Immunologic Research

, Volume 54, Issue 1–3, pp 140–151 | Cite as

Diverse immune evasion strategies by human cytomegalovirus

  • Vanessa Noriega
  • Veronika Redmann
  • Thomas Gardner
  • Domenico Tortorella
Immunology at Mount Sinai

Abstract

Members of the Herpesviridae family have the capacity to undergo both lytic and latent infection to establish a lifelong relationship with their host. Following primary infection, human cytomegalovirus (HCMV) can persist as a subclinical, recurrent infection for the lifetime of an individual. This quiescent portion of its life cycle is termed latency and is associated with periodic bouts of reactivation during times of immunosuppression, inflammation, or stress. In order to exist indefinitely and establish infection, HCMV encodes a multitude of immune modulatory mechanisms devoted to escaping the host antiviral response. HCMV has become a paradigm for studies of viral immune evasion of antigen presentation by both major histocompatibility complex (MHC) class I and II molecules. By restricting the presentation of viral antigens during both productive and latent infection, HCMV limits elimination by the human immune system. This review will focus on understanding how the virus manipulates the pathways of antigen presentation in order to modulate the host response to infection.

Keywords

Human cytomegalovirus MHC antigen presentation Immune evasion Latency Lytic infection Unique short Proteasome Degradation 

References

  1. 1.
    Mocarski ES, Shenk T, Pass RF. Cytomegaloviruses. In: Howley DMKPM, editor. Fields virology. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007.Google Scholar
  2. 2.
    Slobedman B, Cao JZ, Avdic S, Webster B, McAllery S, Cheung AK, et al. Human cytomegalovirus latent infection and associated viral gene expression. Futur Microbiol. 2010;5(6):883–900. doi:10.2217/fmb.10.58.Google Scholar
  3. 3.
    Sinclair J. Human cytomegalovirus: latency and reactivation in the myeloid lineage. J Clin Virol. 2008;41(3):180–5. doi:10.1016/j.jcv.2007.11.014.PubMedGoogle Scholar
  4. 4.
    Gibson W. Structure and formation of the cytomegalovirus virion. Curr Top Microbiol Immunol. 2008;325:187–204.PubMedGoogle Scholar
  5. 5.
    Compton T, Nowlin DM, Cooper NR. Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology. 1993;193(2):834–41. doi:10.1006/viro.1993.1192.PubMedGoogle Scholar
  6. 6.
    Isaacson MK, Juckem LK, Compton T. Virus entry and innate immune activation. Curr Top Microbiol Immunol. 2008;325:85–100.PubMedGoogle Scholar
  7. 7.
    Adler B, Scrivano L, Ruzcics Z, Rupp B, Sinzger C, Koszinowski U. Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J Gen Virol. 2006;87(Pt 9):2451–60. doi:10.1099/vir.0.81921-0.PubMedGoogle Scholar
  8. 8.
    Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, et al. Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol. 2004;78(18):10023–33. doi:10.1128/JVI.78.18.10023-10033.2004.PubMedGoogle Scholar
  9. 9.
    Gerna G, Percivalle E, Lilleri D, Lozza L, Fornara C, Hahn G, et al. Dendritic-cell infection by human cytomegalovirus is restricted to strains carrying functional UL131-128 genes and mediates efficient viral antigen presentation to CD8+ T cells. J Gen Virol. 2005;86(Pt 2):275–84. doi:10.1099/vir.0.80474-0.PubMedGoogle Scholar
  10. 10.
    Ryckman BJ, Jarvis MA, Drummond DD, Nelson JA, Johnson DC. Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol. 2006;80(2):710–22. doi:10.1128/JVI.80.2.710-722.2006.PubMedGoogle Scholar
  11. 11.
    Ryckman BJ, Rainish BL, Chase MC, Borton JA, Nelson JA, Jarvis MA, et al. Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol. 2008;82(1):60–70. doi:10.1128/JVI.01910-07.PubMedGoogle Scholar
  12. 12.
    Straschewski S, Patrone M, Walther P, Gallina A, Mertens T, Frascaroli G. Protein pUL128 of human cytomegalovirus is necessary for monocyte infection and blocking of migration. J Virol. 2011;85(10):5150–8. doi:10.1128/JVI.02100-10.PubMedGoogle Scholar
  13. 13.
    Wang D, Shenk T. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci USA. 2005;102(50):18153–8. doi:10.1073/pnas.0509201102.PubMedGoogle Scholar
  14. 14.
    Cha TA, Tom E, Kemble GW, Duke GM, Mocarski ES, Spaete RR. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J Virol. 1996;70(1):78–83.PubMedGoogle Scholar
  15. 15.
    Dolan A, Cunningham C, Hector RD, Hassan-Walker AF, Lee L, Addison C, et al. Genetic content of wild-type human cytomegalovirus. J Gen Virol. 2004;85(Pt 5):1301–12.PubMedGoogle Scholar
  16. 16.
    Vanarsdall AL, Chase MC, Johnson DC. Human cytomegalovirus glycoprotein gO complexes with gH/gL, promoting interference with viral entry into human fibroblasts but not entry into epithelial cells. J Virol. 2011;85(22):11638–45. doi:10.1128/JVI.05659-11.PubMedGoogle Scholar
  17. 17.
    Lopper M, Compton T. Coiled-coil domains in glycoproteins B and H are involved in human cytomegalovirus membrane fusion. J Virol. 2004;78(15):8333–41. doi:10.1128/JVI.78.15.8333-8341.2004.PubMedGoogle Scholar
  18. 18.
    Ogawa-Goto K, Tanaka K, Gibson W, Moriishi E, Miura Y, Kurata T, et al. Microtubule network facilitates nuclear targeting of human cytomegalovirus capsid. J Virol. 2003;77(15):8541–7.PubMedGoogle Scholar
  19. 19.
    Cherrington JM, Mocarski ES. Human cytomegalovirus ie1 transactivates the alpha promoter-enhancer via an 18-base-pair repeat element. J Virol. 1989;63(3):1435–40.PubMedGoogle Scholar
  20. 20.
    Meier JL, Stinski MF. Effect of a modulator deletion on transcription of the human cytomegalovirus major immediate-early genes in infected undifferentiated and differentiated cells. J Virol. 1997;71(2):1246–55.PubMedGoogle Scholar
  21. 21.
    Kalejta RF. Tegument proteins of human cytomegalovirus. Microbiol Mol Biol Rev. 2008;72(2):249–65. doi:10.1128/MMBR.00040-07. table of contents.PubMedGoogle Scholar
  22. 22.
    Gant TM, Wilson KL. Nuclear assembly. Annu Rev Cell Dev Biol. 1997;13:669–95. doi:10.1146/annurev.cellbio.13.1.669.PubMedGoogle Scholar
  23. 23.
    Radsak KD, Brucher KH, Georgatos SD. Focal nuclear envelope lesions and specific nuclear lamin A/C dephosphorylation during infection with human cytomegalovirus. Eur J Cell Biol. 1991;54(2):299–304.PubMedGoogle Scholar
  24. 24.
    Eickmann M, Gicklhorn D, Radsak K. Glycoprotein trafficking in virion morphogenesis. In: Reddehase M, Lemmermann N, editors. Cytomegaloviruses: molecular biology and immunology. Wymondham: Caister Academic Press; 2006. p. 245–64.Google Scholar
  25. 25.
    Sanchez V, Angeletti PC, Engler JA, Britt WJ. Localization of human cytomegalovirus structural proteins to the nuclear matrix of infected human fibroblasts. J Virol. 1998;72(4):3321–9.PubMedGoogle Scholar
  26. 26.
    Trus BL, Gibson W, Cheng N, Steven AC. Capsid structure of simian cytomegalovirus from cryoelectron microscopy: evidence for tegument attachment sites. J Virol. 1999;73(3):2181–92.PubMedGoogle Scholar
  27. 27.
    Liu W, Zhao Y, Biegalke B. Analysis of human cytomegalovirus US3 gene products. Virology. 2002;301(1):32–42.PubMedGoogle Scholar
  28. 28.
    Loewendorf A, Benedict CA. Modulation of host innate and adaptive immune defenses by cytomegalovirus: timing is everything. J Intern Med. 2010;267(5):483–501. doi:10.1111/j.1365-2796.2010.02220.x.PubMedGoogle Scholar
  29. 29.
    Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J Gen Virol. 2006;87(Pt 7):1763–79. doi:10.1099/vir.0.81891-0.PubMedGoogle Scholar
  30. 30.
    Goodrum FD, Jordan CT, High K, Shenk T. Human cytomegalovirus gene expression during infection of primary hematopoietic progenitor cells: a model for latency. Proc Natl Acad Sci USA. 2002;99(25):16255–60. doi:10.1073/pnas.252630899.PubMedGoogle Scholar
  31. 31.
    Hahn G, Jores R, Mocarski ES. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc Natl Acad Sci USA. 1998;95(7):3937–42.PubMedGoogle Scholar
  32. 32.
    Minton EJ, Tysoe C, Sinclair JH, Sissons JG. Human cytomegalovirus infection of the monocyte/macrophage lineage in bone marrow. J Virol. 1994;68(6):4017–21.PubMedGoogle Scholar
  33. 33.
    Reeves MB, MacAry PA, Lehner PJ, Sissons JG, Sinclair JH. Latency, chromatin remodeling, and reactivation of human cytomegalovirus in the dendritic cells of healthy carriers. Proc Natl Acad Sci USA. 2005;102(11):4140–5. doi:10.1073/pnas.0408994102.PubMedGoogle Scholar
  34. 34.
    Drew WL. Diagnosis of cytomegalovirus infection. Rev Infect Dis. 1988;10(Suppl 3):S468–76.PubMedGoogle Scholar
  35. 35.
    Rubin RH. Impact of cytomegalovirus infection on organ transplant recipients. Rev Infect Dis. 1990;12(Suppl 7):S754–66.PubMedGoogle Scholar
  36. 36.
    Soderberg-Naucler C. Does cytomegalovirus play a causative role in the development of various inflammatory diseases and cancer? J Intern Med. 2006;259(3):219–46. doi:10.1111/j.1365-2796.2006.01618.x.PubMedGoogle Scholar
  37. 37.
    Adler SP. Transfusion-associated cytomegalovirus infections. Rev Infect Dis. 1983;5(6):977–93.PubMedGoogle Scholar
  38. 38.
    Tolpin MD, Stewart JA, Warren D, Mojica BA, Collins MA, Doveikis SA, et al. Transfusion transmission of cytomegalovirus confirmed by restriction endonuclease analysis. J Pediatr. 1985;107(6):953–6.PubMedGoogle Scholar
  39. 39.
    Yeager AS, Grumet FC, Hafleigh EB, Arvin AM, Bradley JS, Prober CG. Prevention of transfusion-acquired cytomegalovirus infections in newborn infants. J Pediatr. 1981;98(2):281–7.PubMedGoogle Scholar
  40. 40.
    Jordan MC. Latent infection and the elusive cytomegalovirus. Rev Infect Dis. 1983;5(2):205–15.PubMedGoogle Scholar
  41. 41.
    de Graan-Hentzen YC, Gratama JW, Mudde GC, Verdonck LF, Houbiers JG, Brand A, et al. Prevention of primary cytomegalovirus infection in patients with hematologic malignancies by intensive white cell depletion of blood products. Transfusion. 1989;29(9):757–60.PubMedGoogle Scholar
  42. 42.
    Stanier P, Taylor DL, Kitchen AD, Wales N, Tryhorn Y, Tyms AS. Persistence of cytomegalovirus in mononuclear cells in peripheral blood from blood donors. BMJ. 1989;299(6704):897–8.PubMedGoogle Scholar
  43. 43.
    Taylor-Wiedeman J, Sissons JG, Borysiewicz LK, Sinclair JH. Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991;72(Pt 9):2059–64.PubMedGoogle Scholar
  44. 44.
    Mendelson M, Monard S, Sissons P, Sinclair J. Detection of endogenous human cytomegalovirus in CD34+ bone marrow progenitors. J Gen Virol. 1996;77(Pt 12):3099–102.PubMedGoogle Scholar
  45. 45.
    Slobedman B, Mocarski ES. Quantitative analysis of latent human cytomegalovirus. J Virol. 1999;73(6):4806–12.PubMedGoogle Scholar
  46. 46.
    Bolovan-Fritts CA, Mocarski ES, Wiedeman JA. Peripheral blood CD14(+) cells from healthy subjects carry a circular conformation of latent cytomegalovirus genome. Blood. 1999;93(1):394–8.PubMedGoogle Scholar
  47. 47.
    Jarvis MA, Fish KN, Soderberg-Naucler C, Streblow DN, Meyers HL, Thomas G, et al. Retrieval of human cytomegalovirus glycoprotein B from cell surface is not required for virus envelopment in astrocytoma cells. J Virol. 2002;76(10):5147–55.PubMedGoogle Scholar
  48. 48.
    Iwasaki A, Medzhitov R. Regulation of adaptive immunity by the innate immune system. Science. 2010;327(5963):291–5. doi:327/5963/291.PubMedGoogle Scholar
  49. 49.
    Kumagai Y, Akira S. Identification and functions of pattern-recognition receptors. J Allergy Clin Immunol. 2010;125(5):985–92. doi:10.1016/j.jaci.2010.01.058.PubMedGoogle Scholar
  50. 50.
    Hirano M, Das S, Guo P, Cooper MD. The evolution of adaptive immunity in vertebrates. Adv Immunol. 2011;109:125–57. doi:10.1016/B978-0-12-387664-5.00004-2.PubMedGoogle Scholar
  51. 51.
    Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35(2):161–8. doi:10.1016/j.immuni.2011.07.010.PubMedGoogle Scholar
  52. 52.
    Sheridan BS, Lefrancois L. Regional and mucosal memory T cells. Nat Immunol. 2011;12(6):485–91.PubMedGoogle Scholar
  53. 53.
    Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011;11(12):823–36. doi:10.1038/nri3084.PubMedGoogle Scholar
  54. 54.
    Kushwah R, Hu J. Complexity of dendritic cell subsets and their function in the host immune system. Immunology. 2011;133(4):409–19. doi:10.1111/j.1365-2567.2011.03457.x.PubMedGoogle Scholar
  55. 55.
    Nace G, Evankovich J, Eid R, Tsung A. Dendritic cells and damage-associated molecular patterns: endogenous danger signals linking innate and adaptive immunity. J Innate Immun. 2012;4(1):6–15. doi:10.1159/000334245.PubMedGoogle Scholar
  56. 56.
    Rocha N, Neefjes J. MHC class II molecules on the move for successful antigen presentation. EMBO J. 2008;27(1):1–5. doi:10.1038/sj.emboj.7601945.PubMedGoogle Scholar
  57. 57.
    Chapman DC, Williams DB. ER quality control in the biogenesis of MHC class I molecules. Semin Cell Dev Biol. 2010;21(5):512–9. doi:10.1016/j.semcdb.2009.12.013.PubMedGoogle Scholar
  58. 58.
    Kurts C, Robinson BW, Knolle PA. Cross-priming in health and disease. Nat Rev Immunol. 2010;10(6):403–14. doi:10.1038/nri2780.PubMedGoogle Scholar
  59. 59.
    Kracker S, Durandy A. Insights into the B cell specific process of immunoglobulin class switch recombination. Immunol Lett. 2011;138(2):97–103. doi:10.1016/j.imlet.2011.02.004.PubMedGoogle Scholar
  60. 60.
    Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL. Viral subversion of the immune system. Annu Rev Immunol. 2000;18:861–926. doi:10.1146/annurev.immunol.18.1.861.PubMedGoogle Scholar
  61. 61.
    Barnes PD, Grundy JE. Down-regulation of the class I HLA heterodimer and beta 2-microglobulin on the surface of cells infected with cytomegalovirus. J Gen Virol. 1992;73(Pt 9):2395–403.PubMedGoogle Scholar
  62. 62.
    Beersma MF, Bijlmakers MJ, Ploegh HL. Human cytomegalovirus down-regulates HLA class I expression by reducing the stability of class I H chains. J Immunol. 1993;151(9):4455–64.PubMedGoogle Scholar
  63. 63.
    del Val M, Hengel H, Hacker H, Hartlaub U, Ruppert T, Lucin P, et al. Cytomegalovirus prevents antigen presentation by blocking the transport of peptide-loaded major histocompatibility complex class I molecules into the medial-Golgi compartment. J Exp Med. 1992;176(3):729–38.PubMedGoogle Scholar
  64. 64.
    Gilbert MJ, Riddell SR, Li CR, Greenberg PD. Selective interference with class I major histocompatibility complex presentation of the major immediate-early protein following infection with human cytomegalovirus. J Virol. 1993;67(6):3461–9.PubMedGoogle Scholar
  65. 65.
    Yamashita Y, Shimokata K, Mizuno S, Yamaguchi H, Nishiyama Y. Down-regulation of the surface expression of class I MHC antigens by human cytomegalovirus. Virology. 1993;193(2):727–36. doi:10.1006/viro.1993.1181.PubMedGoogle Scholar
  66. 66.
    Jones TR, Hanson LK, Sun L, Slater JS, Stenberg RM, Campbell AE. Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains. J Virol. 1995;69(8):4830–41.PubMedGoogle Scholar
  67. 67.
    Ahn K, Angulo A, Ghazal P, Peterson PA, Yang Y, Fruh K. Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc Natl Acad Sci USA. 1996;93(20):10990–5.PubMedGoogle Scholar
  68. 68.
    Jones TR, Wiertz EJ, Sun L, Fish KN, Nelson JA, Ploegh HL. Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sci USA. 1996;93(21):11327–33.PubMedGoogle Scholar
  69. 69.
    Lee S, Park B, Ahn K. Determinant for endoplasmic reticulum retention in the luminal domain of the human cytomegalovirus US3 glycoprotein. J Virol. 2003;77(3):2147–56.PubMedGoogle Scholar
  70. 70.
    Zhao Y, Biegalke BJ. Functional analysis of the human cytomegalovirus immune evasion protein, pUS3 (22 kDa). Virology. 2003;315(2):353–61.PubMedGoogle Scholar
  71. 71.
    Park B, Kim Y, Shin J, Lee S, Cho K, Fruh K, et al. Human cytomegalovirus inhibits tapasin-dependent peptide loading and optimization of the MHC class I peptide cargo for immune evasion. Immunity. 2004;20(1):71–85.PubMedGoogle Scholar
  72. 72.
    Jun Y, Kim E, Jin M, Sung HC, Han H, Geraghty DE, et al. Human cytomegalovirus gene products US3 and US6 down-regulate trophoblast class I MHC molecules. J Immunol. 2000;164(2):805–11.PubMedGoogle Scholar
  73. 73.
