Inhibition of the MHC Class II Antigen Presentation Pathway by Human Cytomegalovirus

  • D. C. Johnson
  • N. R. Hegde
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 269)


Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals. Normally, anti-HCMV immune response controls virus replication following reactivation from latency. However, HCMV, like other large herpesviruses, encodes immune evasion proteins that allow the virus to replicate, for a time or in specific tissues, and produce viral progeny in the face of robust host immunity. HCMV glycoproteins US2, US3, US6 and US11 all inhibit different stages of the MHC class I antigen presentation pathway and can reduce recognition by CD8+ T lymphocytes. Here, we discuss two novel inhibitors of the MHC class II antigen presentation pathway, HCMV glycoproteins US2 and US3. Both US2 and US3 can inhibit presentation of exogenous protein antigens to CD4+ T lymphocytes in in vitro assays. US2 causes degradation of MHC class II molecules: HLA-DR-α and HLA-DM-α, as well as class I heavy chain (HC), but does not affect DR-β or DM-β chains. Mutant forms of US2 have been constructed that can bind to DR-α and class I HC but do not cause their degradation, separating the binding step from other processes that precede degradation. We also found evidence that US2-induced degradation of class I and II proteins involves a cellular component, other than Sec61, that is limiting in quantity. Unlike US2, US3 binds newly synthesized class II α/β complexes, reducing the association with the invariant chain (Ii) and causing mislocalization of class II complexes in cells. US3 expression reduces accumulation of class II complexes in peptide-loading compartments and loading of peptides. Since US2 and US3 are expressed solely within HCMV-infected cells, it appears that these viral proteins have evolved to inhibit presentation of endogenous, intracellular viral antigens to anti-HCMV CD4+ T cells. This is different from how the MHC class II pathway is normally viewed, as a pathway for presentation of exogenous, extracellular proteins. The existence of these proteins indicates the importance of class II-mediated presentation of endogenous antigens in signalling virus infection to CD4+ T cells.


Major Histocompatibility Complex Class Human Leukocyte Antigen Class Human Cytomegalovirus Invariant Chain Presentation Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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 Sci USA 93:10990–10995PubMedCrossRefGoogle Scholar
  2. Ahn K, Gruhler A, Galocha B, Jones TR, Wiertz EJ, Ploegh HL, Peterson PA, Yang Y, Fruh K (1997) The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP1. Immunity 6:613–621PubMedCrossRefGoogle Scholar
  3. Alcami A, Koszinowski UH (2000) Viral mechanisms of immune evasion. Trends Microbiol 8:410–8PubMedCrossRefGoogle Scholar
  4. Bonifaz LC, Arzate S, Moreno J (1999) Endogenous and exogenous forms of the same antigen are processed from different pools to bind MHC class II molecules in endocytic compartments. Eur J Immunol 29:119–131PubMedCrossRefGoogle Scholar
  5. Borysiewicz LK, Sissons JG (1994) Cytotoxic T cells and human herpes virus infections. Curr Top Microbiol Immunol 189:123–150PubMedGoogle Scholar
  6. Brack AR, Klupp BG, Granzow H, Tirabassi R, Enquist LW, Mettenleiter TC (2000) Role of the cytoplasmic tail of Pseudorabies virus glycoprotein E in virion formation. J Virol 74:4004–4016PubMedCrossRefGoogle Scholar
