title: 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.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Pelemans
authors.forename: R
authors.initials: R
authors.lastname: Esnouf
authors.forename: A
authors.initials: A
authors.lastname: Dunkler
authors.forename: M A
authors.initials: MA
authors.lastname: Parniak
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
authors.forename: A
authors.initials: A
authors.lastname: Karlsson
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J P
authors.initials: JP
authors.lastname: Kleim
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
mesh_terms: 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
chemical_list: 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