title: Targeting N-glycan cryptic sugar moieties for broad-spectrum virus neutralization: progress in identifying conserved molecular targets in viruses of distinct phylogenetic origins.
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.
authors.affiliation: Tumor Glycomics Laboratory, SRI International Biosciences Division, Menlo Park, CA 94025, USA. denong.wang@sri.com.
authors.forename: Denong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Tumor Glycomics Laboratory, SRI International Biosciences Division, Menlo Park, CA 94025, USA. jiafengjushi@live.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China. tangjiulai8888@21cn.com.
authors.forename: Jiulai
authors.initials: J
authors.lastname: Tang
authors.affiliation: Instituteof Human Virology, Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. LWang@ihv.umaryland.edu.|Department of Chemistry and Biochemistry, University of Maryland at College Park, College Park, MD 20742, USA. LWang@ihv.umaryland.edu.
authors.forename: Lai-Xi
authors.initials: LX
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism*; D000080908:Broadly Neutralizing Antibodies; D017124:Conserved Sequence; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D018604:Epitope Mapping; D006031:Glycosylation; D057809:HEK293 Cells; D015483:HIV Antibodies; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D037241:Mannose-Binding Lectins / Q000737:chemistry / Q000378:metabolism*; D010802:Phylogeny; D010865:Pilot Projects; D037121:Plant Lectins / Q000737:chemistry / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D040081:Protein Array Analysis / Q000379:methods; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology*
chemical_list: C529157:2G12 monoclonal antibody; D000911:Antibodies, Monoclonal; D000080908:Broadly Neutralizing Antibodies; D015483:HIV Antibodies; D037241:Mannose-Binding Lectins; D037121:Plant Lectins; D011134:Polysaccharides; C063117:snowdrop lectin