Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization

Abimbola O. Kolawole, Ming Li, Chunsheng Xia, Audrey E. Fischer, Nicholas S. Giacobbi, Christine M. Rippinger, Jody B G Proescher, Susan K. Wu, Seneca L. Bessling, Monica Gamez, Chenchen Yu, Rebecca Zhang, Thomas S. Mehoke, James M. Pipas, Joshua T. Wolfe, Jeffrey S. Lin, Andrew B. Feldman, Thomas Smith, Christiane E. Wobus

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

New human norovirus strains emerge every 2 to 3 years, partly due to mutations in the viral capsid that allow escape from antibody neutralization and herd immunity. To understand how noroviruses evolve antibody resistance, we investigated the structural basis for the escape of murine norovirus (MNV) from antibody neutralization. To identify specific residues in the MNV-1 protruding (P) domain of the capsid that play a role in escape from the neutralizing monoclonal antibody (MAb) A6.2, 22 recombinant MNVs were generated with amino acid substitutions in the A'B' and E'F' loops. Six mutations in the E'F' loop (V378F, A382K, A382P, A382R, D385G, and L386F) mediated escape from MAb A6.2 neutralization. To elucidate underlying structural mechanisms for these results, the atomic structure of the A6.2 Fab was determined and fitted into the previously generated pseudoatomic model of the A6.2 Fab/MNV-1 virion complex. Previously, two distinct conformations, A and B, of the atomic structures of the MNV-1 P domain were identified due to flexibility in the two P domain loops. A superior stereochemical fit of the A6.2 Fab to the A conformation of the MNV P domain was observed. Structural analysis of our observed escape mutants indicates changes toward the less-preferred B conformation of the P domain. The shift in the structural equilibrium of the P domain toward the conformation with poor structural complementarity to the antibody strongly supports a unique mechanism for antibody escape that occurs via antigen flexibility instead of direct antibody-antigen binding.

Original languageEnglish (US)
Pages (from-to)4543-4557
Number of pages15
JournalJournal of Virology
Volume88
Issue number8
DOIs
StatePublished - 2014
Externally publishedYes

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Norovirus
capsid
Capsid
neutralization
Viruses
viruses
antibodies
Antibodies
mice
monoclonal antibodies
Monoclonal Antibodies
Herd Immunity
antigens
mutation
Antigens
Mutation
amino acid substitution
Amino Acid Substitution
Neutralizing Antibodies
virion

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Kolawole, A. O., Li, M., Xia, C., Fischer, A. E., Giacobbi, N. S., Rippinger, C. M., ... Wobus, C. E. (2014). Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization. Journal of Virology, 88(8), 4543-4557. https://doi.org/10.1128/JVI.03685-13

Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization. / Kolawole, Abimbola O.; Li, Ming; Xia, Chunsheng; Fischer, Audrey E.; Giacobbi, Nicholas S.; Rippinger, Christine M.; Proescher, Jody B G; Wu, Susan K.; Bessling, Seneca L.; Gamez, Monica; Yu, Chenchen; Zhang, Rebecca; Mehoke, Thomas S.; Pipas, James M.; Wolfe, Joshua T.; Lin, Jeffrey S.; Feldman, Andrew B.; Smith, Thomas; Wobus, Christiane E.

In: Journal of Virology, Vol. 88, No. 8, 2014, p. 4543-4557.

Research output: Contribution to journalArticle

Kolawole, AO, Li, M, Xia, C, Fischer, AE, Giacobbi, NS, Rippinger, CM, Proescher, JBG, Wu, SK, Bessling, SL, Gamez, M, Yu, C, Zhang, R, Mehoke, TS, Pipas, JM, Wolfe, JT, Lin, JS, Feldman, AB, Smith, T & Wobus, CE 2014, 'Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization', Journal of Virology, vol. 88, no. 8, pp. 4543-4557. https://doi.org/10.1128/JVI.03685-13
Kolawole, Abimbola O. ; Li, Ming ; Xia, Chunsheng ; Fischer, Audrey E. ; Giacobbi, Nicholas S. ; Rippinger, Christine M. ; Proescher, Jody B G ; Wu, Susan K. ; Bessling, Seneca L. ; Gamez, Monica ; Yu, Chenchen ; Zhang, Rebecca ; Mehoke, Thomas S. ; Pipas, James M. ; Wolfe, Joshua T. ; Lin, Jeffrey S. ; Feldman, Andrew B. ; Smith, Thomas ; Wobus, Christiane E. / Flexibility in surface-exposed loops in a virus capsid mediates escape from antibody neutralization. In: Journal of Virology. 2014 ; Vol. 88, No. 8. pp. 4543-4557.
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AU - Li, Ming

AU - Xia, Chunsheng

AU - Fischer, Audrey E.

AU - Giacobbi, Nicholas S.

AU - Rippinger, Christine M.

AU - Proescher, Jody B G

AU - Wu, Susan K.

AU - Bessling, Seneca L.

AU - Gamez, Monica

AU - Yu, Chenchen

AU - Zhang, Rebecca

AU - Mehoke, Thomas S.

AU - Pipas, James M.

AU - Wolfe, Joshua T.

AU - Lin, Jeffrey S.

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