Telomere loss and T cell aging in HBV vaccine response in HCV-infected individual

HCV 感染者的 HBV 疫苗反应中的端粒丢失和 T 细胞老化

• 批准号: 10455526
• 负责人: Zhi Q. Yao
• 金额: --
• 依托单位: JAMES H QUILLEN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455526
• 关键词: ATM Signaling Pathway; ATM deficient; Age; Aging; Antigens; Apoptosis; Biological Markers; CD4 Positive T Lymphocytes; Cell Aging; Cells; Chromosomes; Chronic; Chronic Hepatitis C; Communicable Diseases; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; Elderly; Exhibits; Functional disorder; Genome Stability; Goals; HIV; HIV Infections; Hallmark Cell; Hepatic; Hepatitis B Infection; Hepatitis B Prevalence; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immunization; Immunocompetence; Immunocompromised Host; Immunoglobulin Domain; Impairment; Individual; Infection; Killer Cells; Lead; Lectin; Length; Life; Light; Link; Measures; Mediating; Modeling; Morbidity - disease rate; Outcome; Persons; Phosphoric Monoester Hydrolases; Play; Process; Public Health; Risk Factors; Role; Signal Pathway; T cell response; T memory cell; T-Lymphocyte; Telomerase; Testing; Time; Veterans; Viral; Virus; Virus Diseases; aged; ataxia telangiectasia mutated protein; co-infection; exhaustion; improved; mortality; neoantigen vaccine; overexpression; premature; preservation; pressure; prevent; programmed cell death protein 1; receptor; repair enzyme; repaired; response; risk sharing; senescence; seroconversion; superinfection; telomere; telomere loss; translational study; vaccine efficacy; vaccine failure; vaccine response

The overall goal of this proposal is to elucidate the mechanisms by which chronic viral infection mediates telomere loss and T cell aging that may lead to vaccine failure, with an aim to develop effective means to improve vaccine efficacy in virally infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine responses in the setting of hepatitis C virus (HCV) infection. Due to shared risk factors and the prevalence of hepatitis B and hepatitis C (200~300 million people are infected with each of the virus worldwide; the two hepatic viral infections are unequally distributed but more concentrated in some regions than others, increasing the chance of dual infection), co-infection of HBV with HCV is common and is associated with an increased morbidity and mortality; as such, HBV vaccination is required to prevent HBV super-infection in HCV-infected individuals. However, HBV vaccine responses in this setting are often blunted, with only ~50% seroconversion (Anti-HBs > 10 IU/ml) compared to >90% in age-matched healthy subjects (HS). This poor vaccine response is also observed in HIV-infected subjects and in other immunocompromised hosts, including the elderly. Attempts to improve immunization responses in both infected and aged humans have been unsuccessful, in part due to our poor understanding of the mechanisms that can dampen vaccine responses in these settings. Recently, we and others have found that chronic viral (HIV, HCV) infection is often associated with T cell exhaustion and senescence, as demonstrated by overexpression of exhaustion and aging markers (such as PD-1, Tim-3, KLRG-1, and DUSP-6), and, in particular, accelerated erosion of telomeres - suggesting excessive proliferative pressure or telomeric DNA damage. 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 leads to cell dysfunction or apoptosis, therefore telomere repair is essential to life. While the telomere length is maintained in most cases by a telomerase that prolongs telomeric sequences, we found that telomerase activity is intact, whereas ataxia-telangiectasia-mutated (ATM) - a DNA damage repair enzyme - is inhibited, in naïve CD4 T cells derived from HCV-infected subjects. How telomeric DNA damage and repair signaling pathways are dysregulated in the context of HBV vaccine response during HCV infection remain largely unknown. In this proposal, we hypothesize that i) telomere loss-mediated T cell aging plays a pivotal role in HBV vaccine failure in HCV-infected individuals; and ii) lack of ATM-dependent telomeric DNA repair accelerates T cell aging and HBV vaccine failure in HCV infection, thus restoring this telomere repair machinery will open new avenues to protect T cells from aging and to maintain immune competency. To test this hypothesis, we will: 1) characterize the role of telomere loss and T cell aging in HBV vaccine failure during HCV infection; 2) define the mechanisms and impact of ATM deficiency on T cell dysregulation during HCV infection. This translational study is significant in that it will provide a working model to explore mechanisms that may be fundamental to diminishing immune (vaccine) responses that are observed in many chronic infectious diseases, including but not limited to HCV. Understanding such mechanisms is critical for developing approaches to improve vaccine efficacy in the setting of immunocompromised conditions, it is thus significant, timely, and relevant to the Veterans as well as public health.

