HSV-2-Driven Increase in the Expression of α(4)β(7) Correlates with Increased Susceptibility to Vaginal SHIV(SF162P3) Infection

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 α(4)β(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 α(4)β(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 SHIV(SF162P3) infection, had higher frequency of α(4)β(7) (high) CD4(+) T cells in the vaginal tissue and higher expression of α(4)β(7) and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIV(SF162P3). HSV-2 infection increased the frequencies of α(4)β(7) (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 α(4)β(7) (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 α(4)β(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 α(4)β(7) positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission.