Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance
Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance
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DOI：
10.1073/pnas.1018360108
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发表时间：
2011-05-03
影响因子：
11.1
通讯作者：
Siliciano, Robert F.
中科院分区：
文献类型：
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作者：
Sampah, Maame Efua S.;Shen, Lin;Siliciano, Robert F.
HIV-1耐药性是一个主要的临床问题。耐药性是通过体外测定耐药突变引起的IC50倍数变化来评估的。然而，抗逆转录病毒药物的使用浓度高于IC50，只有在剂量-反应曲线的形状已知的情况下，才能根据IC50预测临床浓度的抑制。曲线形状受协同作用的影响，用斜率参数或Hill系数(M)进行数学描述。在目前的耐药性分析中，隐含的假设是突变使剂量-反应曲线右移，而不影响斜率。我们在这里展示了m被抗药性突变所改变。对于逆转录酶和融合抑制剂，单一耐药突变同时影响斜率和IC50。对于蛋白水解酶抑制剂，单一突变主要影响斜率。对于整合酶抑制剂，只有IC50受到影响。因此，对不同药物类别的耐药性存在着根本的药效学差异。瞬时抑制势(IIP)是临床浓度下对单轮传染性的对数抑制，它同时考虑了斜率和IC50，因此提供了一种直接衡量突变导致的敏感性降低和药物对耐药病毒的剩余活性的方法。当突变改变斜率时，标准衡量标准IC50的折叠变化与IIP的变化没有很好的相关性。这些结果挑战了目前对HIV-1耐药性分析的一个基本假设，并表明要更完整地理解耐药性突变如何降低抗病毒活性，需要考虑一个以前被忽略的参数，即剂量-反应曲线斜率。
HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC50 caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC50, however, and inhibition at clinical concentrations can only be predicted from IC50 if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC50. For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC50 is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC50, and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC50, does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope.