Structural and Functional Characterization of a Cross-Reactive Dengue Virus Neutralizing Antibody that Recognizes a Cryptic Epitope.
Understanding the molecular basis of the neutralizing antibody response to dengue virus (DENV) is an essential component in the design and development of effective vaccines and immunotherapeutics. Here we present the structure of a cross-reactive, neutralizing antibody, 3E31, in complex with domain III (DIII) of the DENV envelope (E) protein and reveal a conserved, temperature-sensitive, cryptic epitope on DIII that is not available in any of the known conformations of E on the dengue virion. We observed that 3E31 inhibits E-mediated membrane fusion, suggesting that the antibody is able to neutralize virus through binding an as-yet uncharacterized intermediate conformation of DENV E and sterically block trimer formation. Finally, we show that, unlike cross-reactive fusion peptide-specific antibodies, 3E31 does not promote antibody-dependent enhancement of infection at sub-neutralizing concentrations. Our results highlight the 3E31 epitope on the E protein DIII as a promising target for immunotherapeutics or vaccine design.
['Li|Jie|J|', 'Watterson|Daniel|D|', 'Chang|Chiung-Wen|CW|', 'Che|Xiao-Yan|XY|', 'Li|Xiao-Quan|XQ|', 'Ericsson|Daniel J|DJ|', 'Qiu|Li-Wen|LW|', 'Cai|Jian-Piao|JP|', 'Chen|Jing|J|', 'Fry|Scott R|SR|', 'Cheung|Stacey T M|STM|', 'Cooper|Matthew A|MA|', 'Young|Paul R|PR|', 'Kobe|Bostjan|B|']
D000595:Amino Acid Sequence D000818:Animals D000911:Antibodies, Monoclonal D057134:Antibodies, Neutralizing D000914:Antibodies, Viral D000918:Antibody Specificity D001665:Binding Sites D002522:Chlorocebus aethiops D003429:Cross Reactions D003715:Dengue D053059:Dengue Vaccines D003716:Dengue Virus D018604:Epitope Mapping D000939:Epitopes D006801:Humans D006825:Hybridomas D008561:Membrane Fusion D051379:Mice D008807:Mice, Inbred BALB C D011485:Protein Binding D054730:Protein Interaction Domains and Motifs D017433:Protein Structure, Secondary D016415:Sequence Alignment D017386:Sequence Homology, Amino Acid D013154:Spleen D014709:Vero Cells D014759:Viral Envelope Proteins
cross-reactive dengue neutralizing antibody cryptic epitope membrane fusion antibody-dependent enhancement temperature sensitive