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

• 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
• 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

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.

最近的研究鼓励了丙型肝炎病毒感染的病毒控制。 迫切需要预防性疫苗或有效的免疫疗法来减轻 这种全球流行病。 HCV感染了估计在遍布范围内的1.7亿人，并引起明显的发病率 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。 但是，保护性T细胞免疫的相关性与T细胞失败的机制的相关性 人类HCV感染尚不清楚。清洁，结果是在eari阶段确定的 疾病，因此研究最重要的事件为清除与清除奠定了基础 病毒的持久性。 。我们在这里提出了大型队列中CD8和CD4 T细胞免疫的分析 患有急性HCV感染和不同传输路线的受试者的。我们的中心假设是急性 HCV感染通常会引起CD4和CD8 T细胞反应，但在感染期间的耳朵关键 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， 病毒。为了检验该假设，我们建议定义HCV特异性CD8 T细胞的功能曲线 急性HCV期间抑制性分子组合的表达和活化的背景 感染。我们将在功能障碍的不同阶段使用HCV特异性T细胞的转录曲线 以及与不同的T细胞抑制分子相关的基因表达特征 定义导致T细胞响应失败的复杂事件。我们还将确定CD8 TCELL的作用 将NK标记CDI61表示为初步数据，这表明该人口在病毒中的作用 持久性。为了定义机制导致CD8 T细胞功能障碍和疲惫，我们将 同样（即使不是更多的话）对病毒控制也是如此，但也具有 被详细调查了。我们最近表明，我们可以识别HCV特异性CD4 TCELLS 在几乎所有患有急性HCV感染的受试者中，并且已经开发了试剂来分析这些细胞 直接在我们的大量患有急性HCV感染的受试者中，即直接出现。解剖机制 免疫介导的控制和T细胞故障将是指导发展的重要贡献 预防性疫苗或免疫疗法。