The cause of failure of antiviral treatment with standard therapy, that is, pegylated interferon alpha (pegIFNalpha) combined with ribavirin, in half patients, is unknown, but viral interference with IFNalpha signal transduction through the Jak-STAT pathway could be considered. The expression of HCV proteins leads to an impairment of Jak-STAT signaling because of the inhibition of STAT1 methylation. Unmethylated STAT1 is less active since it can be bound and inactivated by its inhibitor, protein inhibitor of activated STAT1 (PIAS1). The treatment of cells with S-adenosyl-L-methionine (AdoMet) and betaine could restore STAT1 methylation and improve IFN alpha signaling. Furthermore, the antiviral effect of IFNalpha in cell culture could be significantly enhanced by the addition of AdoMet and betaine. S-adenosyl-L-methionine (SAMe) and betaine potentiate IFNα signaling in cultured cells expressing hepatitis C virus (HCV) proteins and enhance the inhibitory effect of IFNα on HCV replicons. SAMe and betaine were found to be safe when used with pegIFNα/ribavirin [73] .