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Resistencia al ddI y sensibilidad al AZT inducida por una mutación en la transcriptasa inversa del VIH-1

M H St Clair¹, J L Martin, G Tudor-Williams

¹Division of Virology, Burroughs Wellcome Co., Research Triangle Park, NC 27709.

Science (New York, N.Y.)

|September 27, 1991

Resumen

El cambio de la terapia del VIH-1 de zidovudina (AZT) a didanosina (ddI) condujo a una disminución de la sensibilidad a la ddI y un aumento de la sensibilidad a la AZT. Surgió una mutación específica, que confería resistencia al ddI y suprimía la resistencia al AZT, destacando la importancia de la terapia combinada.

Área de la Ciencia:

Virología Virología.
Biología Molecular Biología Molecular
Farmacología Farmacología.

Sus antecedentes:

El tratamiento del virus de la inmunodeficiencia humana tipo 1 (VIH-1) a menudo implica terapias antirretrovirales secuenciales.
La zidovudina (AZT) fue un tratamiento primario, pero la resistencia a los medicamentos es un desafío clínico significativo.
El cambio a inhibidores alternativos de la transcriptasa inversa nucleosídica como la didanosina (ddI) es una estrategia común.

Objetivo del estudio:

Para investigar la sensibilidad a fármacos in vitro de los aislados de VIH-1 después de cambiar de AZT a la terapia con IDD.
Para identificar mutaciones genéticas en la transcriptasa inversa del VIH-1 asociada con sensibilidad alterada a los fármacos.
Para evaluar el impacto de mutaciones específicas en los perfiles de resistencia tanto a ddI como a AZT.

Principales métodos:

Se recogieron aislamientos de VIH-1 en serie de cinco pacientes con síndrome de inmunodeficiencia adquirida (SIDA) que se sometieron a cambios de terapia.
Se realizaron ensayos de sensibilidad a fármacos in vitro para el ddI y el AZT.
La región codificante de la transcriptasa inversa del VIH-1 fue secuenciada para identificar mutaciones.

Principales resultados:

Los aislados de VIH-1 mostraron una disminución de la sensibilidad al ddI y una mayor sensibilidad al AZT durante los 12 meses posteriores a la iniciación del ddI.
Se identificó una nueva mutación en el gen de la transcriptasa inversa, que se correlaciona con la sensibilidad reducida a la ddI.
Esta mutación, cuando está presente con la mutación de resistencia al AZT, resulta en una mayor sensibilidad al AZT y confiere resistencia al ddI y ddC, al tiempo que suprime los efectos de la resistencia al AZT.

Conclusiones:

La aparición de mutaciones específicas del VIH-1 puede alterar los perfiles de resistencia a los medicamentos durante la terapia secuencial.
Una sola mutación puede conferir resistencia a múltiples fármacos y modular los efectos de otras mutaciones de resistencia.
La terapia de combinación para el VIH-1 puede ser crucial para prevenir la aparición de variantes virales resistentes a los medicamentos.

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