Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency

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PROJECT SUMMARY Current antiretroviral therapy (ART) regimens have rendered HIV/AIDS a manageable chronic condition rather than a fatal disease, and people living with HIV (PLWH) that initiate ART soon after infection can achieve almost normal life expectancy. This leads to an aging population of PLWH that are increasing subject to a collection of age-associated diseases, including obesity, diabetes, and cardiovascular disease. In spite of effective control of viremia, HIV-induced inflammation is incompletely resolved following ART initiation, and this chronic inflammation leads to a variety of comorbidities, including increased risk for the same age-related diseases. Women living with HIV (WLWH) now comprise the majority of the global HIV/AIDS population and represent the preponderance of new cases. However, women are still underrepresented in clinical studies in spite of significant sex differences in multiple aspects of HIV pathology. As a consequence of the increased survival of PLWH, more WLWH will now undergo menopause and be subject to a disease burden that reflects age, ART-associated chronic inflammation, and, in addition, any adverse consequences of postmenopausal estrogen deficiency. The likely effects of estrogen deficiency will involve changes in systemic metabolic status, white adipose tissue (WAT) function and control of glucose and lipid metabolism, and suppression of the circulating and tissue latent reservoirs based on the recent discovery that estrogen receptor-α is a negative regulator of the HIV reservoir. We hypothesize that estrogen replacement will reduce the scope and severity of ART-associated metabolic comorbidities and facilitate ART suppression of latent reservoirs in WLWH. We propose to address this hypothesis using a unique nonhuman primate model of female rhesus macaques infected with a novel barcoded strain of simian immunodeficiency virus (SIV), then treated with a current ART regimen until full suppression, followed by ovariectomy and subsequent estrogen deficiency or estrogen replacement by silastic implants. This hypothesis will be addressed through pursuit of the following specific aims: Specific Aim 1. Determine the effect of E2 replacement on metabolism and WAT function in an nonhuman primate (NHP) model of postmenopausal WLWH. Female rhesus macaques will be infected with SIV, treated with ART until full suppression, and then ovariectomized with subsequent replacement with premenstrual levels of estrogen or placebo vehicle. Glucose and lipid metabolic parameters and levels of circulating adipocytokines and WAT immune cell profiles and WAT function will be assessed longitudinally throughout the study. Specific Aim 2. Determine the effect of E2 replacement on peripheral, secondary lymphoid, and WAT SIV latent reservoirs. The size, complexity, and clonality of the plasma, cell-associated and inducible, replication-competent reservoirs will be assessed following modulation of estrogen status using multiple quantitation approaches.