The bimodal, elevated expression of HLA-DRB1 and HLA-DRB5 in patients with a history of relapse may signal association of a specific HLA haplotype with relapse in ADAMTS13-deficient TTP. Elevated expression of the same HLA-DRB1 and -DRB5 probes from the same platform utilized in the present study reflected presence of a specific HLA haplotype in a study of multiple sclerosis. Although selected HLA-DR and-DQ alleles have been reported to associate with TTP, there are no reports of selected HLA alleles associating with relapse. To date, several mechanisms underlying RBV antiviral action against HCV have been proposed : the inhibition of NS5B RNA-dependent RNA polymerase activity, the induction of mutagenesis in the HCV genome leading to a so-called ��error catastrophe��, the enhancement of the IFN-signaling pathway, the inhibition of inosine monophosphate dehydrogenase leading to GTP depletion, and immunomodulation of the XL880 switching of the Th cell phenotype from type 2 to type 1. Although most of these mechanisms were proposed based on studies using HuH-7 -derived cells, which are currently used as the only cell culture system for robust HCV replication, the effective concentrations of RBV were much higher than the clinically achievable concentrations. Indeed, the effective concentration of RBV in our HuH-7-derived cell assay system, in which genome-length HCV RNA encoding renilla luciferase replicates efficiently, was more than 100 ��M. Under such a situation, we accidentally found that human hepatoma Li23-derived ORL8c cells, whose gene expression profile was distinct from that of HuH-7 cells, enabling efficient HCV RNA replication and persistent HCV production, had high sensitivity to RBV. Therefore, using Li23-derived HCV RNA-replicating cells, we demonstrated that RBV at clinically relevant concentrations causes the inhibition of IMPDHs activity, resulting in GTP depletion and the inhibition of HCV replication. Furthermore, we recently demonstrated that adenosine kinase, which phosphorylates RBV to generate mono-phosphorylated RBV, which in turn inhibits IMPDHs, is an essential determinant of anti-HCV activity of RBV in cell culture. Although we have found that adenosine kinase is a crucial factor for ORL8 cells to be sensitive to RBV as mentioned above, we thought that this finding was CHIR-99021 obtained by the comparison between specific monoclonal cell lines. Therefore, we hypothesized that there might be other factors determining RBV-sensitivity against HCV RNA replication. To clarify this point, we tried to obtain cells possessing RBV-resistant phenotype from Li23-derived genome- length HCV RNA-replicating OL8 cells possessing an RBV-sensitive phenotype. Here, we report the successful establishment of RBV-resistant OL8-derived cell lines and their characterization.