INVITRO SELECTION AND MOLECULAR CHARACTERIZATION OF HUMAN IMMUNODEFICIENCY VIRUS-1 RESISTANT TO NONNUCLEOSIDE INHIBITORS OF REVERSE-TRANSCRIPTASE

Several newly discovered potent and selective non-nucleoside inhibitor s of human immunodeficiency virus-1 reverse transcriptase (RT) are und ergoing evaluation in clinical trails. We studied the potential for de velopment 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 infec tion in the presence of the drug. Resistant virus was cross-resistant to the non-nucleoside roimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thio ne derivative R82150 but remained susceptible to 2',3'-dideoxynucleosi des and phosphonoformate. Both native (virion-associated) and recombin ant RT derived from resistant virus were insensitive to BI-RG-587 and R82150. Nucleotide sequence analysis of multiple drug-resistant and -s ensitive recombinant RT clones identified a single predicted amino aci d change common to all resistant clones (tyrosine-181 --> cysteine). T hese studies suggest that the viral resistance to non-nucleoside RT in hibitors may develop in vivo. This possibility should be carefully mon itored in clinical trials of these compounds.