The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis

Nucleoside analog chain terminators such as 3'-azido-3'-deoxythymidine (AZT ) and 2',3'-dideoxy-3'-thiacytidine (3TC) represent an important class of d rugs that are used in the clinic to inhibit the reverse transcriptase (RT) of human immunodeficiency virus type 1, Recent data have suggested that mut ant enzymes associated with AZT resistance are capable of removing the chai n-terminating residue with much greater efficiency than wild-type RT and th is may, in turn, facilitate rescue of DNA synthesis; these experiments were performed using physiological concentrations of pyrophosphate or nucleosid e triphosphates, respectively. The present study demonstrates that the M184 V mutation, which confers high-level resistance to 3TC, can severely compro mise the removal of chain-terminating nucleotides. Pyophosphorolysis on 3TC -terminated primer strands was not detectable with M184V containing, as opp osed to wild-type, RT, and rescue of AZT-terminated DNA synthesis was signi ficantly decreased with the former enzyme. Thus, mutated RTs associated wit h resistance to AZT and 3TC possess opposing, and therefore incompatible, p henotypes in this regard. These results are consistent with tissue culture and clinical data showing sustained antiviral effects of AZT in the context of viruses that contain the M184V mutation in the RT-encoding gene.