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 (pegIFN alpha) 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 IFN alpha 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 IFN alpha signaling. Furthermore, the antiviral effect of IFN alpha 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.