1887

Abstract

The Dengue virus (DENV) envelope (E) protein is the major component of the viral surface and is structurally subdivided into three domains, ED1, ED2 and ED3. ED3 elicits potent neutralizing antibodies and contains two major antigenic sites: the DENV-type-specific and DENV-complex-reactive antigenic sites. Each site is composed of a limited subset of residues that are required for monoclonal antibody (mAb) binding. Here we show that DENV-2-type-specific mAb 9A3D-8 utilizes the functionally critical residues K307, V308, K310, I312, P332, L387, L389 and N390 for ED3 binding. Surprisingly, this DENV-type-specific epitope is predicted to overlap with the ED3 DENV-complex-reactive antigenic site on the viral surface. Further, this unique binding site enables mAb 9A3D-8 to neutralize virus infectivity at relatively low occupancy of virions compared to other ED3 mAbs identified to date. Together, the data in this study indicate that this is a new DENV-2-type-specific antigenic site on ED3.

Keyword(s): antibody , DENV-2 , epitopes and neutralization
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/content/journal/jgv/10.1099/jgv.0.000785
2017-06-01
2024-04-18
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References

  1. Modis Y, Ogata S, Clements D, Harrison SC. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc Natl Acad Sci USA 2003; 100:6986–6991 [View Article][PubMed]
    [Google Scholar]
  2. Crill WD, Hughes HR, Delorey MJ, Chang GJ. Humoral immune responses of dengue fever patients using epitope-specific serotype-2 virus-like particle antigens. PLoS One 2009; 4:e4991 [View Article][PubMed]
    [Google Scholar]
  3. Pierson TC, Diamond MS. Molecular mechanisms of antibody-mediated neutralisation of flavivirus infection. Expert Rev Mol Med 2008; 10:e12 [View Article][PubMed]
    [Google Scholar]
  4. Roehrig JT, Bolin RA, Kelly RG. Monoclonal antibody mapping of the envelope glycoprotein of the dengue 2 virus, Jamaica. Virology 1998; 246:317–328 [View Article][PubMed]
    [Google Scholar]
  5. Gromowski GD, Barrett AD. Characterization of an antigenic site that contains a dominant, type-specific neutralization determinant on the envelope protein domain III (ED3) of dengue 2 virus. Virology 2007; 366:349–360 [View Article][PubMed]
    [Google Scholar]
  6. Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE et al. Type- and subcomplex-specific neutralizing antibodies against domain III of dengue virus type 2 envelope protein recognize adjacent epitopes. J Virol 2007; 81:12816–12826 [View Article][PubMed]
    [Google Scholar]
  7. Gromowski GD, Barrett ND, Barrett AD. Characterization of dengue virus complex-specific neutralizing epitopes on envelope protein domain III of dengue 2 virus. J Virol 2008; 82:8828–8837 [View Article][PubMed]
    [Google Scholar]
  8. Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ et al. Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Nat Struct Mol Biol 2008; 15:312–317 [View Article][PubMed]
    [Google Scholar]
  9. Pitcher TJ, Sarathy VV, Matsui K, Gromowski GD, Huang CY et al. Functional analysis of dengue virus (DENV) type 2 envelope protein domain 3 type-specific and DENV complex-reactive critical epitope residues. J Gen Virol 2015; 96:288–293 [View Article][PubMed]
    [Google Scholar]
  10. Beltramello M, Williams KL, Simmons CP, Macagno A, Simonelli L et al. The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 2010; 8:271–283 [View Article][PubMed]
    [Google Scholar]
  11. de Alwis R, Beltramello M, Messer WB, Sukupolvi-Petty S, Wahala WM et al. In-depth analysis of the antibody response of individuals exposed to primary dengue virus infection. PLoS Negl Trop Dis 2011; 5:e1188 [View Article][PubMed]
    [Google Scholar]
  12. Gromowski GD, Roehrig JT, Diamond MS, Lee JC, Pitcher TJ et al. Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape. Virology 2010; 407:237–246 [View Article][PubMed]
    [Google Scholar]
  13. Roehrig JT, Butrapet S, Liss NM, Bennett SL, Luy BE et al. Mutation of the dengue virus type 2 envelope protein heparan sulfate binding sites or the domain III lateral ridge blocks replication in Vero cells prior to membrane fusion. Virology 2013; 441:114–125 [View Article][PubMed]
    [Google Scholar]
  14. Pitcher TJ, Gromowski GD, Beasley DW, Barrett AD. Conservation of the DENV-2 type-specific and DEN complex-reactive antigenic sites among DENV-2 genotypes. Virology 2012; 422:386–392 [View Article][PubMed]
    [Google Scholar]
  15. Maillard RA, Jordan M, Beasley DW, Barrett AD, Lee JC. Long range communication in the envelope protein domain III and its effect on the resistance of West Nile virus to antibody-mediated neutralization. J Biol Chem 2008; 283:613–622 [View Article][PubMed]
    [Google Scholar]
  16. Klasse PJ, Moore JP. Quantitative model of antibody- and soluble CD4-mediated neutralization of primary isolates and T-cell line-adapted strains of human immunodeficiency virus type 1. J Virol 1996; 70:3668–3677[PubMed]
    [Google Scholar]
  17. Pierson TC, Xu Q, Nelson S, Oliphant T, Nybakken GE et al. The stoichiometry of antibody-mediated neutralization and enhancement of West Nile virus infection. Cell Host Microbe 2007; 1:135–145 [View Article][PubMed]
    [Google Scholar]
  18. Crill WD, Roehrig JT. Monoclonal antibodies that bind to domain III of dengue virus E glycoprotein are the most efficient blockers of virus adsorption to Vero cells. J Virol 2001; 75:7769–7773 [View Article][PubMed]
    [Google Scholar]
  19. Kaufmann B, Nybakken GE, Chipman PR, Zhang W, Diamond MS et al. West Nile virus in complex with the Fab fragment of a neutralizing monoclonal antibody. Proc Natl Acad Sci USA 2006; 103:12400–12404 [View Article][PubMed]
    [Google Scholar]
  20. Cockburn JJ, Navarro Sanchez ME, Fretes N, Urvoas A, Staropoli I et al. Mechanism of dengue virus broad cross-neutralization by a monoclonal antibody. Structure 2012; 20:303–314 [View Article][PubMed]
    [Google Scholar]
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