Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.
Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.
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DOI：
10.1371/journal.pone.0000655
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发表时间：
2007-08-01
期刊：
影响因子：
3.7
通讯作者：
Black PL
中科院分区：
文献类型：
--
作者：
Stoddart CA;Bales CA;Bare JC;Chkhenkeli G;Galkina SA;Kinkade AN;Moreno ME;Rivera JM;Ronquillo RE;Sloan B;Black PL
HIV-1感染的SCID-hu Thy/Liv小鼠模型是用于体内抗病毒功效的临床前评价的有用平台。我们进行了这项研究，以验证模型与所有四类许可的抗逆转录病毒药物的代表。用于定量Thy/Liv植入物病毒载量的终点分析包括细胞相关p24的ELISA、HIV-1 RNA的分支DNA测定以及通过Gag-p24的细胞内染色检测感染的胸腺细胞。通过基于CD 3、CD 4和CD 8表面表达的胸腺细胞亚群的流式细胞术分析，评估HIV-1介导的胸腺细胞耗竭的抗病毒保护作用。这些小鼠可以有效地感染HIV-1的分子克隆（例如，X4克隆NL 4 -3）以及原代R5和R5 X4分离株。为了确定该模型中的结果是否与人体中发现的结果一致，我们对同一类别的两种药物进行了直接比较，每种药物在人体中具有已知的效力和剂量水平。在这里，我们发现，第二代抗逆转录病毒药物，如预期的那样，比他们的第一代前辈更有效：恩曲他滨比拉米夫定更有效，依法韦仑比奈韦拉平更有效，阿扎那韦比茚地那韦更有效。在种间药效学缩放后，发现在SCID-hu Thy/Liv小鼠中抑制病毒复制的剂量范围与在人类中使用的剂量范围相似。此外，HIV-1在这些小鼠中的复制在遗传上是稳定的;用拉米夫定治疗小鼠并没有导致逆转录酶中的M184 V取代，并且多药耐药的纽约指数病例HIV-1保留了其耐药取代。鉴于这种比较的保真度，我们得出结论，这种高度可重复的小鼠模型很可能预测人类的临床抗病毒疗效。
The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions. Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans.
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