Tsuruta Yuko, Pereboeva Larisa, Glasgow Joel N, Luongo Cindy L, Komarova Svetlana, Kawakami Yosuke, Curiel David T
Division of Human Gene Therapy, Department of Medicine, and The Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Biochem Biophys Res Commun. 2005 Sep 16;335(1):205-14. doi: 10.1016/j.bbrc.2005.07.054.
Adenovirus serotype 5 (Ad5) has been used for gene therapy with limited success because of insufficient infectivity in cells with low expression of the primary receptor, the coxsackie and adenovirus receptor (CAR). To enhance infectivity in tissues with low CAR expression, tropism expansion is required via non-CAR pathways. Serotype 3 Dearing reovirus utilizes a fiber-like sigma1 protein to infect cells expressing sialic acid and junction adhesion molecule 1 (JAM1). We hypothesized that replacement of the Ad5 fiber with sigma1 would result in an Ad5 vector with CAR-independent tropism. We therefore constructed a fiber mosaic Ad5 vector, designated as Ad5-sigma1, encoding two fibers: the sigma1 and the wild-type Ad5 fiber. Functionally, Ad5-sigma1 utilized CAR, sialic acid, and JAM1 