Skip to main content

Advertisement

SpringerLink
Log in

UL74 of human cytomegalovirus reduces the inhibitory effect of gH-specific and gB-specific antibodies

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

The human cytomegalovirus (HCMV) glycoproteins gH (UL75) and gL (UL115) can form complexes with gO (UL74) or with proteins of the UL128-UL131A locus. Deletion of gO abolishes cell-free virus transmission and renders cell-associated virus transmission in fibroblasts more sensitive to inhibition by human anti-HCMV serum. To test whether the latter effect is specific for gO, we compared mutants with deletions in UL74, UL99 and the UL128-131A locus regarding their sensitivity to anti-HCMV antibodies. UL74 deletion mutants were more sensitive to a further restriction by polyspecific or gH-specific antibodies than control mutants, showing that gO specifically protects focal growth against inhibitory antibodies. This effect was not confined to gH-specific antibodies, as UL74 deletion mutants were also inhibited by an anti-gB antibody. In conclusion, gO specifically promotes focal spread in the presence of gH and gB antibodies, thus contributing to the ability of HCMV to resist the host’s immune response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Adler B, Scrivano L, Ruzcics Z, Rupp B, Sinzger C, Koszinowski U (2006) Role of human cytomegalovirus UL131A in cell type-specific virus entry and release. J Gen Virol 87:2451–2460

    Article  PubMed  CAS  Google Scholar 

  2. Akahori Y, Suzuki K, Daikoku T, Iwai M, Yoshida Y, Asano Y, Kurosawa Y, Shiraki K (2009) Characterization of neutralizing epitopes of varicella-zoster virus glycoprotein H. J Virol 83:2020–2024

    Article  PubMed  CAS  Google Scholar 

  3. Banks T, Huo B, Kousoulas K, Spaete R, Pachl C, Pereira L (1989) A major neutralizing domain maps within the carboxyl-terminal half of the cleaved cytomegalovirus B glycoprotein. J Gen Virol 70(Pt 4):979–985

    Article  PubMed  CAS  Google Scholar 

  4. Borza CM, Hutt-Fletcher LM (2002) Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 8:594–599

    Article  PubMed  CAS  Google Scholar 

  5. Bowden RA, Slichter SJ, Sayers M, Weisdorf D, Cays M, Schoch G, Banaji M, Haake R, Welk K, Fisher L et al (1995) A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant [see comments]. Blood 86:3598–3603

    PubMed  CAS  Google Scholar 

  6. Britt WJ (1984) Neutralizing antibodies detect a disulfide-linked glycoprotein complex within the envelope of human cytomegalovirus. Virology 135:369–378

    Article  PubMed  CAS  Google Scholar 

  7. Cranage MP, Kouzarides T, Bankier AT, Satchwell S, Weston K, Tomlinson P, Barrell B, Hart H, Bell SE, Minson AC et al (1986) Identification of the human cytomegalovirus glycoprotein B gene and induction of neutralizing antibodies via its expression in recombinant vaccinia virus. EMBO J 5:3057–3063

    PubMed  CAS  Google Scholar 

  8. Cui X, Meza BP, Adler SP, McVoy MA (2008) Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infection. Vaccine 26:5760–5766

    Article  PubMed  CAS  Google Scholar 

  9. Hahn G, Revello MG, Patrone M, Percivalle E, Campanini G, Sarasini A, Wagner M, Gallina A, Milanesi G, Koszinowski U, Baldanti F, Gerna G (2004) Human cytomegalovirus UL131-128 genes are indispensable for virus growth in endothelial cells and virus transfer to leukocytes. J Virol 78:10023–10033

    Article  PubMed  CAS  Google Scholar 

  10. Huber MT, Compton T (1998) The human cytomegalovirus UL74 gene encodes the third component of the glycoprotein H-glycoprotein L-containing envelope complex. J Virol 72:8191–8197

    PubMed  CAS  Google Scholar 

  11. Jiang XJ, Adler B, Sampaio KL, Digel M, Jahn G, Ettischer N, Stierhof YD, Scrivano L, Koszinowski U, Mach M, Sinzger C (2008) UL74 of human cytomegalovirus contributes to virus release by promoting secondary envelopment of virions. J Virol 82:2802–2812

    Article  PubMed  CAS  Google Scholar 

  12. Kinzler ER, Compton T (2005) Characterization of human cytomegalovirus glycoprotein-induced cell-cell fusion. J Virol 79:7827–7837

    Article  PubMed  CAS  Google Scholar 

  13. Lipson SM, Shepp DH, Match ME, Axelrod FB, Whitbread JA (2001) Cytomegalovirus infectivity in whole blood following leukocyte reduction by filtration. Am J Clin Pathol 116:52–55

    Article  PubMed  CAS  Google Scholar 

  14. Macagno A, Bernasconi NL, Vanzetta F, Dander E, Sarasini A, Revello MG, Gerna G, Sallusto F, Lanzavecchia A (2010) Isolation of human monoclonal antibodies that potently neutralize human cytomegalovirus infection by targeting different epitopes on the gH/gL/UL128-131A complex. J Virol 84:1005–1013

    Article  PubMed  CAS  Google Scholar 

  15. Masuho Y, Matsumoto Y, Sugano T, Fujinaga S, Minamishima Y (1987) Human monoclonal antibodies neutralizing human cytomegalovirus. J Gen Virol 68(Pt 5):1457–1461

    Article  PubMed  CAS  Google Scholar 

  16. Paterson DA, Dyer AP, Milne RS, Sevilla-Reyes E, Gompels UA (2002) A role for human cytomegalovirus glycoprotein O (gO) in cell fusion and a new hypervariable locus. Virology 293:281–294

    Article  PubMed  CAS  Google Scholar 

  17. Patrone M, Secchi M, Bonaparte E, Milanesi G, Gallina A (2007) Cytomegalovirus UL131-128 products promote gB conformational transition and gB-gH interaction during entry in endothelial cells. J Virol 81:11479–11488

    Google Scholar 

  18. Qadri I, Navarro D, Paz P, Pereira L (1992) Assembly of conformation-dependent neutralizing domains on glycoprotein B of human cytomegalovirus. J Gen Virol 73(Pt 11):2913–2921

    Article  PubMed  CAS  Google Scholar 

  19. Ryckman BJ, Chase MC, Johnson DC (2010) Human cytomegalovirus TR strain glycoprotein O acts as a chaperone promoting gH/gL incorporation into virions but is not present in virions. J Virol 84:2597–2609

    Article  PubMed  CAS  Google Scholar 

  20. Ryckman BJ, Rainish BL, Chase MC, Borton JA, Nelson JA, Jarvis MA, Johnson DC (2008) Characterization of the human cytomegalovirus gH/gL/UL128-131 complex that mediates entry into epithelial and endothelial cells. J Virol 82:60–70

    Article  PubMed  CAS  Google Scholar 

  21. Schoppel K, Hassfurther E, Britt W, Ohlin M, Borrebaeck CA, Mach M (1996) Antibodies specific for the antigenic domain 1 of glycoprotein B (gpUL55) of human cytomegalovirus bind to different substructures. Virology 216:133–145

    Article  PubMed  CAS  Google Scholar 

  22. Scrivano L, Sinzger C, Nitschko H, Koszinowski UH, Adler B (2011) HCMV spread and cell tropism are determined by distinct virus populations. PLoS Pathog 7:e1001256

    Article  PubMed  CAS  Google Scholar 

  23. Shimamura M, Mach M, Britt WJ (2006) Human cytomegalovirus infection elicits a glycoprotein M (gM)/gN-specific virus-neutralizing antibody response. J Virol 80:4591–4600

    Article  PubMed  CAS  Google Scholar 

  24. Silva MC, Schroer J, Shenk T (2005) Human cytomegalovirus cell-to-cell spread in the absence of an essential assembly protein. Proc Natl Acad Sci USA 102:2081–2086

    Article  PubMed  CAS  Google Scholar 

  25. Silva MC, Yu QC, Enquist L, Shenk T (2003) Human cytomegalovirus UL99-encoded pp28 is required for the cytoplasmic envelopment of tegument-associated capsids. J Virol 77:10594–10605

    Article  PubMed  CAS  Google Scholar 

  26. Simpson JA, Chow JC, Baker J, Avdalovic N, Yuan S, Au D, Co MS, Vasquez M, Britt WJ, Coelingh KL (1993) Neutralizing monoclonal antibodies that distinguish three antigenic sites on human cytomegalovirus glycoprotein H have conformationally distinct binding sites. J Virol 67:489–496

    PubMed  CAS  Google Scholar 

  27. Sinzger C, Hahn G, Digel M, Katona R, Sampaio KL, Messerle M, Hengel H, Koszinowski U, Brune W, Adler B (2008) Cloning and sequencing of a highly productive, endotheliotropic virus strain derived from human cytomegalovirus TB40/E. J Gen Virol 89:359–368

    Article  PubMed  CAS  Google Scholar 

  28. Sinzger C, Knapp J, Plachter B, Schmidt K, Jahn G (1997) Quantification of replication of clinical cytomegalovirus isolates in cultured endothelial cells and fibroblasts by a focus expansion assay. J Virol Methods 63:103–112

    Article  PubMed  CAS  Google Scholar 

  29. Sinzger C, Mangin M, Weinstock C, Topp MS, Hebart H, Einsele H, Jahn G (2007) Effect of serum and CTL on focal growth of human cytomegalovirus. J Clin Virol 38:112–119

