1887

Abstract

Human herpesvirus-6 (HHV-6), like other betaherpesviruses, shows cell fusion with wild-type strains, and this cellular spread is mediated by the glycoprotein gH/gL complex. Anti-fusion monoclonal antibodies (MAbs) specific for HHV-6 glycoprotein gH inhibit infection and prevent cellular spread by syncytia formation. Reactivity of these MAbs with gH deletion mutants suggests a conserved C-terminal fusion-associated domain. A conserved motif here has an N-glycosylation site and characteristics of a beta turn. Motif deletion abrogated MAb recognition while co-expression with glycoprotein gL restored this conformational epitope, indicating the importance of folding and not glycosylation at this site. Our previous studies showed gL binding to gH at an N-terminal domain specific for betaherpesviruses. To further examine the function of this N-terminal domain, a betaherpesvirus-specific motif was deleted. This mutant gH still bound gL, and was recognized by the anti-fusion MAbs; however, recognition was now primarily in the immature form and reduced during processing to the mature form. A model is discussed whereby gL binding gH at the N-terminal domain acts to draw together the C-terminal extracellular domain and this interaction affects a functional conformation during glycoprotein maturation.

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1999-06-01
2024-06-17
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References

  1. Anderson R. A., Liu D. X., Gompels U. A. 1996; Definition of a human herpesvirus-6 betaherpesvirus-specific domain in glycoprotein gH that governs interaction with glycoprotein gL: substitution of human cytomegalovirus glycoproteins permits group-specific complex formation. Virology 217:517–526
    [Google Scholar]
  2. Babic N., Klupp B. G., Makoschey B., Karger A., Flamand A., Mettenleiter T. C. 1996; Glycoprotein gH of pseudorabies virus is essential for penetration and propagation in cell culture and in the nervous system of mice. Journal of General Virology 77:2277–2285
    [Google Scholar]
  3. Balachandran N., Amelse R. E., Zhou W. W., Chang C. K. 1989; Identification of proteins specific for human herpesvirus 6-infected human T cells. Journal of Virology 63:2835–2840
    [Google Scholar]
  4. Browne H. M., Bruun B. C., Minson A. C. 1996; Characterization of herpes simplex virus type 1 recombinants with mutations in the cytoplasmic tail of glycoprotein H. Journal of General Virology 77:2569–2573
    [Google Scholar]
  5. Cranage M. P., Smith G. L., Bell S. E., Hart H., Brown C., Bankier A. T., Tomlinson P., Barrell B. G., Minson T. C. 1988; Identification and expression of a human cytomegalovirus glycoprotein with homology to the Epstein–Barr virus BXLF2 product, varicella-zoster virus gpIII, and herpes simplex virus type 1 glycoprotein H. Journal of Virology 62:1416–1422
    [Google Scholar]
  6. Dubin G., Jiang H. 1995; Expression of herpes simplex virus type 1 glycoprotein L (gL) in transfected mammalian cells: evidence that gL is not independently anchored to cell membranes. Journal of Virology 69:4564–4568
    [Google Scholar]
  7. Duus K. M., Grose C. 1996; Multiple regulatory effects of varicella-zoster virus (VZV) gL on trafficking patterns and fusogenic properties of VZV gH. Journal of Virology 70:8961–8971
    [Google Scholar]
  8. Duus K. M., Hatfield C., Grose C. 1995; Cell surface expression and fusion by the varicella-zoster virus gH: gL glycoprotein complex analysis by laser scanning confocal microscopy. Virology 210:429–440
    [Google Scholar]
  9. Foa-Tomasi L., Avitabile E., Boscaro A., Brandimarti R., Gualandri R., Manservigi R., Dall’Olio F., Serafini-Cessi F., Campadelli Fiume G. 1991a; Herpes simplex virus (HSV) glycoprotein H is partially processed in a cell line that expresses the glycoprotein and fully processed in cells infected with deletion or ts mutants in the known HSV glycoproteins. Virology 180:474–482
    [Google Scholar]
  10. Foa-Tomasi L., Boscaro A., Di Gaeta S., Campadelli-Fiume G. 1991b; Monoclonal antibodies to gp100 inhibit penetration of human herpesvirus 6 and polykaryocyte formation in susceptible cells. Journal of Virology 65:4124–4129
    [Google Scholar]
  11. Forghani B., Ni L., Grose C. 1994; Neutralization epitope of the varicella-zoster virus gH:gL glycoprotein complex. Virology 199:458–462
    [Google Scholar]
  12. 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. Journal of Virology 66:341–348
    [Google Scholar]
  13. 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. Journal of Virology 63:3435–3443
    [Google Scholar]
  14. Galdiero M., Whiteley A., Bruun B., Bell S., Minson T., Browne H. 1997; Site-directed and linker insertion mutagenesis of herpes simplex virus type 1 glycoprotein H. Journal of Virology 71:2163–2170
    [Google Scholar]
  15. Gompels U. A. 1998; Human herpesvirus 6 and 7; HHV-6 and HHV-7. In Principles and Practice of Clinical Virology (in press) Edited by Zuckerman A. J., Banatvala J. E., Pattison J. R. Chichester, UK: John Wiley & Sons;
    [Google Scholar]
  16. Gompels U., Minson A. 1986; The properties and sequence of glycoprotein H of herpes simplex virus type 1. Virology 153:230–247
    [Google Scholar]
  17. Gompels U. A., Minson A. C. 1989; Antigenic properties and cellular localization of herpes simplex virus glycoprotein H synthesized in amammalian cell expression system. JournalofVirology 63:4744–4755
    [Google Scholar]
  18. Gompels U. A., Carss A. L., Saxby C., Hancock D. C., Forrester A., Minson A. C. 1991; Characterization and sequence analyses of antibody-selected antigenic variants of herpes simplex virus show a conformationally complex epitope on glycoprotein H. Journal of Virology 65:2393–2401
    [Google Scholar]
  19. Gompels U. A., Carrigan D. R., Carss A. L., Arno J. 1993; Two groups of human herpesvirus 6 identified by sequence analyses of laboratory strains and variants from Hodgkin’s lymphoma and bone marrow transplant patients. Journal of General Virology 74:613–622
    [Google Scholar]
  20. Gompels U. A., Nicholas J., Lawrence G., Jones M., Thomson B. J., Martin M., Efstathiou S., Craxton M., Macaulay H. A. 1995; The DNA sequence of human herpesvirus-6: structure, coding content, and genome evolution. Virology 209:29–51
    [Google Scholar]
  21. Gretch D. R., Kari B., Rasmussen L., Gehrz R. C., Stinski M. F. 1988; Identification and characterization of three distinct families of glycoprotein complexes in the envelopes of human cytomegalovirus. Journal of Virology 62:875–881
    [Google Scholar]
  22. Handler C. G., Eisenberg R. J., Cohen G. H. 1996; Oligomeric structure of glycoproteins in herpes simplex virus type 1. Journal of Virology 70:6067–6075
    [Google Scholar]
  23. Huber M. T., Compton T. 1998; The human cytomegalovirus UL74 gene encodes the third component of the glycoprotein H-glycoprotein L-containing envelope complex. Journal of Virology 72:8191–8197
    [Google Scholar]
  24. 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. Journal of Virology 66:2240–2250
    [Google Scholar]
  25. Kaye J. F., Gompels U. A., Minson A. C. 1992; Glycoprotein H of human cytomegalovirus (HCMV) forms a stable complex with the HCMV UL115 gene product. Journal of General Virology 73:2693–2698
    [Google Scholar]
  26. Klupp B. G., Fuchs W., Weiland E., Mettenleiter T. C. 1997; Pseudorabies virus glycoprotein L is necessary for virus infectivity but dispensable for virion localization of glycoprotein H. Journal of Virology 71:7687–7695
    [Google Scholar]
  27. Kunkel T. A. 1985; Rapid and efficient site-specific mutagenesis without phenotypic selection. Proceedings of the National Academy of Sciences, USA 82:488–492
    [Google Scholar]
  28. 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. Journal of Virology 69:3987–3994
    [Google Scholar]
  29. Li L., Nelson J. A., Britt W. J. 1997a; Glycoprotein H-related complexes of human cytomegalovirus: identification of a third protein of the gclll complex. Journal of Virology 69:3090–3097
    [Google Scholar]
  30. Li Q., Buranathai C., Grose C., Hutt-Fletcher L. M. 1997b; Chaperone functions common to nonhomologous Epstein–Barr virus gL and varicella-zoster virus gL proteins. Journal of Virology 71:1067–1670
    [Google Scholar]
  31. Liu D. X., Gompels U. A., Foa-Tomasi L., Campadelli-Fiume G. 1993a; Human herpesvirus-6 glycoprotein H and L homologs are components of the gp100 complex and the gH external domain is the target for neutralizing monoclonal antibodies. Virology 197:12–22
    [Google Scholar]
  32. Liu D. X., Gompels U. A., Nicholas J., Lelliott C. 1993b; Identification and expression of the human herpesvirus 6 glycoprotein H and interaction with an accessory 40K glycoprotein. Journal of General Virology 74:1847–1857
    [Google Scholar]
  33. Mackett M. 1995; Construction and characterization of vaccinia virus recombinants. In DNA Cloning IV. A PracticalApproach pp 43–83 Edited by Glover D. M., Hames B. D. Oxford, UK: IRL Press;
    [Google Scholar]
  34. Minson A. C., Hodgman T. C., Digard P., Hancock D. C., Bell S. E., Buckmaster E. A. 1986; An analysis of the biological properties of monoclonal antibodies against glycoprotein D of herpes simplex virus and identification of amino acid substitutions that confer resistance to neutralization. Journal of General Virology 67:1001–1013
    [Google Scholar]
  35. Montalvo E. A., Grose C. 1986; Neutralization epitope of varicella zoster virus on native viral glycoprotein gp118 (VZV glycoprotein gpIII). Virology 149:230–241
    [Google Scholar]
  36. Novotny M. J., Parish M. L., Spear P. G. 1996; Variability of herpes simplex virus 1 gL and anti-gL antibodies that inhibit cell fusion but not viral infectivity. Virology 221:1–13
    [Google Scholar]
  37. Okuno T., Sao H., Asada H., Shiraki K., Takahashi M., Yamanishi K. 1990; Analysis of a glycoprotein of human herpesvirus 6 (HHV-6) using monoclonal antibodies. Virology 176:625–628
    [Google Scholar]
  38. Peng T., Ponce de Leon M., Novotny M. J., Jiang H., Lambris J. D., Dubin G., Spear P. G., Cohen G. H., Eisenberg R. J. 1998; Structural and antigenic analysis of a truncated form of the herpes simplex virus glycoprotein gH-gL complex. Journal of Virology 72:6092–6103
    [Google Scholar]
  39. Qian G., Wood C., Chandran B. 1993; Identification and characterisation of glycoprotein gH of human herpesvirus-6. Virology 194:380–386
    [Google Scholar]
  40. Roberts S. R., De Leon M. P., Cohen G. H., Eisenberg R. J. 1991; Analysis of the intracellular maturation of the herpes simplex virus type 1 glycoprotein gH in infected and transfected cells. Virology 184:609–624
    [Google Scholar]
  41. Rodriguez J. E., Moninger T., Grose C. 1993; Entry and egress of varicella virus blocked by same anti-gH monoclonal antibody. Virology 196:840–844
    [Google Scholar]
  42. Roop C., Hutchinson L., Johnson D. C. 1993; A mutant herpes simplex virus type 1 unable to express glycoprotein L cannot enter cells, and its particles lack glycoprotein H. Journal of Virology 67:2285–2297
    [Google Scholar]
  43. Simpson J. A., Chow J. C., Baker J., Avdalovic N., Yuan S., Au D., Man S. C., 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. Journal of Virology 67:489–496
    [Google Scholar]
  44. Spaete R. R., Perot K., Scott P. I., Nelson J. A., Stinski M. F., Pachl C. 1993; Coexpression of truncated human cytomegalovirus gH with the UL115 gene product or the truncated human fibroblast growth factor receptor results in transport of gH to the cell surface. Virology 193:853–861
    [Google Scholar]
  45. Takeda K., Haque M., Sunagawa T., Okuno T., Isegawa Y., Yamanishi K. 1997; Identification of a variant B-specific neutralizing epitope on glycoprotein H of human herpesvirus-6. Journal of General Virology 78:2171–2178
    [Google Scholar]
  46. 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. Journal of Virology 72:873–875
    [Google Scholar]
  47. van Drunen Littel-van den Hurk S., Khattar S., Tikoo S. K., Babiuk L. A., Baranowski E., Plainchamp D., Thiry E. 1996; Glycoprotein H (gpII/gp108) and glycoprotein L form a functional complex which plays a role in penetration, but not in attachment, of bovine herpesvirus 1. Journal of General Virology 77:1515–1520
    [Google Scholar]
  48. Wilson D. W., Davis-Poynter N., Minson A. C. 1994; Mutations in the cytoplasmic tail of herpes simplex virus glycoprotein H suppress cell fusion by a syncytial strain. Journal of Virology 68:6985–6993
    [Google Scholar]
  49. Yaswen L. R., Stephens E. B., Davenport L. C., Hutt-Fletcher L. M. 1993; Epstein–Barr virus glycoprotein gp85 associates with the BKRF2 gene product and is incompletely processed as a recombinant protein. Virology 195:387–396
    [Google Scholar]
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