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

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, Ruth Nduati, D. Noah Sather, Kelly K. Lee, Frederick A. Matsen Iv and Julie Overbaugh ()
Additional contact information
Cassandra A. Simonich: Fred Hutchinson Cancer Research Center
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
Zak Yaffe: University of Washington School of Medicine
Lauren Gentles: University of Washington
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

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09481-7

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