Vaginal estradiol versus moisturizer to improve postmenopausal vaginal aging symptoms, dysbiosis and markers of HIV latency reversal in menopausal women living with HIV

Women with HIV (WWH) are living longer and experiencing menopause, which often occurs earlier than in women without HIV (HIV-), reflecting an accelerated aging phenotype. The genitourinary syndrome of menopause (GSM) affects approximately 50% of menopausal women but fewer than 25% receive treatment. This is particularly concerning for WWH as untreated GSM is associated with poor HIV health outcomes. In addition to the need for symptomatic treatment, GSM and menopause are associated with vaginal microbial dysbiosis, defined as replacement of protective lactobacilli with anaerobes. This anaerobic microbiome is linked to an increase in HIV reactivation and viral shedding, but the underlying mechanisms are not understood. Our lab recently identified a novel mechanism. We found that cervicovaginal secretions collected by lavage (CVL) from women with dysbiosis, but not a lactobacillus dominant microbiome, trigger HIV latency reversal using model cell lines and latently infected primary human CD4+ cells. Vaginal estradiol and moisturizer are equally effective for treating GSM symptoms in HIV- women but randomized studies have not been conducted in WWH. Notably, only estradiol reduced dysbiosis in HIV- women and similarly, I also found a reduction in dysbiosis in WWH and GSM treated with estradiol in my 12 week K23 funded study, although the magnitude of the response was smaller than observed in HIV- women. I hypothesize that the more modest effect observed in WWH may reflect the duration of menopause (median 9 years), the negative impact of HIV on the microbiome, and the need for a longer treatment duration in WWH. Thus, building on this framework, we propose a 16 week, randomized, open label study of vaginal estradiol vs. moisturizer in 50 WWH with GSM for £2 years. We will also include a subset of HIV- women with GSM as a comparator arm. In addition to evaluating safety and efficacy, we will focus on changes in the vaginal microbiome as the primary outcome. We hypothesize that both treatments will provide symptomatic improvement, but only estradiol will reduce dysbiosis. We further hypothesize that the decrease in dysbiosis will be associated with a reduction in the ability of CVL to trigger HIV latency reversal. We will conduct proteomic studies to identify the molecules and pathways by which genital tract secretions (CVL) trigger HIV latency reversal. Using vaginal biopsy tissue obtained before and after estradiol treatment in women with and without HIV, we will phenotype cells using novel spatial tri-omics sequencing (RNA, ATAC and Cite-seq) and explore changes in tissue associated microbiota. We predict that there will be differences in the relative proportion of different cell types and gene expression prior to and in response to estradiol between HIV- vs WWH and hypothesize that these differences will correlate with dysbiosis and HIV latency reversal activity. This study has major potential translational importance and may provide rationale for the optimal treatment for GSM if, as we predict, estradiol but not moisturizers improve the vaginal microbiome and reduce HIV latency reversal. We may also identify new targetable mechanisms linking vaginal dysbiosis with HIV reactivation. Project Number: 1R01AG102277-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Kerry Murphy | Institution: ALBERT EINSTEIN COLLEGE OF MEDICINE, BRONX, NY | Award Amount: $706,734 | Activity Code: R01 | Study Section: HIV Comorbidities and Clinical Studies Study Section[HCCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11411827