Harnessing post-translational modifications for next-generation HIV immunogens

Abstract

The extensive post-translational modifications of the envelope spikes of the human immunodeficiency virus (HIV) present considerable challenges and opportunities for HIV vaccine design. These oligomeric glycoproteins typically have over 30 disulfide bonds and around a 100 N-linked glycosylation sites, and are functionally dependent on protease cleavage within the secretory system. The resulting mature structure adopts a compact fold with the vast majority of its surface obscured by a protective shield of glycans which can be targeted by broadly neutralizing antibodies (bnAbs). Despite the notorious heterogeneity of glycosylation, rare B-cell lineages can evolve to utilize and cope with viral glycan diversity, and these structures therefore present promising targets for vaccine design. The latest generation of recombinant envelope spike mimetics contains re-engineered post-translational modifications to present stable antigens to guide the development of bnAbs by vaccination.

Keywords: glycobiology; glycosylation; immunogen; vaccine; virus.

Figure 1. Representation of the post-translational modifications of BG505 clade A envelope glycoprotein

Models were generated using the cryo-EM structure of BG505 SOSIP.664 PDB ID:5ACO ^[12]. A) 3D representation of the variable loops on gp120 and the heptad repeats of gp41. B) Canonical disulphide bonds found in BG505^[36] with the additional stabilizing disulphide bond found in BG505 SOSIP.664 shown in orange. C) Conservation map of the glycans of BG505 SOSIP.664. The glycans were coloured according to their conservation across 4000 Env strains Huang et al.^[44]. BG505 crystal structure with N-linked glycans modelled by Behrens et al.^[52] D) The frequency of potential N-linked glycan sites across the Env sequence with the PNGs found in BG505 SOSIP.664 labelled on the X axis. E) Schematic showing the locations of proteolytic cleavage for the signal peptide and the furin cleavage site.