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. 1994 Apr;144(4):683–692.

Cytomegalovirus inhibits major histocompatibility class II expression on infected endothelial cells.

D D Sedmak 1, A M Guglielmo 1, D A Knight 1, D J Birmingham 1, E H Huang 1, W J Waldman 1
PMCID: PMC1887242  PMID: 8160770

Abstract

Persistent human cytomegalovirus (HCMV) infections are responsible for significant morbidity and mortality in immunocompromised individuals. One mechanism by which HCMV may develop persistence after primary infection is through inhibition of host cell human leukocyte antigen (HLA) class II expression with resultant escape from normal antiviral immune surveillance. Immunofluorescence flow cytometry of human endothelial cell (EC) cultures infected with HCMV AD169 and an EC propagated strain, VHL/E, showed a marked reduction in interferon-gamma (IFN-gamma)-induced surface expression of HLA-DR. This inhibition did not occur when EC were treated with ultraviolet-inactivated virus and IFN-gamma. HCMV, as determined by dual-labeling immunohistochemistry, inhibited induction of surface and cytoplasmic class II antigens specifically in infected cells. HCMV infection also inhibited IFN-gamma and tumor necrosis factor-alpha up-regulation of HLA class I expression. Northern blot analysis of infected, IFN-gamma-treated human umbilical vein endothelial cells revealed an absence of class II mRNA. Persistence of HCMV may result in part from its ability to inhibit HLA class II induction in infected cells.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alp N. J., Allport T. D., Van Zanten J., Rodgers B., Sissons J. G., Borysiewicz L. K. Fine specificity of cellular immune responses in humans to human cytomegalovirus immediate-early 1 protein. J Virol. 1991 Sep;65(9):4812–4820. doi: 10.1128/jvi.65.9.4812-4820.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnes P. D., Grundy J. E. Down-regulation of the class I HLA heterodimer and beta 2-microglobulin on the surface of cells infected with cytomegalovirus. J Gen Virol. 1992 Sep;73(Pt 9):2395–2403. doi: 10.1099/0022-1317-73-9-2395. [DOI] [PubMed] [Google Scholar]
  3. Beck S., Barrell B. G. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature. 1988 Jan 21;331(6153):269–272. doi: 10.1038/331269a0. [DOI] [PubMed] [Google Scholar]
  4. Browne H., Smith G., Beck S., Minson T. A complex between the MHC class I homologue encoded by human cytomegalovirus and beta 2 microglobulin. Nature. 1990 Oct 25;347(6295):770–772. doi: 10.1038/347770a0. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Colberg-Poley A. M., Santomenna L. D., Harlow P. P., Benfield P. A., Tenney D. J. Human cytomegalovirus US3 and UL36-38 immediate-early proteins regulate gene expression. J Virol. 1992 Jan;66(1):95–105. doi: 10.1128/jvi.66.1.95-105.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Firestein G. S., Paine M. M. Stromelysin and tissue inhibitor of metalloproteinases gene expression in rheumatoid arthritis synovium. Am J Pathol. 1992 Jun;140(6):1309–1314. [PMC free article] [PubMed] [Google Scholar]
  8. Fujinami R. S., Nelson J. A., Walker L., Oldstone M. B. Sequence homology and immunologic cross-reactivity of human cytomegalovirus with HLA-DR beta chain: a means for graft rejection and immunosuppression. J Virol. 1988 Jan;62(1):100–105. doi: 10.1128/jvi.62.1.100-105.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gimbrone M. A., Jr, Cotran R. S., Folkman J. Human vascular endothelial cells in culture. Growth and DNA synthesis. J Cell Biol. 1974 Mar;60(3):673–684. doi: 10.1083/jcb.60.3.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Grundy J. E., Downes K. L. Up-regulation of LFA-3 and ICAM-1 on the surface of fibroblasts infected with cytomegalovirus. Immunology. 1993 Mar;78(3):405–412. [PMC free article] [PubMed] [Google Scholar]
  11. Hirschberg H., Bergh O. J., Thorsby E. Antigen-presenting properties of human vascular endothelial cells. J Exp Med. 1980 Aug 1;152(2 Pt 2):249s–255s. [PubMed] [Google Scholar]
  12. Ho D. D., Rota T. R., Andrews C. A., Hirsch M. S. Replication of human cytomegalovirus in endothelial cells. J Infect Dis. 1984 Dec;150(6):956–957. doi: 10.1093/infdis/150.6.956. [DOI] [PubMed] [Google Scholar]
