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Am J Pathol. 2014 Jan;184(1):214-29. doi: 10.1016/j.ajpath.2013.10.005. Epub 2013 Nov 9.

HCV infection selectively impairs type I but not type III IFN signaling.

Author information

1
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
2
Biogen Idec, Inc., Cambridge, Massachusetts.
3
Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana.
4
Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana.
5
Department of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
6
Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
7
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: sdash@tulane.edu.

Abstract

A stable and persistent Hepatitis C virus (HCV) replication cell culture model was developed to examine clearance of viral replication during long-term treatment using interferon-α (IFN-α), IFN-λ, and ribavirin (RBV). Persistently HCV-infected cell culture exhibited an impaired antiviral response to IFN-α+RBV combination treatment, whereas IFN-λ treatment produced a strong and sustained antiviral response that cleared HCV replication. HCV replication in persistently infected cells induced chronic endoplasmic reticulum (ER) stress and an autophagy response that selectively down-regulated the functional IFN-α receptor-1 chain of type I, but not type II (IFN-γ) or type III (IFN-λ) IFN receptors. Down-regulation of IFN-α receptor-1 resulted in defective JAK-STAT signaling, impaired STAT phosphorylation, and impaired nuclear translocation of STAT. Furthermore, HCV replication impaired RBV uptake, because of reduced expression of the nucleoside transporters ENT1 and CNT1. Silencing ER stress and the autophagy response using chemical inhibitors or siRNA additively inhibited HCV replication and induced viral clearance by the IFN-α+RBV combination treatment. These results indicate that HCV induces ER stress and that the autophagy response selectively impairs type I (but not type III) IFN signaling, which explains why IFN-λ (but not IFN-α) produced a sustained antiviral response against HCV. The results also indicate that inhibition of ER stress and of the autophagy response overcomes IFN-α+RBV resistance mechanisms associated with HCV infection.

PMID:
24215913
PMCID:
PMC3873489
DOI:
10.1016/j.ajpath.2013.10.005
[Indexed for MEDLINE]
Free PMC Article

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