Cracking the Safe
Monday, May 16, 2011
This one-day symposium will cover a range of issues facing researchers working towards the development of an HIV / AIDS vaccine, presenting an update on current challenges and solutions. This includes epidemiological challenges, developments in HIV virology and immunology including ex vivo and in vivo imaging of viruses crossing the mucosal barrier, the latest in the search for HIV vaccines, HIV microbicides and PreP (including results from international trials) and an update on HIV-reactivating factor.
Reception to follow.
*Presentation times are subject to change.
Registration and Breakfast
Defining the Interaction of HIV with Genital Epithelial Barriers to Gain Insights into the Mechanisms of Sexual Transmission.
Friend or Foe: HIV-Specific CD4 T Cells in Vaccine Design
Early Insights in the Quest for Correlates in Thai HIV Vaccine Trial
Combining Vaccine with Topical Microbicide to Limit HIV Transmission
Targeting Latent HIV-1 Infection
Yegor Voronin, PhD
Global HIV Vaccine Enterprise
Michael Watson, MD
Michael Watson Leads the Global Immunisation Policy group at Sanofi Pasteur; based in Lyon, France. He leads the Sanofi Pasteur HIV steering committee. Prior to his current role he was Executive Vice President of Research and Development at the Vaccine company Acambis, based in Cambridge USA and prior to that Head of Clinical and Epidemiology at Sanofi Pasteur MSD. He is a UK-trained physician who led the teams that developed and licensed Pediacel® in the UK and Gardasil® (Quadrivalent 6,11,16,18 HPV vaccine) in Europe and has worked on most classes of vaccines, including Pandemic Influenza vaccines. He is currently chair of the Biotherapeutics and Vaccines Committee of the IFPMA, leads the Pandemic Influenza Preparedness Group of the IFPMA and sits on the Board of the European Vaccines Manufacturers.
Jennifer Henry, PhD
The New York Academy of Sciences
Myron S. Cohen, MD
The University of North Carolina at Chapel Hill
Myron S. Cohen is J. Herbert Bate Distinguished Professor of Medicine, Microbiology and Immunology and Public Health at the University of North Carolina at Chapel Hill. He is Associate Vice Chancellor for Medical Affairs-Global Health. Dr. Cohen received his BS degree (Magna Cum Laude) from the University of Illinois, Champaign-Urbana. He received an MD degree from Rush Medical College, Chicago Illinois. He completed an Infectious Disease Fellowship at Yale University. He is a Fellow of the American College of Physicians and the Infectious Disease Society of America.
Dr. Cohen serves as the Director of the UNC Division of Infectious Disease and the UNC Institute for Global Health and Infectious Disease. Dr. Cohen serves on the Leadership Groups of the NIH Center for HIV Vaccine Immunology (CHAVI) and the NIH HIV Prevention Trials Network (HPTN). Dr. Cohen serves as an Editor of the journal Sexually Transmitted Diseases and of the comprehensive textbook Sexually Transmitted Diseases.
Dr. Cohen received the Distinguished Alumnus Award from Rush Medical College in 2000. He received the Thomas Parran Award (2005) for lifetime achievement in STD research from the American Sexually Transmitted Diseases Association. In 2008 Dr. Cohen received the O. Max Gardner Award, the greatest honor in the University of North Carolina 16 campus system. Doctor Cohen been repeatedly recognized as one of America’s “Top Doctors” and “Best Doctors”.
Dr. Cohen’s research work focuses on the transmission and prevention of transmission of HIV, with emphasis on the role played by STD co-infections. He has conducted landmark studies related to the biology of HIV transmission, and use of antiretroviral agents for prevention. In 2005, Dr. Cohen received an NIH MERIT Award for ongoing support of this work. Dr. Cohen is the author of more than 500 publications. Much of Dr. Cohen’s research has been conducted in resource constrained countries, especially in the African country of Malawi and in the People’s Republic of China.
David Cook, PhD
International AIDS Vaccine Initiative
David Cook is the Chief Operating Officer of the International AIDS Vaccine Initiative, a global non-profit organization working to ensure the development of preventive HIV vaccines. Cook has more than 20 years of experience in organizational management and operations in the biotechnology industry. Before IAVI, Cook served as a consultant for BIO Ventures for Global Health, a nonprofit that seeks to apply the resources and capabilities of biotech to develop vaccines and drugs for neglected diseases, where he led the development of new business, cross-sector partnerships and incentives for commercial enterprises. Immediately before BVGH, Cook was the CEO and co-founder of Anza Therapeutics, a biotechnology start-up company. Cook has led teams to commercialize several biotech products and is an inventor on more than 20 patents. Cook earned a Ph.D from the University of California, Berkeley and received undergraduate degrees from Harvard College and California State University. He completed the Stanford Executive Program at Stanford Graduate School of Business.
