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: 10265317
• 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/10265317
• 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; Failure; Functional disorder; Genome Stability; Goals; HIV; HIV Infections; Hallmark Cell; Hepatic; Hepatitis B; 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; Phosphoric Monoester Hydrolases; Play; Process; Public Health; Risk Factors; Role; Signal Pathway; T cell response; T memory cell; T-Lymphocyte; Telomerase; Testing; Time; Vaccines; 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 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.

这项提案的总体目标是阐明慢性病毒感染介导端粒的机制 研究可能导致疫苗失败的T细胞丢失和老化，旨在开发有效的手段来改善疫苗 对病毒感染者的疗效。为此，我们将使用B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和B型肝炎的流行， 丙型肝炎（全世界有2亿~ 3亿人感染每种病毒;两种肝脏病毒感染是 分布不均，但在某些地区比其他地区更为集中，增加了双重感染的机会）， HBV与HCV的共感染是常见的，并且与增加的发病率和死亡率相关;因此，HBV 需要接种疫苗以防止HCV感染个体中的HBV重叠感染。然而，乙肝疫苗 在这种情况下，反应通常是迟钝的，只有~50%的血清转化（抗-HBs> 10 IU/ml），而>90%的血清转化（抗-HBs> 10 IU/ml）， 年龄匹配的健康受试者（HS）。这种不良的疫苗应答也在HIV感染者中观察到， 其他免疫功能低下的宿主，包括老年人。努力改善两个地区的免疫反应 感染者和老年人一直不成功，部分原因是我们对 在这些环境中会抑制疫苗的反应。最近，我们和其他人发现，慢性病毒（艾滋病毒，丙型肝炎病毒） 感染通常与T细胞耗竭和衰老有关，如通过过度表达 耗竭和老化标记物（如PD-1、Tim-3、KLRG-1和DUSP-6），特别是加速侵蚀 提示过度增殖压力或端粒DNA损伤。端粒的完整性是 保留基因组稳定性和功能的线性染色体的特征，而端粒侵蚀是一个标志 细胞老化或衰老导致细胞功能障碍或凋亡，因此端粒修复对生命至关重要。 虽然在大多数情况下端粒的长度是由端粒酶维持的，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感染受试者的幼稚CD 4 T细胞中，端粒DNA损伤和修复信号 在HCV感染期间，在HBV疫苗应答的背景下，通路失调仍然是未知的。 在这个提议中，我们假设i）端粒缺失介导的T细胞老化在HBV疫苗失败中起关键作用 ii）缺乏ATM依赖性端粒DNA修复加速T细胞老化和HBV感染 因此，恢复这种端粒修复机制将为保护T细胞开辟新的途径。 防止细胞老化和维持免疫能力。为了验证这一假设，我们将：1）描述 HCV感染期间HBV疫苗失败中的端粒丢失和T细胞老化; 2）确定 ATM缺陷对HCV感染时T细胞失调的影响这项翻译研究的意义在于，它将 提供了一个工作模型，以探索可能是免疫（疫苗）减少的根本机制 在许多慢性感染性疾病中观察到的反应，包括但不限于HCV。理解 这种机制对于开发在以下情况下提高疫苗效力的方法至关重要： 免疫功能低下的条件下，因此，它是重要的，及时的，相关的退伍军人以及公共卫生。