1887

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Volume 82, Issue 9

Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus Free

Abstract

Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV), causing severe disease in affected organs of immunocompromised patients. CMV downregulates major histocompatibility complex class I (MHC-I) molecule expression in fibroblasts in order to avoid lysis by CD8 cytotoxic T lymphocytes. However, MHC-I expression in human cytomegalovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-I expression in epithelial cells, new cell culture models for HCMV infection of differentiated hepatobiliary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early and late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2, gpUS3, gpUS6 and gpUS11, that downregulate MHC-I expression were synthesized with temporal kinetics and in a similar quantity to that seen in fibroblasts. As a result, HCMV infection led to a drastic and selective downregulation of MHC-I expression in epithelial cells and was uniformly observed irrespective of the hepatic or biliary origin of the cells. The new models document for the first time a stealth function of HCMV in epithelial cells and indicate that the downregulation of MHC-I expression by HCMV can occur in the virtual absence of virus replication.

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© Microbiology Society
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2001-09-01
2024-04-26
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References

  1. Aden D., Fogel A., Plotkin S., Damjanov I., Knowles B. B. 1979; Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature 282:615–616
     [Google Scholar]
  2. Ahn K., Angulo A., Ghazal P., Peterson P. A., Yang Y., Früh K. 1996; Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proceedings of the National Academy of Sciences, USA 93:10990–10995
     [Google Scholar]
  3. Ahn K., Gruhler A., Galocha B., Jones T. R., Wiertz E. J. H. J., Ploegh H. L., Peterson P. A., Früh K. 1997; The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity6613–621
     [Google Scholar]
  4. Andreoni M., Faircloth M., Vugler L., Britt W. J. 1989; A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. Journal of Virological Methods 23:157–167
     [Google Scholar]
  5. Arnold J. C., Gmelin K., Otto G., Alexander G. J. M., Williams R. 1991; Effect of cytomegalovirus infection on expression of HLA-antigens in liver allografts. Transplantation Proceedings 23:442–443
     [Google Scholar]
  6. Arnold J. C., Portmann B. C., O’Grady J. G., Naoumov N. V., Alexander G. J. M., Williams R. 1992; Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome. Hepatology 16:285–292
     [Google Scholar]
  7. Balk S. P., Burke S., Polischuk J. E., Frantz M. E., Yang L., Porcelli S., Colgan S. P., Blumberg R. S. 1994; β2-microglobulin-independent MHC class Ib molecule expressed by human intestinal epithelium. Science 265:259–262
     [Google Scholar]
  8. Barkholt L. M., Ehrnst A., Veress B. 1994; Clinical use of immunohistopathologic methods for the diagnosis of cytomegalovirus hepatitis in human liver allograft biopsy specimens. Scandinavian Journal of Gastroenterology 29:553–560
     [Google Scholar]
  9. Beersma M. F. C., Bijlmakers M. J. E., Ploegh H. L. 1993; Human cytomegalovirus down-regulates HLA class I expression by reducing the stability of class I H chains. Journal of Immunology 151:4455–4464
     [Google Scholar]
  10. Britt W. J., Alford C. A. 1996; Cytomegalovirus. In Fields Virology pp 2493–2523 Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia: Lippincott–Raven;
     [Google Scholar]
  11. Burakoff R., Eglow R. 1995; Cytomegalovirus infection. In Bockus Gastroenterology pp 503–517 Edited by Haubrich W. S., Schaffner F., Berk J. E. Philadelphia: W. B. Saunders;