  13. Jacobson S., Sekaly R. P., Jacobson C. L., McFarland H. F., Long E. O. HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells. J Virol. 1989 Apr;63(4):1756–1762. doi: 10.1128/jvi.63.4.1756-1762.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jin Y., Shih W. K., Berkower I. Human T cell response to the surface antigen of hepatitis B virus (HBsAg). Endosomal and nonendosomal processing pathways are accessible to both endogenous and exogenous antigen. J Exp Med. 1988 Jul 1;168(1):293–306. doi: 10.1084/jem.168.1.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Joly E., Mucke L., Oldstone M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 1991 Sep 13;253(5025):1283–1285. doi: 10.1126/science.1891717. [DOI] [PubMed] [Google Scholar]
  17. Jordan M. C. Latent infection and the elusive cytomegalovirus. Rev Infect Dis. 1983 Mar-Apr;5(2):205–215. doi: 10.1093/clinids/5.2.205. [DOI] [PubMed] [Google Scholar]
  18. Joseph J., Knobler R. L., Lublin F. D., Hart M. N. Mouse hepatitis virus (MHV-4, JHM) blocks gamma-interferon-induced major histocompatibility complex class II antigen expression on murine cerebral endothelial cells. J Neuroimmunol. 1991 Sep;33(3):181–190. doi: 10.1016/0165-5728(91)90105-G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kaye P. M., Sims M., Feldmann M. Regulation of macrophage accessory cell activity by mycobacteria. II. In vitro inhibition of Ia expression by Mycobacterium microti. Clin Exp Immunol. 1986 Apr;64(1):28–34. [PMC free article] [PubMed] [Google Scholar]
  20. Khoury E. L., Pereira L., Greenspan F. S. Induction of HLA-DR expression on thyroid follicular cells by cytomegalovirus infection in vitro. Evidence for a dual mechanism of induction. Am J Pathol. 1991 May;138(5):1209–1223. [PMC free article] [PubMed] [Google Scholar]
  21. Lapierre L. A., Fiers W., Pober J. S. Three distinct classes of regulatory cytokines control endothelial cell MHC antigen expression. Interactions with immune gamma interferon differentiate the effects of tumor necrosis factor and lymphotoxin from those of leukocyte alpha and fibroblast beta interferons. J Exp Med. 1988 Mar 1;167(3):794–804. doi: 10.1084/jem.167.3.794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lindsley M. D., Torpey D. J., 3rd, Rinaldo C. R., Jr HLA-DR-restricted cytotoxicity of cytomegalovirus-infected monocytes mediated by Leu-3-positive T cells. J Immunol. 1986 Apr 15;136(8):3045–3051. [PubMed] [Google Scholar]
  23. Maciag T., Cerundolo J., Ilsley S., Kelley P. R., Forand R. An endothelial cell growth factor from bovine hypothalamus: identification and partial characterization. Proc Natl Acad Sci U S A. 1979 Nov;76(11):5674–5678. doi: 10.1073/pnas.76.11.5674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Maudsley D. J., Morris A. G. Regulation of IFN-gamma-induced host cell MHC antigen expression by Kirsten MSV and MLV. II. Effects on class II antigen expression. Immunology. 1989 May;67(1):26–31. [PMC free article] [PubMed] [Google Scholar]
  25. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  26. Muller D., Koller B. H., Whitton J. L., LaPan K. E., Brigman K. K., Frelinger J. A. LCMV-specific, class II-restricted cytotoxic T cells in beta 2-microglobulin-deficient mice. Science. 1992 Mar 20;255(5051):1576–1578. doi: 10.1126/science.1347959. [DOI] [PubMed] [Google Scholar]
  27. Myerson D., Hackman R. C., Nelson J. A., Ward D. C., McDougall J. K. Widespread presence of histologically occult cytomegalovirus. Hum Pathol. 1984 May;15(5):430–439. doi: 10.1016/s0046-8177(84)80076-3. [DOI] [PubMed] [Google Scholar]
  28. Oldstone M. B. Molecular anatomy of viral persistence. J Virol. 1991 Dec;65(12):6381–6386. doi: 10.1128/jvi.65.12.6381-6386.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Oldstone M. B. Viral persistence. Cell. 1989 Feb 24;56(4):517–520. doi: 10.1016/0092-8674(89)90573-4. [DOI] [PubMed] [Google Scholar]
