title: The UL41-encoded virion host shutoff (vhs) protein and vhs-independent mechanisms are responsible for down-regulation of MHC class I molecules by bovine herpesvirus 1.
abstract: The virion host shutoff (vhs) protein of alphaherpesviruses causes a rapid shutoff of host cell protein synthesis. We constructed a bovine herpesvirus 1 (BHV1) deletion mutant in which the putative vhs gene, UL41, has been disrupted. Whereas protein synthesis is inhibited within 3 h after infection with wild-type BHV1, no inhibition was observed after infection with the BHV1(vhs-) deletion mutant. These results indicate that the BHV1 UL41 gene product is both necessary and sufficient for shutoff of host cell protein synthesis at early times post-infection. Using the vhs deletion mutant, we investigated the mechanism of BHV1-induced down-regulation of MHC class I cell surface expression. In contrast to BHV1 wild-type infection, the BHV1(vhs-) mutant allows detection of MHC class I molecules at much later time-points after infection. This illustrates the role the vhs protein plays in MHC class I down-regulation. However, even after infection with BHV1(vhs-), MHC class I cell surface expression is impaired. In BHV1(vhs-)-infected cells, MHC class I molecules are retained within the endoplasmic reticulum (ER). Moreover, the transporter associated with antigen presentation (TAP) is still blocked. Temporal control of viral protein expression using chemical inhibitors shows that viral protein(s) expressed within the early phase of BHV1 infection are responsible for ER retention of MHC class I molecules. These results indicate that multiple mechanisms are responsible for down-regulation of MHC class I molecules in BHV1-infected cells.
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
authors.forename: Danijela
authors.initials: D
authors.lastname: Koppers-Lalic
authors.affiliation: Division of Infectious Diseases and Food Chain Quality, ID-Lelystad, PO Box 65, 8200 AB Lelystad, The Netherlands2.
authors.forename: Frans A M
authors.initials: FAM
authors.lastname: Rijsewijk
authors.affiliation: Division of Infectious Diseases and Food Chain Quality, ID-Lelystad, PO Box 65, 8200 AB Lelystad, The Netherlands2.
authors.forename: Sylvia B E
authors.initials: SBE
authors.lastname: Verschuren
authors.affiliation: Laboratory for Vaccine Research, RIVM, PO Box 1, 3720 BA Bilthoven, The Netherlands3.
authors.forename: Jacqueline A M
authors.initials: JAM
authors.lastname: van Gaans-van den Brink
authors.affiliation: Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands4.
authors.forename: Anne
authors.initials: A
authors.lastname: Neisig
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.affiliation: Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands4.
authors.forename: Jacques
authors.initials: J
authors.lastname: Neefjes
authors.affiliation: Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
authors.forename: Emmanuel J H J
authors.initials: EJHJ
authors.lastname: Wiertz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation; D001692:Biological Transport; D002417:Cattle; D002460:Cell Line; D015536:Down-Regulation; D007242:Herpesvirus 1, Bovine / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis / Q000502:physiology*; D011817:Rabbits; D012260:Ribonucleases; D014764:Viral Proteins / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases