title: The Epstein-Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation.
abstract: 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 gamma(1)-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 gamma(2)-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.
authors.affiliation: Cancer Research-UK Institute for Cancer Studies, School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zuo
authors.forename: Andrew
authors.initials: A
authors.lastname: Currin
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Griffin
authors.forename: Claire
authors.initials: C
authors.lastname: Shannon-Lowe
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Thomas
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D014764:Viral Proteins / Q000502:physiology*
chemical_list: C495131:BILF1 protein, Epstein-Barr virus; D015395:Histocompatibility Antigens Class I; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins