HEPATITIS C VIRUS PERSISTENCE AND PATHOGENESIS

该申请为南加州大学（USC）丙型肝炎合作研究中心（HC-CRC）寻求持续资助，以协调和推进对复制感染的研究。丙型肝炎病毒目前是该国慢性肝炎的主要病因。治疗干预和预防的选择是有限的。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，特别是病毒E2和NS5a蛋白对介导干扰素作用的宿主蛋白的影响。2) HCV核心蛋白对免疫调节的研究。通过小鼠腺病毒感染实验模型，我们将研究HCV核心蛋白在肝脏中对TNF信号、细胞毒性T细胞诱导、抗原呈递和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。我们还将研究欧经雄博士实验室发现的一种新型HCV基因产物。1) E2和NS5a序列变异在患者人群干扰素耐药中的作用研究。此外，我们还将研究NS5b突变在临床利巴韦林耐药中的作用。这些项目有望有助于了解病毒的发病机制，并进一步改善丙肝病毒的治疗方法。

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.