Department of Medical Biotechnologies, University of Siena, Siena, Italy.
J Antimicrob Chemother. 2019 Mar 1;74(3):607-613. doi: 10.1093/jac/dky479.
The HIV-1 reverse transcriptase (RT) natural polymorphism E138A is included among the mutations with a minor impact on response to etravirine. However, the interpretation of E138A on etravirine susceptibility is not consistent across different genotypic resistance algorithms. The aim of the study was to investigate the effect of E138A on the genetic barrier to resistance to etravirine in vitro.
A panel of 20 clinically derived recombinant viruses (10 with WT 138E and 10 with 138A, all without any other resistance mutation) were cultured in the presence of increasing etravirine concentrations and analysed for genotypic changes at virus breakthrough. Parallel experiments were conducted with 138E/A/G/K/Q NL4-3-based clones.
In the NL4-3 background, codon 138 changes increased etravirine resistance in the following order: Q > K > A > G > E. The 138A viruses were less susceptible to etravirine compared with the 138E viruses [median (IQR) fold change, 1.8 (1.5-2.8) versus 1.3 (0.8-1.8); P = 0.026], overcame etravirine pressure earlier [HR (95% CI) for viral outgrowth with 138A, 5.48 (2.95-28.24); P < 0.001] and grew at higher drug concentrations [median (IQR), 1350 (1350-1350) versus 0 (0-1350) nM; P = 0.005]. A variety of etravirine resistance-related mutations and changes in the RT connection and RNase H domains accumulated without any consistent pattern depending on baseline codon 138.
E138A can contribute to reduced response to etravirine through a decreased genetic barrier to resistance. In vitro drug resistance selection is a valuable complement to define the full potential of low-level resistance mutations.
HIV-1 逆转录酶（RT）天然多态性 E138A 是对依曲韦林耐药性影响较小的突变之一。然而，不同基因型耐药算法对 E138A 对依曲韦林敏感性的解释并不一致。本研究旨在研究 E138A 对依曲韦林体外耐药遗传屏障的影响。
一组 20 种临床衍生的重组病毒（10 种具有 WT 138E 和 10 种具有 138A，均无其他耐药突变）在逐渐增加的依曲韦林浓度下培养，并在病毒突破时分析基因型变化。用 138E/A/G/K/Q NL4-3 为基础的克隆进行平行实验。
在 NL4-3 背景下，密码子 138 改变增加了依曲韦林的耐药性，顺序为：Q> K> A> G> E。与 138E 病毒相比，138A 病毒对依曲韦林的敏感性较低[中位数（IQR）倍变化，1.8（1.5-2.8）与 1.3（0.8-1.8）；P=0.026]，更早地克服了依曲韦林的压力[138A 病毒生长的 HR（95%CI），5.48（2.95-28.24）；P<0.001]，并在更高的药物浓度下生长[中位数（IQR），1350（1350-1350）与 0（0-1350）nM；P=0.005]。在 RT 连接和 RNase H 结构域中积累了多种依曲韦林耐药相关突变和变化，没有任何一致的模式取决于基线密码子 138。
E138A 可通过降低耐药遗传屏障，导致对依曲韦林的反应降低。体外药物耐药性选择是一种有价值的补充方法，可以确定低水平耐药突变的全部潜力。
