DESCRIPTION (provided by applicant): Medical male circumcision (MMC) reduces the risk of heterosexual HIV acquisition in African men by 60%. In both our MMC trial in Kenya and the Ugandan MMC trial, circumcised men had lower prevalence and amount of penile anaerobic bacteria, several species of which are associated with Bacterial vaginosis (BV). The benefit is transferred to female sex partners of circumcised men, who had a 40-60% reduced risk of BV. MMC reduced genital ulcer disease (GUD) by 37-52%, and reduced GUD in female sex partners of circumcised men by 32%. Among men in our trial in Kenya, Fusobacteria and Sneathia had 6-fold greater odds of recovery from non-herpetic GUD compared to herpetic GUD. These two BV-related anaerobes are more common among uncircumcised men, and cause oral ulcers and periodontal disease. Their reduction may explain the reduction in non-herpetic GUD in circumcised men and their female sex partners. Cuts, abrasions, scratches, and bleeding of the vaginal or penile skin occur in 30-50% of men and women in our studies in Kenya, and are reduced by 40-60% among circumcised men and their female sex partners. Penile anaerobic bacteria are a common link between MMC and reductions in BV and GUD, and may also explain the reduced genital epithelial trauma among circumcised men and their sex partners. We propose to identify under what conditions the penile microbiome leads to BV, GUD, and genital epithelial trauma in men and their female sex partners. Within a prospective cohort of 204 heterosexual couples, we will measure the penile and vaginal microbiome four times over a one year period using pyrotag sequencing of the 16S rRNA gene. We will (Aim 1) determine how the penile microbiome leads to BV, GUD, and genital epithelial trauma, and factors that influence these associations. We will (Aim 2) define factors causing variation in the penile microbiome over time and across men. We will (Aim 3) map specific penile and vaginal bacteria to increased genital inflammatory cytokine levels, and elucidate the link between inflammatory cytokines and genital epithelial trauma. We need to determine how MMC reduces these co-factors for HIV infection to achieve benefits among uncircumcised men and to augment the protective effect of MMC. Pharmacologic interventions to improve penile microbiome health may include systemic or topical antimicrobials, or microbicides incorporating cytokine modulators. We need to identify specific bacteria to determine appropriate classes of antimicrobials, and whether the extent or type of inflammation induced can be modified. If specific behaviors - such as sex during a woman's menstruation or genital hygiene - are associated with types or amounts of harmful penile bacteria, then behavioral interventions will be tested. The potential benefits of interventions stemming from this investigation are: (1) reduced HIV acquisition and transmission through reduction of BV, GUD, and genital epithelial trauma as co-factors for infection, and (2) improved pregnancy outcomes and genitourinary health.

PUBLIC HEALTH RELEVANCE: Using bacterial 16S rRNA gene pyrosequencing to characterize the genital microflora, we will determine how penile anaerobic bacteria increase risk of Bacterial vaginosis, genital ulcer disease, and genital epithelial trauma, and behavioral and biological factors influencing these associations. Interventions stemming from this project would be aimed at improving penile microbiome health, and may include systemic or topical antimicrobials, microbicides incorporating cytokine modulators, or behavioral or hygiene practices that reduce bacteria associated with BV, GUD, and genital epithelial trauma. Such interventions would (1) reduce HIV acquisition and transmission through reduction of BV, GUD, and genital epithelial trauma as co-factors for infection, and (2) improve pregnancy outcomes and genitourinary health.