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. My early work in this area helped to delineate two major pathways by which HIV interacts with LC: an infection pathway and a """"""""capture"""""""" pathway. Infection of LC is mediated through CD4 and HIV co-receptors (CCR5 and CXCR4), whereas capture of virions occurs via the C-type lectin DC-SIGN. We were first to describe a novel ex vivo tissue model of primary HIV infection using skin explants. In single LC that spontaneously emigrated from explants, we could detect and quantify HIV infection by flow cytometry. Using this model, we then showed that pre-treatment of skin explants with chemically modified analogues of RANTES (potential microbicides that prevent binding of HIV to CCR5) blocked HIV infection of LC and subsequent T cell infection in a dose-dependent manner. Also using this explant model, we have recently shown that certain CCR5 genotypic patterns regulate levels of HIV infected within LC. Interestingly, this work has evolved into experiments showing that we can block intravaginal transmission of SIV in female rhesus macaques through topical application of PSC-RANTES, a compound known to block CCR5. We have also recently reported on 1) how different HIV clades infect and affect LC and 2) defining the type and nature of the T cells that preferentially interact with HIV-infected LC. 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, I initially studied the immunologic function of LC taken from the skin of HIV-infected individuals. Recently, we have 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 restores T cell function. These results may have important implications for HIV-infected individuals who have continued immunosuppression despite effective anti-retroviral therapy.
