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

• 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
• 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

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，影响着全世界约 3700 万人。 CD8 T 细胞发挥 在控制艾滋病毒感染方面发挥着重要作用。然而，随着时间的推移，CD8 T 细胞会因持续的 刺激。 HIV 特异性 CD8 T 细胞耗尽，其特征是抑制性受体表达升高 （例如 PD-1）与较高的病毒载量、受损的 T 细胞功能和疾病进展呈正相关。在艾滋病毒中 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 与其他免疫细胞串扰，损害其功能。慢性 HIV 感染导致 T 细胞能量失调 代谢。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 在抗逆转录病毒治疗（ART）多年后，这种现象仍然很明显。 T 细胞上的 PD-1 表达与 线粒体应激。 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)。二甲双胍是一种 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 研究 HIV+ 个体中二甲双胍的使用情况通常是在 ART 存在的情况下进行的。如何进行还有待探讨 在未接受 ART 的环境中，用二甲双胍调节能量代谢会影响宿主的免疫力。艾滋病不仅 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。人们 艾滋病毒感染者非常容易受到引起结核病的结核杆菌（Mtb）的影响。 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 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 模型揭示其在 T 细胞耗竭中的作用。我们将使用一个 综合分析方法，结合了单细胞 RNA 测序、代谢测定和流式细胞术 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新陈代谢 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。