Abstract
Cytotoxic T cells are major players in the immune defence against human cytomegalovirus (HCMV). The virus has, however, developed several mechanisms to escape from this control. In particular, it down-regulates cell surface expression of HLA class I molecules. Because natural killer (NK) cells recognize and eliminate cells that lack HLA class I molecules. HCMV-infected cells could be more susceptible to NK lysis. In this review, we discuss the role played by NK cells in immune defence against HCMV and we describe potential strategies the virus has developed to escape from NK cell-mediated lysis. We focus in particular on a newly described protein, HCMV gpUL40, that induces cell surface expression of HLA-E, a non-classical class I molecule known to regulate NK cell functions.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Ahn K, Angulo A, Ghazal P, Peterson PA, Yang Y, Fruh K (1996) Human cytomegalovirus inhibits antigen presentation by a sequential multistep process. Proc Natl Acad Sei USA 93:10990–10995
Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ, Ploegh HL, Peterson PA, Yang R, Fruh K (1997) The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6:613–621
Allan DS, Colonna M, Lanier LL, Churakova TD. Abrams JS, Ellis SA, McMichael AJ. Braud VM (1999) Tetrameric complexes of human histocompatibility leukocyte antigen (HLA)-G bind to peripheral blood myelomonocytic cells. J Exp Med 189:1149–1156
Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999) Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–729
Beck S, Barreil BG (1988) Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature 331:269–272
Benedict CA, Butrovich KD, Lurain NS, Corbeil J, Rooney I, Schneider P, Tschopp J, Ware CF (1999) Cutting edge: a novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus. J Immunol 162:6967–6970
Biron CA, Byron KS, Sullivan JL (1989) Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med 320:1731–1735
Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviraldefense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220
Borges L, Fanger N, Cosman D (1999) Interactions of LIRs, a family of immunoreceptors expressed in myeloid and lymphoid cells, with viral and cellular MHC class I antigens. Curr Top Microbiol Immunol 244:123–136
Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG (1998) 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 187:813–818
Borysiewicz LK, Rodgers B, Morris S, Graham S, Sissons JG (1985) Lysis of human cytomegalovirus infected fibroblasts by natural killer cells: demonstration of an interferon-independent component requiring expression of early viral proteins and characterization of effector cells. J Immunol 134: 2695–2701
Braud V, Jones EY, McMichael A (1997) The human major histocompatibility complex class lb molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur J Immunol 27:1164–1169
Braud VM, Allan DSJ, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS, Lazetic S, Young.NT, Bell JI, Philips JH, Lanier LL, McMichael AJ (1998) HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795–799
Braud VM, Allan DSJ, Wilson D, McMichael AJ (1998) TAP and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr Biol 8:1–10
Braud VM, McMichael AJ (1999) Regulation of NK cell functions through interaction of the CD94/ NKG2 receptors with the nonclassical class I molecule HLA-E. Curr Top Microbiol Immunol 244:85–95
Brown MG, Dokun AO, Heusel JW, Smith HR, Beckman DL, Blattenberger EA, Dubbelde CE, Stone LR, Scalzo A A, Yokoyama WM (2001) Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292:934–937
Browne H, Smith G, Beck S, Minson T (1990) A complex between the MHC class I homologue encoded by human cytomegalovirus and beta 2 microglobulin. Nature 347:770–772
Bukowski JF, Warner JF, Dennert G, Welsh RM (1985) Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J Exp Med 161:40–52
Bukowski JF, Woda BA, Welsh RM (1984) Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol 52:119–128
Cerboni C, Mousavi-Jazi M, Linde A, Soderstrom K, Brytting M, Wahren B, Karre K, Carbone E (2000) Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts. J Immunol 164:4775–4782
Chapman TL, Bjorkman PJ (1998) Characterization of a murine cytomegalovirus class I major histocompatibility complex (MHC) homolog: comparison to MHC molecules and to the human cytomegalovirus MHC homolog. J Virol 72:460–466
Chapman TL, Heikeman AP, Bjorkman PJ (1999) The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11:603–613
Colonna M, Navarro F, Bellon T, Llano M, Garcia P, Samaridis J, Angman L, Cella M, Lopez-Botet M (1997) A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 186:1809–1818
Colonna M, Navarro F, Lopez-Botet M (1999) A novel family of inhibitory receptors for HLA class I molecules that modulate function of lymphoid and myeloid cells. Curr Top Microbiol Immunol 244:115–122
Cosman D, Fanger N, Borges L, Kubin M, Chin W, Peterson L, Hsu ML (1997) A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7:273–282
Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001) ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14:123–133
