Interferon signaling and treatment outcome in chronic hepatitis C

*Department of Biomedicine, University of Basel, CH-4031 Basel, Switzerland;
^†Friedrich Miescher Institute for Biomedical Research, CH-4002 Basel, Switzerland;
^‡Institute for Pathology, University Hospital Basel, CH-4003 Basel, Switzerland; and
^§Division of Gastroenterology and Hepatology, University Hospital Basel, CH-4031 Basel, Switzerland

Edited by Charles M. Rice III, The Rockefeller University, New York, NY, and approved March 6, 2008 (received for review August 21, 2007)

Abstract

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The current standard therapy for chronic hepatitis C (CHC) consists of a combination of pegylated IFN alpha (pegIFNα) and ribavirin. It achieves a sustained viral clearance in only 50–60% of patients. To learn more about molecular mechanisms underlying treatment failure, we investigated IFN-induced signaling in paired liver biopsies collected from CHC patients before and after administration of pegIFNα. In patients with a rapid virological response to treatment, pegIFNα induced a strong up-regulation of IFN-stimulated genes (ISGs). As shown previously, nonresponders had high expression levels of ISGs before therapy. Analysis of posttreatment biopsies of these patients revealed that pegIFNα did not induce expression of ISGs above the pretreatment levels. In accordance with ISG expression data, phosphorylation, DNA binding, and nuclear localization of STAT1 indicated that the IFN signaling pathway in nonresponsive patients is preactivated and refractory to further stimulation. Some features characteristic of nonresponders were more accentuated in patients infected with HCV genotypes 1 and 4 compared with genotypes 2 and 3, providing a possible explanation for the poor response of the former group to therapy. Taken together with previous findings, our data support the concept that activation of the endogenous IFN system in CHC not only is ineffective in clearing the infection but also may impede the response to therapy, most likely by inducing a refractory state of the IFN signaling pathway.

Footnotes

^¶To whom correspondence should be addressed. E-mail: markus.heim{at}unibas.ch
Author contributions: M.S.-F., W.F., and M.H.H. designed research; M.S.-F., E.J.O., F.H.T.D., V.C., and M.H.H. performed research; M.S.-F., E.J.O., F.H.T.D., V.C., L.T., W.F., and M.H.H. analyzed data; and W.F. and M.H.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE 11190).
This article contains supporting information online at www.pnas.org/cgi/content/full/0707882105/DCSupplemental.