Structural and Functional Characterization of a Cross-Reactive Dengue Virus Neutralizing Antibody that Recognizes a Cryptic Epitope

Jie Li; Daniel Watterson; Chiung-Wen Chang; Xiao-Yan Che; Xiao-Quan Li; Daniel J Ericsson; Li-Wen Qiu; Jian-Piao Cai; Jing Chen; Scott R Fry; Stacey T M Cheung; Matthew A Cooper; Paul R Young; Bostjan Kobe

doi:10.1016/j.str.2017.11.017

Structural and Functional Characterization of a Cross-Reactive Dengue Virus Neutralizing Antibody that Recognizes a Cryptic Epitope

Structure. 2018 Jan 2;26(1):51-59.e4. doi: 10.1016/j.str.2017.11.017. Epub 2017 Dec 14.

Authors

Jie Li¹, Daniel Watterson², Chiung-Wen Chang³, Xiao-Yan Che⁴, Xiao-Quan Li⁴, Daniel J Ericsson⁵, Li-Wen Qiu⁴, Jian-Piao Cai⁴, Jing Chen⁴, Scott R Fry⁶, Stacey T M Cheung³, Matthew A Cooper⁷, Paul R Young⁸, Bostjan Kobe⁹

Affiliations

¹ Division of Laboratory Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou 510282, People's Republic of China; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
² School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
³ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.
⁴ Division of Laboratory Medicine, ZhuJiang Hospital, Southern Medical University, Guangzhou 510282, People's Republic of China.
⁵ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.
⁶ Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia.
⁷ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: m.cooper@uq.edu.au.
⁸ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: p.young@uq.edu.au.
⁹ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: b.kobe@uq.edu.au.

PMID: 29249606
DOI: 10.1016/j.str.2017.11.017

Abstract

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.

Keywords: antibody-dependent enhancement; cross-reactive; cryptic epitope; dengue; membrane fusion; neutralizing antibody; temperature sensitive.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibodies, Monoclonal / biosynthesis
Antibodies, Monoclonal / chemistry*
Antibodies, Monoclonal / immunology
Antibodies, Monoclonal / pharmacology
Antibodies, Neutralizing / biosynthesis
Antibodies, Neutralizing / chemistry*
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology
Antibodies, Viral / biosynthesis
Antibodies, Viral / chemistry*
Antibodies, Viral / immunology
Antibodies, Viral / pharmacology
Antibody Specificity
Binding Sites
Chlorocebus aethiops
Cross Reactions
Dengue / prevention & control
Dengue / virology
Dengue Vaccines / biosynthesis
Dengue Virus / chemistry
Dengue Virus / drug effects
Dengue Virus / immunology*
Epitope Mapping / methods
Epitopes / chemistry*
Epitopes / immunology
Humans
Hybridomas / immunology
Membrane Fusion / drug effects
Mice
Mice, Inbred BALB C
Protein Binding
Protein Interaction Domains and Motifs
Protein Structure, Secondary
Sequence Alignment
Sequence Homology, Amino Acid
Spleen / cytology
Spleen / immunology
Vero Cells
Viral Envelope Proteins / chemistry
Viral Envelope Proteins / immunology*

Substances

Antibodies, Monoclonal
Antibodies, Neutralizing
Antibodies, Viral
Dengue Vaccines
Epitopes
Viral Envelope Proteins
E protein TH Sman, Dengue virus