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

慢性病毒感染似乎导致T细胞过早老化，这一点从T细胞的加速缩短得到了证明。 端粒。然而，端粒如何在病毒感染期间被修剪以驱动T细胞老化仍不清楚。这个 本研究的目的是阐明慢性病毒感染加速端粒磨损的机制。 这可能会导致T细胞过早衰老，从而开发出有效的手段来改善病毒的细胞功能 被感染的人。为此，我们将使用丙型肝炎病毒(丙型肝炎病毒)感染作为模型系统，因为i) 丙型肝炎病毒在人类中的持续率很高(70%-80%)；ii)最近成功地开发了直接作用 抗病毒药物(DAA)的病毒清除率很高(95%)，为研究提供了一个极好的机会 病毒感染在调节人类治疗前后宿主免疫中的作用；iii)没有 到目前为止，可用于丙型肝炎病毒的疫苗，部分原因是诱导T细胞衰老的不清楚的病毒-宿主相互作用 和免疫功能障碍；以及iv)我们最近发现来自丙型肝炎患者的CD4T细胞表现出 DNA损伤和端粒侵蚀增强，与严重的细胞凋亡和衰老有关 表型。从机制上讲，我们最近证明了端粒DNA损伤和修复机制 在丙型肝炎病毒感染期间，CD4T细胞中的端粒酶逆转录酶(hTERT， 延长端粒DNA的端粒酶催化单位)保持完整；端粒重复序列结合因子 2(TRF2，一种保护端粒免受DNA损伤的端粒保护蛋白)和共济失调-毛细血管扩张 突变(ATM，一种修复DNA损伤的激酶)在丙型肝炎病毒CD4T细胞中被抑制。因此，我们假设 要么是核酸酶介导的端粒异常DNA损伤和修复导致的端粒修剪增加 信号转导和/或受损的端粒DNA延长参与了慢性疾病中的端粒磨损 丙型肝炎病毒感染。我们设计了两个特定的目标，并将采用一种翻译方法，使用来自 丙型肝炎病毒感染者在DAA治疗前后，验证我们的假设。在目标1中，我们将确定角色 TRF2在丙型肝炎病毒感染过程中端粒DNA损伤和端粒磨损中的作用在目标2中，我们将阐明 在丙型肝炎病毒感染过程中影响端粒DNA延长的机制。此翻译 这项研究具有新颖性和临床意义，因为它将探索T细胞减少的基本机制 并将解决端粒DNA如何损伤以加速T细胞衰老的重要问题 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提高免疫力的方法至关重要。 应对各种慢性传染病，包括但不限于丙型肝炎病毒感染。

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.