1887

Abstract

Rhesus cytomegalovirus (RhCMV) contains two open reading frames (Rh111 and Rh112) that encode proteins homologous to the phosphoprotein 65 (pp65) of the human cytomegalovirus (HCMV) UL83 gene. As HCMV pp65 elicits protective immune responses in infected humans and represents an important vaccination target, one RhCMV homologue of HCMV pp65, pp65-2 (Rh112), was characterized and analysed for its ability to induce host immune responses. Similar to its HCMV counterpart, RhCMV pp65-2 was expressed as a late gene, localized to the nucleus within pp65-2-expressing cells and was present within infectious virions. Longitudinal and cross-sectional studies of pp65-2 immunity in naturally infected rhesus macaques showed that humoral responses to pp65-2 were elicited early during infection, but were not always sustained over time. In contrast, pp65-2-specific T-cell responses, examined by gamma interferon ELISPOT, were broadly detectable in all of the animals studied during primary infection and persisted in the vast majority of RhCMV-seropositive monkeys. Moreover, there was considerable inter-animal variability in the pattern of the immune responses to pp65-2. Together, these results demonstrated that RhCMV pp65-2 exhibited biological and immunological homology to HCMV pp65. Thus, the rhesus macaque model of HCMV persistence and pathogenesis should be relevant for addressing pp65-based vaccine modalities.

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2006-04-01
2024-03-28
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References

  1. 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]
  2. Arcangeletti M. C., De Conto F., Ferraglia F. & 11 other authors 2003; Human cytomegalovirus proteins PP65 and IEP72 are targeted to distinct compartments in nuclei and nuclear matrices of infected human embryo fibroblasts. J Cell Biochem 90:1056–1067 [CrossRef]
    [Google Scholar]
  3. Barry P. A., Chang W.-L. W. 2005 Primate betaherpesviruses. In Human Herpesviruses: Biology, Therapy and Immunoprophylaxis Edited by Arvin A., Campadielli-Fiume G., Moore P. S., Mocarski E., Roizman B., Whitley R., Yamanishi K. Cambridge: Cambridge University Press;
    [Google Scholar]
  4. Beninga J., Kropff B., Mach M. 1995; Comparative analysis of fourteen individual human cytomegalovirus proteins for helper T cell response. J Gen Virol 76:153–160 [CrossRef]
    [Google Scholar]
  5. Berencsi K., Gyulai Z., Gönczöl E. & 9 other authors 2001; A canarypox vector-expressing cytomegalovirus (CMV) phosphoprotein 65 induces long-lasting cytotoxic T cell responses in human CMV-seronegative subjects. J Infect Dis 183:1171–1179 [CrossRef]
    [Google Scholar]
  6. Boppana S. B., Britt W. J. 1995; Antiviral antibody responses and intrauterine transmission after primary maternal cytomegalovirus infection. J Infect Dis 171:1115–1121 [CrossRef]
    [Google Scholar]
  7. Boppana S. B., Britt W. J. 1996; Recognition of human cytomegalovirus gene products by HCMV-specific cytotoxic T cells. Virology 222:293–296 [CrossRef]
    [Google Scholar]
  8. Bunde T., Kirchner A., Hoffmeister B. & 8 other authors 2005; Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 201:1031–1036 [CrossRef]
    [Google Scholar]
  9. Campbell A. L., Herold B. C. 2004; Strategies for the prevention of cytomegalovirus infection and disease in pediatric liver transplantation recipients. Pediatr Transplant 8:619–627 [CrossRef]
    [Google Scholar]
  10. Chang W. L. W., Kirchoff V., Pari G. S., Barry P. A. 2002; Replication of rhesus cytomegalovirus in life-expanded rhesus fibroblasts expressing human telomerase. J Virol Methods 104:135–146 [CrossRef]
    [Google Scholar]
  11. 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 Top Microbiol Immunol 154:125–169
    [Google Scholar]
  12. Del Val M., Schlicht H.-J., Volkmer H., Messerle M., Reddehase M. J., Koszinowski U. H. 1991; Protection against lethal cytomegalovirus infection by a recombinant vaccine containing a single nonameric T-cell epitope. J Virol 65:3641–3646
    [Google Scholar]
  13. Depto A. S., Stenberg R. M. 1989; Regulated expression of the human cytomegalovirus pp65 gene: octamer sequence in the promoter is required for activation by viral gene products. J Virol 63:1232–1238
    [Google Scholar]
  14. Dolan A., Cunningham C., Hector R. D. & 12 other authors 2004; Genetic content of wild-type human cytomegalovirus. J Gen Virol 85:1301–1312 [CrossRef]
    [Google Scholar]
  15. 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]
