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 H2O2 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 H2O2 and interferon-γ have comparable effects on the HCV subgenomic and genomic RNA replication in Huh7 cells. H2O2 induced a gradual rise in the intracellular calcium concentration ([Ca2+]i). Both rapid and sustained suppression of HCV RNA replication by H2O2 depended on this calcium elevation. The peroxide-induced [Ca2+]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 H2O2 was independent of extracellular calcium but required an intracellular calcium source. Other agents that elevated [Ca2+]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.