The objective of this proposal is to determine the detailed mechanism by which HIV can initiate infection at the mucosal surfaces of the female genital tract, with the ultimate goal of preventing mucosal transmission. Specifically, we will be seeking to answer the following questions using the SW model: To what extent does the virus strain influence the efficiency of infection at mucosal s aces What cell types are involved in virus attachment and subsequent infection? What host factors may influence the susceptibility to HIV, SIV infection at mucosal surfaces? To determine if specific genotypes of SIV are preferentially transmissible by the mucosal route, we will determine if specific sequence changes can be detected in SIV isolates following mucosal inoculation of rhesus macaques with SIV virus stocks obtained from infectious molecular clones. We will also determine if SIV variants with altered cell tropism are selected after passage in primary genital tract cell cultures. We will develop in vitro culture systems to investigate the molecular and cellular determinants of virus binding; the susceptibility of such cell cultures to infection by free vs cell associated virus; identify the receptors which mediate virus infection; study mechanism(s) by which SIV can traverse epithelial cell layers; and determine the effects of specific hormones or growth factors on the susceptibility to infection. In addition, we will determine the role of distinct subsets of epithelial T cells a) as sites for virus replication and b) as effector cells in virus-specific immune responses. To specifically address these issues, we will: 1) characterize T cell subsets and cytokine production in the vaginal mucosa of uninfected and infected macaques, and 2) identify T cell subsets representing cellular targets following infection in vivo with either T cell tropic or macrophage tropic SIV strains. Immunohistochemistry and in situ hybridization techniques will be utilized to accomplish these objectives. The combined expertise of the participating investigators in studies of SIV envelope gene variation and the cell biology of virus-epithelial cell interactions will lead to a highly interactive collaborative group with the central focus of determining the mechanisms of SIV and HIV transmission across mucosal surfaces of the genital tract.
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