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  • Title: Multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360.
    Author: Fikkert V, Hombrouck A, Van Remoortel B, De Maeyer M, Pannecouque C, De Clercq E, Debyser Z, Witvrouw M.
    Journal: AIDS; 2004 Oct 21; 18(15):2019-28. PubMed ID: 15577623.
    Abstract:
    OBJECTIVES: Study of HIV-1 resistance development to the diketo analogue S-1360, the first HIV-1 integrase strand transfer inhibitor that has entered clinical development. DESIGN: HIV-1(IIIB) was passaged in cell culture in the presence of increasing concentrations of S-1360 (IIIB/S-1360(res)). METHODS: The IIIB/S-1360(res) strains selected for 30, 50 and 70 passages in the presence of S-1360 were evaluated genotypically by sequencing analysis and phenotypically using the MT-4/MTT assay. RESULTS: Multiple mutations, nine in total, emerged progressively in the catalytic domain of integrase as a result of the selection process. They included T66I and L74M that have both been associated with resistance against the diketo acid L-708,906. After 30, 50 and 70 passages in the presence of S-1360, IIIB/S-1360(res) displayed a four-, eight- and more than 62-fold reduced susceptibility for S-1360, respectively. Phenotypic cross-resistance to L-708,906 was modest for the IIIB/S-1360(res) strain selected during 50 passages, but pronounced for the strain selected during 70 passages. Interesting, all IIIB/S-1360(res) strains remained fully susceptible to the pyranodipyrimidine V-165, an integrase DNA binding inhibitor. Recombination of the mutant integrase genes into wild-type background by integrase-chimeric virus technology entirely reproduced the resistance profile of the IIIB/S-1360(res) strains. As for the replication kinetics of the selected and recombined strains, reduced replication fitness was measured for all strains when compared with their respective wild-type strains. CONCLUSIONS: The accumulation of integrase mutations coincided with an increasing level of (cross-)resistance of IIIB/S-1360(res). Integrase-chimeric virus technology confirmed that the integrase mutations are indeed fully responsible for the resistance phenotype of IIIB/S-1360.
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