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.

这项建议的总体目标是阐明慢性病毒感染介导端粒的机制。 可能导致疫苗失败的丢失和T细胞老化，目的是开发有效的方法来改进疫苗 对病毒感染者的疗效。为此，我们将使用乙肝病毒(乙肝)疫苗反应的模型 在丙型肝炎病毒(HCV)感染的背景下。由于共同的风险因素和乙肝和 丙型肝炎(全世界有2亿至3亿人感染这两种病毒；这两种肝脏病毒感染是 分布不均，但在一些地区比其他地区更集中，增加了双重感染的机会)， 乙肝病毒和丙型肝炎病毒的混合感染很常见，并与发病率和死亡率增加有关；因此， 需要接种疫苗以防止丙型肝炎病毒感染者中的乙肝病毒重叠感染。然而，乙肝疫苗 在这种情况下，反应通常是迟钝的，只有~50%的血清转换(抗-HBs和gt；10IU/ml)，而&gt；90% 年龄匹配的健康受试者(HS)。这种糟糕的疫苗反应也在艾滋病毒感染者和 其他免疫功能受损的宿主，包括老年人。试图改善这两个国家的免疫反应 感染和衰老的人类一直没有成功，部分原因是我们对 会抑制疫苗在这些环境中的反应。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细胞耗尽和衰老有关，如过度表达的T细胞 衰竭和衰老标记物(如PD-1、TIM-3、KLRG-1和DUSP-6)，尤其是加速侵蚀 端粒--暗示过度的增殖压力或端粒DNA损伤。端粒的完整性是关键 保持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 细胞衰老或衰老导致细胞功能障碍或细胞凋亡，因此端粒修复是生命所必需的。 虽然在大多数情况下，端粒长度是由一种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DNA损伤修复酶--共济失调毛细血管扩张突变(ATM)--则是 在来自丙型肝炎病毒感染者的幼稚的CD4T细胞中被抑制。端粒DNA损伤和修复信号如何 在丙型肝炎病毒感染期间，在乙肝疫苗反应的背景下，通路是不受调控的，这在很大程度上仍然是未知的。 在这项提议中，我们假设i)端粒丢失介导的T细胞老化在乙肝疫苗失败中起着关键作用 丙型肝炎病毒感染者；以及ii)缺乏ATM依赖的端粒DNA修复加速T细胞老化和乙肝病毒 疫苗在丙型肝炎病毒感染中失败，从而恢复这种端粒修复机制将打开保护T细胞的新途径 防止细胞老化，维持免疫能力。为了检验这一假设，我们将：1)描述 丙型肝炎病毒感染中乙肝疫苗失败的端粒丢失和T细胞老化；2)明确端粒丢失和T细胞老化的机制和影响 丙型肝炎病毒感染时ATM缺乏对T细胞调节功能的影响这项翻译研究意义重大，因为它将 提供一个工作模型，以探索可能是降低免疫力(疫苗)的根本机制 在许多慢性传染病中观察到的反应，包括但不限于丙型肝炎病毒。理解 这种机制对于开发提高疫苗效力的方法至关重要。 在免疫受损的情况下，这对退伍军人和公共卫生是重要的、及时的和相关的。