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.

根据我们在病毒感染的 LCMV 模型以及人类 HCV 感染中的结果，病毒逃逸突变以及与 T 细胞功能障碍和抑制相关的分子组合似乎是病毒持续存在的关键因素。重要的是，急性 HCV 感染的数据表明，HCV 感染在疾病早期会引起 PBMC 中可检测到的 CD4 和 CD8 T 细胞反应，但在进展为慢性感染的人中，反应迅速下降。在肝脏中，反应仍然是可检测到的，通常持续数十年并且频率很高，但病毒仍然保持在高水平。我们的总体假设是，T 细胞功能障碍是未能控制 HCV 感染的主要因素，通过结合小鼠和人类对 T 细胞功能障碍的研究，我们可以确定 HCV 感染免疫控制不良的关键途径或免疫缺陷。为了检验这一假设，我们建议通过在人类和小鼠中进行相互告知的实验，进一步定义与不同病毒控制水平相关的不同 T 细胞亚群。我们将根据 LCMV 的最新发现，使用人 PBMC 中的 HCV 特异性 T 细胞和肝源性 T 细胞来定义抑制分子组合的功能特征和表达。与此同时，我们将通过详细区分不同功能障碍阶段的 T 细胞和不同 T 细胞亚群的转录谱，进一步完善我们的小鼠模型。我们还将建立人类 T 细胞的转录谱，这些数据集将共同指导我们未来的研究方向。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，从而导致病毒持续存在。通过 T 细胞抑制性配体或调节性细胞因子的表达。此外，我们还将研究 HCV 特异性 CD4+ T 细胞，它们对于病毒控制同样重要，但研究的细节要少得多。这些研究对于了解 HCV 发病机制、指导预防性疫苗和免疫治疗干预措施的设计以及改进人类持续性病毒感染的一般模型至关重要。