Establishment of laboratory transgenic mouse strains for hepatitis C virus infection

丙型肝炎病毒（HCV）是非甲型/非乙型肝炎的主要病原体。HCV感染的一个主要特征是慢性风险极高（高达80%）；此外，慢性丙型肝炎病毒感染经常会导致肝硬化和肝细胞癌。关于HCV相关肝脏病变发病机制的一个重要问题是确定HCV蛋白是否对细胞表型有直接影响。然而，人们对这方面所知甚少。为了解决这个问题，我们尝试建立HCV动物模型。引入一种高效的Cre/loxP条件转基因，我们用HCVcDNA（核苷酸294-3435）创建了几系转基因小鼠。在给予表达Cre重组酶的腺病毒后，作为转基因基因引入的HCV基因组可以在大多数转基因小鼠的肝细胞中表达几种HCV特异性核心蛋白。此外，病理变化和血清丙氨酸转氨酶水平升高提示表达HCV转基因的小鼠发生肝损伤。CD4和CD8阳性细胞消耗试验使血清丙氨酸转氨酶升高和肝脏病理改变正常化。这些结果表明，HCV蛋白不直接引起细胞病变，宿主免疫反应在HCV感染中起关键作用。因此，这种HCV cDNA转基因小鼠为研究HCV感染的免疫应答和发病机制提供了有力的工具。

The hepatitis C virus (HCV) is the major causative agent of non-A/non-B hepatitis. A major characteristic of HCV infection is the extremely high (up to 80%) risk of chronicity; in addition, chronic infection of HCV can frequently leads to liver cirrhosis and hepatocellular carcinoma. An important issue regarding the pathogenesis of HCV-associated liver lesions is to determine whether HCV proteins might have a direct effect on cellular phenotype. however, little was known about this respect. To address this question, we tried to establish animal model for HCV. Introducing an efficient Cre/loxP conditional transgenesis, we created several lines of transgenic mice with HCVcDNA (nucleotides 294-3435). After administration of adenovirus that expresses Cre recombinase, the HCV genome introduced as a transgene can express several HCV-specific core proteins in most hepatocytes of the transgenic mice. Moreover, pathological changes and elevated level of serum alanine animotransferase suggested that liver injury occurred in the transgenic mice that express the HCV transgene. A CD4 and CD8 positive cells depletion assay normalized both the serum alanine aminotransferase increases and the pathological changes in the liver. These results suggested that HCV proteins are not directly cytopathic and that the host immune response plays a pivotal role in HCV infection. Thus, this HCV cDNA transgenic mouse provides a powerful tool with which to investigate the immune responses and pathogenesis of HCV infection.