Cecilia Cheng-Mayer, PhD
The Aaron Diamond AIDS Research Center
Dr. Cecilia Cheng-Mayer received her Ph.D. degree in Microbiology from Columbia University and post doctoral training in Virology at the University of California San Francisco. She is currently a Staff Investigator and Professor at the Aaron Diamond AIDS Research Center. Her laboratory utilizes nonhuman primate infection models to study the impact of HIV-1 tropism on viral transmission and pathogenesis, and to test prevention modalities against AIDS.
Thomas Hope, PhD
Thomas J. Hope received his Ph.D. from UC Berkeley in Immunology. During his postdoctoral training at UC San Francisco, he began to study the HIV Rev protein. The study of this HIV protein led Tom to begin to utilize the techniques of cell biology. As Tom began to learn more cell biology it became apparent that such approaches were under utilized to study HIV. Therefore, the Hope laboratory developed a series of techniques allow the fluorescent labeling of HIV particles or viral proteins. The Hope laboratory currently utilizes a cell biology approach to study various aspects of HIV from virus entry and assembly, to defining the earliest steps of the sexual transmission of HIV.
Jerome Kim, MD
Walter Reed Army Institute of Research
COL Jerome H. Kim, M.D., is currently Deputy Director (Science) and Chief, Department of Molecular Virology and Pathogenesis, Division of Retrovirology, Walter Reed Army Institute of Research (WRAIR) (U.S. Military HIV Research Program), a multidimensional, international research program encompassing vaccine research and development, HIV prevention research, and clinical research. He also serves as the HIV Vaccines Project Manager, U.S. Army Medical Materiel Development Activity, Fort Detrick, MD. Dr. Kim’s current research interests include HIV molecular epidemiology, host genetics, and HIV vaccine development.
Prior to serving as Deputy Director (Science), Dr. Kim was the Thai Phase III Trial Sponsor Liaison and Chief, Department of Retrovirology, U.S. Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand (2004-2008).
Dr. Kim is an Associate Professor of Medicine, Uniformed Services University of the Health Sciences and a Clinical Associate Professor of Medicine at the John A. Burns School of Medicine, University of Hawaii. He is a Fellow of the American College of Physicians and a Fellow the Infectious Diseases Society of America. Dr. Kim graduated with highest honors in Biology and high honors in History from the University of Hawaii, Manoa in 1980. He graduated from the Yale University School of Medicine in 1984. Dr. Kim completed his training in Internal Medicine (1987) and fellowship in Infectious Diseases (1990) at Duke University Medical Center.
Olaf Kutsch, PhD
University of Alabama at Birmingham
Olaf Kutsch, Ph.D. is currently an Associate Professor, Division of Infectious Diseases, Department of Medicine at the University of Alabama at Birmingham and the Director of the UAB CFAR Flow Cytometry Core.
Dr. Kutsch obtained a Diploma in Biology/Biotechnology in 1992, and doctoral degree in Immunology/Virology in 1997 at the University of Wrzburg, Germany. He then became a post-doctoral fellow in the laboratory of Dr. Etty Benveniste at the University of Alabama in Birmingham, where he initially worked on AIDS dementia related research. He started to work on HIV-1 latency in 2001.
Dr. Kutsch’s current research interests include HIV-1 latency at the level of molecular biology and drug discovery. He further is involved in drug discovery efforts on other anti-HIV-1 and TB drugs.
Hendrik Streeck, MD, PhD
Ragon Institute of MGH, MIT, and Harvard
Dr. Streeck completed his medical training at Charite University, Berlin, Germany in 2006 and received his PhD from Friedrich-Wilhelm University, Bonn, Germany in 2007. After his postdoctoral fellowship with Dr. Marcus Altfeld he was promoted to Junior Faculty at the Ragon Institute of MGH, MIT and Harvard. Dr. Streeck's laboratory focuses on the role and function of HIV-specific CD4 T cells in the context of spontaneously controlled HIV-1 infection and how these responses may be applied to HIV vaccine induced protection.
This program is supported by an educational grant from Gilead Sciences, Inc.
