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Journal of Virology, August 2007, p. 7844-7851, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00325-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Varicella-Zoster Virus IE63, a Major Viral Latency Protein, Is Required To Inhibit the Alpha Interferon-Induced Antiviral Response{triangledown}

Aruna P. N. Ambagala and Jeffrey I. Cohen*

Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 13 February 2007/ Accepted 8 May 2007

Varicella-zoster virus (VZV) open reading frame 63 (ORF63) is the most abundant transcript expressed during latency in human sensory ganglia. VZV with ORF63 deleted is impaired for replication in melanoma cells and fibroblasts and for latency in rodents. We found that replication of the ORF63 deletion mutant is fully complemented in U2OS cells, which have been shown to complement the growth of herpes simplex virus type 1 (HSV-1) ICP0 mutants. Since HSV-1 ICP0 mutants are hypersensitive to alpha interferon (IFN-{alpha}), we examined the effect of IFN-{alpha} on VZV replication. Replication of the ORF63 mutant in melanoma cells was severely inhibited in the presence of IFN-{alpha}, in contrast to other VZV mutants that were similarly impaired for replication or to parental virus. The VZV ORF63 mutant was not hypersensitive to IFN-{gamma}. IFN-{alpha} inhibited viral-gene expression in cells infected with the ORF63 mutant at a posttranscriptional level. Since IFN-{alpha} stimulates gene products that can phosphorylate the {alpha} subunit of eukaryotic initiation factor 2 (eIF-2{alpha}) and inhibit translation, we determined whether cells infected with the ORF63 mutant had increased phosphorylation of eIF-2{alpha} compared with cells infected with parental virus. While phosphorylated eIF-2{alpha} was undetectable in uninfected cells or cells infected with parental virus, it was present in cells infected with the ORF63 mutant. Conversely, expression of IE63 (encoded by ORF63) in the absence of other viral proteins inhibited phosphorylation of eIF-2{alpha}. Since IFN-{alpha} has been shown to limit VZV replication in human skin xenografts, the ability of VZV IE63 to block the effects of the cytokine may play a critical role in VZV pathogenesis.

* Corresponding author. Mailing address: Laboratory of Clinical Infectious Diseases, National Institutes of Health, 10 Center Dr., Building 10, Room 11N234, Bethesda, MD 20892. Phone: (301) 496-5265. Fax: (301) 496-7383. E-mail: jcohen{at}niaid.nih.gov

{triangledown} Published ahead of print on 16 May 2007.

Journal of Virology, August 2007, p. 7844-7851, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00325-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Kyratsous, C. A., Walters, M. S., Panagiotidis, C. A., Silverstein, S. J. (2009). Complementation of a Herpes Simplex Virus ICP0 Null Mutant by Varicella-Zoster Virus ORF61p. J. Virol. 83: 10637-10643 [Abstract] [Full Text]  
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  • Ambagala, A. P., Bosma, T., Ali, M. A., Poustovoitov, M., Chen, J. J., Gershon, M. D., Adams, P. D., Cohen, J. I. (2009). Varicella-Zoster Virus Immediate-Early 63 Protein Interacts with Human Antisilencing Function 1 Protein and Alters Its Ability To Bind Histones H3.1 and H3.3. J. Virol. 83: 200-209 [Abstract] [Full Text]  
  • Walters, M. S., Kyratsous, C. A., Wan, S., Silverstein, S. (2008). Nuclear Import of the Varicella-Zoster Virus Latency-Associated Protein ORF63 in Primary Neurons Requires Expression of the Lytic Protein ORF61 and Occurs in a Proteasome-Dependent Manner. J. Virol. 82: 8673-8686 [Abstract] [Full Text]  


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