Funtional T-cell Failure in Chronic HCV Infection

慢性 HCV 感染中的功能性 T 细胞衰竭

• 批准号: 8376117
• 负责人: GEORG Michael LAUER
• 金额: $ 46.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376117
• 关键词: Acute; Acute Hepatitis C; Address; Animal Model; CD4 Positive T Lymphocytes; CD8B1 gene; Characteristics; Chronic; Chronic Hepatitis C; Clinical; Data; Data Set; Defect; Developed Countries; Developing Countries; Disease; Environment; Failure; Frequencies; Functional disorder; Future; Genetic Transcription; Helper-Inducer T-Lymphocyte; Hepatitis C; Hepatitis C virus; Human; Immune; Immune response; Immunology; Immunotherapeutic agent; Individual; Infection; Intervention; Investigation; Ligands; Liver; Liver diseases; Lymphocytic choriomeningitis virus; Modeling; Molecular Profiling; Mus; Mutation; Organ; Outcome; Pathway interactions; Patients; Pegylated Interferon Alfa; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Property; Regulation; Ribavirin; Signal Transduction; Site; Specificity; Staging; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic Intervention; Tissues; Toxic effect; Treatment Protocols; Vaccines; Viral; Virus; Virus Diseases; base; cohort; cytokine; design; exhaust; improved; intrahepatic; liver infection; prophylactic; research study; response; vaccine development; virus infection mechanism; virus pathogenesis

ased on our results in the LCMV model of viral infection as well as in human HCV Infection it seems likely that viral escape mutations and a combination of molecules associated with T-cell dysfunction and inhibition are key contributors to viral persistence. Importantly, data in acute HCV infection indicate that HCV infection elicits both CD4 and CD8 T cell responses detectable in PBMC during early disease, but the responses decline quickly in persons who progress to chronic infection. In the liver, responses remain detectable, often for decades and at substantial frequencies, yet virus persists at high levels. Our overall hypothesis is that T-cell dysfunction is a major factor in failure to control HCV infection and that by combining both mouse and human studies of T cell dysfunction we can define key pathways or immunological defects underlying poor immunological control of HCV infection. To test this hypothesis we propose to further define the different subsets of T-cells associated with different levels of viral control with experiments in humans and mice informing each other. We will define the functional profile and expressions of a combination of inhibitory molecules using HCV-specific T-cells in human PBMC and liver derived T-cells based on recent findings in LCMV. In parallel we will further refine our murine model by differentiating in detail the transcriptional profiles of T-cells in different stages of dysfunction and different T-cell subsets. We will also establish transcription profiles of human T-cells and the datasets together will direct the future direction of our investigations. In addition to defining the properties of HCV-specific T-cells we will define how the liver environment in chronic HCV infection contributes to T-cell dysfunction and thus viral persistence, e.g. by the expression of T-cell inhibitory ligands or regulatory cytokines. In addition we will also investigate HCV-specific CD4+ T-cells that are equally critical for viral control but have been investigated in much less detail. These studies will be critical for understanding HCV pathogenesis, for guiding the design of prophylactic vaccines and immunotherapeutic interventions, but also for improved general model of persistent viral infections in humans.

在病毒感染的LCMV模型以及人类HCV感染中，我们的结果似乎很可能是病毒逃生突变和与T细胞功能障碍和抑制相关的分子的组合是病毒持久性的关键因素。重要的是，急性HCV感染中的数据表明，HCV感染在早期疾病期间会在PBMC中检测到CD4和CD8 T细胞反应，但发展为慢性感染的人迅速下降。在肝脏中，反应仍然可以检测到数十年，并且在很大的频率上，但病毒持续很高。我们的总体假设是，T细胞功能障碍是无法控制HCV感染的主要因素，并且通过结合T细胞功能障碍的小鼠和人类研究，我们可以定义HCV感染免疫学不良控制的关键途径或免疫缺陷。为了检验这一假设，我们建议进一步定义与不同水平的病毒控制相关的T细胞的不同子集，并通过人类和小鼠相互告知的实验。我们将根据LCMV的最新发现，在人PBMC和肝脏中衍生的T细胞中使用HCV特异性T细胞定义抑制性分子的功能分布和表达。同时，我们将通过详细区分在功能障碍和不同T细胞子集的不同阶段的T细胞的转录曲线，从而进一步完善我们的鼠模型。我们还将建立人类T细胞的转录概况，数据集将我们调查的未来方向指导。除了定义HCV特异性T细胞的特性外，我们还将定义慢性HCV感染中的肝脏环境如何导致T细胞功能障碍，从而导致病毒持久性，例如通过T-细胞抑制性配体或调节细胞因子的表达。此外，我们还将研究对病毒控制同样至关重要但详细研究的HCV特异性CD4+ T细胞。这些研究对于理解HCV发病机理至关重要，对于指导预防性疫苗的设计和免疫治疗干预措施，以及改善人类持续性病毒感染的一般模型。