S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro.
Hepatitis C virus (HCV) infection is an important cause of chronic liver disease. Standard therapy, pegylated interferon alpha (pegIFNalpha) combined with ribavirin, results in a sustained response rate in approximately half of patients. The cause of treatment failure in the other half of the patients is unknown, but viral interference with IFNalpha signal transduction through the Jak-STAT pathway might be an important factor. We have shown previously that the expression of HCV proteins leads to an impairment of Jak-STAT signaling because of an inhibition of STAT1 methylation. Unmethylated STAT1 is less active because it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). We show that treating cells with S-adenosyl-L-methionine (AdoMet) and betaine could restore STAT1 methylation and improve IFNalpha signaling. Furthermore, the antiviral effect of IFNalpha in cell culture could be significantly enhanced by the addition of AdoMet and betaine. In conclusion, we propose that the addition of these drugs to the standard therapy of patients with chronic hepatitis C could overcome treatment resistance.
Department of Research and Division of Gastroenterology and Hepatology, University Hospital Basel, Switzerland.
Francois H T
FH
Duong
Verena
V
Christen
Magdalena
M
Filipowicz
Markus H
MH
Heim
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology; D001622:Betaine / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000201:enzymology / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008745:Methylation / Q000187:drug effects; D010749:Phosphoprotein Phosphatases / Q000378:metabolism / Q000494:pharmacology; D000071636:Protein Phosphatase 2C; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C027579:periodate-oxidized adenosine; D001622:Betaine; D012436:S-Adenosylmethionine; D004247:DNA; D011484:Protein-Arginine N-Methyltransferases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D000241:Adenosine