title: Impaired transporter associated with antigen processing-dependent peptide transport during productive EBV infection.
abstract: Human herpesviruses, including EBV, persist for life in infected individuals. During the lytic replicative cycle that is required for the production of infectious virus and transmission to another host, many viral Ags are expressed. Especially at this stage, immune evasion strategies are likely to be advantageous to avoid elimination of virus-producing cells. However, little is known about immune escape during productive EBV infection because no fully permissive infection model is available. In this study, we have developed a novel strategy to isolate populations of cells in an EBV lytic cycle based on the expression of a reporter gene under the control of an EBV early lytic cycle promoter. Thus, induction of the viral lytic cycle in transfected EBV(+) B lymphoma cells resulted in concomitant reporter expression, allowing us, for the first time, to isolate highly purified cell populations in lytic cycle for biochemical and functional studies. Compared with latently infected B cells, cells supporting EBV lytic cycle displayed down-regulation of surface HLA class I, class II, and CD20, whereas expression levels of other surface markers remained unaffected. Moreover, during lytic cycle peptide transport into the endoplasmic reticulum, was reduced to <30% of levels found in latent infection. Because steady-state levels of TAP proteins were unaffected, these results point toward EBV-induced interference with TAP function as a specific mechanism contributing to the reduced levels of cell surface HLA class I. Our data implicate that EBV lytic cycle genes encode functions to evade T cell recognition, thereby creating a window for the generation of viral progeny.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, The Netherlands.
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: Sinéad E
authors.initials: SE
authors.lastname: Keating
authors.forename: Daphne
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: Danijela
authors.initials: D
authors.lastname: Koppers-Lalic
authors.forename: Isabel Y
authors.initials: IY
authors.lastname: Pappworth
authors.forename: Emmanuel J H J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D002469:Cell Separation; D015536:Down-Regulation / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D017930:Genes, Reporter; D006681:HLA-D Antigens / Q000096:biosynthesis / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D051381:Rats; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014775:Virus Activation / Q000235:genetics / Q000276:immunology; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018528:ATP-Binding Cassette Transporters; D006681:HLA-D Antigens; D015395:Histocompatibility Antigens Class I; D017874:Immediate-Early Proteins; D014764:Viral Proteins; C477327:transporter associated with antigen processing (TAP)