PT  - JOURNAL ARTICLE
AU  - J W Mellors
AU  - G E Dutschman
AU  - G J Im
AU  - E Tramontano
AU  - S R Winkler
AU  - Y C Cheng
TI  - In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase.
DP  - 1992 Mar 01
TA  - Molecular Pharmacology
PG  - 446--451
VI  - 41
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/41/3/446.short
4100  - http://molpharm.aspetjournals.org/content/41/3/446.full
SO  - Mol Pharmacol1992 Mar 01; 41
AB  - 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.