HEPATITIS C VIRUS CORE PROTEIN AND HOST DEFENSE

丙型肝炎病毒（HCV）引起非常高频率的持续性 感染，导致慢性肝炎，肝硬化和 肝细胞癌 病毒的致病机制和 持久性不清楚。 我们的实验室已经获得了初步的 研究发现，HCV核心蛋白可以与几个成员相互作用， 肿瘤坏死因子受体（TNFR）家族，包括TNFR I，TNFR II， β-光敏素受体（LTbetaR）和Fas。 这些受体是 细胞免疫防御机制的重要组成部分， 参与细胞凋亡。 因此，HCV之间的相互作用 核心蛋白和这些受体可以潜在地破坏细胞 防御，解释病毒持续感染。 可选择地， 这些相互作用可使肝细胞对TNF敏感， 肝炎 这些发现为研究HCV提供了新的途径 持久性和发病机制。 该项目计划实现四个具体目标： 1.以描述这些相互作用的生化特性。 2.为了研究这些相互作用的生物学效应，包括 HCV核心蛋白对细胞对TNF反应的影响及信号转导 这些受体的转导。 3.用HCV（+）肝细胞原代培养的肝细胞检测HCV（+）肝细胞的表达。 细胞因子或激素对HCV复制的可能影响。 4.表征酵母中检测到的TNFR以外的分子 双杂交系统，其可与HCV核心蛋白相互作用。 这些项目有望揭示核心的潜在作用 蛋白在丙型肝炎病毒的持久性和发病机制，并可能有助于 丙型肝炎病毒体外培养体系建立 这两个目标 是这个丙型肝炎合作研究中心的主题。 我们提出的项目代表了这些研究的新方向 地区 它们也构成了项目II（HCV核心转基因 小鼠）和项目IV（肿瘤坏死因子受体、淋巴细胞和 HCV治疗。）

Hepatitis C virus (HCV) causes a very high frequency of persistent infection, which leads to chronic hepatitis, cirrhosis and hepatocellular carcinoma. The mechanisms of viral pathogenesis and persistency are not clear. Our laboratory has obtained preliminary findings that the HCV core protein can interact with several members of tumor necrosis factor receptor (TNFR) family, including TNFR I, TNFR II, lymphotoxin-beta receptor (LTbetaR) and Fas. These receptors are important components of the cellular immune defense mechanism and are involved in cellular apoptosis. Thus, the interaction between the HCV core protein and these receptors can potentially disrupt cellular defense, accounting for viral persistent infection. Alternatively, these interactions could sensitize hepatocytes to TNFs, leading to hepatitis. These findings thus provide new avenues for studying HCV persistency and pathogenesis. In this project, four specific aims are planned: 1. To characterize the biochemical properties of these interactions. 2. To study the biological effects of these interactions, including the effects of HCV core on the cellular responses to TNFs and the signal transduction of these receptors. 3. To use primary hepatocytes derived from HCV(+) livers to examine the possible effects of cytokines or hormones on HCV replication. 4. To characterize the molecules other than TNFRs detected in the yeast two-hybrid system, which may interact with the HCV core protein. These projects are expected to reveal the potential role of the core protein in HCV persistency and pathogenesis, and may contribute to the establishment of an in vitro culture system for HCV. These two goals are the major theme of this Hepatitis C Cooperative Research Center. Our proposed projects represent new directions for the research in these areas. They also form the basis for Project II (HCV core transgenic mice) and Project IV (tumor necrosis factors receptors, lymphocyte and HCV therapy.)