[en] Glycoprotein B (gB) is a conserved, essential component of gammaherpes virions and so potentially vulnerable to neutralization. However, few good gB-specific neutralizing antibodies have been identified. Here, we show that murid herpesvirus 4 is strongly neutralized by mAbs that recognize an epitope close to one of the gB fusion loops. Antibody binding did not stop gB interacting with its cellular ligands or initiating its fusion-associated conformation change, but did stop gB resolving stably to its post-fusion form, and so blocked membrane fusion to leave virions stranded in late endosomes. The conservation of gB makes this mechanism a possible general route to gammaherpesvirus neutralization.
Disciplines :
Microbiology
Author, co-author :
Glauser, Daniel L
Kratz, Anne*-Sophie
Gillet, Laurent ; Université de Liège - ULiège > Immunologie et vaccinologie
Stevenson, Philip G
Language :
English
Title :
A mechanistic basis for potent, glycoprotein B-directed gammaherpesvirus neutralization.
Publication date :
2011
Journal title :
Journal of General Virology
ISSN :
0022-1317
eISSN :
1465-2099
Publisher :
Society for General Microbiology, London, United Kingdom
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.
Akula, S. M., Pramod, N. P., Wang, F. Z. & Chandran, B. (2002). Integrin a3b1 (CD 49c/29) is a cellular receptor for Kaposi's sarcomaassociated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 108, 407-419.
Backovic, M., Jardetzky, T. S. & Longnecker, R. (2007). Hydrophobic residues that form putative fusion loops of Epstein-Barr virus glycoprotein B are critical for fusion activity. J Virol 81, 9596-9600.
Backovic, M., Longnecker, R. & Jardetzky, T. S. (2009). Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B. Proc Natl Acad Sci U S A 106, 2880-2885.
Baigent, S. J., Smith, L. P., Nair, V. K. & Currie, R. J. (2006). Vaccinal control of Marek's disease: current challenges, and future strategies to maximize protection. Vet Immunol Immunopathol 112, 78-86.
Balasubramanian, K. & Schroit, A. J. (2003). Aminophospholipid asymmetry: a matter of life and death. Annu Rev Physiol 65, 701-734.
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.
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.
Dollery, S. J., Delboy, M. G. & Nicola, A. V. (2010). Low pH-induced conformational change in herpes simplex virus glycoprotein B. J Virol 84, 3759-3766.
Efstathiou, S., Ho, Y. M., Hall, S., Styles, C. J., Scott, S. D. & Gompels, U. A. (1990). Murine herpesvirus 68 is genetically related to the gammaherpesviruses Epstein-Barr virus and herpesvirus saimiri. J Gen Virol 71, 1365-1372.
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 ONE 3, e2781.
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.
Gillet, L. & Stevenson, P. G. (2007a). Antibody evasion by the N terminus ofmurid herpesvirus-4 glycoprotein B. EMBO J 26, 5131-5142.
Gillet, L. & Stevenson, P. G. (2007b). Evidence for a multiprotein gamma-2 herpesvirus entry complex. J Virol 81, 13082-13091.
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.
Gillet, L., May, J. S. & Stevenson, P. G. (2007a). Post-exposure vaccination improves gammaherpesvirus neutralization. PLoS ONE 2, e899.
Gillet, L., Adler, H. & Stevenson, P. G. (2007b). Glycosaminoglycan interactions in murine gammaherpesvirus-68 infection. PLoS ONE 2, e347.
Gillet, L., May, J. S., Colaco, S. & Stevenson, P. G. (2007c). Glycoprotein L disruption reveals two functional forms of the murine gammaherpesvirus 68 glycoprotein H. J Virol 81, 280-291.
Gillet, L., Colaco, S. & Stevenson, P. G. (2008a). Glycoprotein B switches conformation during murid herpesvirus 4 entry. J Gen Virol 89, 1352-1363.
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.
Gillet, L., May, J. S. & Stevenson, P. G. (2009a). In vivo importance of heparan sulfate-binding glycoproteins for murid herpesvirus-4 infection. J Gen Virol 90, 602-613.
Gillet, L., Alenquer, M., Glauser, D. L., Colaco, S., May, J. S. & Stevenson, P. G. (2009b). Glycoprotein L sets the neutralization profile of murid herpesvirus 4. J Gen Virol 90, 1202-1214.
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.
Greenspan, N. S. & Cooper, L. J. (1995). Complementarity, specificity and the nature of epitopes and paratopes in multivalent interactions. Immunol Today 16, 226-230.
Hannah, B. P., Cairns, T. M., Bender, F. C., Whitbeck, J. C., Lou, H., Eisenberg, R. J. & Cohen, G. H. (2009). Herpes simplex virus glycoprotein B associates with target membranes via its fusion loops. J Virol 83, 6825-6836.
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.
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.
Hutt-Fletcher, L. M. (2007). Epstein-Barr virus entry. J Virol 81, 7825-7832.
Klein, R. J. (1989). Reinfections and site-specific immunity in herpes simplex virus infections. Vaccine 7, 380-381.
Knossow, M. & Skehel, J. J. (2006). Variation and infectivity neutralization in influenza. Immunology 119, 1-7.
Kobayashi, T., Gu, F. & Gruenberg, J. (1998). Lipids, lipid domains and lipid-protein interactions in endocytic membrane traffic. Semin Cell Dev Biol 9, 517-526.
Lopes, F. B., Colaco, S., May, J. S. & Stevenson, P. G. (2004). Characterization of murine gammaherpesvirus 68 glycoprotein B. J Virol 78, 13370-13375.
Mancini, G., Carbonara, A. O. & Heremans, J. F. (1965). Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry 2, 235-254.
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 Virol 91, 2542-2552.
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 Virol 85, 137-146.
May, J. S., Colaco, S. & Stevenson, P. G. (2005). Glycoprotein M is an essential lytic replication protein of the murine gammaherpesvirus 68. J Virol 79, 3459-3467.
May, J. S., Smith, C. M., Gill, M. B. & Stevenson, P. G. (2008). An essential role for the proximal but not the distal cytoplasmic tail of glycoprotein M in murid herpesvirus 4 infection. PLoS ONE 3, e2131.
Navarro, D., Paz, P., Tugizov, S., Topp, K., La Vail, J. & Pereira, L. (1993). Glycoprotein B of human cytomegalovirus promotes virion penetration into cells, transmission of infection from cell to cell, and fusion of infected cells. Virology 197, 143-158.
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.
Okazaki, K., Fujii, S., Takada, A. & Kida, H. (2006). The aminoterminal residue of glycoprotein B is critical for neutralization of bovine herpesvirus 1. Virus Res 115, 105-111.
Roche, S., Bressanelli, S., Rey, F. A. & Gaudin, Y. (2006). Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science 313, 187-191.
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.
Roche, S., Albertini, A. A., Lepault, J., Bressanelli, S. & Gaudin, Y. (2008). Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited. Cell Mol Life Sci 65, 1716-1728.
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.
Roy, A., Kucukural, A. & Zhang, Y. (2010). I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5, 725-738.
Smith, C. M., Gill, M. B., May, J. S. & Stevenson, P. G. (2007). Murine gammaherpesvirus-68 inhibits antigen presentation by dendritic cells. PLoS ONE 2, e1048.
Spear, P. G. & Longnecker, R. (2003). Herpesvirus entry: an update. J Virol 77, 10179-10185.
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.
Stampfer, S. D., Lou, H., Cohen, G. H., Eisenberg, R. J. & Heldwein, E. E. (2010). Structural basis of local, pH-dependent conformational changes in glycoprotein B from herpes simplex virus type 1. J Virol 84, 12924-12933.
Virgin, H. W., IV, Latreille, P., Wamsley, P., Hallsworth, K., Weck, K. E., Dal Canto, A. J. & Speck, S. H. (1997). Complete sequence and genomic analysis of murine gammaherpesvirus 68. J Virol 71, 5894-5904.
Zhang, Y. (2008). I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9, 40.
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.