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.
Highlights
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
We find that 2% somatic hypermutation (SHM) is sufficient for broad neutralization for this antibody lineage and that substitutions in the first complementarity-determining region (CDRL1) of the kappa chain are critical for neutralization breadth
We inferred the naive heavy-chain (VH) and light-chain (VK) ancestors of the BF520.1 monoclonal antibody (mAb), including inference of a previously undocumented variant of VH1-2*02 (G36A) among the per-sample germline results (Supplementary Table 2), and identified all clonally related sequences that descended from these ancestors using the partis software package[22,23,24]
Summary
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. We find that the BF520.1 inferred naive precursor binds HIV Env. We show that heterologous cross-clade neutralizing activity evolved in the infant within six months of infection and that, only 2% SHM is needed to achieve the full breadth of the mature antibody. While the evolutionary pathway of adult bnAbs have been dissected to inform vaccine approaches[2], significant challenges remain to be addressed for inducing bnAb responses by vaccination One such challenge is that most adult bnAbs take years to develop as a result of a complex interplay between viral escape and antibody maturation[2] that often leads to extensive somatic hypermutation (SHM), ranging from ~6 to 29% (averaging ~18%) for adult-derived V3-glycan bnAbs[4,6,8,9,10,11,12,13]. We conclude that this infant bnAb has features desirable for vaccine design and that further study of infant antibody responses is merited
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