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

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. Author summary: The isolation of broadly neutralizing antibodies from HIV-1 patients has shed light on the design of HIV-1 vaccines. Among them, one group consisting of anti-carbohydrate antibodies target N-glycans that compose the glycan shield on the Envelope surface glycoprotein (Env) of HIV-1. Similar to HIV-1, human H3N2 influenza viruses are highly glycosylated due to the accumulation of N-glycosylation sites over the past 50 years of natural evolution. Here, we demonstrate that an anti-HIV-1 antibody, namely 2G12, can neutralize human H3N2 viruses from the past 35 years. Comprehensive analyses by mass spectrometry and negative-stain electron microscopy reveal that oligomannose on two N-glycosylation sites near the receptor binding site are the targets of 2G12. Of note, the distance and disposition between the two glycans are the same as the equivalent oligomannose cluster on HIV-1 Env. Furthermore, mutational study shows that these two N-glycosylation sites are both required for survival of the recent H3N2 strains. Our data suggest that 2G12 can broadly neutralize non-HIV-1 human viruses by targeting oligomannose sugars, if of sufficient density and disposition on the viral surface. Since many viral surface antigens are highly glycosylated, it is worth evaluating 2G12-like antibodies as potential general therapeutics for human viral pathogens. [ABSTRACT FROM AUTHOR]