Redox modulation of the hepatitis C virus replication complex is calcium dependent

Reactive species and perturbation of the redox balance have been implicated in the pathogenesis of many viral diseases, including hepatitis C. Previously, we made a surprising discovery that concentrations of H(2)O(2) that are nontoxic to host cells disrupted the hepatitis C virus (HCV) replication complex (RC) in Huh7 human hepatoma cells in a manner that suggested signaling. Here, we show that H(2)O(2) and interferon-gamma have comparable effects on the HCV subgenomic and genomic RNA replication in Huh7 cells. H(2)O(2) induced a gradual rise in the intracellular calcium concentration (Ca(2+)](i)). Both rapid and sustained suppression of HCV RNA replication by H(2)O(2) depended on this calcium elevation. The peroxide-induced Ca(2+)](i) elevation was independent of extracellular calcium and derived, at least in part, from the endoplasmic reticulum. Likewise, the suppression of the HCV RC by H(2)O(2) was independent of extracellular calcium but required an intracellular calcium source. Other agents that elevated Ca(2+)](i) could also suppress the HCV RC, suggesting that calcium elevation might be sufficient to suppress HCV RNA replication. In conclusion, oxidants may modulate the HCV RC through calcium. Effects on the infectivity and the morphogenesis of HCV remain to be determined. These findings suggest possible regulatory roles for redox and calcium signaling during viral infections.