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J. Virol. doi:10.1128/JVI.00711-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. 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

Departments of Ophthalmology and Molecular Genetics & Biochemistry, and Graduate Program in Molecular Virology and Microbiology, School of Medicine, University of Pittsburgh, PA, 15213; and Center for Virus Research, Westmead Millennium Institute, and University of Sydney, P.O. Box 412, Westmead, 2145 NSW, Australia

^* To whom correspondence should be addressed. Email: Kinchingtonp{at}upmc.edu.

	Abstract

We show here that the varicella-zoster virus (VZV) open reading frame (ORF) 66 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 mostly dependent on kinase activity. Cells infected with recombinant VZV expressing GFP-66 exhibited a significantly greater reduction in MHC-I surface expression over 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 (BHV-1) transporter associated with antigen processing (TAP) 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.

This article has been cited by other articles:

• 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]