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

项目摘要 目前的抗逆转录病毒疗法（ART）使艾滋病毒/艾滋病成为一种可管理的慢性疾病， 艾滋病毒感染者（PLWH）在感染后不久开始ART， 正常的预期寿命这导致艾滋病毒携带者人口老龄化， 与年龄相关的疾病，包括肥胖、糖尿病和心血管疾病。尽管有效控制了 病毒血症，HIV诱导的炎症在ART开始后不完全消退， 炎症导致多种合并症，包括增加患相同年龄相关疾病的风险。 感染艾滋病毒的妇女现在占全球艾滋病毒/艾滋病人口的大多数， 新病例的优势。然而，尽管在临床研究中取得了重大进展， 艾滋病毒病理学的多个方面存在性别差异。由于艾滋病毒携带者存活率的增加， WLWH现在将经历更年期，并受到反映年龄、ART相关疾病的疾病负担的影响。 慢性炎症，以及绝经后雌激素缺乏的任何不良后果。的 雌激素缺乏的可能影响包括全身代谢状态、白色脂肪组织（WAT） 葡萄糖和脂质代谢的功能和控制，以及循环和组织潜伏性 基于最近发现雌激素受体-α是HIV储库的负调节剂。 我们假设雌激素替代治疗将减少ART相关代谢紊乱的范围和严重程度， 合并症和促进ART抑制潜在水库WLWH。我们建议解决这个问题 使用感染新型条形码的雌性恒河猴的独特非人灵长类动物模型的假设 猴免疫缺陷病毒（SIV）株，然后用目前的ART方案治疗直至完全抑制， 随后是卵巢切除术和随后的雌激素缺乏或用硅橡胶植入物替代雌激素。 将通过追求以下具体目标来解决这一假设： 具体目标1。确定E2替代对非人类代谢和WAT功能的影响 绝经后WLWH的灵长类动物（NHP）模型。雌性恒河猴将感染SIV， ART直至完全抑制，然后切除卵巢，随后用经前水平替代 雌激素或安慰剂载体。糖脂代谢指标与循环脂肪细胞因子水平 并且在整个研究中纵向评估WAT免疫细胞谱和WAT功能。 具体目标2。确定E2替代对外周、次级淋巴和WAT SIV潜伏性的影响。 水库血浆的大小，复杂性和克隆性，细胞相关和诱导，复制能力 在调节雌激素状态后，使用多种定量方法评估储库。

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.