1887

Abstract

Herpesviruses characteristically disseminate from immune hosts. Therefore in the context of natural infection, antibody neutralizes them poorly. Murid herpesvirus-4 (MuHV-4) provides a tractable model with which to understand gammaherpesvirus neutralization. MuHV-4 virions blocked for cell binding by immune sera remain infectious for IgG-Fc receptor myeloid cells, so broadly neutralizing antibodies must target the virion fusion complex – glycoprotein B (gB) or gH/gL. While gB-specific neutralizing antibodies are rare, its domains I+II (gB-N) contain at least one potent neutralization epitope. Here, we tested whether immunization with recombinant gB presenting this epitope could induce neutralizing antibodies in naive mice and protect them against MuHV-4 challenge. Immunizing with the full-length gB extracellular domain induced a strong gB-specific antibody response and reduced MuHV-4 lytic replication but did not induce detectable neutralization. gB-N alone, which more selectively displayed pre-fusion epitopes including neutralization epitopes, also failed to induce neutralizing responses, and while viral lytic replication was again reduced this depended completely on IgG Fc receptors. gB and gB-N also boosted neutralizing responses in only a minority of carrier mice. Therefore, it appears that neutralizing epitopes on gB are intrinsically difficult for the immune response to target.

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2010-10-01
2019-11-22
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References

