Background The probability of HIV acquisition after a sexual exposure is low, but surprisingly heterogeneous. Key mucosal immune determinants of susceptibility include genital epithelial disruption and/or the presence of activated CD4+ T cell in the genital mucosa, both of which have been linked to mucosal inflammation. We hypothesise that the genital microbiota may alter mucosal immunology and hence HIV susceptibility.
Methods We have carried out ex vivo studies of cervical, foreskin and semen mucosal immunology and in vivo studies of HIV acquisition in participant cohorts from Canada and East Africa. Studies use endocervical cytobrush samples and ectocervical biopsies from female participants, as well as foreskin tissues obtained during elective penile circumcision and semen samples from male participants. Mucosal T cell parameters and soluble genital immune factors associated with HIV transmission are assessed, co-infection diagnostics performed and the bacterial microflora assayed using 16S rRNA gene-based pyrosequencing and quantitative PCR.
Results In HIV-uninfected individuals, asymptomatic herpes infection was characterised by mucosal T cell immune activation and increased CD4 expression of the HIV co-receptor CCR5 and/or a4b7, in the absence of any local elevation in pro-inflammatory cytokines. However, while a vaginal microbiome characterised by bacterial diversity was not associated with mucosal cellular alterations, microbiota alterations in both the vagina and foreskin were associated with elevated pro-inflammatory cytokines, and the latter with a proteomic profile suggestive of epithelial disruption. In HIV-infected men, the semen microbiome was altered and linked to levels of HIV RNA in the seminal plasma, as well as to local levels of pro-inflammatory cytokines.
Conclusion The microbiota of the vagina and foreskin are associated with HIV susceptibility, and with important alterations in mucosal immunology that appear to be quite distinct to those induced by the HIV-enhancing co-infection HSV-2. This may lead to new clinical HIV prevention strategies.