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 Ri inhibitors (NNRTI), (+)-c alanolide A and nevirapine, in primer extension assays. We found that Ri co ntaining either the V106A or Y181C substitutions, associated with NNRTI res istance, displayed approximate to 90-fold resistance to nevirapine but rema ined fully sensitive to (+)-calanolide A and that the Y181C mutation margin ally enhanced susceptibility to the latter drug. In contrast, the Y188H sub stitution in RT resulted in about 30-fold resistance to (+)-calanolide A in these assays but did not result in diminished sensitivity to nevirapine. T issue culture results indicated that the combination of (+)-calanolide A an d nevirapine possessed an additive to weakly synergistic effect in blocking replication of HIV-1 in tissue culture. These results suggest that (+)-cal anolide A and nevirapine might have rationale as a combination therapy for HIV disease.