  1. Adler, H., Messerle, M., Wagner, M. & Koszinowski, U. H. ( 2000; ). Cloning and mutagenesis of the murine gammaherpesvirus 68 genome as an infectious bacterial artificial chromosome. J Virol 74, 6964–6974.[CrossRef]
    [Google Scholar]
  2. Akula, S. M., Pramod, N. P., Wang, F. Z. & Chandran, B. ( 2001; ). Human herpesvirus 8 envelope-associated glycoprotein B interacts with heparan sulfate-like moieties. Virology 284, 235–249.[CrossRef]
    [Google Scholar]
  3. Bennett, N. J., May, J. S. & Stevenson, P. G. ( 2005; ). Gamma-herpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol 3, e120.[CrossRef]
    [Google Scholar]
  4. Burton, D. R., Stanfield, R. L. & Wilson, I. A. ( 2005; ). Antibody vs. HIV in a clash of evolutionary titans. Proc Natl Acad Sci U S A 102, 14943–14948.[CrossRef]
    [Google Scholar]
  5. Cranage, M. P., Kouzarides, T., Bankier, A. T., Satchwell, S., Weston, K., Tomlinson, P., Barrell, B., Hart, H., Bell, S. E. & other authors ( 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.
    [Google Scholar]
  6. Davison, A. J. & Moss, B. ( 1990; ). New vaccinia virus recombination plasmids incorporating a synthetic late promoter for high level expression of foreign proteins. Nucleic Acids Res 18, 4285–4286.[CrossRef]
    [Google Scholar]
  7. de Lima, B. D., May, J. S. & Stevenson, P. G. ( 2004; ). Murine gammaherpesvirus 68 lacking gp150 shows defective virion release but establishes normal latency in vivo. J Virol 78, 5103–5112.[CrossRef]
    [Google Scholar]
  8. Dialyna, I. A., Graham, D., Rezaee, R., Blue, C. E., Stavrianeas, N. G., Neisters, H. G., Spandidos, D. A. & Blackbourn, D. J. ( 2004; ). Anti-HHV-8/KSHV antibodies in infected individuals inhibit infection in vitro. AIDS 18, 1263–1270.[CrossRef]
    [Google Scholar]
  9. Gangappa, S., Kapadia, S. B., Speck, S. H. & Virgin, H. W. ( 2002; ). Antibody to a lytic cycle viral protein decreases gammaherpesvirus latency in B-cell-deficient mice. J Virol 76, 11460–11468.[CrossRef]
    [Google Scholar]
  10. Gill, M. B., Gillet, L., Colaco, S., May, J. S., de Lima, B. D. & Stevenson, P. G. ( 2006; ). Murine gammaherpesvirus-68 glycoprotein H-glycoprotein L complex is a major target for neutralizing monoclonal antibodies. J Gen Virol 87, 1465–1475.[CrossRef]
    [Google Scholar]
  11. Gillet, L. & Stevenson, P. G. ( 2007a; ). Evidence for a multiprotein gamma-2 herpesvirus entry complex. J Virol 81, 13082–13091.[CrossRef]
    [Google Scholar]
  12. Gillet, L. & Stevenson, P. G. ( 2007b; ). Antibody evasion by the N terminus of murid herpesvirus-4 glycoprotein B. EMBO J 26, 5131–5142.[CrossRef]
    [Google Scholar]
  13. Gillet, L., Gill, M. B., Colaco, S., Smith, C. M. & Stevenson, P. G. ( 2006; ). Murine gammaherpesvirus-68 glycoprotein B presents a difficult neutralization target to monoclonal antibodies derived from infected mice. J Gen Virol 87, 3515–3527.[CrossRef]
    [Google Scholar]
  14. Gillet, L., Adler, H. & Stevenson, P. G. ( 2007a; ). Glycosaminoglycan interactions in murine gammaherpesvirus-68 infection. PLoS ONE 2, e347.[CrossRef]
    [Google Scholar]
  15. Gillet, L., May, J. S. & Stevenson, P. G. ( 2007b; ). Post-exposure vaccination improves gammaherpesvirus neutralization. PLoS ONE 2, e899.[CrossRef]
    [Google Scholar]
  16. Gillet, L., May, J. S., Colaco, S. & Stevenson, P. G. ( 2007c; ). The murine gammaherpesvirus-68 gp150 acts as an immunogenic decoy to limit virion neutralization. PLoS ONE 2, e705.[CrossRef]
    [Google Scholar]
  17. Gillet, L., Colaco, S. & Stevenson, P. G. ( 2008a; ). The murid herpesvirus-4 gH/gL binds to glycosaminoglycans. PLoS ONE 3, e1669.[CrossRef]
    [Google Scholar]
  18. Gillet, L., Colaco, S. & Stevenson, P. G. ( 2008b; ). The murid herpesvirus-4 gL regulates an entry-associated conformation change in gH. PLoS ONE 3, e2811.[CrossRef]
    [Google Scholar]
  19. Gillet, L., Colaco, S. & Stevenson, P. G. ( 2008c; ). Glycoprotein B switches conformation during murid herpesvirus 4 entry. J Gen Virol 89, 1352–1363.[CrossRef]
    [Google Scholar]
  20. Gillet, L., Alenquer, M., Glauser, D. L., Colaco, S., May, J. S. & Stevenson, P. G. ( 2009a; ). Glycoprotein L sets the neutralization profile of murid herpesvirus-4. J Gen Virol 90, 1202–1214.[CrossRef]
    [Google Scholar]
  21. Gillet, L., May, J. S. & Stevenson, P. G. ( 2009b; ). In vivo importance of heparan sulfate-binding glycoproteins for murid herpesvirus-4 infection. J Gen Virol 90, 602–613.[CrossRef]
    [Google Scholar]
  22. 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]
  23. Heldwein, E. E., Lou, H., Bender, F. C., Cohen, G. H., Eisenberg, R. J. & Harrison, S. C. ( 2006; ). Crystal structure of glycoprotein B from herpes simplex virus 1. Science 313, 217–220.[CrossRef]
    [Google Scholar]
  24. Highlander, S. L., Cai, W. H., Person, S., Levine, M. & Glorioso, J. C. ( 1988; ). Monoclonal antibodies define a domain on herpes simplex virus glycoprotein B involved in virus penetration. J Virol 62, 1881–1888.
    [Google Scholar]
  25. Janz, A., Oezel, M., Kurzeder, C., Mautner, J., Pich, D., Kost, M., Hammerschmidt, W. & Delecluse, H. J. ( 2000; ). Infectious Epstein–Barr virus lacking major glycoprotein BLLF1 (gp350/220) demonstrates the existence of additional viral ligands. J Virol 74, 10142–10152.[CrossRef]
    [Google Scholar]
  26. Kim, I. J., Flaño, E., Woodland, D. L. & Blackman, M. A. ( 2002; ). Antibody-mediated control of persistent gamma-herpesvirus infection. J Immunol 168, 3958–3964.[CrossRef]
    [Google Scholar]
  27. Li, Q., Turk, S. M. & Hutt-Fletcher, L. M. ( 1995; ). The Epstein–Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells. J Virol 69, 3987–3994.
