HEPATITIS C VIRUS PERSISTENCE AND PATHOGENESIS

本申请建议设立丙型肝炎合作社 南加州大学（USC）研究中心协调 肝炎的发病机制和迁延过程的研究进展 丙型肝炎病毒（HCV）。 丙型肝炎病毒已成为慢性肝炎的主要原因， 这个国家 治疗干预的选择很少， 预防是可行的。 该中心将促进和 扩大他们在南加州大学的长期合作研究活动。 提出了四个具体项目：（1）丙型肝炎病毒核心蛋白的研究， 根据私家侦探的调查结果，的实验室， HCV核心蛋白与肿瘤坏死因子（TNF）受体相互作用。 这个项目将研究这种相互作用的生化特性 及其生物学后果。 它还建议建立一个 HCV复制的体外细胞培养系统。 (2)建立 研究HCV致病机制的转基因小鼠模型。 我们将 表征表达HCV核心蛋白的转基因小鼠及其用途 细胞毒性T细胞试图诱导肝炎。 这一模式将 用于确定核心蛋白是否在免疫细胞中表达 可以改变免疫功能和对细胞因子的反应。 这 该项目将解决肝脏和肝外感染的作用， HCV发病机制。 (3)核心蛋白的分子生物学研究 RNA复制 这个项目将研究生物化学和 各种形式的HCV核心蛋白的生物学功能。它还将 建立RNA转染试验，以检查RNA序列 HCV RNA的复制。 (4)分子生物学和 治疗期间和治疗期间HCV感染的临床参数 与人类免疫缺陷病毒（HIV）合并感染。 接受过利巴韦林或干扰素治疗的丙型肝炎患者 将针对TNF受体、HCV病毒抗原 表达和其他细胞因子，以试图 证明了这些参数与肝脏病理学之间的相关性。 HCV和HIV感染患者将与 只有HCV感染。 预计这些研究将提供一个 了解肝损伤机制的分子基础 以及各种疗法对人类的影响。 综上所述各项 项目利用南加州大学医学院的独特资源， 包括HCV病毒学、分子生物学和免疫学专业知识， 以及庞大的患者群体。 这些研究预计将 有助于了解病毒的发病机制和持续的 感染

This application proposes to establish a Hepatitis C Cooperative Research Center at University of Southern California (USC) to coordinate and advance research on the pathogenesis and persistency of hepatitis C virus (HCV). HCV has become the major cause of chronic hepatitis in this country. Very few options for therapeutic intervention and prevention are available. This proposed center will facilitate and expand their long-standing collaborative research activities at USC. Four specific projects are proposed: (1) Studies of HCV core protein and host defense, based on the findings made by the P.I.'s laboratory that HCV core protein interacts with tumor necrosis factor (TNF) receptors. This project will examine the biochemical properties of this interaction and their biological consequences. It also proposes to establish an in vitro cell culture system for HCV replication. (2) Establishment of a transgenic mouse model for studying HCV pathogenesis. We will characterize transgenic mice expressing HCV core protein, and use cytotoxic T cells to attempt to induce hepatitis. This model will be used to determine whether the core protein expression in immune cells can alter the immune functions and the responses to cytokines. This project will address the role of hepatic and extrahepatic infection in HCV pathogenesis. (3) Studies of the molecular biology of core protein and RNA replication. This project will examine the biochemistry and biological functions of various forms of HCV core protein. It will also establish an RNA transfection assay to examine the RNA sequence requirement for HCV RNA replication. (4) Study of molecular and clinical parameters of HCV infection during therapies and in the presence of co-infection with human immunodeficiency viruses (HIV). Hepatitis C patients who have received ribavirin or interferon therapies will be studied with respect to TNF receptors, HCV viral antigen expression and other cytokines during and after therapy to attempt to demonstrate a correlation between these parameters and liver pathology. Patients with HCV and HIV infections will be compared with those with HCV infections only. These studies are expected to provide an understanding of the molecular basis of the mechanism of liver injury and the effects of various therapies in humans. Taken together, these projects utilize the unique resources at the USC medical campus, which include expertise in virology, molecular biology, and immunology of HCV, as well as large patient populations. These studies are expected to contribute to the understanding of viral pathogenesis and persistent infection.