1887

Abstract

Glycoprotein B (gB, gpUL55) is the major antigen for the induction of neutralizing antibodies against human cytomegalovirus (HCMV), making it an attractive molecule for active and passive immunoprophylaxis. The region between aa 552 and 635 of HCMV gB (termed AD-1) has been identified as the immunodominant target for the humoral immune response following natural infection. AD-1 represents a complex domain which requires a minimal continuous sequence of more than 70 aa for antibody binding. Neutralizing as well as non-neutralizing antibodies can bind to AD-1 in a competitive fashion. The fine specificity of AD-1-binding monoclonal antibodies (MAbs) and affinity-purified human polyclonal antibodies was analysed by using recombinant proteins containing single amino acid substitutions spanning the entire AD-1 domain. Our results revealed that all MAbs had individual patterns of binding to the mutant proteins indicating the presence of a considerable number of distinct antibody-binding sites on AD-1. The neutralization capacity of antibodies could not be predicted from their binding pattern to AD-1 mutant proteins. Polyclonal human antibodies purified from different convalescent sera showed identical binding patterns to the mutant proteins suggesting that the combined antibody specificities present in human sera are comparable between individuals. Neutralization capacities of polyclonal human AD-1 antibodies did not exceed 50% indicating that, during natural infection, a considerable proportion of non-neutralizing antibodies are induced and thus might provide an effective mechanism to evade complete virus neutralization.

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1999-08-01
2020-01-23
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References

  1. Adler, S. P., Starr, S. E., Plotkin, S. A., Hempfling, S. H., Buis, J., Manning, M. L. & Best, A. M. ( 1995; ). Immunity induced by primary human cytomegalovirus infection protects against secondary infection among women of childbearing age. Journal of Infectious Diseases 171, 26-32.[CrossRef]
    [Google Scholar]
  2. Bonci, A., Bracci, L., Caudai, C., Lozzi, L., Moschettini, D., Niccolai, N., Scarselli, M., Valensin, P. E. & Neri, P. ( 1993; ). Characterization of immunoreactive octapeptides of human-cytomegalovirus gp58. European Journal of Biochemistry 215, 383-387.[CrossRef]
    [Google Scholar]
  3. Britt, W. J. ( 1984; ). Neutralizing antibodies detect a disulfide-linked glycoprotein complex within the envelope of human cytomegalovirus. Virology 135, 369-378.[CrossRef]
    [Google Scholar]
  4. Britt, W. J. & Vugler, L. G. ( 1989; ). Processing of the gp55–116 envelope glycoprotein complex (gB) of human cytomegalovirus. Journal of Virology 63, 403-410.
    [Google Scholar]
  5. Britt, W. J. & Vugler, L. G. ( 1992; ). Oligomerization of the human cytomegalovirus major envelope glycoprotein complex gB (gp55–116). Journal of Virology 66, 6747-6754.
    [Google Scholar]
  6. Britt, W. J., Vugler, L., Butfiloski, E. J. & Stephens, E. B. ( 1990; ). Cell surface expression of human cytomegalovirus (HCMV) gp55–116 (gB): use of HCMV-recombinant vaccinia virus-infected cells in analysis of the human neutralizing antibody response. Journal of Virology 64, 1079-1085.
    [Google Scholar]
  7. Chou, S. W. & Dennison, K. M. ( 1991; ). Analysis of interstrain variation in cytomegalovirus glycoprotein B sequences encoding neutralization-related epitopes. Journal of Infectious Diseases 163, 1229-1234.[CrossRef]
    [Google Scholar]
  8. Darlington, J., Super, M., Patel, K., Grundy, J. E., Griffiths, P. D. & Emery, V. C. ( 1991; ). Use of the polymerase chain reaction to analyse sequence variation within a major neutralizing epitope of glycoprotein B (gp58) in clinical isolates of human cytomegalovirus. Journal of General Virology 72, 1985-1989.[CrossRef]
    [Google Scholar]
  9. Dimmock, N. J. ( 1984; ). Mechanisms of neutralization of animal viruses. Journal of General Virology 65, 1015-1022.[CrossRef]
    [Google Scholar]
  10. Dimmock, N. J. ( 1993; ). Neutralization of animal viruses. Current Topics in Microbiology and Immunology 183, 1-149.
