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JW Mellors, GE Dutschman, GJ Im, E Tramontano, SR Winkler and YC Cheng
Department of Internal Medicine, Yale University School of Medicine, West Haven, Connecticut.
Several newly discovered potent and selective non-nucleoside inhibitors of human immunodeficiency virus-1 reverse transcriptase (RT) are undergoing evaluation in clinical trials. We studied the potential for development of viral resistance to one of the prototype compounds, BI- RG-587, a dipyridodiazepinone derivative. Human immunodeficiency virus- 1 resistant to BI-RG-587 emerged after only one cycle of in vitro infection in the presence of the drug. Resistant virus was cross- resistant to the non-nucleoside tetrahydroimidazo[4,5,1- jk][1,4]benzodiazepin-2(1H)-thione derivative R82150 but remained susceptible to 2',3'-dideoxynucleosides and phosphonoformate. Both native (virion-associated) and recombinant RT derived from resistant virus were insensitive to BI-RG-587 and R82150. Nucleotide sequence analysis of multiple drug-resistant and -sensitive recombinant RT clones identified a single predicted amino acid change common to all resistant clones (tyrosine-181----cysteine). These studies suggest that the viral resistance to non-nucleoside RT inhibitors may develop in vivo. This possibility should be carefully monitored in clinical trials of these compounds.
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