Mechanism of telomere attrition and premature T cell aging during HCV infection

HCV感染过程中端粒磨损和T细胞过早衰老的机制

• 批准号: 10745519
• 负责人: Juan Zhao
• 金额: $ 27.63万
• 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/10745519
• 关键词: Acceleration; Accounting; Administrative Supplement; Affect; Aftercare; Aging; Antiviral Agents; Apoptosis; Apoptotic; Award; Biological Models; Biomedical Research; CD4 Positive T Lymphocytes; Cell Aging; Cell Nucleus; Cell Separation; Cell physiology; Chronic; Chronic Hepatitis C; Communicable Diseases; Competence; DNA; DNA Damage; DNA Repair; DNA biosynthesis; Development; Disease; Down-Regulation; Environment; Enzymes; Exhibits; Functional disorder; Genome Stability; Genomic Instability; Goals; HIV; Health; Heat-Shock Proteins 90; Hepatitis C; Hepatitis C virus; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunocompetence; Impairment; Individual; Infection; Inflammatory; Institution; Mediating; MicroRNAs; Modeling; Molecular; Nuclear Import; Nuclear Pore Complex; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Process; Proteins; RNA-Directed DNA Polymerase; Research; Research Personnel; Research Training; Role; Scientist; Signal Transduction; T cell response; T-Lymphocyte; TERF2 gene; TP53 gene; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Training; Ubiquitin; Viral; Virus Diseases; age related; ataxia telangiectasia mutated protein; career development; clinically significant; design; disadvantaged women; exhaustion; functional disability; functional improvement; improved; next generation; novel; nuclease; premature; prevent; receptor; recruit; senescence; student training; success; telomere; translational approach; translational study; vaccine access; virus host interaction

Chronic viral infections appear to drive premature T cell aging, as evidenced by accelerated shortening of telomeres. However, how telomeres are trimmed to drive T cell aging during viral infection remains unclear. The goal of this study is to elucidate the mechanisms by which chronic viral infection accelerates the telomere attrition that may cause premature T cell aging, so as to develop effective means to improve cellular functions in virally infected individuals. To this end, we will employ hepatitis C virus (HCV) infection as a model system because i) HCV has a high rate (70%-80%) of persistence in humans; ii) the recent success in developing direct-acting antivirals (DAA) has resulted in a high rate (>95%) of viral clearance, providing an excellent opportunity to study the role of viral infection in modulating the host immunity before and after treatment in humans; iii) there is no vaccine available for HCV thus far, in part due to the unclear virus-host interactions that induce T cell senescence and immune dysfunction; and iv) we have recently found that CD4 T cells derived from HCV patients exhibit enhanced DNA damage and telomere erosion that are associated with a profound apoptotic and aging phenotype. Mechanistically, we have recently demonstrated that telomeric DNA damage and repair machineries are impaired in CD4 T cells during HCV infection: while the human telomerase reverse transcriptase (hTERT, the catalytic unit of telomerase that prolongs telomeric DNA) remains intact; 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 in HCV CD4 T cells. We thus hypothesize that either an increased nuclease-mediated telomere trimming by aberrant telomeric DNA damage and repair signaling and/or a compromised telomeric DNA elongation is involved in the telomere attrition during chronic HCV infection. We designed two specific aims and will employ a translational approach using CD4 T cells from HCV-infected subjects before and after DAA treatment, to test our hypothesis. In Aim 1, we will identify the role of TRF2 in the telomeric DNA damage and telomere attrition during HCV infection. In Aim 2, we will elucidate the mechanisms involved in compromising telomeric DNA elongation during HCV 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 viral infection. Understanding such mechanisms is critical for developing approaches to improve immune responses in the setting of various chronic infectious diseases, including but not limited to HCV infection.

慢性病毒感染似乎会导致T细胞过早老化，这一点可以通过T细胞的加速缩短来证明。 端粒然而，在病毒感染期间，端粒如何被修剪以驱动T细胞老化仍不清楚。的 本研究的目的是阐明慢性病毒感染加速端粒磨损的机制 可能导致T细胞过早老化，以便开发有效的手段来改善病毒感染中的细胞功能。 感染的人。为此，我们将采用丙型肝炎病毒（HCV）感染作为模型系统，因为i） HCV在人类中具有高的持续率（70%-80%）; ii）最近成功开发了直接作用的抗HCV药物， 抗病毒药物（DAA）的病毒清除率很高（>95%），为研究 病毒感染在人类治疗前后调节宿主免疫力的作用; iii）没有 迄今为止，HCV疫苗的可用性，部分原因是诱导T细胞衰老的病毒-宿主相互作用尚不清楚 和免疫功能障碍; iv）我们最近发现来自HCV患者的CD 4 T细胞表现出 增强的DNA损伤和端粒侵蚀与严重的细胞凋亡和衰老相关， 表型从机制上讲，我们最近已经证明端粒DNA损伤和修复机制 在HCV感染期间在CD 4 T细胞中受损：而人端粒酶逆转录酶（hTERT， 端粒酶的催化单位（端粒DNA）保持完整;端粒重复结合因子 2（TRF 2，一种保护端粒免受DNA损伤的端粒保护蛋白）和共济失调-毛细血管扩张症 突变的（ATM，一种修复DNA损伤的激酶）在HCV CD 4 T细胞中受到抑制。因此我们假设 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延长参与慢性炎症过程中的端粒磨损。 HCV感染。我们设计了两个特定的目标，并将采用一种使用CD 4 T细胞的翻译方法， HCV感染者在DAA治疗前后，以检验我们的假设。在目标1中，我们将确定 TRF 2在HCV感染时端粒DNA损伤和端粒磨损中的作用。在目标2中，我们将阐明 HCV感染时端粒DNA延长受损的机制。这种平移 这项研究是新颖和具有临床意义的，因为它将探索减少T细胞的基本机制， 反应，并将解决重要的问题，如端粒DNA是如何损坏，以加速T细胞老化 以及干扰参与破坏端粒完整性的酶是否可以重塑T细胞功能 在病毒感染期间。了解这些机制对于开发改善免疫功能的方法至关重要。 在各种慢性感染性疾病，包括但不限于HCV感染的情况下的反应。