Abstract
Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV.
Highlights
Amino acid polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis
Despite clinical evidence for polymorphism-associated susceptibility to IFN treatment, the intra- and extra-cellular HCV core Ag levels of chimeric viruses with polymorphism-transfected cells were reduced by IFN-α 2b treatment
The amounts of phosphorylated protein kinase R (PKR) were markedly higher in TH/JFH1-QL and -QM transfected cells than they were in TH/JFH1-RL- and -RM transfected cells (Fig. 4). These results indicate that the PKR phosphorylation associated with aa polymorphisms is responsible for the attenuated cell-surface expression of major histocompatibility complex (MHC) class I molecules
Summary
Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. The polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFNbased therapy and hepatocarcinogenesis of HCV. We observed HCV-associated attenuation of the IFN-induced cell surface expression of major histocompatibility complex (MHC) class I molecule via PKR phosphorylation[40]
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