     [Google Scholar]
  12. Del Val M., Hengel H., Häcker H., Hartlaub U., Ruppert T., Lucin P., Koszinowski U. H. 1992; Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment. Journal of Experimental Medicine 172:729–738
     [Google Scholar]
  13. Esclatine A., Lemullois M., Servin A. L., Quero A.-M., Geniteau-Legendre M. 2000; Human cytomegalovirus infects Caco-2 intestinal epithelial cells basolaterally regardless of the differentiation state. Journal of Virology 74:513–517
     [Google Scholar]
  14. Gabay C., Silacci P., Genin B., Mentha G., Le Coultre C., Guerne P. A. 1995; Soluble interleukin-6 receptor strongly increases the production of acute-phase protein by hepatoma cells but exerts minimal changes on human primary hepatocytes. European Journal of Immunology 25:2378–2383
     [Google Scholar]
  15. Groh V., Bahram S., Bauer S., Herman A., Beauchamp M., Spies T. 1996; Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proceedings of the National Academy of Sciences, USA 93:12445–12450
     [Google Scholar]
  16. Halwachs-Baumann G., Wilders-Truschnig M., Desoye G., Hahn T., Kiesel L., Klingel K., Rieger P., Jahn G., Sinzger C. 1998; Human trophoblast cells are permissive to the complete replicative cycle of human cytomegalovirus. Journal of Virology 72:7598–7602
     [Google Scholar]
  17. Hemmings D. G., Kilani R., Nykiforuk C., Preiksaitis J., Guilbert L. J. 1998; Permissive cytomegalovirus infection of primary villous term and first trimester trophoblasts. Journal of Virology 72:4970–4979
     [Google Scholar]
  18. Hengel H., Lucin P., Jonjic S., Ruppert T., Koszinowski U. H. 1994; Restoration of cytomegalovirus antigen presentation by gamma interferon combats viral escape. Journal of Virology 68:289–297
     [Google Scholar]
  19. Hengel H., Eßlinger C., Pool J., Goulmy E., Koszinowski U. H. 1995; Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells. Journal of General Virology 76:2987–2997
     [Google Scholar]
  20. Hengel H., Flohr T., Hämmerling G. H., Koszinowski U. H., Momburg F. 1996; Human cytomegalovirus inhibits peptide translocation into the endoplasmic reticulum for MHC class I assembly. Journal of General Virology 77:2287–2296
     [Google Scholar]
  21. Hengel H., Koopmann J. O., Flohr T., Muranyi W., Goulmy E., Hämmerling G. J., Koszinowski U. H., Momburg F. 1997; A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity 6:623–632
     [Google Scholar]
  22. Hengel H., Reusch U., Geginat G., Holtappels R., Ruppert T., Hellebrand E., Koszinowski U. H. 2000; Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus. Journal of Virology 74:7861–7868
     [Google Scholar]
  23. Ito M., Watanabe M., Ihara T., Kamiya H., Sakurai M. 1995; Increased expression of adhesion molecules (CD54, CD29 and CD44) on fibroblasts infected with cytomegalovirus. Microbiology and Immunology 39:129–133
     [Google Scholar]
  24. Jarvis M. A., Wang C. E., Meyers H. L., Smith P. P., Corless C. L., Henderson G. J., Vieira J., Britt W. J., Nelson J. A. 1999; Human cytomegalovirus infection of Caco-2 cells occurs at the basolateral membrane and is differentiation state dependent. Journal of Virology 73:4552–4560
     [Google Scholar]
  25. Jones T. R., Muzithras V. P. 1991; Fine mapping of transcripts expressed from the US6 gene family of human cytomegalovirus strain AD169. Journal of Virology 65:2024–2036
     [Google Scholar]
  26. Jones T. R., Hanson L. K., Sun L., Slater J. S., Stenberg R. M., Campbell A. E. 1995; Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains. Journal of Virology 69:4830–4841
     [Google Scholar]
  27. Jones T. R., Wiertz E. J. H. 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, USA 93:11327–11333
