HIV ENVELOPE PEPTIDE-BASED VACCINE IN SHIV-RHESUS MODEL

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DESCRIPTION (adapted from applicant's abstract): The immunological correlates for protection against human immunodeficiency virus type 1 (HIV-1) infection and development of acquired immunodeficiency syndrome (AIDS) are not clearly understood. The applicants have hypothesized that an effective vaccination strategy against HIV-induced AIDS should involve preferential induction of cell-mediated immunity (CMI). This hypothesis has been supported by recent reports describing presence of helper T-cell responses directed against certain HIV peptides, and/or HIV-specific cytotoxic T lymphocyte (CTL) responses, but not antibodies, in long-term nonprogressors, and in certain individuals who remain HIV-negative despite indulging in high-risk activities. The long-term goal of the application is to formulate a synthetic peptide-based vaccine, for priming HIV-specific CMI, because it offers the advantage of being defined, safe, and economical. In this regard, protection against disease and death induced by certain viruses was demonstrated in animal models using peptide-based vaccines for efficient priming of CMI responses. Using a series of animal models (murine, and rhesus and chimpanzee monkeys), and samples from HIV-infected people, the investigators have previously identified several HIV env peptides, from highly conserved regions, that induce HIV-specific T-cell response in the absence of antibody response. More recently, they have analyzed PBMCs from HIV-seropositive long-term nonprogressors and observed HLA class C-restricted CD8+ CTL responses against the same conserved HIV-1 env peptides. The HIV envelope protein plays a major role in the virus-induced pathogenesis and has been the focus of vaccine strategies. However, the lack of a suitable animal model for HIV-induced AIDS hampered these efforts. The recently developed chimeric virus SHIV, comprised of HIV envelope and SIV core, induces AIDS-like disease in macaques, and thus provides the best alternative for testing HIV env-based vaccines and therapeutics. The investigators hypothesize that the conserved HIV env peptides they identified, can function as a vaccine for inducing efficient CMI and protection against pathogenic SHIV challenge in rhesus monkeys. To test their vaccine strategy, they propose two specific approaches involving immunization of rhesus monkeys: (i) with the peptide-mixture in Freund's adjuvant, and (ii) with autologous dendritic cells (DCs), pretreated in vitro with the peptide-mixture. Upon challenge with the pathogenic SHIV, the applicants expect that animals in both experiments will develop efficient virus-specific CMI responses, and resist infection and/or disease.