DEVELOPMENT OF HEPATITIS THERAPY AND VACCINE USING HEPATITIS C VIRUS TRANSGENIC MICE

丙型肝炎病毒是非甲非乙型慢性肝炎的主要病原体，也被认为与混合性冷球蛋白血症和肾小球肾炎等肝外表现有关。此前已有两个携带丙型肝炎病毒包膜基因的转基因小鼠的独立品系被证明在包括肝脏和唾液腺在内的器官中表达丙型肝炎病毒包膜蛋白，这导致肝脏没有病理变化。对这些动物的进一步分析现在发现，它们会患上一种涉及唾液腺和泪腺的外分泌病。这种病理与干燥综合征相似，后者也可能与慢性丙型肝炎有关。这些观察表明，丙型肝炎病毒可能参与了人类涎腺炎的发病机制，这种转基因小鼠系统将是研究丙型肝炎病毒感染的良好动物模型。丙型肝炎病毒已被认为最终导致肝细胞癌(HCC)的发展。然而，慢性丙型肝炎的肝癌发生机制仍不清楚。丙型肝炎病毒核心蛋白调节细胞内信号通路的能力被认为参与了丙型肝炎的发病机制。在这里，我们描述了作为慢性丙型肝炎的组织学特征的早期发生肝脂肪变性的丙型肝炎病毒核心基因转基因小鼠的肝细胞癌的发生。这些小鼠的肝细胞癌的发展特征与先前在慢性丙型肝炎患者的肝细胞癌早期观察到的组织病理学特征非常相似。这些结果表明，丙型肝炎病毒核心蛋白在肝细胞癌的发生发展中起重要作用，并且丙型肝炎病毒本身直接参与了肝癌的发生。

Hepatitis C virus(HCV), a major causative agent of non-A, non-B chronic hepatitis, is also suggested to be associated with extrahepatic manifestations such as mixed cryoglobulinemia and glomerulonephritis. Two independent lines of transgenic mice carrying the HCV envelope genes have been previously shown to express the HCV envelope proteins in organs including the liver and salivary glands, which results in no pathological changes in the liver. Further analysis of these animals has now revealed that they develop an exocrinopathy involving the salivary and lachrymal glands. This pathology resembles Sjogren's syndrome, which is also suggested to have a possible association with chronic hepatitis C.These observations suggest that HCV may be involved in the pathogenesis of sialadenitis in humans, and this transgenic mouse system would be a good animal model for the study of HCV infection.HCV has been known to finally leads to the development of hepatocellular carcinoma (HCC). However, the mechanism of hepatocarcinogenesis in chronic HCV infection is still unclear. The ability of the core protein of HCV to modulate intracellular signaling pathways has been suggested as being involved in the pathogenesis of HCC.Here we describe the development of HCC in HCV core gene transgenic mice which develop hepatic steatosis early in life as a histological feature characteristic of chronic hepatitis C.The feature in the development of HCC in these mice closely resembled the histopathological characteristics previously observed in the early stage of HCC in patients with chronic hepatitis C.These results indicate that the HCV core protein has a major role in the development of HCC and that HCV itself is directly involved in hepatocarcinogenesis.