Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design

Abstract

The surface of enveloped viruses can be extensively glycosylated. Unlike the glycans coating pathogens such as bacteria and fungi, glycans on viruses are added and processed by the host-cell during biosynthesis. Glycoproteins are typically subjected to α-mannosidase processing and Golgi-mediated glycosyltransferase extension to form complex-type glycans. In envelope viruses, exceptions to this default pathway are common and lead to the presence of oligomannose-type glycan structures on the virion surface. In one extreme example, HIV-1 utilises a high density of glycans to limit host antibody recognition of protein. However, the high density limits glycan processing and the resulting oligomannose structures can be recognised by broadly neutralising antibodies isolated from HIV-1 infected patients. Here we discuss how divergence from host-cell glycosylation can be targeted for vaccine design.

Figure 1. The HIV glycan shield

HIV-1 Env glycosylation contains a population of oligomannose-type glycans that can be ascribed to the intrinsic mannose patch (IMP) and trimer-associated mannose patch (TAMP). Monomeric gp120 expressed outside of the context of the trimer only contains the IMP. The Env protein surface (grey) is derived from the crystal structure [25] and the glycans have been modelled in green (Pritchard et al., unpublished). The glycan structure is Man₉GlcNAc₂.

Figure 2. Regions of immune vulnerability on HIV-1 Env

HIV-1 bnAbs target three main glycan sites; i) the N332 glycan (e.g. 2G12, 10–1074, PGT121, PGT128, PGT135 [30, 39, 40]), ii) the N160 glycan (e.g. PG9, PGT145, CH04 [30, 33, 41]) and iii) the glycans at the gp120-gp41 interface (e.g. PGT151 [42] and 35O22 [43]). The Env protein surface (grey) is derived from the crystal structure [25] and the glycans have been modelled in green (Pritchard et al., unpublished). Regions of vulnerability to bnAbs are indicated with only one copy per trimer shown for simplicity.