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Background Hepatitis C virus (HCV) proteins interfere with the interferon (IFN)-alpha-induced Jak/signal transducer and activator of transcription (STAT) pathway. Which protein is responsible for this effect and whether this interference results in down-regulation of IFN-induced genes remain controversial. We analyzed the effect of HCV core (HCV-Co) protein on expression of IFN-induced antiviral genes. Methods HepG2 cells were transfected with the plasmid pHCV-Co, and, after treatment with IFN-alpha , levels of MxA, protein kinase R (PKR), and 2'-5' oligoadenylate synthetase (2'-5'OAS) mRNA were determined. Chloramphenycol acethyl transferase (CAT) analysis was performed on cells cotransfected with pHCV-Co and pMx4CAT (containing the MxA gene promoter) and treated with IFN. Electrophoretic mobility shift assays were used, and Western-blot analysis of STAT 1 and 2 was performed. Results Levels of MxA mRNA in pHCV-Co-transfected cells decreased in a dose-dependent manner, by down-regulation of the MxA gene promoter. HCV-Co protein inhibits binding of IFN-stimulated gene factor 3 (ISGF3) to the IFN-stimulated response element (ISRE). Intracellular distribution of STAT 1 and 2 was not modified after treatment with IFN. Expression of HCV-Co protein also results in down-regulation of expression of PKR and 2'-5'OAS genes. Conclusion HCV-Co protein inhibits IFN-alpha-induced transcription of antiviral genes by decreasing binding of ISGF3 to the ISRE.