Telomere attrition and T cell aging in vaccine failure during HIV infection

HIV 感染期间疫苗失败时的端粒磨损和 T 细胞老化

• 批准号: 10581156
• 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: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581156
• 关键词: Acceleration; Affect; Age; Aging; Apoptosis; Biological Markers; CD4 Positive T Lymphocytes; CDKN2A gene; Cell Aging; Cell physiology; Cells; Chromosomes; Chronic; Communicable Diseases; DNA; DNA Damage; DNA Repair Enzymes; DNA Sequence; DUSP6 protein; Disease; Elderly; Enzymes; Exhibits; Failure; Functional disorder; Genome Stability; Goals; HIV; HIV Infections; Hallmark Cell; Hepatitis B Infection; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Homing; Immune; Immune response; Immunocompetence; Immunocompromised Host; Impairment; Individual; Inflammatory; Influenza; Lead; Length; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Patients; Play; Proteins; Public Health; Role; Shelter facility; Streptococcus pneumoniae; T cell response; T-Lymphocyte; TCR Activation; TERF2 gene; Telomerase; Telomere Maintenance; Telomere Shortening; Testing; Ubiquitin; Untranslated RNA; Vaccination; Vaccines; Veterans; Viral; Virus Diseases; antiretroviral therapy; clinically significant; co-infection; exhaustion; growth arrest specific transcript 5; improved; insight; mortality; novel; novel strategies; overexpression; posttranscriptional; premature; preservation; prevent; prospective; protein function; recruit; response; senescence; seroconversion; success; superinfection; telomere; telomere loss; translational study; vaccine efficacy; vaccine failure; vaccine response

SUMMARY The overall goal of this proposal is to elucidate the mechanisms by which chronic HIV infection promotes telomere attrition and T cell aging, leading to hepatitis B virus (HBV) vaccine hypo-responsiveness. To this end, we will use a model that emulates HBV vaccine response in the setting of HIV infection. Since co-infection of HBV with HIV is common and associated with an increased morbidity and mortality, HBV vaccine is required to prevent HBV co- infection in HIV patients. However, HBV vaccine response in HIV-infected patients is often blunted with only 30-60% seroconversion (HBsAb > 10 IU/ml) compared to 90-95% success rate in age-matched healthy subjects (HS). This poor vaccine response is also observed with influenza and pneumococcal vaccinations in HIV patients and other immunocompromised hosts, including the elderly. Recently, we have found that chronic HIV or HCV infection can cause premature T cell aging, as evidenced by overexpression of the aging markers KLRG1, DUSP6, CD57, and p16ink4a, dysregulation of age-associated noncoding RNAs GAS5/miR21 and, in particular, accelerated telomere attrition - suggesting excessive proliferative turnover or inadequate telomere maintenance. Telomere integrity is a key feature of linear chromosomes that preserves genomic stability and function, whereas telomere attrition is a hallmark of cell aging or senescence that drives cell dysfunctions and apoptosis. While telomere length is maintained in most cases by a telomerase that prolongs telomeric DNA, telomere-associated proteins (shelterins) protect telomeres from unwanted DNA damage response (DDR). We investigated the mechanisms of telomere attrition in the setting of HCV and HIV infections and discovered that the cellular expression and activity of telomerase are intact, whereas the telomeric repeat binding factor 2 (TRF2) is significantly inhibited in CD4 T cells derived from HCV- or HIV-infected patients. Since the role of TRF2 is to protect telomeres from unwanted DNA damage and recruit DNA repair enzymes (e.g., telomerase) access/function at telomeres, we hypothesize that: i) the mechanisms involved in TRF2 inhibition may accelerate telomere attrition and CD4 T cell aging during HIV infection; ii) TRF2 inhibition may result in poor access/function of telomerase at telomeres during HIV infection; and iii) TRF2-mediated telomere attrition and CD4 T cell aging may play a pivotal role in the failure of HBV vaccine in HIV-infected patients. To test this hypothesis, we will 1) define the mechanisms involved in TRF2 inhibition and telomere attrition in T cell aging during HIV infection; 2) determine how TRF2-mediated telomerase transport to telomeres affects T cell aging during HIV infection; and 3) determine the impact of telomere attrition and T cell aging on HBV vaccine failure during HIV infection and whether restoring TRF2-mediated telomere sheltering and telomerase homing machinery can rescue CD4 T cells from telomere attrition and restore cell functions. This translational study is significant in that it will provide a working model to explore mechanisms underlying the diminished vaccine (immune) responses in many chronic infectious and inflammatory diseases, including but not limited to HIV. Understanding these mechanisms may uncover novel treatment targets to improve vaccine efficacy and/or immune responses in immunocompromised hosts. It is thus clinically significant, timely, and relevant to the Veterans as well as public health.

