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Métodos Terapéuticos y Terapias MTCI
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1.
Proc Natl Acad Sci U S A ; 92(6): 2398-402, 1995 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-7534421

RESUMEN

A set of mutations [Ala-62-->Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides and has been seen in HIV-1 variants isolated from patients receiving combination chemotherapy with 3'-azido-3'-deoxythymidine (AZT) plus 2',3'-dideoxycytidine (ddC) or 2',3'-dideoxyinosine (ddI). The IC50 values of AZT, ddC, ddI, 2',3'-dideoxyguanosine, and 2',3'-didehydro-3'-deoxythymidine against an infectious clone constructed to include the five mutations were significantly higher than those of a wild-type infectious clone. The K1 value for AZT 5'-triphosphate determined for the virus-associated RT from a posttherapy strain was 35-fold higher than that of RT from a pretherapy strain. Detailed analysis of HIV-1 strains isolated at various times during therapy showed that the Q151M mutation developed first in vivo, at the time when the viremia level suddenly increased, followed by the F116Y and F77L mutations. All five mutations ultimately developed, and the viremia level rose even further. Analyses based on the three-dimensional structure of HIV-1 RT suggest that the positions where at least several of the five mutations occur are located in close proximity to the proposed dNTP-binding site of RT and the first nucleotide position of the single-stranded template.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Didesoxinucleósidos/farmacología , Didesoxinucleósidos/uso terapéutico , Resistencia a Múltiples Medicamentos , Variación Genética , VIH-1/genética , Mutación Puntual , ADN Polimerasa Dirigida por ARN/genética , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Cartilla de ADN/química , Cartilla de ADN/metabolismo , Relación Dosis-Respuesta a Droga , Genes pol , Genotipo , Transcriptasa Inversa del VIH , VIH-1/efectos de los fármacos , VIH-1/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Estructura Secundaria de Proteína , ADN Polimerasa Dirigida por ARN/biosíntesis , ADN Polimerasa Dirigida por ARN/química , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Moldes Genéticos , Transfección
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