Bile Acids Promote HCV Replication through the EGFR/ERK Pathway in Replicon-Harboring Cells

Objectives: Bile acids promoted the replication of hepatitis C virus (HCV) and compromised the anti-HCV effects of interferon-alpha (IFN-alpha) in replicon-harboring cells. To explore a potential mechanism for the observation, we studied the effects of bile acids on the epidermal growth factor receptor (EGFR) and the extracellular signal-regulated kinase (ERK) pathway in association with HCV replication in genotype 1a or 1b replicon-harboring cells. Methods: Replicon-harboring cells were treated with various bile acids, IFN-alpha and small molecule inhibitors either individually or combined together. The effects of these treatments were measured using cell cycle analysis, qRT-PCR, and Western blot analysis. Results: Bile acids induced the activation of EGFR/ERK pathway and extended S-phase of cells, which was correlated with the increased levels of viral replication. The inhibitors of EGFR (AG1478) or ERK (U0126) significantly mitigated the bile acid-mediated promotion of HCV replication. When AG1478 or U0126 were added to the treatment of bile acids and IFN-alpha, they were able to restore the anti-HCV effects of IFN-alpha. Conclusion: Our data suggest that the addition of an EGFR or ERK inhibitor to the current IFN-alpha-based regimen may improve overall treatment efficacy by blocking the bile acid-mediated promotion of HCV replication. Copyright (C) 2011 S. Karger AG, Basel