Sensitivity and resistance to (+)-calanolide A of wild-type and mutated forms of HIV-1 reverse transcriptase.
We have tested both wild-type and drug-resistant mutated, recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) molecules for sensitivity to each of two non-nucleoside RT inhibitors (NNRTI), (+)-calanolide A and nevirapine, in primer extension assays. We found that RT containing either the V106A or Y181C substitutions, associated with NNRTI resistance, displayed approximately 90-fold resistance to nevirapine but remained fully sensitive to (+)-calanolide A and that the Y181C mutation marginally enhanced susceptibility to the latter drug. In contrast, the Y188H substitution in RT resulted in about 30-fold resistance to (+)-calanolide A in these assays but did not result in diminished sensitivity to nevirapine. Tissue culture results indicated that the combination of (+)-calanolide A and nevirapine possessed an additive to weakly synergistic effect in blocking replication of HIV-1 in tissue culture. These results suggest that (+)-calanolide A and nevirapine might have rationale as a combination therapy for HIV disease.
Quan
Y
Y
McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montréal, Québec, Canada.
Motakis
D
D
Buckheit
R
R
Xu
Z Q
ZQ
Flavin
M T
MT
Parniak
M A
MA
Wainberg
M A
MA
D003374:Coumarins / Q000494:pharmacology*; D004351:Drug Resistance; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D003374:Coumarins; D039681:Pyranocoumarins; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; C075959:calanolide A