1887

Abstract

Human cytomegalovirus (HCMV) interferes with MHC class I-restricted antigen presentation and thereby reduces recognition by CD8 T-cells. This interference is mediated primarily by endoplasmic reticulum-resident glycoproteins that are encoded in the US2–11 region of the viral genome. Such a suppression of recognition would be of particular importance immediately after infection, because several immunodominant viral antigens are already present in the cell in this phase. However, which of the evasion proteins gpUS2–11 interfere(s) with antigen presentation to CD8 T-cells at this time of infection is not known. Here we address this question, using recombinant viruses (RV) that express only one of the immunoevasins gpUS2, gpUS3 or gpUS11. Infection with RV-US3 had only a limited impact on the presentation of peptides from the CD8 T-cell antigens IE1 and pp65 under immediate-early (IE) conditions imposed by cycloheximide/actinomycin D blocking. Unexpectedly, both RV-US2 and RV-US11 considerably impaired the recognition of IE1 and pp65 by CD8 T-cells, and both US2 and, to a lesser extent, US11 were transcribed under IE conditions. Thus, gpUS2 and gpUS11 are key effectors of MHC class I immunoevasion immediately after HCMV infection.

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2013-02-01
2024-03-29
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References

  1. Ahn K., Angulo A., Ghazal P., Peterson P. A., Yang Y., Früh K. 1996; Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc Natl Acad Sci U S A 93:10990–10995 [View Article][PubMed]
    [Google Scholar]
  2. Ahn K., Gruhler A., Galocha B., Jones T. R., Wiertz E. J., Ploegh H. L., Peterson P. A., Yang Y., Früh K. 1997; The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6:613–621 [View Article][PubMed]
    [Google Scholar]
  3. Andreoni M., Faircloth M., Vugler L., Britt W. J. 1989; A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. J Virol Methods 23:157–167 [View Article][PubMed]
    [Google Scholar]
  4. Babić M., Krmpotić A., Jonjić S. 2011; All is fair in virus–host interactions: NK cells and cytomegalovirus. Trends Mol Med 17:677–685 [View Article][PubMed]
    [Google Scholar]
  5. Barnes P. D., Grundy J. E. 1992; Down-regulation of the class I HLA heterodimer and β2-microglobulin on the surface of cells infected with cytomegalovirus. J Gen Virol 73:2395–2403 [View Article][PubMed]
    [Google Scholar]
  6. Besold K., Plachter B. 2008; Recombinant viruses as tools to study human cytomegalovirus immune modulation. Med Microbiol Immunol (Berl) 197:215–222 [View Article][PubMed]
    [Google Scholar]
  7. Besold K., Frankenberg N., Pepperl-Klindworth S., Kuball J., Theobald M., Hahn G., Plachter B. 2007; Processing and MHC class I presentation of human cytomegalovirus pp65-derived peptides persist despite gpUS2-11-mediated immune evasion. J Gen Virol 88:1429–1439 [View Article][PubMed]
    [Google Scholar]
  8. Besold K., Wills M., Plachter B. 2009; Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition. Virology 391:5–19 [View Article][PubMed]
    [Google Scholar]
  9. Böhm V., Simon C. O., Podlech J., Seckert C. K., Gendig D., Deegen P., Gillert-Marien D., Lemmermann N. A., Holtappels R., Reddehase M. J. 2008; The immune evasion paradox: immunoevasins of murine cytomegalovirus enhance priming of CD8 T cells by preventing negative feedback regulation. J Virol 82:11637–11650 [View Article][PubMed]
    [Google Scholar]
  10. Böhm V., Seckert C. K., Simon C. O., Thomas D., Renzaho A., Gendig D., Holtappels R., Reddehase M. J. 2009; Immune evasion proteins enhance cytomegalovirus latency in the lungs. J Virol 83:10293–10298 [View Article][PubMed]
    [Google Scholar]
  11. Boppana S. B., Britt W. J. 1996; Recognition of human cytomegalovirus gene products by HCMV-specific cytotoxic T cells. Virology 222:293–296 [View Article][PubMed]
    [Google Scholar]
