Determinants of T-Cell mediated control in acute HCV Infection

T 细胞介导的急性 HCV 感染控制的决定因素

基本信息

批准号：
7919779
负责人：
GEORG Michael LAUER
金额：
$ 23.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919779
关键词：
Acute Address CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Clinical Complex Data Developing Countries Development Disease Dissection Epidemic Event Failure Functional disorder Funding Gene Expression Gene Expression Profile Hepatitis C Human Immune Immune response Immunity Immunology Immunotherapy Infection KLRB1 gene Lead Liver diseases Lymphocytic choriomeningitis virus Mediating Modeling Morbidity - disease rate Mutation Outcome Pathway interactions Patients Pegylated Interferon Alfa Peripheral Blood Mononuclear Cell Persons Phase Reagent Reporting Research Ribavirin Role Route Staging T cell response T-Lymphocyte Technology Testing Therapeutic Intervention Time Treatment Protocols Vaccines Viral Virus Virus Diseases Virus Replication base burden of illness cohort design exhaustion human data improved in vivo inhibitor/antagonist mouse model prophylactic response transmission process vaccine development virus pathogenesis

项目摘要

Recent studies have been encouraging that viral control of hepatitis C virus infection is possible. Prophylactic vaccines or efficient immunotherapies are urgently needed to reduce the disease burden of this global epidemic. HCV infects estimated 170 million people woridwide, and causes significant morbidity in developed and developing countries. Various studies report an important role for both CD4+ and CD8+ in the control of HCV replication. However, the correlates of protective T-cell immunity and the mechanisms causal for T-cell failure in human HCV infection are not well understood.Cleariy, the outcome is determined in the eariy phase of the disease, therefore it seems paramount to study the eariiest events that set the stage for clearance versus persistence of the virus. . We propose here the analysis of CD8 and CD4 T-cell immunity in large cohorts of subjects with acute HCV infection and different transmission routes. Our central hypothesis is that acute HCV infection typically elicits both CD4 and CD8 T cell responses, but that eariy during infection critical changes in the quality of the T-cell response either lead to viral control or, in most subjects, persistence of the virus. To test this hypothesis we propose to define the functional profile of HCV-specific CD8 T-cells in the context of expression and activafion of a combination of inhibitory molecules during acute HCV infection. We will use transcriptional profiles of HCV-specific T-cells during different stages of dysfunction together with gene expression signatures associated with distinct T-cell inhibitory molecules in order to define the complex events leading to a failed T-cell response. We will also determine the role of CD8 Tcells expressing the NK marker CDI61 as preliminary data suggest a role for this populafion in viral persistence. In addifion to defining mechanisms leading to CD8 T-cell dysfunction and exhaustion, we will also invesfigate HCV-specific CD4+ T-cells that are equally, if not more, crifical for viral control but have been investigated in much less detail. We have recently shown that we can identify HCV-specific CD4 Tcells in almost all subjects with acute HCV infection and have developed reagents to analyze these cells directly ex-vivo in our large cohorts of subjects with acute HCV infection. Dissection of the mechanisms of immune mediated control and T-cell failure will be an important contribufion to guide the development of prophylactic vaccines or immunotherapies.

最近的研究令人鼓舞的是，丙型肝炎病毒感染的病毒控制是可能的。迫切需要预防性疫苗或有效的免疫疗法来减轻疾病负担这场全球流行病。 HCV 感染全球约 1.7 亿人，并导致严重发病在发达国家和发展中国家。各种研究报告了 CD4+ 和 CD8+ 在控制 HCV 复制中的重要作用。然而，保护性 T 细胞免疫的相关性和导致 T 细胞衰竭的机制人类丙型肝炎病毒感染尚不清楚。显然，结果是在早期阶段决定的因此，研究为清除与清除奠定基础的最早事件似乎至关重要病毒的持续存在。。我们在此建议对大型群体中的 CD8 和 CD4 T 细胞免疫进行分析急性HCV感染和不同传播途径的受试者。我们的中心假设是急性 HCV 感染通常会引发 CD4 和 CD8 T 细胞反应，但这在感染早期至关重要 T 细胞反应质量的变化要么导致病毒控制，要么在大多数受试者中导致病毒持续存在病毒。为了检验这一假设，我们建议定义 HCV 特异性 CD8 T 细胞的功能概况急性 HCV 期间抑制分子组合的表达和激活背景感染。我们将在功能障碍的不同阶段使用 HCV 特异性 T 细胞的转录谱以及与不同 T 细胞抑制分子相关的基因表达特征定义导致 T 细胞反应失败的复杂事件。我们还将确定 CD8 T 细胞的作用表达 NK 标记 CDI61 的初步数据表明该群体在病毒中发挥作用坚持。除了定义导致 CD8 T 细胞功能障碍和衰竭的机制之外，我们还将还研究了 HCV 特异性 CD4+ T 细胞，这些细胞对于病毒控制同样重要（如果不是更重要），但调查的细节要少得多。我们最近证明我们可以识别 HCV 特异性 CD4 T 细胞几乎所有患有急性 HCV 感染的受试者中都存在这种细胞，并已开发出分析这些细胞的试剂在我们大量患有急性 HCV 感染的受试者中直接进行体外实验。机制剖析免疫介导的控制和T细胞衰竭将是指导发展的重要贡献预防性疫苗或免疫疗法。