In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors

Nature. 1995 Apr 6;374(6522):569-71. doi: 10.1038/374569a0.


Inhibitors of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture. We now report the characterization of resistant variants isolated from patients undergoing therapy with the protease inhibitor MK-639 (formerly designated L-735,524). Five of these variants, isolated from four patients, exhibited cross-resistance to all members of a panel of six structurally diverse protease inhibitors. This suggests that combination therapy with multiple protease inhibitors may not prevent loss of antiviral activity resulting from resistance selection. In addition, previous therapy with one compound may abrogate the benefit of subsequent treatment with a second inhibitor.

MeSH terms

  • Base Sequence
  • Cell Line
  • DNA Primers
  • Drug Resistance, Microbial / genetics
  • Drug Resistance, Multiple / genetics
  • Drug Therapy, Combination
  • HIV Infections / drug therapy
  • HIV Infections / virology
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • HIV-1 / isolation & purification
  • HeLa Cells
  • Humans
  • Indinavir
  • Molecular Sequence Data
  • Mutation
  • Pyridines / pharmacology*


  • DNA Primers
  • HIV Protease Inhibitors
  • Pyridines
  • Indinavir