The heavy N-glycosylation and frequent mutation of the HIV-1 outer envelope glycoprotein gp120 constitute two major defense mechanisms for the virus to evade host immune surveillance. However, these viral defenses are not seamless. In fact, recent studies have shown that broadly neutralizing antibodies (bnAbs) could be evolved by the immune system to target both the viral glycan coat and the conserved elements in the variable domains. These include bnAbs PG9 and PG16 that recognize novel glycopeptide epitopes in the V1V2 region, and the PGT128, PGT121, and 10-1074 antibodies that target glycopeptide epitopes in the V3 region. The discovery of this new class of bnAbs provides novel template for HIV-1 vaccine design. Nevertheless, the enormous structurally heterogeneity of glycosylation in the envelope glycoproteins has hampered the characterization of the precise glycopeptide epitopes of these bnAbs. In addition, the complexity in controlling protein glycosylation at the genetic level has also made it difficult in presenting a well-defined glycopeptide epitope in the context of intact proteins. To address these problems, we have initiated a project that aims to characterize and reconstitute the fine glycopeptide epitopes of these bnAbs through construction of synthetic HIV-1 glycopeptide library and antibody binding studies. This presentation describes our work on the chemoenzymatic synthesis of a series of HIV-1 V1V2 and V3 glycopeptides and their binding with various bnAbs. This study led to the identification of the minimal glycopeptide neutralizing epitopes of PG9, 10-1074, PGT121, PGT128 and other related HIV-neutralizing antibodies. In addition, the identified glycopeptide neutralizing epitopes were used as a key component for immunogen design. Preliminary immunization studies in rabbits have demonstrated that the synthetic glycopeptide immunogens are able to raise glycopeptide-specific antibodies that are cross-reactive to various HIV-1 envelope glycoprotein gp120s. These studies suggest that conserved HIV-1 glycopeptide epitopes could serve as an important component for HIV-1 vaccine development.

Recent advance in design of a glycopeptide-based HIV vaccine

2019 Spring National Meeting

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