Background: The injectable hormonal contraceptive depot medroxyprogesterone acetate (DMPA) has been associated with increased risk of HIV-1 acquisition in women, but observations have been inconsistent between studies. We used a proteomics-based systems biology approach to examine whether the vaginal microbiome influences inflammation and rates of HIV incidence in women using different hormonal contraceptives in an HIV prevention trial in South Africa (n=685).
Methods: Cervicovaginal mucosal specimens from 61 women who went on to acquire HIV within the trial (cases), and all available women who remained uninfected (controls, n=624), were analyzed by mass spectrometry-based proteomics.
Results: Nearly all women were using hormonal contraceptives (97.7%) including DMPA (65.6%), norethisterone enanthate (NET-EN) (18.0%), and combined oral contraceptives (COC) (14.2%). Two major vaginal microbiome profiles were observed, one dominated by Lactobacillus species (59.4%), and the other that was non-Lactobacillus dominant (40.6%), where Gardnerella vaginalis predominated with other facultative and anaerobic bacteria. Microbiome groups were similarly distributed among contraceptive types. A case-control analysis showed the probability of HIV infection was not different in those using DMPA when compared to NET-EN and COC users as a single group (OR: 1.56, 95% CI: 0.87 to 2.95, P=0.151). In non-Lactobacillus dominant women, the risk of HIV acquisition was not significantly higher in those using DMPA compared to all other hormonal contraceptives (OR: 0.95, 95% CI: 0.44 to 2.15, P=0.895). However, in Lactobacillus­-dominant women, DMPA use was associated with a >3-fold increase in HIV acquisition risk for DMPA users relative to women using other hormonal contraceptives (OR: 3.27; CI: 1.24 to 11.24, P=0.0305). Interaction analysis suggested a statistical trend toward the vaginal microbiome having an impact on DMPA-associated HIV-risk (P=0.0686). Serum MPA levels associated with increased glucose metabolism and immune activation pathways in cervicovaginal mucosa in Lactobacillus-dominant women, which were already activated in non-Lactobacillus dominant women, and these biomarkers associated with increased frequency of activated cervical CD4+ T-cells (HLA-DR+CD38+).
Conclusions: This study provides evidence that women with vaginal Lactobacillus may be more susceptible to the negative influences of DMPA-associated genital inflammation and HIV acquisition risk.

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