BEFORE WE START THIS PROGRAM ACTUALLY, I WANT TO ACKNOWLEDGE OUR SPONSOR FROM THE NIH OFFICE OF EQUITY, DIVERSITY AND INCLUSION, ALSO NIH OFFICE OF INTRAMURAL RESEARCH, PLUS THE LOCAL CHAPTER WASHINGTON, D.C. CHAPTER OF THE SOCIETY OF CHINESE BIOSCIENTISTS IN AMERICA FOR THE SUPPORT OF THIS RECEPTION AND THE DINNER TONIGHT. THIS IS THE FOURTH YEAR OF THE LECTURE AND WE REALLY HAVE THIS OPPORTUNITY TO REMEMBER THE LEGACY, NOW LET US WELCOME DR. STEVEN HODAN, THE DIRECTOR OF INTRAMURAL RESEARCH PROGRAM OF NIAID, TO INTRODUCE OUR SPEAKER. STEVE? >> THANK YOU VERY MUCH. IT'S A VERY BITTERSWEET HONOR TO BE HERE TO TALK ABOUT REALLY ONE OF MY OLDEST FRIENDS AND ONE OF THE PEOPLE WHO WAS MOST RESPONSIBLE FOR MY COMING TO THE NIH AND WORKING IN THE PLACES I DID. SO TEH, OR K.T., AS MANY PEOPLE HERE KNEW HIM, HAD REALLY QUITE A REMARKABLE LIFE STORY, REALLY DIVIDED INTO BEFORE AND AFTER HE CAME HERE. HE WAS BORN IN TAIWAN, CAME TO THE UNITED STATES AS A VERY YOUNG MAN, AND THEN SHORTLY AFTER ARRIVING, WENT TO MIT, DECIDED THAT, YOU KNOW, THAT WAS JUST SO NERDY, HE WANTED TO GO SOMEPLACE THAT HAD REALLY THE CHANCE TO DO A B.A. AND MD PROGRAM, AND CAME TO JOHNS HOPKINS IN 1977, WHERE HE REALIZED HE WANTED TO BE AN MDHPD, AND JOINED THE DEPARTMENT PHARMACOLOGY IN THE LAB OF GARY HAYWARD, DEDICATED TO THE STUDY OF EPSTEIN-BARR VIRUSES. HE GRADUATED FROM JOHNS HOPKINS WITH HIS B.A. AND M.D. IN 1984, AND THEN WENT ON TO DO HIS MEDICAL INTERNSHIP AT UNIVERSITY OF IOWA. MY FIRST INTERACTION WITH TEH WAS HERE DURING HIS TRAINING AT HOPKINS, BECAUSE I ALSO TRAINED IN THE LAB, GARY HAYWARD'S LAB WAS RUN BY A GUY NAMED TOM AUGUST, AND THAT WAS THE LAB I WORKED IN. SO I MET TEH WHEN I WAS WORKING IN THE LAB, AND THEN I, OF COURSE, HAD A CHANCE TO GO BACK AND MEET TEH AGAIN WHEN HE AND I WERE MEDICAL STUDENTS ON THE WARDS OUT AT THE OLD BAY VIEW HOSPITAL, NOW -- I DON'T EVEN REMEMBER THE NAME THEY CALL IT NOW. IT USED TO BE BALTIMORE CITY HOSPITAL, NOW IT'S CALLED BAY VIEW. SO TEH AND I GOT TO KNOW EACH OTHER THEN, AND WE INTERACTED AROUND SOME PATIENT THINGS AND SOME CONSULT SERVICES. THEN TEH DID HIS MEDICAL INTERNSHIP AND CAME TO THE NIH AND WAS A MEDICAL STAFF FELLOW AND MOVED UP THROUGH THE RANK, WORKING FIRST WITH GEORGE KHOURY, THEN AFTER TRAINING IN MEDICAL VIROLOGY WITH GEORGE, RETRO VIROLOGY, CAME TO THE LAB OF MALCOLM MARTIN. IT WAS HERE HE CAME TO LMM IN 1988, AND I DECIDED AROUND THAT TIME THAT I WANTED TO LEAVE JOHNS HOPKINS AND COME TO THE NIH, AND I CAME DOWN AND I SAW HERE IN THIS LAB WAS THIS GUY, AND THOSE OF YOU WHO EVER WENT TO VISIT TEH, I THINK THAT HE BROUGHT THAT CHAIR, I DON'T KNOW FROM WHERE, BUT I NEVER SAW HIM IN A CHAIR OTHER THAN THAT. AND I SAT DOWN AND TALKED TO HIM AND HE SAID, YOU KNOW, YOU'VE GOT TO COME TO THE NIH. I WASN'T QUITE SURE ABOUT THAT. AND HE SAID STEVE, THE NIH THAT, IS YOUR OYSTER, YOU COME HERE, THIS PLACE IS EXTRAORDINARY. YOU CAN DO ANYTHING HERE, AS LONG AS YOU KNOW WHAT YOU WANT. I HAVE TO SAY, I WASN'T QUITE SO CLEAR ABOUT THAT. TEH NEVER DOUBTED WHAT HE WANTED. SCIENTIFICALLY AND SOCIALLY. HE WAS TREMENDOUSLY DIRECTED. HIS DIRECTION HELPED ME A LOT TO DECIDE TO COME HERE, SO I OWE A LOT TO TEH IN TERMS OF THE DECISION TO COME HERE. AND I JOINED THE LABORATORY OF MOLECULAR MICROBIOLOGY IN 1989, THEN I STAYED THERE FOR A FEW YEARS AND TEH STAYED THERE MUCH LONGER. SO HE WAS TEP YOU'RED THERE IN 1993 AND WENT ON TO AUTHOR HUNDREDS OF PAPERS, AND TRAIN AN EXTRAORDINARY CADRE OF REMARKABLE SCIENTISTS WHO ARE ALL OTHER THE WORLD AND WHOSE DEVOTION TO TEH AND HIS LEGACY IS QUITE PROFOUND. YOU ALL KNOW THAT HIS EFFORTS IN HTLB1 AND TACS AND TAR AND UNDERSTANDING TRANSCRIPTIONAL REGULATION IN THE SETTING OF THE EUKARYOTIC CELL WAS REALLY AN EXTRAORDINARY FEAT. AND HE WENT ON TO BECOME THE EDITOR OF RETRO VIROLOGY AND WAS ENORMOUSLY ACTIVE IN THE CHINESE SCIENTISTS ASSOCIATION AND IN TRAINING AND ADVANCEMENT OF SCIENTISTS WORLDWIDE. SO IT IS MY GREAT PLEASURE TO ACKNOWLEDGE MY PERSONAL DEBT TO MY FRIEND TEH AND ALSO OUR INSTITUTIONAL DEBT TO HIM AS A GUIDE AND A MENTOR, AND I WANT TO MAKE SURE TO ACKNOWLEDGE HIS WIFE, DIANE, WHO IS HERE WITH US TODAY, AND HIS CHILDREN, DAVID AND DIANA AND JOHN, WHO ARE CONTINUING TEH'S LEGACY IN THEIR ACADEMIC AND SOCIAL ACTIVITIES. SO IT IS TO HONOR TEH'S LEGACY THAT TODAY'S SPEAKER, X.J. MENG, IS JOINING US. X.J. DID HIS TRAINING, HIS M.D. AT BIZHOU UNIVERSITY, THEN CAME HERE TO GET HIS MASTERS AT IOWA. HE DID NOT KNOW TEH AT IOWA, BEFORE' HIS PH.D., HE CAME HERE TO THE LABORATORY OF INFECTIOUS DISEASES, THAT WAS BACK IN BUILDING 7 THEN, WHEREAS TEH WAS IN BUILDING 4, BUT THEY BECAME FRIENDS AND STAYED PERMLY ASSOCIATED. STAYED PERSONAL PERSONALLY ASSOCIATED. HE HAS BECOME A UNIVERSITY DISTINGUISHED PROFESSOR, ONE OF ONLY A DOZEN THAT THEY HAVE THERE