Interferon-alpha inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway.
Hepatitis C virus (HCV) persists in the majority of infected individuals and is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis C is currently treated with interferon (IFN)-alpha or with a combination of IFN-alpha and ribavirin. The availability of an HCV replicon system (Lohmann et al., SCIENCE: 285, 110-113, 1999) allowed the investigation of the effects of IFN on genuine HCV replication in cultured cells. It is shown here that IFN-alpha inhibits subgenomic HCV RNA replication in HuH-7 human hepatoma cells. Immunofluorescence, Western blot and Northern blot analysis revealed that levels of both HCV protein and replicon RNA were reduced after treatment with IFN-alpha in a dose-dependent manner. In further experiments, it was investigated whether MxA plays a role in the inhibition of HCV. The human MxA protein is an IFN-induced GTPase that has antiviral activity against various RNA viruses. However, HCV RNA replication was not affected in transfected HuH-7 cells that transiently overexpressed MxA. Moreover, a dominant-negative mutant of MxA did not interfere with the antiviral activity of IFN-alpha against HCV RNA replication. Taken together, these results demonstrate that IFN-alpha inhibits HCV replicons via an MxA-independent pathway.
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany1.
Michael
M
Frese
Institut für Virologie, Universität Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany2.
Thomas
T
Pietschmann
Abteilung Innere Medizin II, Medizinische Universitätsklinik Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany3.
Darius
D
Moradpour
Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany1.
Otto
O
Haller
Institut für Virologie, Universität Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany2.
Ralf
R
Bartenschlager
D000998:Antiviral Agents / Q000494:pharmacology* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D064547:Myxovirus Resistance Proteins; D011506:Proteins / Q000502:physiology*; D012367:RNA, Viral / Q000096:biosynthesis*; D012093:Replicon; D014407:Tumor Cells, Cultured; D017361:Viral Nonstructural Proteins / Q000502:physiology; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D019204:GTP-Binding Proteins; D016898:Interferon-alpha; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C579071:MX1 protein, human; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase