Cracking the Safe

Agenda

*Presentation times are subject to change.

Abstracts

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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