Clinical relevance of the 2′-5′-oligoadenylate synthetase/RNase L system for treatment response in chronic hepatitis C

Background/Aims: Interferon-a induces 2'-5'-oligoadenylate synthetase which activates RNase L. Viral RNA is cleaved by RNase L at UU/-UA dinucleotides. The clinical relevance of RNase L cleavage for response to an interferon-alpha-based therapy in chronic hepatitis C is unknown. Methods: RNase L cleavage sites within pre-treatment sequences coding for structural and non-structural hepatitis C virus proteins were compared between non-responders and responders to an interferon-alpha-based therapy. Furthermore, RNase L cleavage sites were analyzed in full length and partial genome isolates of hepatitis C virus genotype 1b infected non-responders before and during treatment and in different hepatitis C virus genotypes (1b, 2a/b, 3a/b). Results: No differences in RNase L cleavage sites were observed between non-responders and responders within a given hepatitis C genotype. Non-responders with hepatitis C virus genotype 1b infection did not eliminate UA/UU dinucleotides during therapy. Hepatitis C virus genotype 1b isolates showed a lower number of UA/UU dinucleotides than hepatitis C virus genotypes 2/3 (p < 0.001). Conclusions: Response or non-response to an interferon-a-based therapy within a given hepatitis C virus genotype is not explained by differences for RNase L cleavage sites. General differences of interferon sensitivity between hepatitis C virus genotypes correlate significantly with frequencies of RNase L cleavage sites. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.