    [Google Scholar]
  11. Fowler, K. B., Stagno, S., Pass, R. F., Britt, W. J., Boll, T. J. & Alford, C. A. ( 1992; ). The outcome of congenital cytomegalovirus infection in relation to maternal antibody status [see comments]. New England Journal of Medicine 326, 663-667.[CrossRef]
    [Google Scholar]
  12. Gonczol, E., deTaisne, C., Hirka, G., Berencsi, K., Lin, W. C., Paoletti, E. & Plotkin, S. ( 1991; ). High expression of human cytomegalovirus (HCMV)-gB protein in cells infected with a vaccinia-gB recombinant: the importance of the gB protein in HCMV immunity. Vaccine 9, 631-637.[CrossRef]
    [Google Scholar]
  13. Ho, M. (1992). Cytomegalovirus. Biology and Infection, 2nd edn. New York: Plenum.
  14. Jonjic, S., Pavic, I., Polic, B., Crnkovic, I., Lucin, P. & Koszinowski, U. H. ( 1994; ). Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. Journal of Experimental Medicine 179, 1713-1717.[CrossRef]
    [Google Scholar]
  15. Kari, B. & Gehrz, R. ( 1991; ). Biochemical and immunological analysis of discontinuous epitopes in the family of human cytomegalovirus glycoprotein complexes designated gC-I. Journal of General Virology 72, 1975-1983.[CrossRef]
    [Google Scholar]
  16. Kari, B., Liu, Y. N., Goertz, R., Lussenhop, N., Stinski, M. F. & Gehrz, R. ( 1990; ). Structure and composition of a family of human cytomegalovirus glycoprotein complexes designated gC-I (gB). Journal of General Virology 71, 2673-2680.[CrossRef]
    [Google Scholar]
  17. Klein, M., Schoppel, K., Amvrossiadis, N. & Mach, M. ( 1999; ). Strain-specific neutralization of human cytomegalovirus isolates by human sera. Journal of Virology 73, 878-886.
    [Google Scholar]
  18. Kniess, N., Mach, M., Fay, J. & Britt, W. J. ( 1991; ). Distribution of linear antigenic sites on glycoprotein gp55 of human cytomegalovirus. Journal of Virology 65, 138-146.
    [Google Scholar]
  19. Kropff, B. & Mach, M. ( 1997; ). Identification of the gene coding for rhesus cytomegalovirus glycoprotein B and immunological analysis of the protein. Journal of General Virology 78, 1999-2007.
    [Google Scholar]
  20. Kropff, B., Landini, M. P. & Mach, M. ( 1993; ). An ELISA using recombinant proteins for the detection of neutralizing antibodies against human cytomegalovirus. Journal of Medical Virology 39, 187-195.[CrossRef]
    [Google Scholar]
  21. Lehner, R., Stamminger, T. & Mach, M. ( 1991; ). Comparative sequence analysis of human cytomegalovirus strains. Journal of Clinical Microbiology 29, 2494-2502.
    [Google Scholar]
  22. Lussenhop, N. O., Goertz, R., Wabuke-Bunoti, M., Gehrz, R. & Kari, B. ( 1988; ). Epitope analysis of human cytomegalovirus glycoprotein complexes using murine monoclonal antibodies. Virology 164, 362-372.[CrossRef]
    [Google Scholar]
  23. Mach, M., Utz, U. & Fleckenstein, B. ( 1986; ). Mapping of the major glycoprotein gene of human cytomegalovirus. Journal of General Virology 67, 1461-1467.[CrossRef]
    [Google Scholar]
  24. Marshall, G. S., Rabalais, G. P., Stout, G. G. & Waldeyer, S. L. ( 1992; ). Antibodies to recombinant-derived glycoprotein B after natural human cytomegalovirus infection correlate with neutralizing activity. Journal of Infectious Diseases 165, 381-384.[CrossRef]
    [Google Scholar]
  25. Meyer, H., Masuho, Y. & Mach, M. ( 1990; ). The gp116 of the gp58/116 complex of human cytomegalovirus represents the amino-terminal part of the precursor molecule and contains a neutralizing epitope. Journal of General Virology 71, 2443-2450.[CrossRef]
    [Google Scholar]
  26. Meyer, H., Sundqvist, V.-A., Pereira, L. & Mach, M. ( 1992; ). Glycoprotein gp116 of human cytomegalovirus contains epitopes for strain-common and strain-specific antibodies. Journal of General Virology 73, 2375-2383.[CrossRef]
    [Google Scholar]
  27. Myers, R. M. (1989). Region-specific mutagenesis. In Current Protocols in Molecular Biology, unit 8.3. Edited by F. M. Ausubel, R. Brent, R. E. Kingston, D. D. Moore, J. G. Seidman & K. Struhl. New York: John Wiley.
  28. Myers, R. M., Lerman, L. S. & Maniatis, T. ( 1985; ). A general method for saturation mutagenesis of cloned DNA fragments. Science 229, 242-247.[CrossRef]
    [Google Scholar]
  29. Ohlin, M., Sundqvist, V. A., Mach, M., Wahren, B. & Borrebaeck, C. A. ( 1993; ). Fine specificity of the human immune response to the major neutralization epitopes expressed on cytomegalovirus gp58/116 (gB), as determined with human monoclonal antibodies. Journal of Virology 67, 703-710.
    [Google Scholar]
  30. Qadri, I., Navarro, D., Paz, P. & Pereira, L. ( 1992; ). Assembly of conformation-dependent neutralizing domains on glycoprotein B of human cytomegalovirus. Journal of General Virology 73, 2913-2921.[CrossRef]
    [Google Scholar]
  31. Rapp, M., Messerle, M., Lucin, P. & Koszinowski, U. H. ( 1993; ). In vivo protection studies with MCMV glycoproteins gB and gH expressed by vaccinia virus. In Multidisciplinary Approach to Understanding Cytomegalovirus Disease, pp. 327-332. Edited by S. Michelson & S. A. Plotkin. Amsterdam: Excerpta Medica.
  32. Reddehase, M. J., Balthesen, M., Rapp, M., Jonjic, S., Pavic, I. & Koszinowski, U. H. ( 1994; ). The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. Journal of Experimental Medicine 179, 185-193.[CrossRef]
    [Google Scholar]
  33. Roy, D. M., Grundy, J. E. & Emery, V. C. ( 1993; ). Sequence variation within neutralizing epitopes of the envelope glycoprotein B of human cytomegalovirus: comparison of isolates from renal transplant recipients and AIDS patients. Journal of General Virology 74, 2499-2505.[CrossRef]
    [Google Scholar]
  34. Schoppel, K., Hassfurther, E., Britt, W. J., Ohlin, M., Borrebaeck, C. A. & Mach, M. ( 1996; ). Antibodies specific for the antigenic domain 1 (AD-1) of glycoprotein B (gpUL55) of human cytomegalovirus bind to different substructures. Virology 216, 133-145.[CrossRef]
    [Google Scholar]
  35. Schoppel, K., Kropff, B., Schmidt, C., Vornhagen, R. & Mach, M. ( 1997; ). The humoral immune response against human cytomegalovirus is characterized by a delayed synthesis of glycoprotein specific antibodies. Journal of Infectious Diseases 175, 533-544.[CrossRef]
    [Google Scholar]
  36. Spindler, K. R., Rosser, D. S. & Berk, A. J. ( 1984; ). Analysis of adenovirus transforming proteins from early regions 1A and 1B with antisera to inducible fusion antigens produced in Escherichia coli. Journal of Virology 49, 132-141.
    [Google Scholar]
  37. Starr, S. E., Friedman, H. M. & Plotkin, S. A. ( 1991; ). The status of cytomegalovirus vaccine. Reviews of Infectious Diseases 13(Suppl. 11), S964–S965.
    [Google Scholar]
  38. Tanaka, A., Moriuchi, H., Hirota, K. & Numazaki, Y. ( 1991; ). Neutralizing antibody response to cytomegalovirus in seropositive pregnant women. Journal of Medical Virology 34, 85-88.[CrossRef]
    [Google Scholar]
  39. Urban, M., Britt, W. & Mach, M. ( 1992; ). The dominant linear neutralizing antibody-binding site of glycoprotein gp86 of human cytomegalovirus is strain specific. Journal of Virology 66, 1303-1311.
    [Google Scholar]
  40. Urban, M., Winkler, T., Landini, M. P., Britt, W. & Mach, M. ( 1994; ). Epitope-specific distribution of IgG subclasses against antigenic domains on glycoproteins of human cytomegalovirus. Journal of Infectious Diseases 169, 83-90.[CrossRef]
    [Google Scholar]
  41. Urban, M., Klein, M., Britt, W. J., Hassfurther, E. & Mach, M. ( 1996; ). Glycoprotein H of human cytomegalovirus is a major antigen for the neutralizing humoral immune response. Journal of General Virology 77, 1537-1547.[CrossRef]
    [Google Scholar]
  42. Utz, U., Britt, W., Vugler, L. & Mach, M. ( 1989; ). Identification of a neutralizing epitope on glycoprotein gp58 of human cytomegalovirus. Journal of Virology 63, 1995-2001.
    [Google Scholar]
  43. Wagner, B., Kropff, B., Kalbacher, H., Britt, W., Sundqvist, V. A., Ostberg, L. & Mach, M. ( 1992; ). A continuous sequence of more than 70 amino acids is essential for antibody binding to the dominant antigenic site of glycoprotein gp58 of human cytomegalovirus. Journal of Virology 66, 5290-5297.
    [Google Scholar]
  44. Wang, J. B., Adler, S. P., Hempfling, S., Burke, R. L., Duliege, A. M., Starr, S. E. & Plotkin, S. A. ( 1996; ). Mucosal antibodies to human cytomegalovirus glycoprotein B occur following both natural infection and immunization with human cytomegalovirus vaccines. Journal of Infectious Diseases 174, 387-392.[CrossRef]
    [Google Scholar]
  45. Werner, B. G., Snydman, D. R., Freeman, R., Rohrer, R., Tilney, N. L. & Kirkman, R. L. ( 1993; ). Cytomegalovirus immune globulin for the prevention of primary CMV disease in renal transplant patients: analysis of usage under treatment IND status. The Treatment IND Study Group. Transplantation Proceedings 25, 1441-1443.
    [Google Scholar]
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