  16. Elkington R., Walker S., Crough T., Menzies M., Tellam J., Bharadwaj M., Khanna R. 2003; Ex vivo profiling of CD8+-T-cell responses to human cytomegalovirus reveals broad and multispecific reactivities in healthy virus carriers. J Virol 77:5226–5240 [CrossRef]
    [Google Scholar]
  17. 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 [CrossRef]
    [Google Scholar]
  18. Gallina A., Percivalle E., Simoncini L., Revello M. G., Gerna G., Milanesi G. 1996; Human cytomegalovirus pp65 lower matrix phosphoprotein harbours two transplantable nuclear localization signals. J Gen Virol 77:1151–1157 [CrossRef]
    [Google Scholar]
  19. Geballe A. P., Leach F. S., Mocarski E. S. 1986; Regulation of cytomegalovirus late gene expression: γ genes are controlled by posttranscriptional events. J Virol 57:864–874
    [Google Scholar]
  20. Gonczol E., Plotkin S. 2001; Development of a cytomegalovirus vaccine: lessons from recent clinical trials. Expert Opin Biol Ther 1:401–412 [CrossRef]
    [Google Scholar]
  21. González Armas J. C., Morello C. S., Cranmer L. D., Spector D. H. 1996; DNA immunization confers protection against murine cytomegalovirus infection. J Virol 70:7921–7928
    [Google Scholar]
  22. Gyulai Z., Endresz V., Burian K. & 7 other authors 2000; Cytotoxic T lymphocyte (CTL) responses to human cytomegalovirus pp65, IE1-Exon4, gB, pp150, and pp28 in healthy individuals: reevaluation of prevalence of IE1-specific CTLs. J Infect Dis 181:1537–1546 [CrossRef]
    [Google Scholar]
  23. 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 [CrossRef]
    [Google Scholar]
  24. 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 [CrossRef]
    [Google Scholar]
  25. Jin X., Demoitie M. A., Donahoe S. M. & 13 other authors 2000; High frequency of cytomegalovirus-specific cytotoxic T-effector cells in HLA-A*0201-positive subjects during multiple viral coinfections. J Infect Dis 181:165–175 [CrossRef]
    [Google Scholar]
  26. Jonjić S., del Val M., Keil G. M., Reddehase M. J., Koszinowski U. H. 1988; A nonstructural viral protein expressed by a recombinant vaccinia virus protects against lethal cytomegalovirus infection. J Virol 62:1653–1658
    [Google Scholar]
  27. 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]
  28. 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 [CrossRef]
    [Google Scholar]
  29. Kaur A., Kassis N., Hale C. L. & 9 other authors 2003; Direct relationship between suppression of virus-specific immunity and emergence of cytomegalovirus disease in simian AIDS. J Virol 77:5749–5758 [CrossRef]
    [Google Scholar]
  30. Kirchoff V., Wong S., St Jeor S., Pari G. S. 2002; Generation of a life-expanded rhesus monkey fibroblast cell line for the growth of rhesus rhadinovirus (RRV). Arch Virol 147:321–333 [CrossRef]
    [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. Lockridge K. M., Sequar G., Zhou S. S., Yue Y., Mandell C. P., Barry P. A. 1999; Pathogenesis of experimental rhesus cytomegalovirus infection. J Virol 73:9576–9583
    [Google Scholar]
  33. 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 [CrossRef]
    [Google Scholar]
  34. Manley T. J., Luy L., Jones T., Boeckh M., Mutimer H., Riddell S. R. 2004; Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104:1075–1082 [CrossRef]
    [Google Scholar]
  35. McGregor A., Liu F., Schleiss M. R. 2004; Molecular, biological, and in vivo characterization of the guinea pig cytomegalovirus (CMV) homologs of the human CMV matrix proteins pp71 (UL82) and pp65 (UL83). J Virol 78:9872–9889 [CrossRef]
    [Google Scholar]
  36. McLaughlin-Taylor E., Pande H., Forman S. J., Tanamachi B., Li C. R., Zaia J. A., Greenberg P. D., Riddell S. R. 1994; Identification of the major late human cytomegalovirus matrix protein pp65 as a target antigen for CD8+ virus-specific cytotoxic T lymphocytes. J Med Virol 43:103–110 [CrossRef]
    [Google Scholar]
  37. Morello C. S., Cranmer L. D., Spector D. H. 2000; Suppression of murine cytomegalovirus (MCMV) replication with a DNA vaccine encoding MCMV M84 (a homolog of human cytomegalovirus pp65). J Virol 74:3696–3708 [CrossRef]
    [Google Scholar]
  38. Morello C. S., Ye M., Hung S., Kelley L. A., Spector D. H. 2005; Systemic priming-boosting immunization with a trivalent plasmid DNA and inactivated murine cytomegalovirus (MCMV) vaccine provides long-term protection against viral replication following systemic or mucosal MCMV challenge. J Virol 79:159–175 [CrossRef]
    [Google Scholar]
