Human immunodeficiency viruses (HIV-1 and HIV-2) and simian immunodeficiency viruses (SIV) infect CD-4 positive lymphocytes and monoccytes in their respective hosts. the entry of these viruses into target lymphocytes and the eventual destruction of the infected cells are mediated by the viral envelope glycoproteins. HIV-1 entry involves binding of the viral gp120 exterior envelope glycoprotein and CD4, the primary receptor on the target cell. recently, it has been shown that gp120-CD4 interaction creates a high affinity binding site for specific chemokine receptors, which act as second receptors for HIV-1. Laboratory-adapted and T cell line-tropic HIV-1 isolates use the alpha-chemokine, CXCR4, while macrophage-tropic viruses use the beta-chemokine receptor, CCR5, to mediate entry. Binding of the gp120-CD4 complex to CXCR4 or CCR5 presumably triggers subsequent conformational changes in the envelope glycoproteins leading to fusion of the viral target cell membranes.
the specific aims of this proposal are: 1) To define the regions on the HIV-1 gp120 envelope glycoprotein that interact with CCR5 and CXCR4. 2) To define regions on the CD4 glycoprotein that interact with chemokine receptors and to assess the biological significance of this interaction. 3) To define regions on the CCR5 and CXCR4 chemokine receptors important for HIV-1 entry and for the natural function of these receptors.
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