Characterising the Interactions Between HSV and HIV During Coinfection of the Anogenital Mucosa

Abstract

Type II anogenital mucosa are host to a variety of mononuclear phagocytes (MNPs; Langerin+ cells, CD11c+ Dendritic Cells (DCs)) and T lymphocytes (CD3+), which play a role in the sexual transmission of HIV. While it is well known that prior infection with HSV increases the risk of acquiring HIV, likely by inducing a proinflammatory state and ulcerating the mucosal barrier, the precise mechanisms through which this happens during early mucosal infection have not yet been well defined.

We first took a well-optimised HSV1 ex vivo inner foreskin tissue explant model and quantified the impact of HSV1 infection on the migration and densities of epidermal Langerin+ cells, epidermal CD11c+ DCs, subsets of dermal CD3+ T cells, dermal Langerin+ MNPs and dermal CD11c+ DCs. At sites of HSV1 infection, there is potentially migration of epidermal MNPs into the dermis, while dermal MNPs and T lymphocytes are concentrated directly under sites of HSV infection. We also found that several key inflammatory cytokines and chemokines are upregulated in HSV1 infected tissue. The formation of a cell relay to carry virus into a dermis enriched with HIV target cells and a proinflammatory environment could be significant mechanisms by which HSV increases HIV acquisition.

We made substantial progress towards the completion of novel HSV2-HIV coinfection explant. We demonstrated HSV2 infection in vaginal tissue which showed similar T lymphocyte redistributions as observed in the HSV1 foreskin explant. We identified that using a cloning cylinder to deliver HIV 18 hours after HSV2 infection at a TCID50 70 000, and leaving HIV in culture for 24 hours, resulted in optimal HIV infection. Ultimately, although we were not able to achieve true overlapping HSV2-HIV coinfection, we were able to produce an explant that contained both HSV2 and HIV infection, and where we reported HSV2 uptake by a langerin+ cell lining the basement membrane and HIV uptake by an epidermal CD4+ T cell infected with HIV.