May 2004
Volume 45, Issue 13
ARVO Annual Meeting Abstract  |   May 2004
Downregulation of host cell MHC–I surface presentation by Varicella Zoster Virus encoded gene 66 protein kinase and a second VZV gene.
Author Affiliations & Notes
  • P.R. Kinchington
    Ophthalmology/Mol Genetic/Bio, Univ Pittsburgh Eye & Ear Inst, Pittsburgh, PA
  • A.J. Eisfeld
    Graduate Program in Molecular Virology and Microbiology, Univ Pittsburgh, Pittsburgh, PA
  • Footnotes
    Commercial Relationships  P.R. Kinchington, None; A.J. Eisfeld, None.
  • Footnotes
    Support  EY 09397
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 1658. doi:
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      P.R. Kinchington, A.J. Eisfeld; Downregulation of host cell MHC–I surface presentation by Varicella Zoster Virus encoded gene 66 protein kinase and a second VZV gene. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1658.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose: Varicella zoster virus (VZV) is a ubiquitous human herpesvirus that can reactivate and cause ophthalmic zoster, potentially leading to blindness. Herpesviruses are well known to encode one or more genes dedicated to preventing major histocompatability complex I (MHC–1) from presenting antigen to T–lymphocytes, thereby avoiding viral clearance and promoting persistent infection and eventual reactivation. The VZV open reading frame 66 (ORF66) kinase has recently been implicated in MHC–1 downregulation. Studies here are aimed at further characterizing the role of the ORF66 kinase in MHC–1 downregulation. Methods: 293T cells were transfected with plasmid constructs encoding ORF66 and kinase inactive ORF66. Melanoma cells (permissive for VZV infection) were infected with wild type VZV (ROka) or ORF66 minus VZV (ROka66S). Following transfection or infection, cells were stained with antibodies to HLA–ABC and analyzed for MHC–1 surface expression by flow cytometry. Transfected and infected cell lysates were also subjected to western blot analysis to confirm protein expression in analyzed cells. Results: MHC–1 is downregulated in ORF66–transfected 293T cells, but not in vector only transfected cells. Further, kinase activity is not required for ORF66 downregulation of MHC–1, as three different kinase inactive proteins maintained the capacity to downregulate MHC–1. Carefully controlled infection with equal amounts of ROka and ROka66S resulted in downregulation of MHC–1 by both viruses compared to uninfected cells. Moreover, Roka and Roka66S yielded similar kinetics of MHC–1 downregulation. Protein expression of ORF66 or inactive ORF66 and VZV proteins was verified in transfections and infections, respectively. Conclusions: The ORF66 kinase downregulates MHC–1 not through phosphorylation, but possibly through a protein–protein interaction. This protein–protein interaction may represent a new function of ORF66 in infected cells. Because ROka66S–infected cells maintained the ability to downregulate MHC–1, we conclude that there is at least one other unknown VZV protein involved in this process. VZV does not encode an HSV–1 ICP47 homologue, and MHC–1 has been shown to accumulate in the Golgi complex of infected cells, a characteristic unique among the herpesviruses. These observations imply that VZV encodes a novel mechanism for MHC–1 downregulation among herpesviruses.

Keywords: varicella zoster virus • herpes simplex virus • immunomodulation/immunoregulation 

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