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Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies.
PLoS Pathog. 2021 08; 17(8):e1009772.PP

Abstract

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.

Authors+Show Affiliations

Cell Biology of Viral Infection Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.Cell Biology of Viral Infection Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.ITQB NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa; Oeiras, Portugal.ITQB NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa; Oeiras, Portugal.Cell Biology of Viral Infection Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.Lymphocyte Physiology Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.CEDOC NOVA, Centro de Estudos de Doenças Crónicas, Nova Medical School, Universidade Nova de Lisboa; Lisboa, Portugal.Lymphocyte Physiology Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.Genomics Unit, Instituto Gulbenkian de Ciência; Oeiras, Portugal.Bioinformatics Unit, Instituto Gulbenkian de Ciência; Oeiras, Portugal.The Wellcome Trust Sanger Institute; Hinxton, United Kingdom.Disease Genetics Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.CEDOC NOVA, Centro de Estudos de Doenças Crónicas, Nova Medical School, Universidade Nova de Lisboa; Lisboa, Portugal.ITQB NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa; Oeiras, Portugal.Cell Biology of Viral Infection Lab, Instituto Gulbenkian de Ciência; Oeiras, Portugal.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34352039

Citation

Alenquer, Marta, et al. "Signatures in SARS-CoV-2 Spike Protein Conferring Escape to Neutralizing Antibodies." PLoS Pathogens, vol. 17, no. 8, 2021, pp. e1009772.
Alenquer M, Ferreira F, Lousa D, et al. Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. PLoS Pathog. 2021;17(8):e1009772.
Alenquer, M., Ferreira, F., Lousa, D., Valério, M., Medina-Lopes, M., Bergman, M. L., Gonçalves, J., Demengeot, J., Leite, R. B., Lilue, J., Ning, Z., Penha-Gonçalves, C., Soares, H., Soares, C. M., & Amorim, M. J. (2021). Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. PLoS Pathogens, 17(8), e1009772. https://doi.org/10.1371/journal.ppat.1009772
Alenquer M, et al. Signatures in SARS-CoV-2 Spike Protein Conferring Escape to Neutralizing Antibodies. PLoS Pathog. 2021;17(8):e1009772. PubMed PMID: 34352039.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies. AU - Alenquer,Marta, AU - Ferreira,Filipe, AU - Lousa,Diana, AU - Valério,Mariana, AU - Medina-Lopes,Mónica, AU - Bergman,Marie-Louise, AU - Gonçalves,Juliana, AU - Demengeot,Jocelyne, AU - Leite,Ricardo B, AU - Lilue,Jingtao, AU - Ning,Zemin, AU - Penha-Gonçalves,Carlos, AU - Soares,Helena, AU - Soares,Cláudio M, AU - Amorim,Maria João, Y1 - 2021/08/05/ PY - 2021/05/20/received PY - 2021/06/30/accepted PY - 2021/8/5/entrez PY - 2021/8/6/pubmed PY - 2021/8/13/medline SP - e1009772 EP - e1009772 JF - PLoS pathogens JO - PLoS Pathog VL - 17 IS - 8 N2 - Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/34352039/Signatures_in_SARS_CoV_2_spike_protein_conferring_escape_to_neutralizing_antibodies_ DB - PRIME DP - Unbound Medicine ER -