  12. Borysiewicz L. K., Hickling J. K., Graham S., Sinclair J., Cranage M. P., Smith G. L., Sissons J. G. 1988; Human cytomegalovirus-specific cytotoxic T cells. Relative frequency of stage-specific CTL recognizing the 72-kD immediate early protein and glycoprotein B expressed by recombinant vaccinia viruses. J Exp Med 168:919–931 [View Article][PubMed]
    [Google Scholar]
  13. Bresnahan W. A., Shenk T. 2000; A subset of viral transcripts packaged within human cytomegalovirus particles. Science 288:2373–2376 [View Article][PubMed]
    [Google Scholar]
  14. Cherepanov P. P., Wackernagel W. 1995; Gene disruption in Escherichia coli: TcR and KmR cassettes with the option of Flp-catalyzed excision of the antibiotic-resistance determinant. Gene 158:9–14 [View Article][PubMed]
    [Google Scholar]
  15. Depto A. S., Stenberg R. M. 1989; Regulated expression of the human cytomegalovirus pp65 gene: octamer sequence in the promoter is required for activation by viral gene products. J Virol 63:1232–1238[PubMed]
    [Google Scholar]
  16. Elkington R., Walker S., Crough T., Menzies M., Tellam J., Bharadwaj M., Khanna R. 2003; Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol 77:5226–5240 [View Article][PubMed]
    [Google Scholar]
  17. Frankenberg N., Pepperl-Klindworth S., Meyer R. G., Plachter B. 2002; Identification of a conserved HLA-A2-restricted decapeptide from the IE1 protein (pUL123) of human cytomegalovirus. Virology 295:208–216 [View Article][PubMed]
    [Google Scholar]
  18. Furman M. H., Dey N., Tortorella D., Ploegh H. L. 2002; The human cytomegalovirus US10 gene product delays trafficking of major histocompatibility complex class I molecules. J Virol 76:11753–11756 [View Article][PubMed]
    [Google Scholar]
  19. Gilbert M. J., Riddell S. R., Plachter B., Greenberg P. D. 1996; Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature 383:720–722 [View Article][PubMed]
    [Google Scholar]
  20. Greijer A. E., Dekkers C. A., Middeldorp J. M. 2000; Human cytomegalovirus virions differentially incorporate viral and host cell RNA during the assembly process. J Virol 74:9078–9082 [View Article][PubMed]
    [Google Scholar]
  21. Greijer A. E., Verschuuren E. A., Dekkers C. A., Adriaanse H. M., van der Bij W., The T. H., Middeldorp J. M. 2001; Expression dynamics of human cytomegalovirus immune evasion genes US3, US6, and US11 in the blood of lung transplant recipients. J Infect Dis 184:247–255 [View Article][PubMed]
    [Google Scholar]
  22. Gretch D. R., Kari B., Rasmussen L., Gehrz R. C., Stinski M. F. 1988; Identification and characterization of three distinct families of glycoprotein complexes in the envelopes of human cytomegalovirus. J Virol 62:875–881[PubMed]
    [Google Scholar]
  23. Halenius A., Momburg F., Reinhard H., Bauer D., Lobigs M., Hengel H. 2006; Physical and functional interactions of the cytomegalovirus US6 glycoprotein with the transporter associated with antigen processing. J Biol Chem 281:5383–5390 [View Article][PubMed]
    [Google Scholar]
  24. Hansen S. G., Powers C. J., Richards R., Ventura A. B., Ford J. C., Siess D., Axthelm M. K., Nelson J. A., Jarvis M. A. other authors 2010; Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science 328:102–106 [View Article][PubMed]
    [Google Scholar]
  25. 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 [View Article][PubMed]
    [Google Scholar]
  26. Hengel H., Koszinowski U. H., Conzelmann K. K. 2005; Viruses know it all: new insights into IFN networks. Trends Immunol 26:396–401 [View Article][PubMed]
    [Google Scholar]
  27. Jackson S. E., Mason G. M., Wills M. R. 2011; Human cytomegalovirus immunity and immune evasion. Virus Res 157:151–160 [View Article][PubMed]
    [Google Scholar]
  28. Jochum S., Ruiss R., Moosmann A., Hammerschmidt W., Zeidler R. 2012; RNAs in Epstein–Barr virions control early steps of infection. Proc Natl Acad Sci U S A 109:E1396–E1404 [View Article][PubMed]
    [Google Scholar]
  29. Johnson D. C., Hegde N. R. 2002; Inhibition of the MHC class II antigen presentation pathway by human cytomegalovirus. Curr Top Microbiol Immunol 269:101–115 [View Article][PubMed]
    [Google Scholar]
