Characteristics of the Pro225His mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase that appears under selective pressure of dose-escalating quinoxaline treatment of HIV-1.
Treatment of human immunodeficiency virus type 1 (HIV-1)-infected CEM cell cultures with escalating concentrations of the quinoxaline S-2720 resulted in an ordered appearance of single and multiple mutant virus strains that gradually became resistant to the quinoxaline and other nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs). A novel mutation, Pro225His, consistently appeared in a Val106Ala RT-mutated genetic background. The contribution of this mutation to the resistance of the mutant HIV-1 RT to NNRTIs was additive to the resistance caused by the Val106Ala mutation. Interestingly, site-directed mutagenesis studies revealed that the Pro225His-mutated RT had acquired markedly greater sensitivity to bis(heteroaryl)piperazine (BHAP U-90152) (delavirdine) but not to any of the other NNRTIs. The kinetics of inhibition of the Pro225His mutant RT by the NNRTIs (including BHAP U-90152) was not substantially different from that observed for the wild-type RT. The hypersensitivity of the mutant enzyme and virus to BHAP U-90152 could be rationally explained by the molecular-structural determinants of the RT-BHAP complex, which has recently been resolved by X-ray crystallography.
Pelemans
H
H
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Esnouf
R
R
Dunkler
A
A
Parniak
M A
MA
Vandamme
A M
AM
Karlsson
A
A
De Clercq
E
E
Kleim
J P
JP
Balzarini
J
J
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D001665:Binding Sites; D020008:Delavirdine / Q000627:therapeutic use*; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006639:Histidine; D007700:Kinetics; D008024:Ligands; D017354:Point Mutation; D011392:Proline; D011810:Quinoxalines / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013997:Time Factors
D019380:Anti-HIV Agents; D008024:Ligands; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; C083566:S 2720; D006639:Histidine; D011392:Proline; D020008:Delavirdine; D054303:HIV Reverse Transcriptase