Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

Feng Long, Rachel H. Fong, Stephen K. Austin, Zhenguo Chen, Thomas Klose, Andrei Fokine, Yue Liu, Jason Porta, Gopal Sapparapu, Wataru Akahata, Benjamin J. Doranz, James E. Crowe, Michael S. Diamond, Michael G. Rossmann

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis- based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes.

Original languageEnglish (US)
Pages (from-to)13898-13903
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number45
DOIs
StatePublished - Nov 10 2015

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Chikungunya virus
Monoclonal Antibodies
Glycoproteins
Viral Antibodies
Alphavirus
Viruses
Epitope Mapping
Virus Internalization
Immunoglobulin Fragments
Immunoglobulin Fab Fragments
Acute Disease
Therapeutics
Culicidae
Mutagenesis
Alanine
Virion
Chronic Disease
Membranes

Keywords

  • Chikungunya virus-antibody complexes
  • Cryo-electron microscopy structure
  • Neutralizing mechanism
  • Viral fusion inhibition

ASJC Scopus subject areas

  • General

Cite this

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity. / Long, Feng; Fong, Rachel H.; Austin, Stephen K.; Chen, Zhenguo; Klose, Thomas; Fokine, Andrei; Liu, Yue; Porta, Jason; Sapparapu, Gopal; Akahata, Wataru; Doranz, Benjamin J.; Crowe, James E.; Diamond, Michael S.; Rossmann, Michael G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 45, 10.11.2015, p. 13898-13903.

Research output: Contribution to journalArticle

Long, F, Fong, RH, Austin, SK, Chen, Z, Klose, T, Fokine, A, Liu, Y, Porta, J, Sapparapu, G, Akahata, W, Doranz, BJ, Crowe, JE, Diamond, MS & Rossmann, MG 2015, 'Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 45, pp. 13898-13903. https://doi.org/10.1073/pnas.1515558112
Long, Feng ; Fong, Rachel H. ; Austin, Stephen K. ; Chen, Zhenguo ; Klose, Thomas ; Fokine, Andrei ; Liu, Yue ; Porta, Jason ; Sapparapu, Gopal ; Akahata, Wataru ; Doranz, Benjamin J. ; Crowe, James E. ; Diamond, Michael S. ; Rossmann, Michael G. / Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 45. pp. 13898-13903.
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