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。

基本信息

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
项目类别：
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

项目摘要

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，基因组不稳定和端粒缩短就证明了这一点。然而，HIV 期间基因组或端粒维护机制如何失调导致 T 细胞衰老感染情况在很大程度上仍然未知。本研究的目的是阐明 HIV 感染的机制加速可能导致T细胞过早衰老的端粒侵蚀，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，端粒完整性是线性染色体的一个关键特征保持基因组稳定性和功能，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，我们最近发现源自 HIV 的 CD4 T 细胞接受抗逆转录病毒治疗 (ART) 的患者和体外接受 ART 治疗的感染 HIV 的原代 CD4 T 细胞，均表现出增强的 DNA 损伤和端粒侵蚀，两者都与严重的细胞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 - 延长端粒 DNA 的端粒酶催化单元）仍然存在完好无损的; 3) 端粒重复结合因子 2（TRF2 - 一种端粒庇护蛋白，可保护端粒免受 DNA 侵害）损伤）和共济失调毛细血管扩张突变（ATM - 一种修复 DNA 损伤的激酶）受到抑制；和 4) 人类端粒锌指相关蛋白（TZAP——一种新发现的端粒相关蛋白，可以与 TRF2 竞争端粒结合并具有修剪端粒 DNA 的核酸酶活性）在 CD4 中上调 HIV 感染期间的 T 细胞。因此，我们假设核酸酶介导的端粒修剪增加由异常的端粒 DNA 损伤和修复信号，和/或受损的端粒 DNA 复制和伸长，参与 HIV 感染期间的端粒磨损。阐明端粒调节机制完整性可能开辟新途径，保护 T 细胞免受不必要的端粒损伤，防止 T 细胞过早衰老，并维持免疫能力。为了建立这个假设，我们将采用转化方法综合离体和体外系统：从急性和慢性 HIV 感染受试者中分离出 CD4 T 细胞或没有 ART；和感染野生型 HIV 的原代 CD4 T 细胞，无论有或没有 ART——体外模型镜像体内 HIV 感染、ART 控制的患者。在目标 1 中，我们将确定 TRF2 和 TZAP 在端粒中的作用 HIV 感染期间的 DNA 损伤和端粒磨损。在目标 2 中，我们将阐明涉及的机制 HIV 感染期间端粒 DNA 伸长受到影响。这项转化研究具有新颖性和临床意义意义重大，因为它将探索减少 T 细胞反应的基本机制，并将解决重要问题端粒 DNA 是如何被破坏以加速 T 细胞衰老以及是否会干扰该酶的问题参与破坏端粒完整性可以在 HIV 感染期间重塑 T 细胞功能。了解这样的机制对于开发改善许多慢性病环境中免疫反应的方法至关重要传染病，包括但不限于艾滋病毒感染。