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

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.