Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/94167
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Type: Journal article
Title: Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation
Author: Yamane, D.
McGivern, D.
Wauthier, E.
Yi, M.
Madden, V.
Welsch, C.
Antes, I.
Wen, Y.
Chugh, P.
McGee, C.
Widmann, D.
Misumi, I.
Bandyopadhyay, S.
Kim, S.
Shimakami, T.
Oikawa, T.
Whitmire, J.
Heise, M.
Dittmer, D.
Kao, C.
et al.
Citation: Nature Medicine, 2014; 20(8):927-935
Publisher: Nature Publishing Group
Issue Date: 2014
ISSN: 1078-8956
1546-170X
Statement of
Responsibility: 
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
RMID: 0030028780
DOI: 10.1038/nm.3610
Appears in Collections:Microbiology and Immunology publications

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