:45,200 --> 04:03:47,600 RELATIONSHIP BETWEEN VIRAL LYSIS 5229 04:03:47,600 --> 04:03:50,480 AND PEAK VIRAL LOAD FOLLOWING 5230 04:03:50,480 --> 04:03:52,200 INFECTION SHOWN ON THE RIGHT. 5231 04:03:52,200 --> 04:03:54,320 SO THIS WAS PART OF WHAT 5232 04:03:54,320 --> 04:03:56,520 INSPIRED US TO TRY TO DIG INTO 5233 04:03:56,520 --> 04:03:58,560 WHETHER THESE OBSERVATION -- WE 5234 04:03:58,560 --> 04:04:00,160 COULD MECHANISTICALLY BOLSTER 5235 04:04:00,160 --> 04:04:04,680 THESE ASSOCIATIVE OBSERVATIONS. 5236 04:04:04,680 --> 04:04:06,400 PART OF THE REASON WHY THIS 5237 04:04:06,400 --> 04:04:09,200 PATHWAY IS SO COMPLICATED TO 5238 04:04:09,200 --> 04:04:10,600 UNDERSTAND OR PREDICT ITS 5239 04:04:10,600 --> 04:04:13,080 ACTIVITIES LIKELY RELATES TO THE 5240 04:04:13,080 --> 04:04:14,880 STRUCTURAL BIOLOGY INVOLVED SO 5241 04:04:14,880 --> 04:04:17,120 WE KNOW FROM SOME ELEGANT 5242 04:04:17,120 --> 04:04:19,600 STRUCTURAL BIOLOGY STUDIES THAT 5243 04:04:19,600 --> 04:04:21,680 IGG CAN HEXAMERRIZE THROUGH FC 5244 04:04:21,680 --> 04:04:24,200 DOMAIN AND THIS CAN BETTER 5245 04:04:24,200 --> 04:04:27,800 ENGAGE WITH THE 6 GLOBULAR HEADS 5246 04:04:27,800 --> 04:04:31,360 OF Y 1Q, IT VARIES WHETHER BOTH 5247 04:04:31,360 --> 04:04:33,360 FAB ARMS ARE BOUND TO ANTIGEN OR 5248 04:04:33,360 --> 04:04:35,320 NOT BUT IT IS INCREDIBLY 5249 04:04:35,320 --> 04:04:38,320 COMPLICATED AND NOT PERFECTLY 5250 04:04:38,320 --> 04:04:38,800 UNDERSTOOD. 5251 04:04:38,800 --> 04:04:40,800 THIS IS A -- INSTEAD OF SPATIAL 5252 04:04:40,800 --> 04:04:42,280 INFLUENCES THAT ARE DIFFICULT TO 5253 04:04:42,280 --> 04:04:47,280 HAVE A SENSE FOR AFRE A PRIORI 5254 04:04:47,280 --> 04:04:49,000 CERTAINLY IN CONTEXT OF 5255 04:04:49,000 --> 04:04:51,400 POLYCLONAL ANTI-BOUGH BODIES 5256 04:04:51,400 --> 04:04:54,080 WHERE STUDIES ARE PRESENT. 5257 04:04:54,080 --> 04:04:56,560 BUT STUDIES OF ANTI-CANCER MAPS 5258 04:04:56,560 --> 04:04:58,240 IT VARIES ALONG MAPS THAT TARGET 5259 04:04:58,240 --> 04:04:59,640 THE SAME ANTIGEN. 5260 04:04:59,640 --> 04:05:02,600 AND OF COURSE THE SPARSITY OF 5261 04:05:02,600 --> 04:05:05,280 ENVELOPE AND ITS MULTIPLICITY OF 5262 04:05:05,280 --> 04:05:06,840 CONFIRMATIONAL STATES ONLY ADD 5263 04:05:06,840 --> 04:05:09,360 COMPLICATION IN THE CONTEXT OF 5264 04:05:09,360 --> 04:05:11,600 HIV INFECTION. 5265 04:05:11,600 --> 04:05:15,400 SOMETHING ELSE WE KNEW FROM THE 5266 04:05:15,400 --> 04:05:16,440 CONTEXT OF HIV WAS THAT THERE 5267 04:05:16,440 --> 04:05:18,240 WAS A LOT OF SOMEWHAT 5268 04:05:18,240 --> 04:05:19,280 CONFLICTING CONFUSING EVIDENCE 5269 04:05:19,280 --> 04:05:22,080 RELATED TO NATURAL INFECTION. 5270 04:05:22,080 --> 04:05:23,920 BUT THERE WAS ONE DEFINITIVE 5271 04:05:23,920 --> 04:05:26,200 PASSIVE TRANSFER STUDY, SEMINOLE 5272 04:05:26,200 --> 04:05:27,120 ONE IN THE FIELD WHICH AT THE 5273 04:05:27,120 --> 04:05:29,400 SAME TIME IS INDICATED 5274 04:05:29,400 --> 04:05:31,400 ACTIVITIES OTHER THAN 5275 04:05:31,400 --> 04:05:32,400 NEUTRALIZATION DID CONTRIBUTE TO 5276 04:05:32,400 --> 04:05:38,400 PROTECTION FROM INFECTION 5277 04:05:38,400 --> 04:05:39,840 EXCLUDED COMPLIMENT FROM BEING 5278 04:05:39,840 --> 04:05:44,200 IMPORTANT MECHANISM OF ACTION SO 5279 04:05:44,200 --> 04:05:49,400 THE SO ANTIBODY IN RED IS KA 5280 04:05:49,400 --> 04:05:50,000 MUTANT AND ABLATES INTERACTION 5281 04:05:50,000 --> 04:05:56,200 BETWEEN ANTIBODIES AND C 1Q THAT 5282 04:05:56,200 --> 04:05:58,320 DIDN'T DECREASE B 12 TO PREVENT 5283 04:05:58,320 --> 04:06:06,200 INFECTION AT ALL. 5284 04:06:06,200 --> 04:06:07,760 KNOWING ALL THE ASPECTS, WE 5285 04:06:07,760 --> 04:06:09,760 WANTED TO HEAVY SIT THIS GIVEN 5286 04:06:09,760 --> 04:06:11,640 HOW NUANCED COMPLIMENT 5287 04:06:11,640 --> 04:06:12,640 ACTIVATION APPEARED FROM OTHER 5288 04:06:12,640 --> 04:06:13,000 FIELDS. 5289 04:06:13,000 --> 04:06:16,720 SO BEASKED THE QUESTION, UNDER 5290 04:06:16,720 --> 04:06:19,840 WHAT CIRCUMSTANCESES DOES B 12 5291 04:06:19,840 --> 04:06:20,960 EXHIBIT COMPLIMENT ACTIVITY SO 5292 04:06:20,960 --> 04:06:23,840 WE SET PANEL OF B 12 FC VARIANTS 5293 04:06:23,840 --> 04:06:25,600 USED IN ORIGINAL PASSIVE 5294 04:06:25,600 --> 04:06:28,680 TRANSFER EXPERIMENTS, LALA AN FC 5295 04:06:28,680 --> 04:06:30,600 GAMMA REACCEPT TO AND C 1Q KNOCK 5296 04:06:30,600 --> 04:06:34,040 OUT, KA IS A C 1Q BINDING KNOCK 5297 04:06:34,040 --> 04:06:37,160 OUT AND ENHANCED VARIANTS, EG 5298 04:06:37,160 --> 04:06:39,160 AND EFATE WHICH ARE SHOWN IN 5299 04:06:39,160 --> 04:06:42,240 BLUE, REPORTED TO ENHANCE 5300 04:06:42,240 --> 04:06:45,520 COMPLIMENT ACTIVATION BY DIVERSE 5301 04:06:45,520 --> 04:06:45,960 MECHANISMS. 5302 04:06:45,960 --> 04:06:47,600 SO THE ANSWER TO THE QUESTION 5303 04:06:47,600 --> 04:06:51,000 WHETHER B 12 WAS COMPLIMENT 5304 04:06:51,000 --> 04:06:53,840 ACTIVE WAS SOMETIMES SOME WAYS 5305 04:06:53,840 --> 04:06:55,280 SO SHOWN AT LEFT IS ANTIGEN 5306 04:06:55,280 --> 04:06:57,640 BINDING TO TWO RECOMBINANT 5307 04:06:57,640 --> 04:06:58,920 ENVELOPE PROTEINS FOUR WHICH 5308 04:06:58,920 --> 04:07:03,880 VARIANTS SHOWED EQUAL BINDING. 5309 04:07:03,880 --> 04:07:07,880 AND SHOWN IN THE CENTER, IS 5310 04:07:07,880 --> 04:07:11,360 BINDING OF C 1Q TO IGG BOUND TO 5311 04:07:11,360 --> 04:07:13,160 TARGETS, AS WELL AS TO ANTIBODY 5312 04:07:13,160 --> 04:07:15,680 DIRECTLY CODING IN ELISA PLATE 5313 04:07:15,680 --> 04:07:19,600 IS WHAT WAS SHOWN IN THE 5314 04:07:19,600 --> 04:07:21,440 ORIGINAL NHP PASSIVE TRANSFER 5315 04:07:21,440 --> 04:07:23,520 EXPERIMENT SO WILD TYPE B 12 5316 04:07:23,520 --> 04:07:25,760 SHOWS SOME ACTIVITY WHEN BOUND 5317 04:07:25,760 --> 04:07:28,680 TO ELISA PLATE AND THE EFTAE AND 5318 04:07:28,680 --> 04:07:31,040 EG VARIANTS SHOWED MORE BUT WE 5319 04:07:31,040 --> 04:07:33,200 REALLY DIDN'T SEE ANY ACTIVITY 5320 04:07:33,200 --> 04:07:35,400 AGAINST ANTIBODY WHEN BOUND TO 5321 04:07:35,400 --> 04:07:35,800 ANTIGEN. 5322 04:07:35,800 --> 04:07:37,880 WHETHER THAT'S BECAUSE OF WHAT 5323 04:07:37,880 --> 04:07:41,400 GEORGE INTENDED TO TELL US ABOUT 5324 04:07:41,400 --> 04:07:43,280 WHAT HE CUT OUT OF HIS TALK OR 5325 04:07:43,280 --> 04:07:43,800 SOMETHING ELSE. 5326 04:07:43,800 --> 04:07:44,200 I DON'T KNOW. 5327 04:07:44,200 --> 04:07:46,960 BUT THAT WAS THE OBSERVATION. 5328 04:07:46,960 --> 04:07:48,880 SO WILD TYPE B 12 COULDN'T DO 5329 04:07:48,880 --> 04:07:53,080 THIS IN THIS RECOMBINANT ANTIGEN 5330 04:07:53,080 --> 04:07:54,600 ASSAY. 5331 04:07:54,600 --> 04:07:57,000 WE ALSO LOOK AT C 3D DEPOSITION 5332 04:07:57,000 --> 04:07:58,280 IN THIS CONTEXT. 5333 04:07:58,280 --> 04:08:00,280 AND IT WAS DIFFERENT THAN THE C 5334 04:08:00,280 --> 04:08:01,200 1Q BINDING. 5335 04:08:01,200 --> 04:08:03,200 SO THAT SUGGESTED THAT WHATEVER 5336 04:08:03,200 --> 04:08:04,600 PART OF THE QUOTHMENT CASCADE 5337 04:08:04,600 --> 04:08:06,680 YOU LOOKED AT YOU MIGHT GET 5338 04:08:06,680 --> 04:08:09,520 DIFFERENT PATTERNS. 5339 04:08:09,520 --> 04:08:10,760 SO SEEMS DIFFICULT TO 5340 04:08:10,760 --> 04:08:12,120 EXTRAPOLATE. 5341 04:08:12,120 --> 04:08:15,800 OF COURSE WHAT'S SHOWN IN THE 5342 04:08:15,800 --> 04:08:18,040 LOWER RIGHT CORNER IS THE IMPACT 5343 04:08:18,040 --> 04:08:19,360 THAT ANTIGEN CAN HAVE. 5344 04:08:19,360 --> 04:08:23,200 SO HIGHLY GLYCOSYLATED ANTIGEN 5345 04:08:23,200 --> 04:08:25,720 LIKE HIV ENVELOPE DIRECTLY 5346 04:08:25,720 --> 04:08:27,280 INTERACT WITH COMPLIMENT CASCADE 5347 04:08:27,280 --> 04:08:29,520 PROTEINS AND TRIGGER C 3 D 5348 04:08:29,520 --> 04:08:31,280 DEPOSITION. 5349 04:08:31,280 --> 04:08:32,800 BUT IF TREATED THOSE ANTIGENS 5350 04:08:32,800 --> 04:08:35,040 THEN WE HAD BETTER RESOLUTION TO 5351 04:08:35,040 --> 04:08:41,560 SEE ANTIBODY DEPENDENT ACTIVITY. 5352 04:08:41,560 --> 04:08:42,440 SOMETIMES A SMIDGE OF COMPLIMENT 5353 04:08:42,440 --> 04:08:47,200 WAS ACTIVATED BY WILD TYPE B 12. 5354 04:08:47,200 --> 04:08:50,920 WHAT IF WE TARGETED FREE 5355 04:08:50,920 --> 04:08:51,520 VIRIONS? 5356 04:08:51,520 --> 04:08:55,520 ALL THE ANTIBODIES BOUND TO 5357 04:08:55,520 --> 04:08:57,640 VIRUS BUT C 1Q BINDING COULD BE 5358 04:08:57,640 --> 04:09:00,320 DETECTED FOR EFTAE ENHANCED 5359 04:09:00,320 --> 04:09:02,640 VARIANT AND NOT FOR WILD TYPE B 5360 04:09:02,640 --> 04:09:07,960 12 AND CERTAINLY NOT FOR KNOCK 5361 04:09:07,960 --> 04:09:08,480 OUT. 5362 04:09:08,480 --> 04:09:10,000 GIVEN WILD TYPE DIDN'T HAVE THAT 5363 04:09:10,000 --> 04:09:10,600 ACTIVITY. 5364 04:09:10,600 --> 04:09:13,760 SIMILAR FOR C 3 DEPOSITION 5365 04:09:13,760 --> 04:09:17,120 THOUGH A SMIDGE OF ACTIVITY OF 5366 04:09:17,120 --> 04:09:21,600 WILD TYPE B 12 BUT NONE OF THESE 5367 04:09:21,600 --> 04:09:25,200 VARIANTS OF B 12 LYSED VIRUS IN 5368 04:09:25,200 --> 04:09:27,760 OUR HANDS AND POSITIVE CONTROL 5369 04:09:27,760 --> 04:09:30,840 HERE WAS 10 A 8V 4 WITH 5370 04:09:30,840 --> 04:09:32,840 ENHANCING MUTATIONS. 5371 04:09:32,840 --> 04:09:35,800 WHAT ABOUT ON EXPRESSING CELLS>> 5372 04:09:35,800 --> 04:09:39,000 HERE IS HEC 293 CELLS EXPRESSING 5373 04:09:39,000 --> 04:09:41,320 ON SURFACE AND WE SAW AGAIN 5374 04:09:41,320 --> 04:09:42,680 REASONABLY EQUIVALENT ANTIGEN 5375 04:09:42,680 --> 04:09:46,280 BINDING. 5376 04:09:46,280 --> 04:09:48,240 C 1Q BINDING OF THESE CELLS ONLY 5377 04:09:48,240 --> 04:09:53,960 FOR ENHANCED VARIANTS, NOT FOR 5378 04:09:53,960 --> 04:09:55,080 WILD TYPE B 12. 5379 04:09:55,080 --> 04:09:58,520 C 3 DEPOSITION AND C 5B 9 5380 04:09:58,520 --> 04:10:00,200 FORMATION OF ENHANCED VARIANTS 5381 04:10:00,200 --> 04:10:03,960 AND NOT WILD TYPE AND SIMILAR 5382 04:10:03,960 --> 04:10:07,160 OBSERVATION MADE IN TERMS OF 5383 04:10:07,160 --> 04:10:08,000 CELL LYSIS. 5384 04:10:08,000 --> 04:10:09,520 COMPLIMENT DEPENDENT 5385 04:10:09,520 --> 04:10:12,000 CYTOTOXICITY. 5386 04:10:12,000 --> 04:10:16,520 ALSO MADE FOR B 12, WE COULDN'T 5387 04:10:16,520 --> 04:10:22,840 SEE ANY VIR ROLLSIS OR SIGH 5388 04:10:22,840 --> 04:10:25,000 TOLLSIS INDUCED BY B 12. 5389 04:10:25,000 --> 04:10:28,440 FIRST SET OF CONCLUSIONS ARE B 5390 04:10:28,440 --> 04:10:29,760 12 DIDN'T EXHIBIT COMPLIMENT 5391 04:10:29,760 --> 04:10:30,560 ACTIVATING ACTIVITY CERTAINLY 5392 04:10:30,560 --> 04:10:32,880 NOT ROBUSTLY. 5393 04:10:32,880 --> 04:10:33,920 EXPECTED TRENDS WERE GENERALLY 5394 04:10:33,920 --> 04:10:35,760 OBSERVED ACROSS THE VARIANTS BUT 5395 04:10:35,760 --> 04:10:37,520 THE MAGNITUDE AND EXTEND OF 5396 04:10:37,520 --> 04:10:42,400 DIFFERENCES BETWEEN ENHANCED 5397 04:10:42,400 --> 04:10:43,600 WILD TYPE AND KNOCK OUT WERE 5398 04:10:43,600 --> 04:10:47,120 VARIED, DETAILS WERE DIFFERENT. 5399 04:10:47,120 --> 04:10:48,640 SO COMPLIMENT DEPENDENT 5400 04:10:48,640 --> 04:10:50,320 ACTIVITIES KIND OF VARIED BY 5401 04:10:50,320 --> 04:10:51,520 EVERYTHING -- EVERY PARAMETER WE 5402 04:10:51,520 --> 04:10:52,920 HAD EXPLORED. 5403 04:10:52,920 --> 04:10:56,640 WHICH WAS A LITTLE BIT 5404 04:10:56,640 --> 04:10:57,240 FRUSTRATING. 5405 04:10:57,240 --> 04:10:58,920 SOMEONE SITTING IN ENGINEERING 5406 04:10:58,920 --> 04:11:00,160 SCHOOL WHO TENDS TO THINK OF 5407 04:11:00,160 --> 04:11:03,240 THINGS AND MAYBE A LITTLE BIT 5408 04:11:03,240 --> 04:11:05,040 REDUCTIONIST FASHION. 5409 04:11:05,040 --> 04:11:07,600 SO THE CONCLUSION WE CAME TO WAS 5410 04:11:07,600 --> 04:11:09,160 THAT FURTHER IN VIVO EXPERIMENTS 5411 04:11:09,160 --> 04:11:12,800 ARE PROBABLY GOING TO BE 5412 04:11:12,800 --> 04:11:13,640 NECESSARY TOSS TRY TO UNDERSTAND 5413 04:11:13,640 --> 04:11:15,880 WHETHER THIS IS IMPORTANT ASPECT 5414 04:11:15,880 --> 04:11:17,920 OF ANTIBODY BIOLOGY NORTH AND 5415 04:11:17,920 --> 04:11:18,880 WE'LL CONTINUE TO SEE 5416 04:11:18,880 --> 04:11:21,440 CONFLICTING OBSERVATION AN SPIN 5417 04:11:21,440 --> 04:11:24,880 WHEELS IF WE KEPT ALL OF OUR 5418 04:11:24,880 --> 04:11:25,800 INVESTIGATION IN VITRO. 5419 04:11:25,800 --> 04:11:27,480 IT ALSO SUGGESTED THAT THAT 5420 04:11:27,480 --> 04:11:30,720 ORIGINAL PAPER USING B 12 WHICH 5421 04:11:30,720 --> 04:11:33,160 SHOWED COMPLIMENT PLAYED NO 5422 04:11:33,160 --> 04:11:35,200 ROLE, B 12 DIDN'T HAVE A GOOD 5423 04:11:35,200 --> 04:11:36,800 ABILITY TO INDUCE COMPLIMENT 5424 04:11:36,800 --> 04:11:40,040 ANYWAY SO YOU ARE KNOCKING OUT 5425 04:11:40,040 --> 04:11:41,400 SOMETHING THAT WAS ALREADY 5426 04:11:41,400 --> 04:11:42,640 FUNCTIONALLY DEAD, WE THOUGHT 5427 04:11:42,640 --> 04:11:44,960 MAYBE THIS IS GENERALLY TRUE 5428 04:11:44,960 --> 04:11:46,800 GENERALLY TRUE BNAB BUT MAYBE 5429 04:11:46,800 --> 04:11:49,120 NOT AND IT IS CERTAINLY 5430 04:11:49,120 --> 04:11:53,600 SOMETHING WORTH TESTING. 5431 04:11:53,600 --> 04:11:55,280 IF B 12 WAS A DUD WHAT ELSE 5432 04:11:55,280 --> 04:11:56,880 COULD WE USE? 5433 04:11:56,880 --> 04:11:58,800 FOR US TIMOTHY AND OLIVIA 5434 04:11:58,800 --> 04:11:59,720 SCHWARZ WERE WORKING ON 5435 04:11:59,720 --> 04:12:01,400 ANSWERING THAT QUESTION FOR US. 5436 04:12:01,400 --> 04:12:05,840 SO WE PICKED TO INVESTIGATE 10E 5437 04:12:05,840 --> 04:12:07,800 8 WHICH SEEMS TO WORK BETTER IN 5438 04:12:07,800 --> 04:12:12,640 VIVO THAN IN VITRO IN TERMS OF 5439 04:12:12,640 --> 04:12:14,960 ITS WHAT ITS NEUTRALIZATION 5440 04:12:14,960 --> 04:12:17,240 POTENCY PREDICTS, IT IS A LITTLE 5441 04:12:17,240 --> 04:12:18,960 MORE PROTECTIVE IN VIVO THAN 5442 04:12:18,960 --> 04:12:21,480 EXPECTATION AND SHOWED A LITTLE 5443 04:12:21,480 --> 04:12:22,560 COMPLIMENT DEPENDENT 5444 04:12:22,560 --> 04:12:25,960 CYTOTOXICITY AND 10101074 THE 5445 04:12:25,960 --> 04:12:28,560 ANTIBODY THEY TESTED THAT HAD 5446 04:12:28,560 --> 04:12:30,800 THE BEST LITEDDIC ACTIVITY AMONG 5447 04:12:30,800 --> 04:12:33,760 BNABS SCREENED. 5448 04:12:33,760 --> 04:12:35,080 I WON'T SAY MUCH ABOUT 5449 04:12:35,080 --> 04:12:37,400 BIOLOGICAL CONCLUSIONS ABOUT THE 5450 04:12:37,400 --> 04:12:39,440 PASSIVE EPIFUSION STUDY. 5451 04:12:39,440 --> 04:12:41,120 BUT -- INFUSION STUDY THAT ANN 5452 04:12:41,120 --> 04:12:42,360 AND I CONDUCTED BECAUSE IT WAS 5453 04:12:42,360 --> 04:12:43,600 PUBLISHED EARLIER THIS YEAR, BUT 5454 04:12:43,600 --> 04:12:47,440 WE COMPARED WILD TYPE FUNCTIONAL 5455 04:12:47,440 --> 04:12:49,920 KNOCK OUT AND ENHANCED VARIANT 5456 04:12:49,920 --> 04:12:51,280 INFUSE TO ANIMALS AND CHALLENGE 5457 04:12:51,280 --> 04:12:53,920 WITH SINGLE HIGH DOSE VIRUS AND 5458 04:12:53,920 --> 04:12:55,960 THIS EXPERIMENT SHOWED THAT 5459 04:12:55,960 --> 04:12:57,680 EFFECTOR FUNCTION LIKELY 5460 04:12:57,680 --> 04:12:59,000 PHAGOCYTOSIS CONTRIBUTED TO 5461 04:12:59,000 --> 04:13:01,600 REDUCED SET POINT VIRAL LOADS. 5462 04:13:01,600 --> 04:13:03,040 BUT INSTEAD I WOULD LIKE TO 5463 04:13:03,040 --> 04:13:04,800 FOCUS ON SOME OF THE OTHER 5464 04:13:04,800 --> 04:13:08,240 LESSONS THAT WE LEARNED. 5465 04:13:08,240 --> 04:13:10,120 AND THAT TRANSFER TO OTHER 5466 04:13:10,120 --> 04:13:11,640 STUDIES WHICH WERE THE ANTIBODY 5467 04:13:11,640 --> 04:13:16,240 VARIANTS SHOWED PRETTY DIVERGENT 5468 04:13:16,240 --> 04:13:20,800 PK PROFILES SO CHANGING FC IS 5469 04:13:20,800 --> 04:13:23,520 NOT NEUTRAL TO PLASMA HALF LIFE 5470 04:13:23,520 --> 04:13:25,280 AND BIODISTRIBUTION SO THE KNOCK 5471 04:13:25,280 --> 04:13:27,400 OUT SHOWED GREATER SERUM 5472 04:13:27,400 --> 04:13:29,320 PERSISTENCE WHICH IS SOMETHING 5473 04:13:29,320 --> 04:13:32,080 OBSERVED BEFORE AND THE FC 5474 04:13:32,080 --> 04:13:33,760 RECEPTOR AND COMPLIMENT BINDING 5475 04:13:33,760 --> 04:13:35,840 ENHANCED VARIANT SHOWED 5476 04:13:35,840 --> 04:13:36,640 ACCELERATED CLEARANCE. 5477 04:13:36,640 --> 04:13:38,680 BUT BECAUSE THE ANIMALS IN THIS 5478 04:13:38,680 --> 04:13:40,640 STUDY WERE INFECTED COMPARISON 5479 04:13:40,640 --> 04:13:45,080 AMONG ANTIBODY TREATMENT GROUPS 5480 04:13:45,080 --> 04:13:45,600 WAS DIFFICULT. 5481 04:13:45,600 --> 04:13:48,680 SO THIS MADE US HEAVY SIT OTHER 5482 04:13:48,680 --> 04:13:57,400 VARIANTS HOVARIANTS WE RETESTED, DRIVEN BY 5483 04:13:57,400 --> 04:14:00,320 WILD TYPE 101-0374 AT LEFT AND 5484 04:14:00,320 --> 04:14:03,560 THREE ENHANCED MUTANTS, Y 300D 5485 04:14:03,560 --> 04:14:10,520 AND E 345R ON THE RIGHT. 5486 04:14:10,520 --> 04:14:15,560 WE RECAPITULATED OLIVER'S 5487 04:14:15,560 --> 04:14:16,880 COMPLIMENT AT COMPLIMENT AND CAN 5488 04:14:16,880 --> 04:14:19,320 DO BETTER IN CONTAINING 5489 04:14:19,320 --> 04:14:20,640 COMPLIMENT AND ENHANCING 5490 04:14:20,640 --> 04:14:23,920 MUTATION LIKE FTAE AND OTHERS. 5491 04:14:23,920 --> 04:14:28,360 BUT EACH OF THESE MUTATIONS WE 5492 04:14:28,360 --> 04:14:30,800 KNEW OR EXPECTED TO HAVE PK 5493 04:14:30,800 --> 04:14:32,160 PROBLEMS SO WE EXCLUDED FROM 5494 04:14:32,160 --> 04:14:32,680 CONSIDERATION. 5495 04:14:32,680 --> 04:14:35,480 SO THAT LEFT US WITH THE E 435G 5496 04:14:35,480 --> 04:14:36,400 MUTATION. 5497 04:14:36,400 --> 04:14:39,520 WHICH WAS ORIGINALLY DESCRIBED 5498 04:14:39,520 --> 04:14:41,560 BY DEJONG. 5499 04:14:41,560 --> 04:14:43,320 THAT DOESN'T CLANG THE INHERENT 5500 04:14:43,320 --> 04:14:46,040 ATIN -- CHANGE THE INHERENT 5501 04:14:46,040 --> 04:14:48,800 AFFINITY FOR THE C 1Q HEAD BUT 5502 04:14:48,800 --> 04:14:52,320 ALTERS IGG HEXAMERRIZATION 5503 04:14:52,320 --> 04:14:54,680 PROPENSITY BUT NOT IN SOLUTION. 5504 04:14:54,680 --> 04:14:57,080 THIS IS THE TIERRY BEHIND 5505 04:14:57,080 --> 04:15:00,160 ANTIBODIES, IT TAKES BINDING TO 5506 04:15:00,160 --> 04:15:02,160 ANTIGEN AND A CERTAIN EFFECTIVE 5507 04:15:02,160 --> 04:15:06,280 LOCAL CONCENTRATION THEN IT WILL 5508 04:15:06,280 --> 04:15:08,200 FAVOR HEXAMERRIZATION OF THE FC 5509 04:15:08,200 --> 04:15:08,800 DOMAIN. 5510 04:15:08,800 --> 04:15:10,880 AND POTENTIATED INTERACTION WITH 5511 04:15:10,880 --> 04:15:12,680 C 1Q AND COMPLIMENT DEPOSITION. 5512 04:15:12,680 --> 04:15:15,840 SO DEFINITELY OLDER AND LIKE 5513 04:15:15,840 --> 04:15:16,440 DEBATEICALLY WISER BECAUSE WE 5514 04:15:16,440 --> 04:15:18,720 WERE WORKING WITH COMPLIMENT 5515 04:15:18,720 --> 04:15:23,640 FROM OUR PRIOR STUDIES IN B 12 5516 04:15:23,640 --> 04:15:25,720 AND 10 BEFORE, WE DESIGNED AN 5517 04:15:25,720 --> 04:15:28,720 EXPERIMENT WHICH ANIMALS WERE 5518 04:15:28,720 --> 04:15:31,600 TREATED THREE DAYS PRIOR TO 5519 04:15:31,600 --> 04:15:35,200 CHALLENGE WITH FOUR MGS PER KG 5520 04:15:35,200 --> 04:15:37,360 OF 101074 WILE TYPE KNOCK OUT 5521 04:15:37,360 --> 04:15:40,200 AND COMPLIMENT ENHANCED VARIANTS 5522 04:15:40,200 --> 04:15:41,000 SUB Q. 5523 04:15:41,000 --> 04:15:44,400 PRIOR TO REPEATED LOW DOSE 5524 04:15:44,400 --> 04:15:46,960 CHALLENGE COMPRISED OF WEEKLY 5525 04:15:46,960 --> 04:15:49,520 INTERRECTAL EXPOSURE TO 30 CIB 5526 04:15:49,520 --> 04:15:54,800 50s OF SHIV SF 162 P 3. 5527 04:15:54,800 --> 04:15:56,200 THIS WAS THE RESULT. 5528 04:15:56,200 --> 04:15:58,000 SO OUR ENHANCED VARIANT DID 5529 04:15:58,000 --> 04:16:00,200 BETTER THAN THE ISOTYPE CONTROL, 5530 04:16:00,200 --> 04:16:02,120 IT WAS A NEUTRALIZING ANTIBODY 5531 04:16:02,120 --> 04:16:04,600 AFTER ALL. 5532 04:16:04,600 --> 04:16:06,400 RECEIVE BUT LESS WELL THAN 5533 04:16:06,400 --> 04:16:07,800 EITHER WILD TYPE OR COMPLIMENT 5534 04:16:07,800 --> 04:16:08,680 KNOCK OUT KA FORM. 5535 04:16:08,680 --> 04:16:11,800 WHICH HAD LARGELY OVERLAPPING 5536 04:16:11,800 --> 04:16:14,000 KAPLAN MIRE CURVES SO ON ITS 5537 04:16:14,000 --> 04:16:16,360 FACE THIS RESULT SUGGESTS THAT 5538 04:16:16,360 --> 04:16:18,160 NOT DID ENHANCING COMPLIMENT 5539 04:16:18,160 --> 04:16:20,240 ACTIVITY OFFER NO BENEFIT, 5540 04:16:20,240 --> 04:16:22,200 ELIMINATING IT HAD NO EFFECT. 5541 04:16:22,200 --> 04:16:28,200 , IT WASN'T CONTRIBUTING. 5542 04:16:28,200 --> 04:16:32,520 DESPITE THIS BEING BEST MUTATION 5543 04:16:32,520 --> 04:16:33,360 ANTI-BODY ENGINEERING HAD TO 5544 04:16:33,360 --> 04:16:34,720 OFFER US IN IN TERMS OF 5545 04:16:34,720 --> 04:16:36,720 ENHANCING ACTIVITY, WE HAD THE 5546 04:16:36,720 --> 04:16:41,320 STICKY PROBLEM OF VARIABLE PK. 5547 04:16:41,320 --> 04:16:43,280 AND THE PEAK CONCENTRATION OF 5548 04:16:43,280 --> 04:16:45,280 OUR COMPLIMENT ENHANCED EG 5549 04:16:45,280 --> 04:16:47,680 VARIANT WAS LOWER AND CLEARANCE 5550 04:16:47,680 --> 04:16:51,200 ELIMINATION OF EG WAS FASTER 5551 04:16:51,200 --> 04:16:52,400 THAN EITHER WILD TYPE OR KA 5552 04:16:52,400 --> 04:16:53,080 KNOCK OUT MUTANT. 5553 04:16:53,080 --> 04:16:56,200 YOU CAN SEE THAT THE TIME POINT 5554 04:16:56,200 --> 04:16:58,320 WHICH EACH ANTI-BITTY 5555 04:16:58,320 --> 04:17:00,840 CONCENTRATION DROPPED BELOW THE 5556 04:17:00,840 --> 04:17:03,200 PER ML VARIED CONSIDERABLY 5557 04:17:03,200 --> 04:17:06,200 ACROSS THE PANEL. 5558 04:17:06,200 --> 04:17:08,200 SO THIS WAS DISAPPOINTING 5559 04:17:08,200 --> 04:17:09,640 OUTCOME. 5560 04:17:09,640 --> 04:17:12,320 THIS IS LIKE A REAL GOLDBURG 5561 04:17:12,320 --> 04:17:13,200 DESIGN EXPERIMENT TO COME UP 5562 04:17:13,200 --> 04:17:16,560 WITH A CONCLUSION THAT ANTIBODY 5563 04:17:16,560 --> 04:17:19,760 DOSE AT TIME OF CHALLENGE 5564 04:17:19,760 --> 04:17:21,440 MATTERS. 5565 04:17:21,440 --> 04:17:25,880 WE WONDERS WHAT CAN WE LEARN? 5566 04:17:25,880 --> 04:17:26,720 FROM THIS EXPERIMENT? 5567 04:17:26,720 --> 04:17:28,320 WE WANTED TO CONSIDER IF THERE 5568 04:17:28,320 --> 04:17:29,680 WAS ALTERNATIVE WAY OF ANALYZING 5569 04:17:29,680 --> 04:17:31,240 THIS EXPERIMENTAL DATA THAT 5570 04:17:31,240 --> 04:17:32,680 WOULD BETTER ACCOUNT FOR THE 5571 04:17:32,680 --> 04:17:35,880 EFFECT OF VARIABLE PK FOR THESE 5572 04:17:35,880 --> 04:17:37,400 FC MODIFIED ANTI-BODIES. 5573 04:17:37,400 --> 04:17:39,600 SO FOR THAT WE LOOK TO WORK 5574 04:17:39,600 --> 04:17:43,880 COMING OUT OF THE VRC AND SOME 5575 04:17:43,880 --> 04:17:48,000 ARE PAGU'S WORK WHICH CAP PLAN 5576 04:17:48,000 --> 04:17:50,400 MIRE CURVES MODIFY TO REPORT THE 5577 04:17:50,400 --> 04:17:53,320 LEVEL OF ANTIBODY NEUTRALIZATION 5578 04:17:53,320 --> 04:17:55,320 ACTIVITY AND ITS RELATIONSHIP TO 5579 04:17:55,320 --> 04:17:56,920 LEVEL PROTECTION. 5580 04:17:56,920 --> 04:17:59,200 SO BY DOING THIS ANALYSIS YOU 5581 04:17:59,200 --> 04:18:03,440 CAN ARRIVE AT IN VIVO EC 50 5582 04:18:03,440 --> 04:18:04,600 NEUTRALIZATION ACTIVITY. 5583 04:18:04,600 --> 04:18:08,400 SO FOR THIS PARTICULAR VIRUS, IT 5584 04:18:08,400 --> 04:18:09,960 IS MORE SENSITIVE TO THE 5585 04:18:09,960 --> 04:18:13,640 SPECIFIC MAB THAN CD4 BINDING 5586 04:18:13,640 --> 04:18:16,800 SITE OR V 1 V 2 MAB, YOU CAN SEE 5587 04:18:16,800 --> 04:18:18,280 THE LEFT SHIFT OF THE CURVE, IT 5588 04:18:18,280 --> 04:18:21,200 TAKES LOWER IN VITRO NEW TITER 5589 04:18:21,200 --> 04:18:24,600 TO PROTECT HALF THE ANIMALS WITH 5590 04:18:24,600 --> 04:18:27,720 THAT HOE WITH SPECIFIC MABS THAN 5591 04:18:27,720 --> 04:18:29,960 CD4 OR V 1 V 2. 5592 04:18:29,960 --> 04:18:31,320 WE THOUGHT IF YOU COMPARE 5593 04:18:31,320 --> 04:18:33,120 ANTIBODIES WITH DIFFERENT 5594 04:18:33,120 --> 04:18:34,480 SPECIFICITIES IN THIS WAY 5595 04:18:34,480 --> 04:18:36,400 COMPARE THE SAME SPECIFICITY BUT 5596 04:18:36,400 --> 04:18:38,320 WITH DIFFERENT FC MODIFICATIONS. 5597 04:18:38,320 --> 04:18:41,480 SO RELATING THE LEVEL OF 5598 04:18:41,480 --> 04:18:43,280 PROTECTION, OBSERVED, DIRECTLY 5599 04:18:43,280 --> 04:18:46,880 TO THE LEVEL OF ANTIBODY 5600 04:18:46,880 --> 04:18:47,800 REQUIRED. 5601 04:18:47,800 --> 04:18:51,800 SO IF WE DO THAT, FOR THE 101074 5602 04:18:51,800 --> 04:18:55,040 DATA SET AND PLOT CONCENTRATION 5603 04:18:55,040 --> 04:18:57,080 OF ANTIBODY PRESENT AT TIME OF 5604 04:18:57,080 --> 04:18:59,040 BREAK THROUGH, IN THE ANIMALS 5605 04:18:59,040 --> 04:19:01,240 TREATED WITH EACH ANTIBODY, WE 5606 04:19:01,240 --> 04:19:02,640 WOULD COME -- WE MIGHT COME TO A 5607 04:19:02,640 --> 04:19:05,400 VERY DIFFERENT CONCLUSION. 5608 04:19:05,400 --> 04:19:08,120 SO AS MEDIAN CONCENTRATION OF 5609 04:19:08,120 --> 04:19:10,200 BNAB PRESENT AT TIME OF 5610 04:19:10,200 --> 04:19:12,880 INFECTION WAS .6 MICROGRAMS PER 5611 04:19:12,880 --> 04:19:14,560 ML WILD TYPE IT WAS THREE TIMES 5612 04:19:14,560 --> 04:19:17,200 LOWER THAN THAT FOR THE EG 5613 04:19:17,200 --> 04:19:18,920 COMPLIMENT ENHANCED VARIANT. 5614 04:19:18,920 --> 04:19:21,120 IT WAS TWO TIMES HIGHER FOR THE 5615 04:19:21,120 --> 04:19:24,400 KNOCK OUT VARIANT. 5616 04:19:24,400 --> 04:19:26,240 SO WHY WOULD NOT SURE WE CAN 5617 04:19:26,240 --> 04:19:28,400 EXCLUDE THE EFFECTIVE SYSTEMATIC 5618 04:19:28,400 --> 04:19:30,800 BIASES IN ALTERED PK FROM 5619 04:19:30,800 --> 04:19:34,600 IMPACTING THIS ANALYSIS, I THINK 5620 04:19:34,600 --> 04:19:36,680 IT DOES SUGGEST FIRST COMPLIMENT 5621 04:19:36,680 --> 04:19:39,160 MAY PLAY A ROLE IN 101074 5622 04:19:39,160 --> 04:19:41,640 MECHANISM OF ACTION, AND THAT 5623 04:19:41,640 --> 04:19:43,960 THIS ACTIVITY MIGHT BE ABLE TO 5624 04:19:43,960 --> 04:19:45,960 BE ENHANCED IN VIVO THROUGH 5625 04:19:45,960 --> 04:19:47,800 ANTIBODY ENGINEERING. 5626 04:19:47,800 --> 04:19:51,040 OF COURSE ALTERED PK IS A REAL 5627 04:19:51,040 --> 04:19:53,200 PROBLEM IN CLINICAL TRANSLATION 5628 04:19:53,200 --> 04:19:55,640 OF ANY OF THESE INSIGHTS. 5629 04:19:55,640 --> 04:19:57,840 SO IN CONCLUSION I STILL THINK 5630 04:19:57,840 --> 04:20:00,200 COMPLIMENT IS TRICKY AND IF 5631 04:20:00,200 --> 04:20:02,480 MARJORIE HAD ANOTHER CAREER TO 5632 04:20:02,480 --> 04:20:05,280 INVEST IN THIS SPACE MAYBE CHECK 5633 04:20:05,280 --> 04:20:06,600 FIGURE IT OUT. 5634 04:20:06,600 --> 04:20:08,400 PK DIFFERENCES ARE CONFOUNDER 5635 04:20:08,400 --> 04:20:09,480 TRYING TO UNDERSTAND MECHANISM 5636 04:20:09,480 --> 04:20:12,240 OF ACTION USING ANTIBODY 5637 04:20:12,240 --> 04:20:12,600 MUTATIONS. 5638 04:20:12,600 --> 04:20:13,960 WHETHER NAY ARE SINGLE HIGH DOSE 5639 04:20:13,960 --> 04:20:16,800 OR REPEAT LOW DOSE CHALLENGE 5640 04:20:16,800 --> 04:20:18,800 MODELS, BUT I THINK IT IS STILL 5641 04:20:18,800 --> 04:20:20,920 IMPORTANT TO USE THE NHP MODEL 5642 04:20:20,920 --> 04:20:22,080 TO DO THIS. 5643 04:20:22,080 --> 04:20:23,200 AND WE THINK GIVEN THE 5644 04:20:23,200 --> 04:20:24,200 COLLECTION OF STUDIES THAT HAVE 5645 04:20:24,200 --> 04:20:26,960 BEEN REPORTED TO DATE, THE 5646 04:20:26,960 --> 04:20:28,200 MECHANISMS OF ACTION OF 5647 04:20:28,200 --> 04:20:30,600 DIFFERENT BNABs ARE GOING TO 5648 04:20:30,600 --> 04:20:31,600 DIFFER. 5649 04:20:31,600 --> 04:20:33,520 SO WE WOULD WANT TO LOOK AT 5650 04:20:33,520 --> 04:20:36,680 THESE KINDS OF ANALYSES IN THE 5651 04:20:36,680 --> 04:20:38,600 CONTEXT OF ALL CLINICALLY 5652 04:20:38,600 --> 04:20:42,400 RELEVANT BNABs. 5653 04:20:42,400 --> 04:20:44,560 WITH THAT I WANT TO THANK BEN 5654 04:20:44,560 --> 04:20:48,560 THE Ph.D. STUDENT IN THE 5655 04:20:48,560 --> 04:20:50,480 GROUP, DEFENDING I THINK TWO 5656 04:20:50,480 --> 04:20:52,160 WEEKS FROM TODAY IN THIS 5657 04:20:52,160 --> 04:20:54,640 HALLOWEEN PHOTO OF THE LAB HE IS 5658 04:20:54,640 --> 04:20:57,120 HIDING IN THIS RED SUIT. 5659 04:20:57,120 --> 04:20:58,880 WHEN I WENT TO LOOK FOR A BETTER 5660 04:20:58,880 --> 04:21:02,680 PHOTO I FOUND THIS ONE OF HIM 5661 04:21:02,680 --> 04:21:05,000 HIDING FROM MONEY. 5662 04:21:05,000 --> 04:21:06,320 BEN HAS BEEN RESPONSIBLE REALLY 5663 04:21:06,320 --> 04:21:09,160 FOR ALL OF OUR WORK MANY THE 5664 04:21:09,160 --> 04:21:11,800 CONTEXT OF MABS AND COMPLIMENT, 5665 04:21:11,800 --> 04:21:13,680 HE DIDN'T DO THE WORK ALONE, IT 5666 04:21:13,680 --> 04:21:16,880 IS THE RESULT OF A LONG STANDING 5667 04:21:16,880 --> 04:21:19,200 COLLABORATION WITH ANN AT HSU 5668 04:21:19,200 --> 04:21:21,280 AND FORMER POST DOC DAVID 5669 04:21:21,280 --> 04:21:23,280 SPENCER AND EARLIER WORK 5670 04:21:23,280 --> 04:21:24,320 MOTIVATING THIS FOLLOW-UP IN 5671 04:21:24,320 --> 04:21:26,960 TERMS OF CORRELATES OBSERVED IN 5672 04:21:26,960 --> 04:21:29,720 VACCINE STUDIES, REALLY CAME 5673 04:21:29,720 --> 04:21:32,000 FROM THE FLSC VACCINE GEORGE 5674 04:21:32,000 --> 04:21:33,800 TALKED ABOUT AND AS WELL AS SOME 5675 04:21:33,800 --> 04:21:37,600 OF MARJORIE'S OBSERVATIONS. 5676 04:21:37,600 --> 04:21:39,360 AND SO I WANTED TO THANK 5677 04:21:39,360 --> 04:21:42,320 MARJORIE FOR THAT OPPORTUNITY TO 5678 04:21:42,320 --> 04:21:42,880 COLLABORATE. 5679 04:21:42,880 --> 04:21:45,000 ON THAT STUDY AND ALSO FOR 5680 04:21:45,000 --> 04:21:46,240 SENDING YOUR FANTASTIC TRAINEES 5681 04:21:46,240 --> 04:21:47,720 OUT INTO THE WORLD, IT'S BEEN 5682 04:21:47,720 --> 04:21:49,200 GREAT TO HEAR FROM SOME OF THEM 5683 04:21:49,200 --> 04:21:50,440 TODAY. 5684 04:21:50,440 --> 04:21:51,360 THANK YOU. 5685 04:21:51,360 --> 04:22:00,920 [APPLAUSE] 5686 04:22:00,920 --> 04:22:05,600 >> SO VERY INTERESTING OBVIOUSLY 5687 04:22:05,600 --> 04:22:09,000 COMPLEX AS YOU SAID STUDY. 5688 04:22:09,000 --> 04:22:12,960 MAYBE I MISSED IT BUT DID YOU 5689 04:22:12,960 --> 04:22:16,280 LOOK AT DIFFERENCES BETWEEN FC 5690 04:22:16,280 --> 04:22:19,600 GAMMA R 1 R 2 AND R 3 AS IN THE 5691 04:22:19,600 --> 04:22:21,400 WORK OF JEFF RAVAGE WHERE 5692 04:22:21,400 --> 04:22:22,880 OBVIOUSLY THOSE FUNCTIONS ARE 5693 04:22:22,880 --> 04:22:24,400 DIFFERENT AND THAT COULD PLAY A 5694 04:22:24,400 --> 04:22:24,600 ROLE? 5695 04:22:24,600 --> 04:22:26,440 >> SO FOR EACH OF THE PASSIVE 5696 04:22:26,440 --> 04:22:27,440 TRANSFER EXPERIMENTS WE HAVE 5697 04:22:27,440 --> 04:22:29,240 DONE WE HAVE ALSO LOOKED AT 5698 04:22:29,240 --> 04:22:33,520 FINDING AFFINITY OF THE VARIANTS 5699 04:22:33,520 --> 04:22:36,200 TO FC GAMMA Rs AND FCRN. 5700 04:22:36,200 --> 04:22:39,280 SOME WE TRANSFERRED ANTIBODIES 5701 04:22:39,280 --> 04:22:42,000 THAT HAD ENHANCEMENTS TO BOTH FC 5702 04:22:42,000 --> 04:22:44,040 GAMNA RES AND C 1Q IN THE 5703 04:22:44,040 --> 04:22:45,280 PUBLISHED STUDY, I DIDN'T TALK 5704 04:22:45,280 --> 04:22:49,200 ABOUT AS MUCH TODAY. 5705 04:22:49,200 --> 04:22:52,400 WITH EG MUTANT, THE BINDING TO 5706 04:22:52,400 --> 04:22:54,600 FC GAMMAR IS NOT SUBSTANTIALLY 5707 04:22:54,600 --> 04:22:54,880 IMPACTED. 5708 04:22:54,880 --> 04:22:58,600 BUT I THINK THIS IS AN IMPORTANT 5709 04:22:58,600 --> 04:22:59,840 -- AN IMPORTANT TO THINK ABOUT 5710 04:22:59,840 --> 04:23:00,200 THIS. 5711 04:23:00,200 --> 04:23:02,200 WHERE PEOPLE HAVE SEEN ANTIBODY 5712 04:23:02,200 --> 04:23:04,200 ENGINEERING ENHANCE OR FC 5713 04:23:04,200 --> 04:23:06,440 ENGINEERING ENHANCE PROTECTION 5714 04:23:06,440 --> 04:23:08,600 IN ANIMAL MODELS IT HAS BEEN IN 5715 04:23:08,600 --> 04:23:09,080 MICE. 5716 04:23:09,080 --> 04:23:11,880 PEOPLE HAVE NOT SEEN THAT HAPPEN 5717 04:23:11,880 --> 04:23:14,520 IN THE NHP MODEL THOUGH THE SAME 5718 04:23:14,520 --> 04:23:19,320 -- SO PGG 121 IN PUBLICATIONS 5719 04:23:19,320 --> 04:23:21,360 YOU CAN ENHANCE ITS PROTECTIVE 5720 04:23:21,360 --> 04:23:23,360 CAPACITY IN VIVO IN MICE WHEN 5721 04:23:23,360 --> 04:23:24,880 PEOPLE HAVE LOOKED AT THIS IN 5722 04:23:24,880 --> 04:23:26,400 THE NON-HUMAN PRIMATE MODEL 5723 04:23:26,400 --> 04:23:28,400 MULTIPLE LABS THEY DON'T -- THEY 5724 04:23:28,400 --> 04:23:30,280 HAVEN'T SEEN A ROLE. 5725 04:23:30,280 --> 04:23:33,200 I THINK THE EXPERIMENTS DONE 5726 04:23:33,200 --> 04:23:35,920 LOOKING AT OTHER FC RECEPTOR 5727 04:23:35,920 --> 04:23:37,960 BINDING ENHANCED ANTIBODIES THEY 5728 04:23:37,960 --> 04:23:39,920 HAVE ALSO NOT PANNED OUT IN VIVO 5729 04:23:39,920 --> 04:23:42,080 IN THE NON-HUMAN PRIMATE MODEL. 5730 04:23:42,080 --> 04:23:43,520 THAT MAY BE BECAUSE OF 5731 04:23:43,520 --> 04:23:45,360 CHALLENGES RELATED TO LIKE 5732 04:23:45,360 --> 04:23:46,440 FUNDAMENTALLY TO CHALLENGES 5733 04:23:46,440 --> 04:23:47,720 RELATED IN PC. 5734 04:23:47,720 --> 04:23:49,920 SO I THINK IT WOULD BE REALLY 5735 04:23:49,920 --> 04:23:51,960 INTERESTING TO HEAVY SIT THOSE 5736 04:23:51,960 --> 04:23:57,640 EXPERIMENTS -- RE-VISIT THOSE 5737 04:23:57,640 --> 04:23:59,280 EXPERIMENTS FOR UNDERSTANDING 5738 04:23:59,280 --> 04:24:01,600 THE CONCENTRATION ON BOARD BNAB 5739 04:24:01,600 --> 04:24:02,840 INFECTION TO SEE IF THERE IS 5740 04:24:02,840 --> 04:24:04,800 MORE EVIDENCE THIS IS POSSIBLE 5741 04:24:04,800 --> 04:24:07,240 IN NON-HUMAN PRY MATES. 5742 04:24:07,240 --> 04:24:10,880 -- PRIMATES. 5743 04:24:10,880 --> 04:24:13,960 >>WE ARE IN THE LAST SESSION 5744 04:24:13,960 --> 04:24:16,760 HERE ON SEX BIAS AND MICROBE 5745 04:24:16,760 --> 04:24:20,840 SIDES, I WOULD LIKE THE FIRST 5746 04:24:20,840 --> 04:24:24,680 INTRODUCE ISKRA TUERO, FORMER 5747 04:24:24,680 --> 04:24:28,680 POST DOC WITH MARJORIE, NOW 5748 04:24:28,680 --> 04:24:33,200 ASSOCIATE PROFESSOR IN LIMA, 5749 04:24:33,200 --> 04:24:45,240 PERU. 5750 04:24:45,240 --> 04:24:47,920 >> GOOD AFTERNOON, EVERYONE. 5751 04:24:47,920 --> 04:24:49,280 SO FIRST I WANT TO THANK THE 5752 04:24:49,280 --> 04:24:51,680 ORGANIZER FOR INVITING ME. 5753 04:24:51,680 --> 04:24:54,120 I'M REALLY HONORED TO BE HERE 5754 04:24:54,120 --> 04:24:56,600 FOR THIS VERY SPECIAL OCCASION. 5755 04:24:56,600 --> 04:25:00,000 THE TITLE OF MY TALK IS SEX 5756 04:25:00,000 --> 04:25:01,680 DIFFERENCE TO BE CONSIDERED IN 5757 04:25:01,680 --> 04:25:07,040 THE DESIGN OF HIV VACCINES. 5758 04:25:07,040 --> 04:25:11,120 MY NAME IS ISKRA TUERO. 5759 04:25:11,120 --> 04:25:14,000 I WAS POST DOC AT DR. 5760 04:25:14,000 --> 04:25:16,800 (INAUDIBLE) LAB FROM 2011 TO 5761 04:25:16,800 --> 04:25:24,040 2016 AND I'M PROFESSOR AT 5762 04:25:24,040 --> 04:25:28,200 UNIVERSIDAD PERUANA CAYETANO 5763 04:25:28,200 --> 04:25:30,800 HEREDIA IN PERU. 5764 04:25:30,800 --> 04:25:36,280 IT IS WELL KNOWN THE SEX HORMONE 5765 04:25:36,280 --> 04:25:40,040 IMMUNE RESPONSE THROUGH SPECIFIC 5766 04:25:40,040 --> 04:25:43,320 RECEPTOR EXPRESS IN IMMUNOCELLS, 5767 04:25:43,320 --> 04:25:45,040 THE MECHANISM IS MODULATED BY 5768 04:25:45,040 --> 04:25:46,920 THE SEX HORMONE BY IMPACT THE 5769 04:25:46,920 --> 04:25:50,760 VACCINE OUTCOME AND THIS -- 5770 04:25:50,760 --> 04:25:53,960 MIGHT DEFINE THE SEX DIFFERENCE. 5771 04:25:53,960 --> 04:25:58,360 BUT THE SORRY I WILL TELL YOU 5772 04:25:58,360 --> 04:26:01,840 NOW WASN'T REALLY INTENDED TO 5773 04:26:01,840 --> 04:26:08,960 ELEVATE SEX DIFFERENCE. 5774 04:26:08,960 --> 04:26:11,840 SO THIS IS -- WITH THIS PAPER, 5775 04:26:11,840 --> 04:26:16,280 WHICH WE DEMONSTRATE FOR THE 5776 04:26:16,280 --> 04:26:18,240 FIRST TIME THAT EFFICACY SHARED 5777 04:26:18,240 --> 04:26:21,840 IN VACCINATED FEMALES IN MALES 5778 04:26:21,840 --> 04:26:26,480 VERSUS MACAQUE, THIS PAPER WAS 5779 04:26:26,480 --> 04:26:35,000 PUBLISHED IN 2016. 5780 04:26:35,000 --> 04:26:41,080 FOR THIS STUDY WE FOLLOW 5781 04:26:41,080 --> 04:26:44,200 CHALLENGE THE INITIAL AIM FOR 5782 04:26:44,200 --> 04:26:50,320 THIS STUDY IS THE GP 140 5783 04:26:50,320 --> 04:26:51,280 MONOMERIC -- SO THE RATIONALE 5784 04:26:51,280 --> 04:26:56,080 FOR THIS STUDY THAT GP 1 FOR COB 5785 04:26:56,080 --> 04:27:00,840 SERVE CONFIRMATIONAL EPITOPES 5786 04:27:00,840 --> 04:27:04,080 THAT MAYBE MORE PROMISING TO 5787 04:27:04,080 --> 04:27:05,720 INDUCE BROAD NEUTRALIZING 5788 04:27:05,720 --> 04:27:08,160 ANTIBODY BETTER THAN THE 5789 04:27:08,160 --> 04:27:15,160 MONOMERIC GP 120. 5790 04:27:15,160 --> 04:27:21,680 SO WE PRIME OR ANIMAL WITH THE 5791 04:27:21,680 --> 04:27:24,360 ADENOVIRUS EXPRESS IN DIFFERENT 5792 04:27:24,360 --> 04:27:27,680 RECOMBINANT PROTEIN FOLLOWED BY 5793 04:27:27,680 --> 04:27:32,400 CORRESPONDING GP 120 OR GP 140 5794 04:27:32,400 --> 04:27:33,400 TO FINALLY BE CHALLENGE 5795 04:27:33,400 --> 04:27:37,360 REPETITIVE LOW DOSE OF SIV 5796 04:27:37,360 --> 04:27:39,480 MAPPED 251. 5797 04:27:39,480 --> 04:27:42,680 SO IN THE FIRST ANALYSIS WE 5798 04:27:42,680 --> 04:27:44,160 FOUND SOME DIFFERENCE BETWEEN 5799 04:27:44,160 --> 04:27:49,080 TWO GROUPS GP 120 AND GP 140. 5800 04:27:49,080 --> 04:27:51,920 OTHERS SUGGEST MAYBE SHE IS -- 5801 04:27:51,920 --> 04:27:56,640 SHE DID SOMEONE LIKE THIS 5802 04:27:56,640 --> 04:27:57,040 BEFORE. 5803 04:27:57,040 --> 04:27:59,040 BY SEX COMPARE FEMALES WITH 5804 04:27:59,040 --> 04:28:02,160 MALE, AND THAT'S THE RESULT I 5805 04:28:02,160 --> 04:28:07,040 WOULD PRESENT NOW. 5806 04:28:07,040 --> 04:28:10,040 SO ALL ANIMAL -- NOT ALL, ONLY 5807 04:28:10,040 --> 04:28:11,920 ONE FEMALE DIDN'T GET INFECTED, 5808 04:28:11,920 --> 04:28:14,880 SO HERE YOU CAN SEE THE VIRAL 5809 04:28:14,880 --> 04:28:16,880 LOAD IN THE DIFFERENT 5810 04:28:16,880 --> 04:28:17,480 IMMUNIZATION GROUPS. 5811 04:28:17,480 --> 04:28:21,640 YOU CAN SEE THAT VACCINATED 5812 04:28:21,640 --> 04:28:23,840 FEMALES EXHIBITED SIMILAR FOR 5813 04:28:23,840 --> 04:28:26,280 THE DIFFERENT IMMUNIZATION 5814 04:28:26,280 --> 04:28:28,640 GROUP. 5815 04:28:28,640 --> 04:28:31,480 HOWEVER, WHEN WE PERFORM 5816 04:28:31,480 --> 04:28:33,400 ANALYSES TO SEE RATE OF A AND B 5817 04:28:33,400 --> 04:28:43,920 INFECTION AMONG FEMALES OR MALES 5818 04:28:43,920 --> 04:28:49,440 MALES, HERE IS THE RESULT. 5819 04:28:49,440 --> 04:28:51,560 WHEN WE ANALYZE ALL 5820 04:28:51,560 --> 04:28:52,280 IMMUNORECOGNIZE FEMALE COMPARED 5821 04:28:52,280 --> 04:28:55,560 TO CONTROL FEMALE YOU CAN SEE 5822 04:28:55,560 --> 04:28:57,640 STATISTICALLY SIGNIFICANT 5823 04:28:57,640 --> 04:29:02,240 DIFFERENCE IN THE SIV 5824 04:29:02,240 --> 04:29:03,480 (INAUDIBLE) SO FEMALES REQUIRE 5825 04:29:03,480 --> 04:29:05,200 MORE CHALLENGE TO BECOME 5826 04:29:05,200 --> 04:29:11,600 INFECTED COMPARED TO TH TO IMMUNIZE 5827 04:29:11,600 --> 04:29:11,960 MALE. 5828 04:29:11,960 --> 04:29:14,080 SO WE ANALYZE DIFFERENCE IN 5829 04:29:14,080 --> 04:29:17,880 IMMUNE RESPONSE FOCUS ANTIBODY 5830 04:29:17,880 --> 04:29:19,600 RESPONSE. 5831 04:29:19,600 --> 04:29:21,320 SO HERE AS A RESULT REGARDING 5832 04:29:21,320 --> 04:29:26,200 THE IMMUNIZATION GROUP, YOU CAN 5833 04:29:26,200 --> 04:29:27,720 SEE ALSO DIFFERENCE IN THE SIV 5834 04:29:27,720 --> 04:29:29,760 APPLICATION MANY THE GROUP GP 5835 04:29:29,760 --> 04:29:32,360 120 VERY SIGNIFICANT FOR THE 5836 04:29:32,360 --> 04:29:34,680 FEMALES BOTH OF THE CONTROLS BUT 5837 04:29:34,680 --> 04:29:38,480 IMAGINE THAT IN GROUP GP 140 5838 04:29:38,480 --> 04:29:39,080 IMMUNIZE FEMALE. 5839 04:29:39,080 --> 04:29:42,080 BIG DIFFERENCE WAS NOT OBSERVED 5840 04:29:42,080 --> 04:29:44,480 IN BOTH IMMUNIZATION GROUP FOR 5841 04:29:44,480 --> 04:29:47,000 THE MALE, IMMUNIZED MALES THEN 5842 04:29:47,000 --> 04:29:54,880 WE ANALYZED ANTIBODY RESPONSE 5843 04:29:54,880 --> 04:29:55,680 ANTIBODY RESPONSE BETWEEN 5844 04:29:55,680 --> 04:29:57,960 FEMALES AND MALES, AND WE FOUND 5845 04:29:57,960 --> 04:30:00,640 SOME SIMILARITIES. 5846 04:30:00,640 --> 04:30:02,440 THESE INCLUDE SIMILAR IN THE 5847 04:30:02,440 --> 04:30:07,680 NEUTRALIZING ANTIBODY TITERS, IN 5848 04:30:07,680 --> 04:30:10,800 ORDER ACTIVITIES WE MEASURE 5849 04:30:10,800 --> 04:30:11,400 CYTOTOXICITY PHAGOCYTOSIS, WE 5850 04:30:11,400 --> 04:30:13,480 FOUND SIMILARITIES IN THE LEVELS 5851 04:30:13,480 --> 04:30:16,360 OF PLASMA BLAST PLASMA CELLS, 5852 04:30:16,360 --> 04:30:18,800 MEMORY B CELLS ENVELOPE SPECIFIC 5853 04:30:18,800 --> 04:30:22,320 IGA IN BONE MARROW, ALSO SIMILAR 5854 04:30:22,320 --> 04:30:25,440 ENVELOPE SPECIFICALLY MEMORY B 5855 04:30:25,440 --> 04:30:27,440 CELLS IN BLOOD AND WHEN WE 5856 04:30:27,440 --> 04:30:29,440 EVALUATE ENVELOPE SPECIFIC IGG 5857 04:30:29,440 --> 04:30:32,680 AND IGA MUCOSAL SIDE WE DIDN'T 5858 04:30:32,680 --> 04:30:33,080 FIND DIFFERENT. 