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

Citation:
Simonich CA, Doepker L, Ralph D, Williams JA, Dhar A, Yaffe Z, Gentles L, Small CT, Oliver B, Vigdorovich V, Mangala Prasad V, NNduati R. "Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.". 2019.

Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.
Simonich CA1,2, Doepker L1, Ralph D3, Williams JA4, Dhar A3,5, Yaffe Z2, Gentles L6,7, Small CT3, Oliver B8, Vigdorovich V8, Mangala Prasad V4, Nduati R9, Sather DN8, Lee KK4, Matsen Iv FA3, Overbaugh J10,11.
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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.

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