The lack of immunocompetent small animal models and cell culture systems to support the propagation of HCV in patient sera has hampered both the understanding of the HCV life cycle and the development of antiviral drugs [
46]. HCV replicon cells in which the HCV genome autonomously replicates, and pseudotype viruses bearing HCV E1 and E2 glycoproteins were established to assess viral replication and entry, respectively [
47,
48]. Afterwards, an infectious HCV derived from the JFH1 strain of genotype 2a (HCVcc) was developed [
7,
8]. On the basis of the data obtained from these in vitro systems, the HCV life cycle has been clarified, and host factors involved in HCV propagation have been identified as therapeutic targets for chronic hepatitis C [
46]. However, the robust propagation of HCVcc in well-characterized human liver cell lines other than Huh7 had not been successful until recently. Chang et al. [
49] showed that the exogenous expression of miR-122 facilitated the replication of HCV RNA in kidney-derived HEK-293 cells. In addition, Lin et al. have demonstrated that the expression of miR-122 and depletion of interferon regulatory factor 3 (IRF-3) permit replication of the HCV genome in mouse fibroblasts [
50]. These results suggest that the expression of miR-122 might facilitate the efficient replication of HCVcc not only in hepatic cells but also in nonhepatic cells. In fact, the expression level of miR-122 in Huh7 cells has been shown to be higher than that in other hepatic cell lines, including Huh6, HepG2, and Hep3B cells [
10]. Recently, two groups reported that miR-122 expression facilitated the efficient propagation of HCVcc in human hepatic cell lines [
10,
11]. Narbus et al. [
11] showed that HepG2 cells stably expressing CD81 and miR-122 supported efficient replication and the production of infectious particles. Interestingly, internal ribosomal entry site (IRES)-dependent translation of HCV exhibited a slight (1.4–2.1-fold) increase by the expression of miR-122 in HepG2 cells compared with that in parental cells, suggesting that miR-122 is required for efficient RNA replication but not in translation in HepG2 cells upon infection with HCVcc. Kambara et al. [
10] established a novel permissive cell line for the propagation of HCVcc by the expression of miR-122 in Hep3B cells. miR-122 expression facilitated the efficient propagation of HCVcc and the establishment of HCV replicon cells in Hep3B cells. In addition, “cured” Hep3B cells established by the elimination of HCV RNA from the Hep3B replicon cells facilitated the efficient propagation of HCVcc compared to parental cells. Interestingly, the expression of miR-122 in the “cured” Hep3B cells was significantly higher than that in the parental cells. In addition, Ehrhadt et al. [
51] have shown that the expression levels of miR-122 in Huh7-derived cured cells, including Huh7.5 and Huh-Lunet cells, are significantly higher than those in parental Huh7 cells. Collectively, these results suggest that miR-122 is a key determinant of the efficient replication of HCVcc in hepatic cell lines.