HIV-1-specific reverse transcriptase inhibitors show differential activity against HIV-1 mutant strains containing different amino acid substitutions in the reverse transcriptase.
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.
Balzarini
J
J
Rega Institute for Medical Research, K. U. Leuven, Belgium.
Karlsson
A
A
Pérez-Pérez
M J
MJ
Vrang
L
L
Walbers
J
J
Zhang
H
H
Oberg
B
B
Vandamme
A M
AM
Camarasa
M J
MJ
De Clercq
E
E
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
D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase