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|Title:||Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation|
|Citation:||Nature Medicine, 2014; 20(8):927-935|
|Publisher:||Nature Publishing Group|
|Daisuke Yamane, David R McGivern, Eliane Wauthier, MinKyung Yi, Victoria J Madden, Christoph Welsch, Iris Antes, Yahong Wen, Pauline E Chugh, Charles E McGee, Douglas G Widman, Ichiro Misumi, Sibali Bandyopadhyay, Seungtaek Kim, Tetsuro Shimakami, Tsunekazu Oikawa, Jason K Whitmire, Mark T Heise, Dirk P Dittmer, C Cheng Kao, Stuart M Pitson, Alfred H Merrill Jr, Lola M Reid, Stanley M Lemon|
|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.|
|Keywords:||Hepatocytes; Hepacivirus; Hepatitis C; RNA Replicase; Phosphotransferases (Alcohol Group Acceptor); Adaptor Proteins, Signal Transducing; Viral Nonstructural Proteins; RNA, Small Interfering; Antiviral Agents; Virus Replication; RNA Interference; Lipid Peroxidation; Oxidative Stress|
|Rights:||© 2014 Nature America, Inc|
|Appears in Collections:||Microbiology and Immunology publications|
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