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.

总结 这项提案的总体目标是阐明慢性HIV感染促进端粒的机制 磨损和T细胞老化，导致B型肝炎病毒（HBV）疫苗低反应性。为此，我们将使用 模拟HIV感染背景下HBV疫苗应答的模型。由于HBV与HIV的共同感染是 常见并与发病率和死亡率增加相关，需要HBV疫苗来预防HBV合并症。 艾滋病患者的感染。然而，HIV感染者对HBV疫苗的应答通常只有30-60%， 血清转换（抗人球蛋白抗体> 10 IU/ml）的成功率与年龄匹配的健康受试者（HS）中90-95%的成功率相比。这 在艾滋病毒患者和其他感染者中接种流感和肺炎球菌疫苗也观察到疫苗反应较差。 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 导致过早的T细胞老化，如老化标志物KLRG 1、DUSP 6、CD 57和 p16 ink 4a，年龄相关非编码RNA GAS 5/miR 21的失调，特别是加速端粒 磨损-表明过度增殖周转或端粒维持不足。端粒完整性是一个 线性染色体的关键特征，保持基因组的稳定性和功能，而端粒的磨损是一个 细胞老化或衰老的标志，导致细胞功能障碍和凋亡。端粒长度保持不变 在大多数情况下，通过端粒DNA的端粒酶，端粒相关蛋白（shelterins）保护 端粒的DNA损伤反应（DDR）。我们研究了端粒磨损的机制， HCV和HIV感染的背景，并发现端粒酶的细胞表达和活性是 完整，而端粒重复序列结合因子2（TRF 2）在来源于 HCV或HIV感染患者。由于TRF 2的作用是保护端粒免受不必要的DNA损伤， 募集DNA修复酶（例如，端粒酶）进入/功能在端粒，我们假设：i）机制 参与TRF 2抑制可能加速HIV感染期间的端粒磨损和CD 4 T细胞老化; ii）TRF 2 抑制可能导致HIV感染期间端粒处端粒酶的接近/功能差;和iii）TRF 2介导的 端粒磨损和CD 4 T细胞老化可能在HIV感染患者的HBV疫苗失败中起关键作用。 为了验证这一假设，我们将1）确定TRF 2抑制和T细胞端粒磨损的机制， HIV感染期间的衰老; 2）确定TRF 2介导的端粒酶转运到端粒如何影响T细胞衰老 3）确定端粒磨损和T细胞老化对HBV疫苗失败的影响， HIV感染以及恢复TRF 2介导的端粒保护和端粒酶归巢机制是否可以 拯救CD 4 T细胞免于端粒磨损并恢复细胞功能。这种翻译研究的意义在于， 将提供一个工作模型，以探索在许多疾病中疫苗（免疫）反应减弱的机制。 慢性感染性和炎性疾病，包括但不限于HIV。了解这些机制 可能发现新的治疗靶点，以改善免疫功能低下患者的疫苗功效和/或免疫应答。 hosts.因此，它具有临床意义，及时，与退伍军人和公共卫生相关。