Structural basis of differential neutralization of DENV-1 genotypes by an antibody that recognizes a cryptic epitope.
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.
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
S Kyle
SK
Austin
Kimberly A
KA
Dowd
Bimmi
B
Shrestha
Christopher A
CA
Nelson
Melissa A
MA
Edeling
Syd
S
Johnson
Theodore C
TC
Pierson
Michael S
MS
Diamond
Daved H
DH
Fremont
D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology*; D001666:Binding Sites, Antibody; D003715:Dengue / Q000276:immunology / Q000517:prevention & control; D003716:Dengue Virus / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D006801:Humans; D017434:Protein Structure, Tertiary; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000276:immunology*
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes; D014759:Viral Envelope Proteins; C072281:E protein TH Sman, Dengue virus