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Dr. Robert C. Gallo Institute of Human Virology University of Maryland School of Medicine Baltimore, MD July 22, 2012

HIV/AIDS Research: The Practical Accomplishments and the Needs for the Future. Presented at: HIV Prevention, Care and Treatment in the National Capital Region (DC Metropolitan Area): Moving into the Fourth Decade of the Epidemic . Dr. Robert C. Gallo Institute of Human Virology

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Dr. Robert C. Gallo Institute of Human Virology University of Maryland School of Medicine Baltimore, MD July 22, 2012

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  1. HIV/AIDS Research: The Practical Accomplishments and the Needs for the Future Presented at: HIV Prevention, Care and Treatment in the National Capital Region (DC Metropolitan Area): Moving into the Fourth Decade of the Epidemic Dr.Robert C. Gallo Institute of Human Virology University of Maryland School of Medicine Baltimore, MD July 22, 2012

  2. Major Practical Advances from the SCIENCEof HIV/AIDS Research Showing HIV is the Cause of AIDS early ’84 2) Developing the Blood Test- early ’84 3) Anti-HIV Therapy-1986 first with AZT and 1994-96 combination of drugs—it is 1984-86 that therapy “breakthroughs” occurred not ‘96-97 as has become popularized.

  3. FINDING THE VIRUS WAS ONE THING; SHOWING CAUSATION WAS ANOTHER. AIDS PRESENTED UNIQUE CHALLENGES UNLIKE PAST VIRAL EPIDEMIC OR THE RECENT SARS OUTBREAK: • Clinical latency of 5-15 years • Multiple other microbial infections (which one was causative?)

  4. FREQUENT DETECTION OR ISOLATION OF VIRUS (A TOTAL OF 48 ISOLATES FROM 48 DIFFERENT PATIENTS IN OUR FIRST REPORT IN 1984 AND 105 ISOLATES IN OUR EARLY 1985 REPORT as well as some ADDITIONAL ISOLATES FROM PARIS WERE STILL NONETHELESS PROBABLY INSUFFICIENT TO CONCLUDE THAT …

  5. ….HIV WAS THE CAUSE OF AIDS BECAUSE VERIFICATION IS NECESSARY, AND VERIFICATION WOULD BE DIFFICULT SINCE: Tissue specimens were limited and not allowed in some institutions. T cell culture technology was not widely available in virology labs at this time. A patient with AIDS has few CD4+ T cells remaining in the blood, and these are the cells needed for virus isolation. The consequence was that very few groups would soon be involved.

  6. FALL OF 1983- A KEY ADVANCE Capacity for continuous cell line culture of 6 of our 48 isolates of HIV made several things possible: e.g., blood test, drug screening, detailed molecular analysis of HIV genes and proteins, etc. A focus now on blood test.

  7. THE BLOOD TEST WAS ESSENTIAL NOT ONLY FOR MAKING THE BLOOD SUPPLY SAFE, AND FOR ALLOWING THE EPIDEMIC TO BE APPROPRIATELY FOLLOWED FOR THE FIRST TIME, BUT ALSO FOR VERIFYING ETIOLOGY BECAUSE:

  8. The blood test is safe to work with • “ “ “ “ simple • “ “ “ “ sensitive • “ “ “ “ accurate • “ “ “ “ inexpensive • “ “ “ “ rapid Thus, verification was almost instant; it enabled surveys of thousands of sera samples globally

  9. Blood Test Today • Simpler versions are available • Versions which measure plasma HIV RNA—therefore can be + some weeks earlier before antibodies appear • Need for greater use for more frequent and wider testing for prevention, education and therapy

  10. Needed most for the future: Continued development of new approaches to therapy - ?? CURE (Unlikely) Delivery of drugs and training for underdeveloped countries: PEPFAR a success story but needs to grow-- and what about the USA? What about DC? Prevention of infection: Education, microbicides, test and treat, and an effective vaccine

  11. Needs in the U.S.-Earlier, frequent, much more widespread testing, and therapy -This should be enabled by a US PEPFAR, focused on cities and towns with great HIV problems, rivaling those of sub-Saharan Africa: the argument includes but is not limited to DC

  12. The Arguments for a US PEPFAR:1) It is needed and the “spin-offs” will be considerable and relevant to biodefense2) Cost—may not need new money3) Relations with Current countries helped by PEPFAR—Fraternal instead of Paternal

  13. Achievements to Date (FY 11) ● 3.9 Million on treatment (400K by IHV team) ● 40 Million tested in 2011 ● 13 Million care and support ● 200K infants born HIV free

  14. Progress in DC --Has been considerable over past few years --But serious problems remain and need for PEPFAR for DC seems evident --DC health leaders and President’s call for an HIV/AIDS patient centered home is great, and in Baltimore at our Institute of Human Virology (IHV) we have seen it work in Dr. Bob Redfield’s Jacques initiative clinic, Derek Spencer.

  15. THE DIFFICULTIES IN DEVELOPING A SUCCESSFUL HIV PREVENTIVE VACCINE

  16. Attachment and Entry Fusion and entry core gp120 Unmasking of fusion domains gp41 lipid bilayer Uncoating Virus binds to receptor Cell membrane CCR5 or CXCR4 Nucleus CD4

  17. Reverse Transcription and Integration RNA DNA cytoplasm Nuclear transport nucleus Integration Host DNA Reverse transcription integratedprovirus Host DNA

  18. Our Thinking at the Beginning: Sterilizing immunity or close to it will be necessary for a successful HIV vaccine To achieve or come close to sterilizing immunity requires blocking HIV infection at the onset or killing newly infected cells. Both will very likely require antibodies (Abs). The Abs must at least in part target the envelope (gp120 or gp41) Since Env is hyper-variable, the standard gp120 will be ineffective or minimally effective, so…. We selected an Env region which is conserved, functionally needed by HIV, and immunogenic.

