HIV resistance to zidovudine: the role of pyrophosphorolysis

Zidovudine-resistant strains of HIV became apparent in many patients soon a fter advent of zidovudine (AZT) monotherapy. While this resistance could be unequivocally correlated with multiple mutations in HIV reverse transcript ase (D67N, K70R,T215F/Y, K219Q), the mechanism or phenotype for this resist ance has remained obscure for more than a decade, despite active investigat ion. Recent studies indicate that AZT resistance may be related to removal of chain-terminating AZT from the 3'-terminus of the primer, by a process k nown as pyrophosphorolysis. This process is catalyzed by HIV-I reverse tran scriptase (RT), and is the reverse reaction of DNA polymerization. The D67N /K70R mutations result in a significantly increased rate of RT-catalyzed py rophosphorolysis at physiological levels of pyrophosphate, which leads to a decrease in the extent of AZT chain termination of nascent viral DNA. The potential replication deficit of an increased reverse reaction during DNA s ynthesis is compensated by increased DNA synthesis processivity, a phenotyp e that results from the T215F/Y/K219Q mutations in RT.The net result of the se multiple phenotypes imparted by the multiple mutations in RT is the faci le synthesis of full-length viral DNA in the presence of AZT.