Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness.
Identifieur interne : 001C74 ( Main/Exploration ); précédent : 001C73; suivant : 001C75Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness.
Auteurs : Jianhua Sui [États-Unis] ; Meagan Deming [États-Unis] ; Barry Rockx [États-Unis] ; Robert C. Liddington [États-Unis] ; Quan Karen Zhu [États-Unis] ; Ralph S. Baric [États-Unis] ; Wayne A. Marasco [États-Unis]Source :
- Journal of virology [ 1098-5514 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Anticorps antiviraux (immunologie), Femelle, Glycoprotéine de spicule des coronavirus (immunologie), Humains, Mutation, Peptidyl-Dipeptidase A (métabolisme), Récepteurs viraux (métabolisme), Souris, Souris de lignée BALB C, Tests de neutralisation, Virulence, Virus du SRAS (immunologie), Virus du SRAS (pathogénicité), Virus du SRAS (physiologie), Échappement immunitaire.
- MESH :
- immunologie : Anticorps antiviraux, Glycoprotéine de spicule des coronavirus, Virus du SRAS.
- métabolisme : Peptidyl-Dipeptidase A, Récepteurs viraux.
- pathogénicité : Virus du SRAS.
- physiologie : Virus du SRAS.
- Animaux, Femelle, Humains, Mutation, Souris, Souris de lignée BALB C, Tests de neutralisation, Virulence, Échappement immunitaire.
English descriptors
- KwdEn :
- Animals, Antibodies, Viral (immunology), Female, Humans, Immune Evasion, Mice, Mice, Inbred BALB C, Mutation, Neutralization Tests, Peptidyl-Dipeptidase A (metabolism), Receptors, Virus (metabolism), SARS Virus (immunology), SARS Virus (pathogenicity), SARS Virus (physiology), Spike Glycoprotein, Coronavirus (immunology), Virulence.
- MESH :
- chemical , immunology : Antibodies, Viral, Spike Glycoprotein, Coronavirus.
- chemical , metabolism : Peptidyl-Dipeptidase A, Receptors, Virus.
- immunology : SARS Virus.
- pathogenicity : SARS Virus.
- physiology : SARS Virus.
- Animals, Female, Humans, Immune Evasion, Mice, Mice, Inbred BALB C, Mutation, Neutralization Tests, Virulence.
Abstract
The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint.
DOI: 10.1128/JVI.02232-14
PubMed: 25231316
Affiliations:
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<term>Antibodies, Viral (immunology)</term>
<term>Female</term>
<term>Humans</term>
<term>Immune Evasion</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Mutation</term>
<term>Neutralization Tests</term>
<term>Peptidyl-Dipeptidase A (metabolism)</term>
<term>Receptors, Virus (metabolism)</term>
<term>SARS Virus (immunology)</term>
<term>SARS Virus (pathogenicity)</term>
<term>SARS Virus (physiology)</term>
<term>Spike Glycoprotein, Coronavirus (immunology)</term>
<term>Virulence</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Anticorps antiviraux (immunologie)</term>
<term>Femelle</term>
<term>Glycoprotéine de spicule des coronavirus (immunologie)</term>
<term>Humains</term>
<term>Mutation</term>
<term>Peptidyl-Dipeptidase A (métabolisme)</term>
<term>Récepteurs viraux (métabolisme)</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
<term>Tests de neutralisation</term>
<term>Virulence</term>
<term>Virus du SRAS (immunologie)</term>
<term>Virus du SRAS (pathogénicité)</term>
<term>Virus du SRAS (physiologie)</term>
<term>Échappement immunitaire</term>
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<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptidyl-Dipeptidase A</term>
<term>Receptors, Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Anticorps antiviraux</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>SARS Virus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Peptidyl-Dipeptidase A</term>
<term>Récepteurs viraux</term>
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<keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus du SRAS</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term>
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<keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>SARS Virus</term>
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<term>Humans</term>
<term>Immune Evasion</term>
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<term>Mice, Inbred BALB C</term>
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<term>Neutralization Tests</term>
<term>Virulence</term>
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<term>Humains</term>
<term>Mutation</term>
<term>Souris</term>
<term>Souris de lignée BALB C</term>
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<front><div type="abstract" xml:lang="en">The receptor binding domain (RBD) of the spike (S) glycoprotein of severe acute respiratory syndrome coronavirus (SARS-CoV) is a major target of protective immunity in vivo. Although a large number of neutralizing antibodies (nAbs) have been developed, it remains unclear if a single RBD-targeting nAb or two in combination can prevent neutralization escape and, if not, attenuate viral virulence in vivo. In this study, we used a large panel of human nAbs against an epitope that overlaps the interface between the RBD and its receptor, angiotensin-converting enzyme 2 (ACE2), to assess their cross-neutralization activities against a panel of human and zoonotic SARS-CoVs and neutralization escape mutants. We also investigated the neutralization escape profiles of these nAbs and evaluated their effects on receptor binding and virus fitness in vitro and in mice. We found that some nAbs had great potency and breadth in neutralizing multiple viral strains, including neutralization escape viruses derived from other nAbs; however, no single nAb or combination of two blocked neutralization escape. Interestingly, in mice the neutralization escape mutant viruses showed either attenuation (Urbani background) or increased virulence (GD03 background) consistent with the different binding affinities between their RBDs and the mouse ACE2. We conclude that using either single nAbs or dual nAb combinations to target a SARS-CoV RBD epitope that shows plasticity may have limitations for preventing neutralization escape during in vivo immunotherapy. However, RBD-directed nAbs may be useful for providing broad neutralization and prevention of escape variants when combined with other nAbs that target a second conserved epitope with less plasticity and more structural constraint.</div>
</front>
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