Worldwide, most HIV-1 infections in both women and men result from mucosal transmission. In developing countries, the majority of women are infected via the vaginal route of transmission. Although homosexual transmission via anal intercourse among males still accounts for most new infections in developed countries, the incidence of heterosexual transmission in women is rapidly increasing in the U.S. A compound that could be safely applied to the vaginal mucosa immediately before intercourse that would consistently and safely prevent infection with HIV-1 could save millions of lives. Certain chemokine analogs have recently been demonstrated to have remarkable efficacy in blocking CCR5 expression and preventing HIV-1 infection of cells in vitro. However, several factors may affect the ability of a compound to prevent viral transmission across an intact mucosal surface. For example, cell cultures do not contain the abundant numbers of activated T cells, macrophages, and Langerhans cells that are normally found in the vaginal mucosa. Moreover, the effects of repeated application of a compound on the vaginal or rectal mucosa must be carefully examined, since continued use may induce mucosal inflammation. Since HIV-1 optimally infects and replicates within activated (CCR5+) cells, inflammation in the mucosa may lead to increased rates of transmission. The experiments in this proposal are thus designed to test the safety and efficacy of PSC-RANTES and 4 other fusion inhibitors in preventing SHIV/SIV transmission across the vaginal and rectal mucosa using the highly relevant rhesus macaque model.
The Specific Aims of this proposal are to: (1) To examine the histopathologic and immunophenotypic changes in the vagina and rectum after single and multiple exposures to PSC RANTES and other fusion inhibitors; (2) To determine whether PSC-RANTES and other fusion inhibitors can effectively block mucosal transmission of a CCR5-utilizing SHIV (SHIV-162P) using the rhesus macaque vaginal transmission model; and (3) To rigorously examine the efficacy of PSC-RANTES and other fusion inhibitors in a multiple exposure model that will closely mimic a microbicide application in vivo. Combined, these studies will determine whether PSC-RANTES and other fusion inhibitors can be safely applied to the mucosal surfaces and prevent transmission of SHIV-162P, which will provide important information for other investigators in this Program Project, and for preparing clinical trials in humans.
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