1887

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 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 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, MHC class I cell surface expression is impaired. In BHV1-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.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-82-9-2071
2001-09-01
2020-11-25
Loading full text...

Full text loading...

/deliver/fulltext/jgv/82/9/0822071a.html?itemId=/content/journal/jgv/10.1099/0022-1317-82-9-2071&mimeType=html&fmt=ahah

References

  1. Ahn K., Angulo A., Ghazal P., Peterson P. A., Yang Y., Fruh K.. 1996; Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proceedings of the National Academy of Sciences, USA93:10990–10995
    [Google Scholar]
  2. Ahn K., Gruhler A., Galocha B., Jones T. R., Wiertz E. J., Ploegh H. L., Peterson P. A., Yang Y., Fruh K.. 1997; The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity6:613–621
    [Google Scholar]
  3. Ambagala A. P., Hinkley S., Srikumaran S.. 2000; An early pseudorabies virus protein down-regulates porcine MHC class I expression by inhibition of transporter associated with antigen processing (TAP). Journal of Immunology164:93–99
    [Google Scholar]
  4. Brodsky F. M., Lem L., Solache A., Bennett E. M.. 1999; Human pathogen subversion of antigen presentation. Immunological Reviews168:199–215
    [Google Scholar]
  5. Burgert H. G., Kvist S.. 1985; An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens. Cell41:987–997
    [Google Scholar]
  6. Cohen J. I.. 1998; Infection of cells with varicella-zoster virus down-regulates surface expression of class I major histocompatibility complex antigens. Journal of Infectious Diseases177:1390–1393
    [Google Scholar]
  7. Coscoy L., Ganem D.. 2000; Kaposi’s sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proceedings of the National Academy of Sciences, USA97:8051–8056
    [Google Scholar]
  8. Denis M., Slaoui M., Keil G., Babiuk L. A., Ernst E., Pastoret P. P., Thiry E.. 1993; Identification of different target glycoproteins for bovine herpes virus type 1-specific cytotoxic T lymphocytes depending on the method of in vitro stimulation. Immunology78:7–13
    [Google Scholar]
  9. Doherty A. J., Serpell L. C., Ponting C. P.. 1996; The helix–hairpin–helix DNA-binding motif: a structural basis for non-sequence-specific recognition of DNA. Nucleic Acids Research24:2488–2497
    [Google Scholar]
  10. Elgadi M. M., Hayes C. E., Smiley J. R.. 1999; The herpes simplex virus vhs protein induces endoribonucleolytic cleavage of target RNAs in cell extracts. Journal of Virology73:7153–7164
    [Google Scholar]
  11. Fruh K., Ahn K., Djaballah H., Sempe P., van Endert P. M., Tampe R., Peterson P. A., Yang Y.. 1995; A viral inhibitor of peptide transporters for antigen presentation. Nature375:415–418
    [Google Scholar]
  12. Fruh K., Gruhler A., Krishna R. M., Schoenhals G. J.. 1999; A comparison of viral immune escape strategies targeting the MHC class I assembly pathway. Immunological Reviews168:157–166
    [Google Scholar]
  13. Geiss B. J., Smith T. J., Leib D. A., Morrison L. A.. 2000; Disruption of virion host shutoff activity improves the immunogenicity and protective capacity of a replication-incompetent herpes simplex virus type 1 vaccine strain. Journal of Virology74:11137–11144
    [Google Scholar]
  14. Graham F. L., van der Eb A. J.. 1973; A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology52:456–467
    [Google Scholar]
  15. Hariharan M. J., Nataraj C., Srikumaran S.. 1993; Down regulation of murine MHC class I expression by bovine herpesvirus 1. Viral Immunology6:273–284
    [Google Scholar]
  16. Hengel H., Koopmann J. O., Flohr T., Muranyi W., Goulmy E., Hammerling G. J., Koszinowski U. H., Momburg F.. 1997; A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity6:623–632
    [Google Scholar]
  17. Hill A., Jugovic P., York I., Russ G., Bennink J., Yewdell J., Ploegh H., Johnson D.. 1995; Herpes simplex virus turns off the TAP to evade host immunity. Nature375:411–415
    [Google Scholar]
  18. Hinkley S., Hill A. B., Srikumaran S.. 1998; Bovine herpesvirus-1 infection affects the peptide transport activity in bovine cells. Virus Research53:91–96
    [Google Scholar]
