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 损耗和T细胞衰老，导致丙型肝炎病毒（HBV）疫苗低反应性。为此，我们将使用 模拟HIV感染情况下模拟HBV疫苗反应的模型。由于HBV与HIV共同感染 常见并与发病率和死亡率增加有关，需要HBV疫苗以防止HBV共同 艾滋病毒患者感染。但是，HIV感染患者的HBV疫苗反应通常仅为30-60％。 血清转化（HBSAB> 10 IU/mL），而年龄匹配的健康受试者（HS）的成功率为90-95％。这 艾滋病毒患者和其他的流感和肺炎球菌疫苗接种也观察到疫苗反应不佳 包括老年人在内的免疫功能低下的宿主。最近，我们发现慢性HIV或HCV感染可以 引起过早的T细胞衰老，如衰老标记物KLRG1，DUSP6，CD57和 P16INK4A，年龄相关的非编码RNAS GAS5/MIR21的失调，尤其是加速的端粒 损耗 - 表明过度增殖营业额或端粒维护不足。端粒完整性是 保持基因组稳定性和功能的线性染色体的关键特征，而端粒损耗是 驱动细胞功能障碍和凋亡的细胞衰老或衰老的标志。虽然保持端粒长度 在大多数情况下，端粒酶延长端粒DNA，与端粒相关蛋白（庇护素）保护 不需要的DNA损伤反应（DDR）的端粒。我们研究了端粒损耗的机制 HCV和HIV感染的设置，发现端粒酶的细胞表达和活性是 完整，而端粒重复结合因子2（TRF2）在CD4 T细胞中受到显着抑制 HCV或HIV感染的患者。由于TRF2的作用是保护端粒免受不需要的DNA损伤和 招募DNA修复酶（例如，端粒酶）在端粒处的访问/功能，我们假设：i）机制 参与TRF2抑制作用可能会加速端粒损耗和HIV感染期间CD4 T细胞衰老。 ii）TRF2 抑制作用可能导致端粒化感染期间端粒端酶的访问/功能不佳。和iii）TRF2介导的 端粒损耗和CD4 T细胞衰老可能在HIV感染患者中HBV疫苗的衰竭中起关键作用。 为了检验该假设，我们将1）定义T细胞中TRF2抑制和端粒损耗所涉及的机制 艾滋病毒感染期间的衰老； 2）确定TRF2介导的端粒酶向端粒的转运如何影响T细胞衰老 在艾滋病毒感染期间； 3）确定端粒损耗和T细胞衰老对HBV疫苗衰竭期间的影响 艾滋病毒感染以及恢复TRF2介导的端粒庇护和端粒归居机械是否可以 从端粒损耗中拯救CD4 T细胞并恢复细胞功能。这项翻译研究很重要的是 将提供一个工作模型，以探索许多疫苗反应减少的机制 慢性传染性和炎症性疾病，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标，以提高免疫功能低下的疫苗功效和/或免疫反应 主持人。因此，它具有临床意义，及时，并且与退伍军人和公共卫生有关。