Impact of vaginal microbiome communities on HIV antiretroviral-based pre-exposure prophylaxis (PrEP) drug metabolism

Author summary HIV prevention strategies with antiretroviral drugs as pre-exposure prophylactics (PrEP) are not efficacious in women, in part due to biological factors such as the vaginal microbiome. Lactobacillus spp. prevent the colonization of dysbiotic bacteria (i.e. bacterial vaginosis), which is associated with increased HIV transmission. However, the role these microbes play in altering the pharmacokinetics of PrEP drugs is currently unknown. Here we show that primary bacteria from women with dysbiosis impact PrEP drug levels and kinetics. We found that dysbiotic microbes metabolize PrEP drugs faster than target cell uptake, and significantly alter HIV infection rates in vitro, and this can be predicted with novel computational modeling. Our results demonstrate that the vaginal microbiome may play a key role in HIV prevention through altering therapeutic drug levels via metabolism. Thus, better measurements and interventions for vaginal dysbiosis will be critical in improving the efficacy of HIV prevention efforts in women. Despite the efficacy of antiretroviral-based pre-exposure prophylactics (PrEP) in men who have sex with men, studies in women have produced widely varying outcomes. Recent evidence demonstrates that vaginal microbial communities are associated with increased HIV acquisition risk and may impact PrEP efficacy. Here, we investigate the mechanisms underlying how vaginal bacteria alter PrEP drug levels and impact HIV infection rates ex vivo. Using cervicovaginal lavages (CVLs) from women with or without bacterial vaginosis (BV), we identified microbial metabolism of PrEP drugs in BV samples through LC-MS/MS analysis of soluble drug levels and metabolite formation in dual T-cell cultures. CVL samples were assessed for microbiome analysis using sequencing of bacterial 16S rRNA genes. We also observed non-Lactobacillus bacteria that are associated with BV may potentially impact PrEP efficacy through increased HIV infection rates in co-cultures containing Lactobacillus or BV bacteria, PrEP drugs, CEM-GFP cells, and HIV-1(LAI) virus. Finally, we used these data to develop a novel predictive mathematical simulation modeling system to predict these drug interactions for future trials. These studies demonstrate how dysbiotic vaginal microbiota may impact PrEP drugs and provides evidence linking vaginal bacteria to PrEP efficacy in women.