  7. Chen MM, Shirai M, Liu Z, Arichi T, Takahashi H, Hishioka M (1998) Efficient class II major histocompatibility complex presentation of endogenously synthesized hepatitis C virus core protein by Epstein-Barr virus-transformed B-lymphoblastoid cell lines to CD4(+) T cells. J Virol 72:8301–8308PubMedGoogle Scholar
  8. Chiang HL, Terlecky SR, Plant CP (1989) A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science 246:382–385PubMedCrossRefGoogle Scholar
  9. Chicz RM, Urban RG, Gorga JC, Vignali DA, Lane WS, Stominger JL (1993) Specificity and promiscuity among naturally processed peptides bound to HLA-DR alleles. J Exp Med 178:27–47PubMedCrossRefGoogle Scholar
  10. Cresswell P (1994) Assembly, transport, and function of MHC class II molecules. Annu Rev Immunol 2:259–293CrossRefGoogle Scholar
  11. Cresswell P (1996) Invariant chain structure and MHC class II function. Cell 84:505–507PubMedCrossRefGoogle Scholar
  12. Cunningham AL, Turner RR, Miller AC, Para MF, Merigan TC (1985) Evolution of recurrent herpes simplex virus lesions: an immunohistologic study. J Clin Invest 75:226–295PubMedCrossRefGoogle Scholar
  13. Denzin LK, Cresswell P (1995) HLA-DM induces CLIP dissociation from MHC class II α/β dimers and facilitates peptide loading. Cell 82:155–165PubMedCrossRefGoogle Scholar
  14. Dusseljee S, Wubbolts R, Verwoerd D, Tulp A, Janssen H, Calafat J, Neefjes J (1998) Removal and degradation of the free MHC class II β chain in the endoplasmic reticulum required proteasomes and is accelerated by BFA. J Cell Sei 111:2217–2226Google Scholar
  15. Fish KN, Soderberg-Naucler C, Nelson JA (1998) Steady-state plasma membrane expression of human cytomegalovirus gB is determined by the phosphorylation of state of ser900. J Virol 72:6657–6664PubMedGoogle Scholar
  16. Fruh K, Gruhler A, Krishna RM, Schoenhals GJ (1999) A comparison of viral immune escape strategies targeting the MHC class I assembly pathway. Immunol Rev 168:157–166PubMedCrossRefGoogle Scholar
  17. Goldsmith K, Chen W, Johnson DC, Hendricks RL (1998) Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response. J Exp Med 187:341–348PubMedCrossRefGoogle Scholar
  18. Gewurz BE, Gaudet R, Tortorella D, Wang EW, Ploegh HL, Wiley DC (2001a) Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc Natl Acad Sci USA 98:6794–6799PubMedCrossRefGoogle Scholar
  19. Gewurz BE, Wang EW, Tortorella D, Schust DJ, Ploegh HL (2001b) Human cytomegalovirus US2 endoplasmic reticulum-lumenal domain dictates association with major histocompatibility complex class I in a locus-specific manner. J Virol 75:5197–5204PubMedCrossRefGoogle Scholar
  20. Gueguen M, Long EO (1996) Presentation of a cytosolic antigen by major histocompatibility complex class II molecules requires a long-lived form of the antigen. Proc Natl Acad Sci USA 93:14692–14697PubMedCrossRefGoogle Scholar
  21. Hengel H, Reusch U, Geginat R, Holtappels R, Ruppert T, Hellebrand E, Koszinowski UH (2000) Macrophages escape inhibition of major histocompatibility complex class I-dependent antigen presentation by cytomegalovirus. J Virol 74:7861–7868PubMedCrossRefGoogle Scholar
  22. Hershberg RM, Framson PE, Cho DH, Lee LY, Kovats S, Beitz J, Blum J, Nepom GT (1997) Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. J Clin Invest 100:204–215PubMedCrossRefGoogle Scholar
  23. Jacobson S, Sekaly RP, Jacobson CL, McFarland HF, Long EO (1989) HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells. J Virol 63:1756–1762PubMedGoogle Scholar
  24. Jaraquemada D, Marti M, Long EO (1990) An endogenous processing pathway in vaccinia virus-infected cells for presentation of cytoplasmic antigens to class II-restricted T cells. J Exp Med 172:947–954PubMedCrossRefGoogle Scholar
