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Background Adolescent girls and young women aged 15‒24 years in sub-Saharan Africa are at disproportionate risk of human immunodeficiency virus (HIV) infection. Given the known association between vaginal microbial dysbiosis and HIV susceptibility, we performed an age-stratified analysis of the vaginal microbiome in South African women and compared this to their risk of HIV acquisition. Methods Vaginal microbiome data were generated by mass spectrometry–based proteomic analysis of cervicovaginal lavages collected from participants (n = 688) in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial. Participants were grouped by age (18–19 years, n = 93; 20–24 years, n = 326; 25–41 years, n = 269). Results Four microbiome types were identified based on predominant taxa, including Lactobacillus crispatus (CST-LC, 12.2%), Lactobacillus iners (CST-LI, 43.6%), Gardnerella vaginalis (CST-GV, 26.6%), or polymicrobial (CST-PM, 15.1%). Women aged 18–19 and 20–24 years had increased CST-PM and a non- Lactobacillus -dominant microbiome compared to those 25–41 years (odds ratio [OR], 3.14 [95% confidence interval {CI}, 1.12–7.87], P =.017; OR, 2.81 [95% CI, 1.07–7.09], P =.038, respectively; and OR, 1.65 [95% CI, 1.02–2.65], P =.028; OR, 1.40 [95% CI, 1.01–1.95], P =.030, respectively). The HIV incidence rate of women with CST-PM microbiome was 7.19-fold higher compared to women with CST-LC (hazard ratio [HR], 7.19 [95% CI, 2.11–24.5], P =.00162), which was also consistent in women aged 20–24 years (HR, 4.90 [95% CI, 1.10–21.9], P =.0375). Conclusions Younger women were more likely to have a higher-risk polymicrobial microbiome suggesting that vaginal microbiota are contributing to increased HIV-1 susceptibility in this group. Clinical Trials Registration NCT00441298. [ABSTRACT FROM AUTHOR]

Alterations to the mucosal environment of the female genital tract, such as genital inflammation, have been associated with increased HIV acquisition in women. As the microbiome and hormonal contraceptives can affect vaginal mucosal immunity, we hypothesized these components may interact in the context of HIV susceptibility. Using previously published microbiome data from 685 women in the CAPRISA-004 trial, we compared relative risk of HIV acquisition in this cohort who were using injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In women who were Lactobacillus-dominant, HIV acquisition was 3-fold higher in women using DMPA relative to women using NET-EN or COC (OR: 3.27; 95% CI: 1.24–11.24, P = 0.0305). This was not observed in non-Lactobacillus-dominant women (OR: 0.95, 95% CI: 0.44–2.15, P = 0.895) (interaction P = 0.0686). Higher serum MPA levels associated with increased molecular pathways of inflammation in the vaginal mucosal of Lactobacillus-dominant women, but no differences were seen in non-Lactobacillus dominant women. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility. Author summary: Alterations to the mucosal environment of the female genital tract have been associated with increased HIV acquisition in women. As both the vaginal microbiome and hormonal contraceptives affect mucosal immunity, we investigated their interaction with HIV susceptibility. We characterized the vaginal microbiomes in 685 women from the CAPRISA-004 trial, who utilized three major types of hormonal contraceptives including injectable depot medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), and combined oral contraceptives (COC). In the 40% of women with Lactobacillus-depleted microbiomes, HIV acquisition was not different between contraceptive groups. However, in the 60% of women with Lactobacillus as the dominant bacterial taxa, HIV acquisition risk was 3-fold higher (in women using DMPA relative to women using NET-EN and COC). Higher serum medroxyprogesterone acetate levels in Lactobacillus dominant women associated with increased cervicovaginal inflammation pathways in the mucosal proteome, biomarkers of which associated with HIV susceptibility. This study provides data suggesting an interaction between the microbiome, hormonal contraceptives, and HIV susceptibility. [ABSTRACT FROM AUTHOR]

