High-mannose glycans on viral envelope glycoproteins (HMGs)

High-mannose glycans are a type of N-linked carbohydrate structure consisting of a core of two N-acetylglucosamine residues and five to nine mannose residues. On the surface of viral envelope glycoproteins, such as HIV-1 gp120, SARS-CoV-2 spike, and Influenza hemagglutinin, these glycans form a dense "glycan shield" that protects the virus from immune recognition by masking conserved protein epitopes (Watanabe et al., 2020, Nature Communications). This shielding is often the result of "under-processing" by host cell glycosylation machinery due to the high density of glycans on the viral protein surface, which limits the access of processing enzymes (Doores, 2015, Frontiers in Immunology). Despite their role in evasion, these clusters of high-mannose glycans create unique "glycan-dependent" epitopes that are targeted by broadly neutralizing antibodies (bnAbs) and various lectins (Crispin et al., 2018, Chemical Reviews). Therapeutic agents like Griffithsin or bnAbs such as PGT121 bind these glycans to inhibit viral entry or facilitate the destruction of infected cells (O'Keefe et al., 2009, PNAS). Consequently, high-mannose glycans represent a critical focal point for the development of broad-spectrum antivirals and vaccine immunogens.

Other names

Oligomannose glycansHigh-mannose oligosaccharidesMan5-Man9GlcNAc2Viral glycan shieldMannose-rich glycans

Therapeutic agents target high-mannose glycans by binding to specific mannose-rich clusters on the viral surface. This binding can sterically block the interaction between the viral envelope protein and host cell receptors (e.g., CD4 or ACE2), thereby preventing viral entry. Additionally, glycan-binding antibodies can recruit immune effector cells to eliminate the virus or infected cells through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) (Sok & Burton, 2018, Nature Reviews Immunology; Crispin et al., 2018, Chemical Reviews).