Mechanism of telomere attrition and premature T cell aging during HIV infection.

HIV 感染期间端粒磨损和 T 细胞过早衰老的机制。

• 批准号: 10402449
• 负责人: Juan Zhao
• 金额: $ 42.8万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402449
• 关键词: Accounting; Acute; Address; Affect; Aging; Apoptosis; Apoptotic; Base Excision Repairs; Binding; Biomedical Research; CD4 Positive T Lymphocytes; Cell Aging; Cell Nucleus; Cell physiology; Cells; Chromosomes; Chronic; Communicable Diseases; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA topoisomerase II alpha; Down-Regulation; Elderly; Enzymes; Event; Exhibits; Functional disorder; Genome; Genome Stability; Genomic Instability; Goals; HIV; HIV Infections; Hallmark Cell; Heat-Shock Proteins 90; Human; Immune; Immune response; Immunocompetence; Immunocompromised Host; Impairment; In Vitro; Individual; Inflammatory; Light; Mediating; MicroRNAs; Nuclear Import; Nuclear Pore Complex; Nucleotides; Pathway interactions; Patients; Persons; Phenotype; Phosphorylation; Phosphotransferases; Process; Proteins; RNA-Directed DNA Polymerase; Role; Signal Transduction; System; T cell response; T-Lymphocyte; TERF2 gene; TP53 gene; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Ubiquitin; Viral; Virus Diseases; Zinc Fingers; age related; antiretroviral therapy; ataxia telangiectasia mutated protein; base; clinically significant; exhaustion; functional disability; improved; improved functioning; in vitro Model; in vivo; novel; nuclease; premature; preservation; prevent; receptor; recruit; senescence; student training; telomere; translational approach; translational study

HIV infection appears to drive premature T cell aging, as evidenced by genomic instability and shortened telomeres. However, how genome or telomere maintenance machineries are dysregulated to drive T cell aging during HIV infection remains largely unknown. The objective of this study is to elucidate the mechanisms by which HIV infection accelerates telomere erosion that may cause premature T cell aging, so as to develop effective means to improve cellular functions in the immunocompromised host. Indeed, telomere integrity is a key feature of linear chromosomes that preserves genome stability and function, whereas telomere erosion is a hallmark of cell aging or senescence that drives cell dysfunction or apoptosis. Importantly, we have recently found that CD4 T cells derived from HIV patients on antiretroviral therapy (ART), and primary CD4 T cells infected with HIV on ART in vitro, both exhibit enhanced DNA damage and telomere erosion, and both are associated with a profound apoptotic and aging phenotypes. We have also shown that 1) telomeric DNA damage and repair machineries are impaired; 2) the human telomerase reverse transcriptase (hTERT - the catalytic unit of telomerase that prolongs telomeric DNA) remains intact; 3) the telomeric repeat binding factor 2 (TRF2 - a telomere shelterin protein that protects telomeres from DNA damage) and the ataxia-telangiectasia mutated (ATM - a kinase that repairs the DNA damage) are inhibited; and 4) the human telomeric zinc-finger associated protein (TZAP - a newly identified telomere-associated protein that can compete with TRF2 for telomere binding and has nuclease activity in trimming telomeric DNA) is upregulated in CD4 T cells during HIV infection. We thus hypothesize that either an increase in nuclease-mediated telomere trimming by an aberrant telomeric DNA damage & repair signaling, and/or a compromised telomeric DNA replication and elongation, are involved in telomere attrition during HIV infection. Elucidating the mechanisms regulating telomere integrity may open new avenues to protect T cells from unwanted telomere damage, prevent premature T cell aging, and maintain immune competence. To establish this hypothesis, we will employ a translational approach using comprehensive ex vivo and in vitro systems: CD4 T cells isolated from acute and chronic HIV-infected subjects with or without ART; and primary CD4 T cells infected with wild-type HIV with or without ART - an in vitro model mirroring HIV-infected, ART-controlled patients in vivo. In Aim 1, we will identify the role of TRF2 and TZAP in the telomeric DNA damage and telomere attrition during HIV infection. In Aim 2, we will elucidate the mechanisms involved in compromising telomeric DNA elongation during HIV infection. This translational study is novel and clinically significant in that it will explore mechanisms fundamental to diminishing T cell responses, and will address important questions as to how telomeric DNA is damaged to accelerate T cell aging and whether interfering with the enzyme involved in disrupting telomere integrity can remodel T cell function during HIV infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of many chronic infectious diseases, including but not limited to HIV infection.

HIV感染似乎会导致T细胞过早衰老，这可以通过基因组不稳定和端粒缩短来证明。