概括 该提案的总体目标是阐明慢性艾滋病毒感染促进端粒的机制 消耗和 T 细胞老化，导致乙型肝炎病毒 (HBV) 疫苗反应低下。为此，我们将使用一个 模拟 HIV 感染情况下 HBV 疫苗反应的模型。由于乙型肝炎病毒与艾滋病毒同时感染 乙型肝炎病毒很常见，并且与发病率和死亡率增加相关，因此需要接种乙型肝炎疫苗来预防乙型肝炎 HIV患者的感染。然而，HIV 感染者的 HBV 疫苗反应通常会减弱，只有 30-60% 与年龄匹配的健康受试者 (HS) 的 90-95% 成功率相比，血清转化 (HBsAb > 10 IU/ml) 的成功率更高。这 艾滋病毒患者和其他人在接种流感和肺炎球菌疫苗时也观察到疫苗反应不佳 免疫功能低下的宿主，包括老年人。最近，我们发现慢性HIV或HCV感染可以 导致 T 细胞过早衰老，衰老标志物 KLRG1、DUSP6、CD57 和 p16ink4a，年龄相关非编码 RNA GAS5/miR21 的失调，特别是端粒加速 损耗 - 表明过度增殖周转或端粒维护不足。端粒完整性是 线性染色体的关键特征是保持基因组稳定性和功能，而端粒磨损是 细胞衰老或衰老的标志，导致细胞功能障碍和细胞凋亡。在端粒长度保持不变的情况下 在大多数情况下，通过延长端粒 DNA 的端粒酶，端粒相关蛋白（庇护蛋白）可以保护 来自不需要的 DNA 损伤反应 (DDR) 的端粒。我们研究了端粒磨损的机制 HCV 和 HIV 感染的背景，发现端粒酶的细胞表达和活性 完整的，而端粒重复结合因子 2 (TRF2) 在来自来源的 CD4 T 细胞中显着受到抑制 HCV 或 HIV 感染者。由于 TRF2 的作用是保护端粒免受不必要的 DNA 损伤， 在端粒处募集 DNA 修复酶（例如端粒酶）的通路/功能，我们假设： i) 机制 参与 TRF2 抑制可能会加速 HIV 感染期间的端粒磨损和 CD4 T 细胞老化； ii) TRF2 抑制可能导致 HIV 感染期间端粒酶在端粒处的通路/功能不良；和 iii) TRF2 介导的 端粒磨损和 CD4 T 细胞老化可能在 HIV 感染者的 HBV 疫苗失败中发挥关键作用。 为了检验这一假设，我们将 1) 定义 T 细胞中 TRF2 抑制和端粒磨损所涉及的机制 HIV感染期间的衰老； 2) 确定TRF2介导的端粒酶转运至端粒如何影响T细胞衰老 HIV感染期间； 3) 确定端粒磨损和 T 细胞老化对 HBV 疫苗接种失败的影响 HIV感染以及恢复TRF2介导的端粒庇护和端粒酶归巢机制是否可以 将 CD4 T 细胞从端粒磨损中拯救出来并恢复细胞功能。这项转化研究的意义在于 将提供一个工作模型来探索许多疾病中疫苗（免疫）反应减弱的机制 慢性传染病和炎症性疾病，包括但不限于艾滋病毒。了解这些机制 可能会发现新的治疗靶点，以提高免疫功能低下患者的疫苗功效和/或免疫反应 主机。因此，它具有临床意义、及时性，并且与退伍军人和公共卫生相关。