5859 04:30:33,080 --> 04:30:37,040 NOW I WILL SHOW YOU THE 5860 04:30:37,040 --> 04:30:40,440 DIFFERENCE WE FOUND FOR THE 5861 04:30:40,440 --> 04:30:42,680 DIFFERENT -- COMPARISON BETWEEN 5862 04:30:42,680 --> 04:30:44,360 FEMALE AND MALES SO I SHOW YOU 5863 04:30:44,360 --> 04:30:47,240 FINDING ANTIBODY TITERS THROUGH 5864 04:30:47,240 --> 04:30:49,080 GP 120 AND GP 140 AND YOU CAN 5865 04:30:49,080 --> 04:30:53,680 SEE IN THE GP 120 GROUP THE MEN 5866 04:30:53,680 --> 04:30:56,600 HAVE IODINED ANTIBODY TITERS TO 5867 04:30:56,600 --> 04:30:59,400 GP 120 COMPARED TO FEMALES. 5868 04:30:59,400 --> 04:31:04,000 THESE ARE THE DIFFERENT IN WEEK 5869 04:31:04,000 --> 04:31:05,440 14, 53 AND TWO WEEKS POST 5870 04:31:05,440 --> 04:31:08,080 INFECTION M. THE GP FOR THE 5871 04:31:08,080 --> 04:31:11,280 TITLER GP 120 WE HAVE OBSERVE 5872 04:31:11,280 --> 04:31:13,760 DIFFERENCE BETWEEN FEMALES AND 5873 04:31:13,760 --> 04:31:16,280 MALES. 5874 04:31:16,280 --> 04:31:21,520 WE DIDN'T OBSERVE DIFFERENCE IN 5875 04:31:21,520 --> 04:31:25,200 GP 140 GROUP. 5876 04:31:25,200 --> 04:31:26,760 GP 120 AND GP 140. 5877 04:31:26,760 --> 04:31:28,800 ALSO WE TESTED HUMAN IMMUNE 5878 04:31:28,800 --> 04:31:30,960 RESPONSE IN MUCOSAL SIDE. 5879 04:31:30,960 --> 04:31:33,840 SO IN THIS TABLE I SHOW YOU THE 5880 04:31:33,840 --> 04:31:37,480 GP 120 SPECIFIC MEMORY B CELLS, 5881 04:31:37,480 --> 04:31:40,480 WE TEST THESE -- THIS LEVEL OF 5882 04:31:40,480 --> 04:31:44,080 THESE CELLS AT WEEK 53, TWO 5883 04:31:44,080 --> 04:31:46,880 WEEKS POST INFECTION AND EIGHT 5884 04:31:46,880 --> 04:31:48,080 WEEK POST INFECTION. 5885 04:31:48,080 --> 04:31:51,240 AT TWO WEEKS POST INFECTION THE 5886 04:31:51,240 --> 04:31:55,200 FEMALES SHOW HIGHER NUMBER OF 5887 04:31:55,200 --> 04:31:56,880 PORTION OF ENVELOPE SPECIFIC 5888 04:31:56,880 --> 04:31:58,680 MEMORY B CELL COMPARED TO THE 5889 04:31:58,680 --> 04:32:03,680 MALES. 5890 04:32:03,680 --> 04:32:05,320 THEN AT THIS TIME POINT TWO 5891 04:32:05,320 --> 04:32:10,480 WEEKS POST INFECTION, SO WE 5892 04:32:10,480 --> 04:32:13,680 TRIED TO ADD -- FIND IF THIS 5893 04:32:13,680 --> 04:32:15,720 PORTION OF MEMORY B CELL WERE 5894 04:32:15,720 --> 04:32:23,840 ASSOCIATE SO THE SIV -- FOR ALL 5895 04:32:23,840 --> 04:32:27,440 IMMUNIZED FEMALES FOR ALL 5896 04:32:27,440 --> 04:32:30,680 IMMUNIZE FEMALES AND FOR THE GP 5897 04:32:30,680 --> 04:32:32,160 120 GP 140 IMMUNIZE FEMALE YOU 5898 04:32:32,160 --> 04:32:34,360 CAN SEE STATISTICAL DIFFERENCE, 5899 04:32:34,360 --> 04:32:36,280 POSITIVE CORRELATION BETWEEN THE 5900 04:32:36,280 --> 04:32:37,960 ENVELOPE AND SPECIFIC MEMORY B 5901 04:32:37,960 --> 04:32:40,400 CELLS VERSUS THE NUMBER OF -- 5902 04:32:40,400 --> 04:32:42,880 FEMALES REQUIRE MORE CHALLENGE 5903 04:32:42,880 --> 04:32:46,440 TO BE COMPARED TO (INAUDIBLE) 5904 04:32:46,440 --> 04:32:48,920 SAME FOR PLASMA CELL, THIS IS 5905 04:32:48,920 --> 04:32:51,080 MUCOSAL SIDE SO THE SAME FOR 5906 04:32:51,080 --> 04:32:53,120 PLASMA CELL ALSO YOU CAN SEE ALL 5907 04:32:53,120 --> 04:32:55,480 IMMUNIZE FEMALE HAVE POSITIVE 5908 04:32:55,480 --> 04:32:57,120 CORRELATION BETWEEN NUMBER OF 5909 04:32:57,120 --> 04:33:00,280 CHALLENGE REQUIRED TO BECOME 5910 04:33:00,280 --> 04:33:01,520 INFECTED. 5911 04:33:01,520 --> 04:33:06,040 WE COULDN'T FIND ANY 5912 04:33:06,040 --> 04:33:07,680 STATISTICALLY DIFFERENT IN THE 5913 04:33:07,680 --> 04:33:12,040 ALL IMMUNIZED. 5914 04:33:12,040 --> 04:33:15,680 SO WHAT WE TRIED TO FIND THERE 5915 04:33:15,680 --> 04:33:17,640 IS A RELATION BETWEEN ENVELOPE 5916 04:33:17,640 --> 04:33:23,000 SPECIFIC IGG THAT MEASURE IN 5917 04:33:23,000 --> 04:33:24,240 ERECTILE SECRETION WE DID NUMBER 5918 04:33:24,240 --> 04:33:26,520 OF CHALLENGE AND IN THE 5919 04:33:26,520 --> 04:33:32,400 UNIMMUNIZED FEMALE YOU CAN SEE 5920 04:33:32,400 --> 04:33:35,320 -- YOU CAN SEE THAT WE HAVE 5921 04:33:35,320 --> 04:33:36,640 STATISTICALLY SIGNIFICANT 5922 04:33:36,640 --> 04:33:38,320 DIFFERENCE IN ALL IMMUNIZE 5923 04:33:38,320 --> 04:33:41,360 FEMALES AND ONLY IN THE GROUP GP 5924 04:33:41,360 --> 04:33:44,320 120 IMMUNIZE FEMALES. 5925 04:33:44,320 --> 04:33:47,200 SO OUR RESULT, AT THIS POINT OUR 5926 04:33:47,200 --> 04:33:48,880 RESULT HIGHLIGHT THE IMPORTANCE 5927 04:33:48,880 --> 04:33:54,680 OF MUCOSAL IMMUNITY ON MEMORY B 5928 04:33:54,680 --> 04:33:56,800 CELL OF THE (INAUDIBLE) FOR 5929 04:33:56,800 --> 04:33:57,600 PROTECTION AND THIS SHOULD BE 5930 04:33:57,600 --> 04:34:00,640 CONSIDERED FOR DEVELOPMENT OF 5931 04:34:00,640 --> 04:34:01,120 HIV VACCINE. 5932 04:34:01,120 --> 04:34:05,000 THESE WERE THE FIRST REPORT IN 5933 04:34:05,000 --> 04:34:07,520 IN SEX BIAS IN RESPONSE TO SIV 5934 04:34:07,520 --> 04:34:08,800 VACCINE IN RHESUS MACAQUE. 5935 04:34:08,800 --> 04:34:11,680 THIS WAS THE FIRST PAPER SHOWING 5936 04:34:11,680 --> 04:34:14,080 THE RESULT BUT THEN MY 5937 04:34:14,080 --> 04:34:16,840 COLLEAGUES IN THE LAB FOUND 5938 04:34:16,840 --> 04:34:19,680 ADDITIONAL PARAMETERS THAT COULD 5939 04:34:19,680 --> 04:34:22,680 HELP UNDERSTAND THE SEX 5940 04:34:22,680 --> 04:34:24,440 DIFFERENCE. 5941 04:34:24,440 --> 04:34:27,000 HE EVOLUTE THE DIFFERENT IGG OF 5942 04:34:27,000 --> 04:34:29,200 CLASS AND FOUND THAT IGG WAS 5943 04:34:29,200 --> 04:34:30,880 REALLY HIGH IN THE FEMALES 5944 04:34:30,880 --> 04:34:33,400 COMPARED TO THE MALES. 5945 04:34:33,400 --> 04:34:34,880 SO THEN HE TRIED TO UNDERSTAND 5946 04:34:34,880 --> 04:34:41,280 WHAT IS THE ROLE OF IGG 3 IN THE 5947 04:34:41,280 --> 04:34:46,080 SIV APPLICATION AND WHAT HE DID 5948 04:34:46,080 --> 04:34:47,320 IS -- ACQUISITION AND HE 5949 04:34:47,320 --> 04:34:50,880 CORRELATED LEVELS OF GP AND IGG 5950 04:34:50,880 --> 04:34:52,680 3 VERSUS THE DIFFERENT ANTIBODY 5951 04:34:52,680 --> 04:34:56,160 FUNCTIONS LIKE CYTOTOXICITY, 5952 04:34:56,160 --> 04:34:57,280 PHAGOCYTOSIS AND HE FOUND 5953 04:34:57,280 --> 04:35:01,880 POSITIVE CORRELATION IN ONLY IN 5954 04:35:01,880 --> 04:35:05,880 THE UNIMMUNIZED FEMALES AND 5955 04:35:05,880 --> 04:35:08,280 CORRELATED LEVELS WITH PEAK 5956 04:35:08,280 --> 04:35:10,720 VIRAL LOAD, HE FOUND NEGATIVE 5957 04:35:10,720 --> 04:35:13,680 CORRELATION IN THAT MORE IGG 5958 04:35:13,680 --> 04:35:18,320 MAYBE FACILITATED REPLICATION OF 5959 04:35:18,320 --> 04:35:20,520 VIRUS. 5960 04:35:20,520 --> 04:35:21,800 FINALLY ADDITIONAL PARAMETER -- 5961 04:35:21,800 --> 04:35:23,880 SORRY. 5962 04:35:23,880 --> 04:35:28,600 ADDITIONAL PARAMETER THAT 5963 04:35:28,600 --> 04:35:29,840 EVALUATED WAS REGULATORY B 5964 04:35:29,840 --> 04:35:30,520 CELLS. 5965 04:35:30,520 --> 04:35:33,680 HE FOUND SECOND DOSE -- POST 5966 04:35:33,680 --> 04:35:36,520 INFECTION THE MEN HAVE HIGH 5967 04:35:36,520 --> 04:35:39,480 LEVELS OF THE -- COMPARED TO 5968 04:35:39,480 --> 04:35:41,160 FEMALES AND THESE LEVELS HIGH 5969 04:35:41,160 --> 04:35:43,000 LEVELS OF REGULATORY B CELL 5970 04:35:43,000 --> 04:35:46,720 CORRELATE WITH HIGH LEVELS WITH 5971 04:35:46,720 --> 04:35:48,080 HIGH VIRAL LOAD IN THE PEAK OF 5972 04:35:48,080 --> 04:35:49,280 THE INFECTION. 5973 04:35:49,280 --> 04:35:55,240 SO I WANT TO SUMMARIZE THESE 5974 04:35:55,240 --> 04:35:56,480 FINDINGS. 5975 04:35:56,480 --> 04:35:58,560 THIS FIRST DEMONSTRATION OF 6 5976 04:35:58,560 --> 04:36:01,680 DIFFERENT SIV VACCINE PROTECTION 5977 04:36:01,680 --> 04:36:04,480 EMPHASIZE THE NEED FOR SIX 5978 04:36:04,480 --> 04:36:07,040 BALANCE IN VACCINE TRIALS SO 5979 04:36:07,040 --> 04:36:09,000 ALSO A FINDING OF COURSE 5980 04:36:09,000 --> 04:36:11,360 INCREASE COMPLEXITY. 5981 04:36:11,360 --> 04:36:13,480 IN TO THESE AREAS FOR FUTURE 5982 04:36:13,480 --> 04:36:18,880 INVESTIGATION LIKE IGG SUBTYPE, 5983 04:36:18,880 --> 04:36:20,320 GLYCOSYLATION, FC POLL MORPHINE 5984 04:36:20,320 --> 04:36:22,320 AND THE MICROBIOME MIGHT 5985 04:36:22,320 --> 04:36:24,120 INFLUENCE THE VACCINE OUTCOME. 5986 04:36:24,120 --> 04:36:26,160 IN ADDITION, WE NEED TO TAKE 5987 04:36:26,160 --> 04:36:29,280 ACCOUNT INTO ACCOUNT POTENTIAL 5988 04:36:29,280 --> 04:36:30,560 HORMONAL EFFECT BUT PARTICULARLY 5989 04:36:30,560 --> 04:36:33,760 EFFECT IN MUCOSAL IMMUNITY WITH 5990 04:36:33,760 --> 04:36:35,320 THE SITE OF THE CHALLENGE, ALSO 5991 04:36:35,320 --> 04:36:38,120 THINK ABOUT THE VACCINATION THAT 5992 04:36:38,120 --> 04:36:40,640 MIGHT BE IMPORTANT FOR THE 5993 04:36:40,640 --> 04:36:42,120 OUTCOME. 5994 04:36:42,120 --> 04:36:44,480 I THINK IT WOULD BE IMPORTANT TO 5995 04:36:44,480 --> 04:36:45,760 IDENTIFY IMMUNOCORRELATE 5996 04:36:45,760 --> 04:36:48,600 ASSOCIATED WITH PROTECTION IN 5997 04:36:48,600 --> 04:36:50,880 MALE PRIOR TO VACCINE REGIMEN. 5998 04:36:50,880 --> 04:36:53,760 ALSO IT IS IMPORTANT TO IDENTIFY 5999 04:36:53,760 --> 04:36:55,480 POTENTIAL MECHANISM THAT MIGHT 6000 04:36:55,480 --> 04:36:57,400 FACILITATE SIV ACQUISITION AS I 6001 04:36:57,400 --> 04:37:01,280 SHOW YOU IN MALES. 6002 04:37:01,280 --> 04:37:08,360 FINALLY I WANT TO SAY THANKS TO 6003 04:37:08,360 --> 04:37:10,040 MARJORIE, THANKS FOR HER 6004 04:37:10,040 --> 04:37:11,040 KNOWLEDGE, MY DEEPEST 6005 04:37:11,040 --> 04:37:12,360 CONGRATULATIONS FOR YOUR 6006 04:37:12,360 --> 04:37:15,440 INSPIRING CAREER. 6007 04:37:15,440 --> 04:37:17,320 THANK YOU FOR MY GRATITUDE 6008 04:37:17,320 --> 04:37:17,680 FOREVER. 6009 04:37:17,680 --> 04:37:18,240 THANK YOU. 6010 04:37:18,240 --> 04:37:29,080 [APPLAUSE] 6011 04:37:29,080 --> 04:37:30,480 >> THANK YOU FOR KEEPING YOUR 6012 04:37:30,480 --> 04:37:30,880 TALK SHORT. 6013 04:37:30,880 --> 04:37:35,440 ANY QUESTIONS? 6014 04:37:35,440 --> 04:37:38,720 >> THANK YOU FOR THAT, VERY 6015 04:37:38,720 --> 04:37:39,360 INTERESTING. 6016 04:37:39,360 --> 04:37:41,120 DID YOU COLLECT ANY INFORMATION 6017 04:37:41,120 --> 04:37:44,400 ON CYCLING HOW THE FEMALES WERE 6018 04:37:44,400 --> 04:37:47,200 CYCLING? 6019 04:37:47,200 --> 04:37:52,400 THIS IS A CHALLENGE, IF HAS BEEN 6020 04:37:52,400 --> 04:37:53,080 INTRAVAGINAL YOU WOULD HAVE DONE 6021 04:37:53,080 --> 04:37:53,200 -- 6022 04:37:53,200 --> 04:37:56,080 >> BECAUSE THE STUDY WAS NOT 6023 04:37:56,080 --> 04:37:58,560 DESIGN TO CHASE SEX DIFFERENCE 6024 04:37:58,560 --> 04:38:00,200 WE PERFORM THAT ANALYSIS FOR 6025 04:38:00,200 --> 04:38:01,880 SOME OF THE MACAQUES, BUT WE 6026 04:38:01,880 --> 04:38:05,120 DIDN'T HAVE COMPLETE DATA. 6027 04:38:05,120 --> 04:38:09,680 SO WITH THIS WE COULDN'T FIND 6028 04:38:09,680 --> 04:38:10,680 ANY OR SOMETHING INTERESTING FOR 6029 04:38:10,680 --> 04:38:12,520 THE ANALYSIS. 6030 04:38:12,520 --> 04:38:15,240 WE JUST HORMONES YES BUT NOT ALL 6031 04:38:15,240 --> 04:38:16,440 ANIMALS. 6032 04:38:16,440 --> 04:38:19,360 WE DON'T HAVE THIS CYCLING. 6033 04:38:19,360 --> 04:38:21,080 IT WAS NOT THOUGHT FOR THAT ONE. 6034 04:38:21,080 --> 04:38:23,600 BUT COULD BE INTERESTING TOOL TO 6035 04:38:23,600 --> 04:38:27,240 FLOW FUTURE MORE IN DETAIL THIS 6036 04:38:27,240 --> 04:38:40,360 PARAMETER. 6037 04:38:40,360 --> 04:38:43,640 IN FOLLOW-UP HAVE YOU ABLE TO 6038 04:38:43,640 --> 04:38:45,520 APPLY, GIVING HORMONES OR 6039 04:38:45,520 --> 04:38:50,120 BLOCKING HORMONES TO SEE TO TEST 6040 04:38:50,120 --> 04:38:52,880 WHETHER THIS IS FAMILIAL EFFECT 6041 04:38:52,880 --> 04:38:55,040 IN OTHER WORDS YOU CAN BLOCK 6042 04:38:55,040 --> 04:38:56,040 TEST TOAST ROANE PRODUCTION OR 6043 04:38:56,040 --> 04:38:58,360 BLOCK TESTOSTERONE RECEPTORS OR 6044 04:38:58,360 --> 04:39:00,040 GIVE ESTROGEN, ALL THESE THINGS 6045 04:39:00,040 --> 04:39:02,240 THAT YOU CAN DO IN ANIMAL MODELS 6046 04:39:02,240 --> 04:39:03,560 THAT MIGHT HELP ADDRESS THOSE 6047 04:39:03,560 --> 04:39:08,000 QUESTIONS. 6048 04:39:08,000 --> 04:39:13,280 >> MAYBE FUTURE STUDY WE NEED TO 6049 04:39:13,280 --> 04:39:16,560 CONSIDER ALL THAT, THIS STUDY 6050 04:39:16,560 --> 04:39:21,280 WAS NOT THINKING WAS PLANTED 6051 04:39:21,280 --> 04:39:24,720 ACROSS HORMONES OR ANY OTHER 6052 04:39:24,720 --> 04:39:30,440 PARAMETERS. 6053 04:39:30,440 --> 04:39:33,440 >> AS OF LATE THERE HAVE BEEN A 6054 04:39:33,440 --> 04:39:40,360 LOT OF THESE SEX DIFFERENCES, 6055 04:39:40,360 --> 04:39:43,960 HOWEVER I HAVEN'T SEEN ANY 6056 04:39:43,960 --> 04:39:48,200 INDICATOR OF WHAT -- WHY THEY 6057 04:39:48,200 --> 04:39:49,080 WOULD BE. 6058 04:39:49,080 --> 04:39:50,600 THAT DIFFERENCE X AND Y BUT 6059 04:39:50,600 --> 04:39:53,960 BESIDES THAT, WHY IS THERE THAT 6060 04:39:53,960 --> 04:39:55,320 DIFFERENCE IN THE OUTCOME, ANY 6061 04:39:55,320 --> 04:39:58,360 IDEA? 6062 04:39:58,360 --> 04:40:02,600 >> THE SEX HORMONES AFFECT ALL 6063 04:40:02,600 --> 04:40:07,520 TISSUES, NOT ONLY IN FEMALE BUT 6064 04:40:07,520 --> 04:40:10,760 DRUG HORMONES ELIMINATE IMMUNE 6065 04:40:10,760 --> 04:40:12,080 RESPONSE IN MANY IMMUNOCELL 6066 04:40:12,080 --> 04:40:15,800 RECEPTOR SO WE COULD PICK THAT 6067 04:40:15,800 --> 04:40:17,600 SIX HORMONE MODEL IMMUNORESPONSE 6068 04:40:17,600 --> 04:40:24,840 IN ALL TISSUES. 6069 04:40:24,840 --> 04:40:38,680 (OFF MIC) 6070 04:40:38,680 --> 04:40:40,760 >> I HAVE NO ANSWER FOR YOUR 6071 04:40:40,760 --> 04:40:41,600 QUESTION, MAYBE WE CAN DISCUSS 6072 04:40:41,600 --> 04:40:48,800 LATER. 6073 04:40:48,800 --> 04:40:49,960 >> THERE ARE NO FURTHER 6074 04:40:49,960 --> 04:40:50,680 QUESTIONS, THANK YOU. 6075 04:40:50,680 --> 04:41:09,480 [APPLAUSE] 6076 04:41:09,480 --> 04:41:11,360 >> I FEEL LIKE A BIT OF AN 6077 04:41:11,360 --> 04:41:12,120 ENTERLOPER AT THIS MEETING. 6078 04:41:12,120 --> 04:41:15,880 I'M FILLING IN FOR TOM MUSIC WHO 6079 04:41:15,880 --> 04:41:19,360 WAS UNABLE TO JOIN US, HE WAS 6080 04:41:19,360 --> 04:41:20,560 POST DOC WITH MARJORIE BUT 6081 04:41:20,560 --> 04:41:23,200 CURRENTLY HE'S DEPLOYED IN SYRIA 6082 04:41:23,200 --> 04:41:24,960 SO HE CAN COULDN'T COME BACK FOR 6083 04:41:24,960 --> 04:41:25,680 THE MEETING. 6084 04:41:25,680 --> 04:41:29,520 TODAY I WILL BE TALKING ABOUT 6085 04:41:29,520 --> 04:41:33,080 LACTIN V, A LACTOBACILLUS FOR 6086 04:41:33,080 --> 04:41:34,480 PREVENTION OF RECURRENT BV AN 6087 04:41:34,480 --> 04:41:38,360 HIV. 6088 04:41:38,360 --> 04:41:41,880 THE VAGINAL MICROBIOME IN WOMEN 6089 04:41:41,880 --> 04:41:44,760 CAN EXIST IN H TWO STATES. 6090 04:41:44,760 --> 04:41:47,280 IT CAN BE LACTOBACILLUS 6091 04:41:47,280 --> 04:41:48,720 DOMINATED WHETHER YOU YOU LOOK 6092 04:41:48,720 --> 04:41:50,160 AT GRAM STAIN OR BACTERIAL 6093 04:41:50,160 --> 04:41:52,360 COMMUNITIES PLOT YOU CAN SEE LOW 6094 04:41:52,360 --> 04:41:53,080 DIVERSITY. 6095 04:41:53,080 --> 04:41:55,240 PH IS LOW. 6096 04:41:55,240 --> 04:41:57,760 AND THIS ANTAGONIZES PATHOGENS 6097 04:41:57,760 --> 04:41:59,080 AND THERE'S HIGH LEVELS OF 6098 04:41:59,080 --> 04:42:01,560 LACTIC ACID WHICH OF COURSE 6099 04:42:01,560 --> 04:42:02,360 DRIVE PH DOWN. 6100 04:42:02,360 --> 04:42:06,680 THIS IS A NON-INFLAMMATORY 6101 04:42:06,680 --> 04:42:07,000 ENVIRONMENT. 6102 04:42:07,000 --> 04:42:09,480 IF YOU CONTRAST THAT TO 6103 04:42:09,480 --> 04:42:12,960 BACTERIAL VAGINOSIS, A CONDITION 6104 04:42:12,960 --> 04:42:15,000 OF WOMEN DYSBIOSIS OF 6105 04:42:15,000 --> 04:42:16,280 MICROBIOME, LOOK AT GRAM STAIN 6106 04:42:16,280 --> 04:42:17,160 OR BACTERIAL COMMUNITIES PLOT, 6107 04:42:17,160 --> 04:42:19,520 YOU CAN SEE THAT THERE'S HIGH 6108 04:42:19,520 --> 04:42:22,680 DIVERSITY, THERE IS A LOSS OF 6109 04:42:22,680 --> 04:42:24,800 HYDROGEN PEROXIDE PRODUCING 6110 04:42:24,800 --> 04:42:28,600 LACTOBACILLI AND THERE'S HIGH PH 6111 04:42:28,600 --> 04:42:31,920 ABOVE 5, THAT IS HIGH FOR 6112 04:42:31,920 --> 04:42:32,880 VAGINAL VAULT. 6113 04:42:32,880 --> 04:42:34,640 THERE CAN BE ODOR DISCHARGE AND 6114 04:42:34,640 --> 04:42:38,480 INFLAMMATION INCLUDING CYTOKINES 6115 04:42:38,480 --> 04:42:43,560 AND SOME POLYNOR FIN LEUKOCYTES 6116 04:42:43,560 --> 04:42:45,600 AND THIS INCREASE WOMEN OF STI 6117 04:42:45,600 --> 04:42:47,120 AND HIVE. 6118 04:42:47,120 --> 04:42:49,880 THIS IS TREATED WITH ANTIBIOTICS 6119 04:42:49,880 --> 04:42:52,880 BUT RECURRENCE IS COMMON. 6120 04:42:52,880 --> 04:42:55,480 THERE'S A NUMBER OF STUDIES 6121 04:42:55,480 --> 04:42:57,080 LINKING THE VAGINAL MICROBIOME 6122 04:42:57,080 --> 04:42:57,640 TO HIV RISK. 6123 04:42:57,640 --> 04:42:59,440 ONE OF THE FIRST WAS FROM CRAIG 6124 04:42:59,440 --> 04:43:03,680 COHEN AT UCSF IN 1995, THAT 6125 04:43:03,680 --> 04:43:06,120 SHOWED ASSOCIATION OF BV WITH 6126 04:43:06,120 --> 04:43:08,360 HIV ACQUISITION IN WOMEN. 6127 04:43:08,360 --> 04:43:12,000 COHEN WENT ON TO FIND THAT WOMEN 6128 04:43:12,000 --> 04:43:14,600 WITH BV MORE LIKELY TO TRANSMIT 6129 04:43:14,600 --> 04:43:16,040 HIV TO THEIR INTIMATE MALE 6130 04:43:16,040 --> 04:43:16,480 PARTNERS. 6131 04:43:16,480 --> 04:43:19,560 FINALLY A STUDY BIGOSESMAN IN 6132 04:43:19,560 --> 04:43:22,000 IMMUNITY FOUND WOMEN WITH EV 6133 04:43:22,000 --> 04:43:26,840 WERE FOUR FOLD HIGHER RISK OF 6134 04:43:26,840 --> 04:43:27,600 HIV ACQUISITION. 6135 04:43:27,600 --> 04:43:31,880 THIS IS JUST A DIAGRAM FOR THE 6136 04:43:31,880 --> 04:43:33,680 GOSSMAN STUDY. 6137 04:43:33,680 --> 04:43:35,800 WOMEN WITH LACTOBACILLUS 6138 04:43:35,800 --> 04:43:38,880 DOMINANT COMMUNITIES ESPECIALLY 6139 04:43:38,880 --> 04:43:41,640 LACTOBACILLUS KRISPOTUS HAS 6140 04:43:41,640 --> 04:43:43,880 LOWEST LEVELS OF PRO INPROGRAM 6141 04:43:43,880 --> 04:43:45,080 FOUR CYTOKINES AND LOWER RISK OF 6142 04:43:45,080 --> 04:43:48,600 HIV INFECTION LOWER NUMBERS OF 6143 04:43:48,600 --> 04:43:51,120 TARGET CELLS IN LIEU MINUTE OF 6144 04:43:51,120 --> 04:43:51,680 VAGINA. 6145 04:43:51,680 --> 04:43:54,120 WOMEN WITH DIVERSE BACTERIAL 6146 04:43:54,120 --> 04:43:55,320 COMMUNITIES CONVERSELY HAD 6147 04:43:55,320 --> 04:43:57,200 HIGHER LEVELS OF 6148 04:43:57,200 --> 04:43:58,680 PRO-INFLAMMATORY CYTOKININGS AND 6149 04:43:58,680 --> 04:44:02,280 UP TO 17 FOLD INCREASE IN 6150 04:44:02,280 --> 04:44:02,920 ACTIVATED CD4 TARGET CELLS FOR 6151 04:44:02,920 --> 04:44:04,320 HIV. 6152 04:44:04,320 --> 04:44:06,400 AND AGAIN THEY WERE FOUR FOLD 6153 04:44:06,400 --> 04:44:09,160 MORE LIKELY HIV INFECTED IN 6154 04:44:09,160 --> 04:44:09,520 STUDY. 6155 04:44:09,520 --> 04:44:12,200 THIS WAS DONE IN YOUNG SOUTH 6156 04:44:12,200 --> 04:44:13,080 AFRICAN WOMEN. 6157 04:44:13,080 --> 04:44:16,160 SO OUR HYPOTHESIS WAS THAT WE 6158 04:44:16,160 --> 04:44:18,280 COULD ADD A LIVE BIOTHERAPEUTIC 6159 04:44:18,280 --> 04:44:22,680 PRODUCT A LACTOBACILLUS KRESATUS 6160 04:44:22,680 --> 04:44:26,240 TO SHIFT THE VAGINAL MICROBIOME 6161 04:44:26,240 --> 04:44:28,480 TOWARD OPTIMAL STATE TO PREVENT 6162 04:44:28,480 --> 04:44:29,360 AND REDUCE HIV RISK. 6163 04:44:29,360 --> 04:44:31,240 WHAT IS A LIVE BIOTHERAPEUTIC 6164 04:44:31,240 --> 04:44:32,720 PRODUCT AND WHY IS IT DIFFERENT 6165 04:44:32,720 --> 04:44:33,840 THAN PROBIOTIC? 6166 04:44:33,840 --> 04:44:37,800 THIS WAS A TERM COIND BY THE FDA 6167 04:44:37,800 --> 04:44:39,680 LBP IS A BIOLOGICAL PRODUCT THAT 6168 04:44:39,680 --> 04:44:41,360 CONTAINS LIVE ORGANISMS SUCH AS 6169 04:44:41,360 --> 04:44:43,040 BACTERIA BUT IT IS APPLICABLE TO 6170 04:44:43,040 --> 04:44:44,720 PREVENT TREAT AND CURE DISEASES 6171 04:44:44,720 --> 04:44:46,920 OF HUMANS. 6172 04:44:46,920 --> 04:44:49,880 THUS LBP IS BASICALLY A DRUG, IT 6173 04:44:49,880 --> 04:44:51,920 IS MANUFACTURED UNDER GNP 6174 04:44:51,920 --> 04:44:54,600 CONDITIONS AN MEETS POTENCY AND 6175 04:44:54,600 --> 04:44:57,840 PURITY STANDARDS WHEREAS 6176 04:44:57,840 --> 04:44:59,160 PROBIOTICS MAY CONTAIN LIVE 6177 04:44:59,160 --> 04:45:01,840 ORGANISMS BUT THEY ARE REGULATE 6178 04:45:01,840 --> 04:45:03,400 AS DIETARY SUPPLEMENTS OR FOOD 6179 04:45:03,400 --> 04:45:04,640 AND NOT INTENDED TO TREAT 6180 04:45:04,640 --> 04:45:06,720 DIAGNOSE OR CURE OR PREVENT ANY 6181 04:45:06,720 --> 04:45:07,680 DISEASE IN HUMAN IF YOU READ ON 6182 04:45:07,680 --> 04:45:11,320 THE LABEL. 