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-1LAI 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.
Bibliographical noteFunding Information:
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112254) to N.R.K.; National Institute on Drug Abuse (1DP1DA037979091) to N.R.K.; National Institute of Allergy and Infectious Diseases (5R01Al138718-02) to M.L.A.; National Institute of Allergy and Infectious Diseases (R0101AI138718) to M.L.A. and Miami Women's Interagency HIV Infection Study (WIHS) [U01AI103397]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2020 Cheu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright 2020 Elsevier B.V., All rights reserved.
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