Virus specific T cells in replication/evolution of HCV

慢性丙型肝炎是美国乃至全世界严重肝脏疾病的重要病因。丙型肝炎病毒（HCV）具有严格的范围，仅在人类和实验黑猩猩模型中观察到持续感染。在大多数人类和黑猩猩中，尽管存在持续的宿主免疫反应，但丙型肝炎病毒感染会导致持续性和慢性病毒血症。在人类中，几十年来，严重肝炎、肝硬化、肝细胞癌和死亡是慢性丙型肝炎相对常见的后果。目前尚不清楚宿主免疫反应是否对HCV感染具有保护作用。或事实上宿主反应是导致大多数疾病表现的原因。对人类的初步研究表明，HCV突变是由免疫反应引起的，并导致受感染宿主内形成遗传多样性的病毒群。这样的病毒群被称为准种，HCV感染的这种动态特征被认为是病毒持续存在的主要原因。该项目是NIH合作中心拨款的一部分，旨在研究黑猩猩模型中与HCV清除、HCV持久性和肝脏疾病活动相关的病毒和宿主因素。将对16只HCV感染动物进行HCV感染和细胞免疫反应的详细调查。在其他中心收集的组织将被送往西雅图进行病毒学研究。在Gretch博士的指导下，华盛顿大学病毒性肝炎实验室将使用原位杂交技术对肝组织中的HCV复制动力学进行病毒学分析，并在血液和组织中进行HCV准种进化模式。这项工作将为宿主免疫反应与持续复制的HCV准种群体之间的动态相互作用提供重要的新信息。

Chronic hepatitis C is an important cause of severe liver disease in the United States and throughout the world. Hepatitis C virus (HCV) shows a strict range, with persistent infection observed only in humans and the experimental chimpanzee model. In the majority of humans and chimpanzees, infection with HCV results in persistent and chronic viremia despite an ongoing host immune response. In humans, severe hepatitis, liver cirrhosis, hepatocellular carcinoma and death are relatively common consequences of chronic hepatitis C over several decades. It is presently unknown whether the host immune response is protective in HCV infection., or in fact the host response is responsible for most of the disease manifestations. Preliminary studies in humans suggest the HCV mutations result from immune responses and lead to the formation of genetically diverse viral populations within the infected host. Such viral populations are termed quasispecies, and this dynamic feature of HCV infection is thought to contribute in a major way to viral persistence. This project is part of a proposed NIH Cooperative Center grant aimed at studying viral and host factors related to HCV clearance, HCV persistence, and activity of liver disease in the chimpanzee model. Detailed investigation of HCV infection and cellular immune responses will be conducted on 16 animals with HCV infection. Tissue collected at other centers will be forwarded to Seattle for virology studies. Virological analyses of HCV replication kinetics in liver tissue using in situ hybridization techniques, and HCV quasispecies evolution patterns in blood and tissue will be conducted at the University of Washington Viral Hepatitis Laboratory under the direction of Dr. Gretch. The work will provide important new information on the dynamic interactions between the host immune response and the persistently replicating HCV quasispecies populations.