C-104 Defining the glycopeptide epitopes of broadly neutralizing antibodies for HIV vaccine design

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A major recent progress in HIV vaccine research is the discovery of a class of glycan-reactive broadly neutralizing antibodies (bNAbs) that target conserved N-glycans and peptide segments at the variable (V1V2 and V3) regions. Characterization of the neutralizing epitopes of these bNAbs, represented by PG9 and the PGT series (PGT121-135), constitutes an important step for HIV vaccine design. Mutational and structural studies have played a key role in epitope mapping. However, the glycan specificity and fine epitope structures of these antibodies remain to be characterized in details. Further epitope mapping has been complicated by the tremendous glycosylation heterogeneity of the viral envelope glycoproteins. To address this problem, we have launched a chemical approach that combines synthesis and antibody binding to decipher the glycopeptide neutralizing epitopes. Using a convergent chemoenzymatic synthetic method, we synthesized a series of V1V2 and V3 glycopeptides corresponding to the proposed epitopes of PG9, PGT121, PGT128, and 10-1074. Antibody binding studies with the well-defined glycopeptides enabled new discoveries of the glycan specificity and the requirement of the peptide context in the antigen recognition by these bNAbs. Moreover, a synthetic three-component V3 glycopeptide immunogen carrying a T-helper and a TLR2 ligand was able to raise substantial glycan-dependent antibodies in rabbits. The results will be discussed in the presentation.

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