Expression of HCV structural proteins impairs IFN-mediated antiviral response.
Hepatitis C virus (HCV), especially the genotype 1, is naturally resistant to the antiviral effects of interferon-alpha (IFN-alpha). Expression of the whole HCV genome and the NS5A protein has been suggested to interfere with the antiviral activity of IFN-alpha. Here we have analyzed the effect of individual or various combinations of HCV proteins on IFN-alpha-mediated antiviral effect against vesicular stomatitis virus (VSV). When the structural proteins (core-E1-E2) of HCV genotype 1 were expressed in human osteosarcoma cells in a tetracycline-regulated manner, partial VSV resistance to IFN-alpha was established. This was seen as an enhancement of both viral protein synthesis and production of infectious virus. Priming of core-E1-E2-expressing cells with low doses of IFN-gamma (10 IU/ml) partially restored the antiviral activity of IFN-alpha. The core (high-level expression) and NS4B protein expression also showed some rescue of VSV replication. In this model cell system NS3A-NS4A complex and NS5A showed no inhibition of IFN-alpha-induced antiviral activity. Our results indicate that the expression of structural proteins of HCV may impair the antiviral activity of IFNs.
Laboratory of Infectious Disease Immunology, Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
Päivi
P
Keskinen
Krister
K
Melén
Ilkka
I
Julkunen
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016174:Hepacivirus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D014758:Viral Core Proteins / Q000502:physiology; D014759:Viral Envelope Proteins / Q000502:physiology*; D017361:Viral Nonstructural Proteins / Q000502:physiology; D015678:Viral Structural Proteins / Q000502:physiology*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D007372:Interferons; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins; C087035:E1 protein, Hepatitis C virus; C069130:nucleocapsid protein, Hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase