HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription
HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription
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DOI：
10.1073/pnas.0607414104
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发表时间：
2007-01-16
影响因子：
11.1
通讯作者：
Keppler, Oliver T.
中科院分区：
文献类型：
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作者：
Goffinet, Christine;Allespach, Ina;Keppler, Oliver T.
目前抗艾滋病毒药物的测试由于缺乏易于获得和处理的小动物而受到阻碍；可全身感染1型艾滋病毒（HIV-1）；在生理频率、器官分布和激活状态下包含HIV-1主要靶细胞；并被建立为药理学模型。在这里，我们探索了在CD4 T细胞和巨噬细胞上转基因表达HIV-1受体复合物的近交Sprague-Dawley大鼠的潜力，作为针对病毒进入或逆转录抑制剂的临床前评估模型。从人CD4和ccr5转基因大鼠培养的原代CD4 T细胞和巨噬细胞中，抑制HIV-1感染所需的肽融合抑制剂恩福韦肽或非核苷类逆转录酶抑制剂依非韦伦兹的浓度与人参比培养所需的浓度相差不超过3倍。双转基因大鼠在静脉注射HIV-1病毒4天后，用体重适应的儿科给药方案预防性治疗恩福韦肽（s.c c，每日2次）或依非韦伦（口服，每日1次），分别使脾脏中HIV-1 cDNA载量减少92.5%或98.8%。值得注意的是，每日一次给药的恩富韦肽导致感染抑制能力降低了约5倍，在功效试验中揭示了合成肽不利的药代动力学特征。这项工作提供了原理证明，即HIV易感转基因大鼠可以对针对HIV复制周期早期阶段的抗病毒化合物的抑制效力和药代动力学特性进行快速和预测性的临床前评估。
The current testing of anti-HIV drugs is hampered by the lack of a small animal that is readily available and easy to handle; can be infected systemically with HIV type 1 (HIV-1); harbors the major HIV-1 target cells in a physiological frequency, organ distribution, and activation state; and is established as a pharmacological model. Here, we explored the potential of outbred Sprague-Dawley rats that transgenically express the HIV-1 receptor complex on CD4 T cells and macrophages as a model for the preclinical evaluation of inhibitors targeting virus entry or reverse transcription. The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures. Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge. Notably, a once-daily dosing regimen for enfuvirtide resulted in a approximate to 5-fold weaker inhibition of infection, unmasking the unfavorable pharmacokinetic characteristics of the synthetic peptide in the context of an efficacy trial. This work provides proof of principle that HIV-susceptible transgenic rats can allow a rapid and predictive preclinical evaluation of the inhibitory potency and of the pharmacokinetic properties of antiviral compounds targeting early steps in the HIV replication cycle.