A proline-to-histidine substitution at position 225 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) sensitizes HIV-1 RT to BHAP U-90152.
Two mutant virus strains in which the novel P225H mutation appeared in a V106A reverse transcriptase (RT)-mutated genetic background upon treatment of human immunodeficiency virus type 1 (HIV-1) with quinoxaline S-2720 were isolated. Surprisingly, the addition of the P225H mutation to the V106A RT mutant genetic background resensitized the V106A RT mutant virus to the non-nucleoside RT inhibitor (NNRTI) BHAP U-90152, but not to other NNRTIs. Construction of both recombinant viruses and recombinant RTs containing the V106A, P225H and V106A+P225H mutations revealed that P225H was indeed responsible for the marked potentiation of the antiviral activity of BHAP against the P225H single-mutant virus and the V106A+P225H double-mutant virus when compared to wild-type and V106A single-mutant viruses, respectively. An explanation for the markedly increased sensitivity of the P225H mutant HIV-1 RT to BHAP and not to the other NNRTIs was provided by the unique features of the X-ray structure of the RT-BHAP complex.
Pelemans
H
H
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Esnouf
R M
RM
Parniak
M A
MA
Vandamme
A M
AM
De Clercq
E
E
Balzarini
J
J
D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology*; D020008:Delavirdine / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006639:Histidine; D006801:Humans; D011392:Proline; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D006639:Histidine; D011392:Proline; D020008:Delavirdine; D054303:HIV Reverse Transcriptase