  30. Jones T. R., Muzithras V. P. 1991; Fine mapping of transcripts expressed from the US6 gene family of human cytomegalovirus strain AD169. J Virol 65:2024–2036[PubMed]
    [Google Scholar]
  31. Jones T. R., Sun L. 1997; Human cytomegalovirus US2 destabilizes major histocompatibility complex class I heavy chains. J Virol 71:2970–2979[PubMed]
    [Google Scholar]
  32. 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. J Virol 69:4830–4841[PubMed]
    [Google Scholar]
  33. 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. Proc Natl Acad Sci U S A 93:11327–11333 [View Article][PubMed]
    [Google Scholar]
  34. Kern F., Surel I. P., Faulhaber N., Frömmel C., Schneider-Mergener J., Schönemann C., Reinke P., Volk H. D. 1999; Target structures of the CD8+-T-cell response to human cytomegalovirus: the 72-kilodalton major immediate-early protein revisited. J Virol 73:8179–8184[PubMed]
    [Google Scholar]
  35. Kim S., Lee S., Shin J., Kim Y., Evnouchidou I., Kim D., Kim Y. K., Kim Y. E., Ahn J. H. other authors 2011; Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol 12:984–991 [View Article][PubMed]
    [Google Scholar]
  36. Lee S., Yoon J., Park B., Jun Y., Jin M., Sung H. C., Kim I. H., Kang S., Choi E. J. other authors 2000; Structural and functional dissection of human cytomegalovirus US3 in binding major histocompatibility complex class I molecules. J Virol 74:11262–11269 [View Article][PubMed]
    [Google Scholar]
  37. Lee E. C., Yu D., Martinez de Velasco J., Tessarollo L., Swing D. A., Court D. L., Jenkins N. A., Copeland N. G. 2001; A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 73:56–65 [View Article][PubMed]
    [Google Scholar]
  38. 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. Proc Natl Acad Sci U S A 94:6904–6909 [View Article][PubMed]
    [Google Scholar]
  39. Lemmermann N. A., Böhm V., Holtappels R., Reddehase M. J. 2011; In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: facts and thoughts based on murine models. Virus Res 157:161–174 [View Article][PubMed]
    [Google Scholar]
  40. Liu W., Zhao Y., Biegalke B. 2002; Analysis of human cytomegalovirus US3 gene products. Virology 301:32–42 [View Article][PubMed]
    [Google Scholar]
  41. Liu Z., Winkler M., Biegalke B. 2009; Human cytomegalovirus: host immune modulation by the viral US3 gene. Int J Biochem Cell Biol 41:503–506 [View Article][PubMed]
    [Google Scholar]
  42. Manley T. J., Luy L., Jones T., Boeckh M., Mutimer H., Riddell S. R. 2004; Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104:1075–1082 [View Article][PubMed]
    [Google Scholar]
  43. McLaughlin-Taylor E., Pande H., Forman S. J., Tanamachi B., Li C. R., Zaia J. A., Greenberg P. D., Riddell S. R. 1994; Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol 43:103–110 [View Article][PubMed]
    [Google Scholar]
  44. Miyahira Y., Murata K., Rodriguez D., Rodriguez J. R., Esteban M., Rodrigues M. M., Zavala F. 1995; Quantification of antigen specific CD8+ T cells using an ELISPOT assay. J Immunol Methods 181:45–54 [View Article][PubMed]
    [Google Scholar]
  45. Noriega V. M., Tortorella D. 2009; Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules. J Virol 83:1359–1367 [View Article][PubMed]
    [Google Scholar]
  46. Noriega V., Redmann V., Gardner T., Tortorella D. 2012a; Diverse immune evasion strategies by human cytomegalovirus. Immunol Res 54:140–151 [View Article][PubMed]
    [Google Scholar]
  47. Noriega V. M., Hesse J., Gardner T. J., Besold K., Plachter B., Tortorella D. 2012b; Human cytomegalovirus US3 modulates destruction of MHC class I molecules. Mol Immunol 51:245–253 [View Article][PubMed]
    [Google Scholar]
  48. Park B., Lee S., Kim E., Ahn K. 2003; A single polymorphic residue within the peptide-binding cleft of MHC class I molecules determines spectrum of tapasin dependence. J Immunol 170:961–968[PubMed] [CrossRef]
    [Google Scholar]
  49. Park B., Kim Y., Shin J., Lee S., Cho K., Früh K., Lee S., Ahn K. 2004; Human cytomegalovirus inhibits tapasin-dependent peptide loading and optimization of the MHC class I peptide cargo for immune evasion. Immunity 20:71–85 [View Article][PubMed]