  19. OurApproach The gp120 region chosen is the region that interacts with CCR5—but only after gp120 binds to CD4. But this site is only minimally exposed and also covered by a carbohydrate “shield”. Additionally, the Env molecule is flexible and mobile. These characteristics make this a difficult site for antibodies to find. However, linking the gp120 to the binding region of CD4 “fixes” gp120 and opens the CCR5 binding site.

  20. HIV Binding and Fusion

  21. HIV Binding and Fusion and Illustration of IHV Candidate Vaccine Vaccine is gp120 bound to D1D2 of CD4 gp120 with newly exposed epitopes CD4 D1D2 change gp120 conformation

  22. Our Results to Date and Immediate Plans

  23. LOOKING BACK: WERE WE PREPARED? YES and NO Yes, technologically…but No, in attitudes, awareness, and the availability of responsible and qualified basic medical virologists. So what is happening now? Increased awareness and funding of global health needs—now many surveillance groups. It seems to me that there are now many lion finders but insufficient lion tamers.

  24. It Seems that Humans Have Only a 25 to 30 Year Memory Span Think of the great flu (influenza) epidemic of 1918-1919. Polio of the early 1950s. HIV of 1981---

  25. DISCOVERING VIRUSESOUR “OLD” APPROACH:KNOW THE DISEASE, HAVE AN IDEA THAT IT MAY BE CAUSED BY A VIRUS, MAKE THE BEST GUESS AS TO THE VIRUS TYPE, SELECT THE CELLS YOU BELIEVE TO BE THE LOGICAL TARGETS, LEARN HOW TO CULTURE THOSE CELLS, AND FIND SENSITIVE AND SPECIFIC TOOLS FOR DETECTION. HTLV-1, HTLV-2, HIV, AND HHV-6 ARE EXAMPLES*NOTE THAT FINDING A VIRUS IS DIFFERENT FROM SHOWING IT IS A CAUSE OF A DISEASE..

  26. We now have technology FROM MOLECULAR BIOLOGY-GENOMICS for much better potential for virus discoveries, and to detect new epidemics in early stages. NEW APPROACH

  27. The Limitations of Genomics in Virology Although genomics can and does enormously benefit medical virology it has limitations and cannot replace med. virology: 1) The great number of virus types 2) The many false leads which will come from contaminations as well as irrelevant passenger viruses 3) The technologies and thinking to show causation completely differs from that of finding viral sequences. CONSIDER THE XMRV FIASCO

  28. Lessons from HIV and Earlier Virus Epidemics There were (are) many , but for purposes of this report I emphasize : The need for responsiblemed.-virologists with expertise and in total can cover all types of human virus threats

  29. BUT EXPERT MEDICAL VIROLOGISTS ARE DECLINING IN NUMBER BECAUSE OF: DECREASE IN MEDICAL SCHOOL GRADUATES GOING INTO SCIENCE. PERHAPS, ALSO BECAUSE OF THE GREAT EXPANSION (JUSTIFIABLY) IN GENOMICS. THOUGH GENOMICS TECHNOLOGY IS VERY HELPFUL TO VIROLOGISTS, IT MAY DECREASE THE NUMBERS OF YOUNG PEOPLE GOING INTO MEDICAL VIROLOGY. WHAT TO DO ABOUT THIS ANDABOUTOVERALLPREPAREDNESS?

  30. To Address these needs--WE HAVE CREATED THE GLOBAL VIRUS NETWORK (GVN): CREATING GLOBAL-LINKED CENTERS OF EXCELENCE IN VIROLOGY THAT PLAN TO INCLUDE ALL “CLASSES” OF VIRUSES, AND WILL GO BEYOND GENOMICS/INFORMATICS AND EPIDEMIOLOGY. THE FUNCTIONS WILL BE:--REACTIVE (RESPONDING TO VIRUS THREATS OR THE NEEDS OF HEALTH OFFICIALS) BY CONSULTING AND/OR BY RESEARCH. INTERACTIVE--(TO TRAIN NEW VIROLOGISTS), AND PROACTIVE-- (TO HELP ELUCIDATEPOSSIBLE ROLESFOR VIRUSES IN SELECT DISEASES OF UNKNOWN ORIGIN). NOTE---GVN IS INDEPENDENT AND NOT UNDER THE INFLUENCE OF ANY GOVERNMENT

  31. Global Virus Network (GVN) Expertise in the 22 medically-important virus families-32 Countries/28 Centers The International Committee on Taxonomy of Viruses (ICTV) Virosphere

  32. Role of the Global Virus Network Respiratory Threat Blood-borne Threat Food/Water-borne Threat Insect-borne Threat Detection of Threat (Surveillance) WHO, CDC, National Public Health Agencies Characterization of Threat (Epidemiology) WHO, CDC, National Public Health Agencies Expert Consultation Discovery of Cause Training Medical Virologists Global Virus Network Discovery & Testing of Diagnostics, Treatments, Vaccines

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