Molecular mechanisms of HIV-1 resistance to nucleoside and nucleotide reverse transcriptase inhibitors

Abstract

The nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) were the first drugs used to treat HIV-1 infection and they remain integral components of nearly all antiretroviral regimens. However, the long-term efficacy of combination therapies that contain NRTIs is limited by the selection of drug-resistant variants of HIV-1. In general, NRTI therapy selects for viruses that have mutations in reverse transcriptase (RT). These mutations can be broadly categorized into two groups depending on their phenotypic mechanism of resistance. Mutations such as K65R, K70E, L74V, Q151M and M184V allow RT to discriminate against the NRTI triphosphate by increasing the enzyme’s selectivity for incorporation of the natural deoxynucleotide triphosphate substrate. By comparison, the thymidine analog mutations – such as M41L, D67N, K70R, L210W, T215F/Y and K219Q – augment the ability of HIV-1 RT to excise a chain-terminating NRTI monophosphate from a prematurely terminated DNA chain. A comprehensive knowledge of resistance mechanisms, cross-resistance patterns and interplay between mutations – as described in this review – can help optimize antiretroviral treatment strategies and possibly aid in the design of NRTIs that are active against drug-resistant HIV-1.