Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus.

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.

Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection.

In studies of sexual mucosal transmission and early stages of simian immunodeficiency virus (SIV) and HIV infections, productive infection predominates in CD4(+) T cell populations, in both ostensibly resting and activated cells. The surprising ability of SIV and HIV to replicate in resting cells in vivo, in contrast to propagation of infection in vitro, suggested a model in which during the early stages of infection these viruses exploit the greater availability of resting cells to maintain unbroken chains of transmission from an infected resting cell to another resting cell nearby. Because immune activation in response to infection provides more activated CD4(+) T cells, these viruses take advantage of the greater efficiency of virus production and spread in activated cells for propagation and dissemination of infection. In this article, we report the results of experimental tests of this model, including visualization at the light microscopic level and direct analysis of virus production by cells in tissues. Analysis of tissues of rhesus macaques inoculated intravaginally or i.v. with SIV supports the proposed roles of target cell availability, susceptibility, and virus production by infected resting and activated CD4(+) T cells in mucosal transmission and early infection, and points to a potential role for topical anti-inflammatory agents in moderating the initial propagation of infection.