This is a revised proposal that seeks to evaluate the infectability of various cell types within the female reproductive tract and mucosal immune responses that might potentially protect against infection. The heterosexual transmission of HIV-1 is the primary mechanism for the infection of women. Various types of FRT cells are potential targets for infection, and a better understanding of the interaction of these cells with HIV-1 is important for the rational design of antiviral therapeutics and in the evaluation of mucosal vaccines. The P.I. has demonstrated that several FRT cell types are susceptible to infection with primary isolates of HIV-1. Preliminary work has led to the formulation of a set of hypotheses to be tested: 1) The susceptibility of FRT cells to HIV-1 infection is dependent on sex hormone and cytokine status and on chemokine and chemokine co-receptor expression, all of which may vary with the menstrual cycle and 2) That the functional properties of immune cells within the FRT are controlled by sex hormones and cytokines. To address these hypotheses, the P.I. proposes a systematic study using cells and tissues obtained from the FRT of HIV-1 seronegative women to define conditions that influence the infectivity of FRT cells by HIV-1. The effects of sex hormones and immune cytokines, as well as the effects of chemokine and chemokine co-receptor expression by FRT cells, on the susceptibility to HIV-1 infection will be examined. Additionally, the influence of sex hormones and immune cytokines on responses to recall antigens, as well as the mechanisms by which sex hormones and cytokines regulate FRT T cell responses will be defined. Data from these studies will increase our understanding of potential viral and immunologic factors that affect the heterosexual acquisition of HIV-1 infection by women, will be useful in developing approaches to reduce the susceptibility of women to HIV and other STDs, and will provide information important to the development of more effective mucosal vaccines.
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