Article

Molecular Mechanisms of Interferon Resistance Mediated by Viral-Directed Inhibition of PKR, the Interferon-Induced Protein Kinase

DEPARTMENT OF MICROBIOLOGY, SCHOOL OF MEDICINE, BOX 357242 UNIVERSITY OF WASHINGTON, SEATTLE, WA 98195, USA AND; REGIONAL PRIMATE RESEARCH CENTER, BOX 357330, UNIVERSITY OF WASHINGTON, SEATTLE, WA 98195, USA
Pharmacology [?] Therapeutics (impact factor: 8.56). 05/1998; DOI:10.1016/S0163-7258(97)00165-4 pp.29-46

ABSTRACT The interferon (IFN)-induced cellular antiviral response is the first line of defense against viral infection within an animal host. In order to establish a productive infection, eukaryotic viruses must first overcome the IFN-induced blocks imposed on viral replication. The double-stranded RNA-activated protein kinase (PKR) is a key component mediating the antiviral actions of IFN. This IFN-induced protein kinase can restrict viral replication through its ability to phosphorylate the protein synthesis initiation factor eukaryotic initiation factor-2 α-subunit and reduce levels of viral protein synthesis. Viruses, therefore, must block the function of PKR in order to avoid these deleterious antiviral effects associated with PKR activity. Indeed, many viruses have developed effective measures to repress PKR activity during infection. This review will focus primarily on an overview of the different molecular mechanisms employed by these viruses to meet a common goal: the inhibition of PKR function, uncompromised viral protein synthesis, and unrestricted virus replication. The past few years have seen exciting new advances in this area. Rather unexpectedly, this area of research has benefited from the use of the yeast system to study PKR. Other recent advances include studies on PKR regulation by the herpes simplex viruses and data from our laboratory on the medically important hepatitis C viruses. We speculate that IFN is ineffective as a therapeutic agent against hepatitis C virus because the virus can effectively repress PKR function. Finally, we will discuss briefly the future directions of this PKR field. pharmacol. ther. 78(1):29–46, 1998.

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Keywords

animal host
 
antiviral actions
 
common goal
 
double-stranded RNA-activated protein kinase
 
eukaryotic viruses
 
first line
 
future directions
 
hepatitis C viruses
 
herpes simplex viruses
 
IFN)-induced cellular antiviral response
 
IFN-induced protein kinase
 
key component mediating
 
PKR regulation
 
productive infection
 
study PKR
 
unrestricted virus replication
 
viral infection
 
viral protein synthesis
 
viral replication
 
yeast system
 

Michael Gale