title: Monoclonal antibodies that bind to common epitopes on the dengue virus type 2 nonstructural-1 and envelope glycoproteins display weak neutralizing activity and differentiated responses to virulent strains: implications for pathogenesis and vaccines.
abstract: The abilities of monoclonal antibodies (MAbs) that bind to defined sequential epitopes on the dengue virus (DENV) nonstructural-1 (NS1) glycoproteins to cross-react with epitopes on the DENV envelope (E) glycoproteins were investigated. In this study, some of these MAbs cross-reacted with the DENV type 2 (DENV-2) E glycoprotein and with synthetic peptides representing X-ray crystallographically confirmed surface-exposed regions on this glycoprotein. MAb 1G5.3 cross-reacted with the flavivirus-conserved 101-WGNGCGLFG-109 fusion sequence, the 273-SSGNL-277 DENV-2 hinge region sequence, and the 156-GKHGKEIKIT-165 sequence of virulent DENV-2 strains. MAb 1G5.4-A1-C3 cross-reacted with the 67-NTTTESRCPT-76 and 156-GKHGKEIKIT-165 sequences of virulent DENV-2 strains, the 338-EIMDLDNRHV-347 sequence from a highly virulent DENV-2 (M2) strain, and two epitopes on a virulent DENV-3 strain (288-KMDKLELKG-296 and 323-RVEYRGEDAP-332), which all contained target ELK/KLE-type motifs (underlined). These MAbs showed reduced cross-reactions with the corresponding sequences from weakly pathogenic strains of all four DENV serotypes and had either no (MAb 1G5.4-A1-C3) or weak (MAb 1G5.3) neutralizing activity against them. MAb 1G5.3 more strongly neutralized DENV-2 strains with higher pathogenic capacities, while MAb 1G5.4-A1-C3 showed increasing neutralizing titers against the virulent DENV-3 strain and the moderately virulent and highly virulent (M2) DENV-2 strains. These cross-reactions with the E glycoprotein accord with the observation that MAb 1G5.3 caused dramatic and lethal antibody-enhanced replication (AER) of a DENV-2 strain in vivo. Together with in vivo AER studies of these DENV strains using MAb 1G5.4-A1-C3, these results may account for the increased pathogenic capacities of such strains, which is likely to have important implications for pathogenesis and vaccines.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. afalconar@uninorte.edu.co
authors.forename: Andrew K I
authors.initials: AK
authors.lastname: Falconar
mesh_terms: D000330:Aedes; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism*; D000914:Antibodies, Viral / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003429:Cross Reactions; D053059:Dengue Vaccines; D003716:Dengue Virus / Q000276:immunology / Q000472:pathogenicity*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D015151:Immunoblotting; D009500:Neutralization Tests; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000378:metabolism; D014774:Virulence
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D053059:Dengue Vaccines; C051821:E-glycoprotein, Dengue virus type 2; D000939:Epitopes; C079340:NS1 protein, Dengue virus type 2; D014759:Viral Envelope Proteins; D017361:Viral Nonstructural Proteins