In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance
In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance
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DOI：
10.1182/blood-2006-10-049312
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发表时间：
2007-04-01
期刊：
影响因子：
20.3
通讯作者：
Naldini, Luigi
中科院分区：
文献类型：
--
作者：
Brown, Brian D.;Sitia, Giovanni;Naldini, Luigi
肝脏基因转移是治疗遗传性和感染性疾病的一个高度追求的目标。慢病毒载体（LV）具有许多用于肝细胞定向基因递送的期望性质，包括整合到非分裂细胞中的能力。不幸的是，在全身给药时，LV转导肝细胞的效率相对较低，与非实质细胞相比，转基因表达的持续时间往往受到免疫反应的限制。在这里，我们研究了先天性抗病毒反应在这些事件中的作用。我们表明，给小鼠注射LV可引发快速和短暂的IFN α β反应。这种效应依赖于功能性载体颗粒，体外抗原呈递细胞的挑战表明浆细胞样树突状细胞启动的反应。值得注意的是，当将LV给予缺乏对IFN α β应答能力的动物时，肝细胞转导显著增加，并且实现了稳定的转基因表达。这些发现表明，即使在急性递送复制缺陷型载体的情况下，IFN也能以细胞类型特异性的方式有效地干扰转导。此外，由于禁用先天/免疫网络的单个组件足以建立持久的异种抗原表达，我们的结果带来了希望，即基因治疗的免疫障碍并不像预期的那样难以克服。
Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFN alpha beta response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFN alpha beta, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a cell-type-specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected.