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.
