This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Worldwide, the vast majority of HIV-1 cases occur through heterosexual transmission. Although the initial events involved in vaginal transmission are uncertain, studies suggest that dendritic cells in the vaginal epithelium may be involved in trapping viral particles on the surface and transporting them to CD4+ T lymphocytes in the mucosa. As a collaborative, multicenter trial with the Center for HIV and AIDS vaccine Initiative (CHAVI) we are continuing studies to determine the earliest target cells and events involved in vaginal HIV transmission using the macaque model of SIV/HIV transmission. In collaboration with Dr. Tom Hope, Northwestern University, we are continuing to examine the earliest events that occur within tissues after vaginal exposure of HIV. To date, we have examined a total of 26 macaques (12 this fiscal year), inoculated with either photoactivateable virus, dyes, or compounds designed to test the mechanisms of viral penetration into the vaginal mucosa. The results prove that HIV enters intact vaginal squamous epithelium by passive diffusion through multiple layers of squamous epithelial cells, We are now focusing on determining which cell ssupport initial rounds of replication in vivo.