HIV-1 envelope glycan composition influences virus-host interaction

Abstract

Abstract HIV-1 envelope (Env) is densely shrouded with oligomannose- and complex-type glycans. These glycans interact with lectins, a family of carbohydrate-recognizing proteins. We evaluated lectins for the ability to block infection of HIV-1 isolates that differ in their sensitivity to neutralizing antibodies. The antibody-sensitive tier 1 viruses were blocked by lectins more easily than the resistant tier 2 viruses. When tier 2 viruses were produced with glycosidase inhibitors to express homogenously oligomannose-type glycans, they became more sensitive to mannose-binding lectins (GNA, GRFT, CVN), suggesting that glycan homogeneity increases virus sensitivity to antibodies and lectins. Further, we tested the effect of glycan content on HIV-1 capture and transmission via DC-SIGN, a C-type lectin expressed by macrophages and dendritic cells. While the capture of virus enriched with high-mannose glycans was enhanced, transmission was diminished due to increased degradation. Under a biologically relevant setting, glycan composition was influenced by the Env signal sequence (SS), and SS mutations altered DC-SIGN-mediated virus transmission. The SS mutants also displayed altered sensitivity to inhibition by lectins GNA and GRFT. Mutations in gp120 did not have these effects. Env SS sequences and glycan compositions also vary among HIV-1 strains, leading to differences in their interactions with and sensitivity to lectins. These phenotypes were associated with the amounts of terminating Manα1–3 vs Manα1–2 residues on the Env oligosaccharides and their recognition by DC-SIGN, GNA, and GRFT. These data demonstrate the importance of the Env sugar contents for HIV-1 interactions with lectins expressed by the host immune cells.