6183 04:45:11,320 --> 04:45:15,440 SO LACK TIN V OUR PRODUCT IS A 6184 04:45:15,440 --> 04:45:17,800 LACTOBACILLUS CRESTPOTIS. 6185 04:45:17,800 --> 04:45:19,480 THAT IS THE STRAIN DESIGNATION. 6186 04:45:19,480 --> 04:45:22,120 IT IS DELIVER AS A POWDER IN 6187 04:45:22,120 --> 04:45:24,080 VAGINAL APPLICATOR. 6188 04:45:24,080 --> 04:45:26,120 IT HAS BEEN IN A PHASE 1 TRIAL 6189 04:45:26,120 --> 04:45:29,680 WHICH IS SHOWED SAFETY AND WELL 6190 04:45:29,680 --> 04:45:30,480 TOLERATED. 6191 04:45:30,480 --> 04:45:32,320 IT'S BEEN IN A PHASE 2A TRIAL 6192 04:45:32,320 --> 04:45:34,720 WHICH WAS SPONSORED BY NIAID, 6193 04:45:34,720 --> 04:45:38,280 WHERE WE SAW 78% COLONIZATION. 6194 04:45:38,280 --> 04:45:42,800 WE RECENTLY COMPLETED A PHASE 2B 6195 04:45:42,800 --> 04:45:44,760 TRIAL WHICH I WILL TALK ABOUT 6196 04:45:44,760 --> 04:45:47,080 TODAY, THIS WAS 228 WOMEN AND IT 6197 04:45:47,080 --> 04:45:50,600 WAS DIRECTED BY CRAIG COHEN 6198 04:45:50,600 --> 04:45:52,400 UCSF, THE PAPER WAS PUBLISHED IN 6199 04:45:52,400 --> 04:45:53,400 THE NEW ENGLAND JOURNAL OF 6200 04:45:53,400 --> 04:45:55,560 MEDICINE. 6201 04:45:55,560 --> 04:45:59,160 IN A SUCCESSFUL LACTIN 6202 04:45:59,160 --> 04:46:00,440 COLONIZATION OF PHASE 2 WE CAN 6203 04:46:00,440 --> 04:46:02,680 SEE THIS WOMAN HAS HIGH LEVELS 6204 04:46:02,680 --> 04:46:05,680 OF BACTERIAL VAGINOSIS 6205 04:46:05,680 --> 04:46:11,720 ASSOCIATED BACTERIA INCLUDING 6206 04:46:11,720 --> 04:46:16,800 MEGASFERA EBAV, COMBINATION OF 6207 04:46:16,800 --> 04:46:21,320 BACTERIA, AND LOW LEVELS OF 6208 04:46:21,320 --> 04:46:22,160 LACTOBACILLUS INERS. 6209 04:46:22,160 --> 04:46:23,960 YOU CAN SEE A DROP IN BV 6210 04:46:23,960 --> 04:46:26,680 BACTERIA BUT YOU DONE SEE A 6211 04:46:26,680 --> 04:46:29,440 CONCOMITANT INCREASE IN 6212 04:46:29,440 --> 04:46:32,480 LACTOBACILLUS UNTIL YOU ADD 6213 04:46:32,480 --> 04:46:33,640 EXOGENOUS LACTOBACILLUS AND THEN 6214 04:46:33,640 --> 04:46:36,080 YOU SEE LEVELS INCREASE. 6215 04:46:36,080 --> 04:46:40,800 AND THIS HELPS DRIVE DOWN AND 6216 04:46:40,800 --> 04:46:44,120 KEEP THESE AN AEROBIC BACTERIA 6217 04:46:44,120 --> 04:46:47,280 LOW LEVELS SO LACTIN B 6218 04:46:47,280 --> 04:46:49,280 ADMINISTERED FOLLOWING 6219 04:46:49,280 --> 04:46:52,760 ANTIBIOTICS REPLENISHES THE 6220 04:46:52,760 --> 04:46:54,080 MICROBIOME TOWARDS OPTIMAL 6221 04:46:54,080 --> 04:46:54,280 STATE. 6222 04:46:54,280 --> 04:46:56,200 THIS IS FROM PHASE 2A STUDY, YOU 6223 04:46:56,200 --> 04:46:57,680 CAN AGAIN SEE THESE ARE 6224 04:46:57,680 --> 04:47:01,880 BACTERIAL COMMUNITIES. 6225 04:47:01,880 --> 04:47:04,960 THIS WAS A WOMAN BEFORE 6226 04:47:04,960 --> 04:47:08,080 TREATMENT, 28 DAY NOW ALMOST ALL 6227 04:47:08,080 --> 04:47:11,600 LAKOTAS BACILLUS C, CRESPOTIUT 6228 04:47:11,600 --> 04:47:12,880 SHOWN IN PINK SO SUCCESSFUL 6229 04:47:12,880 --> 04:47:13,880 TREATMENT. 6230 04:47:13,880 --> 04:47:17,960 SO IN OUR PHASE 2B STUDY, THE 6231 04:47:17,960 --> 04:47:19,960 OBJECTIVES WERE TO TREAT -- TEST 6232 04:47:19,960 --> 04:47:24,880 TOTAL OF 228 WOMEN RANDOMIZE 2 6233 04:47:24,880 --> 04:47:32,320 TO 1 TO RECEIVE LACTIN V OR 6234 04:47:32,320 --> 04:47:32,560 PLACEBO. 6235 04:47:32,560 --> 04:47:39,080 THEY RECEIVED TOPICAL M&A 6236 04:47:39,080 --> 04:47:41,720 RATANIZOL FIVE DAYS OR PLACEBO 6237 04:47:41,720 --> 04:47:43,080 FIVE DAYS AND TEN WEEKS OF 6238 04:47:43,080 --> 04:47:44,920 TREATMENT TWICE A WEEK. 6239 04:47:44,920 --> 04:47:47,440 THEY WERE TREATED TWICE A WEEK 6240 04:47:47,440 --> 04:47:50,680 TO BE SURE THAT DURING MENSES WE 6241 04:47:50,680 --> 04:47:53,160 WOULD CONTINUE TO ADD 6242 04:47:53,160 --> 04:47:56,080 LACTOBACILLUS AN IT WOULDN'T BE 6243 04:47:56,080 --> 04:47:59,040 RINSED OUT. 6244 04:47:59,040 --> 04:48:01,000 PRIMARY OBJECTIVES OF THE STUDY 6245 04:48:01,000 --> 04:48:03,000 WERE EFFICACY OF EB RECURRENCE 6246 04:48:03,000 --> 04:48:04,560 AND SAFETY AT 24 WEEKS. 6247 04:48:04,560 --> 04:48:06,680 SECONDARY OBJECTIVES WERE TO 6248 04:48:06,680 --> 04:48:09,000 DETERMINE COLONIZATION LEVELS, 6249 04:48:09,000 --> 04:48:10,760 USER ACCEPTABILITY AND 6250 04:48:10,760 --> 04:48:12,080 TOLERABILITY, LONG TERM 6251 04:48:12,080 --> 04:48:16,440 COLONIZATION OF LACTIN B 24 6252 04:48:16,440 --> 04:48:18,120 WEEKS WHICH IS 12 WEEKS POST 6253 04:48:18,120 --> 04:48:19,480 DOSING AFTER THEY RECEIVED LAST 6254 04:48:19,480 --> 04:48:25,200 DOSE AND LONG TERM EFFICACY. 6255 04:48:25,200 --> 04:48:28,280 BV IS A CLINICAL CONDITION. 6256 04:48:28,280 --> 04:48:30,400 THERE ARE SEVERAL DIAGNOSTIC 6257 04:48:30,400 --> 04:48:31,720 CRITERIA, THE CLINICAL CRITERIA 6258 04:48:31,720 --> 04:48:35,360 IS CALLED AN AMSEL SCORE, A 6259 04:48:35,360 --> 04:48:38,760 COMBINATION OF WHETHER THE WOMAN 6260 04:48:38,760 --> 04:48:41,320 HAS A HOMOGENOUS DISCHARGE 6261 04:48:41,320 --> 04:48:43,280 WHETHER SHE HAS CLUE CELLS WHICH 6262 04:48:43,280 --> 04:48:45,560 ARE BACTERIAL VAGINAL CELLS, IS 6263 04:48:45,560 --> 04:48:47,880 A LOT OF BACTERIA STICKING TO 6264 04:48:47,880 --> 04:48:48,840 THEM. 6265 04:48:48,840 --> 04:48:53,480 PH ABOVE 4.5 AND OFTEN A FISHY 6266 04:48:53,480 --> 04:48:54,680 ODOR CALLED THE WENT TEST. 6267 04:48:54,680 --> 04:48:56,560 THE OTHER IS A GRAM STAIN WHICH 6268 04:48:56,560 --> 04:49:00,080 IS CALLED A NUGEN CRY TIERIA. 6269 04:49:00,080 --> 04:49:03,520 YOU LOOK FOR GRAM POSITIVE RODS 6270 04:49:03,520 --> 04:49:07,000 LACTOBACILLI AND OTHER CURVED 6271 04:49:07,000 --> 04:49:11,200 RODS WHICH ARE GARDENERELLA AND 6272 04:49:11,200 --> 04:49:14,000 OTHER PLEA OWE MORPHIC RODS. 6273 04:49:14,000 --> 04:49:18,160 7 TO 10 MEANS BV SO IN OUR 6274 04:49:18,160 --> 04:49:21,920 STUDY, WHEN WE EXAMINE WOMEN 6275 04:49:21,920 --> 04:49:24,360 ENROLLED, 51% HAD HAD MORE THAN 6276 04:49:24,360 --> 04:49:29,880 5 BV EPISODES IN A YEAR AND 6277 04:49:29,880 --> 04:49:32,000 RECURRENT BV IS CONSIDERED THREE 6278 04:49:32,000 --> 04:49:33,840 OR MORE EPISODES IN A YEAR. 6279 04:49:33,840 --> 04:49:35,280 SO MAJORITY OF WOMEN IN OUR 6280 04:49:35,280 --> 04:49:39,440 STUDY REALLY HAD RECALCITRANT 6281 04:49:39,440 --> 04:49:42,600 BV. 6282 04:49:42,600 --> 04:49:44,400 SO THESE ARE DEMOGRAPHICS. 6283 04:49:44,400 --> 04:49:45,760 60% OF THE WOMEN IN STUDY WERE 6284 04:49:45,760 --> 04:49:47,120 WOMEN OF COLOR. 6285 04:49:47,120 --> 04:49:51,080 BV IS MORE COMMON IN HISPANIC 6286 04:49:51,080 --> 04:49:53,480 AND WOMEN OF AFRICAN DESCENT. 6287 04:49:53,480 --> 04:49:55,440 SO WE HAD THOSE NUMBERS WELL 6288 04:49:55,440 --> 04:49:58,480 REPRESENTED IN THE STUDY. 6289 04:49:58,480 --> 04:49:59,360 THOSE KIND OF WOMEN WELL 6290 04:49:59,360 --> 04:50:01,880 REPRESENTED. 6291 04:50:01,880 --> 04:50:07,200 SO IN OUR PHASE 2 BV CURE WAS 6292 04:50:07,200 --> 04:50:11,920 57% IN THE LACTOBACILLUS 6293 04:50:11,920 --> 04:50:14,360 CRESPONDIS ARM AND 39% PLACEBO 6294 04:50:14,360 --> 04:50:15,600 ARM 12 WEEKS. 6295 04:50:15,600 --> 04:50:17,680 THIS CORRELATED WHEN YOU LOOK AT 6296 04:50:17,680 --> 04:50:21,680 ALL THE DATA TOGETHER OF ABOUT A 6297 04:50:21,680 --> 04:50:23,960 46% REDUCTION IN RECURRENT 6298 04:50:23,960 --> 04:50:24,800 BACTERIAL VAGINOSIS. 6299 04:50:24,800 --> 04:50:29,560 AND THE SAME WAS TRUE AT 24 6300 04:50:29,560 --> 04:50:33,800 WEEKS, THREE MONTHS POST DOSING. 6301 04:50:33,800 --> 04:50:37,680 AT THE 12 WEEK VISIT 6302 04:50:37,680 --> 04:50:38,960 CRESPONDUCTIONUS WAS DECKED IN 6303 04:50:38,960 --> 04:50:44,360 79% OF WOMEN IN LACTOBACILLUS 6304 04:50:44,360 --> 04:50:47,920 CRESPONDUS ARM AND ONLY 3% IN 6305 04:50:47,920 --> 04:50:51,520 PLACEBO HAD LACK OF 6306 04:50:51,520 --> 04:50:52,680 LACTOBACILLUS STRAIN. 6307 04:50:52,680 --> 04:50:57,280 WHEN YOU EXOGENOUSLY GIVE IT YOU 6308 04:50:57,280 --> 04:50:59,360 CAN DRIVE WOMEN TOWARD THAT AND 6309 04:50:59,360 --> 04:51:01,760 TREATING ARE ANTIBIOTICS IS NOT 6310 04:51:01,760 --> 04:51:03,480 ENOUGH TO BRING BACK 6311 04:51:03,480 --> 04:51:05,200 LACTOBACILLUS. 6312 04:51:05,200 --> 04:51:09,280 SO HERE WE ARE LOOKING AT PCR 6313 04:51:09,280 --> 04:51:11,880 QPCR FOR TOTAL BACTERIA IN 6314 04:51:11,880 --> 04:51:13,880 VAGINA BACK LOW BACILLUS 6315 04:51:13,880 --> 04:51:18,680 SPECIES, CRISPATUS OR CTV 05 6316 04:51:18,680 --> 04:51:19,680 STRAIN AND PH. 6317 04:51:19,680 --> 04:51:21,400 IN IS AFTER WOMEN HAVE BEEN 6318 04:51:21,400 --> 04:51:23,360 TREAT WITH ANTIBIOTIC SO WE HAVE 6319 04:51:23,360 --> 04:51:26,360 DRIVEN DOWN THE TOTAL NUMBER OF 6320 04:51:26,360 --> 04:51:28,560 BACTERIA IN VAGINAL MICROBIOME 6321 04:51:28,560 --> 04:51:31,160 UX SEE THE PH STARTED HIGH OVER 6322 04:51:31,160 --> 04:51:33,840 HERE ABOUT 6 IN THIS WOMAN. 6323 04:51:33,840 --> 04:51:37,480 AFTER TREATED WITH ANTIBIOTICS 6324 04:51:37,480 --> 04:51:39,080 THE LEVELS COME DOWN AND SHE IS 6325 04:51:39,080 --> 04:51:42,200 TREATED WITH LACTIN V. 6326 04:51:42,200 --> 04:51:45,240 ALL THESE QPCR CURVES PARALLEL 6327 04:51:45,240 --> 04:51:46,760 SHOWING THAT MOST OF THE 6328 04:51:46,760 --> 04:51:50,240 BACTERIA NOW IN THE VAGINA 6329 04:51:50,240 --> 04:51:51,800 LACTOBACILLUS CRISPATUS AND R 6330 04:51:51,800 --> 04:51:55,680 STRAIN. 6331 04:51:55,680 --> 04:51:59,480 IN WOMEN SUCCESSFULLY COLONIZED, 6332 04:51:59,480 --> 04:52:02,480 WE COULD SEE USUALLY THEY HAD 6333 04:52:02,480 --> 04:52:04,520 ABOVE 10 TO 6 LACTOBACILLI. 6334 04:52:04,520 --> 04:52:06,400 YOU CAN SEE HERE THESE ARE WOMEN 6335 04:52:06,400 --> 04:52:09,800 THAT WERE BV POSITIVE, THIS IS 6336 04:52:09,800 --> 04:52:11,680 12 WEEKS AND 24 WEEKS. 6337 04:52:11,680 --> 04:52:14,480 SO AGAIN, BY 24 WEEKS THE WOMEN 6338 04:52:14,480 --> 04:52:17,960 THAT DID NOT HAVE LACTOBACILLUS 6339 04:52:17,960 --> 04:52:19,760 WERE BV POSITIVE. 6340 04:52:19,760 --> 04:52:22,560 SO 10 TO 6 SEEMED TO BE THE 6341 04:52:22,560 --> 04:52:23,680 NUMBER SUFFICIENT TO PREVENT 6342 04:52:23,680 --> 04:52:28,280 RECURRENCE. 6343 04:52:28,280 --> 04:52:29,920 SO IN SOME OF THE NEXT STEPS WE 6344 04:52:29,920 --> 04:52:32,920 ARE STARTING TO ANALYZE META 6345 04:52:32,920 --> 04:52:35,000 GENOMIC TIME COURSE FOR LACTIN 6346 04:52:35,000 --> 04:52:38,800 V, I WILL SHOW YOU THAT DATA. 6347 04:52:38,800 --> 04:52:41,440 CHARACTERIZE VAGINAL MICROBIOME 6348 04:52:41,440 --> 04:52:41,800 ECOSYSTEMS. 6349 04:52:41,800 --> 04:52:43,880 PERFORM SOME INTEGRATIVE 6350 04:52:43,880 --> 04:52:45,560 ANALYSIS TO IDENTIFY 6351 04:52:45,560 --> 04:52:46,800 ASSOCIATIONS WITH BV, THIS IS 6352 04:52:46,800 --> 04:52:48,920 STILL ONGOING. 6353 04:52:48,920 --> 04:52:51,720 AND DEVELOP PREDICT SIGNATURES. 6354 04:52:51,720 --> 04:52:57,000 PILOT STUDY OF 29 WOMEN WERE 6355 04:52:57,000 --> 04:52:58,760 SAMPLES UNDERWAY TO LOOK AT 6356 04:52:58,760 --> 04:53:01,960 MICROBIOME BEING DONE AT THE 6357 04:53:01,960 --> 04:53:05,000 ZUCKERBURG BIOHUB AND LOOKING AT 6358 04:53:05,000 --> 04:53:05,920 CYTOKINES AND CHEM COINS DONE AT 6359 04:53:05,920 --> 04:53:08,760 THE CALL LAB IN TORONTO. 6360 04:53:08,760 --> 04:53:09,480 CHEMOKINES. 6361 04:53:09,480 --> 04:53:12,320 SO IN THAT PRELIMINARY DATA OF 6362 04:53:12,320 --> 04:53:14,240 META GENOMIC TIME COURSE YOU CAN 6363 04:53:14,240 --> 04:53:16,920 SEE WOMEN TREAT WITH LACTIN V 6364 04:53:16,920 --> 04:53:21,280 START WITH A BV PROFILE, HERE 6365 04:53:21,280 --> 04:53:24,400 THEY HAVE GOT HIGH LEVELS BV 6366 04:53:24,400 --> 04:53:28,680 ASSOCIATED BACTERIA, GARNERELLA 6367 04:53:28,680 --> 04:53:30,680 BACKROID DEES AND TREAT WITH 6368 04:53:30,680 --> 04:53:32,920 ANTIBIOTICS AT TIME POINT 1, THE 6369 04:53:32,920 --> 04:53:34,800 FIRST LACK DOE BACILLUS BECOME 6370 04:53:34,800 --> 04:53:38,320 IN WOMEN IS LACTOBACILLUS ENERS. 6371 04:53:38,320 --> 04:53:40,440 IT IS NOT CONSIDERED ONE OF THE 6372 04:53:40,440 --> 04:53:42,680 MOST BENEFICIAL LACTOBACILLI BUT 6373 04:53:42,680 --> 04:53:45,480 IT IS ABLE TO LIVE VERY HAPPILY 6374 04:53:45,480 --> 04:53:47,960 WITH BACTERIAL VAGINOSIS 6375 04:53:47,960 --> 04:53:51,320 ASSOCIATED BACTERIA. 6376 04:53:51,320 --> 04:53:57,080 SO BUT ONCE WE ADD LACTOBACILLUS 6377 04:53:57,080 --> 04:53:59,320 CRISPATIS THESE WOMEN CONVERTED 6378 04:53:59,320 --> 04:54:03,360 TO LACTOBACILLUS CRISPATUS 6379 04:54:03,360 --> 04:54:05,200 MICROBIOME, THIS TIME POINT 7 IS 6380 04:54:05,200 --> 04:54:07,240 24 WEEK TIME POINT SO THAT IS 6381 04:54:07,240 --> 04:54:10,040 AGAIN THREE MONTHS POST DOSING. 6382 04:54:10,040 --> 04:54:13,120 THESE WOMEN CONVERTED TO 6383 04:54:13,120 --> 04:54:15,120 LACTOBACILLUS CRISPATUS 6384 04:54:15,120 --> 04:54:16,680 PHENOTYPE, THIS HAS 6385 04:54:16,680 --> 04:54:19,520 LACTOBACILLUS AT THE SECOND TIME 6386 04:54:19,520 --> 04:54:22,880 POINT, DIDN'T CONVERT AT THIS 6387 04:54:22,880 --> 04:54:25,120 TIME POINT THEN PICKED UP 6388 04:54:25,120 --> 04:54:29,000 CRISPATUS THEN WENT BACK TO THAT 6389 04:54:29,000 --> 04:54:32,320 PHENOTYPE STILL CONSIDERED MORE 6390 04:54:32,320 --> 04:54:36,400 LACTOBACILLUS THAN -- THIS IS 6391 04:54:36,400 --> 04:54:37,400 PRELIMINARY DATA. 6392 04:54:37,400 --> 04:54:42,880 WE ALSO FOUND TREATMENT WITH 6393 04:54:42,880 --> 04:54:46,400 LACTIN V AND WE COULD LOOK FOR 6394 04:54:46,400 --> 04:54:49,360 SOLUBLE IMMUNE FACTORS LACTIN B 6395 04:54:49,360 --> 04:54:51,320 WAS ASSOCIATED WITH SUSTAINED 6396 04:54:51,320 --> 04:54:52,680 REDUCTION IN VAGINAL LEVELS OF 6397 04:54:52,680 --> 04:54:55,200 PRO INFLAMMATORY CYTOKINES 6398 04:54:55,200 --> 04:54:59,320 INCLUDING IL 1 AND E CAD HEREIN. 6399 04:54:59,320 --> 04:55:03,760 SO LACTOBACILLUS TREATMENT TENDS 6400 04:55:03,760 --> 04:55:07,160 TO DECREASE PROINFLAMMATORY 6401 04:55:07,160 --> 04:55:10,840 CYTOKINES AND IMPROVE EPITHELIAL 6402 04:55:10,840 --> 04:55:11,920 BARRIER FUNCTION. 6403 04:55:11,920 --> 04:55:13,080 SO THAT WAS AN INTERESTING 6404 04:55:13,080 --> 04:55:14,080 FINDING THAT WAS SORT OF 6405 04:55:14,080 --> 04:55:17,760 UNEXPECTED. 6406 04:55:17,760 --> 04:55:20,640 IN POST HOCK ANALYSIS, WE FOUND 6407 04:55:20,640 --> 04:55:23,480 A CLINICAL CURE WAS KEY TO 6408 04:55:23,480 --> 04:55:24,160 SUCCESS. 6409 04:55:24,160 --> 04:55:26,680 SO A CLINICAL CURE MEANT WOMEN 6410 04:55:26,680 --> 04:55:32,080 WHO WERE TREATED WITH 6411 04:55:32,080 --> 04:55:33,280 MATRONIDAZOLE THAT DECREASED 6412 04:55:33,280 --> 04:55:35,080 THEIR BUGS TO THE POINT WE COULD 6413 04:55:35,080 --> 04:55:36,720 ADD LACK LOW BACILLUS AND IT WAS 6414 04:55:36,720 --> 04:55:38,400 ABLE TO -- LACTOBACILLUS AND 6415 04:55:38,400 --> 04:55:40,400 ABLE TO DOMINATE OR FULFILL THAT 6416 04:55:40,400 --> 04:55:40,920 NICHE. 6417 04:55:40,920 --> 04:55:46,240 WHEN WE LOOKED AT THIS DATA WAS 6418 04:55:46,240 --> 04:55:49,480 ANALYZED BY MIKE AT EMIS SO 6419 04:55:49,480 --> 04:55:54,240 WOMEN WHO WERE CURED WITH 6420 04:55:54,240 --> 04:55:55,640 METRODANOZOLE BETTER ABLE TO 6421 04:55:55,640 --> 04:55:57,480 STABILIZE AND STAY CURE POST 6422 04:55:57,480 --> 04:55:59,280 HOCK ANALYSIS WE HAD 88% CURE 6423 04:55:59,280 --> 04:56:01,440 RATE IF WE COULD DRIVE DOWN 6424 04:56:01,440 --> 04:56:04,280 THOSE BV BACTERIA, WHEREAS WOMEN 6425 04:56:04,280 --> 04:56:07,920 WHO DIDN'T GET A CLINICAL CURE, 6426 04:56:07,920 --> 04:56:11,240 THERE IS NO ROOM FOR THEM TO 6427 04:56:11,240 --> 04:56:11,840 COME IN AND COLONIZE AND KEEP 6428 04:56:11,840 --> 04:56:13,960 WOMEN FROM GETTING BV AGAIN, YOU 6429 04:56:13,960 --> 04:56:18,280 CAN SEE PLACEBO AND LACTOB 6430 04:56:18,280 --> 04:56:20,120 COMPLETELY OVERLAP HERE. 6431 04:56:20,120 --> 04:56:23,480 SO THERE'S A LOT OF REMAINING 6432 04:56:23,480 --> 04:56:24,840 CHALLENGES IN BV RESEARCH. 6433 04:56:24,840 --> 04:56:26,720 THERE IS INCOMPLETE 6434 04:56:26,720 --> 04:56:28,960 UNDERSTANDING OF THE ETIOLOGY OF 6435 04:56:28,960 --> 04:56:29,760 BV. 6436 04:56:29,760 --> 04:56:32,080 WE KNOW SEX IS A BIG FACTOR THAT 6437 04:56:32,080 --> 04:56:32,880 DRIVES BV. 6438 04:56:32,880 --> 04:56:39,400 THERE IS A STUDY BY SUPRA META 6439 04:56:39,400 --> 04:56:43,880 WHO SHOWED THAT YOUNG UGANDAN 6440 04:56:43,880 --> 04:56:52,760 WOMEN HAD HIGH LEVELS BAC LEVELS LEVELS 6441 04:56:52,760 --> 04:56:54,960 LACTOBACILLUS CRISPOTES BUT WHEN 6442 04:56:54,960 --> 04:56:57,480 HAY STARTED HAVING SEX IT HAD A 6443 04:56:57,480 --> 04:56:59,520 EVERYONE THE PHENOTYPE, AFRICAN 6444 04:56:59,520 --> 04:57:01,800 WOMEN AND AFTER CANMEN WOMEN HAD 6445 04:57:01,800 --> 04:57:03,080 HIGH LEVELS BV AND THEY WENT 6446 04:57:03,080 --> 04:57:04,520 WELL THERE'S SOMETHING 6447 04:57:04,520 --> 04:57:06,400 INTIMATELY DIFFERENT, WHY THAT'S 6448 04:57:06,400 --> 04:57:07,640 WHY THEY HAVE BV BUT IT IS NOT 6449 04:57:07,640 --> 04:57:09,200 REALLY THE CASE. 6450 04:57:09,200 --> 04:57:12,280 BECAUSE YOUNG WOMEN WHO HAVEN'T 6451 04:57:12,280 --> 04:57:14,840 HAD SEX YET DON'T HAVE BV BUT 6452 04:57:14,840 --> 04:57:17,360 ONCE THEY HAVE SEX THEN THEY GET 6453 04:57:17,360 --> 04:57:20,240 BV SO ROLE OF THE BIOFILM AND 6454 04:57:20,240 --> 04:57:22,240 BACTERIA PHAGOAND WHAT EFFECTS 6455 04:57:22,240 --> 04:57:23,760 CANDIDA HAS AND WHAT EFFECTS 6456 04:57:23,760 --> 04:57:26,280 THIS OTHER LACTOBACILLUS HAVE 6457 04:57:26,280 --> 04:57:28,840 ARE STILL UNKNOWNS THAT WE AND 6458 04:57:28,840 --> 04:57:33,080 MANY OTHERS ARE LOOKING INTO. 6459 04:57:33,080 --> 04:57:34,400 PHYSIOLOGICAL VARIATIONS. 6460 04:57:34,400 --> 04:57:38,280 IN THE VAGINAL MICROBIOME CAUSED 6461 04:57:38,280 --> 04:57:39,880 BY MENSTRUATION SEMEN WHICH IS 6462 04:57:39,880 --> 04:57:43,400 VERY ALKALINE, PREGNANCY, 6463 04:57:43,400 --> 04:57:46,280 HORMONE CONTRACEPTION HORMONES 6464 04:57:46,280 --> 04:57:49,120 IN GENERAL, DIET AND THE RECTAL 6465 04:57:49,120 --> 04:57:52,840 MICROBIOME ALSO PLAY A ROLE. 6466 04:57:52,840 --> 04:57:54,600 THE FUNCTION OF THE METABOLOME 6467 04:57:54,600 --> 04:57:57,560 FOR THE VAGINAL MICROBIOME IS 6468 04:57:57,560 --> 04:58:00,480 SOMETHING WE ARE LOOKING INTO. 6469 04:58:00,480 --> 04:58:02,240 FINALLY HOST MICROBE 6470 04:58:02,240 --> 04:58:04,160 INTERACTIONS MAY FACILITATE OR 6471 04:58:04,160 --> 04:58:09,000 INHIBIT SIV TRANSMISSION OR DRUG 6472 04:58:09,000 --> 04:58:09,600 METABOLISM. 6473 04:58:09,600 --> 04:58:12,800 VARYING APPROACHES TO BV 6474 04:58:12,800 --> 04:58:17,400 DIAGNOSIS THE TOOLS TO DIAGNOSE 6475 04:58:17,400 --> 04:58:21,600 BV ARE O AMSEL AND NUGEMT ARE 6476 04:58:21,600 --> 04:58:22,960 SUBJECTIVE SO THAT MAKES 6477 04:58:22,960 --> 04:58:24,280 EVERYONE'S JOB MORE DIFFICULT. 6478 04:58:24,280 --> 04:58:26,840 SO WE ARE PROCEEDING NOW WITH 6479 04:58:26,840 --> 04:58:29,480 THE PHASE 3, TWO PHASE 3 PIVOTAL 6480 04:58:29,480 --> 04:58:33,200 TRIALS IN U.S., WE WILL ENROLL 6481 04:58:33,200 --> 04:58:37,160 WOMEN AGE 16 TO 45, FDA LIKES 6482 04:58:37,160 --> 04:58:38,880 YOU TO HAVE A PEDIATRIC GROUP SO 6483 04:58:38,880 --> 04:58:42,080 WE TRY TO ENROLL WILL TRY TO 6484 04:58:42,080 --> 04:58:45,440 ENROLL AT LEAST A FRACTION OF 6485 04:58:45,440 --> 04:58:46,880 YOUNGER WOMEN 16 TO 18 WHICH IS 6486 04:58:46,880 --> 04:58:48,880 CONSIDERED A PEDIATRIC GROUP, WE 6487 04:58:48,880 --> 04:58:51,080 WILL ENROLL WOMEN WITH 6488 04:58:51,080 --> 04:58:52,280 RECURRENTS BV THREE OR MORE 6489 04:58:52,280 --> 04:58:53,880 EPISODES IN ONE YEAR PERIOD. 6490 04:58:53,880 --> 04:58:55,120 WE WILL CONTINUE TO INCLUDE 6491 04:58:55,120 --> 04:58:57,880 WOMEN OF COLOR. 6492 04:58:57,880 --> 04:59:00,400 AGAIN MONITOR SAFETY EFFICACY 6493 04:59:00,400 --> 04:59:02,200 AND ACCEPTABILITY AND EVENTUALLY 6494 04:59:02,200 --> 04:59:07,080 APPLY FOR A BIOLOGICS LICENSE. 