MOLECULAR MECHANISMS OF HIV-1 INFECTION

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In order to understand the pathogenesis of HIV and to evaluate and develop new therapies for AIDS, we have been studying the molecular events involved in HIV-1 cell attachment and infection of human cells. Studies were directed at characterizing 1) the role of cell surface proteoglycans in HIV binding and cell penetration and 2) novel receptors necessary for CD4-dependent virus infection. The goal of these studies is to understand how HIV enters human cells and to identify the proteins (receptors) on cells which mediate these events. 1. Role of cell surface proteoglycans in HIV infection. Following initial HIV binding to the CD4 receptor, virus envelope is thought to bind to other cell surface molecules during the attachment and fusion process. We are characterizing a second molecule in this entry pathway necessary for CD4-dependent virus infection. After HIV attaches to CD4, we observe that the envelope gp120 binds to cell surface heparin sulfate proteoglycan through a specific region of the envelope called the V3 domain. Heparin sulfate binding requires a conformationally intact site on the oligomeric form of the HIV envelope and stabilizes a trimolecular preinfection complex on the T-cell surface. This interaction is critical for virus entry and infection and is especially important to the entry of the T-cell tropic viruses, those viruses thought to induce rapid progression to AIDS. 2. Identification of novel receptors for HIV. We are characterizing cell surface molecules which are required for infection of primary and T-cell tropic HIV isolates. We are currently generating immunological reagents which specifically react with these HIV binding structures and are using these antibodies to biochemically and functionally characterize these molecules. Genetic probes are being developed to clone genes encoding molecules which interact with HIV during virus infection. Identifying the molecular targets of HIV infection is important to evaluating and developing new therapeutics and vaccines for AIDS.