Propagation and Dissemination of Infection after Vaginal Transmission of Simian Immunodeficiency Virus

Center for Comparative Medicine, University of California-Davis, Davis, CA 95616, USA.
Journal of Virology (Impact Factor: 4.44). 08/2005; 79(14):9217-27. DOI: 10.1128/JVI.79.14.9217-9227.2005
Source: PubMed


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.

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    • "Virus and virus-infected cells leave infected mucosal tissues through afferent lymphatics to enter the draining lymph nodes. In the draining lymph node, HIV-1 and HIV-infected cells come in contact with large numbers of target cells, resulting in significant virus replication, virus dissemination, and establishment of systemic infection throughout the secondary lymphoid organs and the blood stream (Li et al., 2009; Miller et al., 2005). "
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    ABSTRACT: Exosomes are membranous extracellular nanovesicles secreted by diverse cell types. Exosomes from healthy human semen have been shown to inhibit HIV-1 replication and to impair progeny virus infectivity. In this study, we examined the ability of healthy human semen exosomes to restrict HIV-1 and LP-BM5 murine AIDS virus transmission in three different model systems. We show that vaginal cells internalize exosomes with concomitant transfer of functional mRNA. Semen exosomes blocked the spread of HIV-1 from vaginal epithelial cells to target cells in our cell-to-cell infection model and suppressed transmission of HIV-1 across the vaginal epithelial barrier in our trans-well model. Our in vivo model shows that human semen exosomes restrict intravaginal transmission and propagation of murine AIDS virus. Our study highlights an antiretroviral role for semen exosomes that may be harnessed for the development of novel therapeutic strategies to combat HIV-1 transmission. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 08/2015; 482. DOI:10.1016/j.virol.2015.03.040 · 3.32 Impact Factor
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    • "CD8 TRM have been targeted in the quest to develop a vaccine against HIV because CTLs are thought to be most important for killing virally infected cells. Non-human primate models reveal that the simian immunodeficiency virus (SIV) establishes a small founder population of infected cells in the local tissue after infection (65, 66). This founder population serves as an expanding source of virus that contributes to virus dissemination (66), and presents an opportunity for total elimination of mucosal viral infections during a narrow window of time early after infection. "
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    • "Bobardt et al. reported the rate of transcytosis of cell-free HIV-1 through primary genital epithelial cells to be less than 0.02% of the initial inoculum [8]. Despite the low rate of transcytosis of cell-free virus, both cell-associated and cell-free viruses found in semen have been documented to initiate HIV-1 infection [5], [13]–[16]. However, an animal model study has shown that cell associated virus is harder to cause infection in vivo, further implicating the importance of cell-free virus in HIV-1 transmission [17]. "
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