HCV infection increases the risk of chronic liver diseases including hepatocellular carcinoma (HCC) and remains one of the major etiological issues worldwide. The mechanism by which HCV chronic causes inflammation and HCC remains elusive. CD81, Cluadin1, SR-BI and OCLN are the key entry factors for HCV infection and transgenic mice expressing these four human entry factors (EFT4) can support transient HCV replication. We obtained transgenic mice expressing three receptors (CD81, Cluadin1, SR-BI) from Dr. Rice’s group and further crossed with a hOCLN knock-in mouse line which was generated with CRISPR-Cas 9 technique by National Lab animal center (Taiwan). The newly established EFT4 mice were maintained in Stat1-/- and Rosa26-Luc background and used to examine HCV replication.