1887

Abstract

Rhesus cytomegalovirus (RhCMV) exhibits strong parallels with human CMV (HCMV) in terms of nucleic and amino acid identities, natural history, and mechanisms of persistence and pathogenesis in its natural host, rhesus macaques (). To determine whether this non-human primate model would be useful to assess vaccine strategies for HCMV, host immune responses to RhCMV glycoprotein B (gB) were evaluated in RhCMV-infected monkeys. Total protein extracts were prepared from cells transiently transfected with an expression plasmid for either the full-length gB or a derivative (gBΔ, 1–680 aa) lacking both the transmembrane domain and cytoplasmic tail. Western blot analysis showed identical reactivity of macaque sera with full-length gB and its derivative gBΔ, indicating that the immunodominant epitopes of gB are contained in the extracellular portion of the protein. Using gBΔ extract as a solid phase, a sensitive and specific ELISA was established to characterize gB antibody responses in monkeys acutely and chronically infected with RhCMV. During primary infection (seroconversion), gB-specific antibodies developed concurrently and in parallel with total RhCMV-specific antibodies. However, during chronic infection gB-specific antibody responses were variable. A strong correlation was observed between neutralizing and gB-specific antibody levels in RhCMV-seropositive monkeys. Taken together, the results of this study indicate that, similar to host humoral responses to HCMV gB, anti-gB antibodies are an integral part of humoral immunity to RhCMV infection and probably play an important protective role in limiting the extent of RhCMV infection. Thus, the rhesus macaque model of HCMV infection is relevant for testing gB-based immune therapies.

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2003-12-01
2024-04-26
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References

  1. Alberola J., Dominguez V., Cardenoso L. 7 other authors 1998; Antibody response to human cytomegalovirus (HCMV) glycoprotein B (gB) in AIDS patients with HCMV end-organ disease. J Med Virol 55:272–280
    [Google Scholar]
  2. Alberola J., Tamarit A., Cardenoso L., Estelles F., Igual R., Navarro D. 2001; Longitudinal analysis of human cytomegalovirus glycoprotein B (gB)-specific and neutralizing antibodies in AIDS patients either with or without cytomegalovirus end-organ disease. J Med Virol 64:35–41
    [Google Scholar]
  3. Alcendor D. J., Barry P. A., Pratt-Lowe E., Luciw P. A. 1993; Analysis of the rhesus cytomegalovirus immediate-early gene promoter. Virology 194:815–821
    [Google Scholar]
  4. Alford C. A., Britt W. J. 1993; Cytomegalovirus. In The Human Herpesviruses pp  227–255 Edited by Roizman B., Whitley R. J., Lopez C. New York: Raven Press;
    [Google Scholar]
  5. Asher D. M., Gibbs J., J C, Lang D. J., Gadjusek D. C., Chanock R. M. 1974; Persistent shedding of cytomegalovirus in the urine of healthy rhesus monkeys. Proc Soc Exp Biol Med 145:794–801
    [Google Scholar]
  6. Baroncelli S., Barry P. A., Capitanio J. P., Lerche N. W., Otsyula M., Mendoza S. P. 1997; Cytomegalovirus and simian immunodeficiency virus coinfection: longitudinal study of antibody responses and disease progression. J Acquir Immune Defic Syndr 15:5–15
    [Google Scholar]
  7. Baskin G. B. 1987; Disseminated cytomegalovirus infection in immunodeficient rhesus macaques. Am J Pathol 129:345–352
    [Google Scholar]
  8. Boppana S. B., Britt W. J. 1995; Antiviral antibody responses and intrauterine transmission after primary maternal cytomegalovirus infection. J Infect Dis 171:1115–1121
    [Google Scholar]
  9. Boppana S. B., Britt W. J. 1996; Recognition of human cytomegalovirus gene products by HCMV-specific cytotoxic T cells. Virology 222:293–296
    [Google Scholar]
  10. Britt W. J., Auger D. 1985; Identification of a 65 000 dalton virion envelope protein of human cytomegalovirus. Virus Res 4:31–36
    [Google Scholar]
  11. Britt W. J., Mach M. 1996; Human cytomegalovirus glycoproteins. Intervirology 39:401–412
    [Google Scholar]
  12. 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-vaccinia recombinant virus-infected cells in analysis of the human neutralizing response. J Virol 64:1079–1085
    [Google Scholar]
  13. Chang W. L., Barry P. A. 2003; Cloning of the full-length rhesus cytomegalovirus genome as an infectious and self-excisable bacterial artificial chromosome for analysis of viral pathogenesis. J Virol 77:5073–5083
    [Google Scholar]
