title: The Epstein-Barr Virus Glycoprotein gp150 Forms an Immune-Evasive Glycan Shield at the Surface of Infected Cells.
abstract: Cell-mediated immunity plays a key role in host control of viral infection. This is exemplified by life-threatening reactivations of e.g. herpesviruses in individuals with impaired T-cell and/or iNKT cell responses. To allow lifelong persistence and virus production in the face of primed immunity, herpesviruses exploit immune evasion strategies. These include a reduction in viral antigen expression during latency and a number of escape mechanisms that target antigen presentation pathways. Given the plethora of foreign antigens expressed in virus-producing cells, herpesviruses are conceivably most vulnerable to elimination by cell-mediated immunity during the replicative phase of infection. Here, we show that a prototypic herpesvirus, Epstein-Barr virus (EBV), encodes a novel, broadly acting immunoevasin, gp150, that is expressed during the late phase of viral replication. In particular, EBV gp150 inhibits antigen presentation by HLA class I, HLA class II, and the non-classical, lipid-presenting CD1d molecules. The mechanism of gp150-mediated T-cell escape does not depend on degradation of the antigen-presenting molecules nor does it require gp150's cytoplasmic tail. Through its abundant glycosylation, gp150 creates a shield that impedes surface presentation of antigen. This is an unprecedented immune evasion mechanism for herpesviruses. In view of its likely broader target range, gp150 could additionally have an impact beyond escape of T cell activation. Importantly, B cells infected with a gp150-null mutant EBV displayed rescued levels of surface antigen presentation by HLA class I, HLA class II, and CD1d, supporting an important role for iNKT cells next to classical T cells in fighting EBV infection. At the same time, our results indicate that EBV gp150 prolongs the timespan for producing viral offspring at the most vulnerable stage of the viral life cycle.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gram
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Timo
authors.initials: T
authors.lastname: Oosenbrug
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Marthe F S
authors.initials: MF
authors.lastname: Lindenbergh
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Büll
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anouskha
authors.initials: A
authors.lastname: Comvalius
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Kathryn J I
authors.initials: KJ
authors.lastname: Dickson
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Joop
authors.initials: J
authors.lastname: Wiegant
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Vrolijk
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Robert Jan
authors.initials: RJ
authors.lastname: Lebbink
authors.affiliation: Department of Medical Statistics & Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Wolterbeek
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Gosse J
authors.initials: GJ
authors.lastname: Adema
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
authors.affiliation: John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Tscharke
authors.affiliation: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Hutt-Fletcher
authors.affiliation: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015153:Blotting, Western; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D018613:Microscopy, Confocal; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000276:immunology*
chemical_list: C109483:BDLF-3 protein, Human herpesvirus 4; D008562:Membrane Glycoproteins; D014764:Viral Proteins