title: In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors.
abstract: 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.
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Condra
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: O M
authors.initials: OM
authors.lastname: Blahy
authors.forename: L J
authors.initials: LJ
authors.lastname: Gabryelski
authors.forename: D J
authors.initials: DJ
authors.lastname: Graham
authors.forename: J C
authors.initials: JC
authors.lastname: Quintero
authors.forename: A
authors.initials: A
authors.lastname: Rhodes
authors.forename: H L
authors.initials: HL
authors.lastname: Robbins
authors.forename: E
authors.initials: E
authors.lastname: Roth
authors.forename: M
authors.initials: M
authors.lastname: Shivaprakash
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006367:HeLa Cells; D006801:Humans; D019469:Indinavir; D008969:Molecular Sequence Data; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D017320:HIV Protease Inhibitors; D011725:Pyridines; D019469:Indinavir