     [Google Scholar]
  28. Jordan M. C. 1983; Latent infection and the elusive cytomegalovirus. Reviews of Infectious Diseases 5:205–215
     [Google Scholar]
  29. Knuth A., Gabbert H., Dippold W., Klein O., Sachsse W., Bitter-Suermann D., Prellwitz W., Meyer zum Büschenfelde K. H. 1985; Biliary adenocarcinoma. Characterisation of three new human tumor cell lines. Journal of Hepatology 1:579–596
     [Google Scholar]
  30. Krmpotic A., Messerle M., Crnkovic-Mertens I., Polic B., Jonjic S., Koszinowski U. H. 1999; The immunoevasive function encoded by the mouse cytomegalovirus gene m152 protects the virus against T cell control in vivo. Journal of Experimental Medicine 190:1285–1295
     [Google Scholar]
  31. Lautenschlager I., Höckerstedt K., Salmela K., Isoniemi H., Holmberg C., Jalanko H., Hayry P. 1990; Fine-needle aspiration biopsy in the monitoring of liver allografts. Different cellular findings during rejection and cytomegalovirus infection. Transplantation 50:798–803
     [Google Scholar]
  32. Lautenschlager I., Höckerstedt K., Jalanko H., Loginov R., Salmela K., Taskinen E., Ahonen J. 1997; Persistent cytomegalovirus in liver allografts with chronic rejection. Hepatology 25:190–194
     [Google Scholar]
  33. Lehner P. J., Karttunen J. T., Wilkinson G. W. G., Cresswell P. 1997; The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proceedings of the National Academy of Sciences, USA 94:6904–6909
     [Google Scholar]
  34. Miller D. M., Rahill B. M., Boss J. M., Lairmore M. D., Durbin J. E., Waldman J. W., Sedmak D. D. 1998; Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. Journal of Experimental Medicine 187:675–683
     [Google Scholar]
  35. Nakabayashi H., Takeda K., Miyano K., Yamane T., Sato J. 1982; Growth of human hepatoma cell lines with differentiated functions in chemically defined medium. Cancer Research 42:3858–3863
     [Google Scholar]
  36. Ohe Y., Zhao D., Saijo N., Podack E. R. 1995; Construction of a novel bovine papillomavirus vector without detectable transforming activity suitable for gene transfer. Human Gene Therapy 6:325–333
     [Google Scholar]
  37. Parham P., Barnstable C. J., Bodmer W. F. 1979; Use of monoclonal antibody (W6/32) in structural studies of HLA-A, B, C antigens. Journal of Immunology 123:342–349
     [Google Scholar]
  38. Paya C. V., Hermans P. E., Wiesner R. H., Ludwig J., Smith T. F., Rakela J., Krom R. A. 1989; Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations. Journal of Infectious Diseases 160:752–758
     [Google Scholar]
  39. Paya C. V., Holley K. E., Wiesner R. H., Balasubramaniam K., Smith T. F., Espy M. J., Ludwig J., Batts K. P., Hermans P. E., Krom R. A. 1990; Early diagnosis of cytomegalovirus hepatitis in liver transplant recipients: role of immunostaining, DNA hybridization and culture of hepatic tissue. Hepatology 12:119–126
     [Google Scholar]
  40. Plachter B., Britt W., Vornhagen R., Stamminger T., Jahn G. 1993; Analysis of proteins encoded by IE regions 1 and 2 of human cytomegalovirus using monoclonal antibodies generated against recombinant antigens. Virology 193:642–652
     [Google Scholar]
  41. Podlech J., Holtappels R., Wirtz N., Steffens H.-P., Reddehase M. J. 1998; Reconstitution of CD8 T cells is essential for the prevention of multiple-organ cytomegalovirus histopathology after bone marrow transplantation. Journal of General Virology 79:2099–2104
     [Google Scholar]
  42. Sanchez V., Angeletti P. C., Engler J. A., Britt W. J. 1998; Localization of human cytomegalovirus structural proteins to the nuclear matrix of infected human fibroblasts. Journal of Virology 72:3321–3329
     [Google Scholar]
  43. Scholz M., Cinatl J., Blaheta R. A., Kornhuber B., Markus B. H., Doerr H. W. 1997; Expression of human leukocyte antigens class I and class II on cultured biliary epithelial cells after cytomegalovirus infection. Tissue Antigens 49:640–643
     [Google Scholar]
  44. Sigal L. J., Crotty S., Andino R., Rock K. L. 1999; Cytotoxic T-cell immunity to virus-infected non-haematopoietic cells requires presentation of exogenous antigen. Nature 398:77–80
     [Google Scholar]
  45. Sinzger C., Grefte A., Plachter B., Gouw A. S. H., The T. H., Jahn G. 1995; Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues. Journal of General Virology 76:741–750
     [Google Scholar]
  46. Sinzger C., Bissinger A. L., Viebahn R., Oettle H., Radke C., Schmidt C. A., Jahn G. 1999; Hepatocytes are permissive for human cytomegalovirus infection in human liver cell culture and in vivo. Journal of Infectious Diseases 180:976–986
     [Google Scholar]
  47. Snover D. C., Horwitz C. A. 1984; Liver disease in cytomegalovirus mononucleosis: a light microscopical and immunoperoxidase study of six cases. Hepatology 4:408–412
     [Google Scholar]
  48. Spaete R. R., Thayer R. M., Probert W. S., Masiarz F. R., Chamberlain S. H., Rasmussen L., Merigan T. C., Pachl C. 1988; Human cytomegalovirus strain Towne glycoprotein B is processed by proteolytic cleavage. Virology 176:207–225
     [Google Scholar]
  49. Steinhoff G., Wonigeit K., Pichlmayr R. 1988; Analysis of sequential changes in major histocompatibility complex expression in human liver grafts after transplantation. Transplantation 45:394–401
     [Google Scholar]
  50. Stratta R. J., Shaefer M. S., Markin R. S., Wood R. P., Kennedy E. M., Langnas A. N., Reed E. C., Woods G. L., Donovan J. P., Pillen T. J., Duckworth R. M., Shaw B. W. 1989; Clinical patterns of cytomegalovirus disease after liver transplantation. Archives of Surgery 124:1443–1450
     [Google Scholar]
  51. Ten Napel H. H., Houthoff H. J., The T. H. 1984; Cytomegalovirus hepatitis in normal and immune compromised hosts. Liver 4:184–194
     [Google Scholar]
  52. Theise N. D., Conn M., Thung S. N. 1993; Localization of cytomegalovirus antigens in liver allografts over time. Human Pathology 24:103–108
     [Google Scholar]
  53. Thornthwaite J. T., Sugarbaker E. V., Temple W. J. 1980; Preparation of tissue for DNA flow cytometric analysis. Cytometry 1:229–234
     [Google Scholar]
  54. Tugizov S., Maidji E., Pereira L. 1997; Role of apical and basolateral membranes in replication of human cytomegalovirus in polarized retinal pigment epithelial cells. Journal of General Virology 77:61–74
     [Google Scholar]
  55. Warren A. P., Ducroq D. H., Lehner P. J., Borysiewicz L. K. 1994; Human cytomegalovirus-infected cells have unstable assembly of major histocompatibility complex class I complexes and are resistant to lysis by cytotoxic T lymphocytes. Journal of Virology 68:2822–2829
     [Google Scholar]
  56. Wiertz E. J. H. 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. Cell 84:769–779
     [Google Scholar]
  57. Wiertz E. J. H. 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. Nature 384:432–438
     [Google Scholar]
  58. Yamashita Y., Shimokata K., Mizuno S., Yamaguchi H., Nishiyama Y. 1993; Down-regulation of the surface expression of class I MHC antigens by human cytomegalovirus. Virology 193727–736
     [Google Scholar]
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Efficient downregulation of major histocompatibility complex class I molecules in human epithelial cells infected with cytomegalovirus
J. Gen. Virol. 82, 2061 (2001); https://doi.org/10.1099/0022-1317-82-9-2061
/content/journal/jgv/10.1099/0022-1317-82-9-2061
/content/journal/jgv/10.1099/0022-1317-82-9-2061
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