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Principal Investigator: JOHN P MOORE
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $500,527
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
Many potent and effective broadly neutralizing antibodies (bNAbs) directed to the HIV-1 envelope glycoprotein
(Env) trimer have been studied mechanistically and structurally. Combined, their epitopes now cover most of the
external surface of Env. Passive immunization with bNAbs, optimally mixed to minimize viral escape, holds
promise for controlling HIV-1 infection, prevent it, or even helping to cure it. Eliciting bNAbs by active
immunization, however, remains problematic. Our overall long-term goal is to contribute to solving that major
problem. We will develop techniques for quantifying concentrations, affinities, kinetics, and stoichiometry of bNAb
binding in polyclonal sera from infected or immunized animals and humans. We will determine how these
quantities change as germline (GL) responses mature into bNAbs. So far, we have used soluble, native-like
SOSIP trimers to dissect or induce Ab responses. The recent emergence of mRNA vaccination, however, allows
the design of full-length Env constructs, opening the possibility of presenting external bNAb epitopes located
near the membrane while shielding C-terminal neo-epitopes at the base of soluble trimers. We will therefore
make virus-like particles that mimic HIV-1 virions in size, membrane composition, Env density, and Env
interactions with interior viral proteins. The kinetics and stoichiometry of bNAb binding to these full-length
membrane-anchored trimers, with and without changes in the cytoplasmic tail, will be compared with binding to
SOSIP trimers. We will also extend in-depth binding analyses to SOSIP trimers derived from a global panel of
neutralization-resistant HIV-1 isolates. We will dissect binding kinetics, stoichiometry, induced conformational
changes, and the heterogeneity of the interactions, thereby identifying binding characteristics that correlate with
neutralization breadth. In silico analyses of how the midpoints and Hill slopes (h) of the neutralization curves
relate to neutralization breadth, for both single bNAbs and combinations, will guide further experimental
dissections of how binding properties mold cross-reactivity. We will develop assays for measuring entry-fusion
fitness to define the relationship between viral resistance to bNAbs and the efficiency of receptor-facilitated entry.
To achieve these goals, we propose three Specific Aims:
Aim 1. Analyze bNAb binding and neutralization properties relevant to passive and active immunization.
Aim 2. Determine how bNAb breadth and binding properties are interrelated.
Aim 3. Dissect the relationship between entry fitness and escape from bNAbs.
In summary, we seek to define how dynamic properties of Ab binding are linked to neutralization breadth. Such
fundamental information may help improve both active and passive immunization strategies, which are highly
relevant to public health.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AIDS><AIDS Virus><Ab response><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Active Immunization><Active vaccination><Affinity><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody Therapy><Antigenic Determinants><Assay><Autologous><B cell receptor><B-Cell Activation><B-Cell Antigen Receptor><B220><Binding><Binding Determinants><Bioassay><Biological Assay><C-terminal><CD45><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infection><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 virus><COVID-19 virus infection><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 virus><Cell surface><Characteristics><CoV-2><CoV2><Complement><Complement Proteins><Complementarity Determining Regions><Complimentarity Determining Region><Cytoplasmic Domain><Cytoplasmic Tail><Data><Data Bases><Databases><Development><Dimensions><Disease><Disorder><Dissection><Docking><Endosomes><Entropy><Epithelial Cells><Epitopes><Filamentous Fungi><Fingerprint><GP180><Generalized Growth><Germ Lines><Glycans><Glycoproteins><Goals><Growth><HIV><HIV resistance><HIV resistant><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><Heterogeneity><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Hypervariable Loop><Hypervariable Regions><Ig Somatic Hypermutation><Immunization><Immunize><Immunoglobulin Hypervariable Region><Immunoglobulin Somatic Hypermutation><In Vitro><Individual><Infection><Infection prevention><Kinetics><Knowledge><LAV-HTLV-III><LY5><Length><Link><Lymphadenopathy-Associated Virus><Measures><Membrane><Methods><Modern Man><Molds><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><PTPRC><PTPRC gene><Passive Immunization><Passive Immunotherapy><Patients><Peptides><Persons><Polysaccharides><Prevent infection><Preventive><Property><Proteins><Public Health><RNA immunization><RNA vaccination><Receptor Protein><Receptosomes><Remission Induction><Research><Resistance><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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-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 infection><Severe acute respiratory syndrome related corona virus 2><Surface><Surface Plasmon 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