Interferon-Mediated Cytokine Induction Determines Sustained Virus Control in Chronic Hepatitis C Virus Infection

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR), but a significant proportion of patients do not respond to IFN alpha. The underlying mechanisms of an insufficient IFN response remain largely unknown. In this study, we found that patients responding to IFN alpha with viral clearance had significantly higher serum levels of TNF-related apoptosis inducing ligand (TRAIL), compared with patients who failed to control HCV. In addition, upon direct IFN alpha exposure, peripheral blood mononuclear cells (PBMCs) from patients with SVR upregulated TRAIL, as well as IFN-gamma and the chemokines CXCL9 and CXCL10, much more strongly than cells from patients with antiviral treatment failure. As a possible mechanism of the stronger IFN alpha-induced cytokine response, we identified higher levels of expression and phosphorylation of the transcription factor STAT1 in PBMCs from patients with SVR. Increased TRAIL expression additionally involved the NF-kappa B and JNK signaling pathways. Thus, SVR in chronic HCV infection is associated with a strong IFN alpha-induced cytokine response, which might allow for the early prediction of treatment efficacy in HCV infection.