Background: The aim of this study is to evaluate the influence of a possible polymorphism 108I mutation detected in a treatment-naive HIV-1-infected patient on the evolution of EFV resistance.
Methods: HIV-1 clinical isolate (KK141), carrying V/I mixture at position 108 in the RT region, was obtained from a treatment-naive patient. PBMCs were infected with KK141 in the presence of 0.01, μM EFV and cultured with 1.5- to 2-fold increasing concentrations of EFV. Emergence of resistance-associated mutations in escaped viruses was monitored by sequence analysis of the RT gene, and drug-susceptibility was determined by MAGIC5 assay.
Results: 108I mutants became predominant by week 3 with modest resistance to EFV, although no additional resistant-mutation was observed, and the virus replication was suppressed in further cultivation with increased concentrations of EFV. Interestingly, when the EFV-selected V108I variant was cultured in the absence of EFV for 4 more weeks, an A62V mutation emerged instead of a re-growth of 108V wild-type virus, and an additional mutation (K103N or V100I) emerged in the A62V/V108I variants when they were cultured with EFV again. On the other hand, when PBMCs were infected with KK141 in the absence of EFV and then cultured in the presence of EFV, highly-resistant variants harboring K103R/V179D/Y181C/Y188H mutations were induced only from the virus with 108V.
Conclusions: The pre-existing V108I mutation detected in a treatment-naive patient is not likely to lead the emergence of highly-resistant variants to EFV. However, the co-existence of A62V, associated with multi-nucleoside resistance, might increase the fitness of V108I variants under the pressure of EFV and enhance the development of resistance.
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