TRACO 2019 – Non-small cell lung cancer and HIV


OUR FIRST SPEAKER IS EVA SZABO, THE CHIEF OF THE LUNG AND UPPER AIR DIGESTIVE CANCER RESEARCH GROUP AT NCI DIVISION OF CANCER PREVENTION. SHE GRADUATED FROM YALE AND HEN GOT HER M.D. FROM DUKE UNIVERSITY. SHE DID INTERNAL MEDICINE RESIDENCY AT THE BELL VIEW NEW YORK UNIVERSITY MEDICAL CENTER. THEN SHE CAME TO NCI AND DID A FELLOWSHIP. SHE’S GOING TO TALK TO US TODAY ABOUT NON-SMALL CELL LUNG CANCER. EVA.>>THANK YOU, TERRY. CAN YOU GUYS HEAR ME? IS THIS OKAY? SO STRANGE TO TALK TO JUST SMALL NUMBER OF PEOPLE BUT THE BEST ARE HERE SO THANK YOU FOR SHOWING UP IN PERSON. SO WE’RE GOING TO TALK ABOUT LUNG CANCER TODAY AND PRIMARILY NON-SMALL CELL LUNG CANCER. THE REASON THIS IS SO IMPORTANT, IF YOU LOOK THIS IS WORLDWIDE INCIDENCE IN EACH OF THESE IS A SPECIFIC KIND OF CANCER. SO YOU SEE MAYBE 10, 15% OF ALL CANCER DEATHS, ALL CANCER COMES — IS LUNG CANCER BUT WHEN IT COMES TO THE PERCENTAGE THAT IS DUE — PERCENTAGE OF DEATH DUE TO LUNG CANCER IT’S MUCH MORE THAN THAT, IT’S MORE LIKE 30% SO TREMENDOUS SOURCE OF MORBIDITY AND MORE IMPORTANT, MORTALITY IN THE WORLD. SO JUST LOOKING AT THE STATISTICS IN THE UNITED STATES, OVER THE LAST YEAR, ESTIMATED 228,000 NEW CASES LUNG AND BRONCHUS. 142,000 ESTIMATED DEATHS. THIS IS GOING UP EVERY YEAR, MAINLY BECAUSE THE POPULATION IS INCREASING. BUT IT IS THE HEEDING CAUSE OF CANCER — LEADING CAUSE OF CANCER DEATH GREATER THAN THE NEXT THREE LEADING CAUSES OF CANCER DEATH ADDED TOGETHER. FROM NEGLIGENT THE GOOD NEWS IS THE DEATH RATE PER HUNDRED THOUSAND IS DECREASING AND YOU CAN SEE IT HERE. THIS IS MEN PEAKED INCIDENCE OF DEATH PEAKED AROUND 1990s, THIS IS ABOUT TOBACCO. TOBACCO EPIDEMIC PEAK IN THE 1950s, THERE’S A 40 YEAR GAP. AS WE STARTED SEEING A DECREASE OF TOBACCO USAGE, SLOWLY THE NUMBER OF DEATHS IS STARTING TO DECREASE. BUT IT’S STILL A HUGE NUMBER YOU CAN SEE MUCH GREATER THAN EVERYTHING ELSE. FOR WOMEN, THE PEAK CAME AING RILLET BIT LATER BECAUSE — LITTLE BIT LATER BECAUSE WOMEN STARTED SMOKING LATER BECAUSE OF VARIOUS ISSUES OF INEQUALITY SO WOMEN HAD TO CATCH UP AND THERE YOU HAVE IT. THEY ALSO PEAK AND FINALLY THAT PEAK IS ALSO COMING DOWN. SO WE ARE DOING BETTER. THERE ARE FEWER DEATHS PER HUNDRED THOUSAND, BUT INCREASING NUMBER OF CASES, ABSOLUTE ALL TOGETHER AND WE ARE SEEING SOME IMPROVEMENT ALL BE IT SMALL IN FIVE YEAR SURVIVAL, USED TO BE 5% IN THE 1950s, 12% IN THE ’70s MOW UP TO — NOW UP TO 18 TO 20%, IN THE YEARS THAT I HAVE BEEN GIVING THIS TALK IT’S NICE TO SEE IT ACTUALLY GO UP TO 20%. THE RISK FACTORS ARE PRIMARILY TOBACCO. 85% OF LUNG CANCER IS DUE TO TOBACCO, THAT INCLUDES PASSIVE SMOKING SO PEOPLE WHO HAVE EXPOSURE TO PARTNERS AT HOME OR WORKPLACE. A PRIOR DIGESTIVE MALIGNANCY IS ONE OF THE BIGGEST RISK FACTORS FOR FUTURE ONE. AND CHRONIC ON INSTRUCTIVE PULMONARY DISEASE IS ANOTHER INDEPENDENT LINKED IN THAT COPD IS ALSO SEEN WITH TOBACCO EXPOSURE BUT THERE ARE FAMILIAL COPD GENES. THOSE PEOPLE EVEN IF THEY DON’T SMOKE STILL HAVE INCREASE RISK OF LUNG CANCER. THIS IS MY FAVORITE OLD SLIDE THAT TELLS YOU EVERYTHING YOU WANT TO KNOW ABOUT LUNG CANCER. HERE IS THE CANCER. THIS IS A CT SCAN. HERE ARE CHANGES THAT YOU WOULD SEE WITH COPD, FIBROSIS, HARD TO SEE THESE ARE BIGGER GAPS WHERE YOU HAVE TO STRUCTURE — DESTRUCTION OF THE THE ALVEOLI. HERE YOU HAVE THE PACK OF CIGARETTES, EVEN AS THIS PERSON HAS BEEN DIAGNOSED STILL SMOKING. THERE ARE OTHER EXPOSURES, RAY DON IS THE SECOND MOST COMMON LEADING CAUSE OF LUNG CANCER. ASBESTOS, A VERY IMPORTANT ONE, WE ALL THINK OF MESOTHELIOMA WITH ASBESTOS EXPOSURE BUT MORE PEOPLE GET LUNG CANCER FROM ASBESTOS THAN MESOTHELIOMA BECAUSE LUNG CANCER IS MUCH MORE COMMON, MANY PEOPLE WHO HAVE EXPOSURE TO ASBESTOS OFTEN HAVE EXPOSURE TO O TOBACCO. A WHOLE VARIETY OF ENVIRONMENTAL EXPOSURES, OFTEN ASSOCIATED WITH THE WORKPLACE. THERE ARE GENETIC PRE-DISPOSITIONSES AS WELL, A RARE GERM LINE MUTATION IN THE EPIDERMAL GROWTH FACTOR RECEPTOR WHICH WE’LL TALK ABOUT A LITTLE MORE, GIVES YOU FAMILIAL LUNG CANCER TOTALLY INDEPENDENT OF TOBACCO EXPOSURE, THEN A WHOLE LOT OF OTHER NOT AS IMPORTANT IN TERMS OF WHAT PERCENTAGE OF LUNG CANCER THEY ARE RESPONSIBLE FOR BUT FOR INSTANCE THE ACETYLCHOLINE NICOTINIC RECEPTOR SUBUNITS HAVE BEEN FOUND TO BE ASSOCIATED WITH LUNG CANCER. SOME OF THESE ARE ALSO RISK FACTORS OR GIVE YOU GENETIC SUSCEPTIBILITY TO COPD. SO THERE’S SOME COMING TOGETHER FOR THESE TWO DISPARATE DISEASES. SO LUNG CANCER HISTORICALLY HAS BEEN DIVIDED INTO TWO TYPES OF HISTOLOGY. SMALL CELL LUNG CANCER WHICH IS A VERY AGGRESSIVE DISEASE WHICH I THINK YOU HAVE A SEPARATE TALK ON. CENTRAL DISEASE ASSOCIATED WITH LARGE TOBACCO EXPOSURE. THEN EVERYTHING ELSE, NON-SMALL CELL, TURNS OUT EVERYTHING ELSE IS ACTUALLY MANY DIFFERENT CANCERS HISTOLOGICALLY, ABOUT 40% ARE ADENOCARCINOMAS, 20% SQUAMOUS CELL, 15% ARE LARGE CELL, THEY HAVE CHARACTERISTICS APPEARANCES, CHARACTERISTIC NATURAL HISTORIES, AND WHERE IN THE LUNG THEY FORM, FOR INSTANCE THIS IS PERIPHERAL, THIS IS SEN RAIL, LARGE CELL PERIPHERAL, AND THEN A SMATTERING OF OTHERS. IN THE PAST THE REASON WE HAD THESE TWO CATEGORIES IS BECAUSE SMALL CELL HAS BEEN KNOWN TO BE VERY CHEMOTHERAPY RESPONSIVE FOR MANY YEARS AND WAS TREATED ONE WAY, EVERYTHING ELSE WAS TREATED THE SAME WAY. THAT IS NO LONGER THE CASE. BUT SO WE REALLY ARE INTERESTED WHEN SOMEBODY DIAGNOSED THESE DAYS TO KNOW WHETHER IT’S AD MOW CARCINOMA VERSUS SQUAMOUS OR OTHERS. I’M GOING TO TALK LUNG CANCER IN THIS CONTINUUM. BECAUSE LUNG CANCER DEVELOPS FROM THE NORMAL AIRWAYS, THROUGH A SERIES OF PROGRESSIVE ABOUT NORMALITIES THAT RESULT IN THIS INVASIVE AND METASTATIC PHENOTYPE. SO FIRST WE WILL START OUT WITH TALKING TREATMENT. WHICH SHOULD BE A HUGE LECTURE IN AND OF ITSELF SO I WILL GIVE YOU SHORT LEGISLATIVE SO YOU HAVE SORT OF THE BIG PICTURE. LUNG CANCER LIKE EVERY OTHER CANCER WE THINK OF SOMEWHAT ANATOMICALLY. ANATOMICALLY WE USE TO DETERMINE HOW WE’RE GOING TO APPROACH IT, SO SOMETHING — IF LUNG CANCER IS EARLY STAGE, STAGE ONE, IT’S LOCALIZED SURGERY IS THE WAY TO GO. IF IT’S A LITTLE BIT MORE LOCALLY ADVANCED, WITH ONLY SOME LYMPH NODES NEARBY, WE GENERALLY GO WITH SURGERY, WITH ADJUVANT CHEMOTHERAPY FOR STAGE 2 WHEN THE LYMPH NODES ARE INVOLVED IN THE HIGH LEM SO NOT IN THE CENTRAL PART OF THE LUNGER. IF WE FIND THERE WAS SOME INVOLVEMENT IN THE CENTRAL PART OF THE LUNG BUT WE HAD ALREADY DONE THE SURGERY. THAT WAS NOT RECOGNIZED PRE-SURGICALLY. THAT’S A SURGERY AND CHEMO, CHEMOTHERAPY SITUATION. IF THE CANCER IS MOAN TO HAVE SPREAD TO THE MEDIASTINUM, THE CENTER OF THE LUNG WHERE WE HAVE LYMPH NODES AND VESSELS AND SO ON, THEN WE USE COMBINE MODALITY THERAPY, THAT IS USUALLY CHEMOTHERAPY WITH RADIATION. SOMETIMES FOLLOWED BY SURGERY IF THERE’S MINIMAL INVOLVEMENT OF LYMPH NODES ON THE SAME SIDE AS TUMOR IS. MOST OF WHAT WE DEAL WITH IS REALLY METASTATIC CANCER, MEDICAL ONCOLOGIST, THAT’S WHAT WITH I SEE PRIMARILY, THAT’S A SITUATION FOR SYSTEMIC THERAPY, WITH RADIATION GIVEN AS NEEDED TO RELIEVE SYMPTOMS TO PREVENT PROBLEMS. OCCASIONALLY WE WILL TAKE OUT AN ISOLATED METASTASIS IN THE BRAIN ALONE. THAT CAN BE ASSOCIATED WITH IMPROVED FUNCTION AS WELL AS SURVIVAL. FOR THE MOST PART EVERYBODY GETS SYSTEMIC THERAPY. YOU TALK ABOUT SMALL CELL SEPARATELY, THAT IS SYSTEMIC THERAPY FROM THE GET GO, PLUS RADIATION WHEN IT’S STILL SOMEWHAT LIMITED. SO WHAT USED TO BE A SIMPLE DISCUSSION ABOUT TREATMENT FOR METASTATIC LUNG CANCER HAS BECOME A COMPLICATED DISCUSSION BECAUSE WE NOW APPROACH THINGS MUCH DIFFERENTLY. WHAT TERRY DIDN’T SAY IS WE HAVE KNOWN EACH OTHER A FEW DECADES AT THIS POINT, THOUGH I’M MUCH YOUNGER THAN HE IS. BUT NEVERTHELESS WHAT I TRAINED AS A PILLOW AT MES AMIS, THIS IS ALL WE HAD. CHEMOTHERAPY. IT WAS MAINLY TWO DRUGS THAT INCREASE TO VARIOUS CISPLATIN CARBO PLATIN BASED INTRAVENOUS TREATMENT, STILL USED AND MOST PEOPLE WITH ADVANCE LUNG CANCER WILL STILL GET CHEMOTHERAPY AT SOME POINT BUT NOT NECESSARILY AT THE FRONT LINE IN THE INITIAL DIAGNOSIS. IT’S USED FORAGE EVENTUAL TREATMENT, AFTER YOU HAVE TAKEN OUT ALL THE DISEASE SURGERY TO HELP ENSURE THOSE MICROMETASTATIC DEPOSITS ARE AIKEN CARE OF. IT’S USED IN METASTATIC DISEASE BUT USUALLY NOT ALONE ANY MORE FROM BLIND. WHAT YOU HAVE INSTEAD TARGETED THERAPY AND IMMUNOTHERAPY. AND TARGETED THERAPY IS EXACTLY WHAT THE NAME SUGGESTS, IT IS FOR PEOPLE WHO HAVE SPECIFIC TYPES OF MOLECULAR ABNORMALITIES, I WILL SHOW YOU A LIST IN A BIT. FOR WHOM SPECIFIC DRUGS EXIST. THE EPIDERMAL GROWTH FACTOR RECEPTOR EGFR STORY IS THE POSTER CHILD ABOUT 20%, OF ADENOCARCINOMAS. BUT IT’S A MINORITY. THIS IS WHILE GIVING PEOPLE THESE ORAL TYROSINE KINASE INHIBITORS IS VERY BENEFICIAL ABOUT LEADS TO PROLONGED SURVIVAL, IT IS NOT A CURE THERE ARE PEOPLE GENERALLY WIND UP HAVING TO GO TO OTHER TYPES OF TREATMENT SUCH AS CHEMOTHERAPY. THE NEW KID ON THE BLOCK NOT SO NEW ANY MORE IS IMMUNOTHERAPY, WHICH USES REVS UP THE PATIENT’S OWN IMMUNE SYSTEM AND IS NOW FRONT LINE USE AS SINGLE AGENT DEPENDING ON THE PROFILE OR IN COMBINATION WITH CHEMOTHERAPY, AND THESE DAYS ALMOST EVERYBODY GETS IT. ALMOST NOT QUITE. SO LET’S TALK ABOUT THE TARGETABLE MUTATIONS AND HOW WE GET TO PERSONALIZED THERAPY. IF YOU LOOK MOLECULARLY AT ADENOCARCINOMA, THIS IS ONE, 40% NON-SMALL CELL, ADENO, WE ACTUALLY FIND MULTIPLE DRIVER MUTATIONS, ABNORMALITIES THAT ARE RESPONSIBLETOR MALIGNANT PEEN TYPE, ABOUT A QUARTER, 30 PERCENT RKR AS WE DON’T HAVE DRUGS FOR THAT. 20% ARE EGFR MUTATED, WE HAVE MULTIPLE VERY GOOD DRUGS FOR THAT. THIS IS PRIMARILY IN NEVER SMOKERS. THIS IS IN SMOKERS. TRANSLOCATIONS WE HAVE GREAT DRUGS FOR THAT AS WELL, NOW WE ARE STARTING TO GET TO 8% OF EVERYBODY. HEN WE HAVE MORE WHERE ABNORMALITIES LIKE THE RAS 1 TRANSLOCATION, BRAF MUTATIONS, RETINUATIONS, WE HAVE DRUGS THAT ARE APPROVED FOR THESE GUIDES, ALMOST APPROVED FOR RET. WE HAVE DRUGS NOW FOR WHICH YOU FIND IN OTHER TYPES OF CANCER AS WELL. MET HAS A VERY RARE EXON SKIPPING MUTATION AND THAT IS TARGETABLE. AS YOU CAN SEE MAYBE THERE ARE 40% OR SO, 30% OF THESE TUMORS HAVE SPECIFIC THERAPIES. THE RESPONSE RATES WITH THE SPECIFIC THERAPIES ARE EXCELLENT, 50 TO 80%, OPPOSED TO 20% FOR CHEMO. TYPICAL DURATION OF TREATMENT IS MORE LIKE 8 TO 14 MONTHS THEN YOU NEED TO GO UP TO SOMETHING ELSE WHETHER IT BE A SECOND LINE TARGETED THERAPY, OR SOMETHING COMPLETELY DIFFERENT. SO HUGE PROGRESS, NO CURES. IMMUNOTHERAPY ON THE OTHER HAND IS AS I SAID, THE NEW KID ON THE BLOCK, THE POTENTIAL FOR PERHAPS EVEN CURES. SO THE IMMUNOTHERAPY THAT IS USED, I DON’T KNOW WHETHER YOU HAVE HAD A MELANOMA LECTURE BUT MELANOMA