The Effects of Prolonged Treatment with Zidovudine,Lamivudine,and Abacavir on a T-Lymphoblastoid Cell Line

A human T-lymphoblastoid cell line that is resistant to the antiviral activity of zidovudine (ZDV) and moderately resistant to lamivudine (3TC) has been obtained as a result of prolonged treatment with a combination of three nucleoside analogues (NA), ZDV, 3TC, and abacavir (ABV). These cells, called CEM_ZLA, are fully sensitive to ABV. The cellular resistance of the CEM_ZLA cells to ZDV correlates with significant reductions in thymidine kinase (TK) activity and in the amount of intracellular TK protein. Interestingly, the reduction in TK activity led to impairment of the ability of CEM_ZLA to accumulate the triphosphate metabolite of ZDV. However, the moderately 3TC-resistant phenotype of CEM_ZLA cannot be ascribed to a similar reduction in deoxycytidine kinase activity. Compared to the parental CEM cells, CEM_ZLA cells express a high level of multidrug resistance protein 4 (MRP4), which could reduce the intracellular concentration of 3TC. This study shows that the exposure of cells to a combination of NAs is capable of simultaneously affecting more than one target site to confer resistance and that NAs display differing abilities to select cellular resistance mechanisms.