Silman N J, Fooks A R
Centre for Applied Microbiology and Research, Salisbury, Wiltshire, SP4 0JG, UK.
Curr Opin Mol Ther. 2000 Oct;2(5):524-31.
Advances in understanding the interaction of animal viruses with their cognate receptors has led to improvements in the development of cell-specific, targeted viral vectors. Research strategies to generate safe, non-inflammatory viral vectors that are capable of delivering a therapeutic gene to a specific population of cells are currently underway in many laboratories. One approach in the utilization of this cell targeting activity is to ablate the natural interaction of the virus with its native receptor, although this is not an absolute requirement. The initial development of 'viral targeting strategies' was based on the view that by modifying the viral protein/receptor interaction, it would be possible to redirect virus vectors to new host cells. As the understanding of virus/cell interactions increased it was observed, however, that many viruses can use different entry mechanisms for cell attachment and penetration. Adenovirus vectors have been used extensively for the delivery of genes to cells. The entry mechanism for adenoviruses into cells has recently been studied and is relatively well understood, however, there are many aspects of cell receptor/virus interactions, which have still to be elucidated. The single high-affinity receptor on mammalian cells for adenovirus type 5 is recognized as the coxsackie and adenovirus receptor. However, in the absence of coxsackie and adenovirus receptor other receptors are used. A thorough understanding of the biology of adenoviruses is essential in the further development of their use as vectors for cell targeting. One strategy is to modify the viral capsid, either through coating the surface using bispecific antibodies, or by chemically crosslinking the targeting ligand onto the virion surface. Another approach is to genetically modify the virus by incorporating the targeting ligand into the viral 'spike' (fiber) protein. This involves manipulating the adenovirus genome and generating a new targeting ligand on the surface of the fiber protein using recombinant DNA technology. The penton base protein has also received attention as a means of directing adenoviruses via insertion of novel targeting ligands.
在理解动物病毒与其同源受体相互作用方面取得的进展，已推动了细胞特异性靶向病毒载体开发的改进。目前许多实验室正在开展研究策略，以生成能够将治疗性基因传递至特定细胞群体的安全、无炎症的病毒载体。利用这种细胞靶向活性的一种方法是消除病毒与其天然受体的自然相互作用，不过这并非绝对必要条件。“病毒靶向策略”的最初发展基于这样一种观点，即通过修饰病毒蛋白/受体相互作用，有可能将病毒载体重新导向新的宿主细胞。然而，随着对病毒/细胞相互作用理解的增加，人们发现许多病毒可利用不同的进入机制进行细胞附着和穿透。腺病毒载体已被广泛用于向细胞递送基因。最近对腺病毒进入细胞的机制进行了研究，并且相对较为清楚，然而，细胞受体/病毒相互作用的许多方面仍有待阐明。哺乳动物细胞上针对5型腺病毒的单一高亲和力受体被认为是柯萨奇病毒和腺病毒受体。然而，在没有柯萨奇病毒和腺病毒受体的情况下，会使用其他受体。深入了解腺病毒的生物学特性对于其作为细胞靶向载体的进一步开发至关重要。一种策略是修饰病毒衣壳，要么使用双特异性抗体包被表面，要么通过化学交联将靶向配体连接到病毒粒子表面。另一种方法是通过将靶向配体整合到病毒“刺突”（纤维）蛋白中来对病毒进行基因修饰。这涉及操纵腺病毒基因组，并使用重组DNA技术在纤维蛋白表面生成新的靶向配体。五聚体基底蛋白作为通过插入新型靶向配体来引导腺病毒的一种手段也受到了关注。
