This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. HIV-1 infections are acquired most often through sexual contact, with the majority of the sexual transmission of HIV-1 worldwide occurring as a result of heterosexual contact. Women of childbearing age are at the greatest risk for HIV-1 infection, resulting in a corresponding increase in HIV-1 infection in women, newborns, and infants worldwide. However, despite the predominance of sexual transmission in the continued spread of HIV-1, the mechanisms of sexual transmission of HIV-1 to women are still poorly understood. For example, it is not known whether cell-free virus, cell-associated virus or both are essential for HIV-1 transmission in humans. Potential mechanisms of HIV-1 transmission across mucosal epithelium include 1) direct infection of epithelial cells;2) transcytosis through epithelial cells and/or specialized microfold (M) cells;3) epithelial transmigration of infected donor cells;4) uptake of intraepithelial Langerhans cells and 5) circumvention of the epithelial barrier through physical breaches. Successful transfer of virus across epithelial barriers may result in HIV-1 uptake by migratory dendritic cells (by DC-SIGN or another mannose C-type lectin receptor) and subsequent dissemination to draining lymph nodes and/or localized mucosal HIV-1-infection, leading to recruitment of additional susceptible cells. Although many questions remain unanswered, these investigations have revealed potential targets for prevention of HIV transmission in women which are critical for limiting the global AIDS pandemic.