1887

Abstract

Herpesviruses consistently transmit from immunocompetent carriers, implying that their neutralization is hard to achieve. Murid herpesvirus-4 (MuHV-4) exploits host IgG Fc receptors to bypass blocks to cell binding, and pH-dependent protein conformation changes to unveil its fusion machinery only after endocytosis. Nevertheless, neutralization remains possible by targeting the virion glycoprotein H (gH)–gL heterodimer, and the neutralizing antibody responses of MuHV-4 carriers are improved by boosting with recombinant gH–gL. We analysed here how gH–gL-directed neutralization works. The MuHV-4 gH–gL binds to heparan sulfate. However, most gH–gL-specific neutralizing antibodies did not block this interaction; neither did they act directly on fusion. Instead, they blocked virion endocytosis and transport to the late endosomes, where membrane fusion normally occurs. The poor endocytosis of gH–gL-neutralized virions was recapitulated precisely by virions genetically lacking gL. Therefore, driving virion uptake appears to be an important function of gH–gL that provides a major target for antibody-mediated neutralization.

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2012-06-01
2020-07-04
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References

  1. Barton E., Mandal P., Speck S. H.. 2011; Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol29:351–397 [CrossRef][PubMed]
    [Google Scholar]
  2. Chandran B.. 2010; Early events in Kaposi’s sarcoma-associated herpesvirus infection of target cells. J Virol84:2188–2199 [CrossRef][PubMed]
    [Google Scholar]
  3. Chesnokova L. S., Hutt-Fletcher L. M.. 2011; Fusion of Epstein–Barr virus with epithelial cells can be triggered by αvβ5 in addition to αvβ6 and αvβ8, and integrin binding triggers a conformational change in glycoproteins gHgL. J Virol85:13214–13223 [CrossRef][PubMed]
    [Google Scholar]
  4. Chesnokova L. S., Nishimura S. L., Hutt-Fletcher L. M.. 2009; Fusion of epithelial cells by Epstein–Barr virus proteins is triggered by binding of viral glycoproteins gHgL to integrins αvβ6 or αvβ8. Proc Natl Acad Sci U S A106:20464–20469 [CrossRef][PubMed]
    [Google Scholar]
  5. Chowdary T. K., Cairns T. M., Atanasiu D., Cohen G. H., Eisenberg R. J., Heldwein E. E.. 2010; Crystal structure of the conserved herpesvirus fusion regulator complex gH–gL. Nat Struct Mol Biol17:882–888 [CrossRef][PubMed]
    [Google Scholar]
  6. 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 Virol78:5103–5112 [CrossRef][PubMed]
    [Google Scholar]
  7. 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. AIDS18:1263–1270 [CrossRef][PubMed]
    [Google Scholar]
  8. Everett R. D., Chelbi-Alix M. K.. 2007; PML and PML nuclear bodies: implications in antiviral defence. Biochimie89:819–830 [CrossRef][PubMed]
    [Google Scholar]
  9. Forrester A., Farrell H., Wilkinson G., Kaye J., Davis-Poynter N., Minson T.. 1992; Construction and properties of a mutant of herpes simplex virus type 1 with glycoprotein H coding sequences deleted. J Virol66:341–348[PubMed]
    [Google Scholar]
  10. Fuller A. O., Santos R. E., Spear P. G.. 1989; Neutralizing antibodies specific for glycoprotein H of herpes simplex virus permit viral attachment to cells but prevent penetration. J Virol63:3435–3443[PubMed]
    [Google Scholar]
  11. Gangappa S., Kapadia S. B., Speck S. H., Virgin H. W. IV. 2002; Antibody to a lytic cycle viral protein decreases gammaherpesvirus latency in B-cell-deficient mice. J Virol76:11460–11468 [CrossRef][PubMed]
    [Google Scholar]
  12. Gaspar M., Gill M. B., Lösing J. B., May J. S., Stevenson P. G.. 2008; Multiple functions for ORF75c in murid herpesvirus-4 infection. PLoS One3:e2781 [CrossRef][PubMed]
    [Google Scholar]
  13. 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 Virol87:1465–1475 [CrossRef][PubMed]
    [Google Scholar]
  14. Gillet L., Stevenson P. G.. 2007; Evidence for a multiprotein gamma-2 herpesvirus entry complex. J Virol81:13082–13091 [CrossRef][PubMed]
    [Google Scholar]
  15. Gillet L., May J. S., Stevenson P. G.. 2007a; Post-exposure vaccination improves gammaherpesvirus neutralization. PLoS One2:e899 [CrossRef][PubMed]
    [Google Scholar]
  16. Gillet L., May J. S., Colaco S., Stevenson P. G.. 2007b; The murine gammaherpesvirus-68 gp150 acts as an immunogenic decoy to limit virion neutralization. PLoS One2:e705 [CrossRef][PubMed]
    [Google Scholar]
  17. Gillet L., Adler H., Stevenson P. G.. 2007c; Glycosaminoglycan interactions in murine gammaherpesvirus-68 infection. PLoS One2:e347 [CrossRef][PubMed]
    [Google Scholar]
