HIV-1 is heavily glycosylated. A typical gp120 envelope glycoprotein carries more than 20 N-glycans, which constitute a strong defense for the virus to evade host immune response and meanwhile can serve as ligands for dendritic cell-mediated viral transmission. Nevertheless, recent discoveries of a series of glycan-dependent broadly neutralizing antibodies (bnAbs) (PG9, PG16, and the PGT series) from those HIV-infected long-term non-progressors (elite controllers), together with the previously described prototype carbohydrate-specific antibody 2G12, suggest that the strong carbohydrate defense could also be the Achilles' heel of the virus and that the host could mount an immune attack on the viral stronghold. As the complexity and extreme heterogeneity in glycosylation of gp120 makes it difficult to characterize the fine epitopes of these bnAbs, we have launched a program aiming to reconstitute the proposed antigenic structures via a synthetic approach. Toward this end, we have synthesized novel scaffold-based oligomannose clusters to mimic the 2G12 epitope, homogeneous V1V2 glycopeptides for deciphering the binding mode of PG9, PG16, and PGT141-145, and homogeneous V3 glycopeptides to reconstitute the neutralizing epitopes of PGT121-128. The synthesis, antibody binding/detection, and their implications for HIV vaccine design will be discussed.

Synthetic carbohydrate antigens for HIV antibody detection and vaccine design

245th National Meeting (2013)

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