Long-term exposure of HIV type 1-infected cell cultures to combinations ofthe novel quinoxaline GW420867X with lamivudine, abacavir, and a variety of nonnucleoside reverse transcriptase inhibitors

The novel quinoxaline GW420867X has been combined with a variety of nucleos ide reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse tran seriptase inhibitors (NNRTIs) in HIV-1(IIIB)-infected CEM cell cultures. Wh ereas the antiviral efficacy of combinations of GW420867X with the NRTIs la mivudine (3TC) and abacavir (ABC) proved additive when administered to HIV- 1-infected cells in a short-term (4-day) infection experiment, combination of GW420867X,vith the NRTIs 3TC and ABC resulted in a marked delay of virus breakthrough compared with the single drugs alone in a long-term (2-month) infection experiment, Delay of virus breakthrough was less pronounced for combinations of GW420867X with the NNRTIs, Combination of GW420867X with th e NRTIs and NNRTIs resulted in additive inhibitory effects on recombinant H IV-1 reverse transcriptase as evident from isobolograms. Lamivudine plus GW 320867X selected for the 3TC-specific M184I mutation and a number of NNRTI- characteristic mutations (i.e., V106A, V108I, and Y188H). Abacavir plus GW4 20867X selected only for NNRTI-specific mutations (i.e., K101E, K103R, V106 A, and Y181C), including the novel L100V mutation. Combination of GW420867X with five different NNRTIs selected solely for NNRTI-specific mutations, a nd also for the L100V mutation in the combined presence of efavirenz, nevir apine, or emivirine, respectively. Five single-, two double-, and two tripl e-mutated HIV-1 strains that emerged from this study were evaluated for the ir sensitivity/resistance to AZT, lamivudine, and seven different NNRTIs, I n all cases, efavirenz, GW420867X, and UC-781 retained pronounced antiviral potency. Our data suggest that combinations of GW320867X with 3TC, ABC, an d NNRTIs (e.g., efavirenz) would be worth pursuing as therapeutic modalitie s against HIV-1 infections.