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• W2129789020 abstract "HIV-1 reverse transcriptase (RT) mutations associated with antiviral drug resistance have been extensively characterized in the enzyme polymerase domain. Recent studies, however, have verified the involvement of the RT C-terminal domains (connection and RNase H) in drug resistance to RT inhibitors. In this work, we have characterized the correlation of recently described C-terminal domain mutations with thymidine analogue mutations (TAMs), as well as their phenotypic impact on susceptibility to zidovudine and nevirapine.HIV-1 RT sequences from Brazilian patients and from public sequence databases for which the C-terminal RT domains and treatment status were also available were retrieved and analysed for the association of C-terminal mutations and the presence of TAMs and treatment status. Several C-terminal RT mutations previously characterized were introduced by site-directed mutagenesis into an HIV-1 subtype B molecular clone in a wild-type, TAM-1 or TAM-2 pathway context. Mutants were tested for drug susceptibility to the prototypic drugs zidovudine and nevirapine.Subtype B-infected patient database analysis showed that mutations N348I, A360V/T, T377M and D488E were found to be selected independently of TAMs, whereas mutations R358K, G359S, A371V, A400T, K451R and K512R increased in frequency with the number of TAMs in a dose-dependent fashion. Phenotypic analysis of C-terminal mutations showed that N348I, T369V and A371V conferred reduced susceptibility to zidovudine in the context of the TAM-1 and/or TAM-2 pathway, and also conferred dual resistance to nevirapine. Other mutations, such as D488E and Q547K, showed TAM-specific enhancement of resistance to zidovudine. Finally, mutation G359S displayed a zidovudine hypersusceptibility phenotype, both per se and when combined with A371V.This study demonstrates that distinct RT C-terminal mutations can act as primary or secondary drug resistance mutations, and are associated in a complex array of phenotypes with RT polymerase domain mutations." @default.
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• W2129789020 date "2011-01-26" @default.
• W2129789020 modified "2023-10-16" @default.
• W2129789020 title "Phenotypic characterization of drug resistance-associated mutations in HIV-1 RT connection and RNase H domains and their correlation with thymidine analogue mutations" @default.
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• W2129789020 doi "https://doi.org/10.1093/jac/dkr005" @default.
• W2129789020 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3058567" @default.
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