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.

摘要 这项提议的总体目标是阐明慢性艾滋病毒感染促进端粒形成的机制。 磨损和T细胞老化，导致乙肝病毒(乙肝)疫苗的低反应性。为此，我们将使用 在HIV感染的背景下模拟乙肝疫苗反应的模型。由于乙肝病毒与艾滋病病毒混合感染是 乙肝疫苗很常见，而且与发病率和死亡率增加有关，因此需要接种乙肝疫苗来预防乙肝联合感染。 艾滋病毒患者的感染情况。然而，艾滋病毒感染者的乙肝疫苗反应通常是迟钝的，只有30-60%。 与年龄匹配的健康受试者(HS)90-95%的成功率相比，血清转换(乙肝表面抗体和GT；10IU/ml)。这 在艾滋病毒患者和其他人中接种流感和肺炎球菌疫苗也观察到疫苗反应差。 免疫功能受损的宿主，包括老年人。最近，我们发现慢性艾滋病毒或丙型肝炎病毒感染可以 导致T细胞过早衰老，衰老标记物KLRG1、DUSP6、CD57和 P16INK4a，年龄相关非编码RNA Gas5/miR21的失调，特别是加速的端粒 磨损--提示过度的增殖性周转或端粒维护不足。端粒完整性是一种 保持基因组稳定性和功能的线性染色体的关键特征，而端粒磨损是一种 细胞老化或衰老的标志，导致细胞功能障碍和细胞凋亡。在保持端粒长度的同时 在大多数情况下，通过端粒酶延长端粒DNA，端粒相关蛋白(Shelterins)保护 来自不想要的DNA损伤反应(DDR)的端粒。我们研究了端粒磨损的机制。 丙型肝炎病毒和艾滋病病毒感染的背景下，发现端粒酶的细胞表达和活性 而端粒重复序列结合因子2(TRF2)在来源于 感染丙型肝炎病毒或艾滋病病毒的患者。由于TRF2的作用是保护端粒免受不必要的DNA损伤和 在端粒招募DNA修复酶(例如端粒酶)访问/功能，我们假设：i)机制 参与TRF2抑制可能加速HIV感染过程中端粒磨损和CD4T细胞老化；ii)TRF2 抑制可能导致HIV感染期间端粒端粒酶的访问/功能不良；以及iii)TRF2介导的 端粒磨损和CD4T细胞老化可能在HIV感染者接种HBV疫苗失败的原因中起关键作用。 为了验证这一假设，我们将1)确定T细胞中TRF2抑制和端粒磨损的机制 HIV感染过程中的衰老；2)确定TRF2介导的端粒酶转运到端粒如何影响T细胞衰老 在HIV感染过程中；以及3)确定端粒磨损和T细胞老化对在 HIV感染和修复TRF2介导的端粒保护和端粒酶归巢机制是否可以 使CD4T细胞免于端粒磨损，恢复细胞功能。这项翻译研究具有重要意义，因为它 将提供一个工作模型来探索许多疫苗(免疫)反应减弱的潜在机制 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，以提高免疫低下患者的疫苗效力和/或免疫反应 主持人。因此，它对退伍军人和公共卫生具有重要的临床意义、及时性和相关性。