HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling
| Autor: | Nathan Shores, Partha K. Chandra, Lili Bao, Tong Wu, Kyoung-Sub Song, Darren P. Baker, Curt H. Hagedorn, Srikanta Dash, Fatma M. Aboulnasr, William C. Wimley, Shuanghu Liu, Luis A. Balart, Serge Y. Fuchs |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Hepatitis C virus
Blotting Western Hepacivirus Biology medicine.disease_cause Virus Replication Antiviral Agents Pathology and Forensic Medicine 03 medical and health sciences Interferon-gamma 0302 clinical medicine Cell Line Tumor medicine Autophagy Gene silencing Humans 030304 developmental biology 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Regular Article Endoplasmic Reticulum Stress Virology Hepatitis C 3. Good health Viral replication Cell culture Interferon Type I Unfolded protein response Hepatocytes 030211 gastroenterology & hepatology Signal transduction Interferon type I medicine.drug Signal Transduction |
| Zdroj: | The American Journal of Pathology. 184(1):214-229 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2013.10.005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|