HCV infection selectively impairs type I but not type III IFN signaling.
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.
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Partha K
PK
Chandra
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Lili
L
Bao
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Kyoungsub
K
Song
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Fatma M
FM
Aboulnasr
Biogen Idec, Inc., Cambridge, Massachusetts.
Darren P
DP
Baker
Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana.
Nathan
N
Shores
Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana.
William C
WC
Wimley
Department of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
Shuanghu
S
Liu
Department of Medicine and Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
Curt H
CH
Hagedorn
Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania.
Serge Y
SY
Fuchs
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
Tong
T
Wu
Department of Gastroenterology and Hepatology, Tulane University School of Medicine, New Orleans, Louisiana.
Luis A
LA
Balart
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: sdash@tulane.edu.
Srikanta
S
Dash
D000998:Antiviral Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D000998:Antiviral Agents; D007370:Interferon Type I; D007371:Interferon-gamma