Cretney E, Degli-Espoti MA, Densley EH, Farell HE, Davis-Poynter NJ, Smyth MJ (1999) ml44, a murine cytomegalovirus (MCMV)-encoded major histocompatibility complex class I homologue, confers tumor resistance to natural killer cell-mediated rejection. J Exp Med 190:435–443
Daniels KA, Devora G, Lai WC, O’Donnell CL, Bennett M, Welsh RM (2001) Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J Exp Med 194:29–44
Fahnestock ML, Johnson JL, Feldman RM, Neveu JM, Lane WS, Bjorkman PJ (1995) The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides. Immunity 3:583–590
Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L (1998) The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Eur J Immunol 28:3423–3434
Farrell HE, Vally H, Lynch DM, Fleming P, Shellam GR, Scalzo AA, Davis-Poynter NJ (1997) Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 386: 510–514
Fish KN, Stenglein SG, Ibanez C, Nelson JA (1995) Cytomegalovirus persistence in macrophages and endothelial cells. Scand J Infect Dis Suppl 99:34–40
Fletcher JM, Prentice HG, Grundy JE (1998) Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA. J Immunol 161:2365–2374
Furman MH, Ploegh HL, Schust DJ (2000) Can viruses help us to understand and classify the MHC class I molecules at the maternal-fetal interface? Hum Immunol 61:1169–1176
Gilbert MJ, Riddell SR, Li CR, Greenberg PD (1993) Selective interference with class I major histocompatibility complex presentation of the major immediate-early protein following infection with human cytomegalovirus. J Virol 67:3461–3469
Gilbert MJ, Riddell SR, Plachter B, Greenberg PD (1996) Cytomegalovirus selectively blocks antigen processing and presentation of its immediate-early gene product. Nature 383:720–722
Goldmacher VS, Bartie LM, Skaletskaya A, Dionne CA, Kedersha NL, Vatar CA, Han J, Lutz RJ, Watanabe S, McFarland ED, Kieff ED, Mocarski ES, Chittenden T (1999) A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2. Proc Natl Acad Sei USA 96:12536–12541
Hassan-Walker AF, Cope AV, Griffiths PD, Emery VC (1998) Transcription of the human cytomegalovirus natural killer decoy gene. UL18, in vitro and in vivo. J Gen Virol 79:2113–2116
Hengel H, Esslinger C, Pool J, Goulmy E, Koszinowski UH (1995) Cytokines restore MHC class I complex formation and control antigen presentation in human cytomegalovirus-infected cells. J Gen Virol 76, Iss 12:2987–2997
Hengel H, Koopmann JO, Flohr T, Muranyi W, Goulmy E, Hammerling GJ, Koszinowski UH, GJMomburg F (1997) A viral ER-resident glycoprotein inactivates the MHC-encoded peptide transporter. Immunity 6:623–632
Huard B, Fruh K (2000) A role for MHC class I down-regulation in NK cell lysis of herpes virus-infected cells. Eur J Immunol 30:509–515
Jones TR, Wiertz EJ, Sun L, Fish KN, Nelson JA, Ploegh HL (1996) Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sei USA 93:11327–11333
Jun Y, Kim E, Jin M, Sung HC, Han H, Geraghty DE, Ahn K (2000) Human cytomegalovirus gene products US3 and US6 down-regulate trophoblast class I MHC molecules. J Immunol 164:805–811
Karre K (1997) How to recognize a foreign submarine. Immunol Rev 155:5–9
Kubin M, Cassiano L, Chalupny J, Chin W, Cosman D, Fanslow W, Mullberg J, Rousseau AM, Ulrich D, Armitage R (2001) ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Eur J Immunol 31:1428–1437
Lanier LL (1998) NK cell receptors. Annu Rev Immunol 16:359–393
Lee N, Goodlett DR, Ishitani A, Marquardt H, Geraghty DE (1998) HLA-E surface expression depends on binding of TAP-dependent peptides derived from certain HLA class I signal sequences. J Immunol 160:4951–4960
Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94 NKG2A. Proc Natl Acad Sei USA 95:5199–5204
Lee SH, Girard S, Macina D, Busa M, Zafer A, Belouchi A, Gros P, Vidal SM (2001) Susceptibility to mouse cytomegalovirus is associated with deletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nat Genet 28:42–45
Lehner PJ, Karttunen JT, Wilkinson GW, Cresswell P (1997) The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sei USA 94:6904–6909
Lemberg MK, Bland FA, Weihofen A, Braud VM, Martoglio B (2001) Intramembrane proteolysis of signal peptides: an essential step in the generation of HLA-E epitopes. J Immunol (in press)
Leong CC, Chapman TL, Bjorkman PJ, Formankova D, Mocarski ES, Phillips JH, Lanier LL (1998) Modulation of natural killer cell cytotoxicity in human cytomegalovirus infection: the role of endogenous class I major histocompatibility complex and a viral class I homolog [published erratum appears in J Exp Med 1998 Aug 3; 188(3): following 614], J Exp Med 187:1681–1687
Lopez-Botet M, Llano M, Ortega M (2001) Human cytomegalovirus and natural killer-mediated surveillance of HLA class I expression: a paradigm of host-pathogen adaptation. Immunol Rev 181: 193–202
Miller DM, Rahill BM, Boss JM, Lairmore MD, Durbin JE, Waldman JW, Sedmak DD (1998) Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J Exp Med 187:675–683
Miller DM, Zhang Y, Rahill BM, Waldman WJ, Sedmak DD (1999) Human cytomegalovirus inhibits IFN-alpha-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-alpha signal transduction. J Immunol 162:6107–6113