AT VIRGINIA TECH, AND LAST YEAR, BEING ELECTED TO THE UNITED STATES NATIONAL ACADEMY OF SCIENCES. SO IT IS A GREAT PLEASURE TO INTRODUCE DR. X.J. MENG, WHO IS GOING TO TALK ABOUT HEPATITIS E VIRUSES AND THEIR XENOTROPIC ACTIVITIES. X.J.? [APPLAUSE] >> WELL, THANK YOU FOR THE NICE INTRODUCTION. GOOD AFTERNOON, EVERYONE. FIRST OF ALL, I WOULD LIKE TO THANK THE ORGANIZERS FOR THE INVITATION, AS IT'S ALWAYS A PLEASURE COMING BACK TO THE NIH CAMPUS. AND I HAVE KNOWN K-T JEANG SINCE I WAS A POSTDOC HERE, HE WAS REALLY AN INSPIRATIONAL FIGURE FOR THE VIROLOGY COMMUNITY WORLDWIDE, SO IT'S A GREAT HONOR FOR ME TODAY TO BE HERE TO SPEAK IN HONOR OF DR. JEANG'S MEMORY. SO WHAT I'M TRYING TO DO HERE TODAY IS TO PRESENT YOU SOME OF THE LATEST RESEARCH REGARDING THE EXPANDING HOST RANGE OF AN EXTREMELY UNDERSTUDIED HUMAN PATHOGEN, THE HEPATITIS E VIRUS. NOW, AS MOST OF YOU KNOW, HEPATITIS E VIRUS OR HEV IS ONE OF THE MANY VIRUSES THAT CAUSE HEPATITIS IN HUMANS. SHOWN HERE IN THIS SLIDE ARE SOME OF THE WELL-KNOWN AND WELL CHARACTERIZED HEPATITIS VIRUSES. THE HEPATITIS A VIRUS, ASSOCIATED WITH HEPATITIS, THE HEPATITIS B VIRUS, WHICH IS CHRONIC HEPATITIS AND LIVER CANCER. THE HEPATITIS C VIRUS AND RELATED VIRUSES, THESE ARE FLAVOVIRUS AND ALSO ASSOCIATED WITH CHRONIC HEPATITIS E, LIVER CIRRHOSIS AND LIVER CANCER. THE DELTA HEPATITIS VIRUS, WHICH IS OFTEN FOUND DURING COINFECTION WITH THE HEPATITIS B, AND OF COURSE THE HEPATITIS C VIRUS, WHICH I'M GOING TO TALK ABOUT HERE TODAY. THE HEPATITIS C VIRUS WAS ORIGINALLY CLASSIFIED IN THE FAMILY LARGELY BASED UPON SUPERFICIAL SIMILARITY BETWEEN THE HEPATITIS C VIRUS AND THEY ARE MORPHOLOGICALLY SIMILAR, THEY ALSO SHARE SIMILAR GENOMIC ORGANIZATIONS. HOWEVER, THESE TWO VIRUSES DID NOT SHARE SIGNIFICANT -- RECENTLY THEY DECIDED TO DECLASSIFY THE HEPATITIS E VIRUS FROM THE FAMILY, THE VIRUS IS IN A BRAND NEW FAMILY CALLED HEPEVIRIDAE. THIS IS A SINGLE STRAND, 7.2 KB IN SIZE, RELATIVELY SMALL VIRUS, ONLY ABOUT 30 TO 35 NA NO METERS IN SIZE. IT'S A SPHERICAL VIRUS PARTICLES. THE DISEASE CAUSED BY HEV IS HEPATITIS C TYPICALLY IT'S REALLY DIFFICULT TO EXTINGUISH THE SYMPTOMS FROM OTHER KINDS OF HEPATITIS. THEY'RE VERY SIMILAR. THEY HAVE JAUNDICE, ABDOMINAL PAIN, NAUSEA, VOMITING, SO THEY'RE VERY SIMILAR AS TYPICAL HEPATITIS. THE INCUBATION PERIOD CAN RANGE FROM TWO WEEKS TO UP TO TWO MONTHS, AND ONE OF THE UNIQUE FEATURES ASSOCIATED WITH THE HEPATITIS E VIRUS INFECTION IS THE RELATIVELY HIGH FATALITY DURING PREGNANCY IN INFECTED PREGNANT WOMEN, THE MORTALITY CAN BE UP TO 25%, EVEN THOUGH THE OVERALL MORTALITY FOR HEPATITIS C VIRUS INFECTION IN GENERAL POPULATION IS LESS THAN 1%. SO THAT'S VERY UNIQUE. THE VIRUS IS TRANSMITTED THROUGH THE FECAL-ORAL ROUTE, OFTEN THROUGH CONTAMINATED WATER OR CON TOM NATEED CONTAMINATED FOOD. RECENTLY ZOONOTIC TRANSMISSION HAS BEEN CONFIRMED, WHICH I'M GOING TO TALK ABOUT THAT IN JUST A FEW MINUTES. SO HEPATITIS C IS THE IMPORTANT PUBLIC HEALTH PROBLEM IN MANY DEVELOPING COUNTRIES IN THE WORLD, BUT SPORADIC CASES AND CLASSIC CASES OF HEPATITIS C DO OCCUR IN THE UNITED STATES AND MANY OTHER INDUSTRIALIZED COUNTRIES. MORE RECENTLY, CHRONIC HEPATITIS OA. INFECTION HAS BECOME A SIGNIFICANT CLINICAL PROBLEM, ESPECIALLY IN THOSE IMMUNOCOMPROMISED INDIVIDUALS SUCH AS ORGAN TRANSPLANT RECIPIENT, A PATIENT THAT WAS HIV/AIDS OR LEUKEMIA OR LYMPHOMA, AND THOSE INDIVIDUALS, IF THEY ARE INFECTED BY THE HEPATITIS E VIRUS, 60% OF THEM WILL GO INTO CHRONICITY. SO THAT HAS BEEN A POINT IN THE CLINICAL PROBLEM IN THE LAST FEW YEARS. SO HERE SHOWS THE DISTRIBUTION OF HEPATITIS E INFECTION. AS YOU CAN SEE, IT'S A GLOBAL DISEASE. ALTHOUGH IT'S PRIMARILY OCCURRING IN SOUTHEAST ASIA, ALSO AFRICA, THOSE ARE EXPLOSIVE LARGE -- BUT THE SPORADIC CASES OCCUR WORLDWIDE AND THOSE IN DEVELOPING COUNTRIES AND ALSO IN INDUSTRIALIZED COUNTRIES. SO YOU LOOK AT THE DISEASE BURDEN BASED ON WHO, EACH YEAR MORE THAN 20 MILLION HAVE THE HEPATITIS E INFECTION WORLDWIDE, THIS LEADS TO ABOUT 3 MILLION CLINICAL CASE OF ACUTE HEPATITIS E EACH YEAR, AND ABOUT 56,000 HEPATITIS E-RELATED DEATHS. SO THIS IS AN IMPORTANT PUBLIC HEALTH PROBLEM WORLDWIDE. NOW, AS I MENTIONED EARLIER, IN THE UNITED STATES, MANY INDUSTRIALIZED COUNTRY, WE ONLY SEE SPORADIC CASES OF HEPATITIS E. HOWEVER, IF YOU LOOK AT THE BLOOD DONORS AND THE PREVALENCE OF HEV ANTIBODY RANGE FROM 10% FROM SOME OF THE COUNTRIES LIKE AUSTRALIA -- TO UP TO 18% IN THE UNITED STATES. SO THIS HAS BEEN VERY PUZZLING OVER THE YEARS AS TO WHAT IS THE SOURCE OF THE SEROPOSITIVITY FROM BLOOD DONORS IN INDUSTRIALIZED COUNTRIES, AND SO IT HAS BEEN HYPOTHESIZED MAYBE THERE'S ANIMAL RESERVOIR FOR HEPATITIS E VIRUS AND THAT WOULD EXPLAIN THIS RELATIVELY HIGH SEROPOSITIVITY IN BLOOD DONORS. SO IN ATTEMPT TO SEARCH FOR ANIMAL RESERVOIR, WHEN I WAS A WE DISCOVERED