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Journal of Virology, September 2007, p. 9034-9049, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00711-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Downregulation of Class I Major Histocompatibility Complex Surface Expression by Varicella-Zoster Virus Involves Open Reading Frame 66 Protein Kinase-Dependent and -Independent Mechanisms{triangledown}

Amie J. Eisfeld,1,3 Michael B. Yee,1 Angela Erazo,1,3 Allison Abendroth,4,5 and Paul R. Kinchington1,2*

Departments of Ophthalmology,1 Molecular Genetics & Biochemistry,2 Graduate Program in Molecular Virology and Microbiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213,3 Center for Virus Research, Westmead Millennium Institute,4 University of Sydney, P.O. Box 412, Westmead, 2145 NSW, Australia5

Received 3 April 2007/ Accepted 4 June 2007

We show here that the varicella-zoster virus (VZV) open reading frame 66 (ORF66) protein kinase is one mechanism employed to reduce class I major histocompatibility complex (MHC-I) surface expression in VZV-infected cells. Cells expressing enhanced green fluorescent protein-tagged functional and inactivated ORF66 (GFP-66 and GFP-66kd) from replication-defective adenovirus vectors revealed that ORF66 reduced MHC-I surface levels in a manner dependent on kinase activity. Cells infected with recombinant VZV expressing GFP-66 exhibited a significantly greater reduction in MHC-I surface expression than that observed in cells infected with VZV disrupted in GFP-66 expression. MHC-I maturation was delayed in its transport from the endoplasmic reticulum through the Golgi in both adenovirus-transduced cells expressing only GFP-66 and in VZV-infected cells expressing high levels of GFP-66, and this was predominantly kinase dependent. MHC-I levels were reduced in VZV-infected cells, and analyses of intracellular MHC-I revealed accumulation of folded MHC-I in the Golgi region, irrespective of ORF66 expression. Thus, the ORF66 kinase is important for VZV-mediated MHC-I downregulation, but additional mechanisms also may be involved. Analyses of the VZV ORF9a protein, the ortholog of the bovine herpesvirus 1 transporter associated with antigen processing inhibitor UL49.5 revealed no effects on MHC-I. These results establish a new role for viral protein kinases in immune evasion and suggest that VZV utilizes unique mechanisms to inhibit antigen presentation.

* Corresponding author. Mailing address: 1020 Eye and Ear Institute, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15213. Phone: (412) 647-6319. Fax: (412) 647-5880. E-mail: Kinchingtonp{at}upmc.edu

{triangledown} Published ahead of print on 13 June 2007.

Journal of Virology, September 2007, p. 9034-9049, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00711-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sagou, K., Imai, T., Sagara, H., Uema, M., Kawaguchi, Y. (2009). Regulation of the Catalytic Activity of Herpes Simplex Virus 1 Protein Kinase Us3 by Autophosphorylation and Its Role in Pathogenesis. J. Virol. 83: 5773-5783 [Abstract] [Full Text]  
  • Kato, A., Arii, J., Shiratori, I., Akashi, H., Arase, H., Kawaguchi, Y. (2009). Herpes Simplex Virus 1 Protein Kinase Us3 Phosphorylates Viral Envelope Glycoprotein B and Regulates Its Expression on the Cell Surface. J. Virol. 83: 250-261 [Abstract] [Full Text]  
  • Erazo, A., Yee, M. B., Osterrieder, N., Kinchington, P. R. (2008). Varicella-Zoster Virus Open Reading Frame 66 Protein Kinase Is Required for Efficient Viral Growth in Primary Human Corneal Stromal Fibroblast Cells. J. Virol. 82: 7653-7665 [Abstract] [Full Text]  


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