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- Title
Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation.
- Authors
Yamane, Daisuke; McGivern, David R; Wauthier, Eliane; Yi, MinKyung; Madden, Victoria J; Welsch, Christoph; Antes, Iris; Wen, Yahong; Chugh, Pauline E; McGee, Charles E; Widman, Douglas G; Misumi, Ichiro; Bandyopadhyay, Sibali; Kim, Seungtaek; Shimakami, Tetsuro; Oikawa, Tsunekazu; Whitmire, Jason K; Heise, Mark T; Dittmer, Dirk P; Kao, C Cheng
- Abstract
Oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.
- Subjects
TISSUE wounds; HEPATITIS C virus; LIPID peroxidation (Biology); RNA viruses; SPHINGOSINE kinase; ANTIVIRAL agents
- Publication
Nature Medicine, 2014, Vol 20, Issue 8, p927
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm.3610