Tenofovir (PMPA) is less susceptible to pyrophosphorolysis and nucleotide-dependent chain-terminator removal than zidovudine or stavudine

Pyrophosphorolysis, the removal of nucleoside chain-terminators by a pyroph osphate (PPi) acceptor molecule, and a similar mechanism (nucleotide-depend ent chain-terminator removal) which uses ATP as an acceptor molecule have b een proposed as mechanisms of zidovudine (AZT) resistance. Recombinant HIV- 1 wild-type reverse transcriptase (RT) and a mutant RT enzyme containing th e AZT/thymidine analog resistance mutations D67N/K70R/T215Y were analyzed f or pyrophosphorolysis and nucleotide-dependent chain-terminator removal act ivities. Our results confirm that pyrophosphorolysis and nucleotide-depende nt chain-terminator removal are potential mechanisms of AZT and d4T resista nce. However, tenofovir is less efficiently removed by pyrophosphorolysis a nd by nucleotide-dependent mechanisms. These results are consistent with th e minor changes in susceptibility to tenofovir of the AZT/thymidine analog- resistant HIV RT mutants and the corresponding resistance of these mutants to AZT. The inability to remove tenofovir efficiently by these mechanisms m ay contribute to the durability of the HIV RNA response observed in patient s treated with the oral prodrug, tenofovir disoproxil fumarate.