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，全世界约有3700万人受到影响。CD8 T细胞发挥重要作用 在控制艾滋病毒感染方面的关键作用。然而，随着时间的推移，CD8 T细胞会因为持续的 刺激。疲惫的HIV特异性CD8 T细胞，以抑制受体表达升高为特征 (如PD-1)，与较高的病毒载量、T细胞功能受损和疾病进展呈正相关。在艾滋病中 和其他慢性病毒感染，耗尽的抗原特异性CD8T细胞表达PD-1可以创造一个 抑制性环境表明，这种细胞不仅在疾病进展中有直接作用，而且可以 与其他免疫细胞相互干扰，损害它们的功能。慢性HIV感染使T细胞能量调节失调 新陈代谢。从感染者分离的HIV特异性CD8 T细胞显示高线粒体应激 在抗逆转录病毒治疗(ART)多年后，这一点仍然很明显。T细胞上PD-1的表达与 线粒体应激。PD-1介导的信号通过降低T细胞线粒体能量来调节T细胞能量 糖酵解和转变为脂肪酸b氧化和氧化磷酸化(OxPhos)。二甲双胍是一种 FDA批准的通过抑制线粒体复合体I来抑制OxPhos的药物。到目前为止，大多数研究 在HIV+患者中研究二甲双胍的使用通常是在ART存在的情况下进行的。这还有待于探索它是如何 在一种天真的环境中，用二甲双胍调节能量代谢会影响宿主的免疫力。艾滋病毒不仅仅是 削弱了对病毒感染的免疫控制，但也增加了对机会性感染的易感性。人民 艾滋病毒携带者非常容易感染引起结核病的结核分枝杆菌(结核分枝杆菌)。 我们之前发现，感染SIV的毛里求斯食蟹猴(MCM)对结核分枝杆菌更敏感， 我们将其归因于先前存在的SIV感染造成的免疫损害。因此，MTB挑战是一项 对宿主防御的严格评估，鉴于艾滋病毒/结核分枝杆菌混合感染的流行率，具有很大的相关性 为了全球健康。 在这份K01提案中，我们将确定慢性HIV期间CD8T细胞能量代谢的途径 利用我们建立的HIV的MCM模型，揭示它们在T细胞耗竭中的作用。我们将使用 结合单细胞RNA测序、代谢分析和流动分析的综合分析方法 流式细胞术检测T细胞代谢在SIV感染MCM中的作用我们将使用二甲双胍改变新陈代谢 对CD8T细胞重新编程并确定这种代谢重新编程是否通过以下方式提高宿主免疫力 用结核分枝杆菌挑战SIV+动物。