Structural Basis of Differential Neutralization of DENV-1 Genotypes by an Antibody that Recognizes a Cryptic Epitope

PLoS Pathogens

Bimmi Shrestha¹  Daved H. Fremont¹  Melissa A. Edeling²  S. Kyle Austin²  Michael S. Diamond²  Christopher A. Nelson²  Syd Johnson³  Theodore C. Pierson⁴  Kimberly A. Dowd⁴ 

[1] Department of Medicine (Infectious Diseases), Washington University School of Medicine, Saint Louis, Missouri, United States of America;Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America;MacroGenics, Rockville, Maryland, United States of America;Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: Antibodies;    Virions;    Viral structure;    Dengue virus;    Chemical neutralization;    Electron cryo-microscopy;    West Nile virus;    Flow cytometry;   

DOI  :  10.1371/journal.ppat.1002930

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC′ loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC′ loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development.

【 授权许可】

CC BY