HUMORAL AND CELLULAR IMMUNE RESPONSE TO HIV FOR VACCINE DEVELOPMENT

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This project aims to delineate immunologic responses to the human immunodeficiency viruses (HIVs), and to identify viral subfragments which elicit protective humoral and cellular immunity to HIV-1, -2, and simian immunodeficiency virus (SIV). Neutralizing antibodies are being studied in monocyte/macrophage and T-cell systems. Protective immunity of nontransmitting HIV-seropositive mothers is also under investigation. To study the impact of viral heterogeneity on neutralization, serotypes were defined among Zairian isolates using matched sera. While immunologically related V3 loops (the principal HIV-1 neutralizing determinant) have conserved sequences, serotypes deduced by cross-neutralization were not based on V3 loop homology. Thus, alternate or conformational epitopes must play a role in broad neutralization. Enhanced neutralization by Zairian sera of an MN-V3 loop/HXB2D chimera was attributed to better presentation and recognition of either the V3 loop or an alternate epitope(s), depending on the serum studied. Thus, the context in which the V3 loop is presented affects neutralization. Study of neutralization resistant variants immune selected in vitro allows further elucidation of neutralizing epitopes. "Escape mutants' obtained to date exhibit changes outside the V3 loop, further implicating alternate or conformational epitopes. Cell mediated immune responses to the HIVs and SIVs are under investigation in several animal systems including rhesus macaques, mice, and dogs. The low viral load seen in HIV-2 infected macaques is not due to significant neutralizing or cell mediated immune responses. Nevertheless, cytotoxic T lymphocyte (CTL) clones obtained from these infected macaques will allow mapping of CTL epitopes. Humoral and cell mediated immune responses are under investigation in macaques immunized with vaccinia, avipox, or BCG vectors carrying HIV or SIV genes. For future vaccine programs, isolation and characterization of West African retroviruses have been initiated. These studies will elucidate viral heterogeneity in this region and possibly uncover novel retroviruses.