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

雌激素替代对绝经后 ART 相关合并症和病毒潜伏期的影响

• 批准号: 10624286
• 负责人: Paul Kievit
• 金额: $ 84.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624286
• 关键词: AIDS population; Acceleration; Address; Adipocytes; Adipose tissue; Adopted; Adverse effects; Affect; Age; Attenuated; Autopsy; Bar Codes; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cells; Characteristics; Chronic; Clinical Research; Clonality; Collection; DNA; Detection; Diabetes Mellitus; Disease; Endoscopic Biopsy; Epidemic; Estradiol; Estrogen Receptor alpha; Estrogen Replacement Therapy; Estrogen Replacements; Estrogen deficiency; Estrogens; Female; Fibrosis; GAG Gene; Glucose; HIV; HIV Infections; HIV/AIDS; Heart Diseases; Heterosexuals; Homosexuals; Hormone replacement therapy; Hormone use; Hormones; Hybrids; Immune; Implant; In Situ; Incidence; Infection; Inflammation; Ions; Life Expectancy; Lipids; Longevity; Lymphoid; Macaca mulatta; Macrophage; Mediator; Medicine; Menopause; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Monitor; Monkeys; Morbidity - disease rate; Obesity; Ovariectomy; Pathology; Patients; Peripheral; Persons; Placebos; Plasma; Play; Population; Populations at Risk; Postmenopause; Pre-Clinical Model; Predisposition; Proviruses; Quantitative Reverse Transcriptase PCR; RNA; Regimen; Risk; Role; SIV; Severities; Sex Differences; Silastic; Spleen; T-Lymphocyte; Time; Tissue Sample; Tissues; Viral; Viral reservoir; Viremia; Virus; Virus Latency; Visceral; Woman; Women' s Interagency HIV Study; adipokines; adverse outcome; age related; aging population; antiretroviral therapy; blood glucose regulation; burden of illness; comorbidity; demographics; digital; experience; glucose metabolism; latent HIV reservoir; lipid metabolism; lymph nodes; male; men; nonhuman primate; novel; obesity risk; prevent; reproductive senescence; response; subcutaneous; translational model; transmission process; treatment risk

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.

项目概要 当前的抗逆转录病毒治疗（ART）方案已使艾滋病毒/艾滋病成为一种可控制的慢性疾病，而不是 比致命的疾病，艾滋病毒感染者（PLWH）在感染后立即开始抗逆转录病毒治疗几乎可以实现 正常的预期寿命导致感染者人口老龄化，并受到一系列因素的影响。 与年龄相关的疾病，包括肥胖、糖尿病和心血管疾病，尽管得到了有效控制。 病毒血症、HIV 引起的炎症在 ART 开始后未完全解决，并且这种慢性 炎症会导致多种合并症，包括增加患相同年龄相关疾病的风险。 女性艾滋病毒感染者 (WLWH) 目前占全球艾滋病毒/艾滋病人口的大多数，并代表了 尽管新病例占多数，但在临床研究中，女性的代表性仍然不足。 HIV 病理学多个方面的性别差异 由于 PLWH 存活率的增加，更多 WLWH 现在将进入更年期，并承受反映年龄、与 ART 相关的疾病负担 慢性炎症，此外，绝经后雌激素缺乏的任何不良后果。 雌激素缺乏的可能影响将涉及全身代谢状态、白色脂肪组织（WAT）的变化 葡萄糖和脂质代谢的功能和控制，以及循环和组织潜伏的抑制 最近发现雌激素受体-α 是 HIV 病毒库的负调节因子。 我们认为雌激素替代疗法将减少 ART 相关代谢的范围和严重程度 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类灵长类动物模型的假设 猿猴免疫缺陷病毒（SIV）株，然后用当前的 ART 方案治疗直至完全抑制， 随后进行卵巢切除术和随后的雌激素缺乏或通过硅橡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 替代对非人类新陈代谢和 WAT 功能的影响 绝经后 WLWH 的灵长类动物 (NHP) 模型将感染 SIV，并进行治疗。 使用ART直至完全抑制，然后切除卵巢并随后用经前水平替代 雌激素或安慰剂载体的葡萄糖和脂质代谢参数以及循环脂肪细胞因子的水平。 WAT 免疫细胞概况和 WAT 功能将在整个研究过程中进行纵向评估。 具体目标 2. 确定 E2 替代对外周、次级淋巴和 WAT SIV 潜伏的影响 血浆的大小、复杂性和克隆性、细胞相关性和可诱导性、具有复制能力。 将使用多种定量方法调节雌激素状态后评估储存库。