title: In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV type 1 protease.
abstract: Protease inhibitors are another class of compounds for treatment of human immunodeficiency virus (HIV)-caused disease. The emergence of resistance to the current anti-HIV drugs makes the determination of potential resistance to protease inhibitors imperative. Here we describe the isolation of an HIV type 1 (HIV-1) resistant to an HIV-protease inhibitor. Serial passage of HIV-1 (strain RF) in the presence of the inhibitor, [2-pyridylacetylisoleucylphenylalanyl-psi (CHOH)]2 (P9941), failed to yield a stock of virus with a resistance phenotype. However, variants of the virus with 6- to 8-fold reduced sensitivity to P9941 were selected by using a combination of plaque assay and endpoint titration. Genetic analysis and computer modeling of the variant proteases revealed a single change in the codon for amino acid 82 (Val-->Ala), which resulted in a protease with lower affinity and reduced sensitivity to this inhibitor and certain, but not all, related inhibitors.
authors.affiliation: DuPont Merck Pharmaceutical Company, Glenolden, PA 19036.
authors.forename: M J
authors.initials: MJ
authors.lastname: Otto
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: D L
authors.initials: DL
authors.lastname: Winslow
authors.forename: C D
authors.initials: CD
authors.lastname: Reid
authors.forename: P
authors.initials: P
authors.lastname: Aldrich
authors.forename: P K
authors.initials: PK
authors.lastname: Jadhav
authors.forename: C E
authors.initials: CE
authors.lastname: Patterson
authors.forename: C N
authors.initials: CN
authors.lastname: Hodge
authors.forename: Y S
authors.initials: YS
authors.lastname: Cheng
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D003062:Codon; D004279:DNA, Viral / Q000302:isolation & purification; D014644:Genetic Variation; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification*; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D003062:Codon; D004279:DNA, Viral; D017320:HIV Protease Inhibitors; D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D016333:HIV Protease