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.

本研究的总体目标是阐明慢性病毒感染介导端粒的机制