6495 04:59:07,080 --> 04:59:11,640 I THINK THAT IS MY LAST SLIDE 6496 04:59:11,640 --> 04:59:15,280 ACKNOWLEDGE MY COLLABORATORS, I 6497 04:59:15,280 --> 04:59:16,760 LEFT OFF RUPERT WHO DID THE 6498 04:59:16,760 --> 04:59:17,360 IMMUNE WORK. 6499 04:59:17,360 --> 04:59:20,600 I CUT MY TALK SHORT SO THERE'S 6500 04:59:20,600 --> 04:59:21,720 TIME FOR LAST SPEAKER. 6501 04:59:21,720 --> 04:59:29,880 [APPLAUSE] 6502 04:59:29,880 --> 04:59:32,080 >> VERY RECOGNIZE PROGRESS. 6503 04:59:32,080 --> 04:59:33,480 DO YOU HAVE ENOUGH DATA, TREATED 6504 04:59:33,480 --> 04:59:39,600 PEOPLE TO SEE WHETHER LACK TIN V 6505 04:59:39,600 --> 04:59:43,080 RESTORATION OF THE PREDOMINANTLY 6506 04:59:43,080 --> 04:59:46,880 L CRISPATUS FLORA ALSO REDUCED 6507 04:59:46,880 --> 04:59:49,760 FREQUENCY OF EITHER CANDID A 6508 04:59:49,760 --> 04:59:50,840 INFECTIONS OR URINARY TRACT 6509 04:59:50,840 --> 04:59:52,320 INFECTIONS? 6510 04:59:52,320 --> 04:59:56,320 >> WE DO KNOW LACTOBACILLUS 6511 04:59:56,320 --> 04:59:57,640 CRISPATUS DECREASES URINARY 6512 04:59:57,640 --> 04:59:59,480 TRACT INFECTIONS, A SEPARATE 6513 04:59:59,480 --> 05:00:01,840 PHASE 2A STUDY DONE WITH ANN 6514 05:00:01,840 --> 05:00:03,480 STAPLETON AT THE UNIVERSITY OF 6515 05:00:03,480 --> 05:00:04,080 WASHINGTON. 6516 05:00:04,080 --> 05:00:06,720 AND THAT SHOWED THAT 6517 05:00:06,720 --> 05:00:08,920 LACTOBACILLUS CRISPATUS ADDITION 6518 05:00:08,920 --> 05:00:10,800 HAD 50% REDUCTION IN WOMEN WITH 6519 05:00:10,800 --> 05:00:12,280 RECURRENT URINARY TRACT 6520 05:00:12,280 --> 05:00:12,680 INFECTIONS. 6521 05:00:12,680 --> 05:00:15,080 AND THAT IS LIKELY BECAUSE E. 6522 05:00:15,080 --> 05:00:16,880 COLI WHICH IS THE PRIMARY CAUSE 6523 05:00:16,880 --> 05:00:21,120 OF UTI IN WOMEN IS COMES RETRO 6524 05:00:21,120 --> 05:00:23,480 GRADE FROM RECTUM, IF YOU HAVE 6525 05:00:23,480 --> 05:00:25,000 LOTS OF LACTOBACILLUS PRESENT 6526 05:00:25,000 --> 05:00:28,760 YOU WILL PREVENT THAT MOVEMENT 6527 05:00:28,760 --> 05:00:30,600 OF THE BACTERIA. 6528 05:00:30,600 --> 05:00:32,720 AS FAR AS CANDIDA, WE DON'T HAVE 6529 05:00:32,720 --> 05:00:34,520 A LOT OF DATA ON THAT. 6530 05:00:34,520 --> 05:00:36,400 WE DID COLLECT THAT IN THE 6531 05:00:36,400 --> 05:00:38,280 CLINICAL TRIAL BUT THERE REALLY 6532 05:00:38,280 --> 05:00:41,000 WASN'T ENOUGH FOR US TO SHOW 6533 05:00:41,000 --> 05:00:47,840 ANYTHING STATISTICALLY. 6534 05:00:47,840 --> 05:00:50,640 THE LAST SPEAKER IS DAN APPELLA 6535 05:00:50,640 --> 05:01:49,560 FROM NIDDK. 6536 05:01:49,560 --> 05:01:51,480 THANK YOU, VERY MUCH. 6537 05:01:51,480 --> 05:01:53,400 LET ME JUST SAY IT IS AN HONOR 6538 05:01:53,400 --> 05:01:56,280 TO BE SPEAKING TO YOU TODAY. 6539 05:01:56,280 --> 05:01:58,160 BEING PART OF THIS SYMPOSIUM TO 6540 05:01:58,160 --> 05:02:00,680 HONOR MARJORIE WAS REAL KEY 6541 05:02:00,680 --> 05:02:02,080 COLLABORATORS IN THE PROJECT I 6542 05:02:02,080 --> 05:02:06,200 WILL TELL YOU ABOUT TODAY. 6543 05:02:06,200 --> 05:02:08,640 THIS IS THE LAST TALK SO WILL 6544 05:02:08,640 --> 05:02:10,320 TRY TO BE INTERNETTIC AND 6545 05:02:10,320 --> 05:02:11,600 ENTERTAIN YOU AT THE SAME TIME 6546 05:02:11,600 --> 05:02:12,240 IF I CAN. 6547 05:02:12,240 --> 05:02:14,280 SO I WILL TELL YOU ABOUT THIS 6548 05:02:14,280 --> 05:02:14,640 MOLECULE. 6549 05:02:14,640 --> 05:02:17,880 I WILL CALL IT 247 THROUGHOUT 6550 05:02:17,880 --> 05:02:19,200 THIS TALK. 6551 05:02:19,200 --> 05:02:21,280 THIS MOLECULE HAS FASCINATED ME 6552 05:02:21,280 --> 05:02:22,640 A NUMBER OF YEARS AND THE MAIN 6553 05:02:22,640 --> 05:02:24,080 GOAL OF THIS STUDY IS TO REALLY 6554 05:02:24,080 --> 05:02:26,400 LOOK AT THE MECHANISM OF ACTION 6555 05:02:26,400 --> 05:02:28,280 AND REALLY UNDERSTAND ITS 6556 05:02:28,280 --> 05:02:30,720 ANTI-HIV PROPERTIES IN 6557 05:02:30,720 --> 05:02:32,280 PARTICULAR, AND WE ALSO ARE 6558 05:02:32,280 --> 05:02:33,600 INTERESTED IN PERFORMING AS MANY 6559 05:02:33,600 --> 05:02:35,120 PRE-CLINICAL STUDIES AS POSSIBLE 6560 05:02:35,120 --> 05:02:37,200 TO TRY TO GET TO FIRST IN HUMAN 6561 05:02:37,200 --> 05:02:38,480 CLINICAL TRIAL WITH MOLECULE OR 6562 05:02:38,480 --> 05:02:39,120 SOMETHING THAT IS CLOSELY 6563 05:02:39,120 --> 05:02:41,920 RELATED TO THE MOLECULE. 6564 05:02:41,920 --> 05:02:44,560 COUPLE OF THINGS TO TELL YOU. 6565 05:02:44,560 --> 05:02:47,240 I'M AN ORGANIC CHEMIST SO YOU 6566 05:02:47,240 --> 05:02:49,080 WILL SEE QUITE A FEW CHEMICAL 6567 05:02:49,080 --> 05:02:52,200 STRUCTURE, THAT IS HOW I THINK 6568 05:02:52,200 --> 05:02:54,720 AND COMMUNICATE MY MAIN 6569 05:02:54,720 --> 05:02:55,920 CONTRIBUTION IS TO REALLY MAKE 6570 05:02:55,920 --> 05:02:58,480 THIS MOLECULE WHICH IS WHY I 6571 05:02:58,480 --> 05:02:59,200 HAVE $15 PER GRAM. 6572 05:02:59,200 --> 05:03:00,920 THIS IS RESULT OF SYNTHESIS 6573 05:03:00,920 --> 05:03:02,040 PRODUCTION FOR THIS PARTICULAR 6574 05:03:02,040 --> 05:03:03,280 MOLECULE SO NOT TOO HARD TO 6575 05:03:03,280 --> 05:03:03,640 MAKE. 6576 05:03:03,640 --> 05:03:06,200 I ALSO WANT TO MENTION THAT I 6577 05:03:06,200 --> 05:03:08,800 DID NOT INVENT THIS MOLECULE, 6578 05:03:08,800 --> 05:03:10,680 NUMBER OF OTHER WITHIN THE 6579 05:03:10,680 --> 05:03:11,600 INTRAMURAL PROGRAM OF NIH CAME 6580 05:03:11,600 --> 05:03:13,480 UP WITH THIS MOLECULE. 6581 05:03:13,480 --> 05:03:15,520 I SEEM TO BE I GUESS THE LATEST 6582 05:03:15,520 --> 05:03:17,960 SPOKESPERSON TO ADVOCATE MOVING 6583 05:03:17,960 --> 05:03:19,120 THIS MOLECULE FORWARD IN VARIETY 6584 05:03:19,120 --> 05:03:22,040 OF WAYS I WILL TRY TO TELL YOU 6585 05:03:22,040 --> 05:03:22,240 TODAY. 6586 05:03:22,240 --> 05:03:24,120 SO THIS MOLECULE DOES HAVE SOME 6587 05:03:24,120 --> 05:03:26,000 ANTI-HIV PROPERTIES, IF YOU LOOK 6588 05:03:26,000 --> 05:03:28,240 IN STANDARD CELL BASED ANTIVIRAL 6589 05:03:28,240 --> 05:03:30,880 ASSAYS FOR HIV, THE IC 50 VALUES 6590 05:03:30,880 --> 05:03:33,440 IN LOW MICROMOLAR RANGE NOT VERY 6591 05:03:33,440 --> 05:03:35,360 IMPRESSIVE COMPARED TO POTENT 6592 05:03:35,360 --> 05:03:37,520 DRUGS ON THE MARKET. 6593 05:03:37,520 --> 05:03:38,840 TOXICITY DOESN'T SEEM TO BE MUCH 6594 05:03:38,840 --> 05:03:41,480 ISSUE IN CELL BASED ASSAYS 6595 05:03:41,480 --> 05:03:43,360 TOXICITY VALUE ARE WELL OVER 100 6596 05:03:43,360 --> 05:03:44,560 MICROMOLAR, WHILE THE ACTIVITIES 6597 05:03:44,560 --> 05:03:46,120 MAYBE NOT VERY IMPRESSIVE IT IS 6598 05:03:46,120 --> 05:03:46,720 VERY CONSISTENT. 6599 05:03:46,720 --> 05:03:48,800 WE HAVE TESTED THIS WITH A WIDE 6600 05:03:48,800 --> 05:03:50,560 VARIETY OF DIFFERENT FORMS OF 6601 05:03:50,560 --> 05:03:53,440 HIV, DIFFERENT CLADE SUB GROUPS, 6602 05:03:53,440 --> 05:03:55,080 EVEN HIV VARIANTS THAT HAVE 6603 05:03:55,080 --> 05:03:56,960 KNOWN DRUG RESISTANCE TO 6604 05:03:56,960 --> 05:03:58,000 EXISTING DRUGS ON THE MARKET AND 6605 05:03:58,000 --> 05:04:00,000 IT IS ALL PRETTY MUCH THE SAME. 6606 05:04:00,000 --> 05:04:01,960 WE HAVE DONE SOME ANIMAL STUDIES 6607 05:04:01,960 --> 05:04:04,240 WITH THIS MOLECULE, ALWAYS 6608 05:04:04,240 --> 05:04:07,000 SHOWING VERY LOW TOXICITY IN 6609 05:04:07,000 --> 05:04:09,560 ANIMALS WELL TOLERATED. 6610 05:04:09,560 --> 05:04:11,280 ONE FASCINATING THING TO ME FOR 6611 05:04:11,280 --> 05:04:12,880 THIS MOLECULE IS AFTER SEVERAL 6612 05:04:12,880 --> 05:04:14,760 ATTEMPTS TO TRY TO GENERAL RATE 6613 05:04:14,760 --> 05:04:17,080 HIV RESISTANT VIRUS TO THIS 6614 05:04:17,080 --> 05:04:19,000 MOLECULE, IT HASN'T BEEN 6615 05:04:19,000 --> 05:04:20,520 SUCCESSFUL SO WE CONCLUDE 6616 05:04:20,520 --> 05:04:21,760 BASICALLY A HIGH BARRIER TO 6617 05:04:21,760 --> 05:04:26,720 GENERATE RESISTANT VIRUS TO THIS 6618 05:04:26,720 --> 05:04:28,440 MOLECULE, IT SPEAKS TO A UNIQUE 6619 05:04:28,440 --> 05:04:33,320 MECHANISM OF ACTION. 6620 05:04:33,320 --> 05:04:35,480 THIS IS A COLLABORATIVE PROJECT 6621 05:04:35,480 --> 05:04:37,360 AND TRYING TO ADVANCE AS TOPICAL 6622 05:04:37,360 --> 05:04:39,600 MICROBE SIDE TO PREVENT HIV 6623 05:04:39,600 --> 05:04:40,400 INFECTION. 6624 05:04:40,400 --> 05:04:41,880 ONE COLLABORATOR WAS MARJORIE ON 6625 05:04:41,880 --> 05:04:43,680 THIS PARTICULAR WORK AND I WILL 6626 05:04:43,680 --> 05:04:44,520 SUMMARIZE HER DATA ON THIS 6627 05:04:44,520 --> 05:04:45,320 SLIDE. 6628 05:04:45,320 --> 05:04:47,080 THIS IS A MICROBE SIDE CHALLENGE 6629 05:04:47,080 --> 05:04:48,520 IN WHICH OUR MOLECULE WAS 6630 05:04:48,520 --> 05:04:52,360 FORMULATED IN A JELL, ABOUT .8% 6631 05:04:52,360 --> 05:04:55,280 MOLECULE IN HYDROXYHEC GEL. 6632 05:04:55,280 --> 05:04:58,520 ANIMALS ARE CHALLENGED WEEKLY. 6633 05:04:58,520 --> 05:05:00,640 AND THIS GEL IS APPLIED 6634 05:05:00,640 --> 05:05:01,760 VAGINALLY THEN THREE HOURS AFTER 6635 05:05:01,760 --> 05:05:02,960 APPLICATION OF MICROBE SIDE THEY 6636 05:05:02,960 --> 05:05:05,240 ARE CHALLENGED WITH A VIRUS. 6637 05:05:05,240 --> 05:05:08,000 PANELS FOLLOWED A LONG TIME. 6638 05:05:08,000 --> 05:05:09,680 AND THIS WAS GREAT DATA TO SEE 6639 05:05:09,680 --> 05:05:11,640 WITH MICROBE SIDE YOU SEE QUITE 6640 05:05:11,640 --> 05:05:13,800 NICE PROTECTION IN THE TREATED 6641 05:05:13,800 --> 05:05:16,440 ANIMALS IN BLUE LINE WHEREAS 6642 05:05:16,440 --> 05:05:18,160 UNPLACEBO ANIMALS ARE INFECTED. 6643 05:05:18,160 --> 05:05:19,640 WE STARTED THIS COLLABORATION 6644 05:05:19,640 --> 05:05:21,720 WITH MARJORIE HOPING WE COULD 6645 05:05:21,720 --> 05:05:24,080 COMBINE MICROBE SIDE WITH 6646 05:05:24,080 --> 05:05:24,880 ADENOVIRUS VACCINE. 6647 05:05:24,880 --> 05:05:27,200 THOSE DATA DIDN'T LOOK SO GOOD. 6648 05:05:27,200 --> 05:05:28,880 NOT ENTIRELY ALWAYS SURE WHY 6649 05:05:28,880 --> 05:05:31,160 THOSE DATA DESCRIBED IN 6650 05:05:31,160 --> 05:05:33,800 THISBLYCATION. 6651 05:05:33,800 --> 05:05:35,680 -- PUBLICATION. 6652 05:05:35,680 --> 05:05:37,320 IT WAS MARJORIE'S SUGGESTION NOT 6653 05:05:37,320 --> 05:05:39,440 TO STOP THE WORK AND SHE 6654 05:05:39,440 --> 05:05:40,200 INTRODUCED ME TO (INAUDIBLE) 6655 05:05:40,200 --> 05:05:40,800 WITH HER VACCINE. 6656 05:05:40,800 --> 05:05:44,480 WE DECIDED TO REDO EXPERIMENTS 6657 05:05:44,480 --> 05:05:46,760 WITH BETH'S VACCINE AGAINST 6658 05:05:46,760 --> 05:05:49,000 HIV-1 OFFERING AROUND 60 TO 70% 6659 05:05:49,000 --> 05:05:50,320 PROTECTION. 6660 05:05:50,320 --> 05:05:52,760 USED SAME FORMULATION OF OUR 6661 05:05:52,760 --> 05:05:54,520 MICROBE SIDE AND GEL AFTER 6662 05:05:54,520 --> 05:05:55,640 MICROBE SIDE ANIMALS ARE 6663 05:05:55,640 --> 05:05:56,320 CHALLENGED. 6664 05:05:56,320 --> 05:05:57,840 THIS DATA WORKED NICELY. 6665 05:05:57,840 --> 05:06:00,760 I WILL GO THROUGH THIS BRIEFLY. 6666 05:06:00,760 --> 05:06:02,440 IN THE VACCINE ALONE TREATED 6667 05:06:02,440 --> 05:06:04,440 ANIMALS YOU CAN SEE THE EFFECT 6668 05:06:04,440 --> 05:06:06,760 OF VACCINE IN BLUE OVER THE 6669 05:06:06,760 --> 05:06:12,280 CONTROL GROUP. 6670 05:06:12,280 --> 05:06:13,080 MICROBE SIDE ALONE DIDN'T FAIR 6671 05:06:13,080 --> 05:06:14,840 SO WELL WITH MINIMAL PROTECTION 6672 05:06:14,840 --> 05:06:17,320 BUT WHEN YOU COMBINE VACCINE AND 6673 05:06:17,320 --> 05:06:20,880 MICROBE SIDE YOU SAW ENHANCEMENT 6674 05:06:20,880 --> 05:06:23,600 FOR PROTECTION, COMPARISON TWICE 6675 05:06:23,600 --> 05:06:24,280 COMBINATION TREATMENT AND THE 6676 05:06:24,280 --> 05:06:24,640 VACCINE ALONE. 6677 05:06:24,640 --> 05:06:26,680 SO WE WOULD LOVE TO MOVE THIS 6678 05:06:26,680 --> 05:06:29,120 FORWARD TO SOMETHING THAT WOULD 6679 05:06:29,120 --> 05:06:29,960 INVOLVE HUMAN CLINICAL TRIALS. 6680 05:06:29,960 --> 05:06:32,920 WE ARE AWARE THOUGH FROM PRIVATE 6681 05:06:32,920 --> 05:06:34,400 PREVIOUS CLINICAL WORK WITH 6682 05:06:34,400 --> 05:06:36,840 MICROBE SIDES IN PARTICULAR THE 6683 05:06:36,840 --> 05:06:37,960 -- CLINICAL TRIAL THAT GEL 6684 05:06:37,960 --> 05:06:40,160 FORMULATION IS NOT IDEAL FOR 6685 05:06:40,160 --> 05:06:40,680 PATIENT COMPLIANCE. 6686 05:06:40,680 --> 05:06:43,200 WE ARE ALSO AWARE FROM THE -- 6687 05:06:43,200 --> 05:06:43,880 ANOTHER CLINICAL TRIAL THE 6688 05:06:43,880 --> 05:06:46,080 ASPIRE TRIAL THAT A FORMULATION 6689 05:06:46,080 --> 05:06:48,680 OF MOLECULE IN A MONTHLY VAGINAL 6690 05:06:48,680 --> 05:06:50,240 RING WHICH IS SLOW RELEASES 6691 05:06:50,240 --> 05:06:51,800 MOLECULE IS MORE TOLERABLE. 6692 05:06:51,800 --> 05:06:53,040 THIS IS ONE THAT USED A 6693 05:06:53,040 --> 05:06:56,640 DIFFERENT MOLECULE CALLED 6694 05:06:56,640 --> 05:06:58,400 DUPIVERINE SHOWING IMPROVEMENT 6695 05:06:58,400 --> 05:06:59,800 IN REDUCING HIV INFECTION. 6696 05:06:59,800 --> 05:07:01,640 THE GOAL IS TO FORMULATE 6697 05:07:01,640 --> 05:07:06,560 MOLECULE INTO SLOW RELEASE FORM, 6698 05:07:06,560 --> 05:07:08,040 COLLABORATION WITH (INAUDIBLE) 6699 05:07:08,040 --> 05:07:09,680 AT INSTITUTE PROCESS OF 6700 05:07:09,680 --> 05:07:13,080 FORMULATING MOLECULE IN HIS RING 6701 05:07:13,080 --> 05:07:21,920 WE HOPE TO CLINT TO GENOVEFFA 6702 05:07:21,920 --> 05:07:22,880 WOULD TOO MUCH DELAY. 6703 05:07:22,880 --> 05:07:23,880 PART OF THE MAIN QUESTIONS IS 6704 05:07:23,880 --> 05:07:25,960 WHY DOES THIS WORK? 6705 05:07:25,960 --> 05:07:26,320 WELL? 6706 05:07:26,320 --> 05:07:30,080 AND WHAT COULD BE GOING ON? 6707 05:07:30,080 --> 05:07:32,240 A LOT OF GOALS OF MY WORK IS TO 6708 05:07:32,240 --> 05:07:34,760 FIGURE HOW DOES THIS MOLECULE 6709 05:07:34,760 --> 05:07:35,680 INTERFERE WITH HIV? 6710 05:07:35,680 --> 05:07:38,000 WE LIKE TO USE THIS KNOWLEDGE TO 6711 05:07:38,000 --> 05:07:40,120 SUPPORT FUTURE CLINICAL WORK. 6712 05:07:40,120 --> 05:07:42,240 AND MAYBE MAKE DIFFERENT 6713 05:07:42,240 --> 05:07:43,240 DERIVATIVES THAT PERHAPS WORK 6714 05:07:43,240 --> 05:07:43,760 BETTER. 6715 05:07:43,760 --> 05:07:49,800 THERE IS A CHALLENGING PROJECT 6716 05:07:49,800 --> 05:07:51,680 BECAUSE IT DOESN'T BEHAVE LIKE 6717 05:07:51,680 --> 05:07:53,400 ANY DRUG I KNOW OF AGAINST HIV, 6718 05:07:53,400 --> 05:07:55,680 I WOULD DOESN'T INTERFERE WITH 6719 05:07:55,680 --> 05:07:57,080 ESTABLISHED TARGETS BY THE 6720 05:07:57,080 --> 05:07:59,840 EXISTING PANEL OF DRUGS. 6721 05:07:59,840 --> 05:08:02,080 WE HAVE TESTED AGAINST ALL THE 6722 05:08:02,080 --> 05:08:06,240 HIV ENZYMES, REVERSE TRANSCRIPT 6723 05:08:06,240 --> 05:08:07,880 ACE, PROTEASE, VIRAL ENTRY, 6724 05:08:07,880 --> 05:08:08,400 DOESN'T DO ANYTHING. 6725 05:08:08,400 --> 05:08:11,880 WE ARE ALSO AWARE IN IS A 6726 05:08:11,880 --> 05:08:12,280 REACTIVE MOLECULE. 6727 05:08:12,280 --> 05:08:13,800 IN TERMS OF PROTEINS. 6728 05:08:13,800 --> 05:08:19,320 (OFF MIC) 6729 05:08:19,320 --> 05:08:21,280 >> YES WE HAVE TESTED AGAINST 6730 05:08:21,280 --> 05:08:22,280 OTHER -- DO YOU WANT ME TO COME 6731 05:08:22,280 --> 05:08:22,680 BACK LATER? 6732 05:08:22,680 --> 05:08:24,080 I CAN COME BACK LATER AT THE END 6733 05:08:24,080 --> 05:08:29,920 OF THE TALK. 6734 05:08:29,920 --> 05:08:31,560 WE HAVE TESTED THAT, THE ANSWER 6735 05:08:31,560 --> 05:08:33,160 WILL BE A LITTLE MORE CLEAR AT 6736 05:08:33,160 --> 05:08:34,880 THE END. 6737 05:08:34,880 --> 05:08:36,520 THIS IS A ANOTHER MOLECULE THAT 6738 05:08:36,520 --> 05:08:39,280 BINDS TO PROTEINS, BASICALLY AS 6739 05:08:39,280 --> 05:08:41,040 FAR AS WE CAN TELL. 6740 05:08:41,040 --> 05:08:42,400 MOST DRUGS HAVE A PROTEIN 6741 05:08:42,400 --> 05:08:44,640 BINDING INTERACTION THAT'S 6742 05:08:44,640 --> 05:08:44,960 NON-COVALENT. 6743 05:08:44,960 --> 05:08:47,080 THIS IS A REACTIVE MOLECULE, 6744 05:08:47,080 --> 05:08:51,000 MEANING IT DOES A CHEMICAL 6745 05:08:51,000 --> 05:08:52,000 REACTION IN A CERTAIN SPECIFIC 6746 05:08:52,000 --> 05:08:54,120 MANNER I WILL GO THROUGH IN 6747 05:08:54,120 --> 05:08:55,080 DETAIL WITH VARIETY OF CHEMICAL 6748 05:08:55,080 --> 05:08:58,360 STRUCTURE. 6749 05:08:58,360 --> 05:09:01,680 O THE REACTIVE END IS HERE THE 6750 05:09:01,680 --> 05:09:04,320 THYRO ESTER PORTION OF MOLECULE 6751 05:09:04,320 --> 05:09:07,680 ATTACHED TO SULFUR AND THE 6752 05:09:07,680 --> 05:09:08,480 ACETYLGROUP WINDS UP REACTING IN 6753 05:09:08,480 --> 05:09:10,040 PARTICULAR WITH SULFUR. 6754 05:09:10,040 --> 05:09:11,280 IN PARTICULAR IN THIS EXAMPLE 6755 05:09:11,280 --> 05:09:12,640 MOLECULE WITH THE SULFUR AND 6756 05:09:12,640 --> 05:09:15,640 SIDE CHAIN OF CYSTEINE. 6757 05:09:15,640 --> 05:09:16,400 SMEW COMBINING OUR MOLECULE WITH 6758 05:09:16,400 --> 05:09:18,720 THE MODEL COMPOUND WHAT ORGANIC 6759 05:09:18,720 --> 05:09:20,280 CHEM U.S.ES LIKE TO DO WE CAN 6760 05:09:20,280 --> 05:09:22,720 OBSERVE AN ACETYLTRANSFER FROM 6761 05:09:22,720 --> 05:09:26,120 THE 247 MOLECULE TO SULFUR OF 6762 05:09:26,120 --> 05:09:27,080 THE CYSTEINE SIDE CHAIN. 6763 05:09:27,080 --> 05:09:29,920 THE ORIGINAL 247 FORMS THIS AS A 6764 05:09:29,920 --> 05:09:32,760 BY-PRODUCT WHICH IS JUST THE 6765 05:09:32,760 --> 05:09:33,960 PHTHALATE, THIS IS S MINUS 6766 05:09:33,960 --> 05:09:35,800 BECAUSE WE MEASURED PKA OF 6767 05:09:35,800 --> 05:09:39,920 PROTONATED FORM, 5.8 SO UNDER PH 6768 05:09:39,920 --> 05:09:41,960 OF 4 DEPROTONATED AS S MINUS 6769 05:09:41,960 --> 05:09:42,800 SHOWN HERE. 6770 05:09:42,800 --> 05:09:46,680 AFTER THIS INITIAL TRANSFER, WE 6771 05:09:46,680 --> 05:09:48,480 WATCH BY NMR WE CAN SEE IT IS 6772 05:09:48,480 --> 05:09:51,000 FAST IT DOESN'T STAY IS A I CAN 6773 05:09:51,000 --> 05:09:53,320 THE BUT THERE THERE IS AN AMINE 6774 05:09:53,320 --> 05:09:54,680 SHOWN HERE THE ACETYLGROUP 6775 05:09:54,680 --> 05:09:56,320 TRANSFERS FROM THE SULFUR TO THE 6776 05:09:56,320 --> 05:09:59,000 NITROGEN TO FORM A MORE STABLE 6777 05:09:59,000 --> 05:10:00,880 -- WE CAN ALSO OBSERVE BY NMR 6778 05:10:00,880 --> 05:10:01,680 THIS IS A SLOWER PROCESS. 6779 05:10:01,680 --> 05:10:03,480 SO THERE IS A BASIC MODE OF 6780 05:10:03,480 --> 05:10:05,560 REACTIVITY HERE, AND WE KNOW 6781 05:10:05,560 --> 05:10:07,440 THAT THIS MOLECULE LIKES TO 6782 05:10:07,440 --> 05:10:11,680 RAPIDLY TRANSFER ACETYLGROUP 6783 05:10:11,680 --> 05:10:12,600 TOOTHILY GROUP SHORTIAS CYSTEINE 6784 05:10:12,600 --> 05:10:13,640 FOLLOWED BY RERANGEMENT TO MEAN 6785 05:10:13,640 --> 05:10:15,720 GROUP. 6786 05:10:15,720 --> 05:10:17,160 THIS IS THE BAY SING MODEL 6787 05:10:17,160 --> 05:10:18,920 REACTIVITY I WILL EXTEND UP TO 6788 05:10:18,920 --> 05:10:22,080 SHOW YOU HOW THIS IMPACTS HIV. 6789 05:10:22,080 --> 05:10:24,000 IN AN INTERESTING WAY. 6790 05:10:24,000 --> 05:10:27,880 NEXT I WILL SHOW YOU HOW AT A 6791 05:10:27,880 --> 05:10:32,600 VERY BROAD LEVEL HOW 247 6792 05:10:32,600 --> 05:10:34,280 INTERFERES WITH HIV AND WE HAVE 6793 05:10:34,280 --> 05:10:36,840 DATA FROM ELECTROMICROSCOPY 6794 05:10:36,840 --> 05:10:39,600 TREATED HIV INFECTED CELLS WITH 6795 05:10:39,600 --> 05:10:41,040 MOLECULE 247 BY ELECTRON 6796 05:10:41,040 --> 05:10:43,240 MICROSCOPY RESULTS IN VIRUS 6797 05:10:43,240 --> 05:10:50,560 PARTICLES LOCKED IN IMMATURE 6798 05:10:50,560 --> 05:10:51,640 NON-MATURE STATE. 6799 05:10:51,640 --> 05:10:52,960 YOU HAVE VARIETY OF GAG AND 6800 05:10:52,960 --> 05:10:54,160 PROCESS PROTEINS THAT ARE RING, 6801 05:10:54,160 --> 05:10:56,400 THIS IS THE TEXTBOOK IMAGE OF 6802 05:10:56,400 --> 05:11:02,800 IMMATURE HIV PARTICLE AND AFTER 6803 05:11:02,800 --> 05:11:04,320 MATURATION WITH HIV PROTEASE, 6804 05:11:04,320 --> 05:11:06,080 THE VIRUS TAKES ON THIS 6805 05:11:06,080 --> 05:11:07,680 MORPHOLOGY AND WITH CONDENSED 6806 05:11:07,680 --> 05:11:10,240 CAPSID CORE. 6807 05:11:10,240 --> 05:11:12,040 Z SO IN TREATED CELLS YOU CAN 6808 05:11:12,040 --> 05:11:13,760 SEE VIRUS BUTTING AND FREE VIRAL 6809 05:11:13,760 --> 05:11:14,960 PARTICLES IN SOLUTION THAT 6810 05:11:14,960 --> 05:11:18,120 REMAIN LOCKED IN IMMATURE STATE, 6811 05:11:18,120 --> 05:11:20,000 VERSUS CONTROL YOU CAN SEE VIRAL 6812 05:11:20,000 --> 05:11:20,960 PARTICLES NICELY MATURED ALL THE 6813 05:11:20,960 --> 05:11:22,680 WAY. 6814 05:11:22,680 --> 05:11:23,640 AND BECOME INFECTIOUS. 