How sex, host microenvironment, and immune responses shape acquisition of genital bacteria that increase HIV risk

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PROJECT SUMMARY Recently, several genital anaerobic bacteria that are not classically associated with sexually transmitted infections (non-STI) were linked to increased heterosexual transmission of HIV, likely by inducing immune responses that enhances HIV target cell activation and recruitment to the genital mucosa. This project seeks to close critical knowledge gaps regarding acquisition and persistent carriage of this new HIV risk factor. Our long-term goals are to elucidate the determinants of genital microbiome composition and the biological mechanisms that link genital bacteria to host susceptibility to HIV, and to leverage this knowledge to develop innovative solutions to prevent HIV. The objective is to understand the heterosexual transmission dynamics of genital bacteria associated with HIV risk and to determine the abiotic and biotic factors that impact acquisition and persistence of these genital bacteria in men. Our central hypothesis is that perturbations affect penile microbiome composition—including acquisition, loss, or persistence of genital bacteria associated with HIV risk—predictably based a set of abiotic and biotic factors. The rationale for this project is that, by understanding the abiotic and biotic factors that determine acquisition, loss, or persistence of specific genital bacteria, we will be able to identify and develop new strategies to prevent or reduce colonization. Aim 1. Elucidate the sexual transmission of genital bacteria and the determinants of the penile microbiome after sex. We will test this by: (i) Characterize the genital bacteria strains present in adolescent boys before and after sexual debut (n = 200) and (ii) Determine the effect of pre-coital host (penile) and partner (vaginal) genital pH, oxygenation, moisture, metabolites, anti-bacteria IgA, and microbiome on the acquisition or persistence (1, 8, and 72 hour post-sex) of genital bacteria in the host (n = 106 couples). Aim 2. Elucidate the determinants of the penile microbiome after antimicrobial treatment. We will test this by comparing pre- and post- treatment (Day 3, 8, and 28) penile microbiomes in 1 control arm and 4 treatment arms, including 3 topical treatments: (i) 2% clindamycin, (ii) 1% H2O2, (iii) 0.75% metronidazole, and (iv) oral tinidazole. Aim 3. Validate the impact of abiotic and biotic factors on the penile microbiome response to perturbation using an in vitro model. We will achieve this aim by adding: (i) donor vaginal microbiome and (ii) topical antimicrobials to penile microbiome in organotypic foreskin model to assess the effect of abiotic factors and bacterial strains on microbiome outcome. The proposed research is innovative, in our opinion, because it represents a departure from the status quo by elucidating transmissible dysbiosis, and doing so with absolute abundance metrics, innovative study designs, and a novel co-culture model. The proposed research is significant because it is expected to reveal how sex and antimicrobials impact penile microbiome and what drives outcome.