AND NON-SMALL CELL LUNG CANCER IS AIMED AT THE PD 1 PDL 1 PATHWAY, THE PROGRAM CELL DEATH PROTEIN 1 WHICH IS PD 1 IS A T-CELL CO-INHIBITOR RECEPTOR, IT IS INVOLVED IN REGULATION OF T-CELL ACTIVATION, IT’S PART OF THE BODY’S WAY OF TAMPING DOWN OF DEALING WITH INFLAMMATION AND WITH VARIOUS INSULTS. IN THE CANCER SETTING, THIS PATHWAY IS SUPPRESSED. WHAT IT DOES IS IT LIMITS ACTIVITY OF — LET ME REPRAISE THAT. IN THE CANCER SETTING, THIS PATHWAY IS REVVED UP BECAUSE PART OF THE ROLE HERE IS TO INHIBIT T-CELL ACTIVITY IN THE TISSUES. THE LIGANDS WHICH ARE FREQUENTLY EXPRESSED ON TUMORS ARE PRESENT IN MANY TYPES THOUGH THAT IS NOT NECESSARILY FULLY CORRELATED WITH IMMUNOTHERAPY ACTIVITY. BUT THIS HAS BECOME A MAJOR PATHWAY FOR TREATMENT OF MULTIPLE KINDS OF TUMORS. SO WHAT I WANT TO POINT OUT IS THERE’S SEVERAL TYPES OF ANTIBODIES THAT ARE NOW CURRENTLY IN USE AND THE REASON WHY THIS IS SO EXCITING TO PEOPLE IS NOT BECAUSE OF A HIGH RESPONSE RATE, BECAUSE A RESPONSE RATE TO SINGLE AGENT TREATMENT IS GENERALLY 20% OR SO, BUT BECAUSE THE PEOPLE WHO RESPOND A NUMBER OF THEM HAVE THESE LONG, LONG RESPONSES. SOME PEOPLE YEARS OUT WITH METASTATIC LUNG CANCER AFTER HAVING RECEIVED IMMUNOTHERAPY. SO PEOPLE ARE STARTING TO ASK IS THIS ACTUALLY A CURE? WHICH FOR METASTATIC NON-SMALL CELL LUNG CANCER WAS NEVER A POSSIBILITY AND IS NOT A POSSIBILITY WITH TARGETED THERAPIES OR CHEMOTHERAPY. THIS IS A VERY ACCEPTING DEVELOPMENT BUT IT REALLY IS APPLICABLE TO A VERY SMALL MYMORETY OF PEOPLE WITH LUNG CANCER. TO SUM UP A GROSSLY INAPPROPRIATELY HIGH LEVEL VIEW OF TREATMENT OF LUNG CANCER, WE DO IT BY STAGE, IF A PERSON HAS METASTATIC DISEASE, IT IS NOW ABSOLUTELY CRITICAL TO BIOPSY TO HAVE MOLECULAR ANALYSIS DONE. IF THERE IS A TARGETABLE MUTATION LIKE EGFR OR ERL OR RAS 1 YOU GIVE ORAL TREATMENT WITH A TARGETED AGENT. IF THIS PD 1 PDL 1 PATHWAY APPEARS INVOLVED H PDL 11 HIGH, THE IMMUNOTHERAPY ALONE WITH ONE AGENT IS APPROVED WAY TO MOVE FORWARD. IF PDL 1 IS LOW THERE’S NO MUTATION, THEN THESE DAYS WE GIVE CHEMOTHERAPY WITH AN IMMUNOTHERAPY ANTIBODY. OR IN SOME CASES, IF THERE IS REASONS TO BE WORRIED ABOUT IMMUNOTHERAPY LIKE SOMEBODY HAS, AUTOIMMUNE DISEASE WHICH GET REALLY RAMPED UP IN MAJOR SIDE EFFECTS OF IMMUNE THERAPY, YOU MAY DO CHEMO ALONE WITH ANGIOGENIC AGENT. MANY THE OLD DAYS I TALK ABOUT THE ANTI-ANGIOGENIC AGENTS LIKE BENEFITSIVE HAS BEEN ARE BECOMING MORE IMPORTANT FOR THE TREATMENT OF LUNG CANCER. I’M GOING TO PIVOT H NOW. HOW DO WE MAKE A DIFFERENCE? HOW DO WE REDUCE MORBIDITY AND MORTALITY? WE TALKED ABOUT THERAPEUTICS A LOT OF WORK, HUGE EFFORT BY PALMER, BY THE GOVERNMENT, EVERYBODY INVOLVED, TO GET BETTER THERAPEUTICS THAT WILL GIVE LONG TERM TREATMENT. THERE’S LONG TERM BENEFIT BUT THERE’S OTHER WAYS TO DO IT, ONE TO PREVENT A DISEASE AND THOSE HIGH RISK, THE OTHER TO DETECT EARLY O. SINCE I WORK IN THE DIVISION OF CANCER PREVENTION AND MY WORK DEALS WITH PREVENTION YOU WILL HEAR MORE ABOUT THAT. SO THE BEST WAY TO PREVENT LUNG CANCER IS TO TAKE THAT 85% DUE TO SMOKING AND GET RID OF IT. THE BEST WAY WOULD BE PREVENT THOSE YOUNG PEOPLE FROM EVER STARTING. WHAT ABOUT SOMEBODY WHO HAS BEEN SMOKE SOMETHING CAN YOU ACTUAL — SMOKING? CAN YOU UNDO THE DAMAGE TO THE LUNG THAT HAS ACCUMULATED WITH REPEATED EXPOSURE? SO TURNS OUT THAT YOU CAN TO AN EXTENT. THIS IS AN OLD STUDY CALLED THE LUNG HEALTH STUDY WHICH WAS DONE ACTUAL LE IN COPD, PEOPLE WITH EMPHYSEMA. AT THE 14.5 YEAR FOLLOW-UP, WHAT WAS NOTED WAS THAT PEOPLE WHO CONTINUE TO SMOKE, HAD A DEATH RATE OF 3.5 PER THOUSAND YEARS. PEOPLE WHO QUIT AND SUSTAINED THEIR QUITTING, HAD MORE THAN A 50% REDUCTION IN THEIR LUNG CANCER MORTALITY. PEOPLE WHO QUIT INTERMITTENTLY WHERE SOMEWHERE MANY BETWEEN. SO THIS TELLS YOU WITH PROLONGED CESSATION, YOU CAN REDUCE THE DEATH RATE. WHAT WAS INTERESTING IS THAT AT THE FIVE YEAR FOLLOW-UP, THIS IS 14.5 YEARS, FIVE YEAR FOLLOW-UP ALSO NO EFFECT THAT YOU CAN TELL. SO QUITTING SMOKING IS IMPORTANT BUT YOU WILL NOT SEE THE BENEFIT WITH REGARD TO LUNG CANCER UNTIL YEARS OUT. THAT’S BECAUSE THEY CONTINUE TO SMOKE YOUR RISK OF LUNG CANCER CONTINUES TO GO UP, UP, UP. IF YOU QUIT SMOKING YOU STOP THAT CONTINUED INCREASE. QUITTING SMOKING IS HARD. IT’S A SOCIOLOGICAL BEHAVIORAL ISSUE AND THAT’S NOT MY AREA OF EXPERTISE BUT I WANT TO EMPHASIZE HOW SUPER IMPORTANT IT IS AT ANY POINT DURING THE DISEASE. SO HOW ABOUT PREVENTING? CANCER CHEMOPREVENTION IS A FIELD, IT WAS THE USE OF NATURAL SYNTHETIC AGENTS TO SUPPRESS THE PROCESS OF CARCINOGENESIS. LUNG CANCER DOESN’T DEVELOP OUT OF NOTHING, IT’S A CUMULATIVE — IT’S ACCUMULATION OF MOLECULAR ABOUT NORMALITIES DUE TO TOBACCO EXPOSURE. THAT EFFECTS THE ENTIRE FIELD. SO CANCER CHEMOPREVENTION SEEKS TO REVERSE THAT PROCESS TO REGRESS THOSE LESIONS THAT ALREADY HAVE SOME HINT BUT AREN’T YET OVER CANCER, SO TREAT EPITHELIAL NEOPLASIA, PREVENT DEVELOPMENT OF NEW LEAGUES THAT HAVE MOLECULAR ABNORMALITIES, BUT THEY HAVEN’T STARTED TO LOOK ABNORMAL YET. AND THEN ALSO TO SUPPRESS THE RECURRENCE OF LESIONS THAT HAVE BEEN FOR INSTANCE TAKEN OUT AND NOW COME BACK AS A SECOND POST TREATMENT SECOND CANCER. THE ACTION NOW IS METASTATIC CANCER STILL IS NOT CURABLE, I SHOWED YOU INTRIGUING DATA THAT WITH IMMUNOTHERAPY A SMALL PERCENTAGE OF PEOPLE CAN HAVE PROLONGED SURVIVAL BUT BY AND LARGE WE DON’T KNOW THEY’R CURED YET, THAT’S A SMALL PERCENTAGE. WE HAVE DONE MUCH BETTER. IN RECENT YEARS AND HAVE FAR TO GO. CANCER ON THE OTHER HAND IN OTHER SETTINGS SUCH AS BREAST CANCER CAN BE PREVENTED AND WE DEFINITIVELY WITH LARGE STUDIES, USING TAMOXIFEN AND RALOXIFENE, I’M SURE YOU WILL HEAR ABOUT THAT IN THE BREAST CANCER LECTURE, WE CAN MODEL IT VERY WELL IN ANIMALS EVEN LUNG CANCER USING MULTIPLE DIFFERENT AGENTS. WE KNOW TOBACCO EXPOSURE STARTS WHEN YOU ARE YOUNG BUT LUNG CANCER DOESN’T COME UNTIL LATE 40s, 50 E 60s, 7 Os. SO THERE’S A LONG PRE-CLINICAL PHASE WITH INCREASING HISTOLOGIC AND MOLECULAR ABNORMALITIES AND WE KNOW THE POPULATION TO GO AFTER, NAMELY HEAVY SMOKERS. WHO HAVE SOME OF THESE ABNORMALITIES. SO HOW DO WE DO CANCER PREVENTION SOMEHOW DO WE MOVE FORWARD? WE HAVE A LOT OF WORK STILL LEFT TO DO TO UNDERSTAND THE MECHANISMS. IN THE SETTING OF CERVICAL CANCER WHICH IS KNOWN TO BE CAUSED BY THE HUMAN PAPILLOMA VIRUS, THE VACCINE IS 95 PERCENT PLUS PERCENT EFFECTIVE. IF YOU HAVEN’T BEEN EXPOSE AND YOU DON’T — YOU DON’T GET EXPOSURE BECAUSE YOU HAVE BEEN VACCINATED, THEN CERVICAL CANCER WILL NOT OCCUR. WE KNOW THAT. SO UNDERSTANDING THE MOLECULAR PATHOGENESIS IS THE BEST THING BUT LUNG CANCER IS MUCH MORE COMPLICATED THAN CERVICAL CANCER. INSTEAD WE TURN TO PRE-CLINICAL MODELS WHERE WE CAN MODEL THE DISEASE PROCESS, FOR INSTANCE BY GETTING CARCINOGENS OR INTRODUCING THE APPROPRIATE DRIVER MUTATIONS AND WE HAVE SHOWN MANY THE SETTING OF COLON CANCER NON-STEROIDAL LIKE ASPIRIN AND MOTRIN AND OTHERS, CAN ACTUALLY PREEVENTUAL TUMORS IN THE ANIMAL SETTING AND WE HAVE DATA FROM THE HUMAN SETTING THAT YOU CAN ACTUALLY PREVENT WITH RECURRENCE OF POLYPS AND THEREFORE PRESUMABLY COLON CANCER ITSELF. WE GO TO OBSERVATION EPIDEMIOLOGY. A LOT OF THE DATA ON COLON CANCER CAME FROM THE RECOGNITION THAT PEOPLE TOOK ASPIRIN AND OTHER NON-STEROIDALS HAVE DECREASED INCIDENCE AND MORTALITY FROM COLON CANCER. FINALLY, WE LOOK AT CLINICAL TRIALS THAT USE APPROPRIATE AGENTS TO SEE DO THEY HAVE AN EFFECT ON OTHER DISEASE? THIS IS HOW TAMOXIFEN WAS FOUND TO BE PREVENTIVE AND MA LOX PHONE AS WELL FOR BREAST CANCER. NA LOX PHONE. SO WE LOOK THROUGHOUT THE LITERATURE, THROUGHOUT THE BODY OF DATA. AND WE IMMEDIATE TO FOCUS ON HOW WE MOVE THESE PATIENTS FORWARD. THE IDEA IS TO HAVE A TARGET THAT WE CAN WE CAN THEREFORE APPROPRIATELY SELECT AN AGENT THAT WILL IMPACT THAT TARGET. IT’S A LOT MORE DIFFICULT IN LUNG CANCER BECAUSE I TOLD YOU THE DIFFERENT HISTOLOGIC SUBTYPES. SO THESE DIFFERENT PROGENITOR CELL LINEAGES HAVE DIFFERENT PATHOGENESIS. AND MAY NEED A DIFFERENT INTERVENTION. THESE ABNORMALITIES OCCUR OVER A LONG PERIOD OF TIME. SO IT MAY MEAN EARLY ON WE WANT TO USE STRATEGIES THAT PREVENT DNA DAMAGE LATER ON WE WANT TO USE STRATEGIES THAT TARGET THE ABNORMALITIES THAT HAVE OCCURRED. IN THE LIFETIME OF A SMOKER THEY ARE CONSTANTLY GETTING A NEW DNA DAMAGE FROM DECONTINUED SMOKING WHILE OTHER FOCI THAT ARE FURTHER ALONG IN THEIR MOLECULAR PROGRESSION TO CANCER. WE NEED TO SELECT OUR COHORTS, IF WE ARE LOOKING AT SQUAMOUS CELL CARCINOMA, PREVENTION YOU WANT TO LOOK IN THE AIRWAYS WHERE SQUAMOUS CELLS ARISE. BRONCHIAL DYSPLASIA IS WHAT WE LOOK AT. I WILL SHOW YOU HOW WE DO THOSE STUDIES. IF WE ARE LOOKING TO PREVENT ADENOCARCINOMAS WHICH ARISE FROM THE PERIPHERAL LUNG FROM THE TYPE 2 THYMOCYTES AND CLARA CELLS WE PROBABLY NEED TO LOOK AT LUNG NODULES ON CT SCANS. I WILL SHOW YOU EXAMPLES HOW WE HAVE DONE THAT. AND NOR NON-SMOKERS WE HAVE NO IDEA HOW THEY GET INTO THE PROCESS, THAT’S EVERYBODY AT RISK. COUPLE OF OTHER THINGS TO THINK ABOUT, IF YOU ARE GOING TO TREAT SOMEBODY WITH CANCER THEY HAVE SOMETHING THAT IS IMMINENTLY LETHAL YOU CAN GIVE THEM CHEMOTHERAPY, YOU CAN GIVE THEM AGENTS THAT MAKE THEM VERY SICK, YOU CAN TAKE THEM TO SURGERY, WHERE THEY CAN DIE ON THE SURGICAL TABLE. IF THEY HAVE AN 8% LIFETIME RISK OF A LUNG CANCER HOW MUCH RISK ARE YOU WILLING TO TAKE? SO WE NEED TO BALANCE THAT RISK BENEFIT OF MUCH MORE IN THE BENEFIT AND LESS IN THE RISK SIDE WHEN IT COMES TO CANCER PREVENTION. THAT TIES OUR HANDS A LITTLE BIT MANY TERMS OF TYPE OF AGENTS WE CAN USE. IT IS A COMPLICATED FIELD. BUT I’M GOING TO GIVE YOU A COUPLE OF VIGNETTES HOW WE HAVE BEEN APPROACHING IT. ULTIMATELY IF YOU CAN PREVENT CANCER YOU ARE GOING TO HAVE A MUCH HIGHER EFFECTIVENESS HAHN IF YOU TREAT CANCER BUT YOU HAVE TO MAKE SURE YOU TREAT THE PEOPLE WITH PREVENTIVE INTERVENTIONS WHO ARE MOST AT RISK FOR CANCER. LET ME TELL YOU THE INFLAMMATION STORY AND HOW HA HAS BEEN DEVELOPED. SO THERE HAVE BEEN DATA FOR 50 YEARS ABOUT THE ROLE OF STEROIDS. CORTICAL STEROIDS, ANTI-INFLAMMATORY AND HAIR ABILITY TO PREVENT CANCER IN A VARIETY OF ANIMAL MODELS. THE EPIDEMIOLOGICAL DATA NOT THAT MUCH AVAILABLE STUDIES GENERALLY SHORT EXPOSURE. SHORT DURATION OF TREATMENT. THERE WAS ONE STUDY OF THE PATIENTS WITH — INDIVIDUALS WITH EMPHYSEMA COPD THAT SHOWED A MUCH — LESSER INCIDENCE OF LUNG CANCER, THAN THOSE WHO TOOK INHALED STEROIDS VERSUS THOSE WHO DID NOT. BUT IN GENERAL MOST OF THE RATIONALE FOR USING TARGETED INFLAMMATION FOR LUNG CANCER HAS BEEN FROM ANIMAL MODELS. THIS IS ONE EXAMPLE. ONE OF THE DRUGS IS USED FOR TREATMENT OF ASTHMA. AND GIVING VARIOUS AMOUNTS LED TO 80% DECREASE IN TUMORS AND CARCINOGEN EXPOSED MICE. WHEN YOU LOOK AT WHAT THESE TUMORS ARE, THEY ARE PRIMARILY ADENOMAS OPPOSED TO CARCINOMAS. SO MANY FEWER TUMORS AND THESE CARCINOGEN EXPOSED MICE THAT ARE GIVEN (INDISCERNIBLE) THEY ARE LESS HISTOLOGICALLY ADVANCED SO HOW DO WE TAKE THIS TO A CLINICAL TRIAL? WE LOOKED AT PRE-MALIGNANT LESION, SQUAMOUS, CARCINOMA, CALLED BRONCHIAL DYSPLASIA. IF YOU LOOK AT THE LUNGS OF PEOPLE EXPOSED TO TOBACCO YOU WILL FIND INCREASING ABNORMALITIES STARTING WITH NORMAL, AL THE WAY THROUGH MILD MODERATE SEVERE DYSPLASIA, CARCINOMA IN SITU ALL THE WAY TO INVASIVE DISEASE. IF YOU DO — LOOK AT THE MALL HISTORY OF THESE LESIONS, TURNS OUT THAT ABOUT A THIRD OF THEM WILL — THIRD OF PEOPLE WHO HAVE THEM WILL DEVELOP CANCER WITHIN ABOUT A YEAR AND A HALF. SO NOT EVERYBODY WHO HAS GOT DYSPLASIA DEVELOPS CANCER BUT A SIGNIFICANT PORTION DOES. NOT ALL OF THOSE CANCERS DEVELOP FROM THE ABNORMAL SITE. SOME DEVELOP ELSEWHERE IN THE LUNG BUT THE POINT IS PEOPLE WHO HAVE BRONCHIAL DYSPLASIA ARE AT HIGH RISK FOR DEVELOPING A FUTURE CANCER AND DYSPLASIA IS A PRECURSOR AS WELL AS RISK MARKER. SO WE DID A CLINICAL TRIAL OF BRONCHIAL BUDESNIDE INHALED STEROID WITH BRONCHIAL DYSPLASIA. THESE ARE DIFFICULT STUDIES YOU HAVE TO SCREEN PEOPLE WHO HAVE DYSPLASIA, WE FOUND ABOUT 110 OF HEM. THEY UNDERGO A BROSDOSCOPY, YOU — BRONCHOSCOPY, YOU TAKE A TUBE WITH LIGHT AND BIOPSY THE AREAS, THEY WERE GIVEN THE DRUG OR PLACEBO SIX MONTHS, UNDERWENT CP SCREENING TO LOOK AT THE LUNGS, THEN THE END POINTS WERE NUMBER OF SITES AND GRADE OF DYSPLASIA AS WELL AS NUMBER OF OTHER BIOMARKERS. THIS TRIAL TURNED OUT NEGATIVE THOUGH WE LEARNED A LOT. SO 30% PEOPLE HAD VERSION OF DYSPLASIA, COMPLETE REVERSION. REGARDLESS OF WHETHER THEY TOOK THE DRUG OR PLACEBO, WHEREAS THE ABOUT 45 TO 50% HAD MORE OR WORSE DYSPLASIA ON REPEAT BRONCHOSCOPY. THESE ARE NOT DIFFERENT BETWEEN INTERVENTION AND PLACEBO. IT WAS SOMEWHAT INTRIGUING, THIS WAS REALLY THE FIRST TIME THAT ANYBODY WAS IMAGING THE WHOLE LUNG WITH LOW DOSE CT. THERE WAS A DIFFERENCE IN THE REGRESSION RATE OF THESE CT DETECTED NO DUALS. THAT LED TO WHAT IS REALLY DEVELOPING NEW CLINICAL TRIAL MODEL TO LOOK AT PEOPLE WHO HAVE ABNORMALITIES, SMOKERS WITH THESE ABNORMALITIES AND LOOK AT LOW DOSE CT DETECTED PERIPHERAL NODULES, THEN WHEN YOU REPEAT AS PART OF THE SCREENING PROTOCOL, YOU CAN SEE WHETHER YOU HAVE ANY EFFECT. SO THE FIRST STUDY WE DID WITHOUT COLLEAGUE — WITH OUR COLLEAGUES IN EUROPE AND ITALY, LOOKED AT THE SAME DRUG INHALED STEROID, AND LOOKED AT THE EFFECT ON CT DETECTED NO DUALS. WE FOUND DEFINITELY NOT A HOME RUN BUT INTRIGUING. SO MOST OF THE NODULES WERE SOLID. THEY DON’T CHANGE. SO WHEN YOU START IMAGING PEOPLE’S LUNGS, HAY TURN OUT THEY HAVE PRIOR INSULTS OF VARIOUS SORTS SO THESE SMALL SOLID NODULES WHICH WERE NOT HELD TO BE CANCER, THEY DIDN’T CHANGE WHAT DID CHANGE WERE THE NON-SOLID NODULES, GROUND GLASS OPACITIES. WITH A YEAR OF INHALED STEROID TREATMENT WE FOUND THAT THESE CONTINUE TO GET SMALLER OVER TIME WHEREAS THE PLACEBO DID NOT. THEY START TO GET LARGER. AND THERE WAS A STATISTICAL SIGNIFICANT DIFFERENCE THOUGH THIS IS STILL JUST LOOKING AT THE NODULES, NOT AT THE ACTUAL CANCER, THEY WERE VERY FEW DIAGNOSES OF CANCER DURING THIS FIVE YEAR PERIOD. WHAT ARE THESE GROUND GLASS OPACITY? TURNS OUT THAT SOME THESE ARE ATYPICAL HYPERPLASIA, A PRECURSOR TO ADENOCARCINOMA. NOT ALL OF THEM, IT’S ANYWHERE BETWEEN 25 AND 50% IN VARIOUS STUDIES ALVEOLI IN THE LUNG. YES. (OFF MIC) TO BE DETERMINED. SMOKING MARIJUANA FOR INSTANCE, DON’T KNOW YET ABOUT JEWEL AND VAPING. IF THAT’S GOING TO BE A FIVE TO TEN YEARS FROM NOW THE LECTURE WILL BE QUITE DIFFERENT BUT CERTAINLY WITH MARIANNA YOU GET — MARIJUANA YOU GET BRONCHIAL ABNORMALITIES. OLD STUDIES. THE AMOUNT OF EXPOSURE WITH MARIJUANA IS DIFFERENT AND TYPE OF EXPOSURE WITH VAPING AND JEWEL AND OTHERS, IS ALSO QUITE DIFFERENT. SO REMAINS TO BE DETERMINED. OF COURSE SO WHAT YOU ARE THINKING OF IN TERMS OF PEOPLE WHO DIED WHO GOT — WHO GET THIS SEVERE RESPIRATORY DISTRESS, THAT IS DIFFERENT. THAT IS A BIG SYSTEMIC WHOLE LUNG KIND OF ISSUE. WHAT I’M TALKING ABOUT HERE ARE THESE PERSISTENT ABNORMALITIES THAT YOU WILL SEE ON CT. AND THE QUESTION IS WHAT DO YOU DO WITH THEM? AND HOW LONG DO YOU FOLLOW THEM? SO LONG STORY SHORT WE ARE GETTING THE MALL HISTORY OF THESE ABOUT — THE NATURAL HISTORY OF ABNORMALITIES. ONE PERCENT BECOME CANCER, THREE, FIVE, SIX, ABOUT SEVEN AND A HALF PERCENT OVER TIME WILL BECOME CANCER OR A LOW GRADE CANCER MINIMALLY INVASIVE ADENOCARCINOMA OR ADENOCARCINOMA IN SITU OR AH. SO THE NODULES DO NEED TO BE FOLLOWED UP. THOSE ARE THE PEOPLE WHO WE HAVE BEEN FOCUSING ON. A PICTURE IS WORTH A THOUSAND WORDS. THISES A FRIEND WHO CAME TO MY CLINIC BECAUSE SHE HAD CHEST PAIN, WENT TO ER, THIS IS WHAT CT SHOWED IN P 2004. HERE YOU HAVE THE — SHE’S ACTUALLY HAD EXPOSURE TO TOBACCO BUT NOT — WAS NOT A SMOKER. HERE YOU HAVE THIS GLASS OPACITY, COME BACK IN THREE MONTHS, THERE IT IS AGAIN, EVERYTHING WAS FINE AND COME BACK IN A YEAR WHICH SHE WAS SUPPOSED TO, SIX YEARS LATER SHADE ANOTHER EPISODE OF CHEST PAIN, WOUND UP ER, DID A CT SCAN AND NOW HERE IT IS AGAIN BUT AS YOU CAN SEE IT’S BIGGER. THAN IT WAS BEFORE. WHEN THAT WAS FOLLOWED UP IT STARTED TO BECOME MORE DENSE AND TURNED OUT TO BE AN EARLY STAGE ADENOCARCINOMA WITH ADJACENT AH. THIS TELLS YOU THAT’S A SEVEN YEAR PERIOD OF TIME. THESE NODULES TAKE A LONG TIME TO MAKE — MAY TAKE LONG TIME TO DEVELOP. I WILL SPEED THROUGH THIS A LITTLE BIT BUT BOTTOM LINE IS YOU HAVE THESE SLIDES I THINK BOTTOM LINE, THESE GRAM GLASS OPACITIES ARE ASSOCIATED WITH INCREASE RISK BUT FUTURE RISKER THEY ARE NOT TUMORS, THEY ARE THE PRECURSORS. SO HOW DO WE MOVE OUR STUDIES FORWARD AS MUCH SO WE DID — WE LOOKED AT THE ANTI-INFLAMMATORY INHALED STEROIDS, A HINT BUT NOT A HOME RUN. SO WE MOVED ON TO ASPIRIN WHICH IS ANOTHER WELL KNOWN ANTI-INFLAMMATORY. I GUESS EIGHT YEARS EIGHTIES POINT THERE WAS A SERIES OF STUDIES, META NAIL SEIZE SHOWING PEOPLE — META ANALYSES, PEOPLE WHO TAKE ASPIRIN FOR CARDIOVASCULAR DISEASE PREVENTION, NUMBER OF STUDIES DONE, THEY HAVE A 20% DECREASE IN DEATH FROM CANCER. ALL CANCERS, ONE OF THE CANCERS THAT WAS MOST STRIKING WAS LUNG CANCER. LUNG ADENOCARCINOMA IN PARTICULAR. WHAT YOU SEE HERE THIS LITED CURVE IS THAT THOSE WHO TOOK ASPIRIN HAD 30% DECREASE RISK OF DEATH FROM LUNG CANCER, OVER THE LONG TERM. BUT THEY SEPARATE BEFORE FIVE YEARS. SO WITHIN FIVE YEARS YOU CAN TELL A DIFFERENCE IN TERMS OF LUNG CANCER MORTALITY. SO WE TOOK THIS CT NODULE MODEL AND LOOKED AT PEOPLE WHO HAVE HAD BROWN GLASS OPACITIES, INCREASE RISK, THE ONES WHO HAD CHANGE. WE GAVE LOW DOSE ASPIRIN FOR A YEAR VERSUS LOW DOSE PLACEBO FOR A YEAR. AND EVERYBODY UNDERWENT CT. PRE-AND POST TREATMENT. SO THOSE DATA ARE IN THE PROCESS OF BEING WRITTEN UP. IT WAS ALSO A NEGATIVE STUDY AND IT WHEY THAT AGAIN, THE DURATION IS NOT LONG ENOUGH. WE NEED THE LONG TERM FOLLOW-UP TO SEE WHETHER THERE’S TRULY AN EFFECT. WE ARE ALSO LOOKING AT GENE EXPRESSION IN THE NASAL EPITHELIUM, A SURROGATE FOR BRONCHIAL EPITHELIUM TO SEE WHETHER ASPIRIN AS EFFECT THERE AS WELL. SO THESE ARE ALL ONGOING STUDIES. I WILL — SO THE TAKE HOME MESSAGE IS THAT THE RATIONALE FOR TARGETING INFLAMMATION IS HUGE. VERY STRONG FOR PREVENTING LUNG CANCER. BUT WE HAVE STRUGGLED WITH FIGURING OUT HOW TO PROVE THAT IN A SHORT TERM SETTING. LET ME SHOW YOU ONE OTHER AGENT CALLED MYONOSITOL, AN ISOMER OF GLUCOSE. INVOLVED IN SIGNALING OF — AND IS A SOURCE OF — IS OBTAINED FROM RICE AND MANY OTHER DIETARY SOURCES. A NUMBER OF PRE-CLINICAL STUDIES SHOWED INHIBITION OF CARCINOGEN INDUCED TUMORS IN MICE. THEY — EFFICACY IS THERE, SAFETY IS THERE, IT IS GENERALLY REGARDED AS SAFE. GRASS DECISION — DESIGNATION BY U.S. FDA WHICH MEANS YOU CAN USE IT WITHOUT ANY REGULATORY APPROVAL. SO WE PERFORM AD SERIES OF STUDIES, PHASE 1 STUDY WHERE WE SHOWED THAT YOU CAN TAKE UP TO 18 GRAMS EASILY, ALL THESE PEOPLE HAD BRONCHIAL DYSPLASIA WHEN COMPARED TO HISTORICAL CONTROLS, THAT’S A CAVEAT, WE SHOW AD HIGH RATE OF REGRESSION OF BRONCHIAL DYSPLASIA. WHAT WAS INTERESTING WAS THAT ALL THESE SMOKERS HAD BRUSHINGS OF THEIR NORMAL AIRWAYS. AND THROUGH WHOLE SERIES OF STUDIES, IT HAS BEEN SHOWN THE PI 3 KINASE PATHWAY IS ACTIVATED IN THE AIRWAYS OF SMOKERS WITH DYSPLASIA. THIS ACTIVATION WAS INHIBITED BY MYOANOSITOL. THE MECHANISM HOW THIS DRUG COULD WORK. WHAT WE DID IS WHAT’S CALLED A PHASE 2B STUDY. WHICH TOOK SMOKERS WHO HAD BRONCHIAL DYSPLASIA. MORE THAN 30 PACK YEARS SMOKING, AND RETED THEM FOR SIX MONTHS WITH EITHER MYONOTHICOL OR PLACEBO LOOK AT DYSPLASIA AFTER TREATMENT AS PRIMARY END POINT ADS WELL AS NUMBER OF OTHER BIOMARKERS INCLUDING THE PI 3 KINASE GENE SIGNATURE THAT I JUST REFERRED TO. IT SHOWS WHY IT’S IMPORTANT TO HAVE A WELL PERFORMED AND RANDOMIZED STUDY, EVEN IN THIS SETTING WITH GRADE PRE-CLINICAL DATA AND VERY TANTALIZING PHASE 1 DATA ONCE WE TREAT ENOUGH PEOPLE WE WERE REALLY NOT ABLE TO FIND DEMONSTRABLY DIFFERENT GREG RATE FOR BRONCHIAL DYSPLASIA WITH MYONOSITOL. PI 3 KINASE PATHWAY DOWNSTREAM OF IT AKT ACTIVATION REALLY ONLY OCCURRED IN THOSE WHO RESPONDED. SO IT WAS A CORRELATION BUT NOT A GOOD ENOUGH MARKER TO TELL US WHO WE SHOULD TARGET FOR THIS INTERVENTION. AMONG THE MANY END POINTS OF INTEREST WAS AGAIN INFLAMMATION AND INTERLEUKIN 6 IN THE BRONCHIAL FLUID. BRONCHIAL ALVEOLAR LAVAGE THAT WAS SIGNIFICANTLY DECREASED BY MYONOSITOL. THE SUMMARY FROM THE STUDY WAS THAT WHEN IT COMES TO BRONCHIAL DYSPLASIA, WE WERE NOT ABLE TO FIND AN EFFECT THOUGH WE DID FIND REDUCTION IN IL 6. THE REASON I’M TALKING ABOUT THAT, IS BECAUSE THERE’S AGAIN A WHOLE SERIES OF STUDIES IN MICE SUGGESTING THIS IS AN IMPORTANT MECHANISM OF MYONOSITOL BUT THE CURRENT DATA OF INTEREST IS A SECONDARY ANALYSIS FROM A CARDIOVASCULAR STUDY CALLED THE CANTOSE TRIAL WHICH TARGETS ENTERLIEU WIN 1 BETA DOWNSTREAM OF IT IS IL 6. IN THIS STUDY WHICH WAS DONE PERFORMED IN PEOPLE WHO HAD ONGOING INFLAMMATION WHO HAD CARDIOVASCULAR DISEASE, THEY HAD A HIGH C REACTIVE PROTEIN, WHAT WAS MOST VIKING WAS THAT NOT ONLY WAS THERE EFFECT IN DECREASING CARDIOVASCULAR DISEASE BUT THERE WAS A REDUCTION IN TOTAL CANCER MORTALITY BY 50% WHICH WAS PRY MAY RECALL DRIVEN BY LUNG CANCER MORTALITY AND LUNG CANCER INCIDENCE WHICH WAS DOWN BY ALMOST 70%. THIS GIVES US A CLUE THIS PATHWAY MAY BE THE COMPONENT OF THE ANTI— OF THE INFLAMMATION CASCADE THAT SHOULD BE TARGETED FOR LUNG CANCER PREVENTION. SO THERE ARE ONGOING STUDIES MAINLY MANY THE PLANNING TO ADDRESS WHETHER USING FOR INSTANCE THE ANTIBODY AGAINST IL 1 BETA COULD BE PREVENTIVE MANY THE RIGHT POPULATION. TO BE DETERMINED HOW THIS WORKS. LET ME SPEND A FEW MINUTES TALKING ABOUT EARLY DETECTION OF LUNG CANCER, NOT DOING THIS JUSTICE BY ANY STRETCH. YOU WOULD THINK SOMETHING WOULD BE EASY AND IT’S NOT, NOTHING IS EASY. WHEN IT COMES TO CANCER SCREENING IT COMES WITH ITS OWN HOST OF POTENTIAL BIASES WE LIKE TO CALL THEM. SO LEAD TIME BIAS, DIAGNOSE EARLIER, BUT YOU DON’T POST DONE DEATH. YOU ONLY THINK YOU ARE DOING GOOD BECAUSE IF A PERSON IS SUPPOSED TO DIE HERE, YOU DIAGNOSE AND NORMALLY HERE, BUT IT’S REALLY TEN MONTHS EARLIER THEY STILL DIE AT THE SAME TIME, YOU ONLY THINK YOU HAVE DONE SOMETHING OF VALUE. THAT’S LEAD TIME BIAS. LIFE BIAS. DIAGNOSE THE INDOLENT DISEASE WITH LONGER PRE-CLINICAL PHASE. THOSE ARE PEOPLE WHO DO BETTER, THEY HAVE A BETTER OUTCOME. THERE IS A GREAT I’M GETTING MUCH LONGER SURVIVAL IN PEOPLE WHO I DIAGNOSED FOUND ON SCREENING. IN FACT MISSING THE CANCERS, THEY WILL TELL PEOPLE QUICKLY. YOU THINK YOU’RE DOING BETTER THAN REALLY ARE. THIRD ISSUE, OVERDIAGNOSIS, YOU DIAGNOSE THE UNIMPORTANT THINGS THAT YOU PICK UP THAT WOULD HAVE NEVER KILLED THE PERSON ANYWAY, IT JUST HAPPENS TO BE THERE, IF YOU DO AUTOPSY STUDIES OF OLDER MEN, EVERYBODY HAS PROSTATE CANCER. ALMOST EVERYBODY, 90%, 80%. DOES THAT MEAN IF YOU FIND ALIVE THEY WOULD HAVE DIED OF PROSTATE CANCER? ABSOLUTELY NOT. THERE IS SUCH A THING IN LUNG CANCER AS WELL, SHOPPING AS IT MAY BE, THOSE OF US IN THE FIELD. ONE HAS TO BE CAREFUL TO MAKE SURE THESE BIASES ARE NOT GIVING A FALSE SENSE OF PROGRESS. WHEN IT COMES TO SCREENING, EVERYBODY WHO IS ABNORMAL YOU HAVE TO WORK UP. THERE’S MORBIDITY, THERE’S MORTALITY, THERE’S THE COST OF THE SCREENING, COST OF THE WORK UPS, THE PSYCHOLOGICAL COST. SO ALL THESE NEED TO BE CONSIDERED WHEN ENTERTAINING A SCREENING TRIAL, A SCREENING PROGRAM. FOR MANY YEARS ALL WE HAVE TO DIAGNOSE LUNG CANCER WITH CHEST X-RAY, THIS STUDY PLCO OPINIONLY DEFINITIVELY SHOWED THAT SCREENING BY CHEST X-RAY VERSUS USUAL CARE, DOES NOT IMPACT LUNG CANCER MORTALITY. CASE SETTLED. HOWEVER, SCREENING BY CT SCAN LOW DOSE CT SCAN OR HEELICAL CT SCAN ACTUALLY IS EFFECTIVE. THAT’S A MUCH MORE SENSITIVE TEST. THE NATIONAL LUNG SCREENING TRIAL NLSD WAS PERFORMED IN EARLY 2000, OUT IN 2011, 8 YEARS AGO. 53,000 PLUS SMOKERS OCCURRED FORMER, VERY CAREFULLY CONTROLLED, EVERYBODY HAD EITHER A HELICAL CT OR CHEST X-RAY LEE TIMES ALL TOGETHER. AND ESSENTIALLY WHAT YOU FIND IS A 20% REDUCTION IN LUNG CANCER MORTALITY. PEOPLE DYING FROM LUNG CANCER, THERE’S REDUCTION IN ALL CANCER MORTALITY — IN ALL CAUSE MORTALITY. WHICH SHOWS YOU THE OUTSIDE IMPACT OF LUNG CANCER ON HEALTH IN GENERAL. THE CT SCANS LAD A POSITIVE RESULT. WHEREAS ONLY 7% CHEST X-RAYS DID SO MANY MORE WORK UPS. THIS IS WHAT THE GRAPHS LOOK LIKE. IT WAS A HA MOMENT WHEN THESE WERE PUBLISHED. LOW DOSE CT. THE CUMULATIVE NUMBER OF CANCER IS MORE THAN CHEST X-RAY. BUT THE DEATHS FROM LUNG CANCER HERE IS THE CHEST X-RAY VERSUS LOGO CT, 20% REDUCTION. SO THAT’S GREAT. THE FIRST HUGE IMPACT STUDY, THERE HAS SINCE BEEN ANOTHER ONE WE ARE WAITING FOR THE PUBLICATION, THE NELSON STUDY, WHICH USE A DIFFERENT ALGORITHM, THAT WAS DONE IN EUROPE BUT ALSO SHOWED VERY SIGNIFICANT REDUCTION FROM LUNG CANCER. NEXT YEAR HOPEFULLY I’LL HAVE THAT SLIDE. THE QUESTION IS HOW YOU OPERATIONALIZE THIS BECAUSE THEY ARE A HECK OF A LOT OF CURRENT AND FORMER SMOKERS, 90 MILLION IN THE UNITED STATES. THERE ARE 90 MILLION LUNG CANCERS IN THE UNITED STATES EVERY YEAR. SO THE QUESTIO IS HOW TO DO BETTER. THAT’S WHERE ALL THE WORK IS. USING ARTIFICIAL INTELLIGENCE DEVELOPING RISK MODELS, AGE SEX PAMELA HISTORY, EMPHYSEMA, NODULE TYPE THAT HIMSELF IDENTIFY THOSE WHO ARE HIGHEST RISK WHO WE CAN THEN CONTINUE TO SCREEN OR PERHAPS ENTER ON TO CHEMOPREVENTION TRIALS. HOW DO WE MOVE FORWARD WITH ALL THESE PIECES OF INFORMATION THAT I TOLD YOU, WHAT IS STILL MISSING FOR LUNG CANCER IS TRULY UNDERSTANDING THE BIOLOGY AND NATURAL HISTORY OF THE DISEASE. IT’S NOT JUST SMOKE VERSUS NOT SMOKE. THERE ARE DIFFERENT MOLECULAR SUBTYPES OF LUNG CANCER, WE DON’T UNDERSTAND THE MOLECULAR ANALYSIS OF THE PRE-MALIGNANT LESIONS SO WILL IS AN ONGOING EFFORT TO STUDY THOSE LESIONS, NEEDS TO BE DONE OVER TIME. I SHOWED YOU SOME OF THE EXAMPLES OF THE CLINICAL TRIALS WE ARE DOING, BUT THEY HAVE NOT — TOO MANY VARIABLES THUS FAR. WE ARE CARTING TO SAMPLE THE ABNORMAL FIELD USING TECHNOLOGIES BUT THE CLINICAL TRIALS MODELS CAN DO MUCH BETTER. ULTIMATELY WE NEED TO FOCUS AT MOLECULARLY HOMOGENOUS COHORTS. THAT IS WORK BEING DONE. WE NEED TO CONSIDER THE SMOKER IS ACTUALLY AN ENTIRE PERSON, NOT JUST THE LUNGS, AT RISK FOR MULTIPLE CANCERS, MULTIPLE CHRONIC DISEASE SO THE INTERVENTIONS WE CHOOSE NEED TO TAKE ALL THAT INTO ACCOUNT. SO WHERE THE WORK IS GOING ON NOW IS LOOKING AT WHICH OF THESE PRE-MALIGNANT LESIONS FOR BREAST VERSUS — HERE IS ONE STUDY WHICH SHOWS THAT LESIONS PRESENT AT MULTIPLE TIMES, MULTIPLE SEQUENTIAL BIOPSIES ARE MUCH MORE LIKELY TO ACTUALLY DEVELOP INTO SQUAMOUS CELL CARCINOMA. SORT OF MAKES SENSE BUT YOU HAVE TO PROVE THAT. WITH A WELL DONE STUDY. THE MOLECULAR ANALYSES OF THESE SYSTEMS VERSUS REGRESSIVE LESIONS IS VERY CRITICAL. LET ME SUM UP. TREMENDOUS PROGRESS HAS BEEN MADE IN UNDERSTANDING LUNG CARCINOGENESIS. IT IS A MUCH MORE COMPLEX DISEASE THAN EVEN COMPLEX PATHOLOGICAL CLASSIFICATION SUGGESTS AND THERE’S HETEROGENEITY IN THESE INDIVIDUAL TUMORS AND IN PRE-MALIGNANT LESIONS WHICH IS PART OF THE REASON WHY WE ARE NOT CURING PEOPLE OR PREVENTING THEM QUITE SO EFFECTIVELY. PRECISION MEDICINE IS APPLICABLE TO A SIGNIFICANT BUT STILL SMALL SUBSET OF CANCER STAGE PATIENTS WITH INCREASE SURVIVAL. THESE ARE STILL THE EARLY DAYS OF IMMUNOTHERAPY. THE PROLONG SURVIVAL IS REALLY IN SMALL SUBSET OF PATIENTS. WHETHER WE CAN TAKE WHAT WE LEARNED AND MOVE IT TO PREVENTION IS YET TO BE DETERMINED. CT SCREENING IS HERE TO STAY. BUT WE NEED TO FIGURE OUT HOW TO BEST MOVE IT INTO A WHOLE POPULATION OR INTO POPULATION BASED EFFORT. FINALLY WE HAVE LOT OF WORK LEFT TO DO BUT WE NOW HAVE NEW TOOLS AND TARGETS FOR CHEMOPREVENTION, SO THIS IS MOVING FORWARD. THAT IS IT. OUNCE OF PREVENTION IS WORTH A POUND OF CURE BECAUSE WE ARE STILL NOT CURING PEOPLE EFFECTIVELY ENOUGH. QUESTIONS.>>THANK YOU. [APPLAUSE]>>ANY QUESTIONS? PERHAPS YOU CAN COMMENT ON THE DIFFERENT SUBTYPES AND HOW THEY RESPOND TO DRUGS SUCH AS WITH IMMUNOTHERAPY I READ SEVERAL PAPERS TO SQUAMOUS CELL CARCINOMA.>>THE EARLY STUDIES WERE DONE SEPARATELY SQUAMOUS VERSUS NON-SQUAMOUS. THERE IS A LOT OF DATA ABOUT CERTAIN DRUGS PRE-IMMUNOTHERAPY, VERY USEFUL AND ADENOCARCINOMA NON-SQUAMOUS NOT SO MUCH SQUAMOUS. IMMUNOTHERAPY EFFECTIVE ADENOCARCINOMAS TOO. IT’S FAIRLY SIMILAR. I THINK A BETTER CLASSIFICATION IS SMOKER VERSUS NON-SMOKER OR THE TARGETED OR THE NEVER SMOKER ABNORMALITY LIKE EGPR, THOSE DO NOT RESPOND WELL. THERE IS ABOUT, I DON’T KNOW, 30% ADENOCARCINOMAS THAT REALLY DON’T RESPOND WELL AT ALL WHICH ARE NEVER SMOKING — NEVER SMOKING PEOPLE WHO RESPOND TO TARGETED AGENTS. IT’S NOT AS SIMPLE AS SQUAMOUS NON-SQUAMOUS BUT TARGETABLE MUTATIONS ARE GENERALLY EXCLUDED FROM ALL THE STUDIES.>>RIGHT NOW THE FINDINGS, YOU HAVE A GROUND GLASS OPACITY THOUGH NODULAR, I WAS THINKING IT MAY BE SOMETHING ELSE LIKE INFLAMMATION OR LIKE PNEUMONIA. SO WILL IS ANY WAY YOU CAN DIFFERENTIATE LIKE PRE-MALIGNANT INFLAMMATION? I KNOW THAT’S SOMETHING FUNCTIONAL STUDIES LIKE PET SCAN.>>SO PET SCAN IS OUR LIMITED BY SIZE, USUALLY THINGS THAT ARE LESS THAN A SENT METER DON’T SHOW UP ON PET SCAN EVEN IF THEY ARE METABOLICALLY ACTIVE. SO THAT’S ONE PROBLEM. SO THE OPACITIES WE HAVE BEEN TARGETING FOR CHEMOPREVENTION ARE GENERALLY FAIRLY SMALL. THE OTHER THING IS THAT LOW GRADE ADENOCARCINOMA SUCH AS BRONCHIAL ALVEOLAR CARCINOMA, MINIMALLY INVASIVE AD MOW CARCINOMA, TEND TO BE NOTS PET AVID. SO EVEN IF LARGE ENOUGH THE PET CAN BE NEGATIVE. THAT DOES NOT MEAN IT’S NOT ADENOCARCINOMA. PET IS NOT IN THE DIFFERENTIAL FOR THE USEFUL TECHNIQUE FOR SMALL LESIONS SO WHAT WE TEND TO DO WITH THOSE IS FOLLOW THEM OVER TIME, AND THAT SORT OF THE MAIN THING THAT IS DONE, IS TO LOOK AT THE RATE OF GROWTH AND SOME POINT YOU SPREAD OUT HOW LONG. THAT’S WHY YOU HAVE THE THREE MONTH CT SCAN IN THAT SERIES THAT I — FIRST THING IS THREE MONTHS THEN ANOTHER ONE AT SIX MONTHS OR NINE MONTHS. THEN YOU DO THEM YEARLY OVER TIME. THERE ARE SOME NEW STUDIES, THERE IS A GLUCOSE RECEPTOR, OR GLUCOSE TRANSPORTER THAT IS BEING STUDIED AT UCLA SPLG 2 WHICH IS ACTIVE IN HH AND EARLY AD MOW CARCINOMAS, THEN YOU SWITCH OVER TO GLUTE 1 A DIFFERENT GLUCOSE TRANSPORTER WHICH IS WHAT PET SCAN WILL DETECT. SO THERE’S STUDIES LOOKING AT FUNCTIONAL IMAGES BUT NOTHING THAT’S APPROVED YET. WE DO REPEATED CT SCANS.>>THAT WILL DO IT. THANK YOU. OUR NEXT SPEAKER IS FRANK MALDARELLI, HE GOT HIS Ph.D. FROM CITY UNIVERSITY OF NEW YORK, M.D. FOR MOUNT SINAI SCHOOL OF MEDICINE. HE DID A RESIDENCY IN INTERNAL MEDICINE AT THE COLUMBIA PRESBYTERIAN HOSPITAL NEW YORK. HE HEN CAME TO NIH AND JOINED NIAID FIRST AS A STAFF FELLOW, AND THEN HE JOINED THE HIV DRUG RESISTANCE PROGRAM, HE’S GOING TO TALK TO US ABOUT RETRO VIRUSES. VIRUSES MAY NOT BE THE FIRST THING YOU THINK OF, I THINK IT IS IMPORTANT ON A NUMBER OF LEVELS IN TERMS OF HOW WE SEE DISEASE AND EVEN IN A PRACTICAL WAY HOW WE WORK IN THE LABORATORY. SO I MAY ASK YOU, IS ANYBODY DIRECTLY INVOLVED IN LABORATORY RESEARCH? I MOW THIS GROUP GETS SO MANY DIFFERENT KINDS OF PEOPLE. YOU ARE IN THE LAB AND YOU GUYS ALL OF YOU? SOMETIMES THERE ARE POLICY PEOPLE HERE, SOMETIMES EVERYBODY. SO SOMETIMES IT HELPS. SO I GUESS WHAT I WOULD LIKE TO TALK ABOUT THIS AFTERNOON, IS TALK ABOUT THE MOLECULAR BIOLOGY AND HOW THIS VIRUS REPLICATES, WHY IT’S SO IMPORTANT TO UNDERSTAND IN TERMS OF WHERE WE ARE AND HOW IT AFFECTS INDIVIDUALS. WHAT THESE RETRO VIRUSES DO IN HUMAN POPULATIONS, HOW THEY EMERGED AND HOW THEY SPREAD. THEN LITTLE BIT ABOUT THERAPY AND LESSONS THAT MIGHT BE USEFUL ACROSS DISCIPLINES. I WILL FIRST TALK HIV BUT REALIZE IT’S NOT THE ONLY HUMAN RETRO VIRUS. IT’S JUST THE ONE THAT PROBABLY HAS THE MOST IMPAK IN HUMAN DISEASE — IMPACT IN HUMAN DISEASE. A TOTAL OF APPROXIMATELY 37 MILLION PEOPLE ARE INFECTED WITH HIV PRESENTLY. THEY ARE NOT HERE TO, FORMALLY DISTRIBUTE ACROSS THE WORLD. MOST EPIDEMIC IN TERMS OF TOTAL INDIVIDUALS IS CONCENTRATED IN SUBSAHARAN AFRICA WHERE OVER 25 MILLION OF THE 37 MILLION PEOPLE ARE LOCATED. OTHER AREAS SUCH AS SOUTHEAST ASIA, 5 MILLION. LATIN AMERICA CARIBBEAN AND THEN YEARN EUROPE ONE AND A HALF MILLION WE HAVE ALONG WITH CENTRAL EUROPE 2.4 MILLION SO A MILLION PEOPLE IN THE UNITED STATES ARE NOW CURRENTLY LIVING WITH HIV. ON THERAPY, I THINK THAT IS LISTED HERE IN THE NEXT SLIDE, IS A MUCH MORE ENCOURAGING NUMBER. OVER THE LAST FEW YEARS BECAUSE NUMBER OF INITIATIVES GLOBAL ONES AND SOME DRIVEN BY THE UNITED STATES, CLOSE TO HALF OF ALL PEOPLE INFECTD WITH HIV HAVE ACCESS TO AND ARE ON EFFECTIVE COMBINATION AND RETROVIRAL THERAPY. SO THIS SETS UP I THINK A — FIRST OF ALL, IT HAS DECREASED THE TRANSMISSION OF HIV, IT’S DECREASED OBVIOUSLY MORBIDITY AND MORTALITY FROM THE DISEASE. AND IT SETS UP SOME NEW CHALLENGES AS WELL. IT BECOMES A CHALLENGE ON A NUMBER OF LEVELS. HERE IN THE UNITED STATES I THINK THE POINT IS THAT BECAUSE THERE IS NOT AS MUCH MORBIDITY AND MORTALITY AND BECAUSE THE SAME NUMBER OF PEOPLE ARE INFECTED EVERY YEAR, ABOUT 38,000, BUT DEATHS ONLY IN THE RANGE OF 64, 6500 PER YEAR IN THE UNITED STATES. THAT MEANS THAT THE OVERALL PREVALENCE OF HIV IS INCREASING. I THINK IT CAN TAKE ANYTHING FROM THIS LECTURE IN TERMS OF A PUBLIC HEALTH UNDERSTANDING OF THIS DISEASE, IT’S INCAPSLATED IN A COLUMN GRAPH OF THIS SORT. THEY HAVE BEEN FOR THE WHOLE WORLD, FOR THE UNITED STATES AND FOR INDIVIDUAL COUNTRIES. IT’S CALLED THE GARTNER STATE OF ENGAGEMENT THAT HIV CARE AFTER GARDENER WHO DEVELOPED IT OR THE
THE STATE OF ENGAGEMENT. BASICALLY IT SAYS HOW MANY PEOPLE ARE INFECTED AND WHAT IS THEIR DISPOSITIONS? IN ANY GIVEN COUNTRY? IN THE UNITED STATES ABOUT 1.1, 1.2 MILLION PEOPLE ARE INFECTED. THAT IS AN ESTIMATE. HOW MANY OF THEM ARE ACTUALLY KNOW THEIR DIAGNOSIS? SO THAT’S THIS NEXT PART HERE, SOMEWHERE AROUND 900,000. SO WE ARE GETTING VERY CLOSE TO 90% OF ALL INFECTED INDIVIDUALS AND THEIR DIAGNOSIS. OKAY, IT’S CHALLENGE TO GET THAT LAST TEN, 12% BUT THEN WE HAVE OTHER CHALLENGES. HERE IS THE NEXT ONE. HOW MANY OF THOSE PEOPLE ARE DIAGNOSED? THEY KNOW HIV INFECTED, HOW MANY OF THEM ARE ACTUALLY LINKED TO CARE. THERE’S WHERE WE FALL OFF AGAIN AND HEAR 600,000, MAYBE ONLY ABOUT 60% OF INDIVIDUALS INFECTED ARE ACTUALLY LINKED IN TO CARE. THOSE WERE LINKED IN CARE, HOW MANY OF THEM ARE RETAINED IN CARE. NOW WE ARE DOWN TO 400,000, MAYBE 30% OF THE TOTAL. OF THOSE 30% RETAIN IN CARE, HOW MANY SHOULD BE GETTING ANTIRETROVIRAL THERAPY AND NOW DO A LOT OF NEW RESEARCH THAT NUMBER IS THE SAME. SO EVERYBODY WHO IS IN CARE SHOULD BE ON THERAPY. OKAY. HOW MANY ARE? MAYBE IT’S ONLY DOWN AROUND TO 300,000 SO MAYBE 25% OF EVERYBODY WHO IS AFFECTED, THOSE PEOPLE WHO ARE ON ANTI-REROW VIRAL THERAPY HOW MANY ARE ADHERENT SUPPRESS AND WILL NOT BE TRANSMITTING THIS VIRUS TO OTHER PEOPLE? THAT’S SOMEWHERE AROUND 250,000 INDIVIDUALS. SO WITH EACH STEP OF THE WAY WE CAN SEE WE SEE OUR LIMITATIONS. WE SEE CHALLENGES AS WELL AS OUR SUCCESSES. YOU CAN SEE THAT ON A PUBLIC HEALTH LEVEL HE IS CHALLENGES ARE BOTH SOCIAL, MEDICAL, AND EVEN REACH INTO THE LABORATORY. JUST CONSIDER THOSE PEOPLE ON ANTI-REROW VIRAL THERAPY AND ARE NOT SUPPRESSED, THEY WILL DEVELOP DRUG RESISTANCE, FOR THEM WE ARE NEEDING NEW DRUGS, NEW AAPPROACHES. SO BASED ON GRAPHS LIKE THAT AROUND THE WORLD, HHS, THE PEOPLE WHO SUPPLIES ALL OF OUR SALARIES, AND SUPPORT HAS DEVELOPED FOUR DISTINCT AREAS FOR HIV RESEARCH AND STRATEGIES AND THE COMING — I WOULD SAY THIS GETS REVISED FOUR OR FIVE YEARS. SOME OF THEM CUT ACROSS DISCIPLINES BUT THEY HAVE SPECIFIC GOALS. IF THEY ARE INTEREST IN GOING INTO HIV RESEARCH, PICK SOME OF THESE AND START THINKING ABOUT GRANTS. FIRST ONE REDUCE THE INCIDENCE OF HIV, YOU SAW WE HAVE 38,000 PEOPLE A YEAR INFECTED THE GOAL IS TO REDUCE THAT TO ZERO. DEVELOP NEXT GENERATION THERAPIES SO WE HAVE DRUG RESISTANCE. WE NEED NEW THERAPIESND NEW APPROACHES TO THERAPIES. PERHAPS YOU HEARD SOME OF THE DRUGS NOW HAVE EXCEEDINGLY LONG HALF LIVES AND IF OUR PROBLEM IS ADHERENCE WE ONLY GIVE IT ONCE EVERY SEVERAL MONTHS, THAT MIGHT BE A REAL ADVANCE. BECAUSE THE PREVALENCE OF THE DISEASE SIN CREASING, 38,000 A YEAR, ONLY 6,000 DIE, EACH YEAR HIV PREVALENCE.00 PEOPLE TO THE- THOSE FOLKS WILL BE ON ANTIRETROVIRAL THERAPY FOREVER TO SUPPRESS THE VIRUS. THOSE FOLKS WILL HAVE SIDE EFFECTS FROM THOSE MEDICATIONS AS WELL AS OTHER HIV ASSOCIATED ILLNESSES, WHY NOT RESEARCH TOWARD A CURE, NIH IS HEAVILY INVEST IN THAT. THEN FINALLY HIV IS ASSOCIATED WITH A NUMBER OF COMORBIDITIES, CO-INFECTIONS AND COMPLICATIONS SO RESEARCH INTO THAT IS ANOTHER MAJOR INITIATIVE FOR RESEARCH INTO HIV. THIS LIST AS NUMBER — JUST SOME EXAMPLES OF WHAT IS CURRENTLY BEING RESEARCHED IN HIV. SO IF THIS IS ESSENTIALLY A BLUEPRINT GOING FORWARD, IF THIS IS SOMETHING YOU ARE INTERESTED IN, PINED SOMETHING YOU LIKE HERE, FIND A CHALLENGE AND OVERCOME IT. OUR GROUP HERE AT HIV DYNAMICS AND REPLICATION PROGRAM WITHIN NCI IS HEAVILY INVOLVED IN RESEARCH TOWARD A CURE. BUT THE NIH HAS ALSO BROAD INITIATIVES IN REDUCING INCIDENCE AND HIV COMORBIDITIES AND SOME TO DEVELOPING NEW THERAPY. WITH THAT INTRODUCTION I WOULD LIKE TO TALK ABOUT HOW THE VIRUS REPLICATES. I DON’T KNOW HOW THE QUESTIONS ON THIS — IS THERE AN EXAM FOR THIS? DO YOU GIVE TESTS? I DIDN’T HAVE THE NERVE TO EVER ASK. IF I WAS GOING TO ASK QUESTIONS, THESE ARE LIKE FACTUAL THINGS THAT ARE RELATIVELY STRAIGHT FORWARD. BUT IT’S ALSO USEFUL TO UNDERSTAND BECAUSE I NOTICE YOU GUYS A LOT OF LAB WORKERS, KNOWING THIS DEVELOP EVERYTHING WE HAVE IN TERMS OF THERAPY, FOR HIV. SO IF WE WERE GOING TO CHARACTERIZE RETRO VIRUSES, WE WOULD SAY THERE ARE A GROUP OF RNA VIRUSES, THAT REPLICATE VIA DNA INTERMEDIATE USING REVERSE TRANSCRIPT ACE. TRANSCRIPTASE. BEFORE YOU CAME DID YOU KNOW THAT? IS THIS A SURPRISE? THIS IS A THING. THIS IS A VIRUS THAT REPLICATES, IT’S AN RNA VIRUS THAT REPLICATES THROUGH DNA WHEN THIS CAME TO LIGHT IN THE LATE 1960s IT WASN’T ALL THAT MUCH, 15, 20 YEARS AFTER DNA WAS DISCOVERED SO THE IDEA THAT HAD BEEN PROMULGATED, WE HAVE DNA, THAT MAKES RNA. YOU HAVE SEEN THAT RNA CODE THING. DNA, RNA PROTEIN. THAT’S A NATURAL ORDER OF THINGS. ALONG COMES THIS VIRUS THAT REPLICATES BY STARTING OUT AS RNA THEN GOING TO DNA. THEN GOING TO RNA, AND THEN OFF INTO PROTEINS SO THE ENZYME THAT DOES THAT MAKES DNA OUT OF RNA. BECAUSE IT DOES THAT THEY DESCRIBED IT ADS REVERSE TRANSCRIPTASE, SOMETHING THAT TAKES AN RNA MOLECULE AND MOVES INTO DNA MOLECULE. IN REALITY, THAT ENZYME MAY ANSWER AN ANCIENT CHALLENGE, A QUESTION THAT’S RAISED BY HOW WE UNDERSTAND ORGANISMS TODAY BUT CERTAINLY IT’S A DIFFERENT PARADIGM FOR REPLICATION. THE CHALLENGE WAS THIS ENZYME CENTRAL FOR US. WHEN I SAY US, I MEAN EVERYTHING ON PLANET THAT’S ALIVE AND HAS A GENOME, WAS IT IMPORTANT FOR US TO TRANSITION FROM THE INITIAL SET OF ORGANISMS TO THE ONES WE HAVE TODAY. SO WHAT I’M REFERRING TO MAYBE YOU ALL KNOW THIS, WE HAVE PROTEIN ENZYMES WE ALSO HAVE NUCLEIC ACIDS THAT ACT ADS ENZYMES. RIBOSO I’MS. THEY WERE ALL RNA MOLECULES THAT CAN EXERT A CATALYTIC EFFECT. IN TERMS OF EVOLUTION THEY SEEM TO BE THE OLDEST AVAILABLE ENZYMES. THERE IS A THEORY WHICH THERE IS SUBSTANTIAL EVIDENCE THAT LIFE ON THE PLANET BEGAN AS AN RNA WORLD. SO IF EVERYTHING IS RNA AND MAYBE YOU KNOW, DID Y’ALL KNOW THIS ALREADY? AM I TELLING YOU STUFF YOU ALREADY KNOW AS MUCH I WILL TELL YOU AGAIN ANYWAY. IN THEORY THE PLANET DID NOT ALL LOOK LIKE THIS, WELL IT WAS INITIALLY A VERY HIGHLY REDUCING ATMOSPHERE. NO OXYGEN AND THE FIRST ORGANISMS THEMSELVES AT LEAST BY THIS THEORY WERE RNA ORGANISMS SO YOU MAKE RNA, YOU MAKE MORE RNA, ADS LONG AS THERE’S NOT A LOT OF OXYGEN AROUND YOU WILL BE ALL RIGHT. THE MINUTE THERE’S A LITTLE OXYGEN, THAT ACTS TO BE ABLE TO CLEAVE RNA, I DON’T KNOW HOW MANY WORK WITH IT IN THE LABORATORY BUT THE MINUTE YOU SYNTHESIZE IT IT STARTS TO DEGRADE. INITIALLY IT IS GREATLY REDUCING ATMOSPHERE ON THIS PLANET, WE THINK FINE, THE FIRST ORGANISMS ARE SIDE PRODUCTS, WERE MOLECULAR OXYGEN, MOLECULAR OXYGEN STARTED TO ACCUMULATE IN THE ATMOSPHERE, AND THEN POOF WAS GOING TO KILL THEM. SO ONE THEORY IS THAT REVERSE TRANSCRIPTASE OR REVERSE TRANSCRIPTASE LIKE ENZYMES THAT COULD CONVERT, USE RNA AND MAKE A DNA COPY THAT WAS MORE STABLE IN THIS ATMOSPHERE THAT WAS NOW BECOMING MORE FILLED WITH OXYGEN, THOSE WERE THE ORGANISMS THAT WERE GOING TO SURVIVE THIS PERIOD. SO IF YOU LOOK AT THE EXISTENT PHYLA IN THE WORLD, IF YOU EVER DID LEAVE THE NIH CAMPUS, ALLOWED TO LEAVE THE LAB AND HAVE A DAY OFF, YOU MIGHT GO TO A PARK, THIS IS ONE COPPER ROAD AT THE GREAT SENECA PARK. EVERY LIVING THING YOU COULD SEE HAS IN ITS GENOME REVERSE TRANSCRIPTASE. ENZYME THAT CAN TURN RNA TO DNA. MAYBE THAT’S THE REMNANT OF WHAT SAVED THIS PLANET. IF IN — BY THE SAME TOKEN IN ADDITION TO THAT, THERE ARE VIRUSES OF THAT USE THAT ENZYME IN THEIR REPLICATION, AND HERE ARE THE ONES THAT ARE IN FACT MAMMALS AND VERTEBRATES. SO YOU CAN SEE THERE WERE SEVEN MAJOR FAMILIES OF RETRO VIRUSES, AND THE ONES LISTED IN BOLD YOU CAN SEE THE ONES THAT INFECT HUMANS. THE IMPORTANT POINT, HOW MANY PEOPLE HAVE SEEN A FAMILY TREE LIKE THIS FOR PHYLOGENETIC TREE, DIFFERENT BRANCHES MEANS THEY ARE DIFFERENT BY THEIR SEQUENCES, I GUESS THE POINT TO MAKE IS ONE THAT INFECT HUMANS ARE NOT ALL ON THE SAME BRANCH. THEY ARE AS WIDELY DIVERSE AS THE ONES THAT THEY INFECT OTHER ANIMALS. WE HAVE SCHOOL OF VIRUSES THAT INFECT HUMANS. THEY ARE SIMILAR TO INFECTIONS, RETRO VIRUSES OF MICE. LENTIVIRUSES THAT INCLUDE HIV, AND SEMIIMMUNODEFICIENCY VIRUS FORM A LARGE GROUP NOT ANYTHING LIKE THEM. THEY ARE MORE RELATED TO VIRUSES OF OTHER PRIMATES, OR MICE, OR CHICKEN, OR COWS. THEN THERE’S A THIRD LARK GROUP CALLED HUMAN T-CELL LEUKEMIA VIRUS DISCOVERED IN JAPAN, RIGHT HERE ON THIS CAMPUS. THAT’S MUCH MORE SIMILAR TO A BOVINE LEUKEMIA VIRUS THAN ANYTHING ELSE. THESE VIRUSES ARE NOT CONCENTRATED IN SPECIES, THEY ARE SPREAD ACROSS. IF WE CONE DOWN NOW ON THAT GROUP OF VIRUSES THAT HIV BELONGS TO, AGAIN, THERE IS A VARIETY. THEY ARE ALL IMMUNODEFICIENCY VIRUSES, THE I AND THE V IN EACH ONE OF THEIR NAMES BUT YOU CAN SEE SORT OF PICK OUT HERE IS ONE, HIV-1, HERE IS ANOTHER HIV 2, TWO LARGE GROUPS OF VIRUSES THAT INFECT HUMANS BUT ARE NOT ANYTHING LIKE EACH OTHER. THEY ARE ONLY ABOUT 50% HOMOLOGOUS. IN FACT HIV-1 THAT INFECTS 36 OF THE 37 MILLION PEOPLE ON THE PLANET WITH IMMUNODEFICIENCY VIRUS, IS VERY MUCH LIKE A VIRUS THAT’S BEEN IDENTIFIED IN CHIMPANZEES. WE HAVE A SECOND GROUP THAT INFECTS HUMANS, MUCH MORE LIKE A VIRUS THAT INFECTS MANGANESE MONKEY, ONCE AGAIN, THE VIRUSES THAT INFECT HUMANS ARE NOT NECESSARILY ALL PHYLOGENETICALLY RELATED. THEY ARE LIKELY TO BE THE RESULT AS WE’LL SEE OF INDEPENDENT ZOONOTIC EVENTS IN WHICH CONTACT BETWEEN THOSE SPECIES ALLOWED THE VIRUS TO TRANSMIT. THE VIRUSES ARE LISTED BY RETRO VIRUSES ARE DESCRIBED BY CONVENTION. SO IF YOU EVER READ ANYTHING ABOUT THESE VIRUSES, YOU WILL SEE THIS STUFF, I LIST A LITTLE BIT OF IT BUT I WANTED TO MENTION IT BECAUSE IT HELPS US UNDERSTAND EXACTLY HOW THIS VIRUS REPLICATES. IF — IMAGINE THIS IS THE CARTOON DEPICTION OF THE RNA THAT’S ENCODED IN THE BARRIER, YOU SEE A COUPLE OF THINGS INITIALLY. THERE’S THREE LETTER ABBREVIATIONS MOST WHICH I DON’T UNDERSTAND. THOSE REPRESENT THE OPEN READING FRAMES FOR THE VIRUS. THEN THERE ARE LARGER BLOCKS AT EITHER END, NOT UNCOMMON FOR VIRUSES. AND THEY GENERALLY HAVE REGULATORY NUCLEIC ACID SEQUENCES. THERE’S SOMETHING FUNNY HERE. THE FUNNY THING IS THIS IS THE FIVE PRIME END, THIS IS THE THREE PRIME END OF THE RNA. OVER HERE I HAVE DEPICTED IT NOT BY MISTAKE. THE POLYA SEQUENCE IN THE RNA ISN’T THE FIVE PRIME END. IT’S IN THIS REGION CALLED U 5. DIRECTLY UPSTREAM FROM THAT IS ANOTHER REGION CALLED — IF YOU LOOK AT THE OTHER END THERE’S A U-3 REGION, THAT HAS PRONOTTER IN IT AND WE HAVE THIS R REGION AGAIN. I GUESS IT TELLS A LOT ABOUT RETRO VIROLOGISTS. THEY ARE CONCRETE PEOPLE. THEY ARE VERY CONCRETE PEOPLE. SEE SOMETHING UNIQUE. R STANDS FOR REPEAT. IN OTHER WORDS THERE’S 150 NUCLEOTIDES DIRECTLY REPEATED HERE AND HERE. WE CALL THAT REPEAT. U-5, IT’S NOT REPEATED, WE’LL CALL THAT A UNIQUE REGION IN THE FIVE PRIME END. THAT MAKES U 3 EASY. THE UNIQUE REGION OF THE THREE PRIME END. ONCE THEY HAVE THE SEQUENCE AND MAP OF THAT, FINE, BUT THAT DIDN’T EXPLAIN WHY THE POLYA REGION WAS UP THERE AN PROMOTER IS DOWN HERE. THE WAY THE VIRUS REPLICATES EXPLAINS THIS DOING IT BACKWARDS APPROACH. SO REGULATORY NUCLEIC ACIDS AT EITHER END, CODING SEQUENCE IN THE MIDDLE, YOU NOTICE MANY OVERLAPPING READING FRAMES. THAT’S WHAT IT LOOKS LIKE IN RNA. NOW IF YOU MAP THAT SAME VIRUS ONCE INFECT THE CELL IT REVERSE TRANSCRIBES RNA TO DNA, THAT DNA MOLECULE IS INSERTED INTO THE HOST GENOME. HERE SOMEWHAT IT LOOKS LIKE WHEN IT GETS TO THE HOST GENOME, A LITTLE BIT MORE UNDERSTANDING. THE U 3 REGION ARE — U 5 PERFORM WHAT’S CALLED A LONG TERMINAL REPEAT NOW EXACTLY DUPLICATED AT BOTH ENDS. THERE’S THE R REGION WE SAW BEFORE, HERE IS THE U-5 WE SAW BEFORE, NOW THE U-3 IS HERE AND HERE. AND THE U-5 IS HERE AND HERE. THIS WHOLE THING IS DIRECTLY REPEATED AT EITHER END. NOW THE PROMOTER WHICH WE ONLY HAD OVER HERE IS ALSO AT THE FIVE PRIME END. WE CAN HAVE PROMOTER EITHER END BUT WE ARE MORE COMFORTABLE. THE POLYA SEQUENCE HERE IS DUPLICATED HERE IN A PLACE WHERE IT’S MUCH MORE USEFUL FOR THE RNA GOING TO BE MADE FROM THIS PROMOTER. THE INTEGRATED GENOME HERE IS CALLED THE PRO VIRUS, THE NAMES OF GENES ARE LOWER CASE ITALICS. THE PROTEIN GENE PRODUCTSTHEY CODE FOR ARE CAPITALIZED SO YOU WILL SEE THIS AS A CONVENTION IN PAPERS AND SAY WHY IS IT LIKE THAT, AND THE REASON IS AGAIN, BECAUSE THESE PEOPLE ARE VERY CONCRETE. THEY WANT A WAY TO DISTINGUISH GENES FROM GENE PRODUCTS. THEY WANT WAY THE DESCRIBE THESE REGIONS. HOW DO YOU GET FROM HERE TO HERE IS CENTRAL TO UNDERSTANDING REPLICATION OF VIRUS AND PART OF ITS CHARM. I WILL SKIP THIS PART, THIS IS A GLOSSARY, IF YOU END UP READING A LOT OF PAPERS ABOUT HIV OR OTHER RETRO VIRUSES YOU CAN REFER BACK TO THIS, IT TELLS CLUE THE GENES ARE, AND WHAT THE REGIONS IN THE REGULATORY RNAS ARE LIKE. THAT IS THE GENOME. THIS IS AN ARTIST DEPICTION OF THE VIRION ITSELF, IT’S ABOUTMAN METERS IN DIAMETER. IT’S AN ENVELOPED VIRUS. IT HAS ON ITS SURFACE THE ENVELOPE IS DERIVED AS IT BUDS OUTS OF INFECTED CELL. ON THE SURFACE IT HAS SURFACE MOLECULES CALLED ENVELOPE MOLECULES, THEY SIT ON THE ENVELOPE. THEY ARE ENCODED BY HIV AND INVOLVED IN ATTACHMENT INFUSION MANY THE VIRUS. ON THE INSIDE IS A CORE STRUCTURE MADE UP OF VIRAL PROTEIN IN SIDE THE CORE IS TWO RNA MOLECULES, THEY REPLICATE THEY WILL MAKE THE DNA. THE VIRION TAKES WITH IT ALL THE ENZYMES IT NEEDS TO MAKE INITIAL REPLICATION CYCLE, TO GET THAT RNA INTO DNA IT BRINGS EVERYTHING WITH ITS. EVERYTHING ELSE IS NEGOTIATION WITH INFECTED CELLS SO THE EARLY STEPS IN HIV REPLICATION YOU CAN THINK NOTICE I HAVE THIS VIRION, IT HAS TO GET INSIDE, MAKE RNA INTO DNA, HAS TO INTEGRATE. WHEN WE BREAK THOSE STEPS UP WE FIND SPECIFIC PLACES WHERE VIRAL PRODUCTS ARE ESSENTIAL AND WHERE WE COULD SORT OF DEVELOP A DRUG TO INHIBIT IT. SO YOU LOOK AT VIRION ON THE OUTSIDE THE FIRST THING IT HAS TO DO IS ATTACH AND ENTER THE CELL, IT TURNS OUT THOSE THINGS ARE SEPARATE PRABBLE EVENTS, NEXT THING IT HAS TO UNCOPE AND REVERSE TRANSCRIBE ITS DNA, IT HAS TO INTEGRATE THAT, IT HAS TO EXPRESS ITS RNA FROM THAT INTEGRATED PRO VIRUS, THAT HAS TO BE TRANSLATED. THE VIRUS HAS TO BE ASSEMBLED. AND IT MATURES AND BUDS OUT THE INFECTED CELL. IT TURNS ATTACHMENT AND ENTRY ARE TWO DIFFERENT PHENOMENON. WE NEED BOTH VIRAL FACTORS AND HOST CELL FACTORS. ON THE VIRUS SIDE WE NEED ENVELOPE GLYCO PROTEIN ON SURFACE. IT HAS MOLECULAR SIZE OF 120,000 DALTONS AND IS A GLYCO PROTEIN SO THESE CONCRETE INDIVIDUALS CALL GP 120. ON THE SURFACE IS A SECOND ENVELOPE PROTEIN NON-COVALENTLY ASSOCIATED WITH THE GP 120, IT HA A SIZE OF 41,000 DALTONS AND IS CALLED GP 41. THOSE TWO THINGS ARE NON-COVALENTLY LINKED. IT ON THE SURFACE. HOST CELL FACTORS WE NEED FOR ATTACHMENT ARE RECEPTOR AND CO-RECEPTOR. SO SIMPLY ENGAGING THE RECEPTOR IS NOT ENOUGH. IT HAS TO ENGAGE A CO-RECEPTOR, A SECOND MOLECULE ON THE SURFACE OF THE CELL, THAT CAN — RECEPTOR IS ONE, CD 4, CO-RECEPTOR CAN BE ONE OF A NUMBER OF THINGS, CXCR 4 OR CCR 5. WHEN IT ATTACHES TO THE CELL, IT DOES THAT THROUGH GP 120, GP 120 ENGAGING CD4 AND THAT SETS UP BUT DOES NOT DRIVE THE RECEPTOR INTO THE CELL. THAT SIMPLY AN ATTACHMENT BINDING STEP. SO THAT’S A UNIQUE EVENT, IT REQUIRES A VIRAL PROTEIN. THAT’S A TARGET. SO ANTIBODIES HAVE BEEN DEVELOPED THAT ACTUALLY BIND TO CD4 CELL RESUBPOENA TORQUE NOT ENROLL LOPE BUT BINDING CD4 A BLOCK BINDING OF THE GP 120. THEY DO IT IN AN ELEGANT WAY, CD4 IS NEEDED FOR OTHER THINGS OTHER THAN BEING RECEPTOR FOR HIV, IT’S NEEDED IN ALL KINDS OF SIGNALING EVENTS. THIS DRUG APPROVE IN THE LAST YEAR OR SO INLIZ HAS BEEN BINDS TO CD4 WITHOUT INTERFERE FEARING WITH CD4 SIGNALING FUNCTIONS. SO INLIZ HAS BEEN. AT THE GET GO THERE IS A WAY OF PREVENTING HIV TO BE ATTACHING TO THE CELL. THERE’S A SECOND ATTACHMENT REQUIRED TO THE CO-RECEPTOR. AND THERE’S A SECOND DRUG DEVELOPED TO INHIBIT THAT. THAT IS CALLED MARABAROC. IT BLOCKS ONE CO-RECEPTOR INTERACTION HIV CAN USE ONE OF TWO, MOST OF THE TIME. IT USES THIS CELL SURFACE MOLECULE CALLED CCR 5. AND THIS DRUG MARABAROC BLOCKS THAT INTERACTION. SO EVEN BEFORE THE VIRION GETS INSIDE THE CELL, WE HAVE TWO AND THEN A THIRD PLACE WHERE VIRUS IS REPLICATION CAN BE INTERRUPTED SO I MENTION SECOND GLYCO PROTEIN ON THE SURFACE GP 41 NON-COVALENTLY LINKED TO GP 120, UP UNTIL NOW IT’S DONE ALL THE WORK. IT’S INTERACTD WITH CD4, IT’S INTERACTD WITH THE CO-RECEPTOR CXCR 4 OR CCR 5. ONCE THAT HAPPENS, ONCE THOSE TWO THINGS ARE ENGAGED, THAT CAUSES A SECOND CHANGE IN GP 120 THAT CAUSES A CHANGE IN GP 41. NOW GP 41 I KNOW IT DO YOU UNDERSTAND DOPEY, SPRINGS INTO ACTION. IT EXPOSES SIX HELICES THAT ACTUALLY HAVE IN THE HELIX A GREAT DEAL OF POTENTIAL ENERGY. THE POTENTIAL ENERGY IN THOSE HELICES IS ACTUALLY GOING TO FORCE THE VIRION MEMBRANE TO FUSE WITH THE HOST CELL MEMBRANE. THAT FUSION EVENT ALLOWS NOW THE TWO MEMBRANES TO OPEN UP AND WHATEVER IS INSIDE THE VIRION GOES INSIDE THE CELL. SO THAT’S CENTRAL EVENT IN REPLICATION, AGAIN, IT’S A VERY SPECIFIC ONE. IT REQUIRES THESE WELL CONSERVED ALPHA HELICES, AND AS A RESULT THERE’S A DRUG THAT’S BEEN DEVELOPED THAT ACTUALLY BINDS WITHIN THE HELIX AND THE OPPOSITE ORIENTATION ESSENTIALLY FORMING A MONKEY WRENCH THROWN INTO THE ABILITY OF THIS THING TO FUSE. ONCE THE DRUG IS PRESENT IT PREVENTS FUSION. THE DRUG ITSELF IS NOT EASY TO TAKE. YOU MIGHT IMAGINE, A PEPTIDE IS NOT SOMETHING YOU CAN SWALLOW. IT HAS TO BE INJECTED, IT’S SUBQ AND UNCOMFORTABLE. IT’S ALSO 36 AMINO ACIDS IN LENGTH, TURNS OUT UP UNTIL NOW WITH THE LONGEST PEPTIDE MADE FOR PHARMACEUTICAL USE. SO YOU CAN IMAGINE THE IT WASN’T JUST OH WOW WE FIGURED OUT THIS MECHANISM, LET’S DEVELOP A DRUG, IT’S MORE LIKE WE ARE DESPERATE. WE DON’T EVEN BUILD A FACTORY. WE WILL EVEN BUILD A FACTORY TO BUILD A MOLECULE THAT’S 36 AMINO ACIDS, KNOWING THAT WE’RE GOING TO HAVE TO INJECT IT AT THE END OF THE LINE BUT STILL GO TO ALL THOSE TROUBLE ALL THAT TROUBLE BECAUSE WE HAVE WE NEED AS MANY DRUGS AS WE CAN GET FOR THIS VIRUS, IT WAS DEVELOPED I GUESS NOW GOING ON 20 SOMETHING YEARS. WITH NEW DRUGS, IT HELPED BRIDGE THINGS BUT IN THE — IN THIS DAY AND AGE, IT’S NOT USED VERY MUCH. BUT IT IS A SPECTACULAR EXAMPLE OF KNOWING AN EVENT AND DEVELOPING A DRUG BASED PURELY ON A MECHANISM THAT WAS IDENTIFY IN A LABORATORY. SO THIS IS ONE OF THOSE TIMES THERE IS VERY LITTLE DISTANCE& BETWEEN THE LABORATORY AND THE CLINIC. SO AFTER THOSE THREE EVENTS THREE SEPARABLE DISTINGUISHABLE AND INHIBITABLE EVENTS, THE HIV CORE IS UNLOADED INTO THE CYTOPLASM AND REVERSE TRANSCRIPTASE TAKES PLACE. NOW, THIS — YOU MIGHT THINK THIS IS A OLD SLIDE, IT IS. THERE’S NEW DATA, I WILL UPDATE IT BECAUSE I’M A BAD MAN, I DIDN’T DO IT, THAT SUGGESTS THAT THIS PROCESS OF REVERSE TRANSCRIPTION MAY NOT ACTUALLY TAKE PLACE IN THE CYTOPLASM AT ALL. BUT THE CORE, THIS IS WORK AGAIN NCI COLLEAGUES IN FREDERICK, COLLEAGUES FOUND IT’S POSSIBLE FOR THAT CORE TO TRAVEL ALL THE WAY T THE NUCLEUS ENTIRELY INTACT. AND LARGELY INTACT GETTING INTO THE NUCLEUS ITSELF AND REVERSE TRANSCRIPTION IS LIKELY TAKES PLACE EITHER DIRECTLY AT THE NUCLEAR MEMBRANE OR WITHIN THE NUCLEUS ITSELF. EITHER WAY, REVERSE TRANSCRIPTASE TAKES THESE TWO RNA MOLECULES AND MAKES A DNA MOLECULE. OUT OF THEM AND THAT REVERSE TRANSCRIPTION EVENT YIELDS A DNA MOLECULE SUBSEQUENTLY INTEGRATED INTO THE HOST GENOME. THE PROCESS HAS TO BEGIN WITH SOMETHING WE CALL UNCODING. IT’S HALF THE REASON I BRING THIS JACKET. SO SOME PEOPLE GO LIKE THIS, SOME START UP OTHER SIDE, UNCODING IS A VERY POORLY DESCRIBED EVENT. NOBODY IS REALLY TOO SURE HOW IT WORKS. HOWEVER, IF WE DID, WE WOULD HAVE A TERRIFIC TARGET. TO PREVENT HIV FROM INFECTING. I WILL GIVE AN EXAMPLE OF THAT. HOW TERRIFIC IS IT, THAT’S WHAT YOU GUYS ARE FOR, IT’S A TERRIFIC — HOW TERRIFIC? I’LL TELL YOU. IT’S FUNDAMENTAL SO TO VIRUS REPLICATION, IT RESTRICTS VIRUS REPLICATION ORDERS OF MAGNITUDE, IT’S LITERALLY THE SOURCE. OF THE HOST RANGE RESTRICTION. OF HIV AND SOME MONKEY VIRUSES TO TRANSMIT TO HUMANS OR NOT. ONCE AGAIN IT REQUIRES INTERACTIONS BETWEEN THE VIRUS, IN THIS CASE GROUP ANTIGEN GAG, THE THING THAT MAKES THE CORE