Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.
Virology. 2010 Sep 30;405(2):361-9. doi: 10.1016/j.virol.2010.06.020. Epub 2010 Jul 6.
HCV-JFH1 yields subclones that develop cytopathic plaques (Sekine-Osajima Y, et al., Virology 2008; 371:71). Here, we investigated viral amino acid substitutions in cytopathic mutant HCV-JFH1 clones and their characteristics in vitro and in vivo. The mutant viruses with individual C2441S, P2938S or R2985P signature substitutions, and with all three substitutions, showed significantly higher intracellular replication efficiencies and greater cytopathic effects than the parental JFH1 in vitro. The mutant HCV-inoculated mice showed significantly higher serum HCV RNA and higher level of expression of ER stress-related proteins in early period of infection. At 8 weeks post inoculation, these signature mutations had reverted to the wild type sequences. HCV-induced cytopathogenicity is associated with the level of intracellular viral replication and is determined by certain amino acid substitutions in HCV-NS5A and NS5B regions. The cytopathic HCV clones exhibit high replication competence in vivo but may be eliminated during the early stages of infection.
HCV-JFH1 产生致病变异型亚克隆（Sekine-Osajima Y, et al., Virology 2008; 371:71）。在此，我们研究了致病变异型 HCV-JFH1 克隆中的病毒氨基酸替换及其在体外和体内的特征。具有单个 C2441S、P2938S 或 R2985P 特征性替换的突变病毒，以及具有所有三个替换的突变病毒，在体外显示出比亲本 JFH1 更高的细胞内复制效率和更强的致病变异型效应。感染突变 HCV 的小鼠在感染早期血清 HCV RNA 水平显著升高，内质网应激相关蛋白的表达水平也显著升高。在接种后 8 周时，这些特征性突变已恢复为野生型序列。HCV 诱导的细胞病变与细胞内病毒复制水平有关，由 HCV-NS5A 和 NS5B 区域的某些氨基酸替换决定。致病变异型 HCV 克隆在体内具有高复制能力，但在感染早期可能被清除。
