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

 描述(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+)的存活率，但这一成功伴随着包括糖尿病在内的心脏代谢性疾病的沉重负担。对艾滋病毒阴性者的研究表明，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，但缺乏来自艾滋病毒感染者的类似数据，这是一种以先天和获得性免疫功能改变为特征的疾病，这是一个主要的研究差距。迄今关于艾滋病毒阳性者免疫功能和糖耐量的研究一般为1)使用非特异的可溶性炎性生物标志物，而没有研究先天免疫细胞(如单核细胞)和适应性系统的免疫细胞(如T细胞)；2)没有包括艾滋病毒阴性对照，因此不能评估艾滋病毒感染状态是否独立于免疫和其他临床风险因素影响糖尿病风险；3)没有评估免疫细胞亚群、激活和/或衰老与非免疫风险因素，如内脏脂肪和肝脏脂肪，如何相互作用来影响胰岛素抵抗和β细胞功能障碍。我们的建议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细胞和较高的1型T辅助细胞(TH1)，是HIV相关性糖尿病发展的核心。目的1将是第一个检验免疫细胞亚群的表型和功能的差异是否可以解释HIV+和HIV阴性人群中糖尿病发病率差异的研究，这将通过开发退伍军人老龄化队列研究生物标记物队列(Vacs BC)的独特资源而成为可能。Vacs BC是一个预期队列，包括2378名(65%HIV+)成年人，他们拥有可溶的生物标记物、单核细胞和T细胞亚群；纵向健康和行为调查数据，并可以获得综合退伍军人健康系统中的所有临床、实验室和药物数据。这些数据可以在免疫学和临床风险因素的背景下，全面识别艾滋病毒阳性和艾滋病毒阴性受试者中的糖尿病事件(迄今已有222例事件诊断)。目的2将确定HIV感染所特有的免疫细胞激活、耗尽和亚群的深刻变化如何影响胰岛素抵抗和胰岛素分泌。我们将评估最近在范德比尔特大学开始接受抗逆转录病毒治疗的120名HIV+成年人单核细胞和T细胞表型和功能的时间变化与糖耐量变化的关系。我们的方法将包括静脉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的CT测量。我们的研究旨在确定接受抗逆转录病毒治疗的HIV阳性患者的糖尿病前免疫表型。我们的发现可能导致将与代谢性疾病相关的标记物整合到常规护理的流式细胞术中，并为未来的机制研究和治疗试验识别具有高危免疫学特征的患者。

 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.