Abstract
While five arenaviruses cause human hemorrhagic fevers in the Western Hemisphere, only Junin virus (JUNV) has a vaccine. The GP1 subunit of their envelope glycoprotein binds transferrin receptor 1 (TfR1) using a surface that substantially varies in sequence among the viruses. As such, receptor-mimicking antibodies described to date are type-specific and lack the usual breadth associated with this mode of neutralization. Here we isolate, from the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross-neutralize Machupo virus with varying efficiency. Structures of GP1-Fab complexes explain the basis for efficient cross-neutralization, which involves avoiding receptor mimicry and targeting a conserved epitope within the receptor-binding site (RBS). The viral RBS, despite its extensive sequence diversity, is therefore a target for cross-reactive antibodies with activity against New World arenaviruses of public health concern.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antibodies, Neutralizing / chemistry*
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Antibodies, Neutralizing / isolation & purification
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Antibodies, Viral / chemistry*
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Antibodies, Viral / isolation & purification
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Antigens, CD / chemistry
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antigens, Viral / chemistry
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Antigens, Viral / genetics
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Antigens, Viral / immunology
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Arenaviruses, New World / genetics
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Arenaviruses, New World / immunology*
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Binding Sites, Antibody
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Cross Reactions
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Epitopes / chemistry
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Epitopes / genetics
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Epitopes / immunology
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HEK293 Cells
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Hemorrhagic Fever, American / immunology
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Hemorrhagic Fever, American / prevention & control*
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Hemorrhagic Fever, American / virology
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Humans
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Immune Sera / chemistry
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Immunoglobulin Fab Fragments / chemistry*
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Immunoglobulin Fab Fragments / isolation & purification
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Junin virus / genetics
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Junin virus / immunology*
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Models, Molecular
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Protein Structure, Tertiary
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Protein Subunits / chemistry
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Protein Subunits / genetics
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Protein Subunits / immunology
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Receptors, Transferrin / chemistry
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Receptors, Transferrin / genetics
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Receptors, Transferrin / immunology
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Receptors, Virus / chemistry
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Receptors, Virus / genetics
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Receptors, Virus / immunology
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Sequence Alignment
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Sequence Homology, Amino Acid
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Viral Envelope Proteins / chemistry*
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Viral Envelope Proteins / genetics
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Viral Envelope Proteins / immunology
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Viral Vaccines / administration & dosage
Substances
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Antibodies, Neutralizing
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Antibodies, Viral
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Antigens, CD
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Antigens, Viral
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CD71 antigen
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Epitopes
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Immune Sera
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Immunoglobulin Fab Fragments
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Protein Subunits
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Receptors, Transferrin
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Receptors, Virus
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Viral Envelope Proteins
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Viral Vaccines