A mosaic adenovirus possessing serotype Ad5 and serotype Ad3 knobs exhibits expanded tropism
A mosaic adenovirus possessing serotype Ad5 and serotype Ad3 knobs exhibits expanded tropism
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DOI：
10.1016/s0042-6822(03)00067-9
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发表时间：
2003-05-10
期刊：
影响因子：
3.7
通讯作者：
Curiel, DT
中科院分区：
文献类型：
--
作者：
Takayama, K;Reynolds, PN;Curiel, DT
使用基于血清型 5 (Ad5) 的重组腺病毒进行癌症基因治疗的效率受到限制，部分原因是人原代癌细胞中识别纤维蛋白、柯萨奇和腺病毒受体 (CAR) 旋钮结构域的原代细胞受体的表达可变且通常较低。作为规避 CAR 缺陷的一种方法，Ad 载体已通过利用具有替代 Ad 血清型旋钮结构域的嵌合纤维进行重新定位。我们报道了卵巢癌细胞拥有 Ad3 的主要受体，Ad3 旋钮与该受体的结合独立于 CAR-Ad5 旋钮的相互作用。此外，基于Ad5的嵌合载体，命名为Ad5/3，含有具有Ad3旋钮的嵌合纤维蛋白，通过靶向Ad3受体表现出不依赖于CAR的向性。基于这些发现，我们假设在同一病毒粒子上同时拥有 Ad5 旋钮和 Ad3 旋钮的花叶病毒可以利用任一主要受体，从而导致向性扩大。在这项研究中，我们通过使用基于 Ad5 和 Ad5/3 的载体共感染 293 个细胞，产生了双旋钮花叶病毒。所得病毒颗粒的表征证实了 Ad5 和 Ad3 旋钮并入同一颗粒中。此外，这种花叶病毒能够利用任一受体（CAR 和 Ad3 受体）将病毒附着到细胞上。一组细胞系中显示了花叶病毒对 Ad 的感染性增强，其受体谱范围从 CAR 主导型到 Ad3 受体主导型。因此，这种花叶病毒策略可能通过增强感染性和扩大趋向性来改善基于 Ad 的基因治疗方法。 (C) 2003 年爱思唯尔科学（美国）。版权所有。
The efficiency of cancer gene therapy with recombinant adenoviruses based on serotype 5 (Ad5) has been limited partly because of variable, and often low, expression by human primary cancer cells of the primary cellular-receptor which recognizes the knob domain of the fiber protein, the coxsackie and adenovirus receptor (CAR). As a means of circumventing CAR deficiency, Ad vectors have been retargeted by utilizing chimeric fibers possessing knob domains of alternate Ad serotypes. We have reported that ovarian cancer cells possess a primary receptor for Ad3 to which the Ad3 knob binds independently of the CAR-Ad5 knob interaction. Furthermore, an Ad5-based chimeric vector, designated Ad5/3, containing a chimeric fiber proteins possessing the Ad3 knob, demonstrates CAR-independent tropism by virtue of targeting the Ad3 receptor. Based on these findings, we hypothesized that a mosaic virus possessing both the Ad5 knob and the Ad3 knob on the same virion could utilize either primary receptor, resulting in expanded tropism. In this study, we generated a dual-knob mosaic virus by coinfection of 293 cells with Ad5-based and Ad5/3-based vectors. Characterization of the resultant virions confirmed the incorporation of both Ad5 and Ad3 knobs in the same particle. Furthermore, this mosaic virus was able to utilize either receptor, CAR and the Ad3 receptor, for virus attachment to cells. Enhanced Ad infectivity with the mosaic virus was shown in a panel of cell lines, with receptor profiles ranging from CAR-dominant to Ad3 receptor-dominant. Thus, this mosaic virus strategy may offer the potential to improve Ad-based gene therapy approaches by infectivity enhancement and tropism expansion. (C) 2003 Elsevier Science (USA). All rights reserved.