HIV is primarily transmitted by heterosexual contact and approximately equal numbers of men and women are infected with the virus worldwide. Numerous studies to define the biology of HIV transmission have been undertaken with the goal of identifying stages in the processes from mucosal virus transmission through dissemination to distal lymphoid tissues that can be interrupted by vaccination. To large extent this effort has focused on understanding transmission of HIV to women with little effort define the transmission and dissemination in men exposed to HIV by insertive penile intercourse. We recently developed a reliable model of penile HIV transmission using SIV inoculation of mature male rhesus macaques. This model recapitulates the key virologic and epidemiologic features of HIV transmission in men, i.e. transmission is most efficient in to males when the inoculum is placed into the foreskin rather than simply onto the glans and shaft of the penis;and a single viral variant is found in plasma immediately after transmission (Keele, Miller Unpublished and see Preliminary Studies). We have characterized the virology and immunology of vaginally transmitted SIVmac251 in rhesus monkeys and in this application we propose to conduct parallel studies of penile SIV transmission. The studies will lead to a better understanding of how the HIV is transmitted to males by penile intercourse and the range of antiviral effector mechanisms that are present in the penile mucosal surfaces that are the sites of virus transmission. This information is required to rationally design vaccines to elicit immune responses in the male genital tract that can limit or prevent HIV transmission PUBLIC HEALTH RELEVANCE (provided by applicant): Men are regularly infected by penile HIV transmission and the foreskin seems to be a critical target tissue, because uncircumcised men are at higher risk for HIV infection. Despite this, almost nothing is known about the biology of penile HIV transmission. By defining the virology and immunology of SIV in the male genital we will be provide the biologic basis for attempting to elicit immune responses in these tissues by vaccines.