THE FIRST ANIMAL STRAIN OF HEPATITIS E VIRUS FROM PIGS, AND WE NAMED THIS VIRUS THE SWINE HEPATITIS E VIRUS OR SWINE HEV TO DISTINGUISH IT FROM THE HUMAN HEPATITIS E VIE RU BUT RETROSPECTIVELY, IF YOU LOOK AT THE GENOMIC ORGANIZATION OF THIS VIRUS, THERE'S REALLY NOT A THE SWINE HEV AND THE HUMAN HEV. THEY ARE VERY SIMILAR AND THEY ALL HAVE THREE OPEN -- FOR THE -- PROTEIN, SMALL FOS POE PROTEIN INVOLVED IN VIRUS REPLICATIONS. SO SINCE OUR INITIAL DISCOVERY OF SWINE HEV FROM PIGS IN THE UNITED STATES, THIS VIRUS HAS NOT BEEN GENETICALLY IDENTIFIED, ESSENTIALLY FROM ALL SWINE PRODUCING COUNTRIES WORLDWIDE. WE KNOW NOW SWINE HEV INFECTION FROM PIG IS WIDESPREAD, UP TO 80% OF THE PIGS, 80% OF THE PIGS IN THE UNITED STATES IN SOME FARMS ARE ACTUALLY INFECT BID THE HEPATITIS E VIRUS. SO AFTER OUR INITIAL DISCOVERY OF HEPATITIS E VIRUS FROM PIGS, THERE'S A DRASTIC EXPLOSION OF -- THE VIRUS HAS BEEN IDENTIFIED GENETICALLY FROM A NUMBER OF ANIMAL SPECIES, AND YOU CAN SEE HERE FROM THIS SLIDE, IN ADDITION TO DOMESTIC PIG, THE VIRUS HAS BEEN ISOLATED FROM WILD PIGS, FROM DEER, CHICKEN, RABBIT, YOU CAN READ HERE, DOWN THE LIST, A NUMBER OF ANIMAL SPECIES, EVEN FROM FISH. AND THE VIRUS IN THE INFECTED PIG HAS FAIRLY WELL CHARACTERIZED, WE KNOW GENOTYPE 3 AND GENOTYPE 4 INFECTED PIGS. THERE ARE AT LEAST THREE GENERAL TYPE OF VIRUSES, INFECTED CHICKENS WORLDWIDE, BUT IF YOU LOOK AT OTHER ANIMAL STRING OF HEPATITIS E, THE BIOLOGY IS EXTREMELY UNDERSTUDIED. WE KNOW VERY LITTLE ABOUT THEIR BIOLOGY AND THEIR PATHOGENICITIES. SO BECAUSE THE DISCOVERY OF SO MANY ANIMAL STRAIN HAS BEEN TATE -- VIRUS AND -- RECLASSIFIED THE VIRUS, AS I MENTIONED EARLIER, WE GAVE THE VIRUS A NEW NAME CALLED HEPEVIRIDAE. RIGHT NOW WE'RE SEEING, THERE ARE ACTUALLY TWO GENUS, AND FIVE SPECIES. SO GENUS OF THE HEPE VIRUS, THERE ARE FOUR SPECIES, AND THE GENUS PISCIHEPEVIRUS WHICH CONSISTS OF FISH. WE SEE THE SPECIES ORTHOHEPEVIRUS, YOU CAN SEE THERE ARE AT LEAST SEVEN DISTINCT GENOTYPE. THIS STUDY AFFECTED HUMAN, GENOTYPE 1, GENOTYPE 2 ARE RESTRICTED EXCLUSIVELY IN HUMAN, THEY ONLY AFFECT HUMANS. THE GENOTYPE 3 AND GENOTYPE 4, THESE TWO GENOTYPES INFECT HUMANS BUT ALSO A NUMBER OF OTHER ANIMAL SPECIES. YOU CAN SEE HERE, PIG, DEER, MONGOOSE, RABBIT, AND SO THESE TWO GENOTYPE, 3 AND 4, AFFECT MULTIPLE ANIMAL SPECIES. WE ALSO HAVE A GENOTYPE 5 AND A 6, THESE TWO GENOTYPE INFECT WILD PIGS AND GENOTYPE 7 INFECTS CAMEL. SO WHEN WE LOOK AT THIS TREE, ONE THING WE NOTICE IS THAT THOSE ANIMAL STRAIN HABITAT -- THE GENOTYPE 3 AND GENOTYPE 4, THEY CLUSTER VERY CLOSELY WITH THE HUMAN HEPATITIS E VIRUS, SO THIS LED US TO QUESTION WHETHER OR NOT THE HEPATITIS E VIRUS IS NOT A DISEASE. SO ONE OF THE EARLY QUESTIONS WE ASKED WAS, CAN SWINE HEV CROSS THE -- BARRIER AND AFFECT HUMANS? IS HEPATITIS E ON ITS OWN A DISEASE? SO TO ANSWER THAT QUESTION, WE CONDUCTED A NUMBER OF EXPERIMENTAL TRANSMISSION STUDIES, IN AN ATTEMPT TO DETERMINE IF THIS VIRUS CAN INFECT ACROSS SPECIES BARRIER. SO TO MAKE THE LONG STORY SHORT, I'M GOING TO SUMMARIZE SOME OF THE STUDY, WE DID SHOW THAT INDEED THE GENOTYPE 3 AND GENOTYPE 4 SWINE HEPATITIS E VIRUS CAN CROSS TO NON-HUMAN PRIMATE, RHESUS ME MACAQUES AND -- BUT NOT GENOTYPE 1 OR GENOTYPE 2, ALSO INFECT PIGS. SO IT'S A TWO-WAY CROSS SPECIES INFECTION FROM PIG TO NON-HUMAN PRIMATE, SURROGATE OF HUMANS, AND FROM HUMAN TO PIGS. SO I'M JUST GOING TO SHOW YOU A COUPLE OF SLIDES OF THOSE CROSS SPECIES TRANSMISSION STUDIES WE DID, IN THIS PARTICULAR SLIDE, YOU CAN SEE HERE IT SHOWS THAT THIS PARTICULAR RHESUS MACAQUE EXPERIMNTALLY -- THE GENOTYPE 3 SWINE HEPA TITIS E VIRUS. YOU CAN SEE CLEARLY THE RHESUS MACAQUE BECOMING INFECTED AS EVIDENCED BY CONVERTING TO -- ANTIBODY, WE ALSO HAVE VIREMIA AND VIRAL SHEDDING IN THE FECES FROM 1 UP TO 5 WEEKS POST INOCULATIONS. AND ALSO YOU NOTICE THAT THERE'S A SLIGHT ELEVATION OF LIVER ENZYME, BOTH ICD AND ALT AT ABOUT 4 TO 5 WEEKS POST INOCULATION. DURING THE PIG LIVER ENZYME ELEVATION FOUR TO FIVE WEEKS POST INOCULATION, YOU CAN SEE HERE WE ALSO DETECT LIVER HISTOPATHOLOGY CONSISTENT WITH ACUTE VIRAL HEPATITIS. I SHOULD MENTION HERE THE CHIMPANZEE THAT WE EXPERIMENTALLY INOCULATED ALSO BECAME INFECTED. SO CONVERSELY, WE ALSO ATTEMPT TO EXPERIMENTALLY INFECT SPECIFIC PATHOGEN-FREE PIGS WITH THE HUMAN HEPATITIS C VIE RU THE GENOTYPE 3 AND GENOTYPE 4, SO WE USE THE US2 STRAIN OF GENOTYPE 3 FROM ROCH ESTER, MINNESOTA, WE ALSO USED GENOTYPE 4, TW6196E STRAIN, ISOLATED FROM THE PATIENT IN -- 1. SO YOU CAN SEE FROM THIS STUDY CLEARLY BOTH GENOTYPE 3 AND GENOTYPE 4 HUMAN HEV CAN READILY INFECT PIGS. THEY INOCULATE THE ANIMAL RAPIDLY, ZERO CONVERTED HEV ANTIBODY, AS YOU CAN SEE HERE, THE SERO CONVERSION OCCURRED TWO TO THREE WEEKS POST INOCULATIONS, WE ARE ALSO ABLE TO DETECT -- SO CLEARLY THE SWINE VIRUS INFECTS