The global AIDS pandemic continues to expand despite significant advances in understanding HIV-1 pathogenesis and the development of powerful antiviral drugs. HIV-1 is transmitted primarily through sexual contact and more than 30 million people are currently infected worldwide. In some regions of the world such as southern Africa the prevalence of HIV-1 infection exceeds 20%. The devastating spread of HIV-1 in young women in these countries appears out of proportion to the overall risk of infection. Thus it is possible that a biological co-factor contributes to virus spread. The hypothesis of this proposal is that acquisition by HIV- 1 of the envelope glycoprotein of gammaretroviruses (murine leukemia virus-related viruses) in a process we call """"""""""""""""natural pseudotyping"""""""""""""""" expands the cellular tropism of HIV-1 enabling it to directly infect vaginal epithelial cells thereby dramatically increasing the risk of infection during sexual intercourse. We propose a molecular epidemiology study consisting of four major aims. 1) To complete in vitro studies of gammaretrovirus/HIV-1 pseudotyping;2) To demonstrate gammaretrovirus/HIV-1 co-infections in local donors;3) To demonstrate the effect of gammaretrovirus pseudotyping on vaginal transmission in an animal model;4) To determine the prevalence of gammaretrovirus infection and HIV-1 co-infection in southern Africa. Natural pseudotyping of HIV-1 is predicted to occur in individuals co-infected with HIV-1 and a gammaretrovirus (XMRV/MLV) since the cellular tropism of these two viruses overlap to include T cells. The formation of XMRV-pseudoptyped HIV-1 (HIV-1/gp70) (now with the cell tropism of XMRV) in blood or lymphoid tissue would result in HIV-1 infection of normally resistant cells in the urogenital tract. Prior or subsequent infection of these cells with XMRV would result in the release of HIV-1/gp70 into seminal fluid or vaginal secretions. The potential implications of natural pseudotyping of HIV-1 are profound.