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https://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 |
DOI: | 10.1038/nm.3610 |
Published version: | http://dx.doi.org/10.1038/nm.3610 |
Appears in Collections: | Aurora harvest 2 Microbiology and Immunology publications |
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