Journal article

Conformational occlusion of blockade antibody epitopes, a novel mechanism of GII.4 human norovirus immune evasion

  • Lindesmith, Lisa C. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Mallory, Michael L. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Debbink, Kari Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA
  • Donaldson, Eric F. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Brewer-Jensen, Paul D. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Swann, Excel W. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Sheahan, Timothy P. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Graham, Rachel L. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  • Beltramello, Martina Humabs BioMed SA, Bellinzona, Switzerland
  • Corti, Davide Humabs BioMed SA, Bellinzona, Switzerland
  • Lanzavecchia, Antonio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Institute of Microbiology, Zurich, Switzerland
  • Baric, Ralph S. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
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    07.02.2018
Published in:
  • mSphere. - 2018, vol. 3, no. 1, p. e00518-17
English Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross- protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo-evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations.
Language
  • English
Classification
Medicine
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https://susi.usi.ch/usi/documents/319205
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