15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

THE IN VITRO RESISTANCE PROFILE OF NcRTI-1 IS COMPLEMENTARY WITH THE RESISTANCE PROFILE OF TENOFOVIR AND ZIDOVUDINE

Antivir Ther. 2006, 11:S21 (abstract no. 16)

D Jochmans, M Van Ginderen, I De Baere, P Dehertogh, S Hallenberger and K Hertogs
Tibotec, Mechelen, Belgium

BACKGROUND: NcRTIs (nucleotide-competing reverse transcriptase inhibitors) are a novel class of HIV reverse transcriptase (RT) inhibitors. They bind the RT active site in competition with the next incoming nucleotide. This novel mechanism of action translates into a unique resistance profile. The prototype compound NcRTI-1 remains active on NNRTI resistant strains and on multi-drug NRTI resistant strains (Q151M complex, 69ins complex and thymidine-associated mutations (TAMs)). So far, only the mutational pattern M184V+Y115F has been associated with resistance for NcRTI-1 (fold-change in EC₅₀ compared to wild-type (FC)=75), while the presence of K65R is associated with hypersusceptibility (FC 0.5). This profile was shown to be complementary with tenofovir.

RESULTS: It is known that mutation M184V reverses zidovudine resistance. Therefore, we investigated the complementarity between NcRTIs and zidovudine. In two independent experiments, a zidovudine-resistant strain harbouring the TAMs M41L/D67N/K70R/T215Y was replicated in the presence of increasing concentrations of NcRTI-1. Mutation M184V was not selected. In contrast, a novel mutational pattern A62V+P133H appeared in addition to the TAMs. This genotype caused resistance for NcRTI-1 (FC >10) and reversal of TAM- associated zidovudine resistance. These findings were confirmed using site-directed mutants. While the TAM- containing strain had an FC 3.0 for NcRTI-1 and FC 63 for zidovudine, introduction of A62V+P133H in this background resulted in an FC 26 for NcRTI-1 and FC 2.0 for zidovudine. Viral strains containing the TAMs combined with either the A62V or the P133H mutation, showed an intermediate effect on NcRTI-1 resistance (FC 2.7 and 2.3 respectively) and reversal of zidovudine resistance (FC 3.6 and 0.6 respectively). The introduction of A62V+P133H in the backbone of a wild-type virus had no effect on zidovudine susceptibility (FC 0.8) and caused decreased NcRTI-1 susceptibility (FC 9.1).

CONCLUSIONS: In vitro, we identified a novel HIV RT mutational pattern A62V+P133H, associated with NcRTI-1 resistance and reversal of zidovudine resistance. Together with the main pattern of M184V+Y115F-associated resistance and K65R-associated hypersusceptibility, these data indicate that the resistance profile of NcRTIs fits favorably with the resistance profiles of zidovudine and tenofovir. It could be hypothesized that these in vitro findings will translate in favourable synergies in the clinic.

2006-06-13
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