title: Redox modulation of the hepatitis C virus replication complex is calcium dependent.
abstract: 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.
authors.affiliation: School of Natural Sciences, University of California at Merced, CA 95344, USA. jchoi@ucmerced.edu
authors.forename: Jinah
authors.initials: J
authors.lastname: Choi
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
authors.forename: Jing-hsiung
authors.initials: JH
authors.lastname: Ou
authors.forename: Michael M C
authors.initials: MM
authors.lastname: Lai
authors.forename: Scott
authors.initials: S
authors.lastname: Seronello
authors.forename: Anna
authors.initials: A
authors.lastname: Nandipati
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000821:virology*; D018274:Electroporation; D005949:Glucose Oxidase / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development*; D006526:Hepatitis C / Q000378:metabolism / Q000821:virology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000821:virology; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D012367:RNA, Viral / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000821:virology; D014779:Virus Replication
chemical_list: D016877:Oxidants; D012367:RNA, Viral; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D005978:Glutathione; D002118:Calcium