  30. Pober J. S., Collins T., Gimbrone M. A., Jr, Cotran R. S., Gitlin J. D., Fiers W., Clayberger C., Krensky A. M., Burakoff S. J., Reiss C. S. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature. 1983 Oct 20;305(5936):726–729. doi: 10.1038/305726a0. [DOI] [PubMed] [Google Scholar]
  31. Pober J. S., Cotran R. S. Immunologic interactions of T lymphocytes with vascular endothelium. Adv Immunol. 1991;50:261–302. doi: 10.1016/s0065-2776(08)60827-5. [DOI] [PubMed] [Google Scholar]
  32. Päbo S., Nilsson T., Peterson P. A. Adenoviruses of subgenera B, C, D, and E modulate cell-surface expression of major histocompatibility complex class I antigens. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9665–9669. doi: 10.1073/pnas.83.24.9665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Reiner N. E., Ng W., Ma T., McMaster W. R. Kinetics of gamma interferon binding and induction of major histocompatibility complex class II mRNA in Leishmania-infected macrophages. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4330–4334. doi: 10.1073/pnas.85.12.4330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Reiner N. E., Ng W., McMaster W. R. Parasite-accessory cell interactions in murine leishmaniasis. II. Leishmania donovani suppresses macrophage expression of class I and class II major histocompatibility complex gene products. J Immunol. 1987 Mar 15;138(6):1926–1932. [PubMed] [Google Scholar]
  35. Santomenna L. D., Colberg-Poley A. M. Induction of cellular hsp70 expression by human cytomegalovirus. J Virol. 1990 May;64(5):2033–2040. doi: 10.1128/jvi.64.5.2033-2040.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scholz M., Hamann A., Blaheta R. A., Auth M. K., Encke A., Markus B. H. Cytomegalovirus- and interferon-related effects on human endothelial cells. Cytomegalovirus infection reduces upregulation of HLA class II antigen expression after treatment with interferon-gamma. Hum Immunol. 1992 Dec;35(4):230–238. doi: 10.1016/0198-8859(92)90004-7. [DOI] [PubMed] [Google Scholar]
  37. Sedmak D. D., Roberts W. H., Stephens R. E., Buesching W. J., Morgan L. A., Davis D. H., Waldman W. J. Inability of cytomegalovirus infection of cultured endothelial cells to induce HLA class II antigen expression. Transplantation. 1990 Feb;49(2):458–462. doi: 10.1097/00007890-199002000-00043. [DOI] [PubMed] [Google Scholar]
  38. Sekaly R. P., Tonnelle C., Strubin M., Mach B., Long E. O. Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain. J Exp Med. 1986 Nov 1;164(5):1490–1504. doi: 10.1084/jem.164.5.1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Toorkey C. B., Carrigan D. R. Immunohistochemical detection of an immediate early antigen of human cytomegalovirus in normal tissues. J Infect Dis. 1989 Nov;160(5):741–751. doi: 10.1093/infdis/160.5.741. [DOI] [PubMed] [Google Scholar]
  40. Waldman W. J., Adams P. W., Orosz C. G., Sedmak D. D. T lymphocyte activation by cytomegalovirus-infected, allogeneic cultured human endothelial cells. Transplantation. 1992 Nov;54(5):887–896. doi: 10.1097/00007890-199211000-00024. [DOI] [PubMed] [Google Scholar]
  41. Waldman W. J., Roberts W. H., Davis D. H., Williams M. V., Sedmak D. D., Stephens R. E. Preservation of natural endothelial cytopathogenicity of cytomegalovirus by propagation in endothelial cells. Arch Virol. 1991;117(3-4):143–164. doi: 10.1007/BF01310761. [DOI] [PubMed] [Google Scholar]
  42. Waldman W. J., Sneddon J. M., Stephens R. E., Roberts W. H. Enhanced endothelial cytopathogenicity induced by a cytomegalovirus strain propagated in endothelial cells. J Med Virol. 1989 Aug;28(4):223–230. doi: 10.1002/jmv.1890280405. [DOI] [PubMed] [Google Scholar]
  43. Yasukawa M., Zarling J. M. Human cytotoxic T cell clones directed against herpes simplex virus-infected cells. I. Lysis restricted by HLA class II MB and DR antigens. J Immunol. 1984 Jul;133(1):422–427. [PubMed] [Google Scholar]
  44. van Dorp W. T., Jonges E., Bruggeman C. A., Daha M. R., van Es L. A., van Der Woude F. J. Direct induction of MHC class I, but not class II, expression on endothelial cells by cytomegalovirus infection. Transplantation. 1989 Sep;48(3):469–472. doi: 10.1097/00007890-198909000-00024. [DOI] [PubMed] [Google Scholar]

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