1887

Abstract

Human cytomegalovirus (HCMV) encodes several highly polymorphic envelope glycoproteins; however, the biological relevance of this polymorphism is unclear. Glycoprotein N (gN) is one member of this polymorphic protein family. Four major gN genotypes (gN1–4) have been identified. We have tested the hypothesis that the gN polymorphism represents a mechanism to evade a neutralizing antiviral antibody response. Four recombinant viruses that differed only in the expression of the gN genotype were constructed on the genetic background of HCMV strain AD169. Exchange of gN genotypes had a minor detectable influence on virus replication, gN expression and gN–gM complex formation. Randomly selected human sera were analysed for neutralizing activity against the recombinant viruses. Of these, 70 % showed no difference in neutralizing titre between the viruses, whereas 30 % showed strain-specific neutralization. Differences in 50 % neutralization titre reached >8-fold. Viruses expressing the gN4 genotype were neutralized significantly better than those expressing the other gN genotypes. Strain specificity, or lack thereof, could not be attributed to the presence or absence of anti-gN antibodies, as all sera contained antibodies reacting with gN (as determined by ELISA). Thus, polymorphism of gN could contribute to evasion of an efficient neutralizing-antibody response and facilitate reinfection in previously seropositive individuals.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.010967-0
2009-08-01
2019-09-15
Loading full text...

Full text loading...

/deliver/fulltext/jgv/90/8/1951.html?itemId=/content/journal/jgv/10.1099/vir.0.010967-0&mimeType=html&fmt=ahah

References

  1. Abe, Y., Takashita, E., Sugawara, K., Matsuzaki, Y., Muraki, Y. & Hongo, S. ( 2004; ). Effect of the addition of oligosaccharides on the biological activities and antigenicity of influenza A/H3N2 virus hemagglutinin. J Virol 78, 9605–9611.[CrossRef]
    [Google Scholar]
  2. 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. J Infect Dis 171, 26–32.[CrossRef]
    [Google Scholar]
  3. 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.[CrossRef]
    [Google Scholar]
  4. Andreoni, M., Faircloth, M., Vugler, L. & Britt, W. J. ( 1989; ). A rapid microneutralization assay for the measurement of neutralizing antibody reactive with human cytomegalovirus. J Virol Methods 23, 157–167.[CrossRef]
    [Google Scholar]
  5. Baboonian, C., Blake, K., Booth, J. C. & Wiblin, C. N. ( 1989; ). Complement-independent neutralising monoclonal antibody with differential reactivity for strains of human cytomegalovirus. J Med Virol 29, 139–145.[CrossRef]
    [Google Scholar]
  6. Bale, J. F., Jr, Petheram, S. J., Souza, I. E. & Murph, J. R. ( 1996; ). Cytomegalovirus reinfection in young children. J Pediatr 128, 347–352.[CrossRef]
    [Google Scholar]
  7. Boppana, S. B., Rivera, L. B., Fowler, K. B., Mach, M. & Britt, W. J. ( 2001; ). Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 344, 1366–1371.[CrossRef]
    [Google Scholar]
  8. Borst, E. M., Hahn, G., Koszinowski, U. H. & Messerle, M. ( 1999; ). Cloning of the human cytomegalovirus (HCMV) genome as an infectious bacterial artificial chromosome in Escherichia coli: a new approach for construction of HCMV mutants. J Virol 73, 8320–8329.
    [Google Scholar]
  9. Britt, W. ( 2006; ). Human cytomegalovirus infections and mechanisms of disease. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 1–28. Edited by M. J. Reddehase. Wymondham, UK: Caister Academic Press.
  10. Britt, W. J. & Auger, D. ( 1985; ). Identification of a 65 000 dalton virion envelope protein of human cytomegalovirus. Virus Res 4, 31–36.[CrossRef]
    [Google Scholar]
  11. 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. J Virol 64, 1079–1085.
    [Google Scholar]
  12. Chandler, S. H. & McDougall, J. K. ( 1986; ). Comparison of restriction site polymorphisms among clinical isolates and laboratory strains of human cytomegalovirus. J Gen Virol 67, 2179–2192.[CrossRef]
    [Google Scholar]
  13. Chandler, S. H., Handsfield, H. H. & McDougall, J. K. ( 1987; ). Isolation of multiple strains of cytomegalovirus from women attending a clinic for sexually transmitted disease. J Infect Dis 155, 655–660.[CrossRef]
    [Google Scholar]
  14. Chou, S. W. ( 1989; ). Reactivation and recombination of multiple cytomegalovirus strains from individual organ donors. J Infect Dis 160, 11–15.[CrossRef]
    [Google Scholar]
  15. Chou, S. W. ( 1990; ). Differentiation of cytomegalovirus strains by restriction analysis of DNA sequences amplified from clinical specimens. J Infect Dis 162, 738–742.[CrossRef]
    [Google Scholar]
  16. Coaquette, A., Bourgeois, A., Dirand, C., Varin, A., Chen, W. & Herbein, G. ( 2004; ). Mixed cytomegalovirus glycoprotein B genotypes in immunocompromised patients. Clin Infect Dis 39, 155–161.[CrossRef]
    [Google Scholar]
  17. Datsenko, K. A. & Wanner, B. L. ( 2000; ). One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A 97, 6640–6645.[CrossRef]
    [Google Scholar]
  18. Farroway, L. N., Gorman, S., Lawson, M. A., Harvey, N. L., Jones, D. A., Shellam, G. R. & Singleton, G. R. ( 2005; ). Transmission of two Australian strains of murine cytomegalovirus (MCMV) in enclosure populations of house mice (Mus domesticus). Epidemiol Infect 133, 701–710.[CrossRef]
    [Google Scholar]
  19. Ghiasi, H., Perng, G.-C., Nesburn, A. B. & Wechsler, S. L. ( 2000; ). Antibody-dependent enhancement of HSV-1 infection by anti-gK sera. Virus Res 68, 137–144.[CrossRef]
    [Google Scholar]
  20. Gillet, L. & Stevenson, P. G. ( 2007; ). Antibody evasion by the N terminus of murid herpesvirus-4 glycoprotein B. EMBO J 26, 5131–5142.[CrossRef]
    [Google Scholar]
  21. Gorman, S., Harvey, N. L., Moro, D., Lloyd, M. L., Voigt, V., Smith, L. M., Lawson, M. A. & Shellam, G. R. ( 2006; ). Mixed infection with multiple strains of murine cytomegalovirus occurs following simultaneous or sequential infection of immunocompetent mice. J Gen Virol 87, 1123–1132.[CrossRef]
    [Google Scholar]
  22. Grundy, J. E., Lui, S. F., Super, M., Berry, N. J., Sweny, P., Fernando, O. N., Moorhead, J. & Griffiths, P. D. ( 1988; ). Symptomatic cytomegalovirus infection in seropositive kidney recipients: reinfection with donor virus rather than reactivation of recipient virus. Lancet 2, 132–135.
    [Google Scholar]
  23. Inada, T., Chong, K. T. & Mims, C. A. ( 1985; ). Enhancing antibodies, macrophages and virulence in mouse cytomegalovirus infection. J Gen Virol 66, 871–878.[CrossRef]
    [Google Scholar]
  24. Ishibashi, K., Tokumoto, T., Tanabe, K., Shirakawa, H., Hashimoto, K., Kushida, N., Yanagida, T., Inoue, N., Yamaguchi, O. & other authors ( 2007; ). Association of the outcome of renal transplantation with antibody response to cytomegalovirus strain-specific glycoprotein H epitopes. Clin Infect Dis 45, 60–67.[CrossRef]
    [Google Scholar]
  25. Klein, M., Schoppel, K., Amvrossiadis, N. & Mach, M. ( 1999; ). Strain-specific neutralization of human cytomegalovirus isolates by human sera. J Virol 73, 878–886.
