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J. Virol. doi:10.1128/JVI.01999-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibition of the heavy chain and ₂-microglobulin synthesis as a mechanism of MHC class I downregulation during Epstein-Barr virus replication

IRIS Center for Strategic Research, Department of Microbiology, Tumor and Cell Biology, Oncology Pathology Department, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden, Department of Clinical Immunology Karolinska University Hospital, Huddinge 141 86 Stockholm

^* To whom correspondence should be addressed. Email: Victor.Levitsky{at}ki.se.

	Abstract

The mechanisms of major histocompatibility complex (MHC) class I downregulation during Epstein-Barr virus (EBV) replication are not well characterized. Here we show that in several cell lines infected with a recombinant EBV strain encoding for the green fluorescence protein (GFP), virus lytic cycle coincides with GFP expression, which thus can be used as a marker of virus replication. EBV replication resulted in downregulation of MHC class II and all classical MHC class I alleles independently of viral DNA replication or late gene expression. Although assembled MHC class I complexes, total pool of heavy chains and ₂-microglobulin were significantly downreagulated, free class I heavy chains were stabilized at the surface of cell replicating EBV. Calnexin expression was increased in GFP+ cells and calnexin and calreticulin accumulated at the cell surface that could contribute to the stabilization of class I heavy chains. Decreased expression levels of another chaperone ERp57 and TAP2, a transporter associated with antigen processing and presentation, correlated with delayed kinetics of MHC class I maturation. Levels of both class I heavy chain and ₂m mRNA were reduced and metabolic labelling experiments demonstrated a very low rate of class I heavy chains synthesis in lytically infected cells. MHC class I and class II downregulation were mimicked by pharmacological inhibition of protein synthesis in latently infected cells. Our data suggest that although several mechanisms may contribute to MHC class I downregulation in the course of EBV replication, inhibition of MHC class I synthesis plays the primary role in the process.

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