  19. Hinkley S., Ambagala A. P. N., Jones C. J., Srikumaran S.. 2000; A vhs-like activity of bovine herpesvirus-1. Archives of Virology145:2027–2046
    [Google Scholar]
  20. Hughes E. A., Hammond C., Cresswell P.. 1997; Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proceedings of the National Academy of Sciences, USA94:1896–1901
    [Google Scholar]
  21. Ishido S., Wang C., Lee B. S., Cohen G. B., Jung J. U.. 2000; Downregulation of major histocompatibility complex class I molecules by Kaposi’s sarcoma-associated herpesvirus K3 and K5 proteins. Journal of Virology74:5300–5309
    [Google Scholar]
  22. Jones F. E., Smibert C. A., Smiley J. R.. 1995a; Mutational analysis of the herpes simplex virus virion host shutoff protein: evidence that vhs functions in the absence of other viral proteins. Journal of Virology69:4863–4871
    [Google Scholar]
  23. Jones T. R., Hanson L. K., Sun L., Slater J. S., Stenberg R. M., Campbell A. E.. 1995b; Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains. Journal of Virology69:4830–4841
    [Google Scholar]
  24. Jones T. R., Wiertz E. J., Sun L., Fish K. N., Nelson J. A., Ploegh H. L.. 1996; Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proceedings of the National Academy of Sciences, USA93:11327–11333
    [Google Scholar]
  25. Lawman M. J., Griebel P., Hutchings D. L., Davis W. C., Heise J., Qualtiere L., Babiuk L. A.. 1987; Generation of IL-2 dependent bovine cytotoxic T lymphocyte clones reactive against BHV-1 infected target cells: loss of genetic restriction and virus specificity. Viral Immunology1:163–176
    [Google Scholar]
  26. Lee S., Yoon J., Park B., Jun Y., Jin M., Sung H. C., Kim I. H., Kang S., Choi E. J., Ahn B. Y., Ahn K.. 2000; Structural and functional dissection of human cytomegalovirus US3 in binding major histocompatibility complex class I molecules. Journal of Virology74:11262–11269
    [Google Scholar]
  27. Lehner P. J., Karttunen J. T., Wilkinson G. W., Cresswell P.. 1997; The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proceedings of the National Academy of Sciences, USA94:6904–6909
    [Google Scholar]
  28. Levitskaya J., Coram M., Levitsky V., Imreh S., Steigerwald-Mullen P. M., Klein G., Kurilla M. G., Masucci M. G.. 1995; Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature375:685–688
    [Google Scholar]
  29. Ljunggren H. G., Stam N. J., Ohlen C., Neefjes J. J., Hoglund P., Heemels M. T., Bastin J., Schumacher T. N., Townsend A., Karre K.. 1990; Empty MHC class I molecules come out in the cold. Nature346:476–480
    [Google Scholar]
  30. Ludwig G. V., Letchworth G. J.III.. 1987; Temporal control of bovine herpesvirus 1 glycoprotein synthesis. Journal of Virology61:3292–3294
    [Google Scholar]
  31. Nataraj C., Eidmann S., Hariharan M. J., Sur J. H., Perry G. A., Srikumaran S.. 1997; Bovine herpesvirus 1 downregulates the expression of bovine MHC class I molecules. Viral Immunology10:21–34
    [Google Scholar]
  32. Neefjes J. J., Momburg F., Hammerling G. J.. 1993; Selective and ATP-dependent translocation of peptides by the MHC-encoded transporter. Science261:769–771
    [Google Scholar]
  33. Oroskar A. A., Read G. S.. 1987; A mutant of herpes simplex virus type 1 exhibits increased stability of immediate-early (alpha) mRNAs. Journal of Virology61:604–606
    [Google Scholar]
  34. Pak A. S., Everly D. N., Knight K., Read G. S.. 1995; The virion host shutoff protein of herpes simplex virus inhibits reporter gene expression in the absence of other viral gene products. Virology211:491–506
    [Google Scholar]
  35. Parham P., Barnstable C. J., Bodmer W. F.. 1979; Use of a monoclonal antibody (W6/32) in structural studies of HLA-A, B, C, antigens. Journal of Immunology123:342–349
    [Google Scholar]
  36. Ploegh H. L.. 1998; Viral strategies of immune evasion. Science280:248–253
    [Google Scholar]
  37. Read G. S., Karr B. M., Knight K.. 1993; Isolation of a herpes simplex virus type 1 mutant with a deletion in the virion host shutoff gene and identification of multiple forms of the vhs (UL41) polypeptide. Journal of Virology67:7149–7160
    [Google Scholar]
  38. Reusch U., Muranyi W., Lucin P., Burgert H. G., Hengel H., Koszinowski U. H.. 1999; A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO Journal18:1081–1091
    [Google Scholar]
