33 years after the discovery of HIV and after 6 vaccine efficacy trials, no HIV-1 candidate vaccine has proven effective enough for clinical use. One of the major reasons that HIV-1 has proven to be such a challenging target for vaccine design is that the surface of the viral envelope spike protein (Env) is protected by extensive glycosylation. The dense glycosylation paired with high sequence variability of the virus makes it difficult for the immune system to generate broadly-neutralizing antibodies (bnAbs) against the polypeptide surfaces of Env. However, up to 20% of patients with HIV do eventually develop bnAbs, many of which bind to epitopes comprising glycans or glycans and conserved protein residues. Significant interest lies in the development of structures able to mimic bnAb epitopes. Here we work to develop two different methods, RNA-SELMA and dual sugar mRNA display, for the directed evolution of glycoconjugates able to elicit production of bnAbs towards HIV. In RNA-SELMA, or RNA SELection of Modified Aptamers, glyco-modified RNAs, bearing fluoro modifications to impart serum stability, are tagged with their encoding DNAs. Dual sugar mRNA display is an extension of our previous glycopeptide mRNA display system that has been modified for incorporation of two orthogonally-encoded glycans. Utilizing these display methods in selection for bnAb binding, we look to develop glycoconjugates that can mimic bnAb epitopes, with potential utility as HIV vaccines.<br/>

New methods for directed evolution of glycoconjugates targeting broadly-neutralizing HIV antibodies

256th National Meeting (2018)

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