Abstract

BackgroundHIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) have been used in the clinic for over twenty years. Interestingly, the complete resistance pattern to this class has not been fully elucidated. Novel mutations in RT appearing during treatment failure are still being identified. To unravel the role of two of these newly identified changes, E40F and K43E, we investigated their effect on viral drug susceptibility and replicative capacity.ResultsA large database (Quest Diagnostics database) was analysed to determine the associations of the E40F and K43E changes with known resistance mutations. Both amino acid changes are strongly associated with the well known NRTI-resistance mutations M41L, L210W and T215Y. In addition, a strong positive association between these changes themselves was observed. A panel of recombinant viruses was generated by site-directed mutagenesis and phenotypically analysed. To determine the effect on replication capacity, competition and in vitro evolution experiments were performed. Introduction of E40F results in an increase in Zidovudine resistance ranging from nine to fourteen fold depending on the RT background and at the same time confers a decrease in viral replication capacity. The K43E change does not decrease the susceptibility to Zidovudine but increases viral replication capacity, when combined with E40F, demonstrating a compensatory role for this codon change.ConclusionIn conclusion, we have identified a novel resistance (E40F) and compensatory (K43E) change in HIV-1 RT. Further research is indicated to analyse the clinical importance of these changes.

Highlights

  • HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) have been used in the clinic for over twenty years

  • HIV-1 develops these TAMs by two distinct pathways: the TAM-1 pathway consisting of T215Y, M41L, L210W and sometimes D67N or the TAM-2 pathway including T215F, K70R, K219Q/E and D67N [8,9,10]

  • We investigated the association of the E40F and K43E changes with each other and with the known thymidine associated mutations (M41L, D67N, K70R, L210W, T215Y/F and K219Q/E; Table 2)

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Summary

Introduction

HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs) have been used in the clinic for over twenty years. Multiple epidemiological studies have identified novel mutations in HIV-1 RT showing a strong association with NRTI-treatment These mutations include the K20R, V35M, T39A, E40F, K43E/Q/N, A98G, K122E, G196E, E203K/D, H208Y, D218E, H221Y, K223E/Q and L228H/R changes [13,14,15,16,17,18,19,20]. The appearance of a lysine to glutamic acid change at position 43 (K43E) is strongly associated with NRTI-treatment [20] This mutation has an even higher association with NRTI treatment when compared to specific known drug-resistance mutations such as M41L, K219E and K65R (Stanford HIV Drug Resistance database). Both changes are interesting since they are located in close proximity of the known M41L drug resistance mutation

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