The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses

Arvind Sharma; Xiaokang Zhang; Wanwisa Dejnirattisai; Xinghong Dai; Danyang Gong; Wiyada Wongwiwat; Stéphane Duquerroy; Alexander Rouvinski; Marie Christine Vaney; Pablo Guardado-Calvo; Ahmed Haouz; Patrick England; Ren Sun; Z. Hong Zhou; Juthathip Mongkolsapaya; Gavin R. Screaton; Felix A. Rey

doi:https://doi.org/10.1016/j.cell.2021.11.010

The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses

Arvind Sharma, Xiaokang Zhang, Wanwisa Dejnirattisai, Xinghong Dai, Danyang Gong, Wiyada Wongwiwat, Stéphane Duquerroy, Alexander Rouvinski, Marie Christine Vaney, Pablo Guardado-Calvo, Ahmed Haouz, Patrick England, Ren Sun, Z. Hong Zhou, Juthathip Mongkolsapaya, Gavin R. Screaton, Felix A. Rey

Research output: Contribution to journal › Article › peer-review

Abstract

The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes’ geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.

Original language	English
Pages (from-to)	6052-6066.e18
Journal	Cell
Volume	184
Issue number	25
DOIs	https://doi.org/10.1016/j.cell.2021.11.010
State	Published - 9 Dec 2021
Externally published	Yes

Keywords

Dengue virus
Flaviviruses
X-ray crystallography
Zika virus
broadly neutralizing antibodies
cryo-EM
vaccine design

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1016/j.cell.2021.11.010

Cite this

Sharma, A., Zhang, X., Dejnirattisai, W., Dai, X., Gong, D., Wongwiwat, W., Duquerroy, S., Rouvinski, A., Vaney, M. C., Guardado-Calvo, P., Haouz, A., England, P., Sun, R., Zhou, Z. H., Mongkolsapaya, J., Screaton, G. R., & Rey, F. A. (2021). The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses. Cell, 184(25), 6052-6066.e18. https://doi.org/10.1016/j.cell.2021.11.010

@article{2f7be2d69d494ec597d3b8b25d6b9a31,

title = "The epitope arrangement on flavivirus particles contributes to Mab C10{\textquoteright}s extraordinary neutralization breadth across Zika and dengue viruses",

abstract = "The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes{\textquoteright} geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.",

keywords = "Dengue virus, Flaviviruses, X-ray crystallography, Zika virus, broadly neutralizing antibodies, cryo-EM, vaccine design",

author = "Arvind Sharma and Xiaokang Zhang and Wanwisa Dejnirattisai and Xinghong Dai and Danyang Gong and Wiyada Wongwiwat and St{\'e}phane Duquerroy and Alexander Rouvinski and Vaney, {Marie Christine} and Pablo Guardado-Calvo and Ahmed Haouz and Patrick England and Ren Sun and Zhou, {Z. Hong} and Juthathip Mongkolsapaya and Screaton, {Gavin R.} and Rey, {Felix A.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "9",

doi = "https://doi.org/10.1016/j.cell.2021.11.010",

language = "الإنجليزيّة",

volume = "184",

pages = "6052--6066.e18",

journal = "Cell",

issn = "0092-8674",

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number = "25",

}

Sharma, A, Zhang, X, Dejnirattisai, W, Dai, X, Gong, D, Wongwiwat, W, Duquerroy, S, Rouvinski, A, Vaney, MC, Guardado-Calvo, P, Haouz, A, England, P, Sun, R, Zhou, ZH, Mongkolsapaya, J, Screaton, GR & Rey, FA 2021, 'The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses', Cell, vol. 184, no. 25, pp. 6052-6066.e18. https://doi.org/10.1016/j.cell.2021.11.010

TY - JOUR

T1 - The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses

AU - Sharma, Arvind

AU - Zhang, Xiaokang

AU - Dejnirattisai, Wanwisa

AU - Dai, Xinghong

AU - Gong, Danyang

AU - Wongwiwat, Wiyada

AU - Duquerroy, Stéphane

AU - Rouvinski, Alexander

AU - Vaney, Marie Christine

AU - Guardado-Calvo, Pablo

AU - Haouz, Ahmed

AU - England, Patrick

AU - Sun, Ren

AU - Zhou, Z. Hong

AU - Mongkolsapaya, Juthathip

AU - Screaton, Gavin R.

AU - Rey, Felix A.

PY - 2021/12/9

Y1 - 2021/12/9

N2 - The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes’ geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.

AB - The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes’ geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.

KW - Dengue virus

KW - Flaviviruses

KW - X-ray crystallography

KW - Zika virus

KW - broadly neutralizing antibodies

KW - cryo-EM

KW - vaccine design

UR - http://www.scopus.com/inward/record.url?scp=85120623210&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.cell.2021.11.010

DO - https://doi.org/10.1016/j.cell.2021.11.010

M3 - مقالة

C2 - 34852239

SN - 0092-8674

VL - 184

SP - 6052-6066.e18

JO - Cell

JF - Cell

IS - 25

ER -

The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

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