    [Google Scholar]
  28. Lopes, F. B., Colaco, S., May, J. S. & Stevenson, P. G. ( 2004; ). Characterization of the murine gamma-herpesvirus 68 glycoprotein B. J Virol 78, 13370–13375.[CrossRef]
    [Google Scholar]
  29. May, J. S., Coleman, H. M., Boname, J. M. & Stevenson, P. G. ( 2005; ). Murine gammaherpesvirus-68 ORF28 encodes a non-essential virion glycoprotein. J Gen Virol 86, 919–928.[CrossRef]
    [Google Scholar]
  30. Milho, R., Smith, C. M., Marques, S., Alenquer, M., May, J. S., Gillet, L., Gaspar, M., Efstathiou, S., Simas, J. P. & Stevenson, P. G. ( 2009; ). In vivo imaging of murid herpesvirus-4 infection. J Gen Virol 90, 21–32.[CrossRef]
    [Google Scholar]
  31. Naranatt, P. P., Akula, S. M. & Chandran, B. ( 2002; ). Characterization of γ2-human herpesvirus-8 glycoproteins gH and gL. Arch Virol 147, 1349–1370.[CrossRef]
    [Google Scholar]
  32. Nazerian, K., Lee, L. F., Yanagida, N. & Ogawa, R. ( 1992; ). Protection against Marek's disease by a fowlpox virus recombinant expressing the glycoprotein B of Marek's disease virus. J Virol 66, 1409–1413.
    [Google Scholar]
  33. 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. J Virol 67, 703–710.
    [Google Scholar]
  34. Okazaki, K., Fujii, S., Takada, A. & Kida, H. ( 2006; ). The amino-terminal residue of glycoprotein B is critical for neutralization of bovine herpesvirus 1. Virus Res 115, 105–111.[CrossRef]
    [Google Scholar]
  35. Pass, R. F., Zhang, C., Evans, A., Simpson, T., Andrews, W., Huang, M. L., Corey, L., Hill, J., Davis, E. & other authors ( 2009; ). Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 360, 1191–1199.[CrossRef]
    [Google Scholar]
  36. Roche, S., Rey, F. A., Gaudin, Y. & Bressanelli, S. ( 2007; ). Structure of the prefusion form of the vesicular stomatitis virus glycoprotein G. Science 315, 843–848.[CrossRef]
    [Google Scholar]
  37. Rosa, G. T., Gillet, L., Smith, C. M., de Lima, B. D. & Stevenson, P. G. ( 2007; ). IgG Fc receptors provide an alternative infection route for murine gamma-herpesvirus-68. PLoS ONE 2, e560.[CrossRef]
    [Google Scholar]
  38. Sakamoto, K., Asanuma, H., Nakamura, T., Kanno, T., Sata, T. & Katano, H. ( 2010; ). Immune response to intranasal and intraperitoneal immunization with Kaposi's sarcoma-associated herpesvirus in mice. Vaccine 28, 3325–3332.[CrossRef]
    [Google Scholar]
  39. Smith, C. M., Rosa, G. T., May, J. S., Bennett, N. J., Mount, A. M., Belz, G. T. & Stevenson, P. G. ( 2006; ). CD4+ T cells specific for a model latency-associated antigen fail to control a gammaherpesvirus in vivo. Eur J Immunol 36, 3186–3197.[CrossRef]
    [Google Scholar]
  40. Sokal, E. M., Hoppenbrouwers, K., Vandermeulen, C., Moutschen, M., Léonard, P., Moreels, A., Haumont, M., Bollen, A., Smets, F. & Denis, M. ( 2007; ). Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein–Barr virus vaccine in healthy young adults. J Infect Dis 196, 1749–1753.[CrossRef]
    [Google Scholar]
  41. Speckner, A., Glykofrydes, D., Ohlin, M. & Mach, M. ( 1999; ). Antigenic domain 1 of human cytomegalovirus glycoprotein B induces a multitude of different antibodies which, when combined, results in incomplete virus neutralization. J Gen Virol 80, 2183–2191.
    [Google Scholar]
  42. Stevenson, P. G., Cardin, R. D., Christensen, J. P. & Doherty, P. C. ( 1999a; ). Immunological control of a murine gammaherpesvirus independent of CD8+ T cells. J Gen Virol 80, 477–483.
    [Google Scholar]
  43. Stevenson, P. G., Belz, G. T., Castrucci, M. R., Altman, J. D. & Doherty, P. C. ( 1999b; ). A gamma-herpesvirus sneaks through a CD8+ T cell response primed to a lytic-phase epitope. Proc Natl Acad Sci U S A 96, 9281–9286.[CrossRef]
    [Google Scholar]
  44. Stevenson, P. G., May, J. S., Smith, X. G., Marques, S., Adler, H., Koszinowski, U. H., Simas, J. P. & Efstathiou, S. ( 2002; ). K3-mediated evasion of CD8+ T cells aids amplification of a latent gamma-herpesvirus. Nat Immunol 3, 733–740.
    [Google Scholar]
  45. Stevenson, P. G., Simas, J. P. & Efstathiou, S. ( 2009; ). Immune control of mammalian gamma-herpesviruses: lessons from murid herpesvirus-4. J Gen Virol 90, 2317–2330.[CrossRef]
    [Google Scholar]
  46. Thorley-Lawson, D. A. & Poodry, C. A. ( 1982; ). Identification and isolation of the main component (gp350-gp220) of Epstein–Barr virus responsible for generating neutralizing antibodies in vivo. J Virol 43, 730–736.
    [Google Scholar]
  47. Turk, S. M., Jiang, R., Chesnokova, L. S. & Hutt-Fletcher, L. M. ( 2006; ). Antibodies to gp350/220 enhance the ability of Epstein–Barr virus to infect epithelial cells. J Virol 80, 9628–9633.[CrossRef]
    [Google Scholar]
  48. 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]
  49. Willey, D. E., Cantin, E. M., Hill, L. R., Moss, B., Notkins, A. L. & Openshaw, H. ( 1988; ). Herpes simplex virus type 1-vaccinia virus recombinant expressing glycoprotein B: protection from acute and latent infection. J Infect Dis 158, 1382–1386.[CrossRef]
    [Google Scholar]
  50. Wright, D. E., Colaco, S., Colaco, C. & Stevenson, P. G. ( 2009; ). Antibody limits in vivo murid herpesvirus-4 replication by IgG Fc receptor-dependent functions. J Gen Virol 90, 2592–2603.[CrossRef]
    [Google Scholar]
  51. Yewdell, J. W. & Hill, A. B. ( 2002; ). Viral interference with antigen presentation. Nat Immunol 3, 1019–1025.[CrossRef]
    [Google Scholar]
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vol. , part 10, pp. 2542 - 2552

Boosting gB-specific antibody responses by post-exposure vaccination of BALB/c MuHV-4 carrier mice

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