In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity
Identifieur interne : 000354 ( Main/Exploration ); précédent : 000353; suivant : 000355In vitro evolution of an influenza broadly neutralizing antibody is modulated by hemagglutinin receptor specificity
Auteurs : Nicholas C. Wu [États-Unis] ; Geramie Grande [États-Unis] ; Hannah L. Turner [États-Unis] ; Andrew B. Ward [États-Unis] ; Jia Xie [États-Unis] ; Richard A. Lerner [États-Unis] ; Ian A. Wilson [États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2017.
Abstract
The relatively recent discovery and characterization of human broadly neutralizing antibodies (bnAbs) against influenza virus provide valuable insights into antiviral and vaccine development. However, the factors that influence the evolution of high-affinity bnAbs remain elusive. We therefore explore the functional sequence space of bnAb C05, which targets the receptor-binding site (RBS) of influenza haemagglutinin (HA) via a long CDR H3. We combine saturation mutagenesis with yeast display to enrich for C05 variants of CDR H3 that bind to H1 and H3 HAs. The C05 variants evolve up to 20-fold higher affinity but increase specificity to each HA subtype used in the selection. Structural analysis reveals that the fine specificity is strongly influenced by a highly conserved substitution that regulates receptor binding in different subtypes. Overall, this study suggests that subtle natural variations in the HA RBS between subtypes and species may differentially influence the evolution of high-affinity bnAbs.
Url:
DOI: 10.1038/ncomms15371
PubMed: 28504265
PubMed Central: 5440694
Affiliations:
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Wu</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Integrative Structural and Computational Biology, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Grande, Geramie" sort="Grande, Geramie" uniqKey="Grande G" first="Geramie" last="Grande">Geramie Grande</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Chemistry, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Turner, Hannah L" sort="Turner, Hannah L" uniqKey="Turner H" first="Hannah L." last="Turner">Hannah L. Turner</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Integrative Structural and Computational Biology, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ward, Andrew B" sort="Ward, Andrew B" uniqKey="Ward A" first="Andrew B." last="Ward">Andrew B. Ward</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Integrative Structural and Computational Biology, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Xie, Jia" sort="Xie, Jia" uniqKey="Xie J" first="Jia" last="Xie">Jia Xie</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Chemistry, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lerner, Richard A" sort="Lerner, Richard A" uniqKey="Lerner R" first="Richard A." last="Lerner">Richard A. Lerner</name><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Department of Chemistry, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Integrative Structural and Computational Biology, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>The Skaggs Institute for Chemical Biology, The Scripps Research Institute</institution>, La Jolla, California 92037,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The relatively recent discovery and characterization of human broadly neutralizing antibodies (bnAbs) against influenza virus provide valuable insights into antiviral and vaccine development. However, the factors that influence the evolution of high-affinity bnAbs remain elusive. We therefore explore the functional sequence space of bnAb C05, which targets the receptor-binding site (RBS) of influenza haemagglutinin (HA) via a long CDR H3. We combine saturation mutagenesis with yeast display to enrich for C05 variants of CDR H3 that bind to H1 and H3 HAs. The C05 variants evolve up to 20-fold higher affinity but increase specificity to each HA subtype used in the selection. Structural analysis reveals that the fine specificity is strongly influenced by a highly conserved substitution that regulates receptor binding in different subtypes. Overall, this study suggests that subtle natural variations in the HA RBS between subtypes and species may differentially influence the evolution of high-affinity bnAbs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Neher, R A" uniqKey="Neher R">R. A. 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Tang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Z" uniqKey="Yang Z">Z. Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Neumann, G" uniqKey="Neumann G">G. Neumann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crooks, G E" uniqKey="Crooks G">G. E. Crooks</name></author><author><name sortKey="Hon, G" uniqKey="Hon G">G. Hon</name></author><author><name sortKey="Chandonia, J M" uniqKey="Chandonia J">J. M. Chandonia</name></author><author><name sortKey="Brenner, S E" uniqKey="Brenner S">S. E. Brenner</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Wu, Nicholas C" sort="Wu, Nicholas C" uniqKey="Wu N" first="Nicholas C." last="Wu">Nicholas C. Wu</name></noRegion><name sortKey="Grande, Geramie" sort="Grande, Geramie" uniqKey="Grande G" first="Geramie" last="Grande">Geramie Grande</name><name sortKey="Lerner, Richard A" sort="Lerner, Richard A" uniqKey="Lerner R" first="Richard A." last="Lerner">Richard A. Lerner</name><name sortKey="Turner, Hannah L" sort="Turner, Hannah L" uniqKey="Turner H" first="Hannah L." last="Turner">Hannah L. Turner</name><name sortKey="Ward, Andrew B" sort="Ward, Andrew B" uniqKey="Ward A" first="Andrew B." last="Ward">Andrew B. Ward</name><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><name sortKey="Wilson, Ian A" sort="Wilson, Ian A" uniqKey="Wilson I" first="Ian A." last="Wilson">Ian A. Wilson</name><name sortKey="Xie, Jia" sort="Xie, Jia" uniqKey="Xie J" first="Jia" last="Xie">Jia Xie</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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