    [Google Scholar]
  50. Park B., Spooner E., Houser B. L., Strominger J. L., Ploegh H. L. 2010; The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation. J Exp Med 207:2033–2041 [View Article][PubMed]
    [Google Scholar]
  51. Reddehase M. J. 2002; Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat Rev Immunol 2:831–844 [View Article][PubMed]
    [Google Scholar]
  52. Reddehase M. J., Weiland F., Münch K., Jonjic S., Lüske A., Koszinowski U. H. 1985; Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J Virol 55:264–273[PubMed]
    [Google Scholar]
  53. Reusser P., Riddell S. R., Meyers J. D., Greenberg P. D. 1991; Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78:1373–1380[PubMed]
    [Google Scholar]
  54. Schub A., Schuster I. G., Hammerschmidt W., Moosmann A. 2009; CMV-specific TCR-transgenic T cells for immunotherapy. J Immunol 183:6819–6830 [View Article][PubMed]
    [Google Scholar]
  55. Shin J., Park B., Lee S., Kim Y., Biegalke B. J., Kang S., Ahn K. 2006; A short isoform of human cytomegalovirus US3 functions as a dominant negative inhibitor of the full-length form. J Virol 80:5397–5404 [View Article][PubMed]
    [Google Scholar]
  56. Steffens H. P., Kurz S., Holtappels R., Reddehase M. J. 1998; Preemptive CD8 T-cell immunotherapy of acute cytomegalovirus infection prevents lethal disease, limits the burden of latent viral genomes, and reduces the risk of virus recurrence. J Virol 72:1797–1804[PubMed]
    [Google Scholar]
  57. Sylwester A. W., Mitchell B. L., Edgar J. B., Taormina C., Pelte C., Ruchti F., Sleath P. R., Grabstein K. H., Hosken N. A. other authors 2005; Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202:673–685 [View Article][PubMed]
    [Google Scholar]
  58. Tirabassi R. S., Ploegh H. L. 2002; The human cytomegalovirus US8 glycoprotein binds to major histocompatibility complex class I products. J Virol 76:6832–6835 [View Article][PubMed]
    [Google Scholar]
  59. Trgovcich J., Cebulla C., Zimmerman P., Sedmak D. D. 2006; Human cytomegalovirus protein pp71 disrupts major histocompatibility complex class I cell surface expression. J Virol 80:951–963 [View Article][PubMed]
    [Google Scholar]
  60. Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R. 1995; Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038–1044 [View Article][PubMed]
    [Google Scholar]
  61. Weston K. 1988; An enhancer element in the short unique region of human cytomegalovirus regulates the production of a group of abundant immediate early transcripts. Virology 162:406–416 [View Article][PubMed]
    [Google Scholar]
  62. 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. Cell 84:769–779 [View Article][PubMed]
    [Google Scholar]
  63. 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. Nature 384:432–438 [View Article][PubMed]
    [Google Scholar]
  64. Wiesner M., Zentz C., Hammer M. H., Cobbold M., Kern F., Kolb H. J., Hammerschmidt W., Zeidler R., Moosmann A. 2005; Selection of CMV-specific CD8+ and CD4+ T cells by mini-EBV-transformed B cell lines. Eur J Immunol 35:2110–2121 [View Article][PubMed]
    [Google Scholar]
  65. Wills M. R., Carmichael A. J., Mynard K., Jin X., Weekes M. P., Plachter B., Sissons J. G. 1996; The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol 70:7569–7579[PubMed]
    [Google Scholar]
  66. 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 193:727–736 [View Article][PubMed]
    [Google Scholar]
  67. Yu D., Smith G. A., Enquist L. W., Shenk T. 2002; Construction of a self-excisable bacterial artificial chromosome containing the human cytomegalovirus genome and mutagenesis of the diploid TRL/IRL13 gene. J Virol 76:2316–2328 [View Article][PubMed]
    [Google Scholar]
  68. Zhao Y., Biegalke B. J. 2003; Functional analysis of the human cytomegalovirus immune evasion protein, pUS322kDa . Virology 315:353–361 [View Article][PubMed]
    [Google Scholar]
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