NOVEL ANTI-HIV MICROBICIDES

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DESCRIPTION (Adapted from applicant's description): Sexual transmission of HIV now accounts for most new cases of AIDS and the increased transmission to women through heterosexual contact is especially alarming. Locally applied biomedical barriers and microbicides have proven ineffectual in preventing sexual transmission of HIV. We have recently found that HIV requires intact lipid rafts, highly specialized subregions in cell membranes, for entry into cells and for budding of fully infectious particles. In addition we have shown that beta-cyclodextrin, a cyclic heptasaccharide that removes cholesterol from cell membranes and disperses lipid rafts, blocks HIV infection and drastically reduces the infectivity of budding HIV particles. Beta-cyclodextrin is non-toxic and currently in human use as a carrier for polar drugs. Thus properly formulated, this molecule may be an effective anti-HIV microbicide. In this project we will use in vitro models to test the effect of lipid raft dispersion by beta-cyclodextrin on potential modes of sexual transmission of HIV. To that end we will pursue the following aims: 1) To determine the effect of beta-cyclodextrin on HIV-1 infection of primary T cells. beta-cyclodextrin will be tested for inhibition of infection of primary T cells by a panel of clinical HIV isolates from clades B, C, and E. 2) To determine the effect of beta-cyclodextrin on HIV-1 infection of primary macrophages. beta-cyclodextrin will be tested for inhibition of infection of primary T cells by a panel of clinical HIV isolates from clades B, C, and E. 3) To determine the effect of beta-cyclodextrin on HIV-1 infection of dendritic cells and on HIV-1 transmission from dendritic to primary T cells. Beta-cyclodextrin will be tested for inhibition of infection of dendritic cells by a panel of clinical HIV isolates from clades B, C, and E. The compound will also be tested for inhibition of transmission of the virus from dendritic cells to T cells. These studies represent the first important steps toward exploiting the role of lipid rafts in HIV biology to develop safe and effective anti-HIV microbicides. Because this strategy is based on a physical property of the cell membrane, it is highly unlikely that HIV could evolve to become resistant to the effects of beta-cyclodextrin.