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- Title
Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage.
- Authors
Simonich, Cassandra A.; Doepker, Laura; Ralph, Duncan; Williams, James A.; Dhar, Amrit; Yaffe, Zak; Gentles, Lauren; Small, Christopher T.; Oliver, Brian; Vigdorovich, Vladimir; Mangala Prasad, Vidya; Nduati, Ruth; Sather, D. Noah; Lee, Kelly K.; Matsen IV, Frederick A.; Overbaugh, Julie
- 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. Development of broadly neutralizing antibodies (bnAb) against HIV-1 in infected adults is a multi-step process unachievable by current vaccine approaches. Here the authors reconstruct the ontogeny of an infant bnAb, which develops in fewer steps, and identify its unique features that may shorten the path to HIV vaccines.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-09481-7