MARKED INHIBITORY ACTIVITY OF NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 WHEN COMBINED WITH(-)2',3'-DIDEOXY-3'-THIACYTIDINE

Human immunodeficiency virus type 1 (HIV-1)-infected CEM cells were tr eated (as single agents or in combination) with (minus)-2',3'-dideoxy- 3'-thiacytidine (3TC) and the following HIV-1-specific non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs): -(tert-butyldimethylsi lyl)-3'-spiro-5'-(4'-amino-1 1,2'-oxathiole)-2',2'-dioxide derivative of 3-methylthymidine (TSAO-m(3)T), the thiocarboxanilides UC10 and UC4 2, bis(heteroaryl)piperazine (BHAP) derivative U90152, and the 1-(2-hy droxyethoxymethyl)-6-(phenylthio) (HEPT) derivative 5-isopropyl-1-etho xymethyl-6-benzyluracil (MKC-442). When used individually, the compoun ds led to the emergence of HIV-1 strains containing the following muta tions in the RT: Glu(138) to lysine for TSAO-m(3)T, Met(184) to valine for 3TC, Lys(103) to threonine/asparagine for the thiocarboxanilides, and Tyr(181) to cysteine for BHAP and MKC-442. When 3TC was combined with TSAO-m(3)T, UC10, UC42, BHAP, or MKC-442, breakthrough of virus w as markedly delayed or even suppressed. For these drug combinations, t he concentrations of the individual drugs could be lowered by greater than or equal to 25-50-fold to suppress virus breakthrough compared wi th the individual use of the compounds. The concomitant presence of th e Lys(138) and IIe/Val(184) mutations was found in the RT of the mutan t viruses that emerged with combination therapy of the lowest concentr ations of 3TC with either the lowest concentrations of TSAO-m(3)T or U C10 (similar to 0.5-3-fold the EC(50) value). These virus strains reta ined high sensitivity to other NNRTIs such as BHAP or HEPT. The virus mutants that arose in the presence of combinations of the lowest conce ntrations of 3TC with either BHAP or HEPT predominantly contained the Cys(181) mutation in the RT. In one case, the Ile(181) mutation was fo und. The latter mutations, par ticularly the Ile(181) mutation, result ed in markedly decreased sensitivity to the NNRTIs but not to 3'-azido -2',3'-dideoxythymidine or 3TC.