  14. Chang W. L., Tarantal A. F., Zhou S. S., Borowsky A. D., Barry P. A. 2002; A recombinant rhesus cytomegalovirus expressing enhanced green fluorescent protein retains the wild-type phenotype and pathogenicity in fetal macaques. J Virol 76:9493–9504
    [Google Scholar]
  15. Chee M. S., Bankier A. T., Beck S. 12 other authors 1990; Analysis of the protein-coding content of the sequence of human cytomegalovirus strain AD169. Curr Topics Microbiol Immunol 154:125–169
    [Google Scholar]
  16. Davison A. J., Dolan A., Akter P., Addison C., Dargan D. J., Alcendor D. J., McGeoch D. J., Hayward G. S. 2003; The human cytomegalovirus genome revisited: comparison with the chimpanzee cytomegalovirus genome. J Gen Virol 84:17–28
    [Google Scholar]
  17. DuBridge R. B., Tang P., Hsia H. C., Leong P. M., Miller J. H., Calos M. P. 1987; Analysis of mutation in human cells by using an Epstein–Barr virus shuttle system. Mol Cell Biol 7:379–387
    [Google Scholar]
  18. 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. N Engl J Med 326:663–667
    [Google Scholar]
  19. Gibson W. 1983; Protein counterparts of human and simian cytomegaloviruses. Virol 128:391–406
    [Google Scholar]
  20. Gonczol E., Ianacone J., Ho W. Z., Starr S., Meignier B., Plotkin S. 1990; Isolated gA/gB glycoprotein complex of human cytomegalovirus envelope induces humoral and cellular immune-responses in human volunteers. Vaccine 8:130–136
    [Google Scholar]
  21. Hansen S. G., Strelow L. I., Franchi D. C., Anders D. G., Wong S. W. 2003; Complete sequence and genomic analysis of rhesus cytomegalovirus. J Virol 77:6620–6636
    [Google Scholar]
  22. Hopkins J. I., Fiander A. N., Evans A. S., Delchambre M., Gheysen D., Borysiewicz L. K. 1996; Cytotoxic T cell immunity to human cytomegalovirus glycoprotein B. J Med Virol 49:124–131
    [Google Scholar]
  23. Huff J. L., Eberle R., Capitanio J., Zhou S. S., Barry P. A. 2003; Differential detection of B virus and rhesus cytomegalovirus in rhesus macaques. J Gen Virol 84:83–92
    [Google Scholar]
  24. 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. J Exp Med 179:1713–1717
    [Google Scholar]
  25. Kaur A., Daniel M. D., Hempel D., Lee-Parritz D., Hirsch M. S., Johnson R. P. 1996; Cytotoxic T-lymphocyte responses to cytomegalovirus in normal and simian immunodeficiency virus-infected macaques. J Virol 70:7725–7733
    [Google Scholar]
  26. Kaur A., Grant R. M., Means R. E., McClure H., Feinberg M., Johnson R. P. 1998; Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques. J Virol 72:9597–9611
    [Google Scholar]
  27. Kaur A., Hale C. L., Noren B., Kassis N., Simon M. A., Johnson R. P. 2002; Decreased frequency of cytomegalovirus (CMV)-specific CD4+ T lymphocytes in simian immunodeficiency virus-infected rhesus macaques: inverse relationship with CMV viremia. J Virol 76:3646–3658
    [Google Scholar]
  28. Kravitz R. H., Sciabica K. S., Cho K., Luciw P. A., Barry P. A. 1997; Cloning and characterization of the rhesus cytomegalovirus glycoprotein B. J Gen Virol 78:2009–2013
    [Google Scholar]
  29. Kropff B., Mach M. 1997; Identification of the gene coding for rhesus cytomegalovirus glycoprotein B and immunological analysis of the protein. J Gen Virol 78:1999–2007
    [Google Scholar]
  30. Kuhn E. M., Stolte N., Matz-Rensing K., Mach M., Stahl-Henning C., Hunsmann G., Kaup F. J. 1999; Immunohistochemical studies of productive rhesus cytomegalovirus infection in rhesus monkeys ( Macaca mulatta ) infected with simian immunodeficiency virus. Vet Pathol 36:51–56
    [Google Scholar]
  31. Li C. R., Greenberg P. D., Gilbert M. J., Goodrich J. M., Riddell S. R. 1994; Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 83:1971–1979
    [Google Scholar]
  32. Liu Y. N., Klaus A., Kari B., Stinski M. F., Eckhardt J., Gehrz R. C. 1991; The N-terminal 513 amino acids of the envelope glycoprotein gB of human cytomegalovirus stimulates both B- and T-cell immune responses in humans. J Virol 65:1644–1648
    [Google Scholar]
  33. Lockridge K. M., Sequar G., Zhou S. S., Yue Y., Mandell C. M., Barry P. A. 1999; Pathogenesis of experimental rhesus cytomegalovirus infection. J Virol 73:9576–9583
    [Google Scholar]
  34. Loomis-Huff J. E., Eberle R., Lockridge K. M., Rhodes G., Barry P. A. 2001; Immunogenicity of a DNA vaccine against herpes B virus in mice and rhesus macaques. Vaccine 19:4865–4873
    [Google Scholar]
  35. 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. J Infect Dis 165:381–384
    [Google Scholar]
  36. Marshall G. S., Stout G. G., Knights M. E., Rabalais G. P., Ashley R., Miller H., Rossier E. 1994; Ontogeny of glycoprotein gB-specific antibody and neutralizing activity during natural cytomegalovirus infection. J Med Virol 43:77–83
    [Google Scholar]
  37. Marshall G. S., Fenger D. P., Stout G. G., Knights M. E., Hunt L. A. 1996; Processing of human cytomegalovirus glycoprotein B in recombinant adenovirus-infected cells. J Gen Virol 77:1549–1557
    [Google Scholar]
  38. Marshall G. S., Li M., Stout G. G., Louthan M. V., Duliege A. M., Burke R. L., Hunt L. A. 2000; Antibodies to the major linear neutralizing domains of cytomegalovirus glycoprotein B among natural seropositives and CMV subunit vaccine recipients. Viral Immunol 13:329–341
    [Google Scholar]
  39. Navarro D., Lennette E., Tugizov S., Pereira L. 1997; Humoral immune response to functional regions of human cytomegalovirus glycoprotein B. J Med Virol 52:451–459
    [Google Scholar]
  40. Pitcher C. J., Hagen S. I., Walker J. M., Lum R., Mitchell B. L., Maino V. C., Axthelm M. K., Picker L. J. 2002; Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168:29–43
    [Google Scholar]
  41. Polic B., Hengel H., Krmpotic A., Trgovcich J., Pavic I., Luccaronin P., Jonjic S., Koszinowski U. H. 1998; Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188:1047–1054
    [Google Scholar]
  42. Qadri I., Navarro D., Paz P., Pereira L. 1992; Assembly of conformation-dependent neutralizing domains on glycoprotein B of human cytomegalovirus. J Gen Virol 73:2913–2921
    [Google Scholar]
  43. Rasmussen L., Morris S., Zipeto D., Fessel J., Wolitz R., Dowling A., Merigan T. C. 1995; Quantitation of human cytomegalovirus DNA from peripheral blood cells of human immunodeficiency virus-infected patients could predict cytomegalovirus retinitis. J Infect Dis 171:177–182
    [Google Scholar]
  44. Reddehase M. J., Mutter W., Münch K., Bühring H.-J., Koszinowski U. H. 1987; CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 61:3102–3108
    [Google Scholar]
  45. Reusser P., Riddell S. R., Meyers J. D., Greenberg P. D. 1991; Cytotoxic T-lymphocyte response to cytomegalovirus after human alogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78:1373–1380
    [Google Scholar]
  46. Reusser P., Attenhofer R., Hebart H., Helg C., Chapuis B., Einsele H. 1997; Cytomegalovirus-specific T-cell immunity in recipients of autologous peripheral blood stem cell or bone marrow transplants. Blood 89:3873–3879
    [Google Scholar]
  47. Reusser P., Cathomas G., Attenhofer R., Tamm M., Thiel G. 1999; Cytomegalovirus (CMV)-specific T cell immunity after renal transplantation mediates protection from CMV disease by limiting the systemic virus load. J Infect Dis 180:247–253
    [Google Scholar]
  48. Riddell S. R., Watanabe K. S., Goodrich J. M., Li C. R., Agha M. E., Greenberg P. D. 1992; Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones. Science 257:238–241
    [Google Scholar]
  49. Rigoutsos I., Novotny J., Huynh T., Chin-Bow S. T., Parida L., Platt D., Coleman D., Shenk T. 2003; In silico pattern-based analysis of the human cytomegalovirus genome. J Virol 77:4326–4344
    [Google Scholar]
  50. 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. J Infect Dis 175:533–544
    [Google Scholar]
  51. Schoppel K., Schmidt C., Einsele H., Hebart H., Mach M. 1998; Kinetics of the antibody response against human cytomegalovirus- specific proteins in allogeneic bone marrow transplant recipients. J Infect Dis 178:1233–1243
    [Google Scholar]
  52. Sequar G., Britt W. J., Lakeman F. D., Lockridge K. M., Tarara R. P., Canfield D. R., Zhou S. S., Gardner M. B., Barry P. A. 2002; Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: pathogenesis. J Virol 76:7661–7671
    [Google Scholar]
  53. Spaete R. R., Thayer R. M., Probert W. S., Masiarz F. R., Chamberlain S. H., Rasmussen L., Merigan T. C., Pachl C. 1988; Human cytomegalovirus strain Towne glycoprotein B is processed by proteolytic cleavage. Virology 167:207–225
    [Google Scholar]
  54. Swack N. S., Hsiung G. D. 1982; Natural and experimental simian cytomegalovirus infections at a primate center. J Med Primatol 11:169–177
    [Google Scholar]
  55. 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. J Gen Virol 77:1537–1547
    [Google Scholar]
  56. 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
    [Google Scholar]
  57. Vogel P., Weigler B. J., Kerr H., Hendrickx A., Barry P. A. 1994; Seroepidemiologic studies of cytomegalovirus infection in a breeding population of rhesus macaques. Lab Anim Sci 44:25–30
    [Google Scholar]
  58. Walter E. A., Greenberg P. D., Gilbert M. J., Finch R. J., Watanabe K. S., Thomas E. D., Riddell S. R. 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
    [Google Scholar]
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