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Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage

Author

Listed:
  • Cassandra A. Simonich

    (Fred Hutchinson Cancer Research Center
    University of Washington School of Medicine)

  • Laura Doepker

    (Fred Hutchinson Cancer Research Center)

  • Duncan Ralph

    (Fred Hutchinson Cancer Research Center)

  • James A. Williams

    (University of Washington)

  • Amrit Dhar

    (Fred Hutchinson Cancer Research Center
    University of Washington)

  • Zak Yaffe

    (University of Washington School of Medicine)

  • Lauren Gentles

    (University of Washington
    Fred Hutchinson Cancer Research Center)

  • Christopher T. Small

    (Fred Hutchinson Cancer Research Center)

  • Brian Oliver

    (Center for Infectious Disease Research)

  • Vladimir Vigdorovich

    (Center for Infectious Disease Research)

  • Vidya Mangala Prasad

    (University of Washington)

  • Ruth Nduati

    (University of Nairobi)

  • D. Noah Sather

    (Center for Infectious Disease Research)

  • Kelly K. Lee

    (University of Washington)

  • Frederick A. Matsen IV

    (Fred Hutchinson Cancer Research Center)

  • Julie Overbaugh

    (Fred Hutchinson Cancer Research Center
    University of Washington School of Medicine)

Abstract

HIV-infected infants develop broadly neutralizing plasma responses with more rapid kinetics than adults, suggesting the ontogeny of infant responses could better inform a path to achievable vaccine targets. Here we reconstruct the developmental lineage of BF520.1, an infant-derived HIV-specific broadly neutralizing antibody (bnAb), using computational methods developed specifically for this purpose. We find that the BF520.1 inferred naive precursor binds HIV Env. We also show that heterologous cross-clade neutralizing activity evolved in the infant within six months of infection and that, ultimately, only 2% SHM is needed to achieve the full breadth of the mature antibody. Mutagenesis and structural analyses reveal that, for this infant bnAb, substitutions in the kappa chain were critical for activity, particularly in CDRL1. Overall, the developmental pathway of this infant antibody includes features distinct from adult antibodies, including several that may be amenable to better vaccine responses.

Suggested Citation

  • Cassandra A. Simonich & Laura Doepker & Duncan Ralph & James A. Williams & Amrit Dhar & Zak Yaffe & Lauren Gentles & Christopher T. Small & Brian Oliver & Vladimir Vigdorovich & Vidya Mangala Prasad &, 2019. "Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09481-7
    DOI: 10.1038/s41467-019-09481-7
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    Cited by:

    1. Amrit Dhar & Duncan K Ralph & Vladimir N Minin & Frederick A Matsen IV, 2020. "A Bayesian phylogenetic hidden Markov model for B cell receptor sequence analysis," PLOS Computational Biology, Public Library of Science, vol. 16(8), pages 1-27, August.

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