Dataset Information

HSV-2-driven increase in the expression of ?4?7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection.

ABSTRACT: The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of ?4?7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of ?4?7 and other homing receptors in the vaginal tissue and that this correlates with the increased risk of HIV acquisition in HSV-2 positive individuals. To test this hypothesis we used an in vivo rhesus macaque (RM) model of HSV-2 vaginal infection and a new ex vivo model of macaque vaginal explants. In vivo we found that HSV-2 latently infected RMs appeared to be more susceptible to vaginal SHIVSF162P3 infection, had higher frequency of ?4?7high CD4+ T cells in the vaginal tissue and higher expression of ?4?7 and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIVSF162P3. HSV-2 infection increased the frequencies of ?4?7high CD4+ T cells and this directly correlated with HSV-2 replication. A higher amount of inflammatory cytokines in vaginal fluids of the HSV-2 infected animals was similar to those found in the supernatants of the infected explants. Remarkably, the HSV-2-driven increase in the frequency of ?4?7high CD4+ T cells directly correlated with SHIV replication in the HSV-2 infected tissues. Our results suggest that the HSV-2-driven increase in availability of CD4+ T cells and DCs that express high levels of ?4?7 is associated with the increase in susceptibility to SHIV due to HSV-2. This may persists in absence of HSV-2 shedding. Hence, higher availability of ?4?7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.

SUBMITTER: Goode D

PROVIDER: S-EPMC4270786 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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HSV-2-driven increase in the expression of α4β7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection.

Goode Diana D Truong Rosaline R Villegas Guillermo G Calenda Giulia G Guerra-Perez Natalia N Piatak Michael M Lifson Jeffrey D JD Blanchard James J Gettie Agegnehu A Robbiani Melissa M Martinelli Elena E

PLoS pathogens 20141218 12

The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of α4β7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of α4β7 and other homing receptors in the vaginal tissue and that this c ...[more]

PMID: 25521298

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Project description:BackgroundThe menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time.MethodsBlood and vaginal lavage samples were collected from 18 pig-tailed macaques to evaluate immune changes over reproductive cycles, and from 5 additional animals undergoing repeated vaginal exposures to simian HIV (SHIV). Peripheral blood mononuclear cell (PBMC) samples from healthy women (n = 10) were prospectively collected over the course of a menstrual cycle to profile T cell populations. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Plasma progesterone was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression on CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was monitored in plasma by RT-PCR. Immune measures were compared using generalized estimating equations (GEE).FindingsMacaques cycle-phases were associated with fluctuations in systemic immune properties and a type-1 inflammatory T cell response with corresponding CCR5+ memory CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis identified CCR5 oscillation frequencies synchronized with reproductive cycles. In a repetitive low-dose vaginal challenge model, productive SHIV163P3 infection only occurred during intervals of mounting type-1 T cell responses (n = 5/5). Finally, we identify similar type-1 inflammatory T cell responses over the menstrual cycle are occurring in healthy women.InterpretationThese data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drives bystander CCR5+ CD4 T cell recruitment and HIV susceptibility in the female reproductive tract.FundingThis study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407 to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]).DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the views of the U.S. Centers for Disease Control and Prevention or the Department of Health and Human Services.

Dataset Information

HSV-2-driven increase in the expression of ?4?7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection.

Publications

HSV-2-driven increase in the expression of α4β7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection.

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