6815 05:11:23,640 --> 05:11:26,400 IN THE IMMATURE STATE PARTICLES 6816 05:11:26,400 --> 05:11:29,440 HIV PARTICLES ARE CONSIDERED TO 6817 05:11:29,440 --> 05:11:30,520 BE NON-INFECTIOUS. 6818 05:11:30,520 --> 05:11:33,360 SO DRILL DOWN MORE DETAIL TO GAG 6819 05:11:33,360 --> 05:11:35,680 POLYPROTEIN WE SEEM TO THINK IS 6820 05:11:35,680 --> 05:11:37,280 BEING EFFECTED BY OUR PARTICULAR 6821 05:11:37,280 --> 05:11:37,640 MOLECULE. 6822 05:11:37,640 --> 05:11:39,600 SO SHOWN HERE IS CARTOON OF GAG, 6823 05:11:39,600 --> 05:11:41,240 IT IS A POLYPROTEIN HIV PRODUCES 6824 05:11:41,240 --> 05:11:43,800 A LOT OF GAG POLYPROTEIN. 6825 05:11:43,800 --> 05:11:45,880 IT HAS THREE DOMAINS MATRIX 6826 05:11:45,880 --> 05:11:47,880 CAPSID AND NUCLEAR CAPSID 6827 05:11:47,880 --> 05:11:49,400 DOMAIN, NUCLEAR CAPSID BINDS 6828 05:11:49,400 --> 05:11:52,480 NUCLEIC ACID, PARTICULAR HIV 6829 05:11:52,480 --> 05:11:52,880 RNA. 6830 05:11:52,880 --> 05:11:55,320 HIV GAG IS SET UP BEAUTIFULLY TO 6831 05:11:55,320 --> 05:11:56,880 SELF-ASSEMBLE INTO A VIRAL 6832 05:11:56,880 --> 05:12:01,480 PARTICLE WHICH CONTAINS 2,400 6833 05:12:01,480 --> 05:12:03,200 GAG MOLECULES WITH LOCALIZED 6834 05:12:03,200 --> 05:12:06,760 CONCENTRATION OF GAG AS THEY ARE 6835 05:12:06,760 --> 05:12:08,280 CRUNCHED TOGETHER. 6836 05:12:08,280 --> 05:12:10,440 IMMATURE VIRAL PARTICLE IS THEN 6837 05:12:10,440 --> 05:12:11,800 DRIVEN TO MATURATION AFTER HIV 6838 05:12:11,800 --> 05:12:13,680 PROTEASE IS ACTIVATED HIV 6839 05:12:13,680 --> 05:12:15,000 PROTEASE CLEAVE IT IS BONDS 6840 05:12:15,000 --> 05:12:16,680 BETWEEN DOMAINS OF GAG WHICH 6841 05:12:16,680 --> 05:12:18,280 THEN RESULTS IN THE CORE 6842 05:12:18,280 --> 05:12:20,120 CONDENSATION AND THEN INFECTIOUS 6843 05:12:20,120 --> 05:12:22,240 VIRAL PARTICLE. 6844 05:12:22,240 --> 05:12:24,240 SO THIS IS A BASIC REACTIVITY I 6845 05:12:24,240 --> 05:12:25,160 JUST SHOWED. 6846 05:12:25,160 --> 05:12:28,480 AND WE THINK THAT THIS BASIC 6847 05:12:28,480 --> 05:12:29,360 REACTIVITY TRANSLATES UP TO 6848 05:12:29,360 --> 05:12:29,920 INTERACTING WITH GAG. 6849 05:12:29,920 --> 05:12:31,080 THIS IS WHAT WE WANTED TO 6850 05:12:31,080 --> 05:12:32,480 ACTUALLY SHOW. 6851 05:12:32,480 --> 05:12:35,800 BASICALLY THAT OUR MOLECULE HAS 6852 05:12:35,800 --> 05:12:37,240 PATTERN OF REACTIVITY IN THE 6853 05:12:37,240 --> 05:12:38,040 COMPLICATED HIV PROTEIN. 6854 05:12:38,040 --> 05:12:39,360 I WILL GO THROUGH THIS ONE MORE 6855 05:12:39,360 --> 05:12:39,720 TIME BRIEFLY. 6856 05:12:39,720 --> 05:12:41,840 WE KNOW THE ACETYLGROUP HERE IN 6857 05:12:41,840 --> 05:12:43,880 OUR MODEL SYSTEM TRANSFERS TO 6858 05:12:43,880 --> 05:12:44,480 CYSTEINE SIDE CHAINS AND 6859 05:12:44,480 --> 05:12:46,120 EVENTUALLY TO AMINE SIDE CHAIN, 6860 05:12:46,120 --> 05:12:47,360 SO WE WANTED TO STUDY WHETHER 6861 05:12:47,360 --> 05:12:49,920 THE ACETYLGROUP HERE DOES 6862 05:12:49,920 --> 05:12:51,040 SOMETHING SIMILAR IN THIS 6863 05:12:51,040 --> 05:12:53,120 COMPLICATED PROTEIN PUTTING 6864 05:12:53,120 --> 05:12:54,440 ACETYLGROUPS ON HIV GAG. 6865 05:12:54,440 --> 05:12:56,720 THEY WE STUDY THIS IS MASS 6866 05:12:56,720 --> 05:12:58,480 SPECTROMETRY, I WILL MENTION ALL 6867 05:12:58,480 --> 05:12:59,840 DONE BY WORK BY LISA JENKINS AT 6868 05:12:59,840 --> 05:13:01,440 NCI. 6869 05:13:01,440 --> 05:13:03,440 SO I WANT TO GO THROUGH THIS ON 6870 05:13:03,440 --> 05:13:04,480 THE STRUCTURE MODEL OF GAG. 6871 05:13:04,480 --> 05:13:05,360 I WANT TO ORIENT YOU A LITTLE 6872 05:13:05,360 --> 05:13:06,920 BIT AND PROTEIN STRUCTURE SHOWN 6873 05:13:06,920 --> 05:13:09,480 UP HERE IS THE MATRIX DOMAIN OF 6874 05:13:09,480 --> 05:13:09,880 GAG. 6875 05:13:09,880 --> 05:13:12,280 THERE ARE TWO DOMAINS FOR THE 6876 05:13:12,280 --> 05:13:14,680 CAPSID, THERE'S THE END TERMINAL 6877 05:13:14,680 --> 05:13:16,680 DOMAIN OF CAPSID AND C TERMINAL 6878 05:13:16,680 --> 05:13:18,720 AND NUCLEAR CAPSID IS HERE. 6879 05:13:18,720 --> 05:13:19,880 HIGHLIGHTED AMINO ACID SIDE 6880 05:13:19,880 --> 05:13:21,600 CHANGES ARE RESIDUES THAT 6881 05:13:21,600 --> 05:13:23,520 RECEIVE ACETYLGROUP FROM 247 6882 05:13:23,520 --> 05:13:23,800 MOLECULE. 6883 05:13:23,800 --> 05:13:25,000 I WANT TO ZOOM ON THIS 6884 05:13:25,000 --> 05:13:30,840 INDIVIDUAL REGIONS. 6885 05:13:30,840 --> 05:13:34,160 GREEN SIDE CHAINS ARE LIE LYSINE 6886 05:13:34,160 --> 05:13:38,320 THAT IS ACETYLATED BY THE 6887 05:13:38,320 --> 05:13:40,560 MOLECULE, CYSTEINE 57 RECEIVES 6888 05:13:40,560 --> 05:13:40,920 ACETYLGROUP. 6889 05:13:40,920 --> 05:13:42,400 THIS IS AN EXAMPLE BASIC 6890 05:13:42,400 --> 05:13:45,720 REACTIVITY I SHOWED YOU IS 6891 05:13:45,720 --> 05:13:46,760 RECAPITULATED IN PROTEIN FORM. 6892 05:13:46,760 --> 05:13:49,480 YOU CAN SEE CYSTEINE FOLLOWED BY 6893 05:13:49,480 --> 05:13:52,280 LYSINE INDICATING FIRST REACTION 6894 05:13:52,280 --> 05:13:53,480 CYSTEINE FOLLOWED BY TYPE OF 6895 05:13:53,480 --> 05:13:54,720 INTRAMOLECULAR TRANSFER TO 6896 05:13:54,720 --> 05:13:57,640 SURROUNDING LYSINES IN THE 6897 05:13:57,640 --> 05:13:58,000 PROTEIN. 6898 05:13:58,000 --> 05:14:00,280 IF YOU LOOK AT CAPSID, THERE IS 6899 05:14:00,280 --> 05:14:02,200 A SIMILAR SITUATION WITH TWO 6900 05:14:02,200 --> 05:14:03,240 CYSTEINES NEARBY FOLLOWED BY 6901 05:14:03,240 --> 05:14:07,080 SOME LYSINES IN GREEN, PURPLE 6902 05:14:07,080 --> 05:14:08,760 HERE, AND NUCLEAR CAPSID HIGHLY 6903 05:14:08,760 --> 05:14:09,480 AS TELLATED. 6904 05:14:09,480 --> 05:14:11,480 MORE DETAIL IN NUCLEAR CAPSID IN 6905 05:14:11,480 --> 05:14:12,840 THE FOLLOWING SLOT. 6906 05:14:12,840 --> 05:14:14,400 BEFORE I MOVE ON I WANT TO 6907 05:14:14,400 --> 05:14:15,640 MENTION THERE ARE MORE LYSINES 6908 05:14:15,640 --> 05:14:18,480 IN THIS PROTEIN, THEN ARE 6909 05:14:18,480 --> 05:14:20,160 ACETYLATED MEANING NOT EVERY 6910 05:14:20,160 --> 05:14:22,480 LYSINE RECEIVES ACETYLGROUP, 6911 05:14:22,480 --> 05:14:24,440 RATHER THERE SEEMS TO BE A 6912 05:14:24,440 --> 05:14:26,000 SPECIFIC REACTIVITY PATTERN WE 6913 05:14:26,000 --> 05:14:28,360 THINK WHICH IS GOVERNED BY FIRST 6914 05:14:28,360 --> 05:14:29,480 REACTION CYSTEINES FOLLOWED BY 6915 05:14:29,480 --> 05:14:32,080 TRANSFER TO LYSINE. 6916 05:14:32,080 --> 05:14:33,840 NUCLEAR CAPSID IS WHERE WE THINK 6917 05:14:33,840 --> 05:14:35,480 THE ACTUAL BUSINESS END OF THE 6918 05:14:35,480 --> 05:14:37,520 ACTIVITY IS TAKING PLACE. 6919 05:14:37,520 --> 05:14:39,280 WANT TO GO DOWN TO MORE DETAIL 6920 05:14:39,280 --> 05:14:40,880 NUCLEAR CAPSID REPRESENTED BY 6921 05:14:40,880 --> 05:14:41,440 BLUE DOT. 6922 05:14:41,440 --> 05:14:44,040 NUCLEAR CAPSID IN HIV GAG IS 55 6923 05:14:44,040 --> 05:14:46,960 AMINO ACIDS LONG, THE ONLY 6924 05:14:46,960 --> 05:14:48,400 STRUCTURE WITHIN THIS SMALL 6925 05:14:48,400 --> 05:14:50,280 PROTEIN IS THE COORDINATION OF 6926 05:14:50,280 --> 05:14:53,120 TWO ZINCS BY AMINO ACID SIDE 6927 05:14:53,120 --> 05:14:54,080 CHAIN SHOWN HERE. 6928 05:14:54,080 --> 05:14:57,840 THESE ARE REALLY SMALL ZINC 6929 05:14:57,840 --> 05:14:59,840 FINGERS REFERRED TO AS ZINC 6930 05:14:59,840 --> 05:15:04,080 KNUCKLES AND WE KNOW THAT THE 6931 05:15:04,080 --> 05:15:05,640 MOLECULE 247 REACTS SPECIFICALLY 6932 05:15:05,640 --> 05:15:09,520 INITIALLY WITH THE C TERMINAL 6933 05:15:09,520 --> 05:15:11,680 ZINC KNUCKLE IN THIS HIV NUCLEAR 6934 05:15:11,680 --> 05:15:12,520 CAPSID PROTEIN. 6935 05:15:12,520 --> 05:15:13,680 WE THINK WE HAVE AN 6936 05:15:13,680 --> 05:15:15,880 UNDERSTANDING AS TO WHY. 6937 05:15:15,880 --> 05:15:19,640 WHEN WE LOOK FOR CAREFULLY AT 6938 05:15:19,640 --> 05:15:21,880 THIS PARTICULAR ZINC KNUCKLE, 6939 05:15:21,880 --> 05:15:23,480 ONE AT C TERMINAL END WE CAN SEE 6940 05:15:23,480 --> 05:15:26,760 IT IS IN AN INTERESTING E QUICK 6941 05:15:26,760 --> 05:15:27,040 LIB YUM. 6942 05:15:27,040 --> 05:15:29,760 WHEN THE MOST OF THE FORM OF 6943 05:15:29,760 --> 05:15:33,640 THIS MOLECULE HAS ZINC 6944 05:15:33,640 --> 05:15:36,120 COORDINATED BY HISTINE HISTIDINE 6945 05:15:36,120 --> 05:15:37,720 SIDE CHAIN THAT IS UNREACTIVE 6946 05:15:37,720 --> 05:15:39,680 WITH MOLECULE BUT BY NMR 6947 05:15:39,680 --> 05:15:43,480 DETECTED BY 2% SOLUTION HAS ONE 6948 05:15:43,480 --> 05:15:47,880 OF THE SULFUR ATOMS OFF ZINC, 6949 05:15:47,880 --> 05:15:48,400 FREE THIOL IN SOLUTION. 6950 05:15:48,400 --> 05:15:51,080 THIS IS A RAPID EQUILIBRIUM 6951 05:15:51,080 --> 05:15:52,480 FAVOR IT CAN COORDINATED FORM 6952 05:15:52,480 --> 05:15:54,480 BUT A LITTLE FREE THYOL, IF YOU 6953 05:15:54,480 --> 05:15:55,400 RECALL FROM ACTIVITY THE 6954 05:15:55,400 --> 05:15:58,560 MOLECULE LIKES TO REACT WITH 6955 05:15:58,560 --> 05:16:00,320 THYOLS, WITH THE ACETYLGROUP 6956 05:16:00,320 --> 05:16:02,560 INTERFERING WITH FREE FORM THE 6957 05:16:02,560 --> 05:16:03,680 TRANSFER GROUP ON TO SULFUR 6958 05:16:03,680 --> 05:16:04,280 ATOM. 6959 05:16:04,280 --> 05:16:07,080 AFTER THIS REACTION, THIS 6960 05:16:07,080 --> 05:16:08,840 PREVENTS THE SULFUR FROM 6961 05:16:08,840 --> 05:16:10,840 RECOORDINATING TO ZINC, LOOSENS 6962 05:16:10,840 --> 05:16:11,440 COORDINATION. 6963 05:16:11,440 --> 05:16:13,640 WE KNOWNA THE ZINC FALLS OUT 6964 05:16:13,640 --> 05:16:16,600 RESULTING IN A DENATUREATION, 6965 05:16:16,600 --> 05:16:18,840 THE DENATURE PASTE MAYBE 6966 05:16:18,840 --> 05:16:20,160 FACILITATED BY/WHICH COORDINATES 6967 05:16:20,160 --> 05:16:22,160 TO ZINNC. 6968 05:16:22,160 --> 05:16:24,400 WE KNOW ACETYLGROUP DOESN'T STAY 6969 05:16:24,400 --> 05:16:27,240 ON SULFUR IT REARRANGES TO 6970 05:16:27,240 --> 05:16:29,040 NITROGEN ON SIDE CHAINS NEARBY. 6971 05:16:29,040 --> 05:16:34,800 THIS EXPOSES FREE THIOLS IN 6972 05:16:34,800 --> 05:16:36,040 SOLUTION AND LEADS TO CROSS 6973 05:16:36,040 --> 05:16:38,240 LINKING WITH THE GAG DISULFIDE 6974 05:16:38,240 --> 05:16:41,400 FORMATION WHICH IS KEY FOR THAT 6975 05:16:41,400 --> 05:16:44,160 PHENOTYPE WE SAW WITH HIV LOCKED 6976 05:16:44,160 --> 05:16:45,440 IN IMMATURE STATE. 6977 05:16:45,440 --> 05:16:48,680 SO I WANT TO HIGHLIGHT MECHANISM 6978 05:16:48,680 --> 05:16:54,680 ONE MORE CARTOON FASHION. 6979 05:16:54,680 --> 05:16:56,280 REPRESSURE MEMORY WHEN MOLECULES 6980 05:16:56,280 --> 05:16:57,560 -- CELLS INFECT WITH HIV ARE 6981 05:16:57,560 --> 05:16:58,880 TREATED ARE MOLECULE IT RESULTS 6982 05:16:58,880 --> 05:17:01,080 IN NON-INFECTIOUS IMMATURE 6983 05:17:01,080 --> 05:17:02,200 PARTICLES WE THINK THAT WHAT 6984 05:17:02,200 --> 05:17:04,000 HAPPENS IS OUR MOLECULE REACTS 6985 05:17:04,000 --> 05:17:07,280 WITH GAG, TRANSFERS THE 6986 05:17:07,280 --> 05:17:08,520 ACETYLGROUPS NUCLEAR CAPSID 6987 05:17:08,520 --> 05:17:11,880 DENATURED EXPOSES FREE THIOLS 6988 05:17:11,880 --> 05:17:13,960 AND CROSSES DISULFIDE BONDS THAT 6989 05:17:13,960 --> 05:17:17,280 LINK THE POLYPROTEIN TOGETHER. 6990 05:17:17,280 --> 05:17:18,200 SO THAT WAS IN VIVO. 6991 05:17:18,200 --> 05:17:21,080 THEN WE WANTED TO SEE IS THERE 6992 05:17:21,080 --> 05:17:22,400 EVIDENCE THAT THIS 6993 05:17:22,400 --> 05:17:23,760 ACETYLTRANSFER MECHANISM HAPPENS 6994 05:17:23,760 --> 05:17:26,720 IN AT LEAST IN CELLS. 6995 05:17:26,720 --> 05:17:28,360 TO DO THESE EXPERIMENTS WE 6996 05:17:28,360 --> 05:17:30,400 TREATED HIV INFECTED CELLS WITH 6997 05:17:30,400 --> 05:17:33,080 MOLECULE, THAT PRODUCES VIRIONS 6998 05:17:33,080 --> 05:17:34,800 WE ISOLATED AND LOOK AT GAG FROM 6999 05:17:34,800 --> 05:17:37,160 THESE VIRIONS THAT WE NOTICE 7000 05:17:37,160 --> 05:17:41,320 THAT ALL WAS ACETYLATED IN A 7001 05:17:41,320 --> 05:17:42,280 SIMILAR PATTERN TO SOLUTION. 7002 05:17:42,280 --> 05:17:43,360 SO THAT WAS EXCITING TO SEE 7003 05:17:43,360 --> 05:17:45,920 UNTIL WE WENT BACK AND THOUGHT A 7004 05:17:45,920 --> 05:17:47,120 LITTLE MORE ABOUT REACTIVITY 7005 05:17:47,120 --> 05:17:48,640 PATTERN WE HAD ESTABLISHED. 7006 05:17:48,640 --> 05:17:50,360 IN WHICH WE KNOW THAT OUR 7007 05:17:50,360 --> 05:17:52,880 MOLECULE LIKES TO TRANSFER 7008 05:17:52,880 --> 05:17:55,320 ACETYLGROUPS TO ANY SULFUR IN 7009 05:17:55,320 --> 05:17:56,760 THE CELL. 7010 05:17:56,760 --> 05:17:58,280 CYSTEINE SIDE CHAINS GLUE 7011 05:17:58,280 --> 05:18:00,280 TATHIONE COA ANYTHING. 7012 05:18:00,280 --> 05:18:02,480 SO DIDN'T MAKE SENSE IN A CELL 7013 05:18:02,480 --> 05:18:04,680 THIS 247 WITH ACETYLGROUP 7014 05:18:04,680 --> 05:18:06,280 SURVIVE LONG ENOUGH TO BOUND TO 7015 05:18:06,280 --> 05:18:08,080 GAG AND DO THIS REACTION. 7016 05:18:08,080 --> 05:18:09,120 SO THE ANSWER BECAME A LITTLE 7017 05:18:09,120 --> 05:18:11,960 BIT MORE CLEAR WHEN WE THEN WENT 7018 05:18:11,960 --> 05:18:18,880 TO LOOK MORE AT THE GAG WE 7019 05:18:18,880 --> 05:18:23,880 LOOKED AT. 7020 05:18:23,880 --> 05:18:25,320 I DON'T KNOW WHAT I DID. 7021 05:18:25,320 --> 05:18:25,840 SORRY. 7022 05:18:25,840 --> 05:18:28,600 THIS IS WHEN I START APOLOGIZING 7023 05:18:28,600 --> 05:18:34,680 FOR THE COMPUTER. 7024 05:18:34,680 --> 05:18:37,280 I WILL UNPLUG AND PLUG IT BACK 7025 05:18:37,280 --> 05:18:47,800 IN. 7026 05:18:47,800 --> 05:18:48,560 I WAS. 7027 05:18:48,560 --> 05:18:49,680 PUNCH LINE IS RUINED. 7028 05:18:49,680 --> 05:19:10,280 I'M SORRY. 7029 05:19:10,280 --> 05:19:20,400 CABLE MIC WENT BAD. 7030 05:19:20,400 --> 05:19:27,080 WE ARE BACK. 7031 05:19:27,080 --> 05:19:29,840 IT IS TELLING ME TO SPEED UP. 7032 05:19:29,840 --> 05:19:31,960 úANYWAY, SO IF YOU REMEMBERWHAT 7033 05:19:31,960 --> 05:19:33,160 WHERE I WAS LOOKING AT 7034 05:19:33,160 --> 05:19:33,880 ACETYLGROUPS ON THE GAG AFTER 7035 05:19:33,880 --> 05:19:37,560 TREATING WITH CELL AND LOOK AT 7036 05:19:37,560 --> 05:19:39,680 ACETYLGROUPS ON THE GAG NONE 7037 05:19:39,680 --> 05:19:41,680 CAME FROM ORIGINAL MOLECULE, ALL 7038 05:19:41,680 --> 05:19:44,640 FROM ACETYLCOA. 7039 05:19:44,640 --> 05:19:47,160 WHERE DID THE ACETYLGROUPS GO, 7040 05:19:47,160 --> 05:19:49,480 SO IN THIS BASIC REACTION, THIS 7041 05:19:49,480 --> 05:19:51,040 PHTHALATE PRODUCED IS NOT 7042 05:19:51,040 --> 05:19:52,400 INNOCENT. 7043 05:19:52,400 --> 05:19:54,160 RATHER THAT PHTHALATE 7044 05:19:54,160 --> 05:19:55,040 REGENERATES THE ORIGINAL 7045 05:19:55,040 --> 05:19:57,200 MOLECULE BY INTERACTION WITH 7046 05:19:57,200 --> 05:19:57,720 ACETYLCOA. 7047 05:19:57,720 --> 05:20:02,040 SO THE WAY THIS WORKS IS THAT 7048 05:20:02,040 --> 05:20:04,880 CHAIN CELLS WITH 247 LOSES 7049 05:20:04,880 --> 05:20:06,760 ACETYLGROUP TO GLUE TATHIONE AND 7050 05:20:06,760 --> 05:20:08,200 PERFORMS A PHTHALATE, THAT 7051 05:20:08,200 --> 05:20:10,480 REACTS TO ACETYLCOA TO 7052 05:20:10,480 --> 05:20:11,800 REGENERATE ITSELF TO GET 7053 05:20:11,800 --> 05:20:13,320 ACETYLGROUP TO REFORM AND CARRY 7054 05:20:13,320 --> 05:20:14,600 OUT REACTIONS IN CELLS. 7055 05:20:14,600 --> 05:20:17,520 SO THE REALLY INTERESTING 7056 05:20:17,520 --> 05:20:20,200 MECHANISM GOING ON IN CELLS, 7057 05:20:20,200 --> 05:20:22,720 WHICH I AM DIAGRAMMING HERE, IN 7058 05:20:22,720 --> 05:20:24,720 CELLS YELLOW BLOB IS CELL, 7059 05:20:24,720 --> 05:20:27,680 INFECTED WITH HIV, WE CAN TREAT 7060 05:20:27,680 --> 05:20:29,920 THIS CELL WITH 247 BUT IT 7061 05:20:29,920 --> 05:20:33,520 RAPIDLY LOSES ACETYLGROUP TO ANY 7062 05:20:33,520 --> 05:20:35,240 AVAILABLE THIOL, GLUE TATHIONE 7063 05:20:35,240 --> 05:20:38,080 POLYIN PARTICULAR AND IN CELLS 7064 05:20:38,080 --> 05:20:39,320 THIS INTERMEDIATE, PHTHALATE IS 7065 05:20:39,320 --> 05:20:42,680 MAJOR SPECIES THAT HANGS OUT A 7066 05:20:42,680 --> 05:20:44,760 LOT AND DOES PROBABLY NOT MUCH. 7067 05:20:44,760 --> 05:20:47,280 THE MOLECULE CAN INTERACT WITH 7068 05:20:47,280 --> 05:20:49,480 ACETYLCOA TO REGENERATE 247 AND 7069 05:20:49,480 --> 05:20:53,000 PROBABLY CYCLES BACK AND FORTH 7070 05:20:53,000 --> 05:20:54,800 ACETYLATING AND LOSING 7071 05:20:54,800 --> 05:20:55,840 ACETYLGROUP MANY TIMES. 7072 05:20:55,840 --> 05:20:57,480 WE THINK IT IS ONLY REALLY IN 7073 05:20:57,480 --> 05:21:01,040 THE CONTEXT OF WHEN SOMETHING 7074 05:21:01,040 --> 05:21:02,280 LIKE HIV GAG CRUNCHES TOGETHER 7075 05:21:02,280 --> 05:21:04,440 TO FORM A HIGH EFFECTIVE 7076 05:21:04,440 --> 05:21:06,080 CONCENTRATION THAT THERE IS 7077 05:21:06,080 --> 05:21:07,840 ENOUGH 247 IN THE CONTEXT OF 7078 05:21:07,840 --> 05:21:10,760 ASSEMBLY IT IS ABLE TO GO IN 7079 05:21:10,760 --> 05:21:12,440 ACETYLATE THE SMALL AMOUNT OF 7080 05:21:12,440 --> 05:21:14,880 NUCLEAR CAPSID AND THE OTHER 7081 05:21:14,880 --> 05:21:17,080 THIOLS IN GAG START 7082 05:21:17,080 --> 05:21:18,960 DENATUREATION AND LEAD TO CROSS 7083 05:21:18,960 --> 05:21:21,560 NIHING WE SEE COMING OUT. 7084 05:21:21,560 --> 05:21:23,240 SO THAT WAS AN INTERESTING STORY 7085 05:21:23,240 --> 05:21:25,280 BUT I WANT TO GO BACK NOW TO 7086 05:21:25,280 --> 05:21:27,440 THESE DATA AND ALSO MY 7087 05:21:27,440 --> 05:21:30,840 DISCUSSIONS WITH BETHA HOW DO WE 7088 05:21:30,840 --> 05:21:32,480 UNDERSTAND WHY COMBINATION OF 7089 05:21:32,480 --> 05:21:34,160 MOLECULES OF VACCINE WORK SO 7090 05:21:34,160 --> 05:21:36,200 WELL. 7091 05:21:36,200 --> 05:21:38,160 AND IT WAS BETHA WHO POINTED OUT 7092 05:21:38,160 --> 05:21:40,200 WHILE ANTIVIRAL ACTIVITY IN 7093 05:21:40,200 --> 05:21:41,720 MECHANISMS ARE ALL NICE IT 7094 05:21:41,720 --> 05:21:43,200 DOESN'T EXPLAIN THIS IMPROVEMENT 7095 05:21:43,200 --> 05:21:44,400 THAT WE SEE. 7096 05:21:44,400 --> 05:21:46,840 SO THAT RAISES THE QUESTION IS 7097 05:21:46,840 --> 05:21:48,360 THERE ANOTHER MECHANISM FOR THIS 7098 05:21:48,360 --> 05:21:49,680 MOLECULE I ADMIT IS ENTIRELY 7099 05:21:49,680 --> 05:21:52,320 POSSIBLE. 7100 05:21:52,320 --> 05:21:54,680 SO BETHA STARTED LISTING THE 7101 05:21:54,680 --> 05:21:56,400 FACTORS THAT SHE CAREFULLY 7102 05:21:56,400 --> 05:21:57,960 CHARACTERIZED THAT SORT OF LEAD 7103 05:21:57,960 --> 05:22:00,600 TO A REDUCTION IN EFFICACY OF 7104 05:22:00,600 --> 05:22:00,960 HER VACCINE. 7105 05:22:00,960 --> 05:22:02,480 SHE JUST HAPPENED TO MENTION IN 7106 05:22:02,480 --> 05:22:05,920 HER LIST THIS PARTICULAR PROTEIN 7107 05:22:05,920 --> 05:22:08,280 ZZ 3H 7A NEGATIVE REGULARLY TORR 7108 05:22:08,280 --> 05:22:09,360 OF VACCINE, THE Z PROTEIN FOR 7109 05:22:09,360 --> 05:22:11,960 SHORT. 7110 05:22:11,960 --> 05:22:15,600 THIS HAPPENS TO BE RNA BINDING 7111 05:22:15,600 --> 05:22:17,520 ZINC FINGER DOMAIN, THEY ALL 7112 05:22:17,520 --> 05:22:21,400 HAVE ZINC COORDINATED BASISSTEEN 7113 05:22:21,400 --> 05:22:21,920 AND HISTIDINE. 7114 05:22:21,920 --> 05:22:24,040 THERE'S NOT A TON KNOWN ABOUT 7115 05:22:24,040 --> 05:22:26,840 THIS PARTICULAR PROTEIN IT IS 7116 05:22:26,840 --> 05:22:28,920 KNOWN mRNA LEVELS OF PROTEIN 7117 05:22:28,920 --> 05:22:32,280 INCREASE AND LIPO POLYSACCHARIDE 7118 05:22:32,280 --> 05:22:33,880 INDUCE MACROPHAGES BUT MOLECULE 7119 05:22:33,880 --> 05:22:35,360 LIKES TO REACTS WITH THESE TYPES 7120 05:22:35,360 --> 05:22:36,800 OF ZINC FINGERS. 7121 05:22:36,800 --> 05:22:39,000 SO WE THOUGHT THIS COULD BE 7122 05:22:39,000 --> 05:22:40,760 ANOTHER TARGET AND GOING TO 7123 05:22:40,760 --> 05:22:42,760 BRIEFLY MENTION WE HAVE 7124 05:22:42,760 --> 05:22:44,880 COMPLETED A EXPRESSION OF 7125 05:22:44,880 --> 05:22:46,200 RECOMBINANT PORTION OF PROTEIN 7126 05:22:46,200 --> 05:22:49,040 THAT HAS ZINC FINGERS AND WE DO 7127 05:22:49,040 --> 05:22:50,280 KNOW WE OBSERVED THAT OUR 7128 05:22:50,280 --> 05:22:52,000 MOLECULE DOES REACT WITH ONE OF 7129 05:22:52,000 --> 05:22:54,280 THE FOUR ZINC FINGER DOMAINS IN 7130 05:22:54,280 --> 05:22:55,800 RECOMBINANT PROTEIN. 