The impact of HIV on accelerated aging in the female genital tract: a pilot trial of topical estradiol to improve the vaginal microbiome and symptoms of vaginal atrophy in menopausal women with HIV

HIV is associated with accelerated and/or accentuated aging, which may be mediated by chronic inflammation, immune senescence, and/or long-term antiretroviral therapy. This translates to earlier incidence and increased prevalence of aging-related conditions including cardiovascular, neurocognitive and bone disease. Accelerated aging may also manifest as earlier and more significant changes in the female genital tract (FGT) mucosal environment, which may increase risk or severity of vaginal atrophy, urinary tract and other infections. However, the effects of HIV on FGT aging have received scant attention. Aging-associated changes in the FGT include dysbiosis of the vaginal microbiome (characterized by a predominance of diverse anaerobes and a decrease in acid-producing lactobacilli), increased inflammation, and disruption of epithelial integrity. Menopausal women living with HIV (WLWH) are more likely to develop symptoms at an earlier age than HIV- seronegative (HIV-) women. Further, our data suggests that dysbiosis occurs earlier in WLWH and is more pronounced in older compared to younger WLWH suggesting that dysbiosis may be impacted by both HIV infection and age. Although the precise mechanisms by which dysbiosis is linked to inflammation are unclear, coating of bacteria with antibodies may be a key factor. We will utilize a novel technique to measure the microbiome, IgSeq, which combines flow cytometry-based bacterial cell sorting and 16S rRNA sequencing to characterize immunoglobulin (Ig) coating of bacteria in the FGT with the hypothesis that Ig coating of bacteria may be protective and reduced in the setting of HIV and dysbiosis. To determine if HIV is associated with earlier and more significant age-associated changes in the FGT, we will conduct a cross-sectional study in 50 HIV+ and 50 HIV- menopausal women to compare changes in the vaginal microbiome and mucosal inflammation. We hypothesize that menopausal WLWH will develop genital tract aging earlier than HIV- menopausal women and that the magnitude of difference in aging biomarkers including increased dysbiosis, less bacterial Ig coating, and increased mucosal inflammation will be greater when comparing younger (45-55 years) and older (56-70 years) menopausal WLWH to younger and older HIV- menopausal women. Estrogen has been shown to improve atrophy symptoms and the vaginal microbiome in HIV- postmenopausal women but has not been studied in menopausal WLWH. We will therefore conduct a pilot randomized clinical trial in 50 HIV+ menopausal women with symptomatic vaginal atrophy to test the hypothesis that vaginal estradiol treatment will result in a more optimal Ig coated lactobacillus-dominant vaginal microbiome, reduction in mucosal inflammation, and improvement in symptoms. I will develop expertise in the conduct of clinical trials/studies in aging populations and cutting-edge laboratory techniques (IgSeq, RNAseq). I will also pursue training in analysis of microbiome data including metagenomics. This award will allow me to become an independently funded clinician scientist studying the impact of HIV on mucosal immunity and aging in the FGT.