STUDIES OF THE NATURAL HISTORY OF HEPATITIS C IN LIVER

慢性丙型肝炎病毒感染已成为美国最重要的病毒性肝炎形式。 虽然这种疾病通常会持续多年，但大约20%的慢性丙型肝炎患者在20年内进展为肝硬化。 因此，在美国和欧洲，慢性丙型肝炎引起的肝衰竭已成为肝移植的主要指征。 尽管我们对这种疾病的许多方面的理解取得了显着进展，但慢性丙型肝炎患者肝细胞损伤的机制尚未得到很好的理解。不幸的是，既没有有效的细胞培养系统，也没有动物模型可用于研究肝脏疾病的发病机制。 鉴于这些局限性，我们系统地研究了肝移植后复发性丙型肝炎患者肝损伤的演变。 通过将移植器官的损伤程度与病毒复制的详细分析相关联，我们希望为这些慢性感染患者的肝细胞损伤的发病机制提供见解。该建议旨在研究HCV RNA基因组序列中不同突变模式对肝移植后复发性丙型肝炎患者肝损伤严重程度有深远影响的假设。我们的具体目标1是前瞻性地确定复发性丙型肝炎患者中HCV准种演变与肝细胞损伤之间的关系。 在具体目标2中，我们计划深入研究准种的克隆进化，并确定这些病毒株在重度复发性丙型肝炎患者和肝移植后轻度肝细胞损伤患者中的组织来源。 我们计划测试的假设，准种复制的主要网站是至关重要的肝细胞损伤的发展。 我们认为肝移植后出现的非致病性病毒株是由于HCV在肝外持续复制所致，而致病性HCV株则是由于病毒在肝内复制所致。 在具体目标3中，我们计划评估HCV基因型、病毒循环水平和HCV准种演变对移植肝组织学损伤长期演变的影响。通过仔细将病毒的演变与肝移植后复发性丙型肝炎患者所经历的肝细胞损伤程度相关联，我们希望为这种重要肝脏疾病的发病机制提供见解。 从这些详细的分析中，我们还希望分离出致病性病毒株，随后可以在细胞培养系统中进行测试。

Chronic hepatitis C virus infection has emerged as the most important form of viral hepatitis in the United States. Although the disease often remains indolent for many years, approximately 20 percent of patients with chronic hepatitis C progress to cirrhosis within 20 years. As a consequence, liver failure from chronic hepatitis C has become the leading indication for liver transplantation both in the United States and Europe. Despite remarkable progress in our understanding of many aspects of this disease, the mechanism of hepatocellular injury in patients with chronic hepatitis C is not well understood. Unfortunately, neither efficient cell culture systems nor animal models are available to study the pathogenesis of the liver disease. Given these limitations, we have systematically examined the evolution of liver injury in patients with recurrent hepatitis C after liver transplantation. By correlating the degree of injury to the transplanted organ with detailed analyses of viral replication we hope to provide insights into the pathogenesis of liver cell injury in these chronically infected patients. This proposal is designed to examine the hypothesis that differing patterns of mutation in the genomic sequence of HCV RNA have a profound influence on the severity of liver injury in patients with recurrent hepatitis C after liver transplantation. Our Specific Aim 1 is to prospectively determine the relationship between evolution of HCV quasispecies and hepatocellular injury in patients with recurrent hepatitis C. In Specific Aim 2 we plan to intensively investigate the clonal evolution of quasispecies and to determine the tissue origin of these viral strains both in patients with severe recurrent hepatitis C and in those with mild hepatocellular injury after liver transplantation. We plan to test the hypothesis that the primary site of quasispecies replication is critical to the development of hepatocellular injury. We propose that emergence of nonpathogenic strains of virus after liver transplantation result from continuous extrahepatic replication of HCV, whereas pathogenic strains of HCV originate from intrahepatic replication of the virus. In Specific Aim 3 we plan to assess in impact of HCV genotype, circulating levels of virus, and evolution of HCV quasispecies on the long term evolution of histologic injury in the transplanted liver. By carefully correlating the evolution of the virus with the degree of hepatocellular injury experienced by patients who develop recurrent hepatitis C after liver transplantation, we hope to provide insights into to the pathogenesis of this important liver disease. From these detailed analyses we also hope to isolate pathogenic strains of virus which can later be tested in cell culture systems.