Lindesmith, Lisa C. Mallory, Michael L. Debbink, Kari Donaldson, Eric F. Brewer-Jensen, Paul D. Swann, Excel W. Sheahan, Timothy P. Graham, Rachel L. Beltramello, Martina Corti, Davide Lanzavecchia, Antonio Baric, Ralph S. 2018-02-07 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. application/pdf https://susi.usi.ch/global/documents/319205 https://localhost:5000/ark:/12658/srd1319205 https://susi.usi.ch/documents/319205/files/Lindesmith_MS_2018.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1128/mSphere.00518-17 info:eu-repo/semantics/altIdentifier/ark/12658/srd1319205 info:eu-repo/semantics/openAccess CC BY mSphere. - 2018, vol. 3, no. 1, p. e00518-17 Adaptive immunity Blockade antibody Broadly neutralizing antibody Epitope shielding Evolution Immune evasion Monoclonal antibody Norovirus Particle dynamics info:eu-repo/classification/udc/61 Conformational occlusion of blockade antibody epitopes, a novel mechanism of GII.4 human norovirus immune evasion http://purl.org/coar/resource_type/c_6501