  25. Johnson AE, Haigh NG (2000) The ER translocon and retrotranslocation: is the shift into reverse manual or automatic? Cell 102:709–712PubMedCrossRefGoogle Scholar
  26. Johnson DC, McFadden G (2001) Viral immune evasion. In: Kaufmann SHE, Sher A, Ahmed R (eds) Immunology of infectious diseases. American Society for Microbiology (in press)Google Scholar
  27. Jones TR, Hanson LK, Sun L, Slater JS, Stenberg RM Campbell AE (1995) Multiple independent loci within the human cytomegalovirus unique short region down regulate expression of major histocompatibility complex class I heavy chains. J Virol 69:4830–4841PubMedGoogle Scholar
  28. 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 Sci USA 93:11327–11333PubMedCrossRefGoogle Scholar
  29. Lich JD, Elliott JF, Blum JS (2000) Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. J Exp Med 191:1513–1524PubMedCrossRefGoogle Scholar
  30. Loss GE Jr, Elias CG, Fields PE, Ribaudo RK, McKisic M, Sant A (1993) Major histocompatibility complex class II-restricted presentation of an internally synthesized antigen displays cell-type variability and segregates from the exogenous class II and endogenous class I presentation pathways. J Exp Med 178:73–85PubMedCrossRefGoogle Scholar
  31. Maile R, Elsegood KA, Harding TC, Uney JB, Stewart G, Banting G, Dayan CM (2000) Effective formation of major histocompatibility complex class II-peptide complexes from endogenous antigen by thyroid epithelial cells. Immunology 99:367–374PubMedCrossRefGoogle Scholar
  32. Malnati MS, Marti M, LaVaute T, Jaraquemeda D, Biddison W, DeMars R, Long EO (1992) Processing pathways for presentation of cytosolic antigen to MHC class II restricted T cells. Nature 357:702–704PubMedCrossRefGoogle Scholar
  33. McMillan T, Johnson DC (2001) The cytoplasmic domain of herpes simplex virus gE causes accumulation in the trans-Golgi network, a site of virus envelopment and sorting of virions to cell junctions. J Virol 75:1928–1940PubMedCrossRefGoogle Scholar
  34. Miller DM, Rahill BM, Boss JM, Lairmore MD, Durbin JE, Waldman WJ, Sedman DD (1998) Human cytomegalovirus inhibits major histocompatibility complex class II expression by disruption of the Jak/Stat pathway. J Exp Med 187:675–683PubMedCrossRefGoogle Scholar
  35. Miller DM, Zhang Y, Rahill BM, Waldman WJ, Sedmak DD (1999) Human cytomegalovirus inhibits IFNα-stimulated antiviral and immunoregulatory responses by blocking multiple levels of IFN-α signal transduction. J Immunol 162:6107–6113PubMedGoogle Scholar
  36. Munz C, Bickham KL, Subklewe M, Tsang ML, Chahroude A, Kurilla MG, Zhang D, O’Donnell M, Steinman RM (2000) Human CD4(+) T lymphocytes consistently respond to the latent Epstein-Barr virus nuclear antigen EBNA1. J Exp Med 191:1649–1660PubMedCrossRefGoogle Scholar
  37. Neefjes J (1999) CUV, MIIC and other compartments for MHC class II loading. Eur J Immunol 29:1421–1425PubMedCrossRefGoogle Scholar
  38. Nuchtern JG, Biddison WE, Kalusner RD (1990) Class II MHC molecules can use the endogenous pathway of antigen presentation. Nature 343:74–76PubMedCrossRefGoogle Scholar
  39. Pieters J (2000) MHC class II-restricted antigen processing and presentation. Adv Immunol 75:159–208PubMedCrossRefGoogle Scholar
  40. Riddell SR, Greenberg PD (1995) Principles for adoptive T cell therapy of human viral diseases. Annu Rev Immunol 13:545–586PubMedCrossRefGoogle Scholar
  41. Rudensky A, Preston-Hurlbutt P. Hong SC. Barlow A, Janeway CA Jr (1991) Sequence analysis of peptides bound to MHC class II molecules. Nature 353:622–627PubMedCrossRefGoogle Scholar
