Abstract
Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naive progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.
Highlights
Intermediate monoclonal antibodies (mAbs) Int6VH Int5VL, with 6% total somatic hypermutation (SHM), represents the final inferred intermediates 223 from the deep sequencing data, and they were detected in the sampled NGS sequences at 99224 100% nucleotide identity, further validating the sequence of these inferred intermediates
Cryo-EM structure of QA013.2 Fab bound to Envelope protein (Env) trimer demonstrates widespread 280 antibody contacts and shared structural characteristics with other V3-specific bnAbs
We present data detailing the lineage development and structure-function relationships of QA013.2 using antibody variable region deep sequencing and single particle cryo-electron microscopy (cryo-EM) respectively
Summary
Intermediate mAb Int6VH Int5VL, with 6% total SHM, represents the final inferred intermediates 223 from the deep sequencing data, and they were detected in the sampled NGS sequences at 99224 100% nucleotide identity, further validating the sequence of these inferred intermediates
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