Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation

• Published in: Nature medicine Vol. 20; no. 8; pp. 927 - 935
• Main 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, Pitson, Stuart M, Merrill, Alfred H, Reid, Lola M, Lemon, Stanley M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2014; Nature Publishing Group
• Subjects: 13/106; 13/95; 38/109; 42/89; 631/326/596/1905; 82/1; Adaptor Proteins, Signal Transducing - genetics; Antiviral Agents - pharmacology; Biomedicine; Cancer Research; Cell Line; Cell Membrane - pathology; Distribution; Genotypes; Health aspects; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepacivirus - genetics; Hepatitis; Hepatitis C - drug therapy; Hepatitis C virus; Hepatocytes - metabolism; Hepatocytes - virology; Humans; Infectious Diseases; Lipid Peroxidation; Lipids; Membranes; Metabolic Diseases; Molecular Medicine; Neurosciences; Oxidative Stress; Peroxidation; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Physiological aspects; Proteins; Regulation; Ribonucleic acid; RNA; RNA Interference; RNA, Small Interfering - genetics; RNA-Dependent RNA Polymerase - metabolism; Sphingosine; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; North Carolina
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3610

Stanley Lemon and colleagues show that the HCV replicase is sensitive to lipid peroxidation, which may restrict viral replication in vitro and in vivo . 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.