title: Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity.
abstract: OBJECTIVE
  Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed.
  
  
  METHODS
  The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts.
  
  
  RESULTS
  A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients.
  
  
  CONCLUSIONS
  HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Brault
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lévy
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Duponchel
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Michelet
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Aurèlie
authors.initials: A
authors.lastname: Sallé
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Eve-Isabelle
authors.initials: EI
authors.lastname: Pécheur
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Plissonnier
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France DevWeCan Laboratories of Excellence Network (Labex), France.
authors.forename: Romain
authors.initials: R
authors.lastname: Parent
authors.affiliation: Université de Lyon, UMR 1060 INSERM CarMeN, IMBL, INSA-Lyon, Lyon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Véricel
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ivanov
authors.affiliation: Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Münevver
authors.initials: M
authors.lastname: Demir
authors.affiliation: Clinic for Gastroenterology and Hepatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Steffen
authors.affiliation: Institute of Pathology, University of Cologne, Cologne, Germany.
authors.forename: Margarete
authors.initials: M
authors.lastname: Odenthal
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France DevWeCan Laboratories of Excellence Network (Labex), France Hospices civils de Lyon, Lyon, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
authors.affiliation: Inserm U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France DevWeCan Laboratories of Excellence Network (Labex), France.
authors.forename: Birke
authors.initials: B
authors.lastname: Bartosch
mesh_terms: D000328:Adult; D015415:Biomarkers; D001706:Biopsy; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005979:Glutathione Peroxidase / Q000378:metabolism*; D016174:Hepacivirus / Q000378:metabolism / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology / Q000473:pathology / Q000821:virology*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D014771:Virion / Q000378:metabolism / Q000472:pathogenicity*
chemical_list: D015415:Biomarkers; D017382:Reactive Oxygen Species; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
keywords: HEPATITIS C; LIPID PEROXIDATION; OXIDATIVE STRESS