Impact of reproductive aging on the vaginal microbiome and soluble immune mediators in women living with and at-risk for HIV infection

BACKGROUND: Reproductive aging may impact the vaginal microbiome and genital tract mucosal immune environment and contribute to genital tract health in women living with and at-risk for HIV infection. METHODS: A cross-sectional study of 102 HIV+ (51 premenopausal, 51 postmenopausal) and 39 HIV-uninfected (HIV-) (20 premenopausal, 19 postmenopausal) women was performed in Bronx and Brooklyn, NY. Cervicovaginal lavage (CVL) was collected for quantification of innate antimicrobial activity against E. coli, HSV-2 and HIV and immune mediators by Luminex and ELISA. Microbiome studies by qPCR and 16S rRNA sequencing were performed on vaginal swabs. RESULTS: HIV+ postmenopausal compared to premenopausal participants had lower median E. coli bactericidal activity (41% vs. 62%, p = 0.001), lower median gene copies of Lactobacillus crispatus (p = 0.005) and Lactobacillus iners (p = 0.019), lower proportions of Lactobacillus iners, higher proportions of Gardnerella and Atopobium vaginae and lower levels of human beta defensins (HBD-2, HBD-3) and secretory leukocyte protease inhibitor (SLPI), p<0.001. HSV-2 inhibitory activity was higher in HIV+ postmenopausal compared to premenopausal participants (37% vs. 17%, p = 0.001) and correlated with the proinflammatory molecules interleukin (IL) 6, IL-8, human neutrophil peptide (HNP) 1–3, lactoferrin and fibronectin. Similar trends were observed in HIV- postmenopausal compared to premenopausal participants. HIV inhibitory activity did not differ by reproductive status in the HIV+ participants but was significantly higher in HIV- postmenopausal compared to premenopausal participants and in participants with suppressed plasma viral load, and inversely correlated with gene copies of G. vaginalis and BVAB2. A significant proportion of HIV+ participants on ART exhibited HIV enhancing activity. CONCLUSIONS: HIV+ postmenopausal compared to premenopausal participants have less CVL E. coli bactericidal activity, reflecting a reduction in Lactobacilli and a greater proportion of Gardnerella and A. vaginae, and more HSV-2 inhibitory activity, reflecting increased mucosal inflammation. The effect of menopause on mucosal immunity was greater in HIV+ participants, suggesting a synergistic impact. Promotion of a lactobacillus dominant vaginal microbiome and reduced mucosal inflammation may improve vaginal health and reduce risk for shedding of HIV and potential for HIV transmission in HIV+ menopausal women.