Abstract
Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA), for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV), and human cytomegalovirus (HCMV). In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9)-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn). These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.
Highlights
Developing broad-range virus-neutralizing antibodies requires identifying the immunological targets that are conserved among the targeted viruses and are suitable for antibody targeting
In the first set of the experiments, we verified that the preparations of Galanthus nivalis lectin (GNA) or 2G12 we utilized recognize corresponding epitopes presented by the native viral antigens
We performed a comparative carbohydrate microarray analysis to characterize the glycan-binding profiles of 2G12 and GNA and to pinpoint specific glyco-epitopes they recognize
Summary
Developing broad-range virus-neutralizing antibodies (bnAbs) requires identifying the immunological targets that are conserved among the targeted viruses and are suitable for antibody targeting. One intriguing question is whether human viruses of distinct phylogenetic origins, such as HIV-1 and SARS-CoV, may display conserved glycan targets that are suitable for broad virus neutralization. Induction of anti-ASOR auto-antibodies by inactivated SARS-CoV can be attributed to the fact that ASOR and the SARS-CoV spike glycoprotein commonly express the Tri/m-II cryptic glyco-determinants. Of note, this structural glycomics study revealed that SARS-CoV expresses the high-mannose series of carbohydrate structures as its major glycan moieties. The two probes represent distinct classes of virus-neutralizing agents The former is “mono-specific” for HIV-1; the latter is “pauci reactive”, being a potent neutralizer for several viruses, including at least HIV-1, HCMV, and SARS-CoV [20,21,22,23,24]. An essential step toward this goal is to identify the natural ligands of GNA that are preserved among GNA-targeted viral pathogens, which is the focus of this study
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