Propagation and Dissemination of Infection after Vaginal Transmission of Simian Immunodeficiency Virus
Christopher J. Miller,Qingsheng Li,Kristina Abel,Eun Young Kim,Zhong-Min Ma,Stephen W. Wietgrefe,Lisa La Franco-Scheuch,Lara Compton,Lijie Duan,Marta Dykhuizen Shore,Mary Zupancic,Marc Busch,John V. Carlis,Steven Wolinksy,Ashley T. Haase +14 more
TLDR
It is shown that the mucosal barrier greatly limits the infection of cervicovaginal tissues, and thus the initial founder populations of infected cells are small, and 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.Abstract:
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.read more
Citations
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The immune response during acute HIV-1 infection: clues for vaccine development.
TL;DR: The finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia.
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Targeting early infection to prevent HIV-1 mucosal transmission
TL;DR: Studies in animal models and acute HIV-1 infection reviewed here reveal potential viral vulnerabilities at the mucosal portal of entry in the earliest stages of infection that might be most effectively targeted by vaccines and microbicides, thereby preventing acquisition and averting systemic infection, CD4 T-cell depletion and pathologies that otherwise rapidly ensue.
Journal ArticleDOI
Glycerol monolaurate prevents mucosal SIV transmission
Qingsheng Li,Jacob D. Estes,Patrick M. Schlievert,Lijie Duan,Amanda J. Brosnahan,Peter J. Southern,Cavan S. Reilly,Marnie L. Peterson,Nancy Schultz-Darken,Kevin Brunner,Karla R. Nephew,Stefan E. Pambuccian,Jeffrey D. Lifson,John V. Carlis,Ashley T. Haase +14 more
TL;DR: G glycerol monolaurate—a widely used antimicrobial compound with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV.
Journal ArticleDOI
Mucosal Dendritic Cells
TL;DR: Progress is highlighted in understanding of how mucosal DCs process external information and direct appropriate responses by mobilizing various cells of the innate and adaptive immune systems to achieve homeostasis and protection.
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Setting the stage: host invasion by HIV.
TL;DR: The current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur are reviewed.
References
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Journal ArticleDOI
Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.
Zhiqiang Zhang,T. Schuler,Mary Zupancic,Stephen W. Wietgrefe,Katherine Staskus,Keith A. Reimann,Todd A. Reinhart,Michael J. Rogan,Winston Cavert,Christopher J. Miller,Ronald S. Veazey,Daan W. Notermans,Susan J. Little,Sven A. Danner,Douglas D. Richman,Douglas D. Richman,Diane V. Havlir,Joseph K. Wong,Joseph K. Wong,H. L. Jordan,Timothy W. Schacker,Paul Racz,Klara Tenner-Racz,Norman L. Letvin,Steven M. Wolinsky,Ashley T. Haase +25 more
TL;DR: Both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues, and infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells.
Journal ArticleDOI
Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells
TL;DR: SIV enters the vaginal mucosa within 60 min of intravaginal exposure, infecting primarily intraepithelial DC and that SIV-infected cells are located in draining lymph nodes within 18 h of intrabaginal SIV exposure, posing a serious challenge to HIV vaccine development.
Journal ArticleDOI
Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120
Ronald S. Veazey,Robin J. Shattock,Melissa Pope,J. Christian Kirijan,Jennifer Jones,Qinxue Hu,Tom Ketas,Preston A. Marx,Per Johan Klasse,Dennis R. Burton,John P. Moore +10 more
TL;DR: It is described here how vaginal administration of the broadly neutralizing human monoclonal antibody b12 can protect macaques from simian-human immunodeficiency virus (SHIV) infection through the vagina, and observations support the concept that viral entry inhibitors can help prevent the sexual transmission of HIV-1 to humans.
Journal ArticleDOI
Progesterone implants enhance SIV vaginal transmission and early virus load
Preston A. Marx,A I Spira,A I Spira,A Gettie,Peter J. Dailey,Ronald S. Veazey,Andrew A. Lackner,C J Mahoney,Christopher J. Miller,L E Claypool,David D. Ho,Nancy J. Alexander +11 more
TL;DR: This study shows that SIV genital infection and disease course are enhanced by subcutaneous implants containing progesterone when compared with the rate of vaginal transmission in the follicular phase.
Journal ArticleDOI
Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus.
Christopher J. Miller,Nancy J. Alexander,Suganto Sutjipto,Andrew A. Lackner,Agegnehu Gettie,Andrew G Hendrickx,Linda J. Lowenstine,Myra Jennings,P. A. Marx +8 more
TL;DR: It appears that the mucous membranes of the genital tract act as a barrier to SIV infection, and the SIV-rhesus macaque model is suitable for assessing the role of cofactors in heterosexual transmission of HIV and will be useful for testing the effectiveness of spermicides, pharmacologic agents, and vaccines.
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