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

 描述（由申请人提供）：抗逆转录病毒疗法（ART）的引入提高了HIV感染（HIV+）患者的生存率，但这一成功伴随着心脏代谢疾病（包括糖尿病）的高负担。对HIV阴性者的研究证明了单核细胞和T细胞亚群、葡萄糖耐受不良和糖尿病之间的可重复关系，但缺乏来自HIV感染者的类似数据，HIV感染是一种以先天性和适应性免疫功能改变为特征的疾病，这代表了一个主要的研究空白。 迄今为止对HIV+患者的免疫功能和葡萄糖耐量的研究通常1）使用非特异性可溶性炎症生物标志物，并且没有研究先天性免疫细胞（例如，单核细胞）和适应性系统（例如，T细胞）; 2）不包括HIV阴性对照，因此无法评估HIV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）未评估免疫细胞亚群、激活和/或衰老如何与非免疫风险因素（如内脏和肝脏脂肪）相互作用，以影响胰岛素抵抗和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，持续的单核细胞活化和T细胞变化的汇合，包括调节性T细胞比例降低和1型T细胞比例升高， 辅助性T细胞（TH 1）是HIV相关糖尿病发展的核心。目的1将是第一项研究，以检查免疫细胞亚群的表型和功能的差异是否可以解释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）的独特资源成为可能。VACS BC是一个前瞻性队列，包括2，378名（65% HIV+）成人，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，并可访问综合VA卫生系统中的所有临床、实验室和药物数据。这些数据允许在免疫学和临床风险因素的背景下全面识别HIV+和HIV-阴性受试者中的糖尿病事件（迄今为止有222起事件诊断）。 目的2将确定免疫细胞活化、耗竭和亚群的深刻变化是如何影响胰岛素抵抗和胰岛素分泌的。我们将评估单核细胞和T细胞表型和功能的时间变化如何与最近在范德比尔特大学开始ART的120名HIV阳性成年人的葡萄糖耐量变化相关。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艾滋病毒+ART患者的促糖尿病免疫表型。我们的研究结果可能导致将代谢疾病相关标志物整合到常规护理流式细胞术中，并确定具有高风险免疫特征的患者，用于未来的机制研究和治疗试验。

 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.