ZIDOVUDINE-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 STRAINS SUBCULTURED IN THE PRESENCE OF BOTH LAMIVUDINE AND QUINOXALINE HBY-097 RETAIN MARKED SENSITIVITY TO HBY-097 BUT NOT TO LAMIVUDINE

Replication of zidovudine-resistant human immunodeficiency virus type 1 (HIV-1) strains (containing the 41 Met-->Leu and 215 Thr-->Tyr mutat ions in reverse transcriptase [RT]) was inhibited to a significantly g reater extent by the combination of lamivudine and quinoxaline HEY 097 than by either drug alone or even fully suppressed by concomitant HEY 097 and lamivudine administration at relatively low concentrations, T he virus recovered after exposure to the drug combinations individuall y had acquired the 103 Lys-->Arg, 138 Glu-->Lys, 184 Met-->Ile, and 18 9 Val-->Ile mutations in the genetic zidovudine-resistance background of zidovudine-resistant HIV-1, These mutants retained marked sensitivi ty to HEY 097, The genotypic zidovudine-resistance mutations were main tained in the mutant virus RT genomes, and the viruses also remained p henotypically resistant to zidovudine. Given the exquisite potency of the combination of lamivudine and HEY 097 in suppressing viral replica tion, this combination should be further pursued in clinical trials ex amining treatment of HIV-l-infected persons.