The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Human Antibody

Teoh, E.; Kukkaro, Petra; Teo, En Wei; Lim, Angeline; Tan, Ting; Yip, Andy M.; Schul, Wouter; Aung, Myint Thazin; Kostyuchenko, V.A.; Leo, Yee Sin; Chan, Soh Ha; Smith, Kenneth G. C.; Chan, Annie Hoi Yi; Zou, Gang; Ooi, Eng Eong; Kemeny, David M.; Tan, Geok Kheng; Ng, Jack Kit-Chung; Ng, Mah Lee; Alonso, Sylvie; Fisher, Dale; Shi, Pei Yong; Hanson, Brendon J.; Lok, Shee-Mei; MacAry, Paul A.

doi:10.1126/scitranslmed.3003888

Cited by 198 publications

(210 citation statements)

References 46 publications

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“…Our data are consistent with models where the EDI/EDII hinge of each serotype contains a single or multiple overlapping epitopes targeted by primate NAbs. Indeed, structure studies with human mAbs that bind to the EDI/EDII hinge region of flaviviruses indicate that this region contains overlapping quaternary epitopes (9,20). Although primary cross-reactive T-cell responses and antibodies do not confer long-term protection against heterologous challenge in primates, it is possible that the EDI/EDII hinge region contains peptides that can be recognized by DENV-specific T cells that also contribute to protection against DENV reinfection.…”

Section: Nabs Targeting the Edi/edii Are Sufficient To Protect Againsmentioning

confidence: 99%

“…The E structure consists of three distinct domains: I, II, and III (EDI, EDII, and EDIII) (6, 7); EDIII is a continuous peptide extending from domain I and forming an Ig-like fold, whereas EDI and EDII are discontinuous and connect by four peptide linkers that form the EDI/EDII hinge. We and others have recently described potent human DENV NAbs that bind to epitopes around the EDI/EDII hinge (8,9). To more fully explore the significance of this antigenic region, we used reverse genetics and synthetic biology to transplant the EDI/EDII antigenic region from DENV-4 into a DENV-3 background and showed by both gain-and lossof-function assays that the EDI/EDII hinge region is the primary target of the long-lived DENV serotype-specific NAb response.…”

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confidence: 99%

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Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

Messer

Alwis

Yount

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Dengue virus is the most important arthropod-borne viral disease of humans worldwide, with an estimated 390 million acute infections annually. The best means to control this global health threat is a vaccine, but dengue vaccine development has progressed slowly, partly because the antigenic targets required to stimulate long-term immunity are not well-defined. Here, we show a specific region on the viral surface (the envelope domain I/II hinge) that is the target of protective antibodies after primary human infections. These results are critically important for dengue vaccine design, because we hypothesize that a successful dengue vaccine will stimulate antibodies that target this region. More broadly, this study establishes a template for similar approaches for improving vaccines for influenza, HIV, hepatitis C virus, and other clinically important viral pathogens.

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Section: Nabs Targeting the Edi/edii Are Sufficient To Protect Againsmentioning

confidence: 99%

mentioning

confidence: 99%

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

Messer

Alwis

Yount

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the Ab binding sites seemed to include highly conserved amino acids, because most Abs bound to all serotypes in vitro. In fact, recently reported DENV-neutralizing Ab epitopes were shown to consist of quaternary structures, spanning over two adjacent E protein dimers and involving E domains I and II or III (39,40). These findings showed that Ab binding may involve both serotype-specific and conserved epitopes.…”

Section: Discussionmentioning

confidence: 73%

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

Hadinoto

Appanna

et al. 2012

The Journal of Immunology

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Dengue virus immune protection is specific to the serotype encountered and is thought to persist throughout one’s lifetime. Many serotype cross-reactive memory B cells isolated from humans with previous dengue infection are specific for the nonstructural and the prM structural viral proteins, and they can enhance infection in vitro. However, plasmablasts circulating in enormous numbers during acute secondary infection have not been studied. In this study, we analyzed single plasmablasts from two patients by sorting the cells for Ig sequence analysis and for recombinant expression of Abs. In contrast to memory B cells, most plasmablast-derived Abs bound to the structural E protein of dengue, and protection experiments in mice revealed that virus serotypes encountered during past infections were neutralized more efficiently than were the serotypes of the current infection. Together with genetic analyses, we show evidence that plasmablasts in dengue patients are a polyclonal pool of activated E protein–specific memory B cells and that their specificity is not representative of the serum Abs secreted by long-lived plasma cells in the memory phase. These results contribute to the understanding of the phenomenon of original antigenic sin in dengue.

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“…Dejnirattisai et al (22) suggest that differences in epitope presentation between epitope B and epitopes A and C are responsible for the weaker Ab binding to epitope B in EDE2-A11. Most strikingly, Teo et al explain the fact that 14c10 binds to only B and C epitopes by asserting that its epitope spans across the DII/DIII domain of E in one dimer and the DI domain of E in a neighboring dimer, in such a manner that these two putative epitope regions are only adjacent to each other on the twofold and threefold axes (44). However, a close examination of the structure reveals that 13 of the 16 epitope residues for 14c10 are found on DII/DIII of a single E-protein, and there is little consistency between the DI epitope residues between epitopes along the twofold and threefold axes, calling into question whether those DI residues are critical to binding.…”

Section: Partial Occupancy and Heterogeneitymentioning

confidence: 99%

Modeling the Role of Epitope Arrangement on Antibody Binding Stoichiometry in Flaviviruses

Ripoll

Khavrutskii

Wallqvist

et al. 2016

Biophysical Journal

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Cryo-electron-microscopy (cryo-EM) structures of flaviviruses reveal significant variation in epitope occupancy across different monoclonal antibodies that have largely been attributed to epitope-level differences in conformation or accessibility that affect antibody binding. The consequences of these variations for macroscopic properties such as antibody binding and neutralization are the results of the law of mass action-a stochastic process of innumerable binding and unbinding events between antibodies and the multiple binding sites on the flavivirus in equilibrium-that cannot be directly imputed from structure alone. We carried out coarse-grained spatial stochastic binding simulations for nine flavivirus antibodies with epitopes defined by cryo-EM or x-ray crystallography to assess the role of epitope spatial arrangement on antibody-binding stoichiometry, occupancy, and neutralization. In our simulations, all epitopes were equally competent for binding, representing the upper limit of binding stoichiometry that results from epitope spatial arrangement alone. Surprisingly, our simulations closely reproduced the relative occupancy and binding stoichiometry observed in cryo-EM, without having to account for differences in epitope accessibility or conformation, suggesting that epitope spatial arrangement alone may be sufficient to explain differences in binding occupancy and stoichiometry between antibodies. Furthermore, we found that there was significant heterogeneity in binding configurations even at saturating antibody concentrations, and that bivalent antibody binding may be more common than previously thought. Finally, we propose a structure-based explanation for the stoichiometric threshold model of neutralization.

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The Structural Basis for Serotype-Specific Neutralization of Dengue Virus by a Human Antibody

Abstract: The mechanism of action of a serotype-specific natural human antibody against dengue virus has been identified.

Cited by 198 publications

References 46 publications

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity

Plasmablasts Generated during Repeated Dengue Infection Are Virus Glycoprotein–Specific and Bind to Multiple Virus Serotypes

Modeling the Role of Epitope Arrangement on Antibody Binding Stoichiometry in Flaviviruses

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