Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture
Stage-Dependent Inhibition of HIV-1 Replication by Antiretroviral Drugs in Cell Culture
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DOI：
10.1128/aac.01537-09
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发表时间：
2010-03-01
影响因子：
4.9
通讯作者：
Wainberg, Mark A.
中科院分区：
文献类型：
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作者：
Donahue, Daniel A.;Sloan, Richard D.;Wainberg, Mark A.
最近的临床试验表明，使用HIV-1整合酶（IN）抑制剂雷特格韦（RAL）导致病毒载量下降，比使用逆转录酶（RT）抑制剂依法韦仑更快。此前，考虑到药物靶向病毒复制阶段的病毒载量衰减数学模型已经产生了非常接近临床试验结果的数据。该模型预测了在病毒复制周期后期起作用的药物对病毒复制的抑制作用更大。在本研究中，我们添加了靶向急性感染细胞的进入、逆转录、整合或蛋白水解加工的药物，并且相对于无药物对照的生长水平，通过进入抑制剂显示出适度的病毒抑制，通过RT和IN抑制剂显示出中等水平的抑制，以及通过蛋白酶抑制剂显示出高水平的抑制。当将这些药物的双重或三重组合添加到急性感染的细胞中时，我们发现任何给定组合所达到的抑制水平与组合中最晚作用的药物所达到的水平相当。在单轮感染中，逆转录和整合的动力学已通过定量PCR确定，在感染后的不同时间添加IN抑制剂导致抑制水平等于或大于通过添加RT抑制剂所实现的水平。总的来说，我们的数据提供了临床相关药物对HIV-1的阶段依赖性抑制的体外证据。我们讨论了阶段依赖性抑制如何有助于解释RAL临床观察到的独特病毒载量衰减动力学。
Recent clinical trials have shown that the use of the HIV-1 integrase (IN) inhibitor raltegravir (RAL) results in drops in the viral load that are more rapid than those achieved by use of the reverse transcriptase (RT) inhibitor efavirenz. Previously, mathematical modeling of viral load decay that takes into account the stage of viral replication targeted by a drug has yielded data that closely approximate the clinical trial results. This model predicts greater inhibition of viral replication by drugs that act later in the viral replication cycle. In the present study, we have added drugs that target entry, reverse transcription, integration, or proteolytic processing to acutely infected cells and have shown modest viral inhibition by entry inhibitors, intermediate levels of inhibition by RT and IN inhibitors, and high levels of inhibition by protease inhibitors relative to the levels of growth for the no-drug controls. When dual or triple combinations of these drugs were added to acutely infected cells, we found that the levels of inhibition achieved by any given combination were comparable to those achieved by the latest-acting drug in the combination. In single-round infections in which the kinetics of reverse transcription and integration had been determined by quantitative PCR, addition of IN inhibitors at various times postinfection resulted in levels of inhibition equal to or greater than those achieved by addition of RT inhibitors. Collectively, our data provide in vitro evidence of the stage-dependent inhibition of HIV-1 by clinically relevant drugs. We discuss how stage-dependent inhibition helps to explain the unique viral load decay dynamics observed clinically with RAL.