Hepatitis C virus is restricted at both entry and replication in mouse hepatocytes

Human hepatitis C virus (HCV) does not replicate in mouse hepatocytes. The underlying mechanisms are largely unknown. In this study, we took advantage of a series of direct and unique molecular strategies and dissected the HCV life cycle in human hepatoma Huh7.5 cells and mouse hepatoma Hepa1–6 cells. We showed that HCV entry was restricted in Hepa1–6 cells and was not rescued by expression of human HCV receptors. We also showed that HCV RNA replication was impaired in Hepa1–6 cells. In contrast, we showed that the HCV IRES translation activity and HCV production in Hepa1–6 cells were either comparable to, or even slightly higher than those in Huh7.5 cells. Thus, we conclude that entry and RNA replication are the two major HCV restrictions in mouse cells. These studies provide new insights into HCV interaction with mouse cells and new clues for formulating strategies for development of HCV mouse models.