Clinical relevance of the 2'-5'-oligoadenylate synthetase/RNase L system for treatment response in chronic hepatitis C.
OBJECTIVE
Interferon-alpha 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-alpha-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.
Mihm
Ulrike
U
Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany.
Ackermann
Oliver
O
Welsch
Christoph
C
Herrmann
Eva
E
Hofmann
Wolf Peter
WP
Grigorian
Natalia
N
Welker
Martin Walter
MW
Lengauer
Thomas
T
Zeuzem
Stefan
S
Sarrazin
Christoph
C
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D004722:Endoribonucleases / Q000378:metabolism*; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D012367:RNA, Viral / Q000378:metabolism; D012254:Ribavirin / Q000627:therapeutic use; D012680:Sensitivity and Specificity
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease