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.

该提案的总体目的是阐明慢性病毒感染的机制 可能导致疫苗失败的损失和T细胞衰老，而献身于AM 病毒感染的个体的功效。 在丙型肝炎病毒（HCV）感染中 丙型肝炎（200至3亿人都感染了全世界的每种病毒；两种肝病毒感染是 分布不平等，但比其他地区更集中在某些地区，增加了双重感染的机会） HBV与HCV的共同感染是常见的，并且与病态和死亡率增加有关； 需要疫苗接种以防止HCV感染的个体中的HBV超级感染 在这种情况下的响应通常被钝化，只有〜50％的血清转化（抗HBS> 10 IU/ml），而> 90％ 在年龄匹配的健康受试者（HS）中。 包括老年人在内的其他免疫功能低下的宿主。 被感染和老年人的人没有成功 在这些环境中，我们和其他人发现慢性病毒（HIV，HCV）可以抑制疫苗反应。 感染通常与T细胞的呼气和衰老有关，如通过过表达所证明的 呼气和老化标记（例如PD-1，TIM-3，KLRG-1和DUSP-6），特别是加速侵蚀 端粒 - 引起过多的增殖或端粒DNA损害。 保持基因组稳定性和功能的线性染色体的特征，而端粒侵蚀为Aallmark 导致细胞功能障碍或凋亡的细胞衰老或衰老，因此端粒修复对生命至关重要。 虽然大多数casses中的端粒长度通过延长端粒序列的端粒酶维持，但我们发现 该端粒酶活性完好无损，而共济失调-telangiectasiectasia -mutatatatatatatatatatatatatat atatatated（ATM） - DNA损伤修复酶-is 被抑制，在源自HCV中受试者的幼稚CD4 T细胞中。 在HCV感染期间HBV疫苗反应的背景下，途径失调仍然未知。 在此提案中，我们假设i）端粒损失介导的T细胞老化在HBV疫苗衰竭中起关键作用 在HCV感染的个体中； HCV感染中的疫苗衰竭，因此恢复该端粒维修机械将开放新的途径以保护T 细胞从衰老和维持免疫能力来测试这一修辞 HCV感染期间HBV疫苗衰竭中的端粒损失和T细胞衰老； HCV感染期间T细胞失调的ATM缺乏。 提供一个工作模型来探索可能对减少免疫（疫苗）基础的机制 在许多慢性传染病中观察到的反应，不限于HCV 这种机制对于开发方法以提高疫苗功效的方法是批判性的 因此，免疫功能障碍的内容是重要的，及时的，并且与退伍军人作为公共卫生。