Abstract
BackgroundThe polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized.ResultsTo reveal the drug resistance mutations, we compared the gene sequences of pol region of HIV-1 CRF_BC from 631 treatment-naïve and 363 treatment-experienced patients using the selection pressure-based method. We calculated an individual Ka/Ks value for each specific amino acid mutation. Result showed that eight polymorphic mutations (W88C, K101Q, I132L, R135L, T139K/R, H221Y and L228R) in RT for treatment-experienced patients were identified, while they, except for R135L, were completely absent in those from treatment-naïve patients. The I132L and T139K/R mutants exhibited high-level resistance to DLV and NVP and moderate resistance to TMC-125 and EFV, while the K101Q and H221Y mutants exhibited an increased resistance to all four NNRTIs tested. The W88C, R135L, and L228R may be RTI-induced adaptive mutations. Y181C+K101Q mutant showed a 2.5-, 4.4-, and 4.7-fold higher resistance to TMC-125, NVP and EFV, respectively, than Y181C alone mutant, while Y181C+H221Y or K103N+H221Y mutants had significantly higher resistance to all four NNRTIs than Y181C or K103N mutants. K103N+T139K and G190A+T139K mutant induce higher resistance (2.0∼14.2-fold and 1.5∼7.2-fold, respectively) to all four NNRTIs than K103N or G190A alone mutation.ConclusionsI132L and T139K/R are rare but critical mutations associated with NNRTI-resistance for some NNRTIs. K101Q, H221Y and T139K can enhance K103N/Y181C/G190A-assocated NNRTI-resistance. Monitoring these mutations will provide useful information for rational design of the NNRTI-based antiretroviral regimen for HIV-1 CRF_BC-infected patients.
Highlights
Human immunodeficiency virus type 1 (HIV-1) has been categorized into nine genetically distinct subtypes within the M group, including subtypes A, B, C, D, F, G, H, J, and K
The currently available reverse transcriptase inhibitors have been widely used in the world, including China, against both B and non-B HIV-1 strains; the polymorphisms involving in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC pol region have been poorly characterized
We found that HIV-1 subtype B viruses with I132L and T139K/R mutations were resistant to NNRTIs, their resistant level is relatively lower than that of HIV-1 CRF_BC viruses with these mutations (Table 2)
Summary
Human immunodeficiency virus type 1 (HIV-1) has been categorized into nine genetically distinct subtypes within the M group, including subtypes A, B, C, D, F, G, H, J, and K. Recombination between genomes of two viruses of different subtypes results in generation of a circulating recombinant form (CRF) [1]. The distribution of these subtypes and CRFs varies widely by region. The currently available reverse transcriptase inhibitors have been widely used in the world, including China, against both B and non-B HIV-1 strains; the polymorphisms involving in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC pol region have been poorly characterized. The polymorphisms involved in drug resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1 CRF_BC, the most prevalent HIV-1 strain in China, have been poorly characterized
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