Long-term exposure of HIV-1-infected cell cultures to combinations of the novel quinoxaline NNRTI GW420867X with lamuvidine, abacavir and a variety of NNRTIs
ABSTRACT:
The novel quinoxaline non-nucleoside reverse transcriptase Inhibitor (NNRTI), GW420867X, has been combined with a variety of NRTIs and NNRTIs, including lamuvidine, abacavir and nevirapine, delavirdine, efavirenz, MKC-442 and the carboxanilide UC-781 in HIV-1IIB-infected CEM cell cultures. Virus breakthrough was followed from more than 10 subsequent subcultivations. Combination of GW420867X with lamivudine and abacavir resulted in a marked (synergistic) delay of virus breakthrough compared with the single drugs alone, whereas combination of GW420867X with NNRTIs proved additive with respect to delay of virus breakthrough.
Combination of GW420867X with the NNRTIs revealed additive inhibitory effects against recombinant HIV-1 RT. Lamivudine plus GW420867X selected for the N184I mutation and a number of NNRTI-characteristic amino acid changes (V106A, V108I, Y188H). Abacavir plus GW420867X selected only for NNRTI-specific mutations (K101E), K103R, V106A, &181C) including a novel L100V mutation. Combination of GW420867X with five different NNRTIs solely selected for NNRTI-specific mutations. A variety of five single-, two double- and two triple-mutated HIV-1 strains that emerged from this study were evaluated for their sensitivity/resistance to zidovudine, lamuvidine, abacavir and seven different NNRTIs. In all these cases, GW420867X, efavirenz and UC-781 kept pronounced antiviral potency (EC50¾0.050 µg/mL for GW420867X, ¾0.025 µg/mL for efavirenz and ¾0.060 µg/mL for UC-781).
Our data revealed that combination of GW420867X with efavirenz is currently the most obvious combination among NNRTIs, whereas the NRTIs lamuvidine and abacavir are worth pursuing as the promising NRTIs to be combined with GW420867X.
