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The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation

Zuo, Jianmin and Currin, Andrew and Griffin, Bryan D and Shannon-Lowe, Claire and Thomas, Wendy A and Ressing, Maaike E and Wiertz, Emmanuel J. H. J. and Rowe, Martin (2009) The Epstein-Barr Virus G-Protein-Coupled Receptor Contributes to Immune Evasion by Targeting MHC Class I Molecules for Degradation. PLoS Pathogens, 5 (1). ISSN 1553-7366

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URL of Published Version: http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000255

Identification Number/DOI: doi:10.1371/journal.ppat.1000255

Epstein-Barr virus (EBV) is a human herpesvirus that persists as a largely subclinical infection in the vast majority of adults worldwide. Recent evidence indicates that an important component of the persistence strategy involves active interference with the MHC class I antigen processing pathway during the lytic replication cycle. We have now identified a novel role for the lytic cycle gene, BILF1, which encodes a glycoprotein with the properties of a constitutive signaling G-protein-coupled receptor (GPCR). BILF1 reduced the levels of MHC class I at the cell surface and inhibited CD8+ T cell recognition of
endogenous target antigens. The underlying mechanism involves physical association of BILF1 with MHC class I molecules, an increased turnover from the cell surface, and enhanced degradation via lysosomal proteases. The BILF1 protein of the closely related CeHV15 c1-herpesvirus of the Rhesus Old World primate (80% amino acid sequence identity) downregulated surface MHC class I similarly to EBV BILF1. Amongst the human herpesviruses, the GPCR encoded by the ORF74 of the KSHV c2-herpesvirus is most closely related to EBV BILF1 (15% amino acid sequence identity) but did not affect levels of surface MHC class I. An engineered mutant of BILF1 that was unable to activate G protein signaling pathways retained the ability to downregulate MHC class I, indicating that the immune-modulating and GPCR-signaling properties are two distinct functions of BILF1. These findings extend our understanding of the normal biology of an important human pathogen. The discovery of a third EBV lytic cycle gene that cooperates to interfere with MHC class I antigen processing underscores the importance of the need for EBV to be able to evade CD8+ T cell responses during the lytic replication cycle, at a time when such a large number of potential viral targets are expressed.

Type of Work:Article
Date:02 January 2009 (Publication)
School/Faculty:Schools (1998 to 2008) > School of Medicine
Department:Institute of Cancer Studies
Subjects:R Medicine (General)
Institution:University of Birmingham
Copyright Holders:Public Library of Science
ID Code:150
Refereed:YES
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