In the current global AIDS pandemic, more than half of new human immunodeficiency virus type 1 (HIV-1) infections are acquired by women through intravaginal HIV exposure. For this study, we explored pathogenesis issues relevant to the development of effective vaccines to prevent infection by this route, using an animal model in which female rhesus macaques were exposed intravaginally to a high dose of simian immunodeficiency virus (SIV). We examined in detail the events that transpire from hours to a few days after intravaginal SIV exposure through week 4 to provide a framework for understanding the propagation, dissemination, and establishment of infection in lymphatic tissues (LTs) during the acute stage of infection. We show that the mucosal barrier greatly limits the infection of cervicovaginal tissues, and thus the initial founder populations of infected cells are small. While there was evidence of rapid dissemination to distal sites, we also show that continuous seeding from an expanding source of production at the portal of entry is likely critical for the later establishment of a productive infection throughout the systemic LTs. The initially small founder populations and dependence on continuous seeding to establish a productive infection in systemic LTs define a small window of maximum vulnerability for the virus in which there is an opportunity for the host, vaccines, or other interventions to prevent or control infection.The AIDS pandemic, already the most widespread pandemic in recorded human history, has claimed the lives of millions and continues relatively unabated for want of an effective vaccine or other means of prevention. Especially urgent is the need for effective vaccines and microbicides to prevent the vaginal transmission of human immunodeficiency virus type 1 (HIV-1), as women now account for close to 60 percent of newly acquired infections in Africa (27).The simian immunodeficiency virus (SIV)/rhesus monkey model of vaginal HIV transmission is clearly relevant to this objective. It has been used extensively to test vaccines (1,7,12,18,22) and microbicides (16,17,19,25,28) designed to prevent vaginal transmission. Moreover, pathogenesis studies relevant to the design and testing of vaccine and microbicide candidates that would be impossible in humans can be undertaken by use of this animal model. This model uses SIV, a primate lentivirus that is closely related to HIV (5) and that can be efficiently transmitted to macaques by vaginal inoculation of cell-free inocula (11,20,21). Further, the rhesus monkey is similar to humans with regard to the populations of target cells (10) and the physiology (4) and immunology (8, 9) of the female genital tract.Here we describe the use of this animal model to address the following two critical issues for the development of vaccines to prevent systemic infection following intravaginal transmission: the role of local propagation in establishing systemic infection and the dynamics of spread to the lymphatic tissues (LTs). The intravaginal inoculation mo...

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