    Noriega VM, Tortorella D. Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules. J Virol. 2009;83(3):1359–67. doi:10.1128/JVI.01324-08.PubMedGoogle Scholar
  74. 74.
    Hegde NR, Tomazin RA, Wisner TW, Dunn C, Boname JM, Lewinsohn DM, et al. Inhibition of HLA-DR assembly, transport, and loading by human cytomegalovirus glycoprotein US3: a novel mechanism for evading major histocompatibility complex class II antigen presentation. J Virol. 2002;76(21):10929–41.PubMedGoogle Scholar
  75. 75.
    Jones TR, Sun L. Human cytomegalovirus US2 destabilizes major histocompatibility complex class I heavy chains. J Virol. 1997;71(4):2970–9.PubMedGoogle Scholar
  76. 76.
    Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell. 1996;84(5):769–79.PubMedGoogle Scholar
  77. 77.
    Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature. 1996;384(6608):432–8. doi:10.1038/384432a0.PubMedGoogle Scholar
  78. 78.
    Smith MH, Ploegh HL, Weissman JS. Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science. 2011;334(6059):1086–90. doi:10.1126/science.1209235.PubMedGoogle Scholar
  79. 79.
    Lilley BN, Tortorella D, Ploegh HL. Dislocation of a type I membrane protein requires interactions between membrane-spanning segments within the lipid bilayer. Mol Biol Cell. 2003;14(9):3690–8. doi:10.1091/mbc.E03-03-0192.PubMedGoogle Scholar
  80. 80.
    Noriega VM, Tortorella D. A bipartite trigger for dislocation directs the proteasomal degradation of an endoplasmic reticulum membrane glycoprotein. J Biol Chem. 2008;283(7):4031–43. doi:10.1074/jbc.M706283200.PubMedGoogle Scholar
  81. 81.
    Oresic K, Noriega V, Andrews L, Tortorella D. A structural determinant of human cytomegalovirus US2 dictates the down-regulation of class I major histocompatibility molecules. J Biol Chem. 2006;281(28):19395–406. doi:10.1074/jbc.M601026200.PubMedGoogle Scholar
  82. 82.
    Rehm A, Engelsberg A, Tortorella D, Korner IJ, Lehmann I, Ploegh HL, et al. Human cytomegalovirus gene products US2 and US11 differ in their ability to attack major histocompatibility class I heavy chains in dendritic cells. J Virol. 2002;76(10):5043–50.PubMedGoogle Scholar
  83. 83.
    Tomazin R, Boname J, Hegde NR, Lewinsohn DM, Altschuler Y, Jones TR, et al. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat Med. 1999;5(9):1039–43. doi:10.1038/12478.PubMedGoogle Scholar
  84. 84.
    Barel MT, Ressing M, Pizzato N, van Leeuwen D, Le Bouteiller P, Lenfant F, et al. Human cytomegalovirus-encoded US2 differentially affects surface expression of MHC class I locus products and targets membrane-bound, but not soluble HLA-G1 for degradation. J Immunol. 2003;171(12):6757–65.PubMedGoogle Scholar
  85. 85.
    Gewurz BE, Wang EW, Tortorella D, Schust DJ, Ploegh HL. Human cytomegalovirus US2 endoplasmic reticulum-lumenal domain dictates association with major histocompatibility complex class I in a locus-specific manner. J Virol. 2001;75(11):5197–204. doi:10.1128/JVI.75.11.5197-5204.2001.PubMedGoogle Scholar
  86. 86.
    Barel MT, Pizzato N, van Leeuwen D, Bouteiller PL, Wiertz EJ, Lenfant F. Amino acid composition of alpha1/alpha2 domains and cytoplasmic tail of MHC class I molecules determine their susceptibility to human cytomegalovirus US11-mediated down-regulation. Eur J Immunol. 2003;33(6):1707–16. doi:10.1002/eji.200323912.PubMedGoogle Scholar
  87. 87.
    Oresic K, Tortorella D. Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules. J Gen Virol. 2008;89(Pt 5):1122–30. doi:10.1099/vir.0.83516-0.PubMedGoogle Scholar
  88. 88.
    Gewurz BE, Gaudet R, Tortorella D, Wang EW, Ploegh HL, Wiley DC. Antigen presentation subverted: structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc Natl Acad Sci USA. 2001;98(12):6794–9. doi:10.1073/pnas.121172898.PubMedGoogle Scholar
  89. 89.
    Story CM, Furman MH, Ploegh HL. The cytosolic tail of class I MHC heavy chain is required for its dislocation by the human cytomegalovirus US2 and US11 gene products. Proc Natl Acad Sci USA. 1999;96(15):8516–21.PubMedGoogle Scholar
  90. 90.
    Schust DJ, Tortorella D, Seebach J, Phan C, Ploegh HL. Trophoblast class I major histocompatibility complex (MHC) products are resistant to rapid degradation imposed by the human cytomegalovirus (HCMV) gene products US2 and US11. J Exp Med. 1998;188(3):497–503.PubMedGoogle Scholar
  91. 91.
    Besold K, Frankenberg N, Pepperl-Klindworth S, Kuball J, Theobald M, Hahn G, et al. Processing and MHC class I presentation of human cytomegalovirus pp 65-derived peptides persist despite gpUS2-11-mediated immune evasion. J Gen Virol. 2007;88(Pt 5):1429–39. doi:10.1099/vir.0.82686-0.PubMedGoogle Scholar
  92. 92.
    Besold K, Wills M, Plachter B. Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD8 T cell recognition. Virology. 2009;391(1):5–19. doi:10.1016/j.virol.2009.06.004.PubMedGoogle Scholar
  93. 93.
    Vembar SS, Brodsky JL. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol. 2008;9(12):944–57. doi:10.1038/nrm2546.PubMedGoogle Scholar
  94. 94.
    Hegde NR, Chevalier MS, Wisner TW, Denton MC, Shire K, Frappier L, et al. The role of BiP in endoplasmic reticulum-associated degradation of major histocompatibility complex class I heavy chain induced by cytomegalovirus proteins. J Biol Chem. 2006;281(30):20910–9. doi:10.1074/jbc.M602989200.PubMedGoogle Scholar
  95. 95.
    Lilley BN, Ploegh HL. A membrane protein required for dislocation of misfolded proteins from the ER. Nature. 2004;429(6994):834–40. doi:10.1038/nature02592.PubMedGoogle Scholar
  96. 96.
    Mueller B, Klemm EJ, Spooner E, Claessen JH, Ploegh HL. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc Natl Acad Sci USA. 2008;105(34):12325–30. doi:10.1073/pnas.0805371105.PubMedGoogle Scholar
  97. 97.
    Mueller B, Lilley BN, Ploegh HL. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J Cell Biol. 2006;175(2):261–70. doi:10.1083/jcb.200605196.PubMedGoogle Scholar
  98. 98.
    Ye Y, Meyer HH, Rapoport TA. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature. 2001;414(6864):652–6. doi:10.1038/414652a.PubMedGoogle Scholar
  99. 99.
    Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature. 2004;429(6994):841–7. doi:10.1038/nature02656.PubMedGoogle Scholar
  100. 100.
    Loureiro J, Lilley BN, Spooner E, Noriega V, Tortorella D, Ploegh HL. Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature. 2006;441(7095):894–7. doi:10.1038/nature04830.PubMedGoogle Scholar
  101. 101.
    Soetandyo N, Ye Y. The p97 ATPase dislocates MHC class I heavy chain in US2-expressing cells via a Ufd1-Npl4-independent mechanism. J Biol Chem. 2010;285(42):32352–9. doi:10.1074/jbc.M110.131649.PubMedGoogle Scholar
  102. 102.
    Furman MH, Dey N, Tortorella D, Ploegh HL. The human cytomegalovirus US10 gene product delays trafficking of major histocompatibility complex class I molecules. J Virol. 2002;76(22):11753–6.PubMedGoogle Scholar
  103. 103.
    Park B, Spooner E, Houser BL, Strominger JL, Ploegh HL. The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation. J Exp Med. 2010;207(9):2033–41. doi:10.1084/jem.20091793.PubMedGoogle Scholar
  104. 104.
    Lehner PJ, Karttunen JT, Wilkinson GW, Cresswell P. The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci USA. 1997;94(13):6904–9.PubMedGoogle Scholar
  105. 105.
    Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ, Ploegh HL, et al. The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity. 1997;6(5):613–21.PubMedGoogle Scholar
  106. 106.
    Dugan GE, Hewitt EW. Structural and functional dissection of the human cytomegalovirus immune evasion protein US6. J Virol. 2008;82(7):3271–82. doi:10.1128/JVI.01705-07.PubMedGoogle Scholar
  107. 107.
    Hewitt EW, Gupta SS, Lehner PJ. The human cytomegalovirus gene product US6 inhibits ATP binding by TAP. EMBO J. 2001;20(3):387–96. doi:10.1093/emboj/20.3.387.PubMedGoogle Scholar
  108. 108.
    Kyritsis C, Gorbulev S, Hutschenreiter S, Pawlitschko K, Abele R, Tampe R. Molecular mechanism and structural aspects of transporter associated with antigen processing inhibition by the cytomegalovirus protein US6. J Biol Chem. 2001;276(51):48031–9. doi:10.1074/jbc.M108528200.PubMedGoogle Scholar
  109. 109.
    Kim Y, Park B, Cho S, Shin J, Cho K, Jun Y, et al. Human cytomegalovirus UL18 utilizes US6 for evading the NK and T-cell responses. PLoS Pathog. 2008;4(8):e1000123. doi:10.1371/journal.ppat.1000123.PubMedGoogle Scholar
  110. 110.
