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.
Keskinen
Päivi
P
Laboratory of Infectious Disease Immunology, Department of Microbiology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.
Melén
Krister
K
Julkunen
Ilkka
I
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