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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To better understand influenza virus infection of pigs, we examined primary swine respiratory epithelial cells (SRECs, the primary target cells of influenza viruses in vivo), as a model system. Glycomic profiling of SRECs by mass spectrometry revealed a diverse range of glycans terminating in sialic acid or GalαGal. In terms of sialylation, α2–6 linkage was more abundant than α2–3, and NeuAc was more abundant than NeuGc. Virus binding and infection experiments were conducted to determine functionally important glycans for influenza virus infection, with a focus on recently emerged swine viruses. Infection of SRECs with swine and human viruses resulted in different infectivity levels. Glycan microarray analysis with a high infectivity “triple reassortant” virus ((A/Swine/MN/593/99 (H3N2)) that spread widely throughout the North American swine population and a lower infectivity human virus isolated from a single pig (A/Swine/ONT/00130/97 (H3N2)) showed that both viruses bound exclusively to glycans containing NeuAcα2–6, with strong binding to sialylated polylactosamine and sialylated N-glycans. Treatment with mannosamine precursors of sialic acid (to alter NeuAc/NeuGc abundances) and linkage-specific sialidases prior to infection indicated that the influenza viruses tested preferentially utilize NeuAcα2–6-sialylated glycans to infect SRECs. Our data indicate that NeuAcα2–6-terminated polylactosamine and sialylated N-glycans are important determinants for influenza viruses to infect SRECs. As NeuAcα2–6 polylactosamine glycans play major roles in human virus infection, the importance of these receptor components in virus infection of swine cells has implications for transmission of viruses between humans and pigs and for pigs as possible adaptation hosts of novel human influenza viruses.

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