HIV / AIDS Update: Prevention, Treatment and Beyond

HIV / AIDS Update: Prevention, Treatment and Beyond

Friday, May 11, 2012

The New York Academy of Sciences

Presented By

 

This one-day symposium will cover a broad spectrum of the latest developments in the prevention of HIV transmission and towards finding a cure for AIDS.

Vaccines will take the center stage with talks focusing on the design of improved immunogens, which build on the results of the latest clinical trials and new information on the structure of the viral envelope protein. The symposium will also contrast the roles of neutralizing and non-neutralizing antibodies in protection against HIV, as well as the strengths, weaknesses and challenges of non-human primate models for studying vaccine efficacy.

Updates on the search for a cure for AIDS will cover the establishment of viral reservoirs during early infection and the improved humanized mice models, revealing new information on viral persistence in hidden reservoirs despite effective therapy. The symposium will have an extenstive discussion of the role of antibodies in HIV infection in the light of new data from human and NHP trials.

Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

Registration Pricing

Member$30
Student / Postdoc / Fellow Member$15
Nonmember Academia$60
Nonmember Corporate$80
Nonmember Not for Profit$60
Student / Postdoc / Fellow Nonmember$40

Agenda

* Presentation times are subject to change.


Friday, May 11, 2012

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Jennifer Henry, PhD, The New York Academy of Sciences
Bill Snow, Global HIV Vaccine Enterprise

Session I. Antibodies and Correlates

9:15 AM

Update on the Thai Correlates and Next Steps for HIV Vaccine Development
Nelson L. Michael, MD, PhD, Walter Reed Army Institute of Research

9:45 AM

Analysis of the V2 Antibody Response Induced in Vaccinees Participating in the ALVAC/AIDSVAX HIV-1 Clinical Vaccine Trial
Susan Zolla-Pazner, PhD, NYU Langone School of Medicine

10:15 AM

V2, V3 and building on RV144 results
Tim Cardozo, MD, PhD, NYU School of Medicine

10:45 AM

Non-Neutralizing Antibodies and Lentiviral Infections
Donald Forthal, MD, University of California, Irvine

11:15 AM

Coffee Break

Session II. Vaccines and Non-Human Primate Models

11:45 AM

Lessons Learned from Recapitulating the Results of the Step Trial in NHP
Christopher J. Miller, DVM, PhD, University of California, Davis

12:15 PM

SHIVs and Shibboleths
Alan M. Schultz, PhD, NIAID, NIH

12:45 PM

Correlates of Protection Against SIV Infection in Rhesus Monkeys
Dan H. Barouch, MD, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School

1:15 PM

Lunch Break

Session III. Purging the Reservoir and Finding a Cure

2:15 PM

Humanized Mouse models of HIV infection
J. Victor Garcia-Martinez, PhD, University of North Carolina, Chapel Hill

2:45 PM

The Establishment of HIV Reservoirs During Acute Infection
Nicolas Chomont, PhD, Vaccine & Gene Therapy Institute of Florida

3:15 PM

Coffee Break

Session IV. The Great Antibody Debate (moderated by Dan Barouch)

3:45 PM

Broadly-neutralizing vs non-neutralizing antibodies: Which one will realistically provide protection?
     Neutralizing Antibody Team: Tim Cardozo and Nelson Michael
     Non-Neutralizing Antibody Team: Don Forthal and Alan Schultz

4:25 PM

Closing Remarks

4:30 PM

Networking reception

5:30 PM

Close

Speakers

Organizers

Jerome Kim, MD

Walter Reed Army Institute of Research

Jerome H. Kim, MD is the Principal Deputy and the Chief, Laboratory of Molecular Virology and Pathogenesis, U.S. Military HIV Research Program (MHRP), Walter Reed Army Institute of Research (WRAIR) in Silver Spring, MD. He also serves as the HIV Vaccines Project Manager for the US Army Medical Materiel Development Activity. Dr. Kim, a Colonel in the United States Army Medical Corps, was the Army’s product manager for the Prime Boost HIV Vaccine Trial (RV144) while serving as the Chief of the Department of Retrovirology, U.S. Army Medical Component at the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. The RV144 trial provided the first demonstration that a preventive HIV vaccine was possible. Dr. Kim’s research interests include HIV molecular epidemiology, host genetics, and HIV vaccine development. He graduated from Yale University School of Medicine in 1984 and completed his training in Internal Medicine (1987) and fellowship in Infectious Diseases (1989) at Duke University Medical Center. Additional information on COL Kim and the US Military HIV Research Program is available at www.hivresearch.org.

Yegor Voronin, PhD

Global HIV Vaccine Enterprise

Yegor Voronin is Science Officer at the Global HIV Vaccine Enterprise (Enterprise). In this role, he is responsible for the implementation of the vision of the Enterprise through identification, development, and management of Scientific Strategic Plan- related initiatives and activities. Prior to joining the Enterprise, Dr. Voronin did his postdoctoral training with Dr. Michael Emerman and Dr. Julie Overbaugh at the Fred Hutchinson Cancer Research Center (FHCRC). For over ten years he has studied HIV and other retroviruses on a variety of different levels, from their potential use as gene therapy vectors at the West Virginia University, to molecular mechanisms of reverse transcription at the National Cancer Institute, to viral population genetics and evolution at the FHCRC. Dr. Voronin holds a master’s degree in molecular biology from Novosibirsk State University in Russia and Ph.D. in biochemistry from West Virginia University.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Dan H. Barouch, MD, PhD

Beth Israel Deaconess Medical Center, Harvard Medical School

Dr. Dan Barouch received his PhD in immunology from Oxford University and his MD from Harvard Medical School. He is currently Professor of Medicine at Harvard Medical School, Chief of the Division of Vaccine Research at Beth Israel Deaconess Medical Center, and a member of the Steering Committee of the Ragon Institute of MGH, MIT, and Harvard. His laboratory focuses on studying the immunology and virology of HIV-1 infection and developing novel vaccine strategies. His laboratory has explored a series of novel vaccine technologies, including adjuvanted DNA vaccines, poxvirus vectors, and alternative serotype adenovirus vectors in both preclinical and clinical studies. In particular, he has advanced a series of novel adenovirus vector-based HIV-1 vaccine candidates from concept and design to preclinical testing to phase 1 clinical trials that are currently underway in both the U.S. and sub-Saharan Africa. Dr. Barouch is board certified in Internal Medicine and Infectious Disease, and he is highly committed to teaching students, clinical fellows, research fellows, and junior faculty and to providing clinical care to patients with infectious diseases.

Timothy Cardozo, MD, PhD

NYU School of Medicine

Dr. Timothy Cardozo is Associate Professor of Biochemistry and Molecular Pharmacology at NYU School of Medicine (NYUSOM). He is an active clinician, educator and computational structural biologist specializing in drug and vaccine design and protein engineering. His leading research project in HIV is immunogen design to exploit hidden conserved, immunogenic epitopes in the sequence variable loops of the HIV virus for vaccine design. At the time the RV144 results were announced in 2009, Dr. Cardozo was the recipient of the only research project grant active in the NIH portfolio targeting V2 loop immunogen design. Because of his diverse background in liberal arts, medicine, biology, surgery, biophysics, chemistry and computer science, Dr. Cardozo was recognized with a 2008 NIH Director's New Innovator Award. In 2010, he was a Young and Early Career Investigator honoree of the Collaboration for AIDS Vaccine Discovery, funded by the Bill and Melinda Gates Foundation. He has published over 40 papers in bioinformatics, molecular modeling, structural biology, immunology/virology, dermatology, genomics, pharmacology, cell biology, cancer biology and microbiology. At NYUSOM, he serves as Graduate Advisor for the Computational Biology Program and directs a graduate course in drug design. He currently serves on the Young and Early Career Investigator Committee for the Global HIV Enterprise, and is a regular member of the National Library of Medicine Biomedical Library and Informatics Review Committee.