    [Google Scholar]
  26. Klenovsek, K., Weisel, F., Schneider, A., Appelt, U., Jonjic, S., Messerle, M., Bradel-Tretheway, B., Winkler, T. H. & Mach, M. ( 2007; ). Protection from CMV infection in immunodeficient hosts by adoptive transfer of memory B cells. Blood 110, 3472–3479.[CrossRef]
    [Google Scholar]
  27. Knossow, M. & Skehel, J. J. ( 2006; ). Variation and infectivity neutralization in influenza. Immunology 119, 1–7.[CrossRef]
    [Google Scholar]
  28. Lehner, R., Meyer, H. & Mach, M. ( 1989; ). Identification and characterization of a human cytomegalovirus gene coding for a membrane protein that is conserved among human herpesviruses. J Virol 63, 3792–3800.
    [Google Scholar]
  29. Mach, M. ( 2006; ). Antibody-mediated neutralization of infectivity. In Cytomegaloviruses: Molecular Biology and Immunology, pp. 265–283. Edited by M. J. Reddehase. Wymondham, UK: Caister Academic Press.
  30. Mach, M., Kropff, B., Dal-Monte, P. & Britt, W. J. ( 2000; ). Complex formation of human cytomegalovirus glycoprotein M (gpUL100) and glycoprotein N (gpUl73). J Virol 74, 11881–11892.[CrossRef]
    [Google Scholar]
  31. Mach, M., Kropff, B., Kryzaniak, M. & Britt, W. ( 2005; ). Complex formation by glycoproteins M and N of human cytomegalovirus: structural and functional aspects. J Virol 79, 2160–2170.[CrossRef]
    [Google Scholar]
  32. 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.[CrossRef]
    [Google Scholar]
  33. 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. J Gen Virol 71, 2443–2450.[CrossRef]
    [Google Scholar]
  34. Meyer, H., Sundqvist, V. A., Pereira, L. & Mach, M. ( 1992; ). Glycoprotein gp116 of human cytomegalovirus contains epitopes for strain-common and strain-specific antibodies. J Gen Virol 73, 2375–2383.[CrossRef]
    [Google Scholar]
  35. Meyer-Konig, U., Ebert, K., Schrage, B., Pollak, S. & Hufert, F. T. ( 1998; ). Simultaneous infection of healthy people with multiple human cytomegalovirus strains. Lancet 352, 1280–1281.
    [Google Scholar]
  36. Murphy, E., Yu, D., Grimwood, J., Schmutz, J., Dickson, M., Jarvis, M. A., Hahn, G., Nelson, J. A., Myers, R. M. & Shenk, T. E. ( 2003; ). Coding potential of laboratory and clinical strains of human cytomegalovirus. Proc Natl Acad Sci U S A 100, 14976–14981.[CrossRef]
    [Google Scholar]
  37. Novak, Z., Ross, S. A., Patro, R. K., Pati, S. K., Kumbla, R. A., Brice, S. & Boppana, S. B. ( 2008; ). Cytomegalovirus strain diversity in seropositive women. J Clin Microbiol 46, 882–886.[CrossRef]
    [Google Scholar]
  38. Patrone, M., Secchi, M., Fiorina, L., Ierardi, M., Milanesi, G. & Gallina, A. ( 2005; ). Human cytomegalovirus UL130 protein promotes endothelial cell infection through a producer cell modification of the virion. J Virol 79, 8361–8373.[CrossRef]
    [Google Scholar]
  39. Pignatelli, S., Dal Monte, P., Rossini, G., Chou, S., Gojobori, T., Hanada, K., Guo, J. J., Rawlinson, W., Britt, W. & other authors ( 2003; ). Human cytomegalovirus glycoprotein N (gpUL73-gN) genomic variants: identification of a novel subgroup, geographical distribution and evidence of positive selective pressure. J Gen Virol 84, 647–655.[CrossRef]
    [Google Scholar]
  40. Rasmussen, L., Geissler, A., Cowan, C., Chase, A. & Winters, M. ( 2002; ). The genes encoding the gCIII complex of human cytomegalovirus exist in highly diverse combinations in clinical isolates. J Virol 76, 10841–10848.[CrossRef]
