Adipose Tissue T Cell Polarization and Metabolic Health in Persons Living with HIV

HIV 感染者的脂肪组织 T 细胞极化和代谢健康

• 批准号: 10619176
• 负责人: Samuel Stuart Bailin
• 金额: $ 18.69万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619176
• 关键词: Address; Adipocytes; Adipose tissue; Biopsy; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiometabolic Disease; Cells; Clinical; Clinical Research; Clinical Trials Design; Collaborations; Complex; Computer Analysis; Data; Deposition; Development; Development Plans; Disease; Enrollment; Fibrosis; Flow Cytometry; Frequencies; Funding; General Population; Genetic Transcription; Glucose Intolerance; HIV; HIV Infections; HIV Seronegativity; Health; Immune; Immunology; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Integrase; Interferon Type II; Interferons; Knowledge; Lipids; Macrophage; Master of Science; Memory; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic Diseases; Metabolism; Morbidity - disease rate; Pattern; Persons; Phenotype; Population; Positioning Attribute; Protocols documentation; Rain; Regimen; Research; Research Personnel; Risk; Role; Sorting; T cell response; T memory cell; T-Lymphocyte; T-cell receptor repertoire; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Sample; Tissues; Training; Transferase; Translational Research; United States National Institutes of Health; Viral; Viral Antigens; Viral reservoir; Virus; antiretroviral therapy; career development; cell type; comorbidity; cytokine; diabetic; differential expression; experience; factor A; high risk; inhibitor; insight; mortality; multiple omics; polarized cell; poor health outcome; preventive intervention; recruit; response; single cell technology; single-cell RNA sequencing; skills

Project Summary Persons with HIV (PWH) on antiretroviral therapy (ART) suffer from higher rates of cardiometabolic diseases compared with the general population, which contributes to poor health outcomes. Adipose tissue is a critical regulator of systemic metabolic processes, and changes in adipose tissue immune cell populations that modulate adipose tissue function, may in part, contribute to the risk of metabolic disease in PWH. Prior studies have shown striking changes in adipose tissue CD4+ and CD8+ T cell profile in PWH. Yet the current understanding of the role of adipose tissue immune cells in metabolic disease is limited by few studies to date evaluating PWH on contemporary ART, limited studies using single cell technologies to characterize specific cell populations, and finally limited understanding of the relationship of adipose tissue T cell populations with adipose tissue viral reservoir. Defining the mechanisms through which adipose tissue innate and adaptive immune cells contribute to metabolic diseases is critical for identifying preventative and therapeutic strategies that reduce morbidity and mortality in PWH. I leveraged single-cell RNA sequencing (scRNA-seq) to define adipose tissue compositional and transcriptional changes that occur with glucose intolerance in PWH using cross-sectional data, and compared these changes to diabetic HIV-negative adipose tissue. I found that higher proportion of CD4+ and CD8+ T effector memory (TEM) cells and lipid-associated macrophages (LAMs) was associated with glucose intolerance in PWH and higher CD4+ and CD8+ TEM proportion were associated with greater fibroblastic cells in PWH only. Our overall hypothesis is that proinflammatory TEM cells expressing interferon-g and tumor necrosis factor a are increased in PWH on ART, infiltrate adipose tissue and promote macrophage polarization, are associated with the adipose tissue viral reservoir, and contribute to the development of metabolic disease. Building upon my computational analysis skills, my career development plan will enhance my skills and knowledge in: 1) T cell immunology and analyses; 2) conducting clinical and translational research; and 3) application of multi-omic analysis to address critical research gaps. In Aim 1, I will define the cell-type specific transcriptional pattern and adipose tissue composition that are associated with progressive insulin resistance in PWH on long-term ART. In Aim 2, I will investigate the adipose tissue T cell transcriptional and compositional pattern pre-treatment and at one year of integrase strand transferase inhibitor-based regimen in those who develop progressive insulin resistance compared with those who do not. In Aim 3, I will determine the relationship between anti-viral T cells, the adipose tissue viral reservoir, and adipose tissue inflammation. Completion of these aims will greatly increase the understanding of specific immune cells contributing to inflammation and the potential factors that drive inflammation. Additionally, the training and data from the K23 award will allow me to transition to research independence in the HIV co- morbidities field with a concentration on immune cell response.

项目摘要 抗逆转录病毒疗法（ART）患有艾滋病毒（PWH）的人患心脏代谢疾病率较高 与普通人群相比，这导致健康结果不良。脂肪组织是关键 系统性代谢过程的调节剂，以及脂肪组织免疫细胞群的变化 调节脂肪组织功能可能部分导致PWH中代谢疾病的风险。先前的研究 在PWH中显示了脂肪组织CD4+和CD8+ T细胞谱的显着变化。但是电流 了解脂肪组织免疫细胞在代谢疾病中的作用受到迄今为止很少的研究的限制 在当代艺术上评估PWH，使用单细胞技术来表征特定的有限研究 细胞群，最后有限地了解脂肪组织T细胞群体与 脂肪组织病毒储层。定义脂肪组织先天和适应性的机制 免疫细胞有助于代谢疾病对于鉴定预防和治疗策略至关重要 这降低了PWH中的发病率和死亡率。我利用单细胞RNA测序（SCRNA-SEQ）定义 使用PWH中葡萄糖不耐症发生的脂肪组织组成和转录变化 横截面数据，并将这些变化与糖尿病性HIV阴性脂肪组织进行了比较。我发现更高 CD4+和CD8+ T效应记忆（TEM）细胞和脂质相关巨噬细胞（LAM）的比例为 与PWH中的葡萄糖不耐症以及较高的CD4+和CD8+ TEPEPTION相关 仅在PWH中较大的成纤维细胞。我们的总体假设是促炎性TEM细胞表达 干扰素-G和肿瘤坏死因子A在ART，浸润脂肪组织的PWH中增加并促进 巨噬细胞极化与脂肪组织病毒储层有关，并有助于 代谢疾病的发展。在我的计算分析技能的基础上，我的职业发展 计划将增强我的技能和知识：1）T细胞免疫学和分析； 2）进行临床和 翻译研究； 3）应用多OMIC分析以解决关键的研究差距。在AIM 1中，我 将定义与细胞类型的特异性转录模式和脂肪组织组成相关的 长期艺术中PWH的渐进性胰岛素抵抗。在AIM 2中，我将研究脂肪组织T细胞 转录和组成模式预处理以及在整合酶链转移酶的一年 与没有抑制剂的抑制剂相比，基于抑制剂的方案与没有抑制剂相比。 在AIM 3中，我将确定抗病毒T细胞，脂肪组织病毒储层和 脂肪组织炎症。这些目标的完成将大大增加对特定的理解 免疫细胞导致炎症和驱动炎症的潜在因素。另外， 来自K23奖的培训和数据将使我能够过渡到研究HIV共同的独立性 浓缩免疫细胞反应的病态场。