HUMANS AND THE HUMAN VIRUS INFECTS PIGS. BUT AT THIS POINT, WE STILL DON'T HAVE DIRECT EVIDENCE OF ZOONOTIC INFECTION, SO WE AND OTHERS CONDUCTED STAW STUDIES IN ATTEMPT TO SEEK ADDITIONAL EVIDENCE OF ZOONOTIC INFECTION. IN THIS PARTICULAR STUDY, WE LOOK AT SWINE VETERINARIAN, PIG HANDLERS FROM EIGHT DIFFERENT U.S. STATES. WE ALSO COMPARED THEM WITH AGE AND GEOGRAPHY-MATCHED BLOOD DONORS. SO YOU CAN SEE HERE THE PREVALENCE IN THE HEV ANTIBODY IN THOSE VETERINARIANS FROM EIGHT U.S. STATES IS SIGNIFICANTLY HIGHER COMPARED TO THOSE AGE -- BLOOD DONORS. SIMILARLY ANOTHER STUDY FROM NORTH CAROLINA, THEY LOOK AT SWINE WORKERS BASED ON MOSTLY PIG FARMERS AND WORKING ON THE PIG FARMS. YOU CAN SEE HERE THE HEV ANTIBODY IS SIGNIFICANTLY HIGHER THAN -- THE NON-SWINE WORKERS. YOU PROBABLY NOTICE HERE, I SHOULD POINT OUT, EVEN BEFORE THE NORMAL BLOOD DONOR, YOU PROBABLY NOTICE THE RELATIVELY HIGH SEROPOSITIVITY IN A NORMAL BLOOD DONOR. THIS INDICATES THAT PIG IS NOT THE ONLY ANIMAL RESERVOIR FOR THE HEPATITIS E VIRUS. IN FACT WE KNOW MANY OTHER SPECIES CAN SERVE AS RESERVOIRS, SO PIG IS NOT OT ONLY ONE THAT CAN SER AS SERVE AS A RESERVOIR TO TRANSMATE THE HEPATITIS E VIRUS. SO WHEN WE BREAK IT DOWN INTO DIFFERENT REGIONS INTO DIFFERENT STATES, WHAT WE FOUND WAS HAVE INTERESTING, WE FOUND SUBJECT -- SWINE VETERINARIANS AND ALSO -- FROM MAJOR PIG STATE, THEY ARE MORE LIKELY TO BE INFECTED COMPARED TO THOSE SUBJECTS FROM THE TRADITIONALLY NON-PIG STATE. FOR EXAMPL, IF YOU LOOK AT THIS HERE, SUBJECT FROM THE STATE OF MINNESOTA, WHICH US A KNOW IS A MAJOR, MAJOR SWINE STATE, THEY ARE FIVE TIMES MORE LIKELY TO BE INFECTED BY THE HEPATITIS E VIRUS COMPARED TO THE SUBJECT FROM THE STATE OF ALABAMA, WHICH IS NOT A MAJOR SWINE STATE. SO THIS PROVIDES US A MORE COMMERCIAL EVIDENCE OF ZOONOTIC INFECTION FROM ANIMAL TO THANK HUMAN THROUGH THE DIRECT CONTACT WHICH INFECTED THE PIGS. NOW AS I MENTIONED EARLY YES, THE SWINE HEV INFECTION IN PIG IS WIDESPREAD. THIS IS REALLY RAISING THE CONCERN FOR -- RECENTLY WE LOOKED AT THE STUDY AND LOOKED AT THE PORK SAFETY ISSUE, AND WE FOUND THAT 11% OF THE PORK PRODUCTS SOLD IN THE LOCAL GROCERY STORES IN VIRGINIA IS CONTAMINATED BY THE HEPATITIS E VIRUS. BUT MOST IMPORTANTLY, WHEN WE CHARACTERIZED THOSE VIRUSES, ALL THIS WAS BELONG TO THE GENERAL TYPE 3, NOW THIS IS A ZOONOTIC GENOTYPE THAT CAN'T INFECT HUMANS, SO ALL THIS CONTAMINATED VIRUS IN THOSE PORK PRODUCTS BELONG TO THE ZOONOTIC GENERAL TYPE 3. NOW OF COURSE THE DETECTION OF -- IN THOSE CONTAMINATED PORK PRODUCT DOESN'T MEAN THE VIRUS IS STILL INFECTIOUS. SO WE CONDUCTED SUBSEQUENT STUDY TO SEE IF THIS CONTAMINATED VIRUSES IN THOSE COMMERCIAL PRODUCTS REMAINED INFECTIOUS. SO WHEN WE TESTED THOSE PCR PORK LIVER AND PORK SAUSAGES, AND WE -- INTO PIGS AND YOU CAN SEE HERE, THEY ARE RAPIDLY BECOMING INFECTED, CONVERTED TO HEV ANTIBODY, THEY SHED THE VIRUS IN THE FECES AND THEY BECOME VIE REMIC. SO THIS INDICATES THAT THE CONTAMINATED VIRUSES IN THOSE COMMERCIAL PORK PRODUCT ARE STILL INFECTIOUS, SO THAT'S REALLY RAISING CONCERN ABOUT FOOD SAFETY, SO WE DID A SUBSEQUENT STUDY TO LOOK AT WHETHER OR NOT THE CURRENT COOKING CONDITION PEOPLE USE IN THE HOME AND ALSO THE VAWNT CAN EFFECTIVELY INACTIVATE THE VIRUS. ONE OF THE VERY BRAVE STUDIES CONDUCTED IN THE COOKING -- LAB, SHE SHOWED THAT STIR FRIED, THE CONTAMINANT PRODUCT, THE FIVE MINUTES, OR BOIL THEM FOR FIVE MINUTES, YOU CAN COMPLETELY INACTIVATE THE VIRUS. HOWEVER, IF YOU INCUBATE THOSE CONTAMINANT PORK PRODUCT AND 56 DEGREES FOR ONE HOUR THIS, IS SIMILAR TO THE MEDIUM TO RARE COOKING CONDITION IN A RESTAURANT, SO WE MIMIC THAT MEDIUM THE RARE COOKING CONDITION WHEN WE INCUBATE THE 56 DEGREE FOR ONE HOUR, YOU CAN SEE HERE, WE CANNOT INACTIVATE THE VIRUS. WHEN WE INACTIVATED THOSE BACK INTO LIVE ANIMAL, THEY STILL CAUSED INFECTION. SO THIS MEANS THAT MEDIUM TO RARE COOKING CONDITION IN A RESTAURANT CANNOT INACTIVATE THE HEPATITIS E VIRUS. SO IF YOU GO TO A RESTAURANT TONIGHT AND ORDER THE PORK STEAK AND THERE IS A CHANCE YOU MAY BE GETTING INFECTED BY THIS VIRUS IF THAT PORK IS CONTAMINATED. AND 11% OF THEM ARE CONTAMINATED. SO THIS DEFINITELY IS A PUBLIC HEALTH PROBLEM, AND A CONCERN FOR -- HEPATITIS, AND IN FACT, THERE'S SO MANY CLASSIC CASES OF ACUTE HEPATITIS E HAVE BEEN DEFINITIVE LINK TO THE CONSUMPTION OF YOU UNDERSTANDCOOKED ANIMAL MEAT, PARTICULARLY PORK PRODUCTS. AND I'M GOING TO SHOW YOU ONE OF THESE CLASSIC CASES. IN THIS PARTICULAR CASE, IT IS PORK LIVER SAUSAGE, A VERY POPULAR SMOKED SAUSAGE IN SOUTHERN FRANCE. YOU CAN SEE HERE, THIS PARTICULAR CASE, THREE FAMILIES, THEY GET TOGETHER FOR A PARTY, AND OF COURSE THE FIGATELLU SAUSAGE IS ON THE MENU. 7 FAMILY MEMBERS ATE IT, FIVE DID NOT, HOWEVER, NONE OF THE FIVE WHO DID NOT EAT IT HAD ANY EVIDENCE OF INFECTION. BUT MOST