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: 10596151
• 负责人: ERICA CHRISTINE LARSON
• 金额: $ 19万
• 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/10596151
• 关键词: Affect; Anatomy; Animals; Antigens; Autopsy; Bacillus; Biological Assay; Blood; CD8-Positive T-Lymphocytes; Cell Communication; Cell Separation; 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/AIDS; 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; Phosphorylation Inhibition; 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.

项目总结/摘要 艾滋病毒/艾滋病是一种慢性传染病，影响着全世界约3 700万人。CD 8 T细胞发挥着 在控制艾滋病毒感染方面发挥重要作用。然而，CD 8 T细胞随着时间的推移由于持续的免疫应答而变得耗尽。 刺激.耗尽的HIV特异性CD 8 T细胞，特征为抑制性受体表达升高 (e.g. PD-1），与较高的病毒载量、受损的T细胞功能和疾病进展正相关。艾滋病毒 和其他慢性病毒感染时，表达PD-1的耗尽的抗原特异性CD 8 T细胞可以产生一种免疫应答。 抑制性环境，这表明这些细胞不仅在疾病进展中起直接作用， 与其他免疫细胞发生串扰以损害其功能。慢性HIV感染使T细胞能量失调 新陈代谢.从感染个体中分离的HIV特异性CD 8 T细胞表现出线粒体应激升高 这在抗逆转录病毒治疗（ART）后的几年仍然很明显。T细胞上的PD-1表达与 线粒体应激PD-1介导的信号转导通过减少T细胞线粒体能量失调 糖酵解和向脂肪酸b-氧化和氧化磷酸化（OxPhos）转变。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 研究二甲双胍在HIV+个体中的使用通常是在ART存在的情况下进行的。 二甲双胍调节能量代谢影响ART初治环境中的宿主免疫力。艾滋病不仅 削弱对病毒感染的免疫控制，但也增加对机会性感染的易感性。人 艾滋病毒感染者对结核杆菌（Mtb）非常敏感。 我们先前显示SIV感染的猕猴（MCM）对Mtb更敏感， 我们将其归因于先前存在的SIV感染引起的免疫损伤。因此，Mtb挑战是一种 严格评估宿主防御能力，并考虑到艾滋病毒/结核病合并感染的流行， to global全球health健康. 在这个K 01提案中，我们将确定慢性HIV感染期间CD 8 T细胞中参与能量代谢的途径。 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。我们将使用一个 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 流式细胞术以评估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 重编程CD 8 T细胞，并确定这种代谢重编程是否通过以下方式提高宿主免疫力： 用Mtb攻击SIV+动物。