Determinants of Liver Injury in Chronic HCV Infection

描述（由申请人提供）：大多数急性丙型肝炎病毒（HCV）感染者会发展为慢性感染，但并非所有受试者都会发展为慢性感染的并发症，如肝纤维化或脂肪变性。目前的抗病毒治疗对大多数慢性丙型肝炎病毒感染者既无效也不可获得，因此慢性感染仍然是一个重大的健康问题。丙型肝炎病毒肝病的自然病史与这种感染的流行病学相结合，导致慢性丙型肝炎病毒患者的患病率不断上升，肝分解和肝细胞癌的发病率也在上升。然而，我们对肝脏疾病进展的宿主和病毒决定因素了解甚少。该项目将研究慢性丙型肝炎病毒感染中肝损伤的决定因素，使用疾病快速进展的队列和对照，以更好地了解区分丙型肝炎病毒相对良性病程和进展为肝硬化病程的因素。这将在三个综合项目中完成：第一个项目将测试CD4反应失败导致不适当的CD8+细胞毒性T淋巴细胞（CTL）和自然杀伤T （NKT）反应的假设，这些反应有助于驱动纤维化和病毒进化。第二个项目将描述氧化应激在慢性丙型肝炎中的作用和肝脂肪变性的机制。第三个项目将确定哪些病毒和宿主因子驱动肝星状细胞活化作为纤维化的关键步骤。这些项目将得到一个临床中心的支持，该中心将维护一个临床样本库，这些样本来自快速进展（移植、艾滋病毒/丙型肝炎合并感染和曼氏血吸虫合并感染）以及进展较慢的疾病。这种共同临床材料的联合使用将促进结果的最大整合。通过这种独特的合作方法，我们将确定哪些病毒和宿主因素导致纤维化，这是慢性HCV感染的主要并发症，这可能为预防肝脏疾病进展提供新的治疗策略。

DESCRIPTION (provided by applicant): The majority of persons acutely infected with hepatitis C virus (HCV) will develop chronic infection, but not all subjects go on to develop the complications of chronic infection such as hepatic fibrosis or steatosis. Current antiviral treatments are neither effective nor available for most persons with chronic HCV infection, and thus chronic infection remains a significant health problem. The natural history of HCV liver disease combined with the epidemiology of this infection has resulted in an increasing prevalence of persons with chronic HCV, and rising rates of hepatic decomposition and hepatocellular carcinoma. However, our understanding of the host and viral determinants of liver disease progression are poorly understood. This program project will address the determinants of liver injury in chronic HCV infection, using cohorts with rapid disease progression and controls to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. This will be accomplished in three integrated projects: The first Project will test the hypothesis that failure of the CD4 response results in an inappropriate CD8+ cytotoxic T lymphocyte (CTL) and natural killer T (NKT) response that serves to drive fibrosis and viral evolution. The second Project will characterize the role of oxidative stress in chronic HCV and the mechanisms of hepatic steatosis. The third Project will determine which viral and host factors drive hepatic stellate cell activation as a key step in fibrosis. The projects will be supported by a clinical core, which will maintain a repository of clinical samples derived from cohorts with rapid progression (transplant, HIV/HCV co-infection and Schistosoma mansoni co-infection) as well as more slowly progressive disease. This joint use of common clinical material will facilitate maximal integration of results. Through this unique cooperative approach, we will determine which viral and host factors contribute to fibrosis, the major complication of chronic HCV infection, which might suggest new therapeutic strategies to prevent liver disease progression.