The Development of Therapeutic Antibodies That Neutralize Homologous and Heterologous Genotypes of Dengue Virus Type 1

PLoS Pathogens

Michael S. Diamond¹  Soila Sukupolvi-Petty²  Bimmi Shrestha²  Katie M. O'Brien²  James D. Brien²  Melissa A. Edeling³  S. Kyle Austin³  Christopher A. Nelson³  Taekyung Kim³  Daved H. Fremont³  Syd Johnson⁴ 

[1] Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America;Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America;MacroGenics, Inc., Rockville, Maryland, United States of America

关键词: Antibodies;    West Nile virus;    Yeast;    Enzyme-linked immunoassays;    Cell binding;    Dengue virus;    Virions;    Saccharomyces cerevisiae;   

DOI  :  10.1371/journal.ppat.1000823

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of the E protein. To identify an analogous panel of neutralizing antibodies against DENV type-1 (DENV-1), we immunized mice with a genotype 2 strain of DENV-1 virus and generated 79 new MAbs, 16 of which strongly inhibited infection by the homologous virus and localized to DIII. Surprisingly, only two MAbs, DENV1-E105 and DENV1-E106, retained strong binding and neutralizing activity against all five DENV-1 genotypes. In an immunocompromised mouse model of infection, DENV1-E105 and DENV1-E106 exhibited therapeutic activity even when administered as a single dose four days after inoculation with a heterologous genotype 4 strain of DENV-1. Using epitope mapping and X-ray crystallographic analyses, we localized the neutralizing determinants for the strongly inhibitory MAbs to distinct regions on DIII. Interestingly, sequence variation in DIII alone failed to explain disparities in neutralizing potential of MAbs among different genotypes. Overall, our experiments define a complex structural epitope on DIII of DENV-1 that can be recognized by protective antibodies with therapeutic potential.

【 授权许可】

CC BY