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.
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.
Koppers-Lalic
Danijela
D
Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
Rijsewijk
Frans A M
FAM
Division of Infectious Diseases and Food Chain Quality, ID-Lelystad, PO Box 65, 8200 AB Lelystad, The Netherlands2.
Verschuren
Sylvia B E
SBE
Division of Infectious Diseases and Food Chain Quality, ID-Lelystad, PO Box 65, 8200 AB Lelystad, The Netherlands2.
van Gaans-van den Brink
Jacqueline A M
JAM
Laboratory for Vaccine Research, RIVM, PO Box 1, 3720 BA Bilthoven, The Netherlands3.
Neisig
Anne
A
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands4.
Ressing
Maaike E
ME
Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
Neefjes
Jacques
J
Division of Tumor Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands4.
Wiertz
Emmanuel J H J
EJHJ
Department of Medical Microbiology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands1.
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*
D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; C070722:virion host shutoff protein, Simplexvirus; D012260:Ribonucleases