HAS TO INTERACT WITH OR NOT A CELLULAR PROTEIN CALLED TRIM 5 ALPHA. THIS TABLE EXPLAINS WHY I’M EXCITED ABOUT THAT UNCODING EVENT AND THAT PROTEIN TRIM 5 ALPHA. CONSIDER THIS TABLE. HIV INTERACTS WITH HUMAN CELLS AND YOU GET INFECTION. HIV CAN BE INCUBATED WITH CHIMP CELLS OR CHIMPS AND WE GET INFECTION. IF YOU TRY TO INFECT A MONKEY WITH HIV, YOU CAN INFECT MONKEY CELLS CELLS AND HAY DON’T GET INFECTD WITH HIV. TRY ANOTHER ONE HERE. HOW ABOUT THE VIRUS IN CHIMPSSIVE, CPZ CAN THAT AFFECT HUMAN? SURE CAN. CAN THAT INFECT CHIMPS YES, DOESN’T INFECT MONKEYS WELL AT ALL. HOW ABOUT THE VIRUS THAT DOESN’T INFECT MONKEYS. IT INFECTS HUMANS, WE ARE NOT DOING WELL ON THIS SLIDE IS ALL I’M SAYING. IT POORLY INFECTS CHIMPS. THIS ENTIRE SLIDE, THE RESULTS OF THIS SLIDE CAN BE DERIVED FROM THE INTERACTIONS OF HIV CORE WITH THAT PROTEIN TRIM FIVE ALPHA, WE HAVE A TRIM FIVE ALPHA, CHIMP HAS TRIM 5 ALPHA, MONKEY HAS A TRIM 5 ALPHA. THE MONKEY BINDS TO THE HUMAN IMMUNODEFICIENCY VIRUS, PREVENTS ENCODING AND PREVENTS INFECTION. THE CHIMP, NO. THE HUMAN NOT AT ALL. THE MONKEY TRIM 5 ALPHA ALSO RESTRICTS CHIMP VIRUS. THE MONKEY TRIM 5 ALPHA CANNOT RESTRICT SIV STRAIN. IN OTHER WORDS, IS IF ALL WE NEED IS MONKEY TRIM 5 ALPHA, 37 MILLION PEOPLE ON THE PLANET WOULD NOT HAVE HIV INFECTION, IT WOULD HAVE BEEN RESTRICTED ON THE WAY TO REVERSE TRANSCRIPTION, ON THE WAY TO NUCLEUS WE COULD HAVE STOPPED THIS. HOW COME WE GOT SUCH A BAD TRIM 5 ALPHA? FIRST HOW BAD IS — I DON’T KNOW IF I HAVE IT HERE. YEAH. HOW BAD IS IT? PROBABLY ONE MAYBE TWO AMINO ACID DIFFERENCES BETWEEN THE MONKEY TRIM FIVE ALPHA, AND OURS. IN OTHER WORDS, FOR THE WANT OF A NAIL WE LOST THE WAR. BECAUSE OF THESE TWO AMINO ACID CHANGES, THE HUMAN TRIM 5 ALPHA CANNOT RESTRICT HIV AND THE MONKEYS CAN. I THINK WE GET UNLUCKY, WHAT’S GOING ON SNEER THE THEORY IS MUCH MORE INTERESTING THAN BEEN ON MONKEY. LOOK AT TRIM FIVE FALLS OF HUMANS — ALPHAS OF HUMANS, MONKEYS DOWN TO LOWER PRIMATES AND BEYOND. YOU WILL SEE ALL KINDS OF GENES UNDERGO EVOLUTION. TRIM 5 ALPHA IS UNDERGOING THE FASTEST EVOLUTION OF ANY GENE EVER DESCRIBED. SO YOU KNOW CYTOCHROME C YOU CAN JUDGE HOW FAR AWAY WE ARE FROM EACH OTHER BASED ON WELL CONSERVED — THAT’S NOT THIS ONE. THIS ONE CHANGES A LOT. THE WORKING HYPOTHESIS IS, IS THAT OUR POPULATION, OUR SPECIES, OTHER SPECIESES ARE CONSANTLY BEING INVADED. CONSTANTLY OVER MILLIONS OF YEARS BEING INVADED BY WAVES OF VIRUS INFECTION. THE PEOPLE OR THE ANIMALS THAT SURVIVE ARE THE ONES THAT RESIST THOSE VIRUSES. BASICALLY WHAT THIS THEORY SAYS IS WE HAVE A CRUMMY TRIM 5 ALPHA NOW BUT IT WAS THE BOMB A COUPLE OF MILLION YEARS AGO AND SAVED OUR POPULATION FROM A WAVE OF INFECTION BACK THEN. PROBABLY MANY INDIVIDUALS WERE INFECTED, A TON DIED SOME SURVIVED, HERE WE ARE. BUT THAT DIDN’T — THOSE TRIM 5 FALL OF THE PAST COULDN’T PREDICT FUTURE. SO THIS IS CHARLES DEGAL, GENERALS ARE FIGHTING THE LAST WAR. YEAH. THEY ARE MIGHTING THE LAST WAR BECAUSE THEY WON IT SO WE WON THE LAST WAR AGAINST THE LAST WAIF OF VIRUS INFECTION, THAT DOESN’T TELL US WHAT WE NEED TO PREVENT FROM THE NEXT ONE. SO THIS IS INFORMED A GREAT DEAL OF RESEARCH INTO FINDING WAYS TO BLOCK THAT UNCODING. IT’S A PROTEIN PROTEIN INTERACTION. IT’S NOT AN ENZYME SO NOT EASY TO DEVELOP DRUGS. EVOLUTION SOLVED THE PROBLEM OF THE LAST WAVE BUT WE DON’T HAVE THAT KIND OF TIME. SO WE ARE WORKING ON — WE WORK ON DRUGS INSTEAD. SO REVERSE TRANSCRIPTION NOW IS A PROCESS TO TAKE THOSE TWO RNA MOLECULES AND MAKE A DNA MOLECULE OUT OF IT. THE VERY LITTLE SECRET IS THOSE TWO RNA MOLECULES ARE NOT COMPLIMENTARY TO EACH OTHER. THEY ARE IDENTICAL TO EACH OTHER. AND REVERSE TRANSCRIPTION STARTS ONE END AND THROUGH A MORE COMPLEX PROCESS THAN I THINK TERRY’S COURSE DESERVES TURNS THAT RNA INTO A DNA MOLECULE IN THE PROCESS COPYING BOTH ENDS SO THAT AT THE END WE HAVE THESE LONG TERM REPEATS THAT BRING THE PROMOTER TO THE FIVE PRIME END AND THE POLYA SEQUENCE TO THE THREE PRIME END. WHEN THAT DNA IS COMPLETED ITS REVERSE TRANSCRIPTION EVENT, THE ENDS ARE BOUND BY A PROTEIN CALLED INTEGRATION, THAT HIV DEGREES WITH IT INTO THE CELL AND INTO THE CORE. AND THEN THAT MOLECULE INTEGRATE THE HOST GENOME. IT PROBABLY DOES IT BY NEARLY CIRCULARIZING THE DNA. BECAUSE IT HAS TO ATTACK A SINGLE PLACE IN THE GENE. I WILL GET INTO THAT IN A SECOND. I WANT TO POINT OUT REVERSE TRANSCRIPTASE HAS A NUMBER OF POLYMERIZATION ACTIVITIES. IT’S AN RNA DEPENDENT POLYMERASE, IT HAS TO CHEW OUT THE RNA AFTER IT MAKES DNA COPY SO IT HAS AN RNASE ACTIVITY. IT NEEDS TO TURN DNA INTO DNA, FIRST TAKES RNA AND MAKES DNA THEN TAKE DNA TO MAKE THE SECOND COPY DNA. IT’S INTERESTING THAT AN RNA VIRUS CAN’T MAKE RNA. IT CAN TURN RNA INTO DNA, IT CAN TAKE DNA INTO DNA BUT IT CAN’T TAKE ANYTHING AND MAKE RNA. REVERSE TRANSCRIPTASE OF RETRO VIRUSES CAN ONLY MAKE DNA, MAKE IT ARE RNA OR DNA, IT’S ERROR RATE IS SOMEWHERE, PRETTY ERROR PRONE, IT MAKES A MISTAKE EVERY HUNDRED THOUSAND BASES, AND AS POLYMERASES GO, THAT’S ABOUT FOUR OR FIVE LOGS LESS FAITHFUL THAN OUR DNA POLYMERASE. DIRTY LITTLE SECRET, ANYTHING THAT USES RNA IS A TEMPLATE. SO ANY OF THE RNA VIRUSES, THEY HAVE THE SAME PROBLEM, IF YOU ARE TRYING TO MAKE ANYTHING OUT OF RNA, YOU ARE GOING TO HAVE A RELATIVELY HIGH ROAR RATE. RECOMBINATION OCCURS DURING REVERSE TRANSCRIPTION PERMITTING GREAT REASSORTMENT OF SEQUENCES. SO REPLICATION IS ERROR PRONE, IT’S ALSO RAPID IN INDIVIDUALS VIRUS REPLICATES ONCE A DAY. THE OUTCOME OF RAPID ERROR ROANE PRONE REPLICATION PROGRAM IS THERE ARE MUTANTS EVERYWHERE. MOST OF THE THINGS THE VIRUS MAKES ON A DAILY BASIS CAN’T REPLICATE AGAIN. THE GOOD ONES, NO. THERE’S MAYBE A MILLION TO TEN MILLION INFECTED CELLS IN AN INDIVIDUAL GIVING ITS GENES TO THE NEXT GENERATION. MOST OF WHAT IT DOES IS NOT INFECTIOUS BUT ABOUT A MILLION TO TEN MILLION MAKE IT TO THE NEXT. THERE’S A HOST OF VARIANT THAT MAY NOT BE GREAT BUT THEY ARE GOOD ENOUGH AND REPLICATE SO THE POPULATION OF HIV IN AN INDIVIDUAL IS QUITE DIVERSE. THAT IS A PATHOGENIC DETERMINANT FOR THE VIRUS. HERE IS AN EXAMPLE OF THAT. YOU ALREADY GAVE IT UP YOU SAID YOU WORK IN THE LAB SO I ASSUME YOU KNOW EVERYTHING ABOUT THE TRIPLET CODE AND GENETIC INFORMATION. BUT CONSIDER A ONE POSITION IN REVERSE TRANSCRIPT AIS, THAT’S POSITION 151. NORMALLY THERE’S A GLUTAMINE THERE. THAT’S CH. OKAY FINE. IT TOLERATES IT AND A TO T CHANGE INTO CT GENE, THERE’S A LEUCINE INSTEAD OF GLUTAMINE THAT, IS OKAY WITH VIRUS. THERE IS AA GENE SO C TO A CHANGE INSTEAD OF GLUTE MEAN THERE’S A LYSINE. NO BIG ONE, ONE CHANGE HERE AAG OR CTG TO ATG, WE HAVE A ME THIONEINE. ALL FOUR ARE TOLERATE BY THE VIRUS. THIS ONE IS MOST COMMON, PROBABLY 99.99% OF ALL BUT THAT’S — THERE’S THOUSANDS OF THESE. SO AS TURNS OUT WHEN WE START DRUG THERAPY, IT WILL SUPPRESS THIS ONE, THIS ONE AND THIS ONE. BUT OUR DRUG THERAPY TO INHIBITOR — THIS ENZYME WILL NEVER SUPPRESS THIS ONE. SO BEFORE YOU GIVE THE FIRST PILL YOU HAVE ALREADY GOT VIRUSES THAT ARE RESISTANT ON A SINGLE NUCLEOTIDE CHANGE TO MOST OF THE DRUGS WE HAVE. WELL, THAT MEANS WE SHOULD NEVER BE ABLE TO SUPPRETTES THE VIRUS. BUT THERE’S ONLY ONE OR TWO IN ANY GENOME. IF WE USE THREE DRUGS, THREE DIFFERENT TARGETS WE SHOULD BE ABLE TO IN A GAME OF SO CALLED WACK A MOLE, SHOULD BE ABLE TO KNOCK THIS VIRUS DOWN AS TURNS OUT THAT’S EXACTLY THE CASE. THAT REVERSE TRANSCRIPTION EVENT, EVEN THOUGH RAPID AND ERROR PRONE, IS A PATHOGENIC DETERMINATE FOR THE VIRUS. YEAH FOR DRUGS BUT ALSO FOR THE IMMUNE SYSTEM. SO IF YOU HAVE A WIDE HIGHLY DIVERSE POPULATION AND IMMUNE SYSTEM THAT’S TRYING TO INHIBIT IT, IT’S ALWAYS STEPS AHEAD OF IT. WHEN YOU DEVELOP A HIGHLY ACTIVE ANTIBODY, OR CTL RESPONSE, IT’S GOT A LOST OF VARIANT THAT ARE RESISTANT TO IT. SO INTEGRATION EVENT DNA LOSE TO BE INTEGRATE TO HOST GENOME, CENTRAL EVENT IN RETRO VIRUS REPLICATION, AGAIN, AN EVENT FOR WHICH IS UNIQUE TO THE VIRUS SO WE CAN DEVELOP DRUGS FOR THAT. THESE ARE THE MOST POTENT AGENTS WE HAVE. FOR HIV THERAPY INHIBITING THIS REACTION. SO HERE I JUST WANT TO GO BRIEFLY THROUGH THE LINK STEPS IN VIRUS REPLICATION, BECAUSE ONCE VIRUS IS INTEGRATED THE ENEMY IS WITHIN. AT THIS POINT IT’S GOING TO CO-ON CELLULAR PROCESSES. IT WILL USE ITS GENE PRODUCTS TO HELP THINGS ALONG TO DRIVE THINGS BUT IT NEEDS THE CELL AT THIS UPON, IT HAS TO MAKE RNA, USES RNA POLYMERASE, IT DOES IT BY DRIVING HIGH LEVELS OF TRANSCRIPTION THROUGH ONE OF ITS PROTEINS CALLED TAP. THE RNA IS MADE, IT’S GOT TO GET INTO THE CYTOPLASM, IT GETS DRAGGED THROUGH THE NUCLEAR MEMBRANE BY A CELLULAR COMPLEX, WITH CRIPPLE BUT IT NEEDS A VIRAL PROTEIN CALLED RIM. IT GETS TO THE CYTOPLASM, TRANSLATED, ON HOST RIBOSOMES AND NEEDS TO ASSEMBLE A PARTICLE, IT DOES THAT BY CO- CO-OPTING RAF, CELLULAR RAF AND ESCORT PATHWAY TO BUD AND MATURE THE VIRION. THE LAST STEP IN VIRUS REPLICATION IS — IT HAS TO CLEAVE PROTEINS AND ASSEMBLE THEM INTO A VIRION, YOU CAN SEE HERE ELECTRON MICROSCOPIC FIGURE OF VIRUSES BUDDING FROM MOST MEMBRANE, HERE IS MEMBRANE HERE AND THREE VIRIONS T BUDDING OUT. ONE THING YOU NOTICE,, THEY KIND OF LOOK LIKE DONUTS, IMMATURE PARTICLES, HERE IS THE MATURE PARTICLE WITH THAT CORE I KEPT DRONING ON ABOUT. THIS IS WHAT WILL TAKE THE NEXT CELL INTO INFECTION. THESE LOOK VERY, VERY DIFFERENT, THE HIV PROTEASE NEED TO CLEAVE PROTEINS IN THIS IMMATURE VIRUS TO MAKE IT LOOK LIKE THIS. IT’S AN IMPORTANT STEP IN VIRUS REPLICATION. ECAUSE THESE EVEN THOUGH THEY BUDDED OUT OF THE CELL, THEIR VIRIONS, THEY MATURE VIRION AND NON-INFECTIOUS SO IF YOU CAN INHIBIT THIS PROCESS OF MATURATION, WITH INHIBITING THE PROTEASE, THEN YOU LITERALLY GRAB VICTORY FROM THE JAWS OF DEFEAT. SO THE PROTEASE INHIBITORS WERE VERY IMPORTANT PART OF ANTI-REROW VIRAL THERAPY. THEY STOP THE VERY LAST STEP IN THE VIRUSES REPLICATION CYCLE PREVENTING THINGS THAT HAVE ALREADY BUDDED FROM THE MEMBRANE FROM BEING INFECTIOUS. SO THAT’S ESSENTIALLY ONE REPLICATION CYCLE. AND THE STEPS ALONG THE WAY THAT WE CAN INHIBIT IT WITH ANTIRETROVIRAL THERAPY. WHERE DID VIRUSES COME FROM? I MENTION TWO BROAD GROUPS, ONE THAT REPRESENTS ABOUT 36 MILLION AND ONE THAT REPRESENTS MUCH LESS GEOGRAPHICALLY RESTRICTED TO WEST AFRICA, DISTINCT EVENTS LIKELY DISTINCT ZOONOTIC EVENTS FROM ANIMAL POPULATIONS. JUST FOR ONE MOMENT I WANT TO GIVE THE OTHER RETRO VIRUS ITS DUE. THE HUMAN T-CELL LEUKEMIA VIRUS DISTRIBUTED AGAIN GEOGRAPHICALLY THROUGHOUT THE WORLD WHERE IT CAUSES A COUPLE OF DISEASES, ONE IS NEUROLOGIC ONE, CALLED HDLB ASSOCIATED MYLOPOTHY. THE OTHER ONE IS A LEUKEMIA LYMPHOMA. IT’S CONCENTRATED IN A NUMBER OF PLACES, THE CARIBBEAN, THE ASIAN