IMPORTANTLY, THE SICKNESS AMPLIFIED FROM THOSE HUMAN PATIENT IS NEARLY IDENTICAL TO THE SICKNESS AMPLIFIED FROM THE LEFTOVER SAUSAGE. THERE ARE 99.6 IDENTICAL, INDICATING THAT THE SOURCE OF INFECTION IS THE SAUSAGE. AS I MENTIONED, THERE ARE MANY, MANY OTHER CASES, CLASSIC CASES OF THE FOOT-BORN HEPATITIS E INFECTION WORLDWIDE. MORE RECENTLY, THE CHRONIC HEPATITIS E NOW IS BELIEVED TO BE ZOONOTIC ORIGIN, AND AS I MENTIONED EARLIER, THIS BECAME A MAJOR CLINICAL PROBLEM, ESPECIALLY IN EUROPE, AN ORGAN TRANSPLANT RECIPIENT, 60 TO 80% OF THOSE AFFECTED WILL EVENTUALLY GO INTO CHRONICITY, SO THAT'S MAJOR PROBLEMS, BUT ONE THING THAT WAS FOUND THAT'S VERY INTERESTING IS THAT ALMOST EXCLUSIVELY THIS CHRONIC HEPATITIS E WAS CAUSED BY THE ZOONOTIC GENOTYPE 3, ONLY ONE CASE WAS CAUSED BY ZOONOTIC GENOTYPE 4, BUT BOTH OF THEM ARE ZOONOTIC GENOTYPE. SO IT IS BELIEVED NOW IN THE HEV COMMUNITY THAT THOSE CHRONIC HEPATITIS E CASES IS ACQUIRED THROUGH THE CONCEPTION OF UNDERCOOKED ANIMAL MEET. ANIMAL ORIGIN. NORMALLY IF YOU'RE A HEALTHY INDIVIDUAL, IF YOU CONSUME UNDERCOOKED ANIMAL MEAT, YOU MAY GET AN INFECTION BY THE HEPATITIS E VIRUS BUT YOUR IMMUNE SYSTEM WILL QUICK LE CLEAR THE VIRUS INFECTION. HOWEVER, IN THOSE OR DPAN TRANSPLANT PATIENTS OR IMMUNE-COMPROMISED INDIVIDUALS, THEY CANNOT EFFECTIVELY CLEAR THE VIRUS INFECTION AND THEREFORE IT CAN LEAD TO PERSISTENCY AND CHRONIC HEPATITIS E INFECTION. THE PROBLEM IS RIGHT NOW THERE'S NO SPECIFIC THERAPY, EVEN THOUGH THE -- HAS BEEN USED WITH SOME SUCCESS TO TREAT CHRONIC HEV INFECTION. SO THE WORKING HYPOTHESIS RIGHT NOW IS THAT THE CHRONIC HEPATITIS E IS THE ZOONOTIC ANIMAL ORIGINS. SO HOPEFULLY THUS FAR, I'VE CONVINCED YOU THAT HEPATITIS E IS A ZOONOTIC DISEASE, THERE ARE ANIMAL RESERVOIR SO THERE'S A CROSS-SPECIES INFECTION. IN THE LAST TWO OR THREE YEARS, WE'VE SPENT A LOT OF TIME TRYING TO DETERMINE SOME OF THE HOST FACTOR AND VIE ROW GENETIC ELEMENT THAT ARE RESPONSIBLE FOR THE CROSS SPECIES INFECTION. SO I'M JUST GOING TO -- IN THE REMAINING TIME GOING TO TALK ABOUT SOME OF THE GENETIC ELEMENT WE BELIEVE ARE IMPORTANT FOR CROSS-SPECIES INFECTION OF THE HEPATITIS E VIRUS F YOU LOOK AT THE GENOMIC HEPATITIS E VIRUS, IT'S VERY SIMPLE GENOME, ORF3, OVERLAP WITH ORF2, VERY SMALL, INVOLVED IN VIRUS REPLICATION. SO THE CAPS -- SUSPICIOUS DETERMINATION BECAUSE THIS IS THE CAPSYD PROTEIN, IT CAN BIND TO THE HOST CELL AND THEREFORE -- SO WE LOOK AT THAT AND ALSO WE FOCUS ON THE HYPERVARIABLE REGION, OPEN READING FROM 1 AND IS EXTREMELY HYPERVARIABLE. I'M GOING TO TELL YOU IN A FEW MINUTES WHY WE BELIEVE THIS PARTICULAR -- IS INVOLVED IN TISSUE CHROMOSOME AND CROSS SPECIES INFECTIONS. NOW, TO STUDY THE MECHANISM OF CROSS SPECIES INFECTION, OF COURSE YOU NEED AN ANIMAL MODEL SYSTEM AND THANKFULLY WAS THE DISCOVERY OF SO MANY ANIMAL STRING OF HABITAT -- WE NOW -- SMALL ANIMAL MO DID EL IS TIS EM. OF COURSE YOU HAVE THIS NOW HUMAN PRIMATE MODEL WHICH HAS BEEN VERY USEFUL IN THE PAST, WE HAVE A VERY NICE PIG MODEL, A RABBIT MODEL AND ALSO VERY NICE SYSTEM. SO BY TAKING ADVANTAGE OF THIS SMALL ANIMAL MODEL SYSTEM, WE WERE ABLE TO DISSECT THE -- CROSS SPECIES INFECTIONS. THE FIRST GENETIC ELEMENT WE'LL LOOK AT IS THE CAPS -- BECAUSE WE BELIEVE THIS PROTEIN BINDS TO THE RECEPTOR ON THE HOST CELL TSH SO WE UTILIZED TWO VERY UNIQUE STRAIN OF THE HEPATITIS C VIRUS, THE GENOTYPE 1 HUMAN HEV WHICH ONLY AFFECTS HUMAN, THE TYPE 3 SWINE HEV WHICH AFFECTS BOTH HUMANS AND PIGS. SO BY UTILIZING THE GENOMIC BACKBONE OF THE INFECTIOUS -- GENOTYPE 1 HEV WHICH INFECTS ONLY HUMAN, WE WERE ABLE TO -- YOU CAN SEE HERE WE SWAP THE GENO -- THE CAPSID FROM THE GENOTYPE 3 AND THE GENOTYPE 4. NOW THESE TWO GENOTYPES ARE ZOONOTIC XENOTYPE, THEY INFECT NOT ONLY HUMAN BUT ALSO PIGS. SO IF THE IDEA IS WE SWAP THE CAPSID GENE, IF IT'S INVOLVED IN PATIENT -- IN SUSPICIOUS DETERMINATION, WE WOULD EXPECT CHIMERIC VIRUSES TO BE ABLE TO INFECT THE PIGS BECAUSE BOTH GENOTYPE 3 AND GENOTYPE 4 AFFECT THE PIGS. HOWEVER TO OUR SURPRISE, WHEN WE PUT THE VIRUS INTO PIGS, THERE'S NO INFECTIVITY, SO THAT'S VERY SURPRISED. EVEN THOUGH YOU CAN SAY HERE THAT THE C HIMERAS -- THEY ARE STILL FULLY INFECTIOUS, SO WE WERE SURPRISED AT THE BEGINNING, WE ACTUALLY REPEATED THE STUDY, IT WAS THE GENO TIME 4 HE VBAC BONE, WE SHOULD HAVE GOT A SIMILAR RESULT. SO THIS SUGGESTS THE CA PSI D GENE IS NOT INVOLVED IN CROSS SPECIES INFECTION. SO THAT LED US TO LOOK AT THE HYPERVARIABLE REGION, WHICH IS NOW STRUCTURED REGIONS, NORMALLY YOU WOULD NOT THINK -- A NONSTRUCTURAL PRO TEEP WOULD INVOLVE -- SO WE LOOK AT THIS PARTICULAR REGION, YOU CAN SEE HERE, THEY ARE EXTREMELY VARIABLE, AND THEY DEFER BY THEY DIFFERED BY 71%, THEY ARE EXTREMELY HYPERVARIABLE, SO THE FIRST QUESTION WE ASKED WAS, DOES THE VIRUS REALLY NEED THIS PARTICULAR REGION FOR