7131 05:22:55,800 --> 05:22:56,920 THAT IS YET TO BE DETERMINED 7132 05:22:56,920 --> 05:22:58,280 WHETHER IT HAPPENS IN CELLS BUT 7133 05:22:58,280 --> 05:23:01,640 I THINK IT MAY BE ENTIRELY 7134 05:23:01,640 --> 05:23:04,080 POSSIBLE THAT MOLECULE DOES 7135 05:23:04,080 --> 05:23:07,120 KNOCK OUT ONE OF THE NEGATIVE 7136 05:23:07,120 --> 05:23:10,680 REGULATORS OF THAT COULD EXPLAIN 7137 05:23:10,680 --> 05:23:12,160 ENHANCEMENT WE ARE SEEING. 7138 05:23:12,160 --> 05:23:13,880 I STILL HOPE ANTIVIRAL MECHANISM 7139 05:23:13,880 --> 05:23:14,720 IS ALSO CONTRIBUTING. 7140 05:23:14,720 --> 05:23:15,880 BECAUSE WE DID A LOT OF WORK ON 7141 05:23:15,880 --> 05:23:21,000 IT. 7142 05:23:21,000 --> 05:23:22,320 SO THAT IS MY TALK. 7143 05:23:22,320 --> 05:23:23,680 BRIEFLY TO CONCLUDES SHOW YOU 7144 05:23:23,680 --> 05:23:26,680 INTERESTING THINGS, CAN COMBINE 7145 05:23:26,680 --> 05:23:28,440 MICROBE SIDE WITH VACCINE TO 7146 05:23:28,440 --> 05:23:30,880 IMPROVE PROTECTION IN SIV 7147 05:23:30,880 --> 05:23:33,400 INFECTION IN RHESUS MACAQUES. 7148 05:23:33,400 --> 05:23:36,720 IT IS A COMPLICATED MECHANISM 7149 05:23:36,720 --> 05:23:42,840 FOR THE MOLECULE IN ACETYLATES 7150 05:23:42,840 --> 05:23:44,760 AND CYSTEINES IN LYSINES OF HIV 7151 05:23:44,760 --> 05:23:47,040 GAG, BOTH IN VITRO AND IN CELLS. 7152 05:23:47,040 --> 05:23:51,800 E DENATURES NUCLEOCAPSID IN HIV 7153 05:23:51,800 --> 05:23:54,720 GAG, IT INVOLVES ACETYLCOA, 7154 05:23:54,720 --> 05:23:56,960 MULTIPLE ACETYLTRANSFERS AND 7155 05:23:56,960 --> 05:23:58,640 WERE -- YOU CAN FORMULATE THIS 7156 05:23:58,640 --> 05:24:00,760 AS A GEL, TRYING TO FORMULATE 7157 05:24:00,760 --> 05:24:02,800 THIS INTO OTHER DELIVERY DEVICES 7158 05:24:02,800 --> 05:24:05,160 CURRENTLY. 7159 05:24:05,160 --> 05:24:06,480 SO FINALLY, LET ME ACKNOWLEDGE A 7160 05:24:06,480 --> 05:24:08,680 NUMBER OF PEOPLE, POST-DOCS IN 7161 05:24:08,680 --> 05:24:10,680 MY LAB, MARK HAS BEEN THE PLANS 7162 05:24:10,680 --> 05:24:11,760 BILL POE DOC INVOLVED. 7163 05:24:11,760 --> 05:24:14,080 THIS IS A HIGHLY COLLABORATIVE 7164 05:24:14,080 --> 05:24:17,400 PROJECT, I MENTIONED BETHA AND 7165 05:24:17,400 --> 05:24:18,480 MARJORIE KEY NOVEMBERING 7166 05:24:18,480 --> 05:24:19,640 FORWARD. 7167 05:24:19,640 --> 05:24:21,840 LISA DOING MASS SPECTROMETRY. 7168 05:24:21,840 --> 05:24:23,160 MANY COLLABORATORS OVER THE 7169 05:24:23,160 --> 05:24:24,240 YEARS CONTRIBUTE TO THIS. 7170 05:24:24,240 --> 05:24:25,600 AND FINALLY LET ME THANK YOU FOR 7171 05:24:25,600 --> 05:24:26,600 YOUR ATTENTION. 7172 05:24:26,600 --> 05:24:35,000 [APPLAUSE] 7173 05:24:35,000 --> 05:24:36,480 >> I'M GOING TO TAKE THE FIRST 7174 05:24:36,480 --> 05:24:37,240 QUESTION. 7175 05:24:37,240 --> 05:24:38,080 >> OKAY. 7176 05:24:38,080 --> 05:24:40,560 >> SO IS THERE A WAY YOU CAN 7177 05:24:40,560 --> 05:24:43,240 TARGET THIS MOLECULE TO HIV 7178 05:24:43,240 --> 05:24:50,520 INFECTED LATENT CELLS IN PEOPLE? 7179 05:24:50,520 --> 05:24:51,440 >> SORT OF. 7180 05:24:51,440 --> 05:24:55,320 WE PROBABLY COULD IN THEORY. 7181 05:24:55,320 --> 05:24:56,880 IF THERE WAS A GOOD TARGETING 7182 05:24:56,880 --> 05:24:58,800 AGENT. 7183 05:24:58,800 --> 05:25:00,240 THAT YOU WANTED ME TO LINK IT 7184 05:25:00,240 --> 05:25:03,080 WITH I PROBABLY COULD. 7185 05:25:03,080 --> 05:25:04,520 WHEN PEOPLE ASKED ABOUT LATENCY 7186 05:25:04,520 --> 05:25:07,360 I GET A RILLET DEFENSIVE BECAUSE 7187 05:25:07,360 --> 05:25:08,600 I DON'T KNOW AND I DON'T THINK A 7188 05:25:08,600 --> 05:25:09,880 LOT OF PEOPLE KNOW. 7189 05:25:09,880 --> 05:25:12,240 I ALMOST SUGGESTED TO PEOPLE 7190 05:25:12,240 --> 05:25:14,960 JUST BLAST SOMEONE WITH A 7191 05:25:14,960 --> 05:25:17,280 MOLECULE, IT IS PRETTY WELL 7192 05:25:17,280 --> 05:25:18,880 TOLERATED. 7193 05:25:18,880 --> 05:25:19,960 AMONG ANIMALS, YOU CAN GO UP TO 7194 05:25:19,960 --> 05:25:22,400 HIGH CONCENTRATIONS, THE OTHER 7195 05:25:22,400 --> 05:25:24,400 THING I LIKE IS IT IS REALLY 7196 05:25:24,400 --> 05:25:24,600 SMALL. 7197 05:25:24,600 --> 05:25:27,600 COMPARED TO OTHER DRUGS, WHICH I 7198 05:25:27,600 --> 05:25:31,120 ALWAYS FEEL HAVE A BIT OF 7199 05:25:31,120 --> 05:25:35,080 PERMEATION PROBLEM THIS IS TINY 7200 05:25:35,080 --> 05:25:35,960 SO IT SHOULD OOZE ITS WAY AROUND 7201 05:25:35,960 --> 05:25:38,280 REALLY WELL. 7202 05:25:38,280 --> 05:25:42,280 I WOULD LOVE TO TEST IT. 7203 05:25:42,280 --> 05:25:45,040 SO LET ME SAY I'M A KISS PLAYER 7204 05:25:45,040 --> 05:25:46,600 OF THE MOLECULE, IF IT IS 7205 05:25:46,600 --> 05:25:48,040 AVAILABLE COMMERCIALLY DON'T BUY 7206 05:25:48,040 --> 05:25:50,280 IT COMMERCIALLY TALK TO ME. 7207 05:25:50,280 --> 05:25:51,600 I CAN DISTRIBUTE IT OUT. 7208 05:25:51,600 --> 05:25:53,080 ALTHOUGH -- YEAH. 7209 05:25:53,080 --> 05:25:54,640 I SORT OF PICK AND CHOOSE 7210 05:25:54,640 --> 05:25:56,280 BECAUSE I LIKE TO GET DATA BACK 7211 05:25:56,280 --> 05:25:58,280 AND I'M ALWAYS INTERESTED TO SEE 7212 05:25:58,280 --> 05:26:00,080 ANY MORE FEEDBACK HOW WE CAN 7213 05:26:00,080 --> 05:26:03,440 PUSH FORWARD. 7214 05:26:03,440 --> 05:26:07,920 >> VERY INTERESTING CHEMISTRY 7215 05:26:07,920 --> 05:26:09,600 AND -- 7216 05:26:09,600 --> 05:26:12,040 >> THERE IS A LONG HISTORY, 7217 05:26:12,040 --> 05:26:13,800 THERE'S MANY MOLECULES AS YOU 7218 05:26:13,800 --> 05:26:17,000 KNOW THAT INTERACT WITH 7219 05:26:17,000 --> 05:26:20,200 CYSTEINES SH GROUPS, PROTEINS 7220 05:26:20,200 --> 05:26:23,000 AND WITH GROUPS OF LYSINES AND 7221 05:26:23,000 --> 05:26:23,440 SO FORTH. 7222 05:26:23,440 --> 05:26:25,520 THAT MIGHT MIMIC SOME OF THESE 7223 05:26:25,520 --> 05:26:27,640 EFFECTS AND IN PARTICULAR WITH 7224 05:26:27,640 --> 05:26:30,720 ONE OF THE THINGS THAT COMES TO 7225 05:26:30,720 --> 05:26:33,080 MIND IS THAT LYNN HURSTBURG FOR 7226 05:26:33,080 --> 05:26:34,640 MANY YEARS PUSHED THE IDEA OF 7227 05:26:34,640 --> 05:26:38,080 USING N ACETYLCYSTEINE TO TREAT 7228 05:26:38,080 --> 05:26:39,200 HIV AND THERE WERE PEOPLE WHO 7229 05:26:39,200 --> 05:26:42,720 WERE TAKING HIGH DOSES OF NS 7230 05:26:42,720 --> 05:26:46,200 CYSTEINE AS A PROPHYLACTIC 7231 05:26:46,200 --> 05:26:47,320 AGAINST HIV INFECTION. 7232 05:26:47,320 --> 05:26:50,280 THERE WAS SOME EVIDENCE FOR 7233 05:26:50,280 --> 05:26:51,880 POSSIBLE EFFICACY, I HAVEN'T 7234 05:26:51,880 --> 05:26:53,320 FOLLOWED IT IN GREAT DETAIL. 7235 05:26:53,320 --> 05:26:56,520 BUT I'M WONDERING WHETHER 7236 05:26:56,520 --> 05:26:58,360 THERE'S SOME CONNECTION HERE. 7237 05:26:58,360 --> 05:27:00,680 >> POSSIBLY. 7238 05:27:00,680 --> 05:27:02,760 I KNOW SOMEWHAT FAMILIAR WITH 7239 05:27:02,760 --> 05:27:04,520 THE N ACETYLSTORY, PART OF THE 7240 05:27:04,520 --> 05:27:07,240 PROBLEM IS BIOAVAILABILITY AND 7241 05:27:07,240 --> 05:27:09,040 METABOLISM BODIES AN CELLS KNOW 7242 05:27:09,040 --> 05:27:10,200 HOW TO METABOLIZE IT. 7243 05:27:10,200 --> 05:27:12,320 AND THAT MIGHT BE PART OF IT. 7244 05:27:12,320 --> 05:27:15,000 >> PRIMARILY REDUCING AGENT BUT 7245 05:27:15,000 --> 05:27:16,480 PUT TUMOR ETHANOL IN OUR 7246 05:27:16,480 --> 05:27:16,880 CULTURES. 7247 05:27:16,880 --> 05:27:17,120 >> YEAH. 7248 05:27:17,120 --> 05:27:17,440 YEAH. 7249 05:27:17,440 --> 05:27:18,120 YEAH. 7250 05:27:18,120 --> 05:27:18,720 YEAH. 7251 05:27:18,720 --> 05:27:20,240 YEAH VERY HIGH DOSES WERE USED 7252 05:27:20,240 --> 05:27:21,440 AND THEY ARE TOLERATED. 7253 05:27:21,440 --> 05:27:23,520 I DON'T THINK THE EFFECTS WERE 7254 05:27:23,520 --> 05:27:24,600 VERY PROMINENT IF I REMEMBER 7255 05:27:24,600 --> 05:27:26,920 CORRECTLY. 7256 05:27:26,920 --> 05:27:28,520 THAT IS WHAT I REMEMBER. 7257 05:27:28,520 --> 05:27:30,080 BUT IT IS -- YEAH. 7258 05:27:30,080 --> 05:27:32,320 >> STILL TARGETING CYSTEINES. 7259 05:27:32,320 --> 05:27:38,360 >> YOU ARE TARGETING CYSTEINES. 7260 05:27:38,360 --> 05:27:41,000 I HESITATE TO GO IN THIS 7261 05:27:41,000 --> 05:27:42,000 DIRECTION BECAUSE IT GETS FUZZY, 7262 05:27:42,000 --> 05:27:43,800 IT IS A REDUCING AGENTS AND SURE 7263 05:27:43,800 --> 05:27:47,840 OURS IS A A REDUCING AGENT AS 7264 05:27:47,840 --> 05:27:48,520 WELL. 7265 05:27:48,520 --> 05:27:50,840 THERE IS BY-PRODUCT ACETYLATION 7266 05:27:50,840 --> 05:27:52,480 PATHWAYNA MIGHT BE UNIQUE TO 7267 05:27:52,480 --> 05:27:53,520 OURS. 7268 05:27:53,520 --> 05:27:55,840 I FEEL LIKE IN ADDITION TO SORT 7269 05:27:55,840 --> 05:27:56,960 OF CHANGING REDUCING ENVIRONMENT 7270 05:27:56,960 --> 05:28:00,720 TO SOME DEGREE, I THINK WE ARE 7271 05:28:00,720 --> 05:28:03,360 SHUFFLING THIS ACETYLGROUPS IN 7272 05:28:03,360 --> 05:28:06,680 ODD WAY PERHAPS, THERE IS AN 7273 05:28:06,680 --> 05:28:08,080 ACETYLOME IN THE CELLS THAT IS 7274 05:28:08,080 --> 05:28:09,320 IMPORTANT, MAYBE TWEAKING THAT 7275 05:28:09,320 --> 05:28:12,480 ON TOP OF EVERYTHING ELSE. 7276 05:28:12,480 --> 05:28:17,920 >> THERE'S ESTERS PEOPLE USE TO 7277 05:28:17,920 --> 05:28:19,960 TARGET LYSINES OR TO TARGET 7278 05:28:19,960 --> 05:28:20,520 CYSTEINES. 7279 05:28:20,520 --> 05:28:20,760 >> SURE. 7280 05:28:20,760 --> 05:28:21,480 YEAH. 7281 05:28:21,480 --> 05:28:23,280 ABSOLUTELY BUT THOSE ARE -- I 7282 05:28:23,280 --> 05:28:25,720 THINK NOT SORT OF -- THOSE ARE 7283 05:28:25,720 --> 05:28:27,360 ONE AND DONE REACTIONS IF I 7284 05:28:27,360 --> 05:28:28,440 REMEMBER CORRECTLY. 7285 05:28:28,440 --> 05:28:30,560 I MEAN, THERE ARE LOTS OF DRUGS 7286 05:28:30,560 --> 05:28:32,280 THAT HAVE COVALENT WAR HEAD 7287 05:28:32,280 --> 05:28:34,680 WHETHER THEY KIND OF COME IN AND 7288 05:28:34,680 --> 05:28:35,600 SLAP ON A GROUP AND THEY ARE 7289 05:28:35,600 --> 05:28:36,720 DONE AND USUALLY THEY HAVE A 7290 05:28:36,720 --> 05:28:38,600 TARGETING EFFECT WHERE THERE'S 7291 05:28:38,600 --> 05:28:39,440 SOMETHING BINDING. 7292 05:28:39,440 --> 05:28:40,760 THIS DOESN'T BIND TO ANYTHING. 7293 05:28:40,760 --> 05:28:42,080 AS FAR AS I CAN TELL. 7294 05:28:42,080 --> 05:28:43,800 IT JUST HAS A REACTION THAT 7295 05:28:43,800 --> 05:28:48,400 TAKES PLACE, ALMOST LIKE 7296 05:28:48,400 --> 05:28:49,160 METABOLITE. 7297 05:28:49,160 --> 05:28:52,000 ' IN SOME WAY SO SEEMS TO EFFECT 7298 05:28:52,000 --> 05:28:55,080 THINGS AT MUCH SORT OF METABOLIC 7299 05:28:55,080 --> 05:28:59,800 WAY. 7300 05:28:59,800 --> 05:29:00,920 >> I DON'T KNOW IF YOU MENTION 7301 05:29:00,920 --> 05:29:03,200 DON'T YOU EXPECT TO MOLECULAR TO 7302 05:29:03,200 --> 05:29:09,680 BE ANGIOGENIC IN LONG TERM 7303 05:29:09,680 --> 05:29:13,920 BECAUSE (INAUDIBLE) HOW LONG 7304 05:29:13,920 --> 05:29:16,800 HAVE YOU GIVEN IT TO MACAQUES 7305 05:29:16,800 --> 05:29:20,640 AND CAN YOU TELL THAT -- BECAUSE 7306 05:29:20,640 --> 05:29:25,600 YOU WANTED PROLONG LET'S SAY 7307 05:29:25,600 --> 05:29:28,680 EXPOSURE, IS IT REACT GENIC? 7308 05:29:28,680 --> 05:29:30,760 >> WE HAVE NOT THIS PARTICULAR 7309 05:29:30,760 --> 05:29:32,480 FORMULATION BUT I HAVE ORALLY 7310 05:29:32,480 --> 05:29:35,240 BIOAVAILABLE FORMULATION OF THIS 7311 05:29:35,240 --> 05:29:36,080 MOLECULE. 7312 05:29:36,080 --> 05:29:38,080 WE HAVE GIVEN ORALLY TO MACAQUES 7313 05:29:38,080 --> 05:29:41,320 FOR OVER SIX MONTHS AND THEY 7314 05:29:41,320 --> 05:29:42,880 SEEM FINE. 7315 05:29:42,880 --> 05:29:44,600 THIS COMES UP ALL THE TIME AND 7316 05:29:44,600 --> 05:29:46,320 PROBABLY ONE OF THE MAIN REASONS 7317 05:29:46,320 --> 05:29:47,280 WHY I HAVE TROUBLE ADVANCING 7318 05:29:47,280 --> 05:29:49,600 THIS MOLECULE BECAUSE EVERYBODY 7319 05:29:49,600 --> 05:29:50,480 SAYS THIS IS NON-SPECIFIC AND 7320 05:29:50,480 --> 05:29:53,760 GOING TO BE TOXIC AND JUST 7321 05:29:53,760 --> 05:29:55,040 HAVEN'T FOUND TOXICITY YET. 7322 05:29:55,040 --> 05:29:56,480 I'M STILL LOOKING FOR THE 7323 05:29:56,480 --> 05:29:57,360 TOXICITY, I HAVEN'T FOUND IT 7324 05:29:57,360 --> 05:29:58,000 YET. 7325 05:29:58,000 --> 05:30:01,120 NOW, I WILL SAY A COUPLE OF 7326 05:30:01,120 --> 05:30:02,480 THINGS. 7327 05:30:02,480 --> 05:30:05,080 WE ARE PERTURBING THINGS BUT I 7328 05:30:05,080 --> 05:30:09,120 DO THINK THAT THERE IS A 7329 05:30:09,120 --> 05:30:10,400 SELECTIVE ENVIRONMENT WHICH THIS 7330 05:30:10,400 --> 05:30:12,080 MOLECULE EVEN BECOMES ACTIVE. 7331 05:30:12,080 --> 05:30:14,640 I THINK IT IS UNREACTIVE IN MOST 7332 05:30:14,640 --> 05:30:15,080 CASES. 7333 05:30:15,080 --> 05:30:17,680 THOUGH I TALK ABOUT REACTIVITY I 7334 05:30:17,680 --> 05:30:19,080 THINK THE ONLY TIME IT REALLY 7335 05:30:19,080 --> 05:30:20,480 BECOMES ACTIVE IS WHEN YOU HAVE 7336 05:30:20,480 --> 05:30:24,280 A REALLY HIGH CONCENTRATION OF 7337 05:30:24,280 --> 05:30:25,960 PROTEINS SUCH AS WHEN GAG IS 7338 05:30:25,960 --> 05:30:26,760 ASSEMBLING TO. 7339 05:30:26,760 --> 05:30:28,480 EFFECTIVE CONCENTRATION IS OVER 7340 05:30:28,480 --> 05:30:29,960 FOUR MILLIMOLAR IN THOSE 7341 05:30:29,960 --> 05:30:30,880 PARTICULAR CASES. 7342 05:30:30,880 --> 05:30:33,680 I THINK YOU ALSO NEED TO HAVE 7343 05:30:33,680 --> 05:30:36,080 SOMETHING ALONG LINES OF THAT 7344 05:30:36,080 --> 05:30:38,320 EQUILIBRIUM IN ZINC FINGERS I 7345 05:30:38,320 --> 05:30:39,680 SHOWED YOU. 7346 05:30:39,680 --> 05:30:43,080 ONLY 2% OF 1 ZINC FINGER OF HIV 7347 05:30:43,080 --> 05:30:44,360 NUCLEAR CAPSID IS EVEN 7348 05:30:44,360 --> 05:30:44,960 AVAILABLE. 7349 05:30:44,960 --> 05:30:46,280 IF IT IS ALL FULLY COORDINATED 7350 05:30:46,280 --> 05:30:48,360 IT IS NOT DOING ANYTHING SO YOU 7351 05:30:48,360 --> 05:30:50,720 NEED TO HAVE SOME VERY SPECIFIC 7352 05:30:50,720 --> 05:30:52,200 ENVIRONMENTS FOR HIGH PROTEIN 7353 05:30:52,200 --> 05:30:55,080 CONCENTRATION, A LITTLE BIT OF 7354 05:30:55,080 --> 05:30:57,880 AN AVAILABLE UNLIGATED ZINC 7355 05:30:57,880 --> 05:30:59,080 FINGER IN ORDER FOR THE MOLECULE 7356 05:30:59,080 --> 05:31:01,280 TO DO ANYTHING. 7357 05:31:01,280 --> 05:31:03,280 OTHER THAN THAT, EVERYTHING ELSE 7358 05:31:03,280 --> 05:31:04,320 IS BACKGROUND NOISE. 7359 05:31:04,320 --> 05:31:06,240 I LIKE TO TALK ABOUT ACETYLATION 7360 05:31:06,240 --> 05:31:07,760 PATTERN, I SHOWED YOU'RE PLACES 7361 05:31:07,760 --> 05:31:10,760 OF ACETYLATION CYSTEINES AND 7362 05:31:10,760 --> 05:31:11,280 LYSINES. 7363 05:31:11,280 --> 05:31:12,600 I DON'T THINK CELLS CARE VERY 7364 05:31:12,600 --> 05:31:14,280 MUCH ABOUT THAT. 7365 05:31:14,280 --> 05:31:16,520 CELLS HAVE DEACETYLASES THEY CAN 7366 05:31:16,520 --> 05:31:18,000 DEAL WITH THAT AND I DON'T THINK 7367 05:31:18,000 --> 05:31:20,600 IT HAPPENS A WHOLE LOT ACTUALLY. 7368 05:31:20,600 --> 05:31:22,680 I THINK IT IS SOME BACKGROUNDS 7369 05:31:22,680 --> 05:31:24,480 THAT HAPPEN BUT IT IS ONLY THESE 7370 05:31:24,480 --> 05:31:25,800 VERY SPECIALIZED CIRCUMSTANCES 7371 05:31:25,800 --> 05:31:28,640 WHERE WE REALLY SEE THIS 7372 05:31:28,640 --> 05:31:29,040 HAPPENING. 7373 05:31:29,040 --> 05:31:33,240 THAT IS SORT OF MY ANSWER TO 7374 05:31:33,240 --> 05:31:35,720 THAT AREA. 7375 05:31:35,720 --> 05:31:38,680 >> FASCINATING, FASCINATING 7376 05:31:38,680 --> 05:31:38,920 FININGS. 7377 05:31:38,920 --> 05:31:43,240 I WAS WONDERING HOW YOUR 7378 05:31:43,240 --> 05:31:45,800 APPROACH COMPARES TO THAT OF 7379 05:31:45,800 --> 05:31:51,760 LARRY FROM NCI Z WHO USED A T 2 7380 05:31:51,760 --> 05:31:54,720 TO TARGET ZINC FINGERS, ACTIVATE 7381 05:31:54,720 --> 05:31:58,600 VIRUS PARTICLES. 7382 05:31:58,600 --> 05:32:03,640 AT 2 STANDS FOR (INAUDIBLE) 7383 05:32:03,640 --> 05:32:03,840 THIOL. 7384 05:32:03,840 --> 05:32:06,400 >> THAT IS ADMINISTERED AS A 7385 05:32:06,400 --> 05:32:07,600 DISULFIDE, NEEDS TO GET REDUCED. 7386 05:32:07,600 --> 05:32:09,960 PROBABLY NOT A LOT DIFFERENT. 7387 05:32:09,960 --> 05:32:11,960 I THINK THAT MOLECULE DID HAVE 7388 05:32:11,960 --> 05:32:13,200 TOXICITY IN THE END WHICH I 7389 05:32:13,200 --> 05:32:15,280 THINK SORT OF BLOCKED THE 7390 05:32:15,280 --> 05:32:16,280 ADVANCEMENT. 7391 05:32:16,280 --> 05:32:18,640 I THAT MOLECULE WAS ALSO BEING 7392 05:32:18,640 --> 05:32:23,040 USED TO STERILIZE CELL 7393 05:32:23,040 --> 05:32:25,760 EXTERNALLY FOLLOWED BY 7394 05:32:25,760 --> 05:32:26,800 INTRODUCING TO PEOPLE. 7395 05:32:26,800 --> 05:32:28,480 I CAN'T REMEMBER THE DETAILS 7396 05:32:28,480 --> 05:32:30,880 ABOUT APPROACH OF AT 2. 7397 05:32:30,880 --> 05:33:07,240 (OFF MIC) 7398 05:33:07,240 --> 05:33:08,000 >> THANK YOU. 7399 05:33:08,000 --> 05:33:08,440 >> YEAH. 7400 05:33:08,440 --> 05:33:10,560 YEAH. 7401 05:33:10,560 --> 05:33:12,680 >> THIS IS A COMMENT BECAUSE IT 7402 05:33:12,680 --> 05:33:14,880 IS RELEVANT TO THIS PARTICULAR 7403 05:33:14,880 --> 05:33:15,240 MEETING. 7404 05:33:15,240 --> 05:33:18,720 THAT THE DATA WE HAVE NOW WHICH 7405 05:33:18,720 --> 05:33:21,160 ARE COMING -- NOT FINISHED BUT 7406 05:33:21,160 --> 05:33:23,840 SHOW CLEARLY THIS DRUG IS DOES 7407 05:33:23,840 --> 05:33:28,800 HAVE EFFECT OF NK ACTIVITY IS 7408 05:33:28,800 --> 05:33:29,720 INCREASING GRANZYME AND 7409 05:33:29,720 --> 05:33:36,760 PATHOGEN, INCREASING ALSO THE 7410 05:33:36,760 --> 05:33:41,000 CYTOSIS THE MONOCYTES TO EAT 7411 05:33:41,000 --> 05:33:42,680 NECROTIC CELLS AND THOSE 7412 05:33:42,680 --> 05:33:45,560 DECREASING T-CELL ACT 7413 05:33:45,560 --> 05:33:46,320 ACTIVATION. 7414 05:33:46,320 --> 05:33:47,280 DO YOU THINK A SPECIAL 7415 05:33:47,280 --> 05:33:52,760 (INAUDIBLE) AS WELL AS 7416 05:33:52,760 --> 05:34:00,480 (INAUDIBLE) SO BECAUSE OF ALL 7417 05:34:00,480 --> 05:34:01,680 THIS EFFECT THAT IS MY QUESTION 7418 05:34:01,680 --> 05:34:04,280 TO YOU. 7419 05:34:04,280 --> 05:34:07,600 WHAT WE THOUGHT ABOUT IS PERHAPS 7420 05:34:07,600 --> 05:34:09,600 ZINC BEING FREED RESPONSIBLE FOR 7421 05:34:09,600 --> 05:34:11,880 BOTH EFFECT BECAUSE ZINC IS THE 7422 05:34:11,880 --> 05:34:16,200 SECOND MESSENGER RNA AFTER 7423 05:34:16,200 --> 05:34:17,400 (INAUDIBLE) WE HAVE IN THE BODY 7424 05:34:17,400 --> 05:34:19,160 AND THERE IS INCREDIBLE EFFECT 7425 05:34:19,160 --> 05:34:22,480 ON IMMUNE SYSTEM SO IT COULD BE 7426 05:34:22,480 --> 05:34:26,120 THAT I WAS QUESTION ASKING YOU 7427 05:34:26,120 --> 05:34:28,000 DO YOU THINK 2% OF NUCLEAR 7428 05:34:28,000 --> 05:34:30,880 CAPSID CAN BE AVAILABLE COULD 7429 05:34:30,880 --> 05:34:32,720 EXPLAIN SMALL ANTIVIRAL EFFECT 7430 05:34:32,720 --> 05:34:36,920 BUT THEN ZINC FREEING THE ZINC 7431 05:34:36,920 --> 05:34:38,120 FROM TRANSCRIPTION FACTOR FROM 7432 05:34:38,120 --> 05:34:42,000 OTHER FACTOR IN THE CELLS COULD 7433 05:34:42,000 --> 05:34:44,280 REALLY BE IMPORTANT FOR SEEN IN 7434 05:34:44,280 --> 05:34:45,400 COMBINATION WITH VACCINE? 7435 05:34:45,400 --> 05:34:47,080 >> AT THIS POINT NOTHING 7436 05:34:47,080 --> 05:34:49,840 SURPRISES ME ABOUT THIS 7437 05:34:49,840 --> 05:34:50,080 MOLECULE. 7438 05:34:50,080 --> 05:34:51,520 IT'S SMALL BUT VERY COMPLICATED 7439 05:34:51,520 --> 05:34:52,760 IN A LOT OF WAYS. 7440 05:34:52,760 --> 05:34:55,240 I COULD ENVISION A SITUATION 7441 05:34:55,240 --> 05:34:56,760 WHERE SOME DEGREE WE ARE 7442 05:34:56,760 --> 05:34:59,240 SELECTIVELY PERTURBING CERTAIN 7443 05:34:59,240 --> 05:35:01,160 POOL OF ZINC SOMEWHERE WHICH 7444 05:35:01,160 --> 05:35:03,920 MAYBE HARD TO PIN DOWN 7445 05:35:03,920 --> 05:35:05,400 SPECIFICALLY. 7446 05:35:05,400 --> 05:35:06,880 BUT SURE I THINK IT IS ENTIRELY 7447 05:35:06,880 --> 05:35:07,240 POSSIBLE. 