Glycan Shielding and Modulation of Hepatitis C Virus Neutralizing Antibodies

Abstract

Hepatitis C virus (HCV) envelope glycoprotein heterodimer, E1E2, plays an essential role in virus entry and assembly. Furthermore, due to their exposure at the surface of the virion, these proteins are the major targets of anti-HCV neutralizing antibodies. Their ectodomain are heavily glycosylated with up to 5 sites on E1 and up to 11 sites on E2 modified by N-linked glycans. Thus, one-third of the molecular mass of E1E2 heterodimer corresponds to glycans. Despite the high sequence variability of E1 and E2, N-glycosylation sites of these proteins are generally conserved among the seven major HCV genotypes. N-glycans have been shown to be involved in E1E2 folding and modulate different functions of the envelope glycoproteins. Indeed, site-directed mutagenesis studies have shown that specific glycans are needed for virion assembly and infectivity. They can notably affect envelope protein entry functions by modulating their affinity for HCV receptors and their fusion activity. Importantly, glycans have also been shown to play a key role in immune evasion by masking antigenic sites targeted by neutralizing antibodies. It is well known that the high mutational rate of HCV polymerase facilitates the appearance of neutralization resistant mutants, and occurrence of mutations leading to glycan shifting is one of the mechanisms used by this virus to escape host humoral immune response. As a consequence of the importance of the glycan shield for HCV immune evasion, the deletion of N-glycans also leads to an increase in E1E2 immunogenicity and can induce a more potent antibody response against HCV.

Optimised cell systems for the investigation of hepatitis C virus E1E2 glycoproteins

“…The observed disparity in the antigenicity between 293T-and 293F-produced sE2 is probably a direct result of the difference in glycosylation pattern between the two. Glycans, directly and indirectly, influence E1E2 folding through their interactions with ER chaperones such as calnexin (59,60). Several E2 glycans have been shown to play an important role in folding and E1 and E2 heterodimerization (61).…”

Targeting STT3A‐oligosaccharyltransferase with NGI‐1 causes herpes simplex virus 1 dysfunction

“…Our results indicate that the potential antiviral range of NGI-1 type "pan-OST" agents extend beyond flaviviruses and have unanticipated implications for the treatment of, and host response to, HSV-1 infection. In addition to any effect of hypoglycosylation on HSV-1 infectivity or replication, which may be cell-type specific (infectivity with Vero cells, but not HEK293 lines, was mainly altered) NGI-1 type agents could also increase HSV-1 particle immunogenicity by elimination of oligosaccharides that block immune recognition of the underlying polypeptide [the so-called viral glycan shield (44,45)]. NGI-1 is expected to cause accumulation of mixtures of hypoglycosylated HSV-1 envelope proteins, but as discussed above (Fig.…”

Recent advances in “universal” influenza virus antibodies: the rise of a hidden trimeric interface in hemagglutinin globular head

“…Several strategies focused on the rational design of HA antigens that could expose conserved epitopes to generate bnAbs [73][74][75][76]. The glycosylation in the HA domain is involved in the antigenic drift of influenza viruses; influenza viruses have been found to introduce or remove glycans to change the viral structure and shield the sites near the RBS on its surface to reduce or evade host immune response [77][78][79]. A number of studies engineered glycans to expose the hidden conserved epitopes in the HA domain.…”