This event is funded in part by the Life Technologies™ Foundation
Antiretroviral to Prevent HIV-1: Before and After the (F)Act(s)
Myron S. Cohen, MD, The University of North Carolina at Chapel Hill
Oral antiretroviral therapy can be used to prevent HIV transmission as either pre-exposure prophylaxis (PrEP), post exposure prophylaxis (PEP) and to reduce the secondary transmission of HIV from an infected patient to their partner(s). The pharmacology of virtually all of the available antiretroviral agents has been studied and the basis for the penetration and activity of these agents in the male and female genital tract is increasingly well understood. However, not all agents penetrate the genital mucosa and HIV can be detected in the genital tract of men and women in spite of suppression of HIV in blood. More than 21,000 patients are participating in trials of ART used as PrEP and the study populations include men who have sex with men (MSM), intravenous drug users, and HIV discordant couples. Results to date demonstrate that the combination of tenofovir and emtricitabine are safe and well-tolerated and the iPREX study demonstrated some degree of protection from HIV infection, perhaps depending on adherence to therapy. The actual utility of PrEP for HIV prevention in special at risk populations remains to be determined, and the use of PrEP will demand a cohesive repeat testing strategy to detect seroconversion events so as to avoid HIV resistance, or the spread of resistant variants. The use of HIV “treatment as prevention” has generated great interest since ART therapy is increasingly available world-wide, and is increasingly deployed earlier in HIV disease. Five observational studies demonstrate that people receiving ART are less contagious. However, the exact magnitude and durability of ART are unknown. A randomized clinical trial of 1800 discordant couples in 9 countries (NIH HPTN052) will be completed by 2013. Population level studies to increase treatment for the purpose of HIV prevention are underway. In Botswana a study to treat patients with the highest viral load is being piloted. In the US a feasibility study to increase HIV detection and linkage to care has started in the Bronx and Washington DC. A limitation to this approach is the difficulty in inclusion of patients with acute and early infection, who are likely very contagious, difficult to identify, and who may or may not be well-served by immediate ART. Fourth generation HIV testing strategies are designed to detect at least some patients with acute HIV infection. In summary, current research results suggest that ART will play an important role in HIV prevention.
Defining the Interaction of HIV with Genital Epithelial Barriers to Gain Insights into the Mechanisms of Sexual Transmission
Thomas Hope, PhD, Northwestern University
To date, little is known about the mechanisms of the sexual transmission of HIV. To gain insights into this process we have developed methods that allow individual HIV particles to be visualized by fluorescent microscopy. Using these systems, we find that HIV is able to penetrate intact genital epithelium in human tissue explants and the living rhesus macaque. We find that HIV can enter the epithelial barriers of both men and women that are exposed to virus during sexual transmission. Further analysis reveals that this viral penetration can allow the virus to enter to a depth where it can interact with immune cells that are the target of infection and transmission. Defining these interactions has revealed potential new strategies that might be utilized for vaccine development. For example, in the course of our studies we have found that cervical mucus provides a protective layer to the surface of the female reproductive tract. Studying the interaction of HIV and cervical mucus we find that the diffusion of the virus is greatly slowed as it attempts to move through this barrier. Additionally we have found that the presence of antibodies bound to the virus can further slow virus transport. Importantly, the ability of virus to slow HIV transport is seen in both neutralizing and non-neutralizing antibodies. Therefore, it is possible that a vaccine, which will elicit the appropriate broadly binding antibodies, rather than broadly neutralizing antibodies might be able to protect women from HIV acquisition by sexual contact.
Friend or Foe: HIV-specific CD4 T Cells in Vaccine Design
Hendrik Streeck, MD, PhD, Ragon Institute of MGH, MIT and Harvard
The fundamental goal of any successful prophylactic vaccine is to induce live-long protective immunity. However, the generation of efficacious memory responses for CD8+ T cells and B cells is critically dependent on CD4+ T helper signals. Indeed, it has been demonstrated that licensed vaccines induce robust levels of CD4 T cell responses, which are critical modulators of the quality of the ensuing antiviral response. As HIV-specific CD4 T cells are thought to be preferentially infected and depleted, not much attention has been paid to the role, function and specificity of these cells in HIV infection. A deeper analysis of HIV-specific CD4 T cells in the setting of acute and chronic HIV infection has revealed an important role of these cells in the early control of viral replication. Moreover, important distinctions exist in the phenotype and character of these cells in subjects who are able to spontaneously control viral replication compared to those who progress to AIDS. An evaluation of these responses and their role in the initial control of viral replication will be critical for the creation of a successful vaccine against HIV.
