RESUMEN
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.
Asunto(s)
Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/química , Arenavirus del Nuevo Mundo/inmunología , Fiebre Hemorrágica Americana/prevención & control , Fragmentos Fab de Inmunoglobulinas/química , Virus Junin/inmunología , Proteínas del Envoltorio Viral/química , Secuencia de Aminoácidos , Anticuerpos Neutralizantes/aislamiento & purificación , Anticuerpos Antivirales/aislamiento & purificación , Antígenos CD/química , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos Virales/química , Antígenos Virales/genética , Antígenos Virales/inmunología , Arenavirus del Nuevo Mundo/genética , Sitios de Unión de Anticuerpos , Reacciones Cruzadas , Epítopos/química , Epítopos/genética , Epítopos/inmunología , Células HEK293 , Fiebre Hemorrágica Americana/inmunología , Fiebre Hemorrágica Americana/virología , Humanos , Sueros Inmunes/química , Fragmentos Fab de Inmunoglobulinas/aislamiento & purificación , Virus Junin/genética , Modelos Moleculares , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Estructura Terciaria de Proteína , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/inmunología , Receptores de Transferrina/química , Receptores de Transferrina/genética , Receptores de Transferrina/inmunología , Receptores Virales/química , Receptores Virales/genética , Receptores Virales/inmunología , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Vacunas Virales/administración & dosificaciónRESUMEN
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.