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细胞过早老化，这可以通过基因组不稳定性和端粒缩短来证明。 然而，基因组或端粒维持机制如何失调，以推动艾滋病毒感染期间的T细胞老化， 感染情况仍然不明。本研究的目的是阐明艾滋病毒感染的机制， 加速端粒侵蚀，可能导致T细胞过早老化，从而开发有效的手段来改善 免疫受损宿主的细胞功能。事实上，端粒的完整性是线性染色体的一个关键特征 而端粒侵蚀是细胞衰老或衰老的标志 导致细胞功能障碍或细胞凋亡。重要的是，我们最近发现来自HIV的CD 4 T细胞 接受抗逆转录病毒治疗（ART）的患者和体外ART中感染HIV的原代CD 4 T细胞均表现出 增强的DNA损伤和端粒侵蚀，两者都与深刻的凋亡和衰老有关。 表型我们还表明：1）端粒DNA损伤和修复机制受损; 2）人类 端粒酶逆转录酶（hTERT -端粒酶的催化单位，即端粒DNA）仍然存在 端粒重复序列结合因子2（TRF 2-一种保护端粒免受DNA损伤的端粒保护蛋白 损伤）和共济失调-毛细血管扩张突变（ATM -修复DNA损伤的激酶）被抑制;和4） 人类端粒锌指相关蛋白（TZAP）是一种新发现的端粒相关蛋白， 与TRF 2竞争端粒结合，并在修剪端粒DNA中具有核酸酶活性）在CD 4+细胞中上调 HIV感染时的T细胞因此，我们假设，核酸酶介导的端粒修剪增加， 通过异常的端粒DNA损伤和修复信号传导，和/或受损的端粒DNA复制， 延长，参与端粒磨损在HIV感染。阐明端粒的调控机制 完整性可能会开辟新的途径，以保护T细胞免受不必要的端粒损伤，防止T细胞过早老化， 维持免疫能力为了建立这一假设，我们将采用一种翻译方法， 全面的离体和体外系统：从急性和慢性HIV感染受试者分离的CD 4 T细胞， 或不使用ART;以及用野生型HIV感染的原代CD 4 T细胞，使用或不使用ART -一种体外模型， 体内HIV感染、ART控制的患者。在目标1中，我们将确定TRF 2和TZAP在端粒调控中的作用。 HIV感染过程中DNA损伤和端粒磨损。在目标2中，我们将阐明 在HIV感染期间损害端粒DNA延长。这项转化研究是新颖的， 重要的是，它将探索减少T细胞反应的基本机制，并将解决重要的 关于端粒DNA如何被破坏以加速T细胞老化以及是否干扰酶的问题 参与破坏端粒完整性可以重塑HIV感染期间的T细胞功能。理解这些 在许多慢性疾病的背景下，免疫机制对于开发改善免疫应答的方法至关重要。 感染性疾病，包括但不限于HIV感染。