COUNTRIES, IT’S DISAPPEARING BECAUSE AS YOU WILL SEE WE CAN GET RID OF IT BY PREVENTING TRANSMISSION. BUT JAPAN HAD A BIG — WAS ENDEMIC THERE, IT’S ENDEMIC IN CENTRAL AFRICA. THERE’S A SECOND VIRUS THAT’S LIKE ATLB CALLED HTLB 2, IT’S ENDEMIC IN A NUMBER OF PLACES LISTED HERE IN YELLOW, TRIBES. THOUGH IT’S A RETRO VIRUS IT DOESN’T CAUSE ANY DISEASE AT ALL. SO IN THIS FAMILY, ONE OF THEM CAN EITHER GIVE NEUROLOGIC DISEASE OR A CANCER, THE OTHER ONE PRETTY MUCH DOESN’T DO ANYTHING AT ALL. HTLB AFFECTS ABOUT 15 MILLION, 20 MILLION PEOPLE IN THE WORLD SAME ORDER AS HIV. WE DON’T HEAR ABOUT IT ADS MUCH BECAUSE ONLY A SMALL FRACTION OF INFECTED INDIVIDUALS ACTUALLY HAVE, GE DISEASE. SO WHEREAS WITH HIV PRETTY MUCH EVERYBODY WHO GUESS INFECTED WILL DIE IF NOT TREATED, 95% OF THE PEOPLE WITH HTLV WHO GET IT WILL NOT HAVE ANY DISEASE AT ALL. SO T-CELL LEUKEMIA, WHEN IT DOES OCCUR, IN APPROXIMATELY ONE TO THREE PERCENT OF ALL INFECTED INDIVIDUALS, USUALLY TAKES OVER 30 OR MORE YEARS TO INFECT. TO CAUSE DISEASE. JUST BACK TO HIV, HOW DID IT GET INTO HUMAN POPULATION? BASICALLY WHAT PEOPLE DID IS GO OUT SURVEY THINKING IT CAME FROM AFRICA, BUT FIND OUT WHERE. SO THEY LOOKED AT PRIMATES, MONKEYS AND CHIMPANZEES AND FOUND THAT CHIMPANZEES A VIRUS LOOKS VERY MUCH LIKE HIV. YOU CAN SEE IT HERE, THIS IS THE PRINCIPLE HIV VIRUS, HERE VIRUSES THAT ARE IN DIFFERENT CHIMPANZEE POPULATIONS, DIDN’T KNOW THIS BUT THERE ARE FOUR SUBSPECIES OF CHIMPS COLOR CODED HERE, GEOGRAPHICALLY DISTRIBUTED THROUGHOUT AFRICA. THESE ALL HAVE AND MY LIKE VIRUS. THIS ONE DOES NOT. — AN HIV LIKE VIRUS. THIS DOES NOT. SO THE CHIMP POPULATIONS WITH THE HIV LIKE VIRUS, PROBABLY GOT A VIRUS FROM MONKEYS THOUSANDS OF YEARS AGO THAT EVOLVED IN THE CHIMPS TO BE MORE LIKE HIV. THAT OCCURRED, THAT EVENT OCCURRED AFTER THIS POPULATION, AFTER ALL THE CHIMPS THAT EVOLVE AND THIS POPULATION BECOME GEOGRAPHICALLY ISOLATED, PROBABLY BY THIS ACROSS SOME OF THESE RIVERS, THIS IS THE NIGERIA RIVER AND PARENTALLY CHIMPS DON’T LIKE TO CROSS RIVERS SO ONE POINT THIS POPULATION BECAME ISOLATED AND IT WAS BEFORE SIV LIKE VIRUS INTO THE CHIMP POPULATION. HOW DOES IT GET INTO PEOPLE? THERE ARE MANY OPPORTUNITIES FOR ZOONOTIC EVENTS IN HUMANS. THIS IS I DAY AND AGE IT’S POACHERS BUT IN THE PAST THERE WERE ALWAYS INDIVIDUALS LOOKS FOR PROTEIN AND ANIMALS, CHIMPS AND MONKEYS ARE SOURCES OF THAT PROTEIN. LIKELY THESE EVENTS SPARKS MAY HAVE OCCURRED MANY, MANY TIMES BUT WITH POPULATION INCREASING GREATLY IN AFRICA THOSE SPARKS TURN INTO THE FLAME AND FIRE THAT BECAME THE HIV EPIDEMIC. SO POACHERS, THIS IS WHERE HIV 2 COMES FROM, THEY WILL TAKE THEIR ANIMALS TO A PLACE CALLED THE CHOP HOUSE, BUTCHERING THEM. YOU CAN IMAGINE THERE IS VIRUS IN THE BLOOD, THE BUTCHERS AND PEOPLE WHO PREPARE THE FOOD WOULD BE ABLE TO GET IT AND SOLD AT BUSH MEAT MARKETS. WE CAN DATE INTRODUCTION. THIS HIV EPIDEMIC INTO HUMANS FROM THE LATE 1800S AND EARLY 1900s KNOWING IT WAS LIKELY OCCURRING BEFORE BUT BECAUSE THERE WERE ISOLATED EVENTS AND ISOLATED COMMUNITIES, IT NEVER TOOK OFF AS A — WHY DID WE GET SO LUCKY? WAS PROBABLY BECAUSE THERE ARE LARGE INCREASES IN POPULATION BUT ALSO NON-BIOLOGIC POLITICAL ECONOMIC EVENTS. SO IF YOU LOOK AT THE MAP OF AFRICA, IN THE LATE 1800s AROUND THE TIME WHEN WE THINK HIV WAS ENTERING — THIS ONE WAS Q. ING THE HUMAN POPULATIONS, THAT’S WHAT THE MAP LOOKED LIKE COLONIALISM DIVIDEED THAT AREA UP — DIVIDED THAT AREA UP INTO MANY COUNTRIES, AND IN SOME WAYS ISOLATING THE PEOPLE, AND SOME WAYS SUBJEW GATING THE PEOPLE, SOME WAYS A GREAT DEAL OF INDIVIDUALS NOW NOURISHED IN THAT MALL NOURISHMENT IS A RELATIVE IMMUNE SUPPRESSION PROBABLY FACILITATING THE SPREAD OF THE VIRUS. OTHER THINGS, LARGE POLITICAL UPHEAVALS CONTRIBUTED AS WELL AS MAL MYTRITION TO IMMUNODEFICIENCY. HERE IS POPULATION IN AFRICA FROM THE 1910s AROUND THE TIME WHEN WE THINK IT FIRST HIV WAS INTRODUCE IN THE POPULATION. AND HERE IS HOW THINGS TOOK OFF, NOTE THIS IS A LOG SCALE. SO THE POPULATION GOES FROM LESS THAN 10 MILLION TO OVER A BILLION IN A VERY SHORT PERIOD. THE OPPORTUNITIES TO TRANSMIT VIRUS AT THAT TIME MADE THE EPIDEMIC ESSENTIALLY INEVITABLE. THINGS LIKE DEVELOPMENT. THIS IS THE TRANSAFRICA HIGHWAY. THAT BROUGHT PEOPLE AND GOODS ACROSS AFRICA IN THE 1960s. AND THE VIRUS WENT. IF WE LOOK HOW THE VIRUS GOT INTO HUMAN POPULATIONS IN THE UNITED STATES, WE — THERE’S BEEN SOME VERY ELEGANT PHYLOGENETIC WORK TO INDICATE THAT THE VIRUSES THAT ARE HERE IN THE UNITED STATES, ARE NOT NEARLY AS OLDS AS THE ONES IN AFRICA, AND ARE SLIGHTLY YOUNGER THAN THE ONES IN HAITI. SO THE PREVAILING THEORY IS VIRUSES ORIGINATED IN AFRICA AND HUMAN POPULATIONS, 80 OTHER COUNTRIES HAD CLOSE ASSOCIATION WITH CENTRAL AFRICA, SENDING WORKERS EDUCATORS, THERE IN THE 1950s AND ’60s, PERHAPS HARVESTING SOME OF THOSE VIRUSES, BRINGING THEM HERE. THEN WE WERE SUBSEQUENTLY INFECTED. I THINK WE ARE DOING WORK HERE IN WASHINGTON, TO LOOK AT THIS. I THINK THAT THIS THEORY IS A GOOD ONE. I’M NOT SURE IT EXPLAINS THE ENTIRE EPIDEMIC. IN THE UNITED STATES THE VIRUS STARTED TO EMERGE IN THE EARLY 1980s. T HERE IS A SLIDE FROM THE CDC IN 1983. ABOUT A THOUSAND CASES AND YOU CAN SEE EACH ONE OF THESE DOTS REPRESENTING 30 IN HIGHLY POPULATED AREAS. TWO YEARS LATER, WITHIN TWO YEARS WE HAVE GONE UP TENFOLD FROM A THOUSAND TO 10,000. FOUR YEARS LATER NOTE IT TAKES TWICE AS LONG TO GET TO 100,000 AS I MENTION, WE HAVE PROBABLY CLOSE TO A MILLION NOW, WE WERE 90% OF THE WAY, WE HAD GOTTEN TO 100,000, BY 1989 WITHIN A FEW YEARS, WE GOT TO CLOSE TO A MILLION. THERE’S 95 1/2 MILLION AND YOU CAN SEE THAT THE VIRUS IS POPULATED MANY OF THE HIGHLY POPULATED AREAS BUT IS NOW MOVING OUT INTO LESS POPULATED AREAS. SO IN THE UNITED STATES NOW, 12% OF THE CASES ARE IN POPULATIONS WITH LESS THAN 50,000. WOMEN COME PRIDES OVER QUARTER OF ALL THE CASES. AND THE EPIDEMIC IS MATURING. BY NOW ABOUT 50% OF ALL CASES OF HIV LIVING PEOPLE WITH LIVE ARE OVER 50. IT IS LARGELY AN AFRICAN AMERICAN EPIDEMIC. THERAPY NOW HAS CHANGED THE ENTIRE LANDSCAPE. SO WHEN I FIRST CAME, I’M SURE TERRY DOESN’T REMEMBER THIS BECAUSE HE IS SO YOUNG. BUT THERE WERE BUSES THAT HAD POSTERS LIKE THIS. IF YOU GET THE AIDS VIRUS NOW YOU AND YOUR LICENSE COULD EXPIRE AT THE SAME TIME. BEFORE THERAPY, EVERYTHING WAS CONCENTRATED ON MEASURES TO PREVENT TRANSMISSION IN THOSE, ALL EXCLUSIVELY BEHAVIORAL. SINCE THAT TIME, WE DEVELOPED A HOST OF ANTIRETROVIRAL THAT ATTACK AS WE SAW MANY DIFFERENT STEPS IN REPLICATION. NOW THE HOPE IS THAT WE WILL GET 90% OF THE PEOPLE INFECTED DIAGNOSED, 90% OF THOSE ON THERAPY, AND 90% OF THOSE ON THERAPY SUPPRESSED. YOU SAW OUR GARDENER STATE OF CARE. YOU SEE WHERE OUR LIMITATIONS ARE. BUT TREATMENT FOR ALL WILL GET US TO ZERO. THE LAST COUPLE OF YEARS, WHAT WE HAVE LEARNED IS THAT IF YOU ARE SUPPRESSED, YOUR VIRAL LOAD IS SUPPRESSED LESS THAN 50 THEN YOU DON’T TRANSMIT THE VIRUS. UNDETECTABLE AND I HATE THAT TERM BECAUSE WE CAN ALWAYS DETECT IT BUT UNDETECTABLE MEANS UNRAINS MISSABLE. IF WE GET THOSE PEOPLE — UNTRANSMISSIBLE. IF WE KEEP THEM AT 50 THEY WILL NOT TRAN METHOD THIS VIRUS. SO THE NEED IS GREAT, CHALLENGE IS NUMEROUS LEVELS. REMEMBER THIS, OUR GOAL IS TO GET THIS DIAGNOSIS UP TO OVER 90% TO GET THIS UP TO OVER 90%, TO GET THIS UP TO OVER 90%. AND THAT WILL KEEP THE VIRUS FROM BEING TRANSMITTED. I THINK A LOT — I THINK WE ARE CONCENTRATING THIS BIG GROUP HERE AT NIH WORKING ON VACCINES. ANOTHER GROUP WORKING ON CURATIVE STRATEGIES. SO OUR LESSONS, VIRUSES ARE BAD AND SHOULD BE AVOIDED, EXCEPT THEY MAY HAVE SAVED LIFE ON THIS PLANET. AND O THEY PROBABLY SAVED US FROM THE LAST WAVE, WE JUST HAVE TO TAKE THIS ONE ACROSS THE GOAL POST. EPIDEMICS ARE NOT SINGLE EVENTS, EPIDEMICS EVOLVE AND DETAILED UNDERSTANDING OF REPLICATION WHAT YOU GUYS DO, ON A DAILY BASIS LEADS TO NEW THERAPIES. ANTIVIRALSES ARE USEFUL, WHEN INSTITUTED EARLY AS POSSIBLE, ADHERENCE IS ESSENTIAL. SO I’LL STOP THERE. SORRY TO RUSH A LITTLE BIT.>>ANY QUESTIONS? PERHAPS YOU CAN COMMENT OUR THEY GET THE H DRUGS TO AFRICA AND DISTRIBUTED?>>WE DEVELOP THEM, WE — FDA APPROVE THEM, AND THEN THEY WERE LARGE PROGRAMS THAT BROUGHT THOSE DRUGS TO AFRICA. AND THEY WERE COLLABORATIONS BETWEEN GOVERNMENTS, AND BETWEEN FUNDING AGENCIES AND BETWEEN INDEPENDENT FUNDS TO GET MONEY THERE. LIKE WHAT? OKAY. LIKE ONE. IN THE EARLY 2000s, SOME OF YOU MAY KNOW ANTHONY FAUCI IS HEAD OF NIAID. HE HAS BEEN SINCE THE LATE ’80s. WHEN HE SAW HOW COMPELLING THE DATA WERE FOR TREATMENT MAY PREVENT TRANSMISSION, HE CONVINCED PEOPLE, THERE ARE PEOPLE WHO ARE ABOVE HIS PAY GRADE, HARD TO BELIEVE. THAT ARE ABOVE AN INSTITUTE DIRECTOR. HE CONVINCED THE ADMINISTRATION OF GEORGE W. BUSH THAT THE APPLICATION OF MONEY NOW CONCENTRATED IN AFRICA CAN SAVE LIVES. $5 BILLION WAS INVESTED IN AFRICA. AT THE SAME TIME THE CLINTON FOUNDATION WAS INVESTING IN AFRICA. AT THE SAME TIME COUNTRIES WHAT THINGS CAN BE DONE. AND THE TWO EXAMPLES I THINK ARE SOUTH AFRICA, WHICH CAME LATE TO THE PARTY, AND SAID I ONLY HAVE 40 CENTS TO SPEND ON HEALTHCARE WHY TRY TO SPEND IT ON ANTIRETROVIRAL? SO THEN THEY HAD PROBABLY THE WORST EPIDEMIC OF ALL. ADS OPPOSED TO ANOTHER COUNTRY IN SUBSAHARAN AFRICA, BOTSWANA. BOTH OF THOSE COUNTRIES GOT DIAGNOSED AND BOTSWANA DECIDED TO SPEND MONEY ON INFRASTRUCTURE AND IT WAS A LONG RANGE PROJECT. 25% OF THE PEOPLE IN BOTSWANA IN 2000 WERE INFECTD WITH HIV. A QUARTER OF EVERYBODY, THEY SAID LOOK, WE ARE NOT GIVING UP, WE ARE GOING AFTER IT AND THEY INVESTED A HUGE AMOUNT OF MONEY, THEY HAVE — THEY GOT FIRST 90 THEY ARE GETTING TO THE SECOND 90, THEY HAVE HUGE IMPACT IN THEIR POPULATION. OKAY. YOU MIGHT SAY, WHEN YOU START 25% THERE’S HARDLY ANYWHERE ELSE YOU CAN GO BUT DOWN BUT LOWER IF YOU DO ANYTHING AT ALL. TO SYSTEM DEGREE THAT’S TRUE BUT THEY MADE A — SOME DEGREE THAT’S TRUE U BUT THEY MADE A LONG RANGE COMMITMENT THAT IS REAPING BENEFITS. SOUTH AFRICA, ALL RIGHT. SO THEY STARTED LATE. BUT THEY STARTED MAKING THE SAME COMMITMENTS AND NOW IN BOTH OF THOSE PLACES, THEY ARE TRANSMISSIONS ARE LESS. BUT IT REQUIRED AN EXAMPLE THAT IT COULD BE DONE, THAT INQUIRED A LOT OF MONEY. AND SOME CAME FROM US, SOME CAME FROM WHO SOME CAME FROM CLINTON FOUNDATION AND OTHER FOUNDATIONS. AND SOME OF IT HAD TO COME FROM THE COUNTRY ITSELF. BUT KNOWING THAT YOU COULD — AND THIS WAS NO QUESTION, THIS WAS THE BRILLIANCE OF ANTHONY FAUCI, HE KNEW WHEN TO SAY WHAT TO SAY AND HOW MUCH IT WAS GOING TO COST. AND THAT SAVED MILLIONS OF LIVES. NO TWO WAYS ABOUT IT.>>THAT WILL DO.
02:03:18.591,00:00:00.000
GREAT STORY.

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