A fresh look at interferon-alpha signaling and treatment outcomes in chronic hepatitis C

October 8, 2008

Hepatology. 2008 Oct;48(4):1330-3.

A fresh look at interferon-alpha signaling and treatment outcomes in chronic

hepatitis C.

Bellecave P, Moradpour D.

Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire

Vaudois, University of Lausanne, Lausanne, Switzerland.

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 (pegIFNalpha) 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 pegIFNalpha. In patients with a rapid virological response to

treatment, pegIFNalpha 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 pegIFNalpha 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.

PMID: 18821612 [PubMed - in process]

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