title: EBV BILF1 evolved to downregulate cell surface display of a wide range of HLA class I molecules through their cytoplasmic tail.
abstract: Coevolution of herpesviruses and their hosts has driven the development of both host antiviral mechanisms to detect and eliminate infected cells and viral ploys to escape immune surveillance. Among the immune-evasion strategies used by the lymphocryptovirus (γ(1)-herpesvirus) EBV is the downregulation of surface HLA class I expression by the virally encoded G protein-coupled receptor BILF1, thereby impeding presentation of viral Ags and cytotoxic T cell recognition of the infected cell. In this study, we show EBV BILF1 to be expressed early in the viral lytic cycle. BILF1 targets a broad range of HLA class I molecules, including multiple HLA-A and -B types and HLA-E. In contrast, HLA-C was only marginally affected. We advance the mechanistic understanding of the process by showing that the cytoplasmic C-terminal tail of EBV BILF1 is required for reducing surface HLA class I expression. Susceptibility to BILF1-mediated downregulation, in turn, is conferred by specific residues in the intracellular tail of the HLA class I H chain. Finally, we explore the evolution of BILF1 within the lymphocryptovirus genus. Although the homolog of BILF1 encoded by the lymphocryptovirus infecting Old World rhesus primates shares the ability of EBV to downregulate cell surface HLA class I expression, this function is not possessed by New World marmoset lymphocryptovirus BILF1. Therefore, this study furthers our knowledge of the evolution of immunoevasive functions by the lymphocryptovirus genus of herpesviruses.
authors: Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
authors: Bryan D
authors: BD
authors: Griffin
authors: Anna M
authors: AM
authors: Gram
authors: Arend
authors: A
authors: Mulder
authors: Daphne
authors: D
authors: Van Leeuwen
authors: Frans H J
authors: FH
authors: Claas
authors: Fred
authors: F
authors: Wang
authors: Maaike E
authors: ME
authors: Ressing
authors: Emmanuel
authors: E
authors: Wiertz
mesh_terms: D000483:Alleles; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D003593:Cytoplasm / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation / Q000276:immunology*; D019143:Evolution, Molecular; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D018390:Gene Targeting; D004854:Herpesvirus 4, Human / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010446:Peptide Fragments / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D014764:Viral Proteins / Q000502:physiology*
chemical_list: C495131:BILF1 protein, Epstein-Barr virus; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins