Epigenetic silencing of interferon-inducible genes is implicated in interferon resistance of hepatitis C virus replicon-harboring cells

J Hepatol 44(5):10 (2006) PMID 16545484

Background/Aims: We previously established hepatitis C virus (HCV) replicon-harboring cell lines possessing two interferon (IFN)-resistant phenotypes: a partially resistant phenotype (@aR series) and a severely resistant phenotype (@bR series). We recently found that the severe IFN resistance of the @bR-series cells is caused by the functional disruption of type I IFN receptors. Here, we aimed to clarify the mechanism(s) underlying the partial IFN resistance of the @aR-series cells. Methods: @aR-series cells were pre-treated with 5-azacytidine to evaluate the effects of DNA demethylation on IFN resistance. cDNA microarray analysis was carried out in order to compare 1@aR cells, which belong to the @aR series, treated with both 5-azacytidine and IFN-@a with cells treated with 5-azacytidine or IFN-@a alone. Results: We found that the IFN-resistant phenotype of @aR-series cells was impaired by treatment with 5-azacytidine. cDNA microarray analysis identified seven IFN-stimulated genes, which were up-regulated by 5-azacytidine treatment. We demonstrated here that the ectopic expression of each of these seven genes in 1@aR cells frequently weakened the IFN resistance of these cells. Conclusions: The present results suggest that the epigenetic silencing of IFN-stimulated genes is implicated in the acquisition of a partially IFN-resistant phenotype of HCV replicon-harboring cells.