Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy

J Virol. 1993 Sep;67(9):5353-9. doi: 10.1128/JVI.67.9.5353-5359.1993.


Human immunodeficiency virus type 1 (HIV-1)-infected CEM cells were treated by the HIV-1-specific inhibitors bis-heteroarylpiperazine (BHAP), 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)-on e (TIBO) R82913, nevirapine, and the N3-methylthymine derivative of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO-m3T), as single agents or in combination, at escalating concentrations. When used individually, the compounds led to the emergence of drug-resistant virus strains within two to five subcultivations. The resulting strains were designated HIV-1/BHAP, HIV-1/TIBO, HIV-1/Nev, and HIV-1/TSAO-m3T, respectively. The mutant viruses showed the following amino acid substitutions in their reverse transcriptase (RT): Leu-100-->Ile for HIV-1/BHAP; Lys-103-->Asn for HIV-1/TIBO; Val-106-->Ala for HIV-1/Nev; and Glu-138-->Lys for HIV-1/TSAO-m3T. Both the Tyr-181-->Cys and Val-106-->Ala mutations were found in another mutant emerging following treatment with nevirapine at escalating concentrations. The BHAP-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and TSAO-m3T, whereas the TSAO-m3T-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and BHAP. When different pairs of nonnucleoside RT inhibitors (i.e., BHAP plus TSAO-m3T, nevirapine plus TSAO-m3T, TIBO plus TSAO-m3T, nevirapine plus TIBO, and BHAP plus nevirapine) were used, resistant virus emerged as fast as with single-drug therapy. In all cases the Tyr-181-->Cys mutation appeared; the virus showed markedly reduced sensitivity to all HIV-1-specific inhibitors but retained sensitivity to 2',3'-dideoxynucleoside analogs such as zidovudine, ddC, and ddI. Our findings argue against simultaneous combination of two different nonnucleoside RT inhibitors that are unable to inhibit HIV-1 mutant strains containing the Tyr-181-->Cys mutation when administered as single drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / toxicity*
  • Benzodiazepines / toxicity
  • Cell Line
  • Dideoxynucleosides / toxicity
  • Drug Interactions
  • Drug Resistance, Microbial / physiology*
  • HIV Reverse Transcriptase
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • HIV-1 / genetics
  • Humans
  • Imidazoles / toxicity
  • Mutagenesis*
  • Nevirapine
  • Piperazines / toxicity*
  • Pyridines / toxicity
  • Pyridones / toxicity
  • RNA-Directed DNA Polymerase / genetics
  • Spiro Compounds*
  • Thymidine / analogs & derivatives
  • Thymidine / toxicity
  • Uridine / analogs & derivatives


  • Antiviral Agents
  • Dideoxynucleosides
  • Imidazoles
  • Piperazines
  • Pyridines
  • Pyridones
  • Spiro Compounds
  • Benzodiazepines
  • R-82913
  • Nevirapine
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Thymidine
  • TSAO-T
  • Uridine