INFECTIVITY? BECAUSE THEY ARE SO VARIABLE, WE THOUGHT MAYBE THE VIRUS DID NOT NEED THESE. SO TO DETERMINE IF THIS PARTICULAR READING IS REQUIRED FOR VIRUS INFECTION, THE INFECTIVITY, AGAIN PLAY INTO SOME OF THE ANIMAL MODEL SYSTEM, WE USE THE SWINE HEV AND THE PIG MODEL SYSTEM, WE ALSO USE THE -- MODEL SYSTEM. THE SWINE HEV AND PIG MODEL SYSTEM, WE CREATED FOUR -- MUTANT, THEN WE KNOCKED THOSE FOUR MUTANTS INTO PIGS, THREE OF THOSE FOUR STILL CAUSE INFECTION, THEY'RE SERO CONVERTED TO HIV ANTIBODY, ONE OF THE MUTANTS THAT CONTAINED THE COMPLETE -- IN THE HYPERVARIABLE REGIONS CAUSED SERO CONVERGING IN THE PIG BUT DID NOT HAVE VIREMIA OR FECAL SHEDDING. SO ALSO STILL VIABLE IN INFECTIONS. YOU CAN SEE HERE, ALL SERO CONVERTED TO HEV ANTIBODY. SO CLEARLY WE SHOW HERE THIS PARTICULAR REGION IS DISPENSABLE FOR HEV INFECTIVITIES. BUT AS YOU KNOW, THE VIRUS IS SMART, THEY WILL NOT KEEP SOMETHING IN THEIR GENOME IF THIS READING DOES NOT PLAY -- SO WE WANT TO KNOW WHAT ROLE THIS PARTICULAR REGION PLAYS, IF THEY ARE NOT IMPORTANT FOR INFECTIVITY, THEY MUST PLAY SOME ROLE THAT BENEFITS THE VIRUS REPLICATION. SO WE DECIDE TO LOOK AT THE REPLICATION EFFICIENCY OF THE VIRUS. FOR THAT, WE CREATED -- YOU CAN SEE HERE, WE'LL CREATE THIS, REPLICON SYSTEM, WE REMAIN A HVR DELETIONS, WE ALSO HAVE DELETION IN THE MIDDLE OF THIS PIPER VARIABLE REGIONS. WHEN TESTED, THE EFFECT OF THE DELETION ON VIRUS REPLICATION -- YOU CAN SEE HERE THAT THE DELETIONS SIGNIFICANTLY DECREASED THE VIRUS REPLICATION EFFICIENCY. THE MIDDLE REGION HAS MORE DRASTIC EFFECT ON VIRUS REPLICATION EFFICIENCY. SO EVEN THOUGH THE HYPOVARIABLE REGION IS DISPENSABLE FOR VIRUS INFECTIVITY, THIS PARTICULAR REGION MAY INTERACT WITH HOST OR SELL TO REPLICATE THE -- EFFICIENCY OF THE HEPATITIS E VIRUS. SO AT ABOUT THE TIME WE FINISH UP THIS STUDY, THERE WAS A VERY EXCITING STUDY HERE AT NIH, THEY DISCOVER A NATURALLY OCCURRING RECOME TANT WITH THE INSERTION OF THE -- THE INSERTION OF RIBOSOME PRO TEAM S17 -- S19 IN THE SAME WRAITING, YOU CAN SEE HERE S17, S19, THEY INSERTED INTO THESE HYPERVARIABLE REGIONS, BUT -- INTO THE BACKBONE OF THE GENOTYPE 1 HUMAN HEV, AS YOU RECALL, THE GENOTYPE 1 INFECT ONLY HUMANS, SO WHEN SHE -- YOU -- IN TO THE GENOTYPE GENOTYPE -- HAS EXPANDING THE HOST RANGE, IT CANNOT INFECT SELL LINE, SUCH AS CATTLE, DEER, HAMSTER, FIGURE, AND A CHICKEN, YOU CAN SEE HERE WITH THIS SLIDE, SHE SHOWED THAT THIS RECOMBINANT VIRUS CAN NOW EFFECT CELL LIVES FROM PIGS AND DEER. SO WE DECIDED TO DO SOME FOLLOW-UP STUDY TO SAY WHY THIS THIS -- SO ONE THING WE LOOK AT FIRST IS SO SAY THERE'S ANY SIMILARITY BETWEEN S17, S19 SEQUENCES, THE S19 WAS MORE PRPL CHARACTERIZED AT THE TIME, BUT WE SPEND A LOT OF TIME CHARACTERIZING -- THE ONE THING WE FOUND WAS THAT WE FOUND THAT THE S17 ACTUALLY HAS A LOCALIZATION SIGNAL, AND WE FURTHER CHARACTERIZE AND CONFIRM THIS INDEED -- SIGNALS, SO WE THOUGHT MAYBE THIS NUCLEAR -- SIGNAL MAY BE RESPONSIBLE SOMEHOW FOR THE ENHANCED -- REPLICATION AND THE -- EXPANDING THE HOST RANGE, SO WE CONDUCTED A LOT OF STUDY, AND TO MAKE THE LONG STORY SHORT, WHAT WE FOUND WAS THAT ACTUALLY THE INSERTION OF ROBINSON PROTEIN BESTOWED TRACKING CAPABILITY FROM ONE PROTEIN OF THE VIRUS, YOU CAN SEE HERE, THIS IS THE P6 -- THIS PARTICULAR VIRUS CONTAINED THIS INSERTED S17. CAN YOU SEE HERE THE P6 VIRUS, THE ORF-1 IS EXPRESSED IN THE NUCLEUS, WHEREAS THE P1 VIRUSES TO NOT HAVE THE S17 INSTRUCTION, THEY ARE EXPRESSED, IF YOU LOOK AT JUST THE HIECIAL VARIABLE REGION THAT HAS THIS S17 INSERTION, AND YOU CAN SEE THEY ARE EXPRESSED IN THE NUCLEUS, WHERES P1 VIRUS HYPER -- REGION WITHOUT INSERTION THEY ARE EXPRESSED PREDOMINANTLY IN THE CYTOPLASMIC. SO THIS IS VERY EXCITING FOR U WE THOUGHT OKAY, MAYBE THIS NOVEL -- CAPABILITY IS RESPONSIBLE FOR THE EXPANDING THE HEALTH RANGE -- REPLICATIONS. SO WE DID SEVERAL FOLLOW-UP STUDIES, AND I'M JUST GOING TO SHOW YOU ONE SLIDE AND IN THIS PARTICULAR SLIDE, YOU CAN SEE HERE, WE MUTATE -- IN INSERTED S17 SEQUENCES, SINGLE MEU TAN, DOUBLE MUTANT, DOUBLE MUTATIONS, AND WHAT WE FOUND WAS THAT WAS THAT IF YOU OMIT ONE OR TWO -- THERE'S NO EFFECT ON THE NUCLEAR LOCALIZATION OF THE HEPATITIS C VIRUS OF ONE PROTEIN. HOWEVER, IF YOU MUTATE MORE THAN TWO, AND THEY CHANGE THE FROM LOCALIZATION BACK TO THE CYTOPLASM. BUT REGARDLESS THE NUCLEAR CYTOPLASM OR LOCALIZATIONINGS, WHAT WE FOUND WAS ALL THIS MUTANT, THEY HAVE DRASTICALLY REDUCED -- ALL THIS MUTATION, SOME OF THE SINK EL MUTANT, WE HAVE DRASTIC -- OF OUR REPLICATIONS BOTH IN -- ALSO IN INFECTION -- SO THIS SUGGESTED TO US THAT IT IS THE LASTING RESIDUE, WE'RE SIGHING -- REPLICATION. SO CURRENTLY WE ARE CONDUCTING ANIMAL STUDY TO SEE IF ANY OF THIS MUTANT, EXPANDING THE HEALTH RANGE IN DIFFERENT ANIMAL SPECIES. SO TO SUMMARIZE, HOPEFULLY I HAVE CONVINCED YOU HEPATITIS E IS A ZOONOTIC DISEASE, THERE EXISTS MULTIPLE ANIMAL RESERVOIR, WE TALKED ABOUT ACTUALLY ONLY ONE OF THESE VOYEURS, THE PIGS, BUT GENOTYPE NUMBER OF SPECIES. THE DEER, THE MONGOOSE, THE RABBIT AND THEY ALL ARE KNOWN TO BE ABLE TO INFECT HUMANS. IF YOU LOOK AT THIS SLIDE, THEY WILL SAY THERE ARE NUMEROUS OTHER ANIMAL STRAINS OF HEPATITIS E HAS BEEN GENETICALLY IDENTIFIED, HOWEVER, THEIR BIOLOGY AND PATHOGENICITY IS STILL UNKNOWN. SO CLEARLY THERE'S A LOT OF WORK THAT NEEDS TO BE DONE IN ORDER TO FULLY UNDERSTAND THE ECOLOGY AND THE NATURAL HISTORY OF THIS VERY IMPORTANT HUMAN DISEASE. SO I'M GOING TO STOP HERE BY ACKNOWLEDGING THOSE IN THE LAP WHO ACTUALLY DID THE WORK. THEY DID THE WORK I PRESENTED HERE TODAY, AND I HAVE TO THANK MY COLLABORATOR, THEY'RE ON A FLIGHT SOMEWHERE IN EAST ASIA, AND THEY'VE BEEN A TREMENDOUS HELP OVER THE YEARS. TANYA FROM IOWA STATE, THEY HELPED OUT WITH SOME OF THE PROJECT. DR. SHIVAPRASAD AND DR. WOOLCOCK FROM UC DAISTLES. WE ALSO RECEIVE FUNDING FROM THE NIH, THE USDA AND THE NATIONAL PORK BOARD. THANK YOU AGAIN FOR THE INVITATION. I WOULD BE HAPPY TO ANSWER ANY QUESTIONS YOU MAY HAVE. THANK YOU. [APPLAUSE] >> X.J., THANKS FOR TAKING US THROUGH THIS FASCINATING JOURNEY. I WAS INTRIGUE BID YOUR WORK ON THE CROSS SPECIES TROPISM OF THE VIRUS, SEEMS LIKE IT'S REALLY RESIDING ON A NON-STRUCTURED PROTEIN, ORF-1, RATHER DIFFERENT FROM OTHER HEPATITIS VIRUS LIKE B AND C, WHICH THE TROPIS RESIDES AT THE ENTRY STEP OR THE STRUCTURAL PROTEIN. SO JUST WANT TO KIND OF MAYBE EXPLORE THOSE FURTHER. SO THE STRUCTURE PROTEIN FOR HEPATITIS E VIRUS IS ORF-2, RIGHT? THAT SORT OF THE GENERALLY RECOGNIZED IN ALL SPECIES THAT CAN GET IN? DO WE KNOW WHAT THE RECEPTORS FOR THE HEPATITIS E VIRUS IS AND DOES THAT EXPLAIN SORT OF THE SPECIES PROAPISMS? TROPISMS? >> THAT'S A GREAT QUESTION, JAKE. FIRST AS FOR THE RECEPTOR, THERE'S NO SPECIFIC RECEPTOR THAT HAS BEEN IDENTIFIED FOR THE HEV. THERE HAS BEEN -- AS WE ALL KNOW, BUT NO SPECIFIC RECEPTOR HAS BEEN IDENTIFIED SO FAR. NOW, IN TERMS OF WHY KIND OF A VERY STRANGE -- YOU WOULD EXPECT THE STRUCTURE PROTEIN WHICH BINDS THE RECEPTOR, THE RESULT WE FOUND THAT THE NONSTRUCTURAL PROTEIN IS EVOLVING -- IT'S KIND OF REALLY SURPRISING TO US ALSO. MY THINKING IS THAT MAYBE THIS HYPERVARIABLE REGION, THEY MAYBE INTERACT WITH SOME OF THE HOST FACTOR. I THINK THERE'S A HOST FACTOR SOMEWHERE THERE THAT TO BE DETERMINED, THAT PLAY A ROLE IN DETERMINING THE HEALTH STRAIN. IT MAY NOT BE THE VIRUS, BUT IT'S A HEALTH FACTOR. WE NEED TO LOOK AT THE HOST FACTOR THAT -- SPECIES DETERMINATION. WE DID A STUDY, WHEN WE SWAP THE HYPERVARIABLE REGION BETWEEN DIFFERENT GENOTYPE, BETWEEN THE PIG VIRUS AND THE HUMAN VIRUS, WE CAN GET A VIABLE VIRUS, BUT WE SEE VERY DIFFERENT LEVEL OF REPLICATION. SO THAT'S INDICATION TO ME THAT MAYBE THE HOST FACTOR IS INVOLVED IN TISSUE TROPISM. >> DOES THAT ALSO EXPLAIN HEPATOTROPISM OF THE VIRUS? >> THAT COULD BE, DEFINITELY. THAT'S ANOTHER QUESTION, BUT I WE KNOW THE VIRUS -- REPLICATED THERE, BUT I WAS TALKING TO PATRICIA EARLIER TODAY, WE BELIEVE ACTUALLY -- WHEN WE LOOK AT THIS HEPATIC DAMAGE, IT ALWAYS, AT THE TIME OF PEAK SERO CONVERGENCE, SO WE HAVE A WORKING HYPOTHESIS THAT WE BELIEVE ACTUALLY THE LIVER DAMAGE IS NOT CAUSED BY THE VIRUS REPLICATION IN THE CELL, WE BELIEVE IT WAS CAUSED BY -- SEE IF WE CAN PROVE THAT. >> THANK YOU VERY MUCH TO UPDATE WHAT'S GOING ON WITH HEPATITIS E. DOES THE USDA HAVE A SPECIAL PROGRAM NOW TO SCREEN ALL THOSE FOOD, YOU KNOW, THE MEAT FROM THE GROCERY STORE IN ORDER TO PREVENT THIS KIND OF TRANSMISSION FROM MEALS? >> THAT'S A GREAT QUESTION. YOU KNOW, I HAVE BEEN TALKING TO THE NATIONAL PORK BOARD FOR I DON'T KNOW HOW MANY YEARS BECAUSE IF YOU -- WE TELL THEM, WE CAN DEVELOP VACCINE AND VACCINATE THOSE PIGS, IF YOU CAN VACCINATE THOSE PIGS, THEN YOU DON'T HAVE TO WORRY ABOUT FOOD SAFETY AND PORK SAFETY. BUT THE PROBLEM RIGHT NOW IS THAT THE DISEASE IN PIGS -- THE INFECTION IN PIG DOES NOT CAUSE DISEASE. SO YOU HAVE 80% INFECTION IN FOAS THOSE PIGS BUT THERE'S NO CLINICAL DISEASE. SO IT'S SO DIFFICULT TO CONVINCE THOSE FARMERS TO BUY YOUR VACCINE. YOU HAVE A FANTASTIC VACCINE, THEY'RE NOT GOING TO BUY IT, THEY'RE NOT GOING TO INVEST IN THE ANIMALS. THAT'S THE PROBLEM RIGHT NOW. IT WILL BE NICE IF YOU CAN VAX NAIS THOUGHT ANIMALS, THEREFORE YOU DON'T HAVE TO WORRY ABOUT THE PORK SAFETY. BUT IT'S DIFFICULT TO CONVINCE THE USDA AND THOSE PIG PRODUCERS TO BUY THE VACCINE, THE VIRUS DOES NOT CAUSE ANY DISEASE. SO THAT'S THE ISSUE RIGHT NOW. >> OKAY. ANOTHER QUESTION REGARDING THE VIRUS ITSELF. I KNOW YOU'RE -- HAVE YOU EVER TRIED TO DELETE THE -- UTR IN THOSE -- VIRUS CONTRIBUTE TO THE PATHOGENESIS, THE ENTEROVIRUS AND THE FLAVOVIRUS? >> ACTUALLY WE DID, AS A MATTER OF FACT, WE DID IT ABOUT SIX YEARS AGO, BECAUSE THAT'S A VERY SHORT -- IT RESULT IN DEAD VIRUS ACTUALLY. WE COULD NOT RECOVER LIVE VIRUS. >> JAY HOOF, WONDERFUL TALK, FASCINATING VIRUS, IT HAS SO MANY MYSTERIES TO T1 OF THE MYSTERIES IS WHY ANTIBODY TO THIS VIRUS IS SO COMMON IN AMERICA AND THE DISEASE IS SO RARE. AND I GUESS ONE EXPLANATION IS THIS IS A PIG VIRUS AND IT DOESN'T INFECT HUMANS VERY WELL, THEY DON'T GET VERY SICK WITH IT. >> THAT'S ONE OF THE QUESTIONS, AGAIN I DON'T KNOW HOW MANY TIMES WE ASKED THAT QUESTION. MY PERSONAL BELIEF IS THAT MANY OF THOSE SEROPOSITIVITY PROBABLY BECAUSE OF THE CONSUMPTION OF ANIMAL PRODUCTS. THAT'S MY BELIEF. FOR EXAMPLE, WE KNOW THERE'S ONLY ONE SEROKINE, WE KNOW ALSO THE CHICKEN EGGS CONTAIN AVIAN HEPATITIS E VIRUS, AND THAT VIRUS ACTUALLY -- RELATED TO THE HUMAN HEPATITIS E VIRUS, SO IF YOU CONSUME AG REPEATEDLY, YOU'RE GOING TO HAVE SOME LEVEL OF ZEROACTIVITY, SO AT LEAST THAT'S MY PERSONAL BELIEF. OF COURSE THE OTHER EXPLANATION WOULD BE THOSE SUBCLINICAL INFECTION THROUGH CONTACT WITH INFECTED ANIMALS. >> NOW THE OTHER QUESTION IS WHETHER THIS IS FOOD-BORNE OR WATER-BORNE. THERE'S THIS NICE STUDY FROM FRANCE WHERE THEY DID EPIDEMIOLOGICAL SURVEY THAT SUGGESTED THAT THE ANTIBODY WAS ASSOCIATED WITH WELL WATER USE AS OPPOSED TO CITY WATER OR BOTTLED WATER. >> CERTAINLY, THE WATER -- IF YOU LOOK AT ESPECIALLY THOSE EXPLOSIVE -- THEY ARE ALL LINKED TO THE CONTAMINATED SEWAGE, THE SEWAGE OR CONTAMINATED WATERS, MOSTLY INDIA AND THOSE CASES, SO THERE IT'S BEEN WELL DOCUMENTED. ALSO, CONTAMINATED WATER CAN SUBSEQUENTLY CONTAMINATE FOOD. IF YOU USE CONTAMINATED WATER TO WASH PRODUCE, THEN YOU CAN CONTAMINATE THE FOOD. THERE ARE CASES ACTUALLY DOCUMENTED CASES OF STRAWBERRY AND LETTUCE AND THERE'S ONE -- BELIEVED TO BE CAUSED BY THE CONTAMINATED STRAWBERRY. SO WATER DEFINITELY IS THE SOURCE, THE RECOGNIZED SOURCE OF TRANSMISSION, BUT FOOD, OF COURSE, IS ALSO ANOTHER ONE. >> SO THIS MEANS THE QUESTION IS, IS THIS A BLOOD-BORNE DISEASE, IS THIS A FOOD-BORNE DISEASE OR IS THIS LIKE A PUBLIC HEALTH WATER-BORNE DISEASE? >> I WOULD SAY THIS IS WATER-BORNE. >> IT REALLY MEANS VERY MUCH DIFFERENT WAYS OF PREVENTION, DOESN'T IT? >> I DOES. I WOULD SAY IT'S A WATER-BORNE DISEASE PRIMARILY BUT ALSO CAN BE TRANSMITTED THROUGH CONTAMINATED FOOD. IF YOU LOOK FROM THE EPIDEMIOLOGIC POINT OF VIEW, ALL THOSE EXPLOSIVE -- THEY ALWAYS -- CONTAMINATED WATER, OR WATER SUPPLY. SO THE FOOD-BORNE IS MOSTLY SPORADIC CASES. SO I WOULD SAY IT'S A WATER-BORNE DISEASE BUT DEFINITELY FOOD CAN TRANSMIT BUT BLOOD-BORNE ALSO, AS YOU KNOW, THERE ARE QUITE A FEW REPORTED BLOOD-BORN TRANSMISSION OF THE HEPATITIS C VIRUS, MAINLY IN JAPAN, BUT THOSE COMPARED TO -- >> SO HEPATITIS E IN THE UNITED STATES, IT'S REALLY QUITE A MILD DISEASE, UNLESS YOU HAVE A PRE-EXISTING LIVER DISEASE. IF YOU HAVE CIRRHOSIS, THIS CAN BE FATAL. SO THE MAJORITY OF THE SEVERE CASES IN THE UNITED STATES ARE OCCURRING IN PEOPLE WITH PRE-EXISTING LIVER DISEASE. I THINK THIS GOES WITH THE IDEA IT'S REALLY A PIG VIE RU IT'S NOT A HUMAN VIRUS. >> THAT IS ABSOLUTELY TRUE FOR THE HEPATITIS E VIRUS. THE VAST MAJORITY OF KIDNEY INFECTION, THEY HAVE SELF-LIMITING DISEASE. PEOPLE RECOVER, THEY HAVE NO RECOLLECTION. THE STUDY WAS THE PIG VETERINARIANS, WE HAVE, I THINK, MORE THAN 300 VETERINARIANS THAT SAMPLE THEM, DRAW THE BLOOD. I REMEMBER WHEN WE DRAW THE BLOOD, WE WILL TELL THEM THE RESULT AND REMEMBER I CALL EACH ONE OF THEM AND TELL THEM, WELL, YOU ARE POSITIVE FOR THE HEPATITIS C VIRUS ANTIBODY, OTHER END OF THE PHONE, WHAT I'M GOING TO DO? I SAY YOU DO NOTHING, THEY HAVE NO RECOLLECTION OF ANY DISEASE. SO THE VAST MAJORITY OF THOSE ARE SUBCLINICAL, ONLY AS YOU MENTIONED THOSE HAVE A PRE-EXISTING CONDITION, MOSTLY IMMUNE-COMPROMISED CONDITION,& THEY BECOME SEVERELY, YOU KNOW, HAVE SEVERE CLINICAL MANIFESTATION. >> AGAIN, THANK YOU VERY MUCH FOR COMING AND THAT WONDERFUL PRESENTATION. >> THANK YOU. [APPLAUSE] >> I HAVE A QUESTION REGARDING THE HYPER TROPISM OF THE VIRUS. IN ONE SLIDE, YOU SHOW HEV CAN ALSO INFECT -- 21 -- KIDNEY -- SO DOES THIS SUGGEST THAT PROBABLY HEV INFECTION DOES NOT REQUIRE ANY LIVER-SPECIFIC HOST FACTORS? >> A GREAT QUESTION. THAT PARTICULAR STRAIN, THOUGH, IS THE P6 STRAIN, THAT'S THE ONE DISCOVERED BY C.ERMESON, THAT CONTAINED THE INSERTION OF THE S17. IT HAS EXPAND PPEDED HOST RANGE, SO VARIETY OF CELL LINE. FOR THAT PARTICULAR STRAIN. THE VAST MAJORITY OF STRAIN, WE CAN ONLY INFECT THOSE HALF THE SIZE AND THEY ARE GROSSLY INEFFICIENT. WE CAN ONLY GROW THE VIRUS PROBABLY -- IT'S VERY DIFFICULT TO GROW THESE VIRUS. >> THANK YOU. >> THANK YOU VERY MUCH. [APPLAUSE] >> WE DO HAVE A RECEPTION OUTSIDE OF THE LOBBY, YOU'RE WELCOME TO JOIN WITH US FOR THE RECEPTION, IF YOU WANT TO MEET WITH HIM, NOW IS THE TIME FOR YOU TO TALK WITH HIM, OUR SPEAKER. THANK YOU VERY MUCH.