Abstract
During HIV-1 infection, antibodies are generated against the region of the viral gp120 envelope glycoprotein that binds CD4, the primary receptor for HIV-1. Among these antibodies, VRC01 achieves broad neutralization of diverse viral strains. We determined the crystal structure of VRC01 in complex with a human immunodeficiency virus HIV-1 gp120 core. VRC01 partially mimics CD4 interaction with gp120. A shift from the CD4-defined orientation, however, focuses VRC01 onto the vulnerable site of initial CD4 attachment, allowing it to overcome the glycan and conformational masking that diminishes the neutralization potency of most CD4-binding-site antibodies. To achieve this recognition, VRC01 contacts gp120 mainly through immunoglobulin V-gene regions substantially altered from their genomic precursors. Partial receptor mimicry and extensive affinity maturation thus facilitate neutralization of HIV-1 by natural human antibodies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AIDS Vaccines
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Amino Acid Sequence
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Antibodies, Neutralizing / chemistry*
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Antibodies, Neutralizing / immunology*
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Antibody Affinity
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Antigenic Variation
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Base Sequence
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Binding Sites, Antibody
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CD4 Antigens / chemistry
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CD4 Antigens / immunology
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CD4 Antigens / metabolism
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Crystallography, X-Ray
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Epitopes / immunology
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HIV Antibodies / chemistry*
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HIV Antibodies / immunology*
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HIV Envelope Protein gp120 / chemistry
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HIV Envelope Protein gp120 / genetics
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HIV Envelope Protein gp120 / immunology*
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HIV-1 / immunology*
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Humans
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Fab Fragments / metabolism
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Models, Molecular
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Molecular Mimicry
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Molecular Sequence Data
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Neutralization Tests
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Protein Conformation
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Protein Structure, Tertiary
Substances
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AIDS Vaccines
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Antibodies, Neutralizing
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CD4 Antigens
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Epitopes
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HIV Antibodies
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HIV Envelope Protein gp120
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Immunoglobulin Fab Fragments
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gp120 protein, Human immunodeficiency virus 1