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.