Belousova Natalya, Korokhov Nikolay, Krendelshchikova Valentina, Simonenko Vera, Mikheeva Galina, Triozzi Pierre L, Aldrich Wayne A, Banerjee Papia T, Gillies Stephen D, Curiel David T, Krasnykh Victor
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, USA.
J Virol. 2003 Nov;77(21):11367-77. doi: 10.1128/jvi.77.21.11367-11377.2003.
The success of gene therapy depends on the specificity of transgene delivery by therapeutic vectors. The present study describes the use of an adenovirus (Ad) fiber replacement strategy for genetic targeting of the virus to human CD40, which is expressed by a variety of diseased tissues. The tropism of the virus was modified by the incorporation into its capsid of a protein chimera comprising structural domains of three different proteins: the Ad serotype 5 fiber, phage T4 fibritin, and the human CD40 ligand (CD40L). The tumor necrosis factor-like domain of CD40L retains its functional tertiary structure upon incorporation into this chimera and allows the virus to use CD40 as a surrogate receptor for cell entry. The ability of the modified Ad vector to infect CD40-positive dendritic cells and tumor cells with a high efficiency makes this virus a prototype of choice for the derivation of therapeutic vectors for the genetic immunization and targeted destruction of tumors.
基因治疗的成功取决于治疗性载体转基因递送的特异性。本研究描述了一种腺病毒（Ad）纤维替换策略，用于将病毒基因靶向人CD40，CD40在多种患病组织中表达。通过将包含三种不同蛋白质结构域的蛋白质嵌合体掺入病毒衣壳，改变了病毒的嗜性：Ad血清型5纤维、噬菌体T4纤维蛋白和人CD40配体（CD40L）。CD40L的肿瘤坏死因子样结构域在掺入该嵌合体后保留其功能性三级结构，并允许病毒将CD40用作细胞进入的替代受体。修饰后的Ad载体高效感染CD40阳性树突状细胞和肿瘤细胞的能力，使其成为用于基因免疫和肿瘤靶向破坏的治疗性载体衍生的首选原型。
