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

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.