The Molecular Mechanism of Zidovudine Resistance Unraveled

The very first anti-HIV drug for which resistancehad been observed to occur in cell culture and indrug-treated HIV-infected individuals was zidovudine(AZT). Although AZT resistance was unambigouslyshown to be due to the appearance ofwell-defined mutations in the reverse transcriptaseof AZT-resistant HIV-1 variants, investigations havealways failed to show AZT-TP (the active metaboliteof AZT) resistance at the level of the enzymatic activityof the mutated reverse transcriptase. Theamino acid mutations that are characteristic for AZTresistance include, but are not limited to, M4IL,D67N, K70R, T215F and K219Q. The discrepancybetween the genotypic and phenotypic characteristicsof mutant viruses and the phenotypic propertiesof the corresponding mutant enzymes is insharp contrast with the resistance mutations in theHIV RT shown for other nucleoside RT inhibitors,and for the non-nucleoside RT inhibitors.