    Park B, Oh H, Lee S, Song Y, Shin J, Sung YC, et al. The MHC class I homolog of human cytomegalovirus is resistant to down-regulation mediated by the unique short region protein (US)2, US3, US6, and US11 gene products. J Immunol. 2002;168(7):3464–9.PubMedGoogle Scholar
  111. 111.
    Kim S, Lee S, Shin J, Kim Y, Evnouchidou I, Kim D, et al. Human cytomegalovirus microRNA miR-US4-1 inhibits CD8(+) T cell responses by targeting the aminopeptidase ERAP1. Nat Immunol. 2011;12(10):984–91. doi:10.1038/ni.2097.PubMedGoogle Scholar
  112. 112.
    Saric T, Chang SC, Hattori A, York IA, Markant S, Rock KL, et al. An IFN-gamma-induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat Immunol. 2002;3(12):1169–76. doi:10.1038/ni859.PubMedGoogle Scholar
  113. 113.
    Gilbert MJ, Riddell SR, Plachter B, Greenberg PD. Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature. 1996;383(6602):720–2. doi:10.1038/383720a0.PubMedGoogle Scholar
  114. 114.
    Trgovcich J, Cebulla C, Zimmerman P, Sedmak DD. Human cytomegalovirus protein pp 71 disrupts major histocompatibility complex class I cell surface expression. J Virol. 2006;80(2):951–63. doi:10.1128/JVI.80.2.951-963.2006.PubMedGoogle Scholar
  115. 115.
    Gallina A, Simoncini L, Garbelli S, Percivalle E, Pedrali-Noy G, Lee KS, et al. Polo-like kinase 1 as a target for human cytomegalovirus pp 65 lower matrix protein. J Virol. 1999;73(2):1468–78.PubMedGoogle Scholar
  116. 116.
    Browne EP, Shenk T. Human cytomegalovirus UL83-coded pp 65 virion protein inhibits antiviral gene expression in infected cells. Proc Natl Acad Sci USA. 2003;100(20):11439–44. doi:10.1073/pnas.1534570100.PubMedGoogle Scholar
  117. 117.
    Odeberg J, Plachter B, Branden L, Soderberg-Naucler C. Human cytomegalovirus protein pp 65 mediates accumulation of HLA-DR in lysosomes and destruction of the HLA-DR alpha-chain. Blood. 2003;101(12):4870–7. doi:10.1182/blood-2002-05-1504.PubMedGoogle Scholar
  118. 118.
    Khan N, Bruton R, Taylor GS, Cobbold M, Jones TR, Rickinson AB, et al. Identification of cytomegalovirus-specific cytotoxic T lymphocytes in vitro is greatly enhanced by the use of recombinant virus lacking the US2 to US11 region or modified vaccinia virus Ankara expressing individual viral genes. J Virol. 2005;79(5):2869–79. doi:10.1128/JVI.79.5.2869-2879.2005.PubMedGoogle Scholar
  119. 119.
    Hansen SG, Powers CJ, Richards R, Ventura AB, Ford JC, Siess D, et al. Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science. 2010;328(5974):102–6. doi:10.1126/science.1185350.PubMedGoogle Scholar
  120. 120.
    Lemmermann NA, Bohm V, Holtappels R, Reddehase MJ. In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: facts and thoughts based on murine models. Virus Res. 2011;157(2):161–74. doi:10.1016/j.virusres.2010.09.022.PubMedGoogle Scholar
  121. 121.
    Beck S, Barrell BG. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature. 1988;331(6153):269–72. doi:10.1038/331269a0.PubMedGoogle Scholar
  122. 122.
    Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L, et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity. 1997;7(2):273–82.PubMedGoogle Scholar
  123. 123.
    Kubin M, Cassiano L, Chalupny J, Chin W, Cosman D, Fanslow W, et al. ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Eur J Immunol. 2001;31(5):1428–37. doi:10.1002/1521-4141(200105)31:5<1428:AID-IMMU1428>3.0.CO;2-4.PubMedGoogle Scholar
  124. 124.
    Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, et al. Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. Eur J Immunol. 2003;33(1):194–203. doi:10.1002/immu.200390022.PubMedGoogle Scholar
  125. 125.
    Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med. 1998;187(5):813–8.PubMedGoogle Scholar
  126. 126.
    Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature. 1998;391(6669):795–9. doi:10.1038/35869.PubMedGoogle Scholar
  127. 127.
    Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, et al. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci USA. 1998;95(9):5199–204.PubMedGoogle Scholar
  128. 128.
    Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9(5):495–502. doi:10.1038/ni1581.PubMedGoogle Scholar
  129. 129.
