Norovirus escape from broadly neutralizing antibodies is limited to allostery-like mechanisms

Abimbola O. Kolawole, Hong Q. Smith, Sophia A. Svoboda, Madeline S. Lewis, Michael B. Sherman, Gillian Lynch, B. Montgomery Pettitt, Thomas J. Smith, Christiane E. Wobus

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Ideal antiviral vaccines elicit antibodies (Abs) with broad strain recognition that bind to regions that are difficult to mutate for escape. Using 10 murine norovirus (MNV) strains and 5 human norovirus (HuNoV) virus-like particles (VLPs), we identified monoclonal antibody (MAb) 2D3, which broadly neutralized all MNV strains tested. Importantly, escape mutants corresponding to this antibody were very slow to develop and were distal to those raised against our previously studied antibody, A6.2. To understand the atomic details of 2D3 neutralization, we determined the cryo-electron microscopy (cryo-EM) structure of the 2D3/MNV1 complex. Interestingly, 2D3 binds to the top of the P domain, very close to where A6.2 binds, but the only escape mutations identified to date fall well outside the contact regions of both 2D3 and A6.2. To determine how mutations in distal residues could block antibody binding, we used molecular dynamics flexible fitting simulations of the atomic structures placed into the density map to examine the 2D3/MNV1 complex and these mutations. Our findings suggest that the escape mutant, V339I, may stabilize a salt bridge network at the P-domain dimer interface that, in an allostery-like manner, affects the conformational relaxation of the P domain and the efficiency of binding. They further highlight the unusual antigenic surface bound by MAb 2D3, one which elicits cross-reactive antibodies but which the virus is unable to alter to escape neutralization. These results may be leveraged to generate norovirus (NoV) vaccines containing broadly neutralizing antibodies.

Original languageEnglish (US)
Article numbere00334-17
JournalmSphere
Volume2
Issue number5
DOIs
StatePublished - Sep 1 2017

Keywords

  • Antibody
  • Neutralization
  • Noroviruses
  • Protein structure-function

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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