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Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.

ABSTRACT: A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.

SUBMITTER: Alam SM

PROVIDER: S-EPMC5562351 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.

Alam S Munir SM Aussedat Baptiste B Vohra Yusuf Y Meyerhoff R Ryan RR Cale Evan M EM Walkowicz William E WE Radakovich Nathan A NA Anasti Kara K Armand Lawrence L Parks Robert R Sutherland Laura L Scearce Richard R Joyce M Gordon MG Pancera Marie M Druz Aliaksandr A Georgiev Ivelin S IS Von Holle Tarra T Eaton Amanda A Fox Christopher C Reed Steven G SG Louder Mark M Bailer Robert T RT Morris Lynn L Abdool-Karim Salim S SS Cohen Myron M Liao Hua-Xin HX Montefiori David C DC Park Peter K PK Fernández-Tejada Alberto A Wiehe Kevin K Santra Sampa S Kepler Thomas B TB Saunders Kevin O KO Sodroski Joseph J Kwong Peter D PD Mascola John R JR Bonsignori Mattia M Moody M Anthony MA Danishefsky Samuel S Haynes Barton F BF

Science translational medicine 20170301 381

A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man<sub>9</sub>-V3). V3-glycan bnAbs bound to Man<sub>9</sub>-V3 glycopeptide and native-like gp140 trimers with similar affinities. F ...[more]

PMID: 28298421

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Project description:BackgroundRecent efforts in HIV-1 vaccine design have focused on immunogens that evoke potent neutralizing antibody responses to a broad spectrum of viruses circulating worldwide. However, the development of effective vaccines will depend on the identification and characterization of the neutralizing antibodies and their epitopes. We developed bioinformatics methods to predict epitope networks and antigenic determinants using structural information, as well as corresponding genotypes and phenotypes generated by a highly sensitive and reproducible neutralization assay.282 clonal envelope sequences from a multiclade panel of HIV-1 viruses were tested in viral neutralization assays with an array of broadly neutralizing monoclonal antibodies (mAbs: b12, PG9,16, PGT121 - 128, PGT130 - 131, PGT135 - 137, PGT141 - 145, and PGV04). We correlated IC50 titers with the envelope sequences, and used this information to predict antibody epitope networks. Structural patches were defined as amino acid groups based on solvent-accessibility, radius, atomic depth, and interaction networks within 3D envelope models. We applied a boosted algorithm consisting of multiple machine-learning and statistical models to evaluate these patches as possible antibody epitope regions, evidenced by strong correlations with the neutralization response for each antibody.ResultsWe identified patch clusters with significant correlation to IC50 titers as sites that impact neutralization sensitivity and therefore are potentially part of the antibody binding sites. Predicted epitope networks were mostly located within the variable loops of the envelope glycoprotein (gp120), particularly in V1/V2. Site-directed mutagenesis experiments involving residues identified as epitope networks across multiple mAbs confirmed association of these residues with loss or gain of neutralization sensitivity.ConclusionsComputational methods were implemented to rapidly survey protein structures and predict epitope networks associated with response to individual monoclonal antibodies, which resulted in the identification and deeper understanding of immunological hotspots targeted by broadly neutralizing HIV-1 antibodies.

Dataset Information

Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.

Publications

Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.

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