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Clinical and Vaccine Immunology, March 2008, p. 549-561, Vol. 15, No. 3
1071-412X/08/$08.00+0     doi:10.1128/CVI.00351-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Andrew K. I. Falconar*

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom, and Grupo de Investigaciones en Enfermedades Tropicales, Departamento de Ciencias Basicas Medicas, Universidad del Norte, Barranquilla, Colombia

Received 28 August 2007/ Returned for modification 9 October 2007/ Accepted 14 December 2007

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.

* Mailing address: Grupo de Investigaciones en Enfermedades Tropicales, Departamento de Ciencias Basicas Medicas, Universidad del Norte, Km5 Antigua via Puerto Colombia, Barranquilla, Colombia. Phone: (57) 5 3509478. Fax: (57) 5 3509233. E-mail: afalconar{at}uninorte.edu.co

{triangledown} Published ahead of print on 26 December 2007.

Clinical and Vaccine Immunology, March 2008, p. 549-561, Vol. 15, No. 3
1071-412X/08/$08.00+0     doi:10.1128/CVI.00351-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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