    Article  PubMed  CAS  Google Scholar 

  30. Spector SA, Hsia K, Crager M, Pilcher M, Cabral S, Stempien MJ (1999) Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. J Virol 73:7027–7030

    PubMed  CAS  Google Scholar 

  31. Stanton RJ, Baluchova K, Dargan DJ, Cunningham C, Sheehy O, Seirafian S, McSharry BP, Neale ML, Davies JA, Tomasec P, Davison AJ, Wilkinson GW (2010) Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. J Clin Invest 120:3191–3208

    Article  PubMed  CAS  Google Scholar 

  32. Tischer BK, von Einem J, Kaufer B, Osterrieder N (2006) Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. Biotechniques 40:191–197

    Article  PubMed  CAS  Google Scholar 

  33. Tugizov S, Navarro D, Paz P, Wang Y, Qadri I, Pereira L (1994) Function of human cytomegalovirus glycoprotein B: syncytium formation in cells constitutively expressing gB is blocked by virus-neutralizing antibodies. Virology 201:263–276

    Article  PubMed  CAS  Google Scholar 

  34. Urban M, Britt W, Mach M (1992) The dominant linear neutralizing antibody-binding site of glycoprotein gp86 of human cytomegalovirus is strain specific. J Virol 66:1303–1311

    PubMed  CAS  Google Scholar 

  35. Urban M, Klein M, Britt WJ, Hassfurther E, Mach M (1996) Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response. J Gen Virol 77(Pt 7):1537–1547

    Article  PubMed  CAS  Google Scholar 

  36. Utz U, Britt W, Vugler L, Mach M (1989) Identification of a neutralizing epitope on glycoprotein gp58 of human cytomegalovirus. J Virol 63:1995–2001

    PubMed  CAS  Google Scholar 

  37. Wang D, Shenk T (2005) Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci USA 102:18153–18158

    Article  PubMed  CAS  Google Scholar 

  38. Wang D, Yu QC, Schroer J, Murphy E, Shenk T (2007) Human cytomegalovirus uses two distinct pathways to enter retinal pigmented epithelial cells. Proc Natl Acad Sci USA 104:20037–20042

    Article  PubMed  CAS  Google Scholar 

  39. Wille PT, Knoche AJ, Nelson JA, Jarvis MA, Johnson DC (2010) A human cytomegalovirus gO-null mutant fails to incorporate gH/gL into the virion envelope and is unable to enter fibroblasts and epithelial and endothelial cells. J Virol 84:2585–2596

    Article  PubMed  CAS  Google Scholar 

  40. Wirtz N, Schader SI, Holtappels R, Simon CO, Lemmermann NA, Reddehase MJ, Podlech J (2008) Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues. Med Microbiol Immunol 197:151–158

    Article  PubMed  CAS  Google Scholar 

  41. Zanghellini F, Boppana SB, Emery VC, Griffiths PD, Pass RF (1999) Asymptomatic primary cytomegalovirus infection: virologic and immunologic features. J Infect Dis 180:702–707

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft through SPP1130, ‘Infections of the endothelium’ (SI 779/3-3) and MA 929/6. The technical assistance of Dagmar Ripper with electron microscopy is greatly appreciated. Hybridomas 14-4b and 28-4 were a kind gift of W. Britt, Univ. of Alabama. Antibody C23 (Ti23) was a kind gift from Teijin LTD. Japan.

Author information

Authors and Affiliations

  1. Institut für Medizinische Virologie, Universitätsklinikum, Tübingen, Germany

    Xiao Jing Jiang, Kerstin Laib Sampaio, Nicole Ettischer & Gerhard Jahn

  2. Zentrum für Molekularbiologie der Pflanzen Eberhard-Karls-Universität, Tübingen, Germany

    York-Dieter Stierhof

  3. Institut für Klinische und Molekulare Virologie, Universitätsklinikum, Erlangen, Germany

    Barbara Kropff & Michael Mach

  4. Department of Infectious Diseases, Wuhan General Hospital, Wuhan, China

    Xiao Jing Jiang

  5. Institut für Virologie, Universitätsklinikum Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany

    Christian Sinzger

Authors
  1. Xiao Jing Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kerstin Laib Sampaio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicole Ettischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. York-Dieter Stierhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gerhard Jahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Barbara Kropff
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Mach
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christian Sinzger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Sinzger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, X.J., Sampaio, K.L., Ettischer, N. et al. UL74 of human cytomegalovirus reduces the inhibitory effect of gH-specific and gB-specific antibodies. Arch Virol 156, 2145–2155 (2011). https://doi.org/10.1007/s00705-011-1105-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-011-1105-x

Keywords

Search

Navigation