    Orange JS, Fassett MS, Koopman LA, Boyson JE, Strominger JL. Viral evasion of natural killer cells. Nat Immunol. 2002;3(11):1006–12. doi:10.1038/ni1102-1006.PubMedGoogle Scholar
  130. 130.
    Wilkinson GW, Tomasec P, Stanton RJ, Armstrong M, Prod’homme V, Aicheler R, et al. Modulation of natural killer cells by human cytomegalovirus. J Clin Virol. 2008;41(3):206–12. doi:10.1016/j.jcv.2007.10.027.PubMedGoogle Scholar
  131. 131.
    Chang WL, Baumgarth N, Yu D, Barry PA. Human cytomegalovirus-encoded interleukin-10 homolog inhibits maturation of dendritic cells and alters their functionality. J Virol. 2004;78(16):8720–31. doi:10.1128/JVI.78.16.8720-8731.2004.PubMedGoogle Scholar
  132. 132.
    Jenkins C, Abendroth A, Slobedman B. A novel viral transcript with homology to human interleukin-10 is expressed during latent human cytomegalovirus infection. J Virol. 2004;78(3):1440–7.PubMedGoogle Scholar
  133. 133.
    Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA. 2000;97(4):1695–700.PubMedGoogle Scholar
  134. 134.
    Raftery MJ, Wieland D, Gronewald S, Kraus AA, Giese T, Schonrich G. Shaping phenotype, function, and survival of dendritic cells by cytomegalovirus-encoded IL-10. J Immunol. 2004;173(5):3383–91.PubMedGoogle Scholar
  135. 135.
    Spencer JV, Lockridge KM, Barry PA, Lin G, Tsang M, Penfold ME, et al. Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10. J Virol. 2002;76(3):1285–92.PubMedGoogle Scholar
  136. 136.
    Slobedman B, Mocarski ES, Arvin AM, Mellins ED, Abendroth A. Latent cytomegalovirus down-regulates major histocompatibility complex class II expression on myeloid progenitors. Blood. 2002;100(8):2867–73. doi:10.1182/blood.V100.8.2867.PubMedGoogle Scholar
  137. 137.
    Cheung AK, Gottlieb DJ, Plachter B, Pepperl-Klindworth S, Avdic S, Cunningham AL, et al. The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency. Blood. 2009;114(19):4128–37. doi:10.1182/blood-2008-12-197111.PubMedGoogle Scholar
  138. 138.
    Gredmark S, Soderberg-Naucler C. Human cytomegalovirus inhibits differentiation of monocytes into dendritic cells with the consequence of depressed immunological functions. J Virol. 2003;77(20):10943–56.PubMedGoogle Scholar
  139. 139.
    Rolle A, Olweus J. Dendritic cells in cytomegalovirus infection: viral evasion and host countermeasures. APMIS. 2009;117(5–6):413–26. doi:10.1111/j.1600-0463.2009.02449.x.PubMedGoogle Scholar
  140. 140.
    Carlier J, Martin H, Mariame B, Rauwel B, Mengelle C, Weclawiak H, et al. Paracrine inhibition of GM-CSF signaling by human cytomegalovirus in monocytes differentiating to dendritic cells. Blood. 2011;118(26):6783–92. doi:10.1182/blood-2011-02-337956.PubMedGoogle Scholar
  141. 141.
    Frascaroli G, Varani S, Mastroianni A, Britton S, Gibellini D, Rossini G, et al. Dendritic cell function in cytomegalovirus-infected patients with mononucleosis. J Leukoc Biol. 2006;79(5):932–40. doi:10.1189/jlb.0905499.PubMedGoogle Scholar
  142. 142.
    Kvale EO, Dalgaard J, Lund-Johansen F, Rollag H, Farkas L, Midtvedt K, et al. CD11c+ dendritic cells and plasmacytoid DCs are activated by human cytomegalovirus and retain efficient T cell-stimulatory capability upon infection. Blood. 2006;107(5):2022–9. doi:10.1182/blood-2005-05-2016.PubMedGoogle Scholar
  143. 143.
    Reeves MB, Compton T. Inhibition of inflammatory interleukin-6 activity via extracellular signal-regulated kinase-mitogen-activated protein kinase signaling antagonizes human cytomegalovirus reactivation from dendritic cells. J Virol. 2011;85(23):12750–8. doi:10.1128/JVI.05878-11.PubMedGoogle Scholar
  144. 144.
    Shamu CE, Flierman D, Ploegh HL, Rapoport TA, Chau V. Polyubiquitination is required for US11-dependent movement of MHC class I heavy chain from endoplasmic reticulum into cytosol. Mol Biol Cell. 2001;12(8):2546–55.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Vanessa Noriega
    • 1
  • Veronika Redmann
    • 1
  • Thomas Gardner
    • 1
  • Domenico Tortorella
    • 1
  1. 1.Department of MicrobiologyMount Sinai School of MedicineNew YorkUSA

Personalised recommendations