title: Equine herpesvirus type 4 UL56 and UL49.5 proteins downregulate cell surface major histocompatibility complex class I expression independently of each other.
abstract: Major histocompatibility complex class I (MHC-I) molecules are critically important in the host defense against various pathogens through presentation of viral peptides to cytotoxic T lymphocytes (CTLs), a process resulting in the destruction of virus-infected cells. Herpesviruses interfere with CTL-mediated elimination of infected cells by various mechanisms, including inhibition of peptide transport and loading, perturbation of MHC-I trafficking, and rerouting and proteolysis of cell surface MHC-I. In this study, we show that equine herpesvirus type 4 (EHV-4) modulates MHC-I cell surface expression through two different mechanisms. First, EHV-4 can lead to a significant downregulation of MHC-I expression at the cell surface through the product of ORF1, a protein expressed with early kinetics from a gene that is homologous to herpes simplex virus 1 UL56. The EHV-4 UL56 protein reduces cell surface MHC-I as early as 4 h after infection. Second, EHV-4 can interfere with MHC-I antigen presentation, starting at 6 h after infection, by inhibition of the transporter associated with antigen processing (TAP) through its UL49.5 protein. Although pUL49.5 has no immediate effect on overall surface MHC-I levels in infected cells, it blocks the supply of antigenic peptides to the endoplasmic reticulum (ER) and transport of peptide-loaded MHC-I to the cell surface. Taken together, our results show that EHV-4 encodes at least two viral immune evasion proteins: pUL56 reduces MHC-I molecules on the cell surface at early times after infection, and pUL49.5 interferes with MHC-I antigen presentation by blocking peptide transport in the ER.
authors.affiliation: Institut für Virologie, Freie Universität Berlin, Berlin, German.
authors.forename: Abdelrahman
authors.initials: A
authors.lastname: Said
authors.forename: Walid
authors.initials: W
authors.lastname: Azab
authors.forename: Armando
authors.initials: A
authors.lastname: Damiani
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Osterrieder
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004285:Dogs; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D023141:Herpesvirus 4, Equid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006736:Horses; D006801:Humans; D051379:Mice; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D014709:Vero Cells; D015678:Viral Structural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015395:Histocompatibility Antigens Class I; D015678:Viral Structural Proteins