The Impact of the Vaginal Microbiome and Microbial Metabolites on HIV Transmission at the Female Reproductive Tract Epithelial Barrier

ABSTRACT

Despite major advances in biomedical HIV prevention strategies, almost 50% of the 1.3 million new HIV infections in 2024 occurred in women and girls through heterosexual transmission. Choice in HIV prevention modalities is needed throughout a women's lifespan to increase pre‐exposure prophylaxis uptake; however, there is a paucity of topical, on‐demand options. To establish HIV infection, the virus translocates across the epithelial barrier of the upper and lower female reproductive tract to infect CD4 + HIV target cells in the submucosa. The vaginal microbiome modulates this process. Women colonised with an optimal Lactobacillus ‐dominated vaginal microbiota are more protected against acquiring HIV compared to women with a non‐optimal vaginal microbiota including bacterial vaginosis (BV), characterised by an overgrowth of diverse anaerobes and a paucity of beneficial lactobacilli. Optimal Lactobacillus spp. produce ∼1% lactic acid, which in women with a Lactobacillus ‐dominant microbiota acidifies the vaginal pH to less than 4.5, inactivates HIV, exerts antimicrobial effects against BV–associated bacteria, directly inhibits inflammatory responses elicited from cervicovaginal epithelial cells and blocks HIV translocation in vitro. Beneficial properties of optimal vaginal lactobacilli and/or lactic acid can potentially be exploited in vaginal delivery strategies to help prevent vaginal dysbiosis and its adverse sexual and reproductive outcomes including HIV.