RT Journal Article
SR Electronic
T1 Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 144
OP 154
DO 10.1136/gutjnl-2014-307904
VO 65
IS 1
A1 Brault, Charlène
A1 Lévy, Pierre
A1 Duponchel, Sarah
A1 Michelet, Maud
A1 Sallé, Aurèlie
A1 Pécheur, Eve-Isabelle
A1 Plissonnier, Marie-Laure
A1 Parent, Romain
A1 Véricel, Evelyne
A1 Ivanov, Alexander V
A1 Demir, Münevver
A1 Steffen, Hans-Michael
A1 Odenthal, Margarete
A1 Zoulim, Fabien
A1 Bartosch, Birke
YR 2016
UL http://gut.bmj.com/content/65/1/144.abstract
AB 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.Design 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.