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Desarrollo rápido de anticuerpos neutralizantes de la influenza en general a través de mutaciones redundantes
Leontios Pappas1, Mathilde Foglierini1, Luca Piccoli1
1Insitute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
Nature
|October 9, 2014
Resumen
Los anticuerpos ampliamente neutralizantes dirigidos al tallo de la hemaglutinina de la influenza son raros. Este estudio revela elementos genéticos y mutaciones clave, incluido el polimorfismo de alelos VH1-69, necesarios para su desarrollo y amplia reactividad.
Área de la Ciencia:
- Inmunología Inmunología.
- Virología Virología.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Las vacunas contra la gripe requieren una reformulación anual debido a la deriva antigénica en la cabeza de la hemaglutinina.
- Los raros anticuerpos neutralizantes dirigidos al tallo de hemaglutinina conservado ofrecen potencial para las vacunas universales contra la influenza.
- Los anticuerpos VH1-69 son una clase prometedora de anticuerpos anti-tronco, pero están altamente mutados y no se producen universalmente.
Objetivo del estudio:
- Caracterizar los anticuerpos anti-tronco y dilucidar las vías de desarrollo de los clones VH1-69.
- Identificar los requisitos clave de mutación genética y somática para la generación de anticuerpos VH1-69 ampliamente neutralizantes.
Principales métodos:
- Caracterización de 197 anticuerpos anti-tronco de un solo donante.
- Reconstrucción de las vías de desarrollo de los clones de anticuerpos VH1-69.
- Análisis estructural de las interacciones anticuerpo-antígeno.
Principales resultados:
- Se identificó una fenilalanina polimórfica codificada por línea germinal (posición 54) y una tirosina conservada (posición 98 en HCDR3) como cruciales para el desarrollo inicial de anticuerpos VH1-69.
- Una sola mutación de prolina a alanina (posición 52a en HCDR2) fue suficiente para la unión de alta afinidad al antígeno H1, lo que indica una rápida maduración de afinidad.
- Se acumularon más mutaciones, aumentando la amplitud de reactividad y haciendo que las mutaciones iniciales y la fenilalanina en la posición 54 fueran funcionalmente redundantes.
Conclusiones:
- El polimorfismo del alelo VH1-69, el reordenamiento del gen VDJ y las mutaciones somáticas específicas son esenciales para generar anticuerpos ampliamente neutralizantes.
- El proceso de maduración de afinidad para estos anticuerpos exhibe redundancia inesperada, con mutaciones posteriores compensando las anteriores.
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