Problem: Pregnant women are at increased risk of HIV acquisition, but the biological mechanisms contributing to this observation are not well understood. Method of Study: Here, we assessed host immune and microbiome differences in the vaginal mucosa of healthy pregnant and non‐pregnant women using a metaproteomics approach. Cervicovaginal lavage (CVL) samples were collected from 23 pregnant and 25 non‐pregnant women. Results: Mass spectrometry analysis of CVL identified 550 human proteins and 376 bacterial proteins from 11 genera. Host proteome analysis indicated 56 human proteins (10%) were differentially abundant (P <.05) between pregnant and non‐pregnant women, including proteins involved in angiogenesis (P = 3.36E‐3), cell movement of phagocytes (P = 1.34E‐6), and permeability of blood vessels (P = 1.27E‐4). The major bacterial genera identified were Lactobacillus, Gardnerella, Prevotella, Megasphaera, and Atopobium. Pregnant women had higher levels of Lactobacillus species (P =.017) compared with non‐pregnant women. Functional pathway analysis indicated that pregnancy associated with changes to bacterial metabolic pathway involved in energy metabolism, which were increased in pregnant women (P =.035). Conclusion: Overall, pregnant women showed differences in the cervicovaginal proteome and microbiome that may be important for HIV infection risk. [ABSTRACT FROM AUTHOR]

Problem: Susceptibility to HIV is associated with the menstrual cycle and vaginal microbiome, but their collective impact on vaginal inflammation remains unclear. Here, we characterized the cervicovaginal proteome, inflammation, and microbiome community structure and function during the menstrual cycle. Method of study: Cervicovaginal secretions were collected from regularly cycling women (n = 16) at median day 10, 16, and 24 of each menstrual cycle and analyzed by mass spectrometry, 16S rRNA gene sequencing, and a multiplex bead array immunoassay. Follicular, ovulatory, and luteal phases were defined by serum sex hormone levels. Results: Ovulation showed the largest mucosal proteome changes, where 30% and 19% of the 406 human proteins identified differed compared to the luteal and follicular phases, respectively. Neutrophil/leukocyte migration pathways were lowest during ovulation and peaked in the luteal phase, while antimicrobial and epithelial barrier promoting proteins were highest during ovulation. Vaginal microbial community structure and function did not vary significantly during the menstrual cycle, with the majority consistently Lactobacillus‐dominant (63%) or non‐Lactobacillus‐dominant (25%). Fluctuations in the epithelial barrier protein RPTN between the ovulatory and luteal phase were amplified in women with Gardnerella vaginalis and anaerobic bacteria and reduced when Lactobacillus was dominant. Conclusion: This small study demonstrates that sex hormones modulate neutrophil/leukocyte inflammation, barrier function, and antimicrobial pathways in the female genital tract with the strongest changes occurring during ovulation. The data further suggest a microbiome context for hormone‐driven changes in vaginal immunity which may have implications for HIV susceptibility. [ABSTRACT FROM AUTHOR]

Antiretroviral-based strategies for HIV prevention have shown inconsistent results in women. We investigated whether vaginal microbiota modulated tenofovir gel microbicide efficacy in the CAPRISA (Centre for the AIDS Program of Research in South Africa) 004 trial.Two major vaginal bacterial community types—one dominated by Lactobacillus (59.2%) and the other where Gardnerella vaginalis predominated with other anaerobic bacteria (40.8%)—were identified in 688 women profiled. Tenofovir reduced HIV incidence by 61%(P = 0.013) in Lactobacillus-dominant women but only 18% (P = 0.644) in women with non-Lactobacillus bacteria, a threefold difference in efficacy. Detectible mucosal tenofovir was lower in non-Lactobacillus women, negatively correlating with G. vaginalis and other anaerobic bacteria, which depleted tenofovir by metabolism more rapidly than target cells convert to pharmacologically active drug. This study provides evidence linking vaginal bacteria to microbicide efficacy through tenofovir depletion via bacterial metabolism. [ABSTRACT FROM AUTHOR]