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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.

项目总结/文摘