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.
Subject(s)
Antibodies, Neutralizing/chemistry , Antibodies, Viral/chemistry , Arenaviruses, New World/immunology , Hemorrhagic Fever, American/prevention & control , Immunoglobulin Fab Fragments/chemistry , Junin virus/immunology , Viral Envelope Proteins/chemistry , Amino Acid Sequence , Antibodies, Neutralizing/isolation & purification , Antibodies, Viral/isolation & purification , Antigens, CD/chemistry , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Viral/chemistry , Antigens, Viral/genetics , Antigens, Viral/immunology , Arenaviruses, New World/genetics , Binding Sites, Antibody , Cross Reactions , Epitopes/chemistry , Epitopes/genetics , Epitopes/immunology , HEK293 Cells , Hemorrhagic Fever, American/immunology , Hemorrhagic Fever, American/virology , Humans , Immune Sera/chemistry , Immunoglobulin Fab Fragments/isolation & purification , Junin virus/genetics , Models, Molecular , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Protein Subunits/chemistry , Protein Subunits/genetics , Protein Subunits/immunology , Receptors, Transferrin/chemistry , Receptors, Transferrin/genetics , Receptors, Transferrin/immunology , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/immunology , Sequence Alignment , Sequence Homology, Amino Acid , Viral Envelope Proteins/genetics , Viral Envelope Proteins/immunology , Viral Vaccines/administration & dosageABSTRACT
In the Western hemisphere, at least five mammarenaviruses cause human viral hemorrhagic fevers with high case fatality rates. Junín virus (JUNV) is the only hemorrhagic fever virus for which transfusion of survivor immune plasma that contains neutralizing antibodies ("passive immunity") is an established treatment. Here, we report the structure of the JUNV surface glycoprotein receptor-binding subunit (GP1) bound to a neutralizing monoclonal antibody. The antibody engages the GP1 site that binds transferrin receptor 1 (TfR1)-the host cell surface receptor for all New World hemorrhagic fever mammarenaviruses-and mimics an important receptor contact. We show that survivor immune plasma contains antibodies that bind the same epitope. We propose that viral receptor-binding site accessibility explains the success of passive immunity against JUNV and that this functionally conserved epitope is a potential target for therapeutics and vaccines to limit infection by all New World hemorrhagic fever mammarenaviruses.
