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

项目总结 目前的抗逆转录病毒疗法(ART)已经使艾滋病毒/艾滋病成为一种可控的慢性疾病 一种致命的疾病，感染后不久启动抗逆转录病毒治疗的艾滋病毒携带者(PLWH)几乎可以实现 正常预期寿命。这导致了PLWH人口的老龄化，这些人口正在增加，这是由于 与年龄相关的疾病，包括肥胖、糖尿病和心血管疾病。尽管有效地控制了 病毒血症，艾滋病毒引起的炎症在ART开始后没有完全解决，这是慢性 炎症会导致各种共病，包括增加与年龄相关的疾病的风险。 妇女艾滋病毒携带者(WLWH)现在构成全球艾滋病毒/艾滋病人口的大多数，是 以新发病例为主。然而，女性在临床研究中的代表性仍然不足，尽管有显著的 HIV病理多方面的性别差异。作为PLWH存活率提高的结果，更多 WLWH现在将经历更年期，并受到反映年龄、与ART相关的疾病负担的影响 慢性炎症，以及绝经后雌激素缺乏的任何不良后果。这个 雌激素缺乏的可能影响包括全身代谢状态的改变，白色脂肪组织(WAT) 糖脂代谢的功能和控制，循环和组织潜伏期的抑制 基于最近发现的雌激素受体-α是艾滋病毒宿主的负调节因子。 我们假设雌激素替代将减少ART相关代谢的范围和严重程度。 WLWH潜伏油气藏的共生和促进ART抑制。我们建议解决这个问题 使用独特的非人灵长类动物模型对感染新型条形码的雌性恒河猴的假说 猴免疫缺陷病毒(SIV)株，然后用目前的ART方案治疗，直到完全抑制， 然后是卵巢切除和随后的雌激素缺乏症或硅胶植入物替代雌激素。 这一假设将通过追求以下具体目标来解决： 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的灵长类动物模型。雌性恒河猴将感染SIV，接受治疗 ART，直到完全抑制，然后卵巢切除，随后用经前水平替换 雌激素或安慰剂。糖脂代谢参数与循环脂肪细胞因子水平 WAT免疫细胞图谱和WAT功能将在整个研究过程中进行纵向评估。 特定目的2.确定E2替代对外周血、次级淋巴系统和Wat SIV潜伏期的影响 水库。胞浆的大小、复杂性和克隆性，与细胞相关且可诱导，具有复制能力 在调节雌激素状态后，将使用多种定量方法对水库进行评估。

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.