Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies

Jason Porta, Joyce Jose, John T. Roehrig, Carol D. Blair, Richard J. Kuhn, Michael G. Rossmann

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Alphaviruses are serious, sometimes lethal human pathogens that belong to the family Togaviridae. The structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy and homology modeling. We characterize these monoclonal antibody Fab fragments, which are known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both of these antibody Fab fragments cross-link the surface E2 glycoproteins and therefore probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain.

Original languageEnglish (US)
Pages (from-to)9616-9623
Number of pages8
JournalJournal of virology
Volume88
Issue number17
DOIs
StatePublished - Jan 1 2014

Fingerprint

Venezuelan equine encephalitis virus
Alphavirus
Immunoglobulin Fab Fragments
Neutralizing Antibodies
neutralizing antibodies
glycoproteins
pathogenicity
Togaviridae
Immunoglobulin Fragments
Venezuelan Equine Encephalitis Viruses
Membrane Glycoproteins
binding sites
monoclonal antibodies
proteins
viruses
receptors
antibodies
pathogens
Cryoelectron Microscopy
Virus Attachment

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Porta, J., Jose, J., Roehrig, J. T., Blair, C. D., Kuhn, R. J., & Rossmann, M. G. (2014). Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies. Journal of virology, 88(17), 9616-9623. https://doi.org/10.1128/JVI.01286-14
Porta, Jason ; Jose, Joyce ; Roehrig, John T. ; Blair, Carol D. ; Kuhn, Richard J. ; Rossmann, Michael G. / Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies. In: Journal of virology. 2014 ; Vol. 88, No. 17. pp. 9616-9623.
@article{e749aa3dd0f5418bb211cc81d1507de0,
title = "Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies",
abstract = "Alphaviruses are serious, sometimes lethal human pathogens that belong to the family Togaviridae. The structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy and homology modeling. We characterize these monoclonal antibody Fab fragments, which are known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both of these antibody Fab fragments cross-link the surface E2 glycoproteins and therefore probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain.",
author = "Jason Porta and Joyce Jose and Roehrig, {John T.} and Blair, {Carol D.} and Kuhn, {Richard J.} and Rossmann, {Michael G.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1128/JVI.01286-14",
language = "English (US)",
volume = "88",
pages = "9616--9623",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "17",

}

Porta, J, Jose, J, Roehrig, JT, Blair, CD, Kuhn, RJ & Rossmann, MG 2014, 'Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies', Journal of virology, vol. 88, no. 17, pp. 9616-9623. https://doi.org/10.1128/JVI.01286-14

Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies. / Porta, Jason; Jose, Joyce; Roehrig, John T.; Blair, Carol D.; Kuhn, Richard J.; Rossmann, Michael G.

In: Journal of virology, Vol. 88, No. 17, 01.01.2014, p. 9616-9623.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Locking and blocking the viral landscape of an alphavirus with neutralizing antibodies

AU - Porta, Jason

AU - Jose, Joyce

AU - Roehrig, John T.

AU - Blair, Carol D.

AU - Kuhn, Richard J.

AU - Rossmann, Michael G.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Alphaviruses are serious, sometimes lethal human pathogens that belong to the family Togaviridae. The structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy and homology modeling. We characterize these monoclonal antibody Fab fragments, which are known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both of these antibody Fab fragments cross-link the surface E2 glycoproteins and therefore probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain.

AB - Alphaviruses are serious, sometimes lethal human pathogens that belong to the family Togaviridae. The structures of human Venezuelan equine encephalitis virus (VEEV), an alphavirus, in complex with two strongly neutralizing antibody Fab fragments (F5 and 3B4C-4) have been determined using a combination of cryo-electron microscopy and homology modeling. We characterize these monoclonal antibody Fab fragments, which are known to abrogate VEEV infectivity by binding to the E2 (envelope) surface glycoprotein. Both of these antibody Fab fragments cross-link the surface E2 glycoproteins and therefore probably inhibit infectivity by blocking the conformational changes that are required for making the virus fusogenic. The F5 Fab fragment cross-links E2 proteins within one trimeric spike, whereas the 3B4C-4 Fab fragment cross-links E2 proteins from neighboring spikes. Furthermore, F5 probably blocks the receptor-binding site, whereas 3B4C-4 sterically hinders the exposure of the fusion loop at the end of the E2 B-domain.

UR - http://www.scopus.com/inward/record.url?scp=84921966916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921966916&partnerID=8YFLogxK

U2 - 10.1128/JVI.01286-14

DO - 10.1128/JVI.01286-14

M3 - Article

C2 - 24920796

AN - SCOPUS:84921966916

VL - 88

SP - 9616

EP - 9623

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 17

ER -