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 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 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 α4β7 high CD4+ T cells in the vaginal tissue and higher expression of α4β7 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 α4β7 high 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 α4β7 high 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 α4β7 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 α4β7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.
Highlights
Vaginal HIV transmission is a relatively rare event [1] and virions and host characteristics influence the probability of this rare event to occur
We determined that Herpes Simplex Virus Type 2 (HSV-2) infection is associated with an increase in subsets of immune cells that express high levels of a4b7, a molecule needed by the cells to reach the gut and the gut lymphoid tissues
Our results suggest that an increased availability of a4b7high cells at the mucosal site of HIV exposure may constitute a risk factor for HIV acquisition in HSV-2 positive and, possibly, negative individuals
Summary
Vaginal HIV transmission is a relatively rare event [1] and virions and host characteristics influence the probability of this rare event to occur. In particular Herpes Simplex Virus Type 2 (HSV-2) infection is associated with a three-fold increased risk of HIV acquisition even in the absence of HSV-2 replication [8,9]. An increased total number of CD4+ T cells expressing CCR5 and chronic activation markers CD38 and HLA-DR was found in the cytobrush samples of HSV-2 positive asymptomatic women [12]. These factors may partially explain the enhanced risk of HIV acquisition in HSV-2 positive individuals. A direct association between the HSV-2-driven increased frequency of these cell subsets and the HSV-2-driven increase in the risk of HIV acquisition has never been demonstrated
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