Innate and Adaptive Immunity in HIV-associated Impaired Glucose Tolerance and Diabetes

HIV 相关糖耐量受损和糖尿病中的先天免疫和适应性免疫

• 批准号: 9260968
• 负责人: John Koethe
• 金额: $ 41.24万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9260968
• 关键词: Innate; Adaptive; Immunity; HIV; associated

 DESCRIPTION (provided by applicant): The introduction of antiretroviral therapy (ART) has improved survival among people with HIV infection (HIV+), but this success is accompanied by a high burden of cardiometabolic diseases, including diabetes mellitus. Studies of HIV-negative persons demonstrate reproducible relationships between monocyte and T- cell subsets, glucose intolerance, and diabetes, but the lack of similar data from persons with HIV infection, a disease characterized by alterations in innate and adaptive immune function, represents a major research gap. Studies to date of immune function and glucose tolerance in HIV+ persons generally 1) used non- specific soluble inflammatory biomarkers and did not investigate immune cells of the innate (e.g., monocytes) and adaptive systems (e.g., T-cells); 2) did not included HIV-negative controls, and therefore could not assess whether HIV status affects diabetes risk independent of immune and other clinical risk factors; and 3) did not assess how immune cell subsets, activation, and/or senescence interact with non-immune risk factors, such as visceral and hepatic fat, to affect insulin resistance and beta-cell dysfunction. Our proposal addresses these research gaps. Our overarching hypothesis is that persistent monocyte activation and a confluence of T-cell changes, including a lower proportion of regulatory T-cells and higher Type 1 T-helper (TH1) cells, are central to the development of HIV-associated diabetes. Aim 1 will be the first study to examine if differences in the phenotype and function of immune cell subsets can explain differences in incident diabetes cases in HIV+ versus HIV-negative people, which will be possible by exploiting the unique resources of the Veterans Aging Cohort Study biomarker cohort (VACS BC). The VACS BC is a prospective cohort of 2,378 (65% HIV+) adults with soluble biomarkers, monocyte and T-cell subsets; longitudinal health and behavior survey data, and access to all clinical, laboratory, and medication data in the integrated VA health system. These data allow for the comprehensive identification of incident diabetes in HIV+ and HIV- negative subjects (222 incident diagnoses to date) in the context of immunologic and clinical risk factors. Aim 2 will determine how the profound changes in immune cell activation, exhaustion, and subsets that are characteristic of HIV infection impact insulin resistance and insulin secretion. We will assess how temporal changes in monocyte and T-cell phenotype and function are related to changes in glucose tolerance among 120 HIV+ adults recently started on ART at Vanderbilt University. Our approach will incorporate intravenous and oral glucose tolerance assessments, monocyte and T-cell flow cytometry, health and behavior assessments, and CT measurements of visceral, hepatic, and other adipose tissue deposits. Our study is designed to define the pro-diabetic immunologic phenotype in HIV+ persons on ART. Our findings could lead to the integration of markers relevant to metabolic disease into routine-care flow cytometry, and identify patients with high-risk immunologic profiles for future mechanistic studies and therapeutic trials.

 描述（由申请人提供）：抗逆转录病毒疗法（ART）的引入提高了艾滋病毒感染者（HIV+）的生存率，但这一成功也伴随着包括糖尿病在内的心脏代谢疾病的沉重负担。对 HIV 阴性者的研究表明，单核细胞和 T 细胞亚群、葡萄糖耐受不良和糖尿病之间存在可重复的关系，但缺乏来自 HIV 感染者的类似数据（一种以先天性和适应性免疫功能改变为特征的疾病），这是一个重大的研究空白。 迄今为止，HIV+人群的免疫功能和葡萄糖耐量研究通常1）使用非特异性可溶性炎症生物标志物，并且没有研究先天免疫细胞（例如单核细胞）和适应性系统（例如T细胞）； 2) 未纳入 HIV 阴性对照，因此无法评估 HIV 状态是否会独立于免疫和其他临床危险因素而影响糖尿病风险； 3) 没有评估免疫细胞亚群、激活和/或衰老如何与非免疫危险因素（例如内脏脂肪和肝脂肪）相互作用，从而影响胰岛素抵抗和β细胞功能障碍。我们的提案解决了这些研究空白。我们的总体假设是，持续的单核细胞激活和 T 细胞变化的汇合，包括较低比例的调节性 T 细胞和较高比例的 1 型辅助性 T (TH1) 细胞，是 HIV 相关糖尿病发生的核心。目标 1 将是第一项研究，检验免疫细胞亚群的表型和功能差异是否可以解释 HIV+ 与 HIV 阴性人群中糖尿病发病病例的差异，这将通过利用退伍军人衰老队列研究生物标志物队列 (VACS BC) 的独特资源来实现。 VACS BC 是一个由 2,378 名（65% HIV+）成年人组成的前瞻性队列，具有可溶性生物标志物、单核细胞和 T 细胞亚群；纵向健康和行为调查数据，以及访问综合 VA 卫生系统中的所有临床、实验室和药物数据。这些数据可以在免疫学和临床危险因素的背景下，全面识别 HIV+ 和 HIV 阴性受试者的糖尿病发病情况（迄今为止已确诊 222 例）。 目标 2 将确定 HIV 感染特征性免疫细胞激活、耗竭和亚群的深刻变化如何影响胰岛素抵抗和胰岛素分泌。我们将评估范德比尔特大学最近开始接受 ART 的 120 名 HIV+ 成年人中单核细胞和 T 细胞表型和功能的时间变化与糖耐量变化之间的关系。我们的方法将结合静脉内和口服葡萄糖耐量评估、单核细胞和 T 细胞流式细胞术、健康和行为评估以及内脏、肝脏和其他脂肪组织沉积物的 CT 测量。 我们的研究旨在确定接受 ART 治疗的 HIV+ 患者的促糖尿病免疫表型。我们的研究结果可能导致将与代谢疾病相关的标记物整合到常规护理流式细胞术中，并识别具有高风险免疫特征的患者，以用于未来的机制研究和治疗试验。