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La integrasa del VIH-1 se une al genoma del ARN viral y es esencial durante la morfogénesis viral
Jacques J Kessl1, Sebla B Kutluay2, Dana Townsend3
1Center for Retrovirus Research, Ohio State University, Columbus, OH 43210, USA; College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
Cell
|August 28, 2016
Resumen
La integrasa del VIH-1 se une al genoma del ARN viral, lo que influye en el ensamblaje del virión. Esta interacción es crucial para la producción de partículas virales infecciosas y es el objetivo de los inhibidores alostéricos de la IN (ALLINIs).
Área de la Ciencia:
- Virología
- Biología molecular
- Biología estructural
Sus antecedentes:
- La integrasa del VIH-1 (IN) es esencial para la integración del ADN viral en el genoma del huésped.
- La evidencia sugiere que la IN también juega un papel en la maduración y la morfogénesis de las partículas virales.
- El mecanismo preciso de la participación de IN en el ensamblaje de viriones no estaba claro.
Objetivo del estudio:
- Investigar el papel de la integrasa del VIH-1 en la morfogénesis del virión.
- Para determinar si el IN interactúa directamente con el genoma del ARN viral dentro de los viriones maduros.
- Para aclarar el mecanismo de acción de los inhibidores alostéricos de la IN (ALLINIs).
Principales métodos:
- Ensayos de unión in vitro para evaluar las interacciones IN-ARN.
- Análisis de viriones del VIH-1 producidos por mutantes de la IN y tratados con ALLINIs.
- Microscopía electrónica para evaluar la morfología del virión.
- Inmunoprecipitación de ARN para confirmar la unión al ARN-IN en los viriones.
Principales resultados:
- La integrasa del VIH-1 (IN) se une directamente a elementos estructurales específicos del genoma del ARN viral dentro de los viriones.
- Las mutaciones que alteran la unión al ARN-IN conducen a viriones excéntricos y no infecciosos.
- Los inhibidores alostéricos de la IN (ALLINIs) interrumpen la unión de la IN al ARN viral en el VIH-1 de tipo salvaje, pero no en los mutantes de escape.
- Las interacciones nucleocáptido-ARN no se ven afectadas por estas sustituciones de IN.
Conclusiones:
- La integrasa del VIH-1 tiene un papel no caracterizado en la morfogénesis de partículas virales a través de la unión directa al genoma del ARN viral.
- Esta interacción IN-ARN es crítica para la producción de viriones infecciosos.
- Los inhibidores alostéricos de la IN (ALLINIs) funcionan interrumpiendo esta interacción esencial entre el IN y el ARN durante el ensamblaje del virión.
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