  39. Rijsewijk F. A. M., Kaashoek M. J., Langeveld J. P. M., Meloen R., Judek J., Bienkowska-Szewczyk K., Maris-Veldhuis M. A., van Oirschot J. T.. 1999; Epitopes on glycoprotein C of bovine herpesvirus-1 (BHV-1) that allow differentiation between BHV-1.1 and BHV-1.2 strains. Journal of General Virology80:1477–1483
    [Google Scholar]
  40. Rock D. L.. 1994; Latent infection with bovine herpesvirus type 1. Seminars in Virology5:233–240
    [Google Scholar]
  41. Schwyzer M., Styger D., Vogt B., Lowery D. E., Simard C., LaBoissiere S., Misra V., Vlcek C., Paces V.. 1996; Gene contents in a 31-kb segment at the left genome end of bovine herpesvirus-1. Veterinary Microbiology53:67–77
    [Google Scholar]
  42. Smibert C. A., Johnson D. C., Smiley J. R.. 1992; Identification and characterization of the virion-induced host shutoff product of herpes simplex virus gene UL41. Journal of General Virology73:467–470
    [Google Scholar]
  43. Smith T. J., Ackland-Berglund C. E., Leib E. A.. 2000; Herpes simplex virus virion host shutoff (vhs) activity alters periocular disease in mice. Journal of Virology74:3598–3604
    [Google Scholar]
  44. Sparks-Thissen R. L., Enquist L. W.. 1999; Differential regulation of Dk and Kk major histocompatibility complex class I proteins on the cell surface after infection of murine cells by pseudorabies virus. Journal of Virology73:5748–5756
    [Google Scholar]
  45. Stevenson P. G., Efstathiou S., Doherty P. C., Lehner P. J.. 2000; Inhibition of MHC class I-restricted antigen presentation by gamma 2-herpesviruses. Proceedings of the National Academy of Sciences, USA97:8455–8460
    [Google Scholar]
  46. Strelow L. I., Leib D. A.. 1995; Role of the virion host shutoff (vhs) of herpes simplex virus type 1 in late pathogenesis. Journal of Virology69:6779–6786
    [Google Scholar]
  47. Strelow L. I., Leib D. A.. 1996; Analysis of conserved domains of UL41 of herpes simplex virus type 1 in virion host shutoff and pathogenesis. Journal of Virology70:5665–5667
    [Google Scholar]
  48. Tigges M. A., Leng S., Johnson D. C., Burke R. L.. 1996; Human herpes simplex virus (HSV)-specific CD8+ CTL clones recognize HSV-2-infected fibroblasts after treatment with IFN-gamma or when virion host shutoff functions are disabled. Journal of Immunology156:3901–3910
    [Google Scholar]
  49. Tomazin R., Hill A. B., Jugovic P., York I., van Endert P., Ploegh H. L., Andrews D. W., Johnson D. C.. 1996; Stable binding of the herpes simplex virus ICP47 protein to the peptide binding site of TAP. EMBO Journal15:3256–3266
    [Google Scholar]
  50. Townsend A., Bodmer H.. 1989; Antigen recognition by class I-restricted T lymphocytes. Annual Review of Immunology7:601–624
    [Google Scholar]
  51. Wiertz E. J., Jones T. R., Sun L., Bogyo M., Geuze H. J., Ploegh H. L.. 1996a; The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell84:769–779
    [Google Scholar]
  52. Wiertz E. J., Tortorella D., Bogyo M., Yu J., Mothes W., Jones T. R., Rapoport T. A., Ploegh H. L.. 1996b; Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature384:432–438
    [Google Scholar]
  53. Wiertz E. J., Mukherjee S., Ploegh H. L.. 1997; Viruses use stealth technology to escape from the host immune system. Molecular Medicine Today3:116–123
    [Google Scholar]
  54. Yewdell J. W., Bennink J. R.. 1992; Cell biology of antigen processing and presentation to major histocompatibility complex class I molecule-restricted T lymphocytes. Advances in Immunology52:1–123
    [Google Scholar]
  55. York I. A., Roop C., Andrews D. W., Riddell S. R., Graham F. L., Johnson D. C.. 1994; A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell77:525–535
    [Google Scholar]
  56. Ziegler H., Thale R., Lucin P., Muranyi W., Flohr T., Hengel H., Farrell H., Rawlinson W., Koszinowski U. H.. 1997; A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. Immunity6:57–66
    [Google Scholar]
  57. Ziegler H., Muranyi W., Burgert H. G., Kremmer E., Koszinowski U. H.. 2000; The luminal part of the murine cytomegalovirus glycoprotein gp40 catalyzes the retention of MHC class I molecules. EMBO Journal19:870–881
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-82-9-2071
Loading
/content/journal/jgv/10.1099/0022-1317-82-9-2071
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error