A cross-neutralizing antibody between HIV-1 and influenza virus

Abstract

Incessant antigenic evolution enables the persistence and spread of influenza virus in the human population. As the principal target of the immune response, the hemagglutinin (HA) surface antigen on influenza viruses continuously acquires and replaces N-linked glycosylation sites to shield immunogenic protein epitopes using host-derived glycans. Anti-glycan antibodies, such as 2G12, target the HIV-1 envelope protein (Env), which is even more extensively glycosylated and contains under-processed oligomannose-type clusters on its dense glycan shield. Here, we illustrate that 2G12 can also neutralize human seasonal influenza A H3N2 viruses that have evolved to present similar oligomannose-type clusters on their HAs from around 20 years after the 1968 pandemic. Using structural biology and mass spectrometric approaches, we find that two N-glycosylation sites close to the receptor binding site (RBS) on influenza hemagglutinin represent the oligomannose cluster recognized by 2G12. One of these glycan sites is highly conserved in all human H3N2 strains and the other emerged during virus evolution. These two N-glycosylation sites have also become crucial for fitness of recent H3N2 strains. These findings shed light on the evolution of the glycan shield on influenza virus and suggest 2G12-like antibodies can potentially act as broad neutralizers to target human enveloped viruses.

Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies

“…Finally, that FDG Abs can bind multiple glycan clusters and use multiple BCRs, combined with FDG precursors being well represented in human B cell repertoire make this new category of glycan-reactive B cells an attractive target to consider for induction by HIV-1 vaccines. Since the submission of this paper, Lee et al have reported that the FDG Ab 2G12 can neutralize strains of influenza (Lee et al, 2021), further demonstrating the breadth of cross-binding activity of the 2G12 FDG Ab for glycosylated virus pathogens.…”

Lentil lectin derived from Lens culinaris exhibit broad antiviral activities against SARS-CoV-2 variants

“…However, surface glycans could also be the target of antibodies and glycan-binding agents. Several broad and potent neutralizing mAbs target the specific glycan of viral surface glycoproteins were identified [ 35–37 ], and glycan-binding proteins such as lectins exhibit antiviral activities [ 11 ]. Although the highly glycosylated SARS-CoV-2 S protein is continuously mutated and antigenic variants resistant to mAbs and vaccine-generated antibodies emerged, the glycosylation sites are conserved so far, which provide a candidate target for anti-SARS-CoV-2 strategy against variants.…”

Glycans in Virus-Host Interactions: A Structural Perspective

“…Glycan clustering is amplified at the quaternary junctions formed by protein oligomers, such as trimeric viral proteins like SARS-CoV-2 spike protein and Influenza HA. Indeed, Lee et al provide evidence that the 2G12 glycoepitope on Influenza H3N2 is quaternary and neutralizing, though the neutralizing effect may also be driven by the glycoepitope's location proximal to the functionally-important receptor binding site (Lee et al, 2021). The 2G12 topological glycoepitope on SARS-CoV-2 is also quaternary (Acharya et al, 2020).…”

“…However, topological glycoepitopes do not appear unique to HIV, and recent evidence suggests that 2G12 recognizes topological glycoepitopes on additional viruses. At the time of this writing, 2G12 glycoepitopes have been identified on Influenza H3N2 Lee et al (2021) and SARS-CoV-2 ( Acharya et al, 2020 ; Mannar et al, 2021 ).…”