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首页> 外文期刊>The journal of clinical investigation >Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance
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Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance

机译：多步骤抑制解释了HIV-1蛋白酶抑制剂的药效学和耐药性

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HIV-1 protease inhibitors (PIs) are among the most effective antiretroviral drugs. They are characterized by highly cooperative dose-response curves that are not explained by current pharmacodynamic theory. An unresolved problem affecting the clinical use of PIs is that patients who fail PI-containing regimens often have virus that lacks protease mutations, in apparent violation of fundamental evolutionary theory. Here, we show that these unresolved issues can be explained through analysis of the effects of PIs on distinct steps in the viral life cycle. We found that PIs do not affect virion release from infected cells but block entry, reverse transcription, and post–reverse transcription steps. The overall dose-response curves could be reconstructed by combining the curves for each step using the Bliss independence principle, showing that independent inhibition of multiple distinct steps in the life cycle generates the highly cooperative dose-response curves that make these drugs uniquely effective. Approximately half of the inhibitory potential of PIs is manifest at the entry step, likely reflecting interactions between the uncleaved Gag and the cytoplasmic tail (CT) of the Env protein. Sequence changes in the CT alone, which are ignored in current clinical tests for PI resistance, conferred PI resistance, providing an explanation for PI failure without resistance.
机译：HIV-1蛋白酶抑制剂（PIs）是最有效的抗逆转录病毒药物。它们的特征是高度协同的剂量反应曲线，目前的药效学理论无法解释。影响PI的临床使用的一个尚未解决的问题是，含PI方案失败的患者通常具有缺乏蛋白酶突变的病毒，这明显违反了基本进化论。在这里，我们表明这些未解决的问题可以通过分析PI对病毒生命周期不同步骤的影响来解释。我们发现PI不会影响病毒颗粒从感染细胞中释放，但会阻止进入，逆转录和逆转录后步骤。可以通过使用Bliss独立性原理组合每个步骤的曲线来重构总体剂量反应曲线，表明对生命周期中多个不同步骤的独立抑制会产生高度协同的剂量反应曲线，从而使这些药物具有独特的疗效。在进入步骤中，PI的抑制潜力约为一半，可能反映了未切割的Gag与Env蛋白的胞质尾部（CT）之间的相互作用。单独的CT序列变化在当前的PI耐药临床试验中被忽略，这赋予了PI耐药性，为没有耐药的PI失败提供了解释。

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