MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs

Dideoxynucleosides, which are potent inhibitors of HIV reverse transcriptas e and other viral DNA polymerases, are a common component of highly active anti-retroviral therapy (HAART) (ref. 1). Six reverse transcriptase inhibit ors have been approved for human use: azidothymidine; 2'3'-dideoxycytidine; 2'3'-dideoxyinosine; 2',3'-didehydro-3'deoxythymidine; 2',3'-dideoxy-3'-th iacytidine; and 4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopente ne-1-methanol. Although drug-resistant HIV strains resulting from genetic m utation have emerged in patients treated with HAART (ref. 1), some patients show signs of drug resistance in the absence of drug-resistant viruses(2,3 ). In our study of alternative or additional mechanisms of resistance opera ting during antiviral therapy, overexpression and amplification of the MRP4 gene correlated with ATP-dependent efflux of PMEA (9-(2-phosphonylmethoxye thyl)adenine) and azidothymidine monophosphate from cells and, thus, with r esistance to these drugs. Overexpression of MRP4 mRNA and MRP4 protein seve rely impaired the antiviral efficacy of PMEA, azidothymidine and other nucl eoside analogs. Increased resistance to PMEA and amplification of the MRP4 gene correlated with enhanced drug efflux; transfer of chromosome 13 contai ning the amplified MRP4 gene conferred resistance to PMEA. MRP4 is the firs t transporter, to our knowledge, directly linked to the efflux of nucleosid e monophosphate analogs from mammalian cells.