Identification of the critical sites of NNRTI-resistance in reverse transcriptase of HIV-1 CRF_BC strains.
Identification of the critical sites of NNRTI-resistance in reverse transcriptase of HIV-1 CRF_BC strains.
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HIV-1 CRF_BC 株逆转录酶中 NNRTI 抗性关键位点的鉴定
DOI：
10.1371/journal.pone.0093804
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Huang Y;Li Z;Xing H;Jiao Y;Ouyang Y;Liao L;Jiang S;Armstrong R;Shao Y;Ma L
背景 HIV-1 CRF_BC（中国最流行的 HIV-1 毒株）中与非核苷类逆转录酶抑制剂 (NNRTI) 耐药相关的多态性尚未得到充分表征。结果 为了揭示耐药突变，我们使用基于选择压力的方法比较了 631 名初治患者和 363 名接受过治疗的患者的 HIV-1 CRF_BC pol 区的基因序列。我们计算了每个特定氨基酸突变的单独 Ka/Ks 值。结果显示，接受过治疗的患者在放疗中发现了 8 个多态性突变（W88C、K101Q、I132L、R135L、T139K/R、H221Y 和 L228R），而除 R135L 外，这些突变在未接受过治疗的患者中完全不存在。 I132L和T139K/R突变体表现出对DLV和NVP的高水平抗性以及对TMC-125和EFV的中度抗性，而K101Q和H221Y突变体表现出对所有四种测试的NNRTIs的增强的抗性。 W88C、R135L和L228R可能是RTI诱导的适应性突变。 Y181C+K101Q突变体对TMC-125、NVP和EFV的抗性分别比Y181C单独突变体高2.5、4.4和4.7倍，而Y181C+H221Y或K103N+H221Y突变体对所有四种NNRTI的抗性比Y181C或K103N突变体显着更高。 K103N+T139K 和 G190A+T139K 突变体比单独的 K103N 或 G190A 突变体对所有四种 NNRTI 诱导更高的耐药性（分别为 2.0∼14.2 倍和 1.5∼7.2 倍）。结论 I132L 和 T139K/R 是罕见但与某些 NNRTI 耐药相关的关键突变。 K101Q、H221Y 和 T139K 可以增强 K103N/Y181C/G190A 相关的 NNRTI 抗性。监测这些突变将为合理设计针对 HIV-1 CRF_BC 感染患者的基于 NNRTI 的抗逆转录病毒治疗方案提供有用的信息。
Background 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. Results To 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. Conclusions I132L 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.
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