Initial biologic events that underlie sexual transmission of HIV are poorly understood. LC, which are dendritic cells (DC) found within mucosal epithelial surfaces, are potent antigen presenting cells and are the most likely initial targets for HIV following sexual exposure to virus. My scientific work has attempted to uncover the types of cellular and molecular interactions that occur between HIV and LC/DC. Recently, we described a novel ex vivo tissue model of primary HIV infection using skin explants. We could detect and quantify HIV infection in single LC that spontaneously emigrated from explants by flow cytometry. Interestingly, pre-treatment of explants with aminooxypentane-RANTES (a potential microbicide) blocked HIV infection of LC and subsequent T cell infection in a dose-dependent manner. Currently, we are using this model to perform more blocking experiments using a panel of novel RANTES analogues, to examine genetic susceptibility of LC, and to compare LC infection levels using a variety of HIV clades. Taken together, this work has helped in understanding (and potentially blocking) the early biologic events that occur following sexual exposure to HIV. In regard to the antigen presenting cell function of HIV-infected LC/DC, we recently have performed extensive phenotypic and functional analyses on purified populations of HIV-infected DC. We determined that HIV-infected DC secrete HIV gp120, even in the presence of potent anti-retroviral drugs, and that this protein induces marked dysfunction in co-cultured T cells. Interestingly, addition of soluble CD4 to co-cultures completely restored T cell function. These results may have important implications for HIV-infected individuals who have continued immunosuppression despite effective anti-retroviral therapy. 100% AIDS-RELATED
