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Journal of Virology, March 2001, p. 2345-2352, Vol. 75, No. 5
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.5.2345-2352.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Latently Expressed Human Herpesvirus 8-Encoded Interferon Regulatory Factor 2 Inhibits Double-Stranded RNA-Activated Protein Kinase

Ladislav Burýsek1,dagger and Paula M. Pitha1,2,*

Oncology Center1 and Department of Molecular Biology and Genetics,2 The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Received 28 April 2000/Accepted 29 November 2000

Human herpesvirus 8 (HHV-8; Kaposi's sarcoma herpesvirus) encodes four open reading frames with homology to cellular proteins of interferon regulatory factor (IRF) family. Three of them, viral IRF-1 (vIRF-1), vIRF-2, and vIRF-3, have been cloned and found, when overexpressed, to down-regulate the transcriptional activity of interferon type I gene promoters in infected cells by interfering with the transactivating activity of cellular IRFs. In this study, we have further characterized vIRF-2 and shown that it is a nuclear protein which is constitutively expressed in HHV-8-positive pleural effusion lymphoma cell lines. Nuclear localization of vIRF-2 was confirmed by in situ detection of ectopically expressed enhanced green fluorescent protein/vIRF-2 fusion protein. We found that the expression of vIRF-2 in HEK293 cells inhibited the antiviral effect of interferon and rescued translation of vesicular stomatitis virus mRNA from interferon-induced translational block. To provide insight into the mechanism of this effect we have demonstrated that vIRF-2 physically interacts with PKR consequently inhibiting autophosphorylation of double-stranded RNA-activated protein kinase (PKR) and blocking phosphorylation of PKR substrates histone 2A and eukaryotic translation initiation factor 2alpha . These results suggest that the latently expressed vIRF-2 has a role in viral mimicry which targets the activity of interferon-induced PKR kinase. By inhibiting the kinase activity of PKR and consequent down-modulation of protein synthesis, HHV-8 has evolved a mechanism by which it can overcome the interferon-mediated antiviral effect. Thus, the anti-interferon functions of vIRF-2 may contribute to the establishment of a chronic or latent infection.

* Corresponding author. Mailing address: The Johns Hopkins University Oncology Center, 1650 Orleans St., Baltimore, MD 21231-1001. Phone: (410) 955-8871. Fax: (410) 955-0840. E-mail: parowe{at}jhmi.edu.

dagger Present address: Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.

Journal of Virology, March 2001, p. 2345-2352, Vol. 75, No. 5
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.5.2345-2352.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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