Affinity maturation in a human humoral response to influenza hemagglutinin

McCarthy, Kevin R.; Raymond, Donald D.; Do, Khoi T.; Schmidt, Aaron G.; Harrison, Stephen C.

doi:10.1073/pnas.1915620116

Title: Affinity maturation in a human humoral response to influenza hemagglutinin

Journal Article · Mon Dec 16 00:00:00 EST 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1915620116· OSTI ID:1581820

McCarthy, Kevin R. ^[1]; Raymond, Donald D. ^[2]; Do, Khoi T. ^[3]; Schmidt, Aaron G. ^[4];

^[5]

Boston Children's Hospital and Harvard Medical School, Boston, MA (United States)
Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Broad Institute of MIT and Harvard, Cambridge, MA (United States)
Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Ragon Inst. of Massachusetts General Hospital, Massachusetts Inst. of Technology, and Harvard, Cambridge, MA (United States)
Boston Children's Hospital and Harvard Medical School, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)

Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: P01 AI089618; U19 AI117892

OSTI ID:: 1581820

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 52; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 12 works

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References (25)

Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans Garces, Fernando; Lee, Jeong Hyun; de Val, Natalia Immunity, Vol. 43, Issue 6 https://doi.org/10.1016/j.immuni.2015.11.007	journal	December 2015
Complex Antigens Drive Permissive Clonal Selection in Germinal Centers Kuraoka, Masayuki; Schmidt, Aaron G.; Nojima, Takuya Immunity, Vol. 44, Issue 3 https://doi.org/10.1016/j.immuni.2016.02.010	journal	March 2016
Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. McKean, D.; Huppi, K.; Bell, M. Proceedings of the National Academy of Sciences, Vol. 81, Issue 10 https://doi.org/10.1073/pnas.81.10.3180	journal	May 1984
Viral Receptor-Binding Site Antibodies with Diverse Germline Origins Schmidt, Aaron G.; Therkelsen, Matthew D.; Stewart, Shaun Cell, Vol. 161, Issue 5 https://doi.org/10.1016/j.cell.2015.04.028	journal	May 2015
Intraclonal generation of antibody mutants in germinal centres Jacob, Joshy; Kelsoe, Garnett; Rajewsky, Klaus Nature, Vol. 354, Issue 6352 https://doi.org/10.1038/354389a0	journal	December 1991
Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody Schmidt, A. G.; Xu, H.; Khan, A. R. Proceedings of the National Academy of Sciences, Vol. 110, Issue 1 https://doi.org/10.1073/pnas.1218256109	journal	November 2012
Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site Schmidt, Aaron G.; Do, Khoi T.; McCarthy, Kevin R. Cell Reports, Vol. 13, Issue 12 https://doi.org/10.1016/j.celrep.2015.11.063	journal	December 2015
B-cell–lineage immunogen design in vaccine development with HIV-1 as a case study Haynes, Barton F.; Kelsoe, Garnett; Harrison, Stephen C. Nature Biotechnology, Vol. 30, Issue 5 https://doi.org/10.1038/nbt.2197	journal	May 2012
Reconstructing a B-cell clonal lineage. I. Statistical inference of unobserved ancestors Kepler, Thomas B. F1000Research, Vol. 2 https://doi.org/10.12688/f1000research.2-103.v1	journal	January 2013
Variations in Affinities of Antibodies during the Immune Response ^* Eisen, Herman N.; Siskind, Gregory W. Biochemistry, Vol. 3, Issue 7 https://doi.org/10.1021/bi00895a027	journal	July 1964
H3N2 Influenza Infection Elicits More Cross-Reactive and Less Clonally Expanded Anti-Hemagglutinin Antibodies Than Influenza Vaccination Moody, M. Anthony; Zhang, Ruijun; Walter, Emmanuel B. PLoS ONE, Vol. 6, Issue 10 https://doi.org/10.1371/journal.pone.0025797	journal	October 2011
Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires McCarthy, Kevin R.; Watanabe, Akiko; Kuraoka, Masayuki Immunity, Vol. 48, Issue 1 https://doi.org/10.1016/j.immuni.2017.12.009	journal	January 2018
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage: Key Mutations in Antibody Affinity Maturation Xu, Huafeng; Schmidt, Aaron G.; O'Donnell, Timothy Proteins: Structure, Function, and Bioinformatics, Vol. 83, Issue 4 https://doi.org/10.1002/prot.24745	journal	February 2015
Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain Raymond, Donald D.; Stewart, Shaun M.; Lee, Jiwon Nature Medicine, Vol. 22, Issue 12 https://doi.org/10.1038/nm.4223	journal	November 2016
Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin Whittle, J. R. R.; Zhang, R.; Khurana, S. Proceedings of the National Academy of Sciences, Vol. 108, Issue 34 https://doi.org/10.1073/pnas.1111497108	journal	August 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6 https://doi.org/10.1007/s00775-020-01814-y	journal	August 2020
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Taking the Broad View on B Cell Affinity Maturation Neu, Karlynn E.; Wilson, Patrick C. Immunity, Vol. 44, Issue 3 https://doi.org/10.1016/j.immuni.2016.03.001	journal	March 2016
Immunopaleontology reveals how affinity enhancement is achieved during affinity maturation of antibodies to influenza virus Eisen, Herman N.; Chakraborty, Arup K. Proceedings of the National Academy of Sciences, Vol. 110, Issue 1 https://doi.org/10.1073/pnas.1219396110	journal	December 2012
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/s0907444909042073	journal	December 2009
Affinity Enhancement of Antibodies: How Low-Affinity Antibodies Produced Early in Immune Responses Are Followed by High-Affinity Antibodies Later and in Memory B-Cell Responses Eisen, H. N. Cancer Immunology Research, Vol. 2, Issue 5 https://doi.org/10.1158/2326-6066.cir-14-0029	journal	May 2014

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