Primer unblocking by HIV-1 reverse transcriptase and resistance to nucleoside RT inhibitors (NRTIs)

During zidovudine and stavudine treatment, HIV-1 selects several mutations (thymidine-associated mutations, TAMs) in the reverse transcriptase gene that confer high- and moderate-levels of resistance, respectively, to these nucleoside reverse transcriptase inhibitors (NRTIs). The mechanism of the resistance provided by these mutations has long remained elusive. However, recent data showed that ATP-phosphorolysis, a reaction analogous to pyrophosphorolysis (the reverse of the nucleotide incorporation reaction) in which ATP is the pyrophosphate donor, is central to this mechanism by allowing repair of the chain-terminated primer. A detailed structural and mechanistic model accounting for the specificity of the ATP-phosphorolysis and its inhibition by the next complementary nucleotide is now available. In the context of multiresistant viruses, the TAMs are also associated with resistance to abacavir, and to a lesser extent to didanisone, zalcitabine and tenofovir. When associated with the TAMs, a dipeptide insertion in the fingers of reverse transcriptase increases the ATP-phosphorolysis of most chain terminators, stressing the increasing importance of this mechanism. However, some non-nucleoside reverse transcriptase inhibitors (NNRTIs) inhibit this process. In addition, point mutations conferring resistance to NNRTIs (Y181C and L100I) or NRTIs (K65R, L74V, and M184V) partially resensitize the resistant viruses to AZT by inhibiting ATP-phosphorolysis. These findings allow rationalizing the beneficial effects of some drug combinations and should contribute to improve drug cocktails. The development of NRTIs that would not allow the ATP-mediated excision to take place should prove beneficial for future treatments, even though high-level resistance to multiple NRTIs can ultimately develop in the absence of any significant primer unblocking.