7448 05:35:07,240 --> 05:35:09,000 IT IS NOT PERTURBING THINGS TOO 7449 05:35:09,000 --> 05:35:12,080 MUCH BECAUSE ZINC CAN BE TOXIC 7450 05:35:12,080 --> 05:35:15,160 TOO, IF IT IS TOO STRONG AND TOO 7451 05:35:15,160 --> 05:35:17,200 MANY TRANSCRIPTION FACTORS YOU 7452 05:35:17,200 --> 05:35:17,800 STOBBINGICS EFFECTS WHICH WE 7453 05:35:17,800 --> 05:35:19,880 DON'T SEE. 7454 05:35:19,880 --> 05:35:23,080 SO I FEEL THERE COULD BE A ZINC 7455 05:35:23,080 --> 05:35:25,480 INCREASE BUT PROBABLY SOMEWHAT 7456 05:35:25,480 --> 05:35:27,360 TARGETED AT THE SAME TIME IN A 7457 05:35:27,360 --> 05:35:29,880 UNIQUE COMPLICATED WAY. 7458 05:35:29,880 --> 05:35:33,240 >> I KNOW YOU MENTIONED THE ZINC 7459 05:35:33,240 --> 05:35:35,920 MOLECULE THAT BETHA IDENTIFIED 7460 05:35:35,920 --> 05:35:41,200 WHY WITH ALL THESE FACTORS THIS 7461 05:35:41,200 --> 05:35:42,560 MOLECULE DOES WHY DIDN'T IT WORK 7462 05:35:42,560 --> 05:35:47,600 WITH MARJORIE'S VENOSUM I DON'T 7463 05:35:47,600 --> 05:36:01,840 THINK WE KNOW. 7464 05:36:01,840 --> 05:36:06,280 >> IN THAT EXPERIMENT WE USED AN 7465 05:36:06,280 --> 05:36:07,240 ADJUVANT CONTROL. 7466 05:36:07,240 --> 05:36:08,240 GAVE SOME PROTECTION. 7467 05:36:08,240 --> 05:36:09,280 >> YEAH. 7468 05:36:09,280 --> 05:36:12,800 IN COMBINATION. 7469 05:36:12,800 --> 05:36:13,680 >> (OVERLAPPING SPEAKERS) 7470 05:36:13,680 --> 05:36:16,040 >> SO WE SHOULD HAVE USED NO 7471 05:36:16,040 --> 05:36:16,640 ADJUVANT. 7472 05:36:16,640 --> 05:36:17,880 AND WE MIGHT HAVE HAD A MUCH 7473 05:36:17,880 --> 05:36:18,800 BETTER RESULT. 7474 05:36:18,800 --> 05:36:22,280 BUT IT'S GREAT THAT YOU ARE 7475 05:36:22,280 --> 05:36:23,160 USING ANOTHER VACCINE. 7476 05:36:23,160 --> 05:36:23,880 >> YEAH. 7477 05:36:23,880 --> 05:36:25,280 GETTING BACK TO YOUR ORIGINAL 7478 05:36:25,280 --> 05:36:26,760 QUESTION ABOUT OTHER VIRUSES WE 7479 05:36:26,760 --> 05:36:28,440 HAVE SCREENED A PANEL OF NUMBER 7480 05:36:28,440 --> 05:36:30,280 OF OTHER VIRUSES AND DIDN'T SEE 7481 05:36:30,280 --> 05:36:31,600 MUCH ACTIVITY AT ALL. 7482 05:36:31,600 --> 05:36:33,880 WE DO SEE SOME EFFECT WITH SARS 7483 05:36:33,880 --> 05:36:36,000 COV-2 BUT WHAT IS INTERESTING IS 7484 05:36:36,000 --> 05:36:38,080 ALSO SARS COV-2 HAS ZINC 7485 05:36:38,080 --> 05:36:39,880 DEPENDENCE THERE IS A LOT OF 7486 05:36:39,880 --> 05:36:41,880 ZINC THAT IS VERY IMPORTANT FOR 7487 05:36:41,880 --> 05:36:45,560 THAT PARTICULAR VIRUS AS WELL. 7488 05:36:45,560 --> 05:36:45,840 (OFF MIC) 7489 05:36:45,840 --> 05:36:47,120 >> THAT IS MY GUESS. 7490 05:36:47,120 --> 05:36:52,120 ALSO TRYING TO CHASE A PROTEIN 7491 05:36:52,120 --> 05:36:54,480 TARGET WITHIN SARS COV-2 AND TRY 7492 05:36:54,480 --> 05:36:57,720 TO RECAPITULATE SIMILAR WORK 7493 05:36:57,720 --> 05:36:59,800 MASS SPECTROMETRY THAT SHOWS 7494 05:36:59,800 --> 05:37:00,840 DISSOCIATES ZINC. 7495 05:37:00,840 --> 05:37:14,240 [APPLAUSE] 7496 05:37:14,240 --> 05:37:15,680 >> WHILE DOING THAT I WOULD LIKE 7497 05:37:15,680 --> 05:37:16,680 TO THANK THE SPEAKERS IN THIS 7498 05:37:16,680 --> 05:37:17,600 SESSION AND THE SPEAKERS IN ALL 7499 05:37:17,600 --> 05:37:20,720 THE SESSIONS AND WE LIKE TO CALL 7500 05:37:20,720 --> 05:37:24,520 MARJORIE UP TO GIVE HER FINAL 7501 05:37:24,520 --> 05:37:33,680 THOUGHTS. 7502 05:37:33,680 --> 05:37:35,160 >> WELL, THANK YOU ALL. 7503 05:37:35,160 --> 05:37:36,160 THANK YOU ALL VERY MUCH FOR 7504 05:37:36,160 --> 05:37:40,880 COMING. 7505 05:37:40,880 --> 05:37:42,800 I WOULD LIKE TO FIRST THANK ALL 7506 05:37:42,800 --> 05:37:45,320 THE SPEAKERS, I THINK ESPECIALLY 7507 05:37:45,320 --> 05:37:47,520 THOSE WHO CAME PARTICULARLY LONG 7508 05:37:47,520 --> 05:37:48,160 DISTANCE. 7509 05:37:48,160 --> 05:37:51,080 THESE DAYS IT STILL IS NOT EASY 7510 05:37:51,080 --> 05:37:52,960 TO TRAVEL SO THANK YOU FOR 7511 05:37:52,960 --> 05:37:53,320 COMING. 7512 05:37:53,320 --> 05:37:55,200 I WOULD LIKE TO MENTION EACH OF 7513 05:37:55,200 --> 05:37:58,800 YOU IN TURN JUST WITH A FEW 7514 05:37:58,800 --> 05:38:00,320 SENTENCES. 7515 05:38:00,320 --> 05:38:01,840 I ALREADY COMMENTED FOLLOWING 7516 05:38:01,840 --> 05:38:04,560 BOB'S TALK SOMEHOW I KNEW 7517 05:38:04,560 --> 05:38:05,920 SOMEHOW I KNEW SOMETHING WOULD 7518 05:38:05,920 --> 05:38:11,480 CALL HIM AWAY. 7519 05:38:11,480 --> 05:38:13,000 BUT HE WAS GRACIOUS AND PLANNING 7520 05:38:13,000 --> 05:38:14,240 TO STAY THE WHOLE TIME AND 7521 05:38:14,240 --> 05:38:15,400 CALLED AWAY BY A POLITICAL 7522 05:38:15,400 --> 05:38:16,480 MEETING I THINK. 7523 05:38:16,480 --> 05:38:20,640 IN ANY CASE, I WILL STARTS WITH 7524 05:38:20,640 --> 05:38:22,400 RUTH RUPRECHT. 7525 05:38:22,400 --> 05:38:23,880 WE DID MANY FACT HAVE A NUMBER 7526 05:38:23,880 --> 05:38:27,520 OF GREAT COLLABORATIONS BUT ONE 7527 05:38:27,520 --> 05:38:29,480 THING THAT I VALUE VERY MUCH 7528 05:38:29,480 --> 05:38:33,000 OVER THE YEARS FROM YOU WAS YOUR 7529 05:38:33,000 --> 05:38:34,960 ADVICE. 7530 05:38:34,960 --> 05:38:36,440 BOTH FORMAL ADVICE AS A 7531 05:38:36,440 --> 05:38:38,080 SCIENTIFIC ADVISOR TO THE 7532 05:38:38,080 --> 05:38:42,040 VACCINE BRANCH AND ALSO JUST 7533 05:38:42,040 --> 05:38:44,440 INFORMAL DISCUSSIONS YOU 7534 05:38:44,440 --> 05:38:45,680 COMMENTED ON WHAT WAS GOING ON 7535 05:38:45,680 --> 05:38:46,880 WHAT I SHOULD DO, IT WAS VERY 7536 05:38:46,880 --> 05:38:50,880 VALUABLE. 7537 05:38:50,880 --> 05:38:51,880 THANK YOU VERY MUCH. 7538 05:38:51,880 --> 05:38:53,800 GRAB OUR COLLABORATIONS LED TO 7539 05:38:53,800 --> 05:38:56,440 INTERESTING EX-- GLAD OUR 7540 05:38:56,440 --> 05:38:57,280 COLLABORATIONS LED TO 7541 05:38:57,280 --> 05:39:00,960 INTERESTING EXPERIMENTS FOR YOU. 7542 05:39:00,960 --> 05:39:02,200 MARK, DELIGHTED YOU ARE GOING 7543 05:39:02,200 --> 05:39:03,880 FORWARD WITH REPLICATING 7544 05:39:03,880 --> 05:39:04,480 ADENOVIRUS. 7545 05:39:04,480 --> 05:39:05,920 I COULDN'T HAVE DONE IT, I'M NOT 7546 05:39:05,920 --> 05:39:07,680 A CLINICAL PERSON AND YOU ARE 7547 05:39:07,680 --> 05:39:09,280 MOVING US FORWARD, IT IS NOT 7548 05:39:09,280 --> 05:39:11,800 EASY, AND THE STORY YOU 7549 05:39:11,800 --> 05:39:12,920 PRESENTED WITH THE COVID, THAT 7550 05:39:12,920 --> 05:39:18,040 IS GREAT. 7551 05:39:18,040 --> 05:39:20,560 I WISH YOU GREAT SUCCESS, I HOPE 7552 05:39:20,560 --> 05:39:21,760 YOU HAVE SUCCESS WITH HIV AS 7553 05:39:21,760 --> 05:39:22,760 WELL AND LOOK FORWARD TO SEEING 7554 05:39:22,760 --> 05:39:24,640 THAT IN THE LITERATURE ONE DAY. 7555 05:39:24,640 --> 05:39:25,480 THANK YOU. 7556 05:39:25,480 --> 05:39:26,560 THANK YOU FOR YOUR SHARING YOUR 7557 05:39:26,560 --> 05:39:31,480 DATA. 7558 05:39:31,480 --> 05:39:32,440 MICHAEL TO MASS. 7559 05:39:32,440 --> 05:39:35,240 GREAT TO SEE YOU PRESENT SOME 7560 05:39:35,240 --> 05:39:36,120 INTERESTING AND IMPORTANT DATA 7561 05:39:36,120 --> 05:39:37,600 NOW THAT YOU HAVE LEFT THE NIH 7562 05:39:37,600 --> 05:39:42,280 YOU HAVE YOUR OWN GROUP AND I 7563 05:39:42,280 --> 05:39:43,440 THINK YOU HAVE ALWAYS BEEN 7564 05:39:43,440 --> 05:39:45,640 INTERESTED IN ADENOVIRUSES, YOU 7565 05:39:45,640 --> 05:39:48,480 ARE MOVING THEM FORWARD AS 7566 05:39:48,480 --> 05:39:49,720 AGENTS FOR VACCINES FOR ALL 7567 05:39:49,720 --> 05:39:53,480 KINDS OF INFECTIOUS AGENTS AS 7568 05:39:53,480 --> 05:39:55,480 WELL AS CANCER, LOOK FORWARD TO 7569 05:39:55,480 --> 05:39:57,480 YOUR FUTURE STUDIES AND FUTURE 7570 05:39:57,480 --> 05:40:01,240 DIRECTIONS. 7571 05:40:01,240 --> 05:40:02,440 ASHLEY, WE MENTIONED YOU WERE 7572 05:40:02,440 --> 05:40:04,080 ONE OF MY FIRST POST-DOCS YOU OF 7573 05:40:04,080 --> 05:40:05,880 COURSE AS WE SET UP HERE 7574 05:40:05,880 --> 05:40:09,920 INFORMALLY CAME TO WORK WITH BOB 7575 05:40:09,920 --> 05:40:11,840 BUT HE HAPPILY SUGGESTED YOU 7576 05:40:11,840 --> 05:40:13,200 JOIN MY GROUP AND I THINK WE HAD 7577 05:40:13,200 --> 05:40:18,680 A VERY PRODUCTIVE FUN TIME WE 7578 05:40:18,680 --> 05:40:21,680 WORKED ON NIGERIAN ISOLATES ON 7579 05:40:21,680 --> 05:40:24,040 HIV 2 AND IT IS REWARDING TO SEE 7580 05:40:24,040 --> 05:40:28,040 YOUR SUCCESS AT THE IHV AND ALSO 7581 05:40:28,040 --> 05:40:31,680 INTERNATIONALLY ESPECIALLY. 7582 05:40:31,680 --> 05:40:36,560 BEST OF LUCK. 7583 05:40:36,560 --> 05:40:41,080 RRAUL, YOU MADE A GREAT 7584 05:40:41,080 --> 05:40:41,920 CONTRIBUTION TO MY GROUP BY 7585 05:40:41,920 --> 05:40:43,480 SUGGESTING WE CHANGE THE ASSAY 7586 05:40:43,480 --> 05:40:45,520 FOR ADCC, YOU WENT TO DEVELOP 7587 05:40:45,520 --> 05:40:47,960 THAT ASSAY AND YOU MADE A VERY 7588 05:40:47,960 --> 05:40:51,360 NICE FINDING SHOWING THAT ADCC 7589 05:40:51,360 --> 05:40:53,080 ACTIVITY WAS ASSOCIATED WITH 7590 05:40:53,080 --> 05:40:54,400 REDUCED ACUTE VIREMIA. 7591 05:40:54,400 --> 05:40:57,080 THIS I THINK REALLY DID 7592 05:40:57,080 --> 05:41:01,280 STIMULATE THE FIELD AND LET YOU 7593 05:41:01,280 --> 05:41:03,720 WARN INVESTIGATORS LOOKING AT 7594 05:41:03,720 --> 05:41:05,120 THIS ACTIVITY AND ITS POTENTIAL 7595 05:41:05,120 --> 05:41:06,160 SO THANK YOU FOR THAT AND THANK 7596 05:41:06,160 --> 05:41:09,240 YOU FOR COMING ALL THE WAY FROM 7597 05:41:09,240 --> 05:41:11,880 OSLO TO TALK TO US. 7598 05:41:11,880 --> 05:41:14,960 GEORGE LEWIS, I ALSO VALUE VERY 7599 05:41:14,960 --> 05:41:16,520 MUCH ALL THE ADVICE YOU HAVE 7600 05:41:16,520 --> 05:41:19,280 GIVEN US OVER THE YEARS. 7601 05:41:19,280 --> 05:41:21,840 ALSO AS A SCIENTIFIC ADVISOR AND 7602 05:41:21,840 --> 05:41:23,840 INDEPENDENTLY OR INFORMALLY. 7603 05:41:23,840 --> 05:41:25,800 YOU HAVE BEEN A GREAT 7604 05:41:25,800 --> 05:41:28,360 COLLABORATOR AND YOU REALLY DID, 7605 05:41:28,360 --> 05:41:30,880 I MEAN, YOUR IMPROVEMENTS ON THE 7606 05:41:30,880 --> 05:41:33,240 ADCC ASSAY WERE REALLY VERY 7607 05:41:33,240 --> 05:41:35,080 HELPFUL AND YOU HAVE BEEN VERY 7608 05:41:35,080 --> 05:41:36,960 GENEROUS IN DISCUSSING THAT 7609 05:41:36,960 --> 05:41:39,720 APPROACH, SHARING YOUR REAGENTS 7610 05:41:39,720 --> 05:41:41,440 AND IN FACT YOU ARE ALWAYS 7611 05:41:41,440 --> 05:41:43,520 TELLING US WHAT YOU ARE DOING 7612 05:41:43,520 --> 05:41:45,640 AND SHARING YOUR THOUGHTS AND 7613 05:41:45,640 --> 05:41:47,400 THAT'S REALLY A GREAT 7614 05:41:47,400 --> 05:41:47,760 COLLABORATOR. 7615 05:41:47,760 --> 05:41:51,520 SO THANK YOU SO MUCH. 7616 05:41:51,520 --> 05:41:54,960 MARGIE ACKERMAN, RATHER THAN 7617 05:41:54,960 --> 05:41:57,680 FOCUSING JUST ON ANTIBODY 7618 05:41:57,680 --> 05:41:59,480 ACTIVITIES, I THINK YOU TOOK A 7619 05:41:59,480 --> 05:42:01,120 SOMEWHAT DIFFERENT APPROACH LOOK 7620 05:42:01,120 --> 05:42:04,600 AT FC RECEPTOR WHICH WAS -- THAT 7621 05:42:04,600 --> 05:42:06,440 ALSO STILL LATED THE FIELD 7622 05:42:06,440 --> 05:42:09,720 GREATLY. 7623 05:42:09,720 --> 05:42:11,080 LEADING TO INSIGHTS TO WHAT WAS 7624 05:42:11,080 --> 05:42:13,320 GOING ON, IN THE SYSTEMS BIOLOGY 7625 05:42:13,320 --> 05:42:14,040 IT'S BEEN GREAT. 7626 05:42:14,040 --> 05:42:17,360 WE DID ACTUALLY HAVE THAT ONE 7627 05:42:17,360 --> 05:42:19,240 NICE COLLABORATION ON 7628 05:42:19,240 --> 05:42:19,600 COMPLIMENT. 7629 05:42:19,600 --> 05:42:21,280 SO THANK YOU FOR THAT. 7630 05:42:21,280 --> 05:42:23,480 I WILL ALSO LOOK FORWARD TO YOUR 7631 05:42:23,480 --> 05:42:26,800 FUTURE STUDIES. 7632 05:42:26,800 --> 05:42:28,520 TWO YEARS AGO ABOUT THE TIME 7633 05:42:28,520 --> 05:42:30,000 THAT I WAS THINKING I MIGHT 7634 05:42:30,000 --> 05:42:33,480 ACTUALLY RETIRE, THE TOPICS OF 7635 05:42:33,480 --> 05:42:35,920 INTEREST TO ME OR WHAT I WOULD 7636 05:42:35,920 --> 05:42:36,840 HAVE CONTINUED WOULD HAVE BEEN 7637 05:42:36,840 --> 05:42:42,680 TO STUDY THE SEX BIAS 7638 05:42:42,680 --> 05:42:44,960 MICROBIOME, AND ALSO 7639 05:42:44,960 --> 05:42:47,120 COMBINATIONS OF VACCINES AND 7640 05:42:47,120 --> 05:42:47,960 MICROBE SIDE. 7641 05:42:47,960 --> 05:42:50,200 SO THAT LAST SESSION WAS MADE UP 7642 05:42:50,200 --> 05:42:52,400 OF THOSE THINGS THAT NEVER -- 7643 05:42:52,400 --> 05:42:54,200 THAT I WOULD STILL BE DOING 7644 05:42:54,200 --> 05:42:56,480 BECAUSE I THOUGHT THEY WERE OF 7645 05:42:56,480 --> 05:42:58,600 GREAT IMPORTANCE. 7646 05:42:58,600 --> 05:43:00,280 SO ISKRA AS SHE DESCRIBED WAS 7647 05:43:00,280 --> 05:43:02,720 THE FIRST TO SHOW A SEX BIAS IN 7648 05:43:02,720 --> 05:43:04,640 ONE OF OUR MONKEY STUDIES. 7649 05:43:04,640 --> 05:43:06,400 THIS REALLY OPENED MY EYES I 7650 05:43:06,400 --> 05:43:09,360 THINK TO A WHOLE BODY OF 7651 05:43:09,360 --> 05:43:09,720 LITERATURE. 7652 05:43:09,720 --> 05:43:12,920 THERE IS A SEX BIAS IN MANY 7653 05:43:12,920 --> 05:43:16,680 IMMUNE RESPONSES, ACTUALLY AS I 7654 05:43:16,680 --> 05:43:19,080 RECALL, WOMEN RESPOND BETTER TO 7655 05:43:19,080 --> 05:43:20,840 VACCINES BUT IN TERMS OF HIV 7656 05:43:20,840 --> 05:43:25,080 THEY BECOME INFECTED THEN OR 7657 05:43:25,080 --> 05:43:29,200 THEY SUCCUMB TO DISEASE MORE 7658 05:43:29,200 --> 05:43:30,520 QUICKLY, THERE IS A LOT WE DON'T 7659 05:43:30,520 --> 05:43:31,760 KNOW SO ENCOURAGE YOU TO 7660 05:43:31,760 --> 05:43:32,520 CONTINUE FOLLOWING THE EFFECTS 7661 05:43:32,520 --> 05:43:38,280 OF THE SEX BIAS ON VACCINE 7662 05:43:38,280 --> 05:43:39,080 OUTCOME. 7663 05:43:39,080 --> 05:43:41,440 LAUREL, THANK YOU SO MUCH. 7664 05:43:41,440 --> 05:43:42,440 WHERE ARE YOU? 7665 05:43:42,440 --> 05:43:45,040 YOU ARE AN EXPERT IN MICROBIOME, 7666 05:43:45,040 --> 05:43:47,080 THANK YOU FOR COMING. 7667 05:43:47,080 --> 05:43:50,640 TOM MUSIC WAS GOING TO SPEAK HE 7668 05:43:50,640 --> 05:43:53,360 WAS A POST DOC ANY GROUP, NOW 7669 05:43:53,360 --> 05:43:55,480 BACK IN THE ARMY AS YOU 7670 05:43:55,480 --> 05:43:59,320 MENTIONED, HE IS MAJOR MUSIC. 7671 05:43:59,320 --> 05:44:02,920 HE HAD SOME NICE FINDINGS ON 7672 05:44:02,920 --> 05:44:04,920 DIFFERENCES IN THE MICROBIOME 7673 05:44:04,920 --> 05:44:09,720 ASSOCIATED WITH VACCINATION. 7674 05:44:09,720 --> 05:44:11,360 YOU HAVE ALWAYS BEEN THOUGH WE 7675 05:44:11,360 --> 05:44:14,000 HAVE NEVER COLLABORATED DIRECTLY 7676 05:44:14,000 --> 05:44:16,440 YOU HAVE ALWAYS BEEN VERY 7677 05:44:16,440 --> 05:44:18,840 GRACIOUS AND SHARING YOUR 7678 05:44:18,840 --> 05:44:20,440 KNOWLEDGE ANSWERING QUESTIONS 7679 05:44:20,440 --> 05:44:23,040 ABOUT STUDIES ONGOING IN MY 7680 05:44:23,040 --> 05:44:25,400 GROUP SO THANK YOU VERY MUCH. 7681 05:44:25,400 --> 05:44:29,480 FINALLY DANIEL APPELLA, WE DID 7682 05:44:29,480 --> 05:44:33,480 START A COLLABORATION ON VACCINE 7683 05:44:33,480 --> 05:44:35,880 MICROBE SIDE AS YOU POINTED OUT 7684 05:44:35,880 --> 05:44:38,440 AND I MIGHT MENTION THAT 7685 05:44:38,440 --> 05:44:41,440 ACTUALLY THAT WAS INITIALLY I 7686 05:44:41,440 --> 05:44:43,880 WAS STIMULATED IN THAT BY STUDY 7687 05:44:43,880 --> 05:44:48,840 OF CECILIA JANE MAYOR AND ETTA 7688 05:44:48,840 --> 05:44:51,240 RAY APPELLA WHO REPORTED A 7689 05:44:51,240 --> 05:44:52,640 VACCINE MICROBE SIDE COMBINATION 7690 05:44:52,640 --> 05:44:54,120 THAT WAS PROMISING. 7691 05:44:54,120 --> 05:44:55,520 CECILIA RETIRED BEFORE WE COULD 7692 05:44:55,520 --> 05:44:56,560 DO A COLLABORATION TOGETHER BUT 7693 05:44:56,560 --> 05:44:59,680 I WAS HAPPY TO GO FORWARD WITH 7694 05:44:59,680 --> 05:45:03,120 YOUR TWO FOUR SEVEN, DIDN'T HAVE 7695 05:45:03,120 --> 05:45:06,000 QUITE THE EFFECT THAT I HAD 7696 05:45:06,000 --> 05:45:07,760 HOPED THOUGH 247 WORKED GREAT 7697 05:45:07,760 --> 05:45:11,880 AND DELIGHTED THAT YOU AND BETHA 7698 05:45:11,880 --> 05:45:12,680 HAVE GOTTEN TOGETHER AND ARE 7699 05:45:12,680 --> 05:45:15,320 WORKING ON THIS AND REALLY 7700 05:45:15,320 --> 05:45:17,120 EXPANDED THE APPROACH, I CAN'T 7701 05:45:17,120 --> 05:45:19,400 WAIT TO SEE THE FULL STUDY, IT 7702 05:45:19,400 --> 05:45:20,880 WILL BE HOPEFULLY SOON. 7703 05:45:20,880 --> 05:45:22,560 I THINK WE WILL BE VERY EXCITING 7704 05:45:22,560 --> 05:45:29,360 AND IMPORTANT FOR THE FIELD. 7705 05:45:29,360 --> 05:45:30,880 IN MANY WAYS. 7706 05:45:30,880 --> 05:45:31,880 FINALLY, I WOULD LIKE TO THANK 7707 05:45:31,880 --> 05:45:37,520 THE PIs OF THE VACCINE BRANCH, 7708 05:45:37,520 --> 05:45:39,120 BETHA, GEORGE, BARBARA, I WAS 7709 05:45:39,120 --> 05:45:44,080 ALSO GOING TO MENTION -- SHE HAD 7710 05:45:44,080 --> 05:45:45,240 TO LEAVE OUR CLINICAL PERSON. 7711 05:45:45,240 --> 05:45:46,560 YOU HAVE GIVEN A LOT OF SUPPORT 7712 05:45:46,560 --> 05:45:48,720 OVER THE YEARS, COLLABORATIVE 7713 05:45:48,720 --> 05:45:51,120 HELP, YOU SHARED REAGENTS, YOU 7714 05:45:51,120 --> 05:45:53,520 HAVE GIVEN CRITICAL ADVICE. 7715 05:45:53,520 --> 05:45:56,120 AND YOU HAVE GIVEN FRIENDSHIP. 7716 05:45:56,120 --> 05:45:58,480 THOSE THINGS HAVE BEEN REALLY -- 7717 05:45:58,480 --> 05:46:00,720 NOW IS THE TIME THAT I GET 7718 05:46:00,720 --> 05:46:04,480 EMOTIONAL, THAT IS WHY I HAVE 7719 05:46:04,480 --> 05:46:07,000 NOTES. 7720 05:46:07,000 --> 05:46:08,680 ALL OF THAT IS REALLY IMPORTANT 7721 05:46:08,680 --> 05:46:09,800 TO ME. 7722 05:46:09,800 --> 05:46:14,320 I THANK THE ADMINISTRATIVE 7723 05:46:14,320 --> 05:46:15,440 STAFF, JACKIE MCVAIL SITTING 7724 05:46:15,440 --> 05:46:16,680 OVER THERE MY SECRETARY FOR A 7725 05:46:16,680 --> 05:46:19,040 LONG TIME WHO WORKED VERY HARD 7726 05:46:19,040 --> 05:46:20,800 IN ORGANIZING THIS MEETING. 7727 05:46:20,800 --> 05:46:22,840 I SEE TANYA IS SITTING THERE, 7728 05:46:22,840 --> 05:46:24,080 TECHNICAL STAFF. 7729 05:46:24,080 --> 05:46:26,280 NOW WORKING WITH JAY WHO HAS 7730 05:46:26,280 --> 05:46:28,400 DONE A GREAT JOB. 7731 05:46:28,400 --> 05:46:32,200 I THANK ALL POST DOCS WHO HAVE 7732 05:46:32,200 --> 05:46:35,480 COME, RUTH, ARIF. 7733 05:46:35,480 --> 05:46:39,480 ANYWAY, I CAN'T MENTION 7734 05:46:39,480 --> 05:46:43,240 EVERYBODY. BUT I HAVE SO 7735 05:46:43,240 --> 05:46:44,120 ENJOYED WORKING WITH Y'ALL. 7736 05:46:44,120 --> 05:46:49,160 I JUST AS A FINAL PERSONAL NOTE, 7737 05:46:49,160 --> 05:46:51,680 RETIRING IS EASY, YOU JUST 7738 05:46:51,680 --> 05:46:53,280 LEAVE, YOU WALK AWAY. 7739 05:46:53,280 --> 05:46:55,600 IT IS MAKING THE DECISION TO 7740 05:46:55,600 --> 05:47:03,800 RETIRE THAT'S SO DIFFICULT. 7741 05:47:03,800 --> 05:47:06,080 BECAUSE BEING A SCIENTIST IT IS 7742 05:47:06,080 --> 05:47:07,840 A WONDERFUL CAREER. 7743 05:47:07,840 --> 05:47:10,120 YOU COME TO WORK EVERY DAY, YOU 7744 05:47:10,120 --> 05:47:12,360 DECIDE WHAT YOU WANT TO DO, YOU 7745 05:47:12,360 --> 05:47:16,400 DO IT THE WAY YOU WANT TO DO IT, 7746 05:47:16,400 --> 05:47:18,680 SCIENCE IS ALWAYS CHALLENGING, 7747 05:47:18,680 --> 05:47:20,280 IT'S NEVER BORING. 7748 05:47:20,280 --> 05:47:22,440 IT IS ALWAYS LEADING IN A NEW 7749 05:47:22,440 --> 05:47:25,280 DIRECTION, NEW AVENUES TO 7750 05:47:25,280 --> 05:47:26,320 EXPLORE. 7751 05:47:26,320 --> 05:47:30,840 AND IT BRINGS YOU YOUNG PEOPLE 7752 05:47:30,840 --> 05:47:33,120 WHO ARE ENTHUSIASTIC AND 7753 05:47:33,120 --> 05:47:35,200 TALENTED AND CONTRIBUTE TO YOUR 7754 05:47:35,200 --> 05:47:35,440 STUDIES. 7755 05:47:35,440 --> 05:47:37,520 IT BRINGS YOU SENIOR SCIENTISTS 7756 05:47:37,520 --> 05:47:41,600 WITH WHOM YOU CAN COLLABORATE 7757 05:47:41,600 --> 05:47:48,280 AND ADVANCE THE FIELD HOPEFULLY. 7758 05:47:48,280 --> 05:47:49,880 FINALLY, SCIENCE MAKES YOU 7759 05:47:49,880 --> 05:47:52,400 INTERACT WITH A WHOLE WORLD AT 7760 05:47:52,400 --> 05:47:53,680 LEAST IT HAS FOR ME. 7761 05:47:53,680 --> 05:47:58,080 SO THAT'S BEEN GREAT. 7762 05:47:58,080 --> 05:48:01,080 SO ALTHOUGH NEW EXPERIENCES 7763 05:48:01,080 --> 05:48:04,280 AWAIT ME, LEAVING IS BITTERSWEET 7764 05:48:04,280 --> 05:48:06,680 BUT I THANK YOU ALL FOR THIS FOR 7765 05:48:06,680 --> 05:48:10,400 TODAY, IT'S MADE IT EASIER TO 7766 05:48:10,400 --> 05:48:10,760 LEAVE. 7767 05:48:10,760 --> 05:48:12,080 AND THAT IS REALLY ALL I CAN 7768 05:48:12,080 --> 05:48:12,480 SAY. 7769 05:48:12,480 --> 05:48:13,680 THANK YOU VERY MUCH. 7770 05:48:13,680 --> 05:48:53,880 [APPLAUSE] 7771 05:48:53,880 --> 05:48:56,400 >> I ALSO WANT TO THANK EVERYONE 7772 05:48:56,400 --> 05:48:58,960 FOR PARTICIPATING, ALL THE 7773 05:48:58,960 --> 05:48:59,280 SPEAKERS AND EVERYONE ELSE WHO 7774 05:48:59,280 --> 05:49:00,000 CAME AND STAYED THROUGH THE 7775 05:49:00,000 --> 00:00:00,000 WHOLE THING, IT'S BEEN GREAT.