    [Google Scholar]
  41. Rasmussen, L., Geissler, A. & Winters, M. ( 2003; ). Inter- and intragenic variations complicate the molecular epidemiology of human cytomegalovirus. J Infect Dis 187, 809–819.[CrossRef]
    [Google Scholar]
  42. 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]
  43. 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.[CrossRef]
    [Google Scholar]
  44. 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.[CrossRef]
    [Google Scholar]
  45. Shen, S., Wang, S., Britt, W. J. & Lu, S. ( 2007; ). DNA vaccines expressing glycoprotein complex II antigens gM and gN elicited neutralizing antibodies against multiple human cytomegalovirus (HCMV) isolates. Vaccine 25, 3319–3327.[CrossRef]
    [Google Scholar]
  46. Shimamura, M., Mach, M. & Britt, W. J. ( 2006; ). Human cytomegalovirus infection elicits a glycoprotein M (gM)/gN-specific virus-neutralizing antibody response. J Virol 80, 4591–4600.[CrossRef]
    [Google Scholar]
  47. Simpson, J. A., Chow, J. C., Baker, J., Avdalovic, N., Yuan, S., Au, D., Co, M. S., Vasquez, M., Britt, W. J. & Coelingh, K. L. ( 1993; ). Neutralizing monoclonal antibodies that distinguish three antigenic sites on human cytomegalovirus glycoprotein H have conformationally distinct binding sites. J Virol 67, 489–496.
    [Google Scholar]
  48. Stanton, R., Westmoreland, D., Fox, J. D., Davison, A. J. & Wilkinson, G. W. ( 2005; ). Stability of human cytomegalovirus genotypes in persistently infected renal transplant recipients. J Med Virol 75, 42–46.[CrossRef]
    [Google Scholar]
  49. Talbot, P. & Almeida, J. D. ( 1977; ). Human cytomegalovirus: purification of enveloped virions and dense bodies. J Gen Virol 36, 345–349.[CrossRef]
    [Google Scholar]
  50. 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.
    [Google Scholar]
  51. 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.[CrossRef]
    [Google Scholar]
  52. Varnum, S. M., Streblow, D. N., Monroe, M. E., Smith, P., Auberry, K. J., Pasa-Tolic, L., Wang, D., Camp, D. G., Rodland, K. & other authors ( 2004; ). Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J Virol 78, 10960–10966.[CrossRef]
    [Google Scholar]
  53. Waner, J. L. & Weller, T. H. ( 1978; ). Analysis of antigenic diversity among human cytomegaloviruses by kinetic neutralization tests with high-titered rabbit antisera. Infect Immun 21, 151–157.
    [Google Scholar]
  54. Wang, D. & Shenk, T. ( 2005; ). Human cytomegalovirus UL131 open reading frame is required for epithelial cell tropism. J Virol 79, 10330–10338.[CrossRef]
    [Google Scholar]
  55. Wei, X., Decker, J. M., Wang, S., Hui, H., Kappes, J. C., Wu, X., Salazar-Gonzalez, J. F., Salazar, M. G., Kilby, J. M. & other authors ( 2003; ). Antibody neutralization and escape by HIV-1. Nature 422, 307–312.[CrossRef]
    [Google Scholar]
  56. Zinkernagel, R. M. & Hengartner, H. ( 2006; ). Protective ‘immunity’ by pre-existent neutralizing antibody titers and preactivated T cells but not by so-called ‘immunological memory’. Immunol Rev 211, 310–319.[CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.010967-0
Loading
/content/journal/jgv/10.1099/vir.0.010967-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error