Summary of effects of acute ethanol on HCV replication. Ethanol effects in this system are independent of ethanol metabolism and as such may involve ethanol-induced perturbations in cell membranes, such as membrane fluidity. Left side, acute ethanol activates p38 MAPK which leads to Stat1 serine phosphorylation, Jak-Stat signaling and inhibition of HCV replication. Activated Stat1 may be involved in ISRE transcription but it is possible that other ISRE binding transcription factors such as Stat3 are involved in this process. Right side, ethanol inhibits the antiviral actions of exogenously applied IFN and this involves inhibition of IFN-induced Stat1 tyrosine phosphorylation, decreased Jak-Stat signaling and increased HCV replication in the presence of IFN. Inhibition of Jak-Stat signaling may involve ethanol perturbation of IFN-α induced changes in membrane fluidity, inhibition of IFN binding to its receptor, direct inhibition of Jak kinases, and/or induction of negative regulators of the Jak-Statpathway such as SOCS proteins.