title: HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase.
abstract: Serial passage of HIV-1 in CEM or MT-4 cell cultures in the presence of different HIV-1-specific reverse transcriptase (RT) inhibitors yielded mutant viruses which were resistant (i.e., 200- to 1000-fold less sensitive) to the homologous compounds. The RT of these mutant HIV-1 strains showed different amino acid substitutions depending on the class of the HIV-1-specific RT inhibitors. The following amino acid substitutions were found: 138 Glu-->Lys (TSAO-T), 181 Tyr-->Cys (nevirapine), 181 Tyr-->Cys (pyridinone), and 100 Leu-->Ile (TIBO R82150). Four TIBO (R82913)-resistant HIV-1 strains contained different amino acid substitutions: 103 Lys-->Asn (strain 2), 100 Leu-->Ile and 138 Glu-->Lys (strain B02), 100 Leu-->Ile and 181 Tyr-->Cys (strain 1), 100 Leu-->Ile and 188 Tyr-->His (strain B22). The level of cross-resistance (or sensitivity) highly depends on the nature of the amino acid substitutions. As a rule, the TSAO-resistant HIV-1 strains (138 Glu-->Lys) and TIBO (R82150 or R82913)-resistant HIV-1 strains (Leu 100-->Ile or 103 Lys-->Asn) are sensitive to the other HIV-1-specific RT inhibitors, whereas the amino acid change 181 Tyr-->Cys results in a significant reduction of sensitivity to all classes of the HIV-1-specific RT inhibitors.
authors.affiliation: Rega Institute for Medical Research, K. U. Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
authors.forename: M J
authors.initials: MJ
authors.lastname: Pérez-Pérez
authors.forename: L
authors.initials: L
authors.lastname: Vrang
authors.forename: J
authors.initials: J
authors.lastname: Walbers
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Oberg
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: M J
authors.initials: MJ
authors.lastname: Camarasa
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015751:Genes, pol; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology* / Q000254:growth & development; D008969:Molecular Sequence Data; D009154:Mutation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase