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Inhibition of Heavy Chain and ß₂-Microglobulin Synthesis as a Mechanism of Major Histocompatibility Complex Class I Downregulation during Epstein-Barr Virus Replication

Andre Ortlieb Guerreiro-Cacais,^1,4, Mehmet Uzunel,³ Jelena Levitskaya,^2,4, and Victor Levitsky^1,4*

IRIS Center for Strategic Research, Department of Microbiology, Tumor and Cell Biology,¹ Oncology and Pathology Department, Cancer Centrum Karolinska, Karolinska Institute, Stockholm, Sweden,² Department of Clinical Immunology, Karolinska University Hospital, Huddinge 141 86, Sweden,³ Division of Biomedical Sciences, Johns Hopkins Singapore, Singapore⁴

Received 14 September 2006/ Accepted 5 November 2006

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 green fluorescent protein (GFP), the 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 synthesis or late gene expression. Although assembled MHC class I complexes, the total pool of heavy chains, and ß₂-microglobulin (ß₂m) were significantly downregulated, free class I heavy chains were stabilized at the surface of cells 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 ß₂m mRNA were reduced, and metabolic labeling experiments demonstrated a very low rate of class I heavy chain synthesis in lytically infected cells. MHC class I and MHC class II downregulation was 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.

Published ahead of print on 15 November 2006.

Present address: Division of Biomedical Sciences, Johns Hopkins in Singapore, 31 Biopolis Way #02-01, Nanos Building, Singapore 138669.

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