Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.

TitleHidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.
Publication TypeJournal Article
Year of Publication2017
AuthorsHe L, Lin X, de Val N, Saye-Francisco KL, Mann CJ, Augst R, Morris CD, Azadnia P, Zhou B, Sok D, Ozorowski G, Ward AB, Burton DR, Zhu J
JournalFront Immunol
Volume8
Pagination1025
Date Published08/24/2017
ISSN1664-3224
Abstract

Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development.

DOI10.3389/fimmu.2017.01025
Alternate JournalFront Immunol
PubMed ID28883821
PubMed Central IDPMC5573810
Grant ListUM1 AI100663 / AI / NIAID NIH HHS / United States
R01 AI129698 / AI / NIAID NIH HHS / United States
R01 AI084817 / AI / NIAID NIH HHS / United States
R56 AI084817 / AI / NIAID NIH HHS / United States
P01 AI124337 / AI / NIAID NIH HHS / United States
R56 AI125078 / AI / NIAID NIH HHS / United States
P01 AI110657 / AI / NIAID NIH HHS / United States
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