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.

项目摘要/摘要 艾滋病毒/艾滋病是一种慢性传染病，影响了全球约3700万人。 CD8 T细胞播放 在控制艾滋病毒感染中的关键作用。但是，CD8 T细胞随着时间的推移而耗尽 刺激。耗尽的HIV特异性CD8 T细胞，其特征是抑制受体的表达升高 （例如，PD-1），与较高的病毒载量，T细胞功能受损和疾病进展正相关。在艾滋病毒中 和其他慢性病毒感染，耗尽的抗原特异性CD8 T细胞表达PD-1可以产生 抑制性环境表明，这种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以损害其功能。慢性HIV感染失调T细胞能量 代谢。从受感染个体暴露升高的线粒体应激中分离出的HIV特异性CD8 T细胞 在抗逆转录病毒疗法（ART）之后，这仍然是显而易见的。 T细胞上的PD-1表达与 线粒体应力。 PD-1介导的信号传导通过降低T细胞线粒体能量的失调可减少T细胞线粒体能量传导 糖酵解和向脂肪酸B氧化和氧化磷酸化（OXPHOS）转移。二甲双胍是一个 通过抑制线粒体复合物I的FDA批准的药物I.迄今为止，大多数研究 研究在艾滋病毒+个体中使用二甲双胍的使用通常在艺术存在下。它尚未探讨如何 用二甲双胍调节能量代谢会在不可用的环境中影响宿主免疫。不仅艾滋病毒 损害病毒感染的免疫控制，但也会增加对机会性感染的敏感性。人们 患有艾滋病毒的人非常容易受到结核病，结核分枝杆菌（MTB）的影响。 我们先前显示了SIV感染的毛里求斯cynomolgus猕猴（MCM）更容易受到MTB的影响 我们归因于先前存在的SIV感染的免疫学障碍。因此，MTB挑战是 严格评估宿主防御措施，并且鉴于艾滋病毒/MTB共同感染的流行率很大 全球健康。 在此K01提案中，我们将在慢性HIV期间确定参与CD8 T细胞中能量代谢的途径 使用我们已建立的MCM HIV模型，感染并揭示其在T细胞耗尽中的作用。我们将使用一个 结合单细胞RNA测序，代谢测定和流动的综合分析方法 评估T细胞代谢在SIV感染的MCM中的作用的细胞仪。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编程是否通过 用MTB挑战SIV+动物。