  18. Gillet L., May J. S., Colaco S., Stevenson P. G.. 2007d; Glycoprotein L disruption reveals two functional forms of the murine gammaherpesvirus 68 glycoprotein H. J Virol81:280–291 [CrossRef][PubMed]
    [Google Scholar]
  19. Gillet L., Colaco S., Stevenson P. G.. 2008a; The murid herpesvirus-4 gH/gL binds to glycosaminoglycans. PLoS One3:e1669 [CrossRef][PubMed]
    [Google Scholar]
  20. Gillet L., Colaco S., Stevenson P. G.. 2008b; The Murid Herpesvirus-4 gL regulates an entry-associated conformation change in gH. PLoS One3:e2811 [CrossRef][PubMed]
    [Google Scholar]
  21. Gillet L., Colaco S., Stevenson P. G.. 2008c; Glycoprotein B switches conformation during murid herpesvirus 4 entry. J Gen Virol89:1352–1363 [CrossRef][PubMed]
    [Google Scholar]
  22. Gillet L., Alenquer M., Glauser D. L., Colaco S., May J. S., Stevenson P. G.. 2009; Glycoprotein L sets the neutralization profile of murid herpesvirus 4. J Gen Virol90:1202–1214 [CrossRef][PubMed]
    [Google Scholar]
  23. Glauser D. L., Kratz A. S., Gillet L., Stevenson P. G.. 2011; A mechanistic basis for potent, glycoprotein B-directed gammaherpesvirus neutralization. J Gen Virol92:2020–2033 [CrossRef][PubMed]
    [Google Scholar]
  24. Glauser D. L., Kratz A. S., Stevenson P. G.. 2012; Herpesvirus glycoproteins undergo multiple antigenic changes before membrane fusion. PLoS One7:e30152 [CrossRef][PubMed]
    [Google Scholar]
  25. Hahn A., Birkmann A., Wies E., Dorer D., Mahr K., Stürzl M., Titgemeyer F., Neipel F.. 2009; Kaposi’s sarcoma-associated herpesvirus gH/gL: glycoprotein export and interaction with cellular receptors. J Virol83:396–407 [CrossRef][PubMed]
    [Google Scholar]
  26. Hutchinson L., Browne H., Wargent V., Davis-Poynter N., Primorac S., Goldsmith K., Minson A. C., Johnson D. C.. 1992; A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH. J Virol66:2240–2250[PubMed]
    [Google Scholar]
  27. Kim I. J., Flaño E., Woodland D. L., Blackman M. A.. 2002; Antibody-mediated control of persistent gamma-herpesvirus infection. J Immunol168:3958–3964[PubMed][CrossRef]
    [Google Scholar]
  28. Lété C., Machiels B., Stevenson P. G., Vanderplasschen A., Gillet L.. 2012; Bovine herpesvirus type 4 glycoprotein L is nonessential for infectivity but triggers virion endocytosis during entry. J Virol86:2653–2664[CrossRef]
    [Google Scholar]
  29. Mancini G., Carbonara A. O., Heremans J. F.. 1965; Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry2:235–254 [CrossRef][PubMed]
    [Google Scholar]
  30. May J. S., Stevenson P. G.. 2010; Vaccination with murid herpesvirus-4 glycoprotein B reduces viral lytic replication but does not induce detectable virion neutralization. J Gen Virol91:2542–2552 [CrossRef][PubMed]
    [Google Scholar]
  31. May J. S., Coleman H. M., Smillie B., Efstathiou S., Stevenson P. G.. 2004; Forced lytic replication impairs host colonization by a latency-deficient mutant of murine gammaherpesvirus-68. J Gen Virol85:137–146 [CrossRef][PubMed]
    [Google Scholar]
  32. Miller N., Hutt-Fletcher L. M.. 1988; A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein–Barr virus. J Virol62:2366–2372[PubMed]
    [Google Scholar]
  33. Naranatt P. P., Akula S. M., Chandran B.. 2002; Characterization of gamma2-human herpesvirus-8 glycoproteins gH and gL. Arch Virol147:1349–1370 [CrossRef][PubMed]
    [Google Scholar]
  34. Parry C., Bell S., Minson T., Browne H.. 2005; Herpes simplex virus type 1 glycoprotein H binds to αvβ3 integrins. J Gen Virol86:7–10 [CrossRef][PubMed]
    [Google Scholar]
  35. 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 One2:e560 [CrossRef][PubMed]
    [Google Scholar]
  36. 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 Dis196:1749–1753 [CrossRef][PubMed]
    [Google Scholar]
  37. Stevenson P. G., Doherty P. C.. 1998; Kinetic analysis of the specific host response to a murine gammaherpesvirus. J Virol72:943–949[PubMed]
    [Google Scholar]
  38. Stevenson P. G., Simas J. P., Efstathiou S.. 2009; Immune control of mammalian gammaherpesviruses: lessons from murid herpesvirus-4. J Gen Virol90:2317–2330 [CrossRef][PubMed]
    [Google Scholar]
  39. 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 Virol43:730–736[PubMed]
    [Google Scholar]
  40. Turner A., Bruun B., Minson T., Browne H.. 1998; Glycoproteins gB, gD, and gHgL of herpes simplex virus type 1 are necessary and sufficient to mediate membrane fusion in a Cos cell transfection system. J Virol72:873–875[PubMed]
    [Google Scholar]
  41. 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 Virol90:2592–2603 [CrossRef][PubMed]
    [Google Scholar]
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