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Principal Investigator: Priyamvada Acharya
Organization: DUKE UNIVERSITY
Fiscal Year: 2023
Award: $683,445
Funding agency: National Institute of Allergy and Infectious Diseases
Structural characterization of Fab-dimerized glycan-reactive antibodies that neutralize HIV-1
A glycan shield covers the HIV-1 envelope (Env) limiting antibody access to broadly neutralizing
antibody (bnAb) epitopes. 2G12 had for long been the only example of a HIV-1 bnAb that interacts solely with
the Env glycan shield. Its unique VH domain-swapped architecture, with two Fab arms swapped to create a
Fab-dimerized IgG, allows 2G12 to simultaneously interact with 4 glycans, thus bolstering typically weak
protein-glycan binding through avidity. We have recently characterized structurally diverse Fab-dimerized,
glycan-reactive (FDG) antibodies that target the HIV-1 Env glycan shield. Unlike 2G12, these newly identified
FDG antibodies are not domain-swapped; instead, Fab dimerization occurred by mechanisms including inter-
Fab disulfide linkage, hydrophobic and hydrogen bond interactions. We further showed that the HIV-1 Env-
targeting FDG antibodies recognized a glycan cluster in the S2 subunit of the SARS-CoV-2 spike. While our
results reveal diverse ways antibodies can Fab dimerize to recognize glycans clusters, several questions
remain regarding the mechanisms of Fab dimerization and glycan recognition. Understanding these will
provide insights into the development of B cell responses to glycans.
The overall goals of this study are to understand structural determinants of antibody Fab dimerization
leading to high affinity glycan recognition. That 2G12 and other FDG bnAbs specifically recognize a conserved
glycan cluster on HIV-1 Envs that consists of self-sugars in a unique non-self presentation provides basis for
immunological discrimination between glycans on host and invading pathogens. The scientific premise of this
grant is that defining structural mechanisms for glycan recognition by Fab dimerized antibodies will allow
specific targeting of diverse glycosylated pathogens. The innovations in this grant derive from (i) an expanded
repertoire of FDG antibodies, (ii) the demonstration that FDG antibodies are prevalent, (iii) the finding that
domain-swapped VH conformation is not necessary for HIV-1 neutralization.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><Address><Affinity><Amino Acid Substitution><Antibodies><Antigenic Determinants><Antigens><Architecture><Avidity><B-Cell Development><Binding><Binding Determinants><Biological><Biology><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CoV S protein><CoV glycoprotein S><CoV spike glycoprotein><CoV spike protein><CoV-2><CoV2><Cognitive Discrimination><Complex><Coronaviridae><Coronavirus><Coronavirus glycoprotein S><Coronavirus spike protein><Cryo-electron Microscopy><Cryoelectron Microscopy><Dimerization><Discrimination><Disulfide Linkage><Electron Cryomicroscopy><Engineering / Architecture><Epitopes><Evolution><Glycans><Goals><Grant><H-bond><HIV Infections><HIV-1><HIV-I><HIV1><HTLV-III Infections><HTLV-III-LAV Infections><Human><Human Immunodeficiency Virus Type 1><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Hydrogen Bonding><Hydrophobicity><Ig Somatic Hypermutation><IgG><Immunochemical Immunologic><Immunoglobulin G><Immunoglobulin Somatic Hypermutation><Immunologic><Immunological><Immunologically><Immunologics><Invaded><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><Macaca><Macaque><Metabolic Glycosylation><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Negative Staining><Polysaccharides><Population><Property><Protein Dimerization><Proteins><Resolution><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SHIV><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shapes><Single Crystal Diffraction><Structure><Variant><Variation><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><arm><biologic><conformation><conformational><conformational state><conformationally><conformations><corona virus><coronavirus S protein><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus spike glycoprotein><cross reactivity><cryo-EM><cryoEM><cryogenic electron microscopy><design><designing><expectation><experiment><experimental research><experimental study><experiments><glycosylation><hCoV19><immunogen><innovate><innovation><innovative><insight><mutant><nCoV2><natural antibodies><neutralizing antibody><novel><pathogen><resolutions><response><severe acute respiratory syndrome-CoV><simian HIV><simian human immunodeficiency virus><somatic hypermutation><structural determinants><structural factors><sugar>