Navarro F, Llano M, Bellon T, Colonna M, Geraghty DE, Lopez-Botet M (1999) The ILT2(LIR1) and CD94/NKG2 A NK ccll receptors respectively recognize HLA-G1 and HLA-E molecules co-expressed on target cells. Eur J Immunol 29:277–283
Plachter B, Sinzger C, Jahn G (1996) Cell types involved in replication and distribution of human cytomegalovirus. Adv Virus Res 46:195–261
Polic B, Hengel H, Krmpotic A. Trgovcich J, Pavic I. Luccaronin P, Jonjic S, Koszinowski UH (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188:1047–1054
Reusser P, Riddell SR, Meyers JD, Greenberg PD (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
Reyburn HT, Mandelboim O, Vales Gomez M, Davis DM, Pazmany L, Strominger JL (1997) The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386: 514–517
Riddell SR, Watanabe KS, Goodrich JM, Li CR, Agha ME, Greenberg PD (1992) Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238–241
Scalzo AA, Fitzgerald NA, Simmons A, La Vista AB, Shellam GR (1990) Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J Exp Med 171:1469–1483
Scalzo AA, Fitzgerald NA, Wallace CR, Gibbons AE, Smart YC, Burton RC, Shellam GR (1992) The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J Immunol 149:581–589
Scalzo AA, Lyons PA, Fitzgerald NA, Forbes CA, Yokoyama WM, Shellam GR (1995) Genetic mapping of Cmvl in the region of mouse chromosome 6 encoding the NK gene complex-associated loci Ly49 and musNKR-Pl. Genomics 27:435–441
Schust DJ, Tortorella D, Seebach J, Phan C, Ploegh HL (1998) Trophoblast class I major histocompatibility complex (MHC) products are resistant to rapid degradation imposed by the human cytomegalovirus (HCMV) gene products US2 and US 11. J Exp Med 188:497–503
Shellam GR, Allan JE, Papadimitriou JM, Bancroft GJ (1981) Increased susceptibility to cytomegalovirus infection in beige mutant mice. Proc Natl Acad Sci USA 78:5104–5108
Sinzger C, Grefte A, Plachter B, Gouw AS, The TH, Jahn G (1995) Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues. J Gen Virol 76:741–750
Soderberg-Naucler C, Fish KN, Nelson JA (1997) Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91:119–126
Sutherland CL, Chalupny NJ, Cosman D (2001) The UL16-binding proteins, a novel family of MHC class I-related ligands for NKG2D, activate natural killer cell functions. Immunol Rev 181:185–192
Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP, Gadola S, Cerundolo V, Borysiewicz LK, McMichael AJ, Wilkinson GW (2000) Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287:1031–1033
Tortorella D, Gewurz BE, Furman MH, Schust DJ, Ploegh HL (2000) Viral subversion of the immune system. Annu Rev Immunol 18:861–926
Ulbrecht M, Martinozzi S, Grzeschik M, Hengel H, Ellwart JW, Pla M, Weiss EH (2000) Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J Immunol 164:5019–5022
Vitale M, Castriconi R, Parolini S, Pende D, Hsu ML, Moretta L, Cosman D, Moretta A (1999) The leukocyte Ig-like receptor (LIR)-l for the cytomegalovirus UL18 protein displays a broad specificity for different HLA class I alleles: analysis of LIR-1 + NK cell clones. Int Immunol 11:29–35
Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (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
Warren AP, Ducroq DH, Lehner PJ, Borysiewicz LK (1994) Human cytomegalovirus-infected cells have unstable assembly of major histocompatibility complex class I complexes and are resistant to lysis by cytotoxic T lymphocytes. J Virol 68:2822–2829
Welsh RM, Brubaker JO, Vargas-Cortes M, O’Donnell CL (1991) Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med 173:1053–1063
Welsh RM, O’Donnell CL, Shultz LD (1994) Antiviral activity of NK 1.1 + natural killer cells in C57BL/ 6 scid mice infected with murine cytomegalovirus. Nat Immun 13:239–245
Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996) The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84:769–779
Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, Rapoport TA, Ploegh HL (1996) Sec61- mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384:432–438
Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, Phillips JH (1999) An activating immunore-ceptor complex formed by NKG2D and DAP10. Science 285:730–732
Zhu H, Cong JP, Shenk T (1997) Use of differential display analysis to assess the effect of human cytomegalovirus infection on the accumulation of cellular RNAs: induction of interferon-responsive RNAs. Proc Natl Acad Sci USA 94:13985–13990
Zhu H, Shen Y, Shenk T (1995) Human cytomegalovirus 1E1 and IE2 proteins block apoptosis. J Virol 69:7960–7970
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Braud, V.M., Tomasec, P., Wilkinson, G.W.G. (2002). Viral Evasion of Natural Killer Cells During Human Cytomegalovirus Infection. In: Koszinowski, U.H., Hengel, H. (eds) Viral Proteins Counteracting Host Defenses. Current Topics in Microbiology and Immunology, vol 269. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-59421-2_8
Download citation
DOI: https://doi.org/10.1007/978-3-642-59421-2_8
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-63974-6
Online ISBN: 978-3-642-59421-2
eBook Packages: Springer Book Archive