SUMMARY
2C06; A.C. provided BG505 DS-SOSIP
MUTANTS
AUTHOR CONTRIBUTIONSS.W. determined cryo-EM structures, analyzed the data, and wrote the manuscript; F.M. performed B cell sorting; B.Z. and T.L. expressed and purified antibodies and performed BLI assays; C.-H.S. analyzed antibody sequences and binding motifs; T.B. calculated Shannon entropyfromthe208-strain panel and analyzed fusion-peptide-directed antibodiesforepitope overlaps; T.J., A.R.H., and J.R.-T. carried out RATP-Ig for the sorted B cells; I.-T.T. and D.W. produced trimer probes; P.T. performed AlphaLISA and Carterra assays; J.E.B. and N.C.M. collected cryo-EM data for 2C06; A.C. provided BG505 DS-SOSIP and ConC trimers; R.C. and A.S.O. prepared BG505 DS-SOSIP mutants and analyzed for antibody binding by BLI; C.C. and D.K.P. performed ELISA; M.G. and L.N. provided serum samples from VRC 018 trial; J.G., R.R., and A.S.O. designed glycan-base BG505; D.R.H. and A.S.O. produced trimersfor binding analysis; M.L. modeled glycan241 conformation and calculated energies for epitope residue mutations; S.O. and N.A.D.-R. performed neutralization assays; T.S. and Y.T. collected cryo-EM data for 2C09; D.J.V.W. and T.Z. performed SPR assays; R.A.K. oversaw neutralization and ELISA experiments; L.S. supervised data collection for 2C06; D.C.D. supervised RATP-Ig experiments; A.B.M. supervised B cell sorting; P.D.K. oversaw the project and–with S.W.–wrote the manuscript, with all authors providing revisions and comments.Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with prefusion-stabilized envelope trimers eliciting autologous neutralizing antibodies has been reported in multiple vaccine-test species, though not in humans. To investigate elicitation of HIV-1 neutralizing antibodies in humans, here, we analyze B cells from a phase I clinical trial of the “DS-SOSIP”-stabilized envelope trimer from strain BG505, identifying two antibodies, N751-2C06.01 and N751-2C09.01 (named for donor-lineage.clone), that neutralize the autologous tier-2 strain, BG505. Though derived from distinct lineages, these antibodies form a reproducible antibody class that targets the HIV-1 fusion peptide. Both antibodies are highly strain specific, which we attribute to their partial recognition of a BG505-specific glycan hole and to their binding requirements for a few BG505-specific residues. Prefusion-stabilized envelope trimers can thus elicit autologous tier-2 neutralizing antibodies in humans, with initially identified neutralizing antibodies recognizing the fusion-peptide site of vulnerability.