HEPATITIS C VIRUS PERSISTENCE AND PATHOGENESIS

这项申请寻求继续资助丙型肝炎合作研究中心（HC-CRC）在南加州大学（USC），以协调和推进研究，以了解复制感染。HCV是目前我国慢性肝炎的主要病因。治疗干预和预防的选择有限。持续的资金将促进和扩大南加州大学HC-CRC的长期合作研究活动。提出了四个具体的项目：1. HCV蛋白对宿主功能影响的研究。重点将放在HCV蛋白对干扰素活性的影响上，特别是病毒E2和NS 5a蛋白对介导干扰素作用的宿主蛋白的影响。2)丙型肝炎病毒核心蛋白免疫调节作用的研究本研究利用腺病毒感染小鼠的实验模型，研究HCV核心蛋白对肝内TNF信号转导、细胞毒性T细胞诱导、抗原提呈和NK细胞功能的影响。3)HCV复制机制的研究。我们将开发用于研究HCV复制的体外细胞培养系统。我们也将研究一种新的丙型肝炎病毒基因产物发现在博士Jing-Hsiung欧的实验室。1)研究E2和NS 5a序列变异在患者人群干扰素耐药性中的作用。此外，我们还将研究NS 5 b突变在利巴韦林临床耐药中的作用。这些项目预计将有助于理解病毒的发病机制和进一步改善治疗丙型肝炎病毒。

This application seeks continuing funding for the Hepatitis C Cooperative Research Center (HC-CRC) at the University of Southern California (USC) to coordinate and advance research toward understanding the replication infection. HCV is currently the major cause of chronic hepatitis in this country. Options for therapeutic intervention and prevention are limited. Continued funding will facilitate and expand the long-standing collaborative research activities at the USC HC-CRC. Four specific projects are proposed: 1. Study of the effects of HCV proteins on host functions. Emphasis will be placed on the effects of HCV proteins on the interferon activities, particularly the effect of viral E2 and NS5a proteins on host proteins mediating interferon actions. 2) Study of the immune modulation by the HCV core protein. By using an experimental model of adenovirus infection of mouse, we will study the effects of HCV core protein on TNF signaling, induction of cytotoxic T cells, antigen presentation and NK cell function in the liver. 3) Study of the mechanisms of HCV replication. We will develop in vitro cell culture systems for studying HCV replication. We will also study a novel HCV gene product discovered in Dr. Jing-Hsiung Ou's laboratory. 1) Study of the role of E2 and NS5a sequence variations in interferon resistance in patient populations. Furthermore, we will also study the role of NS5b mutations in the clinical resistance to ribavirin. These projects are expected to contribute to the understanding of viral pathogenesis and further improvement in therapies for HCV.