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

项目摘要 接受抗逆转录病毒治疗(ART)的艾滋病毒携带者(PWH)患心脏代谢性疾病的几率较高。 与普通人群相比，这导致了较差的健康结果。脂肪组织是一个关键 全身代谢过程的调节者，以及脂肪组织免疫细胞群的变化 调节脂肪组织的功能，可能在一定程度上导致PWH代谢性疾病的风险。先前的研究 在PWH中，脂肪组织中的CD4+和CD8+T细胞比例发生了显著的变化。然而，目前的情况 到目前为止，对脂肪组织免疫细胞在代谢性疾病中的作用的了解还很少。 评估当代艺术的PWH，有限的研究使用单细胞技术来表征特定的 细胞群体，最终限制了对脂肪组织T细胞群体与 脂肪组织病毒库。确定脂肪组织先天和适应性的机制 免疫细胞参与代谢性疾病是确定预防和治疗策略的关键 可降低PWH的发病率和死亡率。我利用单细胞RNA测序(scRNA-seq)来定义 糖耐量低减患者脂肪组织的成分和转录变化 横断面数据，并将这些变化与糖尿病艾滋病毒阴性的脂肪组织进行比较。我发现更高的 CD4+和CD8+T效应记忆细胞和脂质相关巨噬细胞的比例 与PWH中的葡萄糖耐受相关，以及较高的CD4+和CD8+透射电镜比例与 仅在PWH中有较大的成纤维细胞。我们的总体假设是促炎的透射电子显微镜细胞表达 干扰素-g和肿瘤坏死因子a在ART引起的PWH中升高，渗透脂肪组织，促进 巨噬细胞极化，与脂肪组织病毒库有关，并有助于 代谢性疾病的发展。以我的计算分析技能为基础，我的职业发展 Plans将增强我在以下方面的技能和知识：1)T细胞免疫学和分析；2)进行临床和 翻译研究；以及3)应用多元经济学分析来填补关键的研究空白。在目标1中，我 将定义与以下相关的细胞类型特定转录模式和脂肪组织组成 慢性阻塞性肺疾病患者长期应用抗逆转录病毒治疗后的进行性胰岛素抵抗。在目标2中，我将研究脂肪组织T细胞 整合酶链转移酶治疗前和治疗一年后的转录和组成模式 进展性胰岛素抵抗患者与非进展性胰岛素抵抗患者的以抑制剂为基础的治疗方案比较。 在目标3中，我将确定抗病毒T细胞、脂肪组织病毒库和 脂肪组织发炎。这些目标的完成将极大地提高对具体目标的理解 促进炎症的免疫细胞和驱动炎症的潜在因素。此外， 来自K23奖项的培训和数据将使我能够过渡到艾滋病毒联合研究的独立研究- 疾病领域主要集中在免疫细胞反应上。

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.