  39. Nakai K., Horton P. 1999; psort: a program for detecting sorting signals in proteins and predicting their subcellular localization. Trends Biochem Sci 24:34–36 [CrossRef]
    [Google Scholar]
  40. Nakai K., Kanehisa M. 1992; A knowledge base for predicting protein localization sites in eukaryotic cells. Genomics 14:897–911 [CrossRef]
    [Google Scholar]
  41. Nigro G., Adler S. P., La Torre R., Best A. M. 2005; Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 353:1350–1362 [CrossRef]
    [Google Scholar]
  42. Ohlin M., Plachter B., Sundqvist V.-A., Steenbakkers P. G. A., Middeldorp J. M., Borrebaeck C. A. K. 1995; Human antibody reactivity against the lower matrix protein (pp65) produced by cytomegalovirus. Clin Diagn Lab Immunol 2:325–329
    [Google Scholar]
  43. Pande N. T., Powers C., Ahn K., Früh K. 2005; Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11. J Virol 79:5786–5798 [CrossRef]
    [Google Scholar]
  44. Penedo M. C. T., Bontrop R. E., Heijmans C. M. C. & 7 other authors 2005; Microsatellite typing of the rhesus macaque MHC region. Immunogenetics 57:198–209 [CrossRef]
    [Google Scholar]
  45. Reusser P., Riddell S. R., Meyers J. D., Greenberg P. D. 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
    [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 [CrossRef]
    [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 [CrossRef]
    [Google Scholar]
  49. Sanchez V., Angeletti P. C., Engler J. A., Britt W. J. 1998; Localization of human cytomegalovirus structural proteins to the nuclear matrix of infected human fibroblasts. J Virol 72:3321–3329
    [Google Scholar]
  50. Schleiss M. R., Heineman T. C. 2005; Progress toward an elusive goal: current status of cytomegalovirus vaccines. Expert Rev Vaccines 4:381–406 [CrossRef]
    [Google Scholar]
  51. Schleiss M. R., McGregor A., Jensen N. J., Erdem G., Aktan L. 1999; Molecular characterization of the guinea pig cytomegalovirus UL83 (pp65) protein homolog. Virus Genes 19:205–221 [CrossRef]
    [Google Scholar]
  52. Schmolke S., Drescher P., Jahn G., Plachter B. 1995; Nuclear targeting of the tegument protein pp65 (UL83) of human cytomegalovirus: an unusual bipartite nuclear localization signal functions with other portions of the protein to mediate its efficient nuclear transport. J Virol 69:1071–1078
    [Google Scholar]
  53. 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 [CrossRef]
    [Google Scholar]
  54. Sindre H., Rollag H., Degré M., Hestdal K. 2000; Human cytomegalovirus induced inhibition of hematopoietic cell line growth is initiated by events taking place before translation of viral gene products. Arch Virol 145:99–111 [CrossRef]
    [Google Scholar]
  55. Sylwester A. W., Mitchell B. L., Edgar J. B. & 9 other authors 2005; Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 202:673–685 [CrossRef]
    [Google Scholar]
  56. van Zanten J., Harmsen M. C., van der Giessen M., van der Bij W., Prop J., de Leij L., The T. H. 1995; Humoral immune response against human cytomegalovirus (HCMV)-specific proteins after HCMV infection in lung transplantation as detected with recombinant and naturally occurring proteins. Clin Diagn Lab Immunol 2:214–218
    [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 [CrossRef]
    [Google Scholar]
  59. Wang Z., La Rosa C., Mekhoubad S. & 9 other authors 2004; Attenuated poxviruses generate clinically relevant frequencies of CMV-specific T cells. Blood 104:847–856 [CrossRef]
    [Google Scholar]
  60. Wills M. R., Carmichael A. J., Mynard K., Jin X., Weekes M. P., Plachter B., Sissons J. G. P. 1996; The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol 70:7569–7579
    [Google Scholar]
  61. Yao Z.-Q., Gallez-Hawkins G., Lomeli N. A., Li X., Molinder K. M., Diamond D. J., Zaia J. A. 2001; Site-directed mutation in a conserved kinase domain of human cytomegalovirus-pp65 with preservation of cytotoxic T lymphocyte targeting. Vaccine 19:1628–1635 [CrossRef]
    [Google Scholar]
  62. Ye M., Morello C. S., Spector D. H. 2002; Strong CD8 T-cell responses following coimmunization with plasmids expressing the dominant pp89 and subdominant M84 antigens of murine cytomegalovirus correlate with long-term protection against subsequent viral challenge. J Virol 76:2100–2112 [CrossRef]
    [Google Scholar]
  63. Yue Y., Zhou S. S., Barry P. A. 2003; Antibody responses to rhesus cytomegalovirus glycoprotein B in naturally infected rhesus macaques. J Gen Virol 84:3371–3379 [CrossRef]
    [Google Scholar]
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