Lack of clinical evidence for involvement of hepatitis C virus interferon-? sensitivity-determining region variability in RNA-dependent protein kinase-mediated cellular antiviral responses
✍ Scribed by Mihm, Sabine; Monazahian, Masyar; Grethe, Stefanie; Meier, Volker; Thomssen, Reiner; Ramadori, Giuliano
- Publisher
- John Wiley and Sons
- Year
- 2000
- Tongue
- English
- Weight
- 426 KB
- Volume
- 61
- Category
- Article
- ISSN
- 0146-6615
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✦ Synopsis
The hepatitis C virus (HCV) interferon-␣ (IFN-␣) sensitivity-determining region (ISDR) has been shown to suppress double-stranded RNAdependent protein kinase (PKR) activity in vitro in a yeast PKR expression system. Since variability of ISDR was shown to correlate with nonresponsiveness to IFN-␣ therapy in chronically HCV-infected patients, it has been suggested that prototype ISDR might be a viral inhibitor of cellular PKR. The present study evaluates the biological significance of ISDR variability in situ, relating it to PKR-mediated cellular antiviral responses within the liver. ISDR variability was determined in patients chronically infected with HCV genotypes 1a, 1b, and 3a by direct sequencing using liver-derived RNA preparations as starting material. As surrogate parameters for PKR-mediated cellular responses, hepatic endogenous IFN-␣ gene expression as well as MxA expression were analysed by a competitive, quantitative reverse transcription-polymerase chain reaction technique. Irrespectively of intraor intergenotypic ISDR amino acid substitutions, ISDR variability was found not to correlate with endogenous hepatic IFN-␣ or with hepatic MxA gene expression. The data suggest that at least two prominent PKR-mediated cellular responses might be largely unaffected by HCV ISDR variability.