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PMID: 10400746 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Antiapoptotic and oncogenic potentials of hepatitis C virus are linked to interferon resistance by viral repression of the PKR protein kinase.

Journal of virology ·Vol. 73 ·No. 8 ·1999-08-00 ·Pages 6506-16

Gale M, Kwieciszewski B, Dossett M, Nakao H, Katze MG

Abstract

Hepatitis C virus (HCV) is prevalent worldwide and has become a major cause of liver dysfunction and hepatocellular carcinoma. The high prevalence of HCV reflects the persistent nature of infection and the large frequency of cases that resist the current interferon (IFN)-based anti-HCV therapeutic regimens. HCV resistance to IFN has been attributed, in part, to the function of the viral nonstructural 5A (NS5A) protein. NS5A from IFN-resistant strains of HCV can repress the PKR protein kinase, a mediator of the IFN-induced antiviral and apoptotic responses of the host cell and a tumor suppressor. Here we examined the relationship between HCV persistence and resistance to IFN therapy. When expressed in mammalian cells, NS5A from IFN-resistant HCV conferred IFN resistance to vesicular stomatitis virus (VSV), which normally is sensitive to the antiviral actions of IFN. NS5A blocked viral double-stranded RNA (dsRNA)-induced PKR activation and phosphorylation of eIF-2alpha in IFN-treated cells, resulting in high levels of VSV mRNA translation. Mutations within the PKR-binding domain of NS5A restored PKR function and the IFN-induced block to viral mRNA translation. The effects due to NS5A inhibition of PKR were not limited to the rescue of viral mRNA translation but also included a block in PKR-dependent host signaling pathways. Cells expressing NS5A exhibited defective PKR signaling and were refractory to apoptosis induced by exogenous dsRNA. Resistance to apoptosis was attributed to an NS5A-mediated block in eIF-2alpha phosphorylation. Moreover, cells expressing NS5A exhibited a transformed phenotype and formed solid tumors in vivo. Disruption of apoptosis and tumorogenesis required the PKR-binding function of NS5A, demonstrating that these properties may be linked to the IFN-resistant phenotype of HCV.

MeSH Terms
Antiviral Agents/pharmacology Apoptosis Binding Sites Drug Resistance, Microbial Eukaryotic Initiation Factor-2/metabolism HeLa Cells Hepacivirus/drug effects,physiology Humans Interferon-alpha/pharmacology Mutagenesis Phosphorylation Poly I-C Protein Biosynthesis RNA, Double-Stranded RNA, Messenger RNA, Viral Viral Nonstructural Proteins/genetics,metabolism eIF-2 Kinase/antagonists & inhibitors,metabolism
Chemicals
Antiviral Agents Eukaryotic Initiation Factor-2 Interferon-alpha NS-5 protein, hepatitis C virus RNA, Double-Stranded RNA, Messenger RNA, Viral Viral Nonstructural Proteins eIF-2 Kinase Poly I-C
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Gale M
Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195, USA. mgale@mednet.swmed.edu
Kwieciszewski B
Dossett M
Nakao H
Katze M G
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Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.73.8.6506-6516.1999
Email
mgale@mednet.swmed.edu
Published
1999-08-00
Pages
6506-16
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC112733
Subset
IM
Grants
NCRR NIH HHS · P51 RR000166 · United States
NIAID NIH HHS · AI22646 · United States
NIAID NIH HHS · R01 AI022646 · United States
NCRR NIH HHS · RR00166 · United States
NIAID NIH HHS · AI41629 · United States
External Links
PubMed source DOI: 10.1128/JVI.73.8.6506-6516.1999 PMC Full Text View journal details
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