Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways

通过调节代谢途径重新训练 SIV 中 T 细胞介导的免疫

基本信息

批准号：
10481246
负责人：
ERICA CHRISTINE LARSON
金额：
$ 19.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10481246
关键词：
AIDS/HIV problem Affect Anatomy Animals Antigens Autopsy Bacillus Biological Assay Blood CD8-Positive T-Lymphocytes Cell Survival Cell physiology Cells Cellular Immunity Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular Metabolic Process Chronic Communicable Diseases Complex Disease Progression Energy Metabolism Environment Exhibits FDA approved Fatty Acids Flow Cytometry Genus Hippocampus Glycolysis Goals HIV HIV Antigens HIV Infections HIV/TB Host Defense Human Immune Immunity Immunologics Impairment Individual Infection Investigation Macaca fascicularis Measures Mediating Metabolic Metabolic Pathway Metabolism Metformin Mitochondria Modality Modeling Monitor Mycobacterium tuberculosis Opportunistic Infections Oxidative Phosphorylation PET/CT scan Pathology Pathway interactions Patients Peptides Peripheral Persons Pharmaceutical Preparations Phenotype Plasma Play Predisposition Prevalence Process Role SIV Sampling Signal Transduction Stress T-Lymphocyte Testing Time Tissues Tuberculosis Viral Load result Viral reservoir Virus Diseases X-Ray Computed Tomography antiretroviral therapy co-infection exhaust exhaustion global health immune activation improved lymph nodes nonhuman primate oxidation pathogen programmed cell death protein 1 programs receptor response single-cell RNA sequencing tool uptake

项目摘要

Project Summary/Abstract HIV/AIDS is a chronic infectious disease that affects around 37 million people worldwide. CD8 T cells play a critical role in controlling HIV infection. However, CD8 T cells become exhausted over time due to continuous stimulation. Exhausted HIV-specific CD8 T cells, characterized by elevated expression of inhibitory receptors (e.g. PD-1), positively correlate with higher viral load, impaired T cell function, and disease progression. In HIV and other chronic viral infections, exhausted antigen-specific CD8 T cells expressing PD-1 can create a suppressive environment suggesting that such cells not only have a direct role in disease progression but can cross-talk with other immune cells to impair their function. Chronic HIV infection dysregulates T cell energy metabolism. HIV-specific CD8 T cells isolated from infected individuals exhibit elevated mitochondrial stress which is still apparent years after antiretroviral therapy (ART). PD-1 expression on T cells is associated with mitochondrial stress. PD-1-mediated signaling dysregulates T cell mitochondrial energetics by reducing glycolysis and shifting towards fatty acid b-oxidation and oxidative phosphorylation (OxPhos). Metformin is an FDA-approved drug that dampens OxPhos by inhibiting mitochondrial complex I. To date, most studies investigating metformin use in HIV+ individuals are often in the presence of ART. It has yet to be explored how modulating energy metabolism with metformin impacts host immunity in an ART-naïve setting. HIV not only impairs immune control of the viral infection, but also increases susceptibility to opportunistic infections. People living with HIV are incredibly susceptible to the tuberculosis-causing bacilli, Mycobacterium tuberculosis (Mtb). We previously showed SIV-infected Mauritian cynomolgus macaques (MCM) to be more susceptible to Mtb, which we attributed to immunologic impairment by preexisting SIV infection. Therefore, Mtb challenge is a stringent assessment of host defenses and, given the prevalence of HIV/Mtb co-infection, has great relevance to global health. In this K01 proposal, we will identify pathways involved in energy metabolism in CD8 T cells during chronic HIV infection and reveal their role in T cell exhaustion using our established MCM model of HIV. We will use a comprehensive analytic approach that combines single cell RNA sequencing, metabolic assays, and flow cytometry to assess the role of T cell metabolism in SIV-infected MCM. We will alter metabolism using metformin to reprogram CD8 T cells and determine whether this metabolic reprogramming improves host immunity by challenging SIV+ animals with Mtb.

项目概要/摘要 HIV/艾滋病是一种慢性传染病，影响全球约 3700 万人，CD8 T 细胞发挥着重要作用。然而，CD8 T 细胞在控制 HIV 感染方面发挥着关键作用，但随着时间的推移，由于持续的作用，CD8 T 细胞会耗尽。耗尽的 HIV 特异性 CD8 T 细胞，其特征是抑制性受体表达升高。（例如 PD-1），与 HIV 病毒载量升高、T 细胞功能受损和疾病进展呈正相关。和其他慢性病毒感染时，表达 PD-1 的耗尽的抗原特异性 CD8 T 细胞可以产生抑制环境表明这些细胞不仅在疾病进展中具有直接作用，而且可以与其他免疫细胞的串扰会损害其功能，慢性 HIV 感染会导致 T 细胞能量失调。从感染个体中分离出的 HIV 特异性 CD8 T 细胞表现出线粒体应激升高。 T 细胞上的 PD-1 表达在抗逆转录病毒治疗 (ART) 数年后仍然很明显。 PD-1 介导的信号传导通过减少 T 细胞线粒体能量失调。糖酵解并转向脂肪酸 b-氧化和氧化磷酸化 (OxPhos) 是一种。 FDA 批准的药物通过抑制线粒体复合物 I 来抑制 OxPhos。迄今为止，大多数研究调查 HIV + 个体中二甲双胍的使用通常是在 ART 存在的情况下进行的。目前尚不清楚如何进行。用二甲双胍调节能量代谢不仅会影响未接受过抗逆转录病毒治疗的宿主的免疫力。损害病毒感染的免疫控制，但也会增加对机会性感染的易感性。艾滋病毒感染者疑似易受结核杆菌、结核分枝杆菌 (Mtb) 的感染。我们之前表明感染 SIV 的毛里求斯食蟹猴 (MCM) 更容易感染 Mtb，我们将其归因于先前存在的 SIV 感染导致的免疫损伤，因此 Mtb 挑战是一种挑战。鉴于 HIV/Mtb 混合感染的流行，对宿主防御的严格评估具有很大的相关性为了全球健康。在这个 K01 提案中，我们将确定慢性 HIV 期间 CD8 T 细胞能量代谢的相关途径感染并使用我们建立的 HIV MCM 模型揭示它们在 T 细胞耗竭中的作用。结合单细胞 RNA 测序、代谢测定和流式细胞仪的综合分析方法细胞计数法评估 T 细胞代谢在 SIV 感染的 MCM 中的作用我们将使用二甲双胍改变代谢。重新编程 CD8 T 细胞并确定这种代谢重新编程是否可以通过以下方式改善宿主免疫力：用 Mtb 挑战 SIV+ 动物。