Early Insights in the Quest for Correlates in Thai HIV Vaccine Trial
Jerome Kim, MD, Walter Reed Army Institute of Research
The RV144 Thai Phase III HIV vaccine trial yielded only a modest efficacy of 31.2% at 42 months, though post-hoc analyses showed efficacy as high as 60% at month 12 and 44% at month 18. These findings, by analogy with other vaccines, suggested that a vaccine-induced but transient immune response might underlie the observed efficacy. An international group of collaborating laboratories has taken on the task of identifying potential correlates. A key finding was the observation both the prime (ALVAC-HIV) and the boost (AIDSVAX B/E) might have unusual antigenicity. Using several conformation/quaternary structure specific monoclonal antibodies, data suggest that, in the case of the prime, the attachment of gp120 to a truncated gp41 appears to constrain the antigen, and in the case of gp120, the use of an HSV gD protein tag (27 aa) may have the effect of exposing epitopes that are more often cryptic or shielded. These antigens also served to induce a unique antigenic profile that blocks the binding of several of the quaternary/ conformational MAbs. Linear epitope mapping further focused attention of the Env V2 domain, and in particular that part of V2 which contains the α4β7 integrin binding site. V2 responses are found in a large number of vaccine recipients (> 80%), and those responses decrease dramatically 6 months post-vaccination. In addition, both ADCC and NAb responses are observed. Several cellular responses were notable, including responses to V2, which included CD4+CD107+ T cells and cytokine induction patterns. Finally, sieve analysis of breakthrough viruses is nearly complete and will be used to compare signature sequences in vaccine and placebo breakthrough infections. Laboratory work looking at potential correlates of protection in RV144 have advanced our understanding of antigenicity and induced immune responses considerably. A formal case-control analysis for correlates is planned for the summer of 2011.
Combining Vaccine with Topical Microbicide to Limit HIV Transmission
Cecilia Cheng-Mayer, PhD, The Aaron Diamond AIDS Research Center
We tested, in a nonhuman primate model of heterosexual HIV-1 transmission, whether a topical microbicide that reduces infectivity of the virus can potentiate the efficacy of a partially effective T-cell-based HIV vaccine to prevent R5 SHIV infection, and/or to control viremia in those that got infected with repeated exposures. We found that neither a DNA prime-recombinant Ad5 boost vaccine regimen nor a formulation containing a sub-optimal dose of a HIV-1 nucleocapsid zinc finger inhibitor (ZFI) alone efficiently blocked SHIV vaginal transmission or blunted virus replication in the infected host in comparison to naïve and untreated monkeys. However, a significant delay in SHIV acquisition (Log-rank test; p=0.0416) was seen in vaccinated macaques that were repeatedly challenged in the presence of the ZFI microbicide. Moreover, peak acute viremia was lower (Mann-Whitney test; p=0.0387) and viral burden was reduced (Mann-Whitney test; p=0.0252) in the vaccines infected in the presence of the ZFI microbicide. These findings have implications for future HIV-1 prevention strategy design.
Targeting Latent HIV-1 Infection
Olaf Kutsch, PhD, University of Alabama at Birmingham
The ability of HIV-1 to persist in latently infected memory T cells and possibly other long-lived cell types in the face of ART is considered a major obstacle to the development of a curative therapy. Therapeutic eradication of these viral reservoirs will be a prerequisite to achieve this goal. Based on results from our research, we will discuss how this goal could possibly be achieved. The presentation will address three main areas regarding HIV-1 latency and reactivation.
(1) Validity of the various cell-based model systems used to study latent HIV-1 infection, both for molecular research or drug screening.
(2) Utilization of drug combinations that target latent HIV-1 infection at different levels of molecular control to optimize reactivation efficacy.
(3) Identification and characterization of novel targets and compounds to reactivate latent HIV-1 infection.
IAVI’s Strategy for Ensuring the Development of an AIDS Vaccine
David Cook, PhD, International AIDS Vaccine Initiative
The International AIDS Vaccine Initiative (IAVI), a global not-for-profit, public-private partnership, is dedicated to ensuring the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. IAVI’s scientific team, drawn largely from the vaccine industry, designs AIDS vaccine candidates and conducts AIDS vaccine trials and related research through partnerships with more than 50 academic, biotechnology, pharmaceutical and government institutions. The organization applies project-management systems similar to those employed by the pharmaceutical industry to direct a portfolio of R&D projects and supports two global consortia of leading HIV researchers to address major obstacles in the design and development of effective AIDS vaccines. IAVI has contributed significantly to the clinical assessment of AIDS vaccine candidates as well, most notably by establishing a network of clinical research centers in sub-Saharan Africa. IAVI’s R&D approach is focused on prioritizing the most promising vaccine candidates and translating them rapidly into clinical candidates. In addition, IAVI conducts policy analyses and serves as an advocate to support funding for the AIDS vaccine field. This presentation will review IAVI’s R&D objectives over the next 5 years in light of the present state of the AIDS vaccine field and available data. These objectives include: 1) Defining one or more immunogens capable of eliciting a broadly neutralizing antibody response against HIV; 2) Increasing the number and diversity of clinical candidates to be tested in Phase 1 trials; and 3) Participating in a consortium testing the clinical efficacy of a novel vaccine candidate based on low seroprevalence, non-replicating adenovirus (Ad26/Ad35) expressing mosaic HIV antigens.
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