该提案的总体目标是阐明慢性病毒感染介导端粒的机制 T细胞的丢失和老化可能导致疫苗失败，旨在开发有效的手段来改进疫苗 对病毒感染个体的功效。为此，我们将使用乙型肝炎病毒 (HBV) 疫苗反应模型 在丙型肝炎病毒（HCV）感染的情况下。由于共同的危险因素以及乙型肝炎和 丙型肝炎（全世界有 200~3 亿人感染每种病毒；这两种肝脏病毒感染是 分布不均，但某些地区比其他地区更集中，增加了双重感染的机会）， 乙型肝炎病毒与丙型肝炎病毒合并感染很常见，并且与发病率和死亡率增加有关；因此，乙肝病毒 需要接种疫苗来预防 HCV 感染者的 HBV 重复感染。然而，乙肝疫苗 在这种情况下的反应通常会减弱，血清转化率只有约 50%（抗 HBs > 10 IU/ml），而血清转化率 >90% 在年龄匹配的健康受试者（HS）中。这种不良的疫苗反应也出现在 HIV 感染者和 其他免疫功能低下的宿主，包括老年人。尝试改善两国的免疫反应 感染者和老年人未能成功，部分原因是我们对感染的机制了解甚少。 可以抑制这些环境中的疫苗反应。最近，我们和其他人发现慢性病毒（HIV、HCV） 感染通常与 T 细胞耗竭和衰老相关，这一点通过过表达 疲劳和老化标记（例如 PD-1、Tim-3、KLRG-1 和 DUSP-6），特别是加速侵蚀 端粒 - 表明过度增殖压力或端粒 DNA 损伤。端粒完整性是关键 线性染色体的特征，保持基因组稳定性和功能，而端粒侵蚀是一个标志 细胞衰老或衰老会导致细胞功能障碍或凋亡，因此端粒修复对于生命至关重要。 虽然在大多数情况下端粒长度是通过延长端粒序列的端粒酶来维持的，但我们发现 端粒酶活性是完整的，而共济失调毛细血管扩张突变 (ATM)——一种 DNA 损伤修复酶——是 在来自 HCV 感染受试者的初始 CD4 T 细胞中受到抑制。端粒 DNA 损伤和修复信号如何 HCV 感染期间 HBV 疫苗反应背景下的通路失调仍然很大程度上未知。 在此提议中，我们假设 i) 端粒丢失介导的 T 细胞衰老在 HBV 疫苗失败中发挥着关键作用 HCV 感染者； ii) 缺乏 ATM 依赖性端粒 DNA 修复会加速 T 细胞衰老和 HBV HCV 感染疫苗失败，从而恢复端粒修复机制将为保护 T 开辟新途径 细胞免于老化并维持免疫能力。为了检验这个假设，我们将：1）描述 HCV 感染期间 HBV 疫苗失败导致端粒丢失和 T 细胞老化； 2) 定义机制和影响 HCV 感染期间 ATM 缺陷导致 T 细胞失调。这项转化研究意义重大，因为它将 提供一个工作模型来探索可能对降低免疫（疫苗）至关重要的机制 在许多慢性传染病（包括但不限于 HCV）中观察到的反应。理解 此类机制对于制定提高疫苗功效的方法至关重要 免疫功能低下的情况，因此对于退伍军人和公共卫生来说具有重要、及时和相关的意义。