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

Abstract

Vaginal HIV transmission is a relatively rare event [1] and virions and host characteristics influence the probability of this rare event to occur. Host-related factors include the epithelial and mucus thickness, hormonal environment, presence of inflammation and infection with other sexually transmitted pathogens [2]–[7]. 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].

Clarifying the mechanisms involved in the increased susceptibility of HSV-2 positive individuals to HIV infection may help understanding the characteristics of mucosal microenvironment that facilitate HIV transmission. It was reported that the vaginal mucosa of HSV-2 infected women retains an increased number of CCR5+ CD4+ T cells long after HSV-2 replication abates. Likewise, plasmacytoid and myeloid dendritic cells (DCs), which infiltrate areas of skin infected with HSV-2, persist after lesion healing even in the context of acyclovir therapy [10], [11]. More recently, 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. However, 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.

Immune cell trafficking can affect the susceptibility of the genital mucosa to HIV infection by influencing the availability of HIV cell targets at the site of exposure, the immune response to the virus and the ability of infected cells to reach sites of viral expansion and dissemination, such as draining lymph nodes, gut and the gut inductive sites. Thus changes in the expression of integrins or other adhesion molecules influence the susceptibility to vaginal HIV infection. Integrin α4β7 (α4β7) is an adhesion molecule specifically involved in trafficking of immune cells in the gut and gut inductive sites [13], [14]. However, α4β7+ cells are also involved in immune response in the vaginal tissue [15]–[17]. CD4+ T cells that express high levels of α4β7, α4β7high CD4+ T cells, are highly susceptible to HIV infection [18]–[20], they are preferentially depleted during acute SIV infection [21] and we recently reported that their frequency correlates with susceptibility to rectal SIV infection [22]. Moreover, administration of a monoclonal antibody (mAb) against α4β7 prior to intravenous challenge with SIVmac251 resulted in lower plasma and tissue viral load and lower proviral DNA compared to the control animals [23]. Notably the animals treated with the anti-α4β7 mAb showed no signs of progression to AIDS. Finally, pre-treatment with the mAb significantly reduced vaginal SIV infection of rhesus macaques (RM) (Byrareddy et al., Nature, in press).

We previously showed that rectal HSV-2 infection increases the frequency of α4β7high CD4+ T cells at the site of exposure, in the rectal draining LNs and in blood [22]. In this report we explored the possibility that HSV-2 infection increases the frequencies of α4β7+ cell subsets in the vaginal tissue. We further asked if these increases persist in absence of HSV-2 replication in vivo and whether these and other changes in the expression of adhesion molecules correlate with the HSV-2-driven increase in SIV acquisition.

Using a model of HSV-2 vaginally infected macaques, we found that, as in humans, HSV-2 positive animals appeared to be more susceptible to SHIVSF162P3 vaginal infection even when challenged with SHIVSF162P3 over a year after HSV-2 infection. Notably, HSV-2 positive animals had a trend toward higher frequency of α4β7high CD4+ T cells and higher expression of α4β7 and CD11c on DCs in the vaginal tissue. Moreover, we found that HSV-2 infection of vaginal tissue ex vivo increased the susceptibility of the tissue to SHIVSF162P3 and that specific HSV-2-driven changes in the expression of α4β7 and other adhesion molecules correlated with the HSV-2-driven increase in susceptibility to SHIV.