Department of Biomedicine, University of Aarhus, Wilh. Meyers Allé, Aarhus C, Denmark.
Curr Gene Ther. 2011 Oct;11(5):350-62. doi: 10.2174/156652311797415881.
Gene vehicles derived from lentiviruses have become highly esteemed tools for gene transfer and genomic insertion in a wealth of cell types both in vivo and ex vivo. However, accumulating evidence of preferred insertion into actively transcribed genes, driven by biological properties of the parental human immunodeficiency virus type 1, has questioned the safety of this vector technology. As a consequence, integrase-defective lentiviral vectors [IDLVs], carrying an inactive integrase protein, have been developed and used with success for persistent in vivo gene transfer to quiescent or slowly dividing cells. We and others have shown that episomal DNA delivered by IDLVs may serve as a substrate for heterologous integration machineries, including recombinases and transposases, and homologous recombination triggered by nuclease-induced DNA damage. New vector systems that combine the best of lentiviral gene delivery and nonviral integration systems are under development. The first prototypes of such hybrid lentiviral vectors facilitate efficient gene transfer and show profiles of insertion that are not dictated by the biological constraints of the normal integration pathway and are, therefore, significantly different from the profile of conventional lentiviral vectors. The stage is set for further exploration of these vectors. In this review, we summarize the background and short history of hybrid IDLV-based vector systems and discuss their applicability in gene therapy and treatment of genetic disease.
基于慢病毒的基因载体已成为在体内和体外的大量细胞类型中进行基因转移和基因组插入的重要工具。然而，越来越多的证据表明，亲本人类免疫缺陷病毒 1 的生物学特性导致其优先插入活跃转录的基因，这引发了对该载体技术安全性的质疑。因此，已经开发并成功使用整合酶缺陷型慢病毒载体（IDLVs），将其携带的无活性整合酶蛋白用于持续的体内基因转移到静止或缓慢分裂的细胞。我们和其他人已经表明，IDLV 传递的游离型 DNA 可作为异源整合机制（包括重组酶和转座酶）和核酸酶诱导的 DNA 损伤引发的同源重组的底物。正在开发结合慢病毒基因传递和非病毒整合系统优势的新型载体系统。这些杂交慢病毒载体的第一个原型能够有效地进行基因转移，并显示出不受正常整合途径的生物学限制决定的插入谱，因此与传统慢病毒载体的插入谱有显著差异。为进一步探索这些载体奠定了基础。在这篇综述中，我们总结了基于杂交 IDLV 的载体系统的背景和简要历史，并讨论了它们在基因治疗和遗传疾病治疗中的适用性。
