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Type- and Subcomplex-Specific Neutralizing Antibodies against Domain III of Dengue Virus Type 2 Envelope Protein Recognize Adjacent Epitopes

Soila Sukupolvi-Petty,^1, S. Kyle Austin,^2, Whitney E. Purtha,² Theodore Oliphant,³ Grant E. Nybakken,² Jacob J. Schlesinger,⁴ John T. Roehrig,⁵ Gregory D. Gromowski,⁶ Alan D. Barrett,⁶ Daved H. Fremont,² and Michael S. Diamond^1,2,3*

Departments of Medicine,¹ Pathology & Immunology,² Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri,³ Department of Medicine, University of Rochester, Rochester, New York,⁴ Centers for Disease Control and Prevention, Fort Collins, Colorado,⁵ Center for Biodefense and Emerging Infectious Diseases, Sealy Center for Vaccine Development, Institute for Human Infections and Immunity, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas⁶

Received 28 February 2007/ Accepted 30 August 2007

Neutralization of flaviviruses in vivo correlates with the development of an antibody response against the viral envelope (E) protein. Previous studies demonstrated that monoclonal antibodies (MAbs) against an epitope on the lateral ridge of domain III (DIII) of the West Nile virus (WNV) E protein strongly protect against infection in animals. Based on X-ray crystallography and sequence analysis, an analogous type-specific neutralizing epitope for individual serotypes of the related flavivirus dengue virus (DENV) was hypothesized. Using yeast surface display of DIII variants, we defined contact residues of a panel of type-specific, subcomplex-specific, and cross-reactive MAbs that recognize DIII of DENV type 2 (DENV-2) and have different neutralizing potentials. Type-specific MAbs with neutralizing activity against DENV-2 localized to a sequence-unique epitope on the lateral ridge of DIII, centered at the FG loop near residues E383 and P384, analogous in position to that observed with WNV-specific strongly neutralizing MAbs. Subcomplex-specific MAbs that bound some but not all DENV serotypes and neutralized DENV-2 infection recognized an adjacent epitope centered on the connecting A strand of DIII at residues K305, K307, and K310. In contrast, several MAbs that had poor neutralizing activity against DENV-2 and cross-reacted with all DENV serotypes and other flaviviruses recognized an epitope with residues in the AB loop of DIII, a conserved region that is predicted to have limited accessibility on the mature virion. Overall, our experiments define adjacent and structurally distinct epitopes on DIII of DENV-2 which elicit type-specific, subcomplex-specific, and cross-reactive antibodies with different neutralizing potentials.

Published ahead of print on 19 September 2007.

S.S.-P. and S.K.A. contributed equally to the manuscript.

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