  42. Sanchez V, Greis KD, Sztul E, Britt WJ (2000a) Accumulation of virion tegument and envelope proteins in a stable cytoplasmic compartment during human cytomegalovirus replication: characterization of a potential site of virus assembly. J Virol 74:975–986PubMedCrossRefGoogle Scholar
  43. Sanchez V, Sztul E, Britt WJ (2000b) Human cytomegalovirus pp28 (UL99) localizes to a cytoplasmic compartment which overlaps the endoplasmic reticulum-golgi-intermediate compartment. J Virol 74:3842–3851PubMedCrossRefGoogle Scholar
  44. Schmid DS, Rouse BT (1992) The role of T cell immunity in control of herpes simplex virus. Curr Top Microbiol Immunol 179:57–74PubMedGoogle Scholar
  45. Schust D, 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 188:497–503PubMedCrossRefGoogle Scholar
  46. Soderberg-Naucler C, Fish KN, Nelson JA (1998) Growth of human cytomegalovirus in primary macrophages. Methods Enzymol 16:126–138CrossRefGoogle Scholar
  47. Sponaas A, Carstens C, Koch N (1999) C-terminal extension of the MHC class II associated invariant chain by an antigenic sequence triggers activation of naive T cells. Gene Ther 6:1826–1834PubMedCrossRefGoogle Scholar
  48. Tomazin R, Boname J, Hegde NR. Lewinsohn DM, Altshuler Y. Jones TR. Cresswell P, Nelson JA, Riddell SR, Johnson DC (1999) Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition bv CD4+ T cells. Nat Med 5:1039–1043PubMedCrossRefGoogle Scholar
  49. Tooze J, Hollinshead M, Reis B. Radsak K. Kern H (1993) Progeny vaccinia and human cytomegalovirus particles utilize early endosomal cisternae for their envelopes. Eur J Cell Biol 60:163–178PubMedGoogle Scholar
  50. Tortorella D. Gewurz BE, Furman MH, Schust DJ, Ploegh HL (2000) Viral subversion of the immune system. Annu Rev Immunol 18:861–926PubMedCrossRefGoogle Scholar
  51. Tortorella D, Story CM, Huppa JB. Wiertz EJ, Jones TR. Bacik I, Bennink JR. Yewdell JW. Ploegh HL (1998) Dislocation of type I membrane proteins from the ER to the cytosol is sensitive to changes in redox potential. J Cell Biol 142:365–376PubMedCrossRefGoogle Scholar
  52. Villadangos JA, Bryant RA, Deussing J, Driessen C, Lennon-Dumenil AM, Riese RJ. Roth W, Saftig P. Shi GP, Chapman HA, Peters C. Ploegh HL (1999) Proteases involved in MHC class II antigen presentation. Immunol Rev 172:109–120PubMedCrossRefGoogle Scholar
  53. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996a) The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84:769–779PubMedCrossRefGoogle Scholar
  54. Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR. Rapoport TA, Ploegh HL (1996b) Sec61- mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384:432–438PubMedCrossRefGoogle Scholar
  55. Wu TC, Guarnieri FG. Staveley-CTCarroll KF. Viscidi RP, Levitsky HI. Hedrick L. Cho KR. August R. Pardoll DM (1995) Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens. Proc Natl Acad Sci USA 92:11671–11675PubMedCrossRefGoogle Scholar
  56. Yang M, Omura S, Bonifacino JS. Weissman AM (1998) Novel aspects of degradation of T cell receptor subunits from the endoplasmic reticulum (ER) in T cells: importance of oligosaccharide processing, ubiquitination, and proteasome-dependent removal from ER membranes. J Exp Med 187:835–846PubMedCrossRefGoogle Scholar
  57. York I, Roop C, Andrews DW, Riddell SR, Graham FL. Johnson DC (1994) A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8 -r T lymphocytes. Cell 77:525–535CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • D. C. Johnson
    • 1
  • N. R. Hegde
    • 1
  1. 1.Department of Molecular Microbiology and ImmunologyOregon Health & Science UniversityPortlandUSA

Personalised recommendations