Nicolas Chomont, PhD

Vaccine & Gene Therapy Institute of Florida

Dr. Nicolas Chomont is an Assistant Member at VGTI-Florida since December 2009. He obtained his PhD in Medical Virology at University Paris VI in 2004 where he extensively studied the interactions between HIV and the genital mucosa. He joined Dr Sekaly’s team in Montreal to perform a post-doctoral training from 2004 to 2009. He described for the first time distinct immunological mechanisms that contribute to the persistence of latently infected cells in HIV-infected subjects receiving suppressive HAART. His earlier work unveiled mechanism of HIV-specific CD8 T cell dysfunction driven by PD-1 in chronic HIV infection. He was awarded by the American Foundation for AIDS Research and by the Bill and Melinda Gates Foundation as Principal Investigator to characterize T cell reservoirs and strategies to control them. At VGTI Florida, Dr. Chomont is currently overseeing the studies of 2 post-doctoral scientists to unravel the molecular mechanisms involved in HIV latency, and to develop novel therapeutic strategies aimed at reducing the size of the HIV reservoir.

Donald Forthal, MD

University of California, Irvine, School of Medicine

Donald Forthal is chief of the Division of Infectious Diseases and a member of the Center for Virus Research and the Institute of Immunology at the University of California, Irvine. He received an undergraduate degree in linguistics at UCLA and an MD degree at UC Irvine. After residency at UC San Francisco and UCLA/Harbor General, he completed a fellowship in pediatric and adult infectious diseases at LA County/USC Medical Center. He served as an Epidemic Intelligence Service Officer at the CDC and subsequently served with the WHO in Brazzaville, Republic of Congo before joining the faculty at UC Irvine. Dr. Forthal’s research centers on interactions between the Fc fragment of antibody and Fc receptors.

J. Victor Garcia-Martinez, PhD

University of North Carolina, Chapel Hill

Dr. J. Victor Garcia-Martinez received his PhD in Chemistry from Georgetown University. He received postdoctoral training at the NCI and MIT. He was a Research Associate at the Fred Hutchinson Cancer Research Center. He was an Assistant and subsequently an Associate Member of St. Jude Children's Research Center and a Professor of Medicine at the University of Texas Southwestern Medical Center. Dr. Garcia is currently a Professor of Medicine, Microbiology and Immunology in the Center for AIDS Research, Division of Infectious Diseases, School of Medicine at the University of North Carolina, Chapel Hill. Throughout his career Dr. Garcia has made seminal contributions to our understanding of HIV pathogenesis in particular to our understanding of the function of Nef, an important determinant of HIV pathogenesis and disease progression. More recently, Dr. Garcia and the members of his group have established an outstanding track record in the development, implementation and use of humanized mice. Since their landmark publication describing the humanized BLT mouse model, it has been widely used to address key questions regarding a variety of aspects of HIV infection, transmission, and prevention.

Nelson L. Michael, MD, PhD

Walter Reed Army Institute of Research

Nelson L. Michael, MD, PhD is the Director of the US Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research (WRAIR), an international HIV vaccine research program that successfully integrates HIV/AIDS prevention, care and treatment. Dr. Michael, a Colonel in the United States Army Medical Corps, entered his Army service in 1989 in WRAIR's Department of Vaccine Research, Division of Retrovirology, and later served as the Chief, Department of Molecular Diagnostics and Pathogenesis. Dr. Michael was appointed Director of MHRP in January 2006, and guided MHRP through the completion of the RV144 HIV prime-boost vaccine study. This clinical trial, an international collaboration that involved more than 16,000 Thai volunteers, provided the world’s first demonstration that a preventive HIV vaccine was possible. Dr. Michael's research interests include HIV molecular pathogenesis and host genetics, HIV clinical research, and HIV vaccine development. He is an Associate Professor of Medicine, Uniformed Services University and is a Diplomat, American Board of Internal Medicine. He serves as a peer reviewer of many scientific journals and is author, coauthor of more than 130 scientific publications, and eight textbooks. Honors include Army Commendation Medal (1992, 1996), Army Achievement Medal (1996), and Army Meritorious Service Medal (2004, 2010). Dr. Michael currently serves on President Obama’s Presidential Commission for the Study of Bioethical Issues, the Vaccine Research Center Scientific Advisory Working Group (NIAID, NIH), Office of AIDS Research Advisory Committee (NIH), AIDS Research Advisory Committee (NIAID, NIH), AIDS Vaccine Research Working Group (DAIDS, NIAID, and NIH), Center for HIV/AIDS Vaccine Immunology Scientific Advisory Board, Office of the Global AIDS Coordinator Scientific Steering Committee, the Scientific Committee of the Global HIV AIDS Vaccine Enterprise and the PEPFAR Scientific Advisory Board. Dr. Michael graduated summa cum laude from University of California, Los Angeles in 1979 with a degree in biology and from Stanford University with MD and PhD (cancer biology) degrees in 1986. He trained in internal medicine at Harvard Medical School, Massachusetts General Hospital from 1986-1989.

Christopher J. Miller, DVM, PhD

University of California, Davis

Christopher J. Miller, DVM, PhD is a Professor of Pathology, Microbiology and Immunology in the School of Veterinary Medicine and an Adjunct Professor of Medicine in the School of Medicine. Dr Miller is a veterinarian and virologist, a core faculty member of the Center for Comparative Medicine and a Staff Scientist at the California National Primate Research Center. His laboratory utilizes non-human primate models of AIDS and influenza A virus infection to define the pathogenesis of these viral infections, study the nature of protective antiviral immunity, and test vaccines and immunotherapeutic strategies to prevent AIDS and influenza.

Alan M. Schultz, PhD

NIAID, NIH

Dr. Schultz is a virologist with a long research history in retroviruses. He received an undergraduate degree in Chemistry from the University of Rochester, a PhD in Biology from the Johns Hopkins University, and later worked in Dr. Robert Gallo's laboratory, where he was introduced to the field of retrovirology. In an 11 year stint at the Frederick Cancer R&D center, working in the Stephen Oroszlan laboratory, which discovered the retroviral protease, did the first amino acid sequence from an HIV protein (then known as HTLV-III), and defined N-terminal myristylation of the gag polyprotein, Dr. Schultz made many contributions to the biochemistry of the life cycle of the family Retroviridae, working with retroviruses from mice, cats, cows, monkeys and humans. He then joined the fledgling AIDS Program of the NIAID in 1988, where he became a recognized expert in primate models for AIDS, helped create the extramural grants and contracts funding infrastructure to support that work, finally serving as Chief of the Vaccine Research & Development Branch from 1992 to 1999. A ten-year period at the International AIDS Vaccine Initiative (IAVI) then broadened his experience in vaccine manufacturing, downstream processing and regulatory compliance. In 2010, Dr. Schultz returned to the Division of AIDS, NIAID, where he continues his focus on promoting optimization of primate models for AIDS vaccines.

Bill Snow

Global HIV Vaccine Enterprise

Mr. William (Bill) Snow is a Director of the Global HIV Vaccine Enterprise, an alliance of organizations dedicated to accelerating the development of preventive HIV vaccines. Bill oversees a Secretariat who helps to facilitate coordination, collaboration, knowledge sharing and resource optimization in the HIV vaccine field. Bill has a long and distinguished history in the HIV vaccine field, advising on and advocating for funding, legislation and a wide variety of activities to help accelerate development of a safe, effective and affordable AIDS vaccine for more than 20 years. He is a co-founder and long-time Board member of AVAC: Global Advocacy for HIV Prevention, and was a member of the Coordinating Committee and Board of the Enterprise when it received its initial funding in 2005. Bill was instrumental in establishing national, local and global community-advisory boards at the NIH clinical trial networks AVEG, HIVNET and HVTN and today sits on the NIAID AIDS Vaccine Research Subcommittee, the NIH Vaccine Research Center Scientific Advisory Working Group and has at times served in the leadership groups of every HIV vaccine clinical trials group to date.

Susan Zolla-Pazner, PhD

NYU Langone School of Medicine

Dr. Zolla-Pazner is an immunologist whose research focus is on the intersection between basic immunology and human disease. She has received continuous funding and served as PI on investigator-initiated research grants, program project grants and training grants from the NIH, Department of Veterans Affairs and the Bill and Melinda Gates Foundation since 1969. Her research, since 1981, has focused on the immunologic abnormalities in HIV infection, the human antibody response to HIV, the production and characterization of human anti-HIV monoclonal antibodies, the development of HIV vaccine candidates, and the study of antibody responses to various HIV candidate vaccines. She has also worked extensively on the antibody response in humans with TB and HIV/TB co-infection; this latter work has served as the basis for the development of a TB serodiagnostic assay which is being developed commercially, and for the identification of immunogens for use as TB vaccine candidates. She is a recognized expert in the development and characterization of human monoclonal antibodies and the epitopes they recognize. She has published >270 papers, many in high impact journals including Science, Journal of Infectious Diseases, Journal of Immunology, Journal of Virology, Nature Structural and Molecular Biology, etc.

Abstracts

Update on the Thai Correlates and Next Steps for HIV Vaccine Development
Nelson L. Michael, MD, PhD1 for the RV 144 Correlates Discovery Group. 1US Military HIV Research Program, Walter Reed Army Institute of Research, US

The Thai Phase III HIV vaccine trial, RV144, involved more than 16,000 volunteers and showed that ALVAC® HIV and AIDSVAX® B/E prime-boost HIV vaccine regimen was safe and reduced the risk of HIV infection by 31.2%.

MHRP, NIAID and international collaborators sought to determine immune correlates of infection risk. A large number of assays of innate, humoral, and cellular immunity were evaluated for downselection based on operating characteristics in preliminary studies. 41 vaccinees who became HIV infected and 205 vaccinees who remained HIV uninfected were selected for a case control study using a pre-specified statistical analysis plan. Six primary assays were downselected to cover unique immunologic variables.

Antibodies to a scaffolded HIV consensus B V1V2 loop protein correlated with the lowest infection rate among those who were vaccinated. Vaccinees with high levels of plasma IgA binding to a panel of 14 HIV gp120s had a higher infection rate similar to placebo subjects. Vaccine-induced mAbs of both IgG and IgA subclasses, have been recovered from RV 144 vaccinees. Some of these Mabs exhibit Tier 1 virus neutralizing and ADCC activity, and two antibodies bind to the V2 gp120 region. The binding specificities of these Mabs will be presented. These Mabs will ultimately be used in NHP SHIV-E challenge models to determine their ability to prevent mucosal infection.

These results reinforce the immunogen specific effector responses evoked in RV 144 and lend biological credence to the RV 144 clinical results. Whether or not these correlates of risk will be relevant to the ALVAC-HIV/AIDSVAX B/E regimen in different populations or other HIV vaccine types will require experimental determination.

Analysis of the V2 Antibody Response Induced in Vaccinees Participating in the ALVAC/AIDSVAX HIV-1 Clinical Vaccine Trial
Susan Zolla-Pazner, PhD1 and the RV 144 Correlates Discovery Group, 1New York Veterans Affairs Medical Center and NYU School of Medicine

The RV144 HIV-1 vaccine trial of ALVAC-HIV and AIDSVAX B/E had an estimated vaccine efficacy of 31.2%. Only one primary variable displayed a significant inverse correlation with risk of infection: the binding antibody (Ab) response to a fusion protein containing the V1V2 loops of gp120, a reagent which contains conformational epitopes expressed on virions and infected cells. Only one secondary variable displayed an inverse correlation with risk of infection: the Ab response specific for overlapping V2 linear peptides. Data from all 13 V2 Ab assays used in the RV144 immune correlates analysis will be discussed which show that the V2 assay-related odds ratios for HIV-1 infection risk were all <1, lending support to the hypothesis that V2-specific Abs contributed to reduced infection risk. V2-specific Abs were induced that were cross-reactive between HIV-1 subgroups and recognized linear and conformational epitopes. The dominant linear V2 epitope region maps to residues 165-178, immediately N-terminal to the α4β7 binding motif. Identification of Ab responses to the V1V2 and/or the V2 region of gp120 as an inverse correlate of infection risk may illuminate mechanisms of protection from HIV-1 infection and facilitate the development of an effective HIV vaccine.

V2, V3 and Building on RV144 Results
Timothy Cardozo, MD, PhD, NYU School of Medicine

Like the neutralization epitopes targeted by antibodies elicited with prior successful vaccines (influenza, polio, etc), the epitopes in the second (V2) and third (V3) variable loops of the surface envelope glycoprotein of the HIV virus are naturally immunogenic in humans. Unfortunately, the V2 and V3 loops have historically been viewed as immunogenic decoys, within the context of the general vaccinology corpus, because they frequently elicit type-specific or narrowly cross-reactive antibody responses. The first departure from this view was based on the fundamental biochemistry tenet that a three-dimensional (3D) structural fold may be conserved between sequences that are largely or completely dissimilar. Thus, my lab theorized that both the V3 and V2 loops were sequence variable, 3D fold-conserved domains, within which conserved neutralization epitopes are hidden amid decoy non-conserved epitopes. I will review the current evidence supporting this view. The significance of this shift in perspective for HIV vaccinology is profound, as simply immunofocusing immunogens on these hidden conserved epitopes, with appropriate cell-mediated immune stimulation, may place HIV vaccinology back within the realm of traditionally successful vaccinology approaches. Indeed, there is some statistical evidence of protection from HIV acquisition in humans by specific Abs elicited by vaccination and targeted at the V2 and V3 loops in both the Vax003 and RV144 trials. The RV144 trial, in particular, provided the paradigm-shifting result of revealing conserved, potentially protective epitopes in the V2 loop.

Non-neutralizing Antibodies and Lentiviral Infections
Donald Forthal, MD, University of California, Irvine, School of Medicine

Antibodies function in many ways to inhibit or modulate lentiviral infections. Apart from neutralizing the infectivity of cell-free virus, antibodies can mediate the killing of virus infected cells, trigger the production of virus-inhibiting ß-chemokines, enhance phagocytosis of cell-free virus or of virus-infected cells, and, under the right conditions, increase virus infectivity. If one defines neutralizing antibodies as those which, by themselves, directly inhibit virus from infecting susceptible target cells, then at a minimum, non-neutralizing antibody function can augment the in vivo protective effect of a neutralizing antibody. It is much less clear whether or not antibodies that completely lack any neutralizing activity can prevent infection. Nonetheless, there is correlative evidence that such non-neutralizing antibodies do provide protection to animals or humans from SIV, SHIV or HIV-1 infections.

Lessons Learned from Recapitulating the Results of the Step Trial in NHP
Christopher J. Miller, DVM, PhD, University of California, Davis, California

The Step trial showed that the MRKAd5 HIV-1 subtype B Gag-Pol-Nef vaccine did not protect men from HIV infection or reduce setpoint plasma vRNA levels but, unexpectedly, it did modestly enhance susceptibility to HIV infection in Ad5-seropositive, uncircumcised men. As part of the process to understand the results of the Step Trial, we designed a study to determine if rhesus macaques chronically infected with a host range mutant adenovirus type-5 (Ad5hr) and then immunized with a replication defective Ad5 SIVmac239 Gag-Pol-Nef vaccine were more resistant or susceptible to SIV infection than unimmunized rhesus macaques challenged with a series of escalating dose penile exposures to SIVmac 251. The Ad5 SIV vaccine induced CD8+T cell responses in approximately 70% monkeys, which is similar to the proportion of humans that responded to the vaccine in the Step trial. However, the vaccine did not protect vaccinated animals from penile SIV challenge. At the lowest SIV exposure dose (103 TCID50), 2 of 9 Ad5 seropositive animals immunized with the Ad5 SIV vaccine became infected compared to 0 of 34 animals infected in the other animal groups (naïve animals, Ad5 seropositive animals immunized with the empty Ad5 vector, Ad5 seronegative animals immunized with the Ad5 SIV vaccine and Ad5 seronegative animals immunized with the empty Ad5 vector). Penile exposure to more concentrated virus inoculums produced similar rates of infection in all animals groups. Although setpoint viral loads were unaffected in Step vaccinees, the Ad5 SIV immunized animals had significantly lower acute phase plasma vRNA levels compared to unimmunized animals. Thus, the results of the NHP study described here recapitulate the lack of protection against HIV acquisition seen in the Step trial and suggest a greater risk of infection in the Ad5 seropositive animals immunized with the Ad5 SIV vaccine. Further, vaccine-induced vector-specific immune responses did not contribute to altered susceptibility in the immunized NHP. Rather, it seems vaccine-induced SIV-specific immune responses are responsible for the enhanced susceptibility in Ad5-seropositive, immunized NHP. Further studies are necessary to confirm enhancement of virus acquisition and discern associated mechanisms.

(P01 AI8227 , R37 AI054165 in part by the Intramural Research Program of the NIH, National Cancer Institute)

SHIVs and Shibboleths
Alan M. Schultz, PhD, NIAID, NIH

The choice of virus to use in an experimental animal model system obviously depends on the question being addressed. Hybrid SHIVs have been developed to be used when there is need for an HIV env or pol target, by inserting those genes into an SIV backbone. There is often a fitness cost that accompanies this alteration and many researchers prefer to rely on an analog system, viz. SIV in the various subspecies of macaque, as the “naturally” matched virus and species. This presentation will cover some of the subtleties uncovered through our developing understanding of the virus/host interaction that affect the appropriate choice of virus.

Correlates of Protection Against SIV Infection in Rhesus Monkeys
Dan H. Barouch, MD, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School

Alternative serotype adenovirus (Ad) vectors such as Ad26 and Ad35 are biologically substantially different than Ad5 vectors. We have evaluated Ad26, Ad35, and MVA vectors expressing SIV antigens in immunogenicity and challenge studies in rhesus monkeys, and we have shown that Ad35/Ad26 as well as Ad26/MVA prime-boost regimens afford partial protection against both acquisition of infection as well as virologic control following fully heterologous, intrarectal SIVmac251 challenges. We observed different immune correlates for blocking acquisition of infection compared with controlling viral replication. We have also advanced prototype Ad26 vectors expressing HIV-1 Env into phase 1 clinical trials. These vectors have proven safe and immunogenic in humans at doses of 109 vp, 1010 vp, and 1011 vp. We propose to advance an Ad26/MVA prime-boost vector regimen expressing bioinformatically optimized mosaic HIV-1 antigens into clinical trials.

Humanized Mouse Models of HIV Infection
J. Victor Garcia-Martinez, PhD, University of North Carolina, Chapel Hill

HIV is a human retrovirus with very limited tropism. Due to a variety of restriction factions it only infects humans and chimpanzee. However, it is only capable of causing disease in humans. Humanized mice are reconstituted with human hematopoietic cells including those known to be targets of HIV. This renders humanized mice susceptible to HIV infection providing remarkable opportunities to investigate clinically relevant aspects of HIV disease, treatment and prevention. Specifically, humanized mice have been used to study parenteral, rectal and vaginal HIV transmission. In addition, humanized mice have also been used to investigate a variety of HIV prevention approaches including the use of topical microbicides, topical antivirals and pre-exposure prophylaxis. More recently, humanized mouse models have also been used to investigate HIV reservoirs and latency.

The Establishment of HIV Reservoirs During Acute Infection
Nicolas Chomont, PhD, Vaccine & Gene Therapy Institute of Florida

Current antiretroviral regimens do not eradicate HIV as demonstrated by the rapid return of high-level viremia whenever ART is interrupted, even after years of continuous suppressive therapy. This rebound in HIV replication is attributed to the persistence of a small pool of cells harboring replication competent virus that is not targeted by antiviral drugs. We hypothesized that early ART initiation may prevent the establishment of the HIV reservoir. Thai subjects from the RV254 study who fit the acute HIV infection criteria for Fiebig stages I to V were enrolled and started ART on average 3 days from enrollment. We determined the size of the HIV reservoir by measuring the frequency of cells harboring HIV DNA before initiating therapy and after prolonged ART. The total HIV DNA in PBMCs was significantly higher in subjects at Fiebig II (median 96 copies/106 PBMCs, n=5) and Fiebig III (median 550 copies/106 PBMCs, n=15) compared to those at Fiebig I (median 8 copies/106 PBMCs, n=7). The total HIV DNA in PBMCs at baseline predicted reservoir size at week 24, p=0.0002. By week 24, acutely treated subjects achieved total DNA levels (median 40 copies/106 PBMCs) lower than those observed in virally suppressed subjects who started HAART during chronic infection (median 109 copies/106 PBMCs, n=14), and 9 patients had levels as low as those seen in elite controllers who maintain undetectable viremia without ART (median 4.5 copies/106 PBMCs, n=13). Three of 15 acutely treated subjects had undetectable total HIV DNA in PBMCs.Our data suggest that there is a window of opportunity during early acute HIV infection to intervene and limit HIV reservoir establishment with the ultimate goal of achieving drug-free remission of HIV.

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