Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis, cirrhosis, and liver cancer. 1-4 HCV is a member of the Flaviviridae, and its genome is a positive, single-strand RNA molecule, with a length averaging 9.4 kb, that encodes a 3,000-amino acid polyprotein. This polyprotein is then cleaved into structural and nonstructural proteins. The structural proteins include the core protein, followed by two envelope (E1, E2) and p7 proteins. The various HCV isolates show significant sequence divergence, especially in the E2 envelope protein, the N-terminal part of which shows one or two hypervariable regions (HVR), according to the HCV type (reviewed in Bréchot 5 and Major 6 ). The high rate of mutations in the HCV genome also accounts for the circulation of a complex population of HCV-RNA molecules, referred to as quasispecies. 5,7,8 The major feature of HCV infection is the extremely high risk (60% to 80%) of developing a chronic carrier state following acute infection. The mechanisms involved are still poorly known, but it is striking that chronic infection occurs despite a strong humoral and cellular immune response to various viral proteins. In this context, the actual pattern and impact of neutralizing anti-HCV antibodies during the natural course of HCV infection or during antiviral therapy remain subject to debate. [9][10][11] The cellular tropism of HCV is another much-debated topic that may have major implications for the understanding of viral pathogenesis. There is compelling evidence for the hepatotropism of HCV, and adult as well as fetal human and chimpanzee hepatocytes can be infected by HCV. [12][13][14] Several results also point to in vivo infection by HCV of mononuclear blood cells, but this is still an unsettled issue. [15][16][17][18][19] In addition, it has been demonstrated that human T-and B-lymphocyte cell lines and nonhuman cell lines can hold out long-term HCV replication. [20][21][22][23][24][25] Despite these numerous studies, there is presently no information on the potential permissivity to HCV of nonhepatocytic liver cells and in particular, biliary epithelial cells. However, certain HCV infection characteristics point to this possibility: bile duct damage is one of the histological hallmarks of HCV infection. 26 Furthermore, an increase in the blood level of ␥-glutamyl transpeptidase, which reflects in part bile duct lesions, has been shown in some studies to correlate with a poor response to interferon alfa treatment. 27 Finally, two recent reports using anti-HCV antibodies and in situ hybridization on liver sections from HCV-infected patients have revealed the presence of HCV genomes in intrahepatic biliary cells. 28,29 Various model systems for studying biliary epithelial function have been developed in the past few years. Gallbladder epithelial cells (GBEC) have been proposed as a model of the more proximal biliary epithelium. [30][31][32] This view is supported Abbreviations: HCV, hepatitis C virus; HVR1, hypervariable region 1; GBEC, gallbladder biliary epithelia...