HIV-1 envelope glycan composition is a key determinant of efficient virus transmission via DC-SIGN and resistance to antibodies and inhibitory lectins

Abstract

Abstract HIV-1 envelope (Env) undergoes extensive N-linked glycosylation that cloaks its surface with an assortment of oligomannose-, hybrid-, and complex-type glycans and enables virus interaction with carbohydrate-recognizing lectins. This study examined the importance of Env glycan heterogeneity for HIV-1 transmission via DC-SIGN, a mannose-binding lectin expressed on macrophages and immature dendritic cells. A diversity of glycan content was observed among HIV-1 strains and associated with varying degrees of trans-infection via DC-SIGN. When Env glycans were modified to display only oligomannose-type, DC-SIGN-mediated virus capture was enhanced. However, virus trans-infection was diminished due to increased degradation, which was alleviated by incorporation of hybrid-type glycans. HIV-1 strains also displayed varying sensitivity to trans-infection blockage by antiviral lectins GNA and GRFT, which correlated with sensitivity to neutralizing antibodies. Tier 1 viruses sensitive to neutralizing antibodies were more readily inhibited by GNA and GRFT than tier 2 and tier 3 viruses. Correspondingly, tier 1 Envs showed a greater reactivity with GNA and GRFT, which recognizes high-mannose-type N-glycans, suggesting enrichment of high-mannose type on tier 1 Envs. Of note, HIV-1 Env glycan content is influenced by amino-acid variations in the Env signal peptide (SP) and single-point mutations in the Env SP were sufficient to affect Env glycan content, leading to alterations in DC-SIGN-dependent trans-infection and virus sensitivity to antiviral lectins. Hence, SP variation and glycosylation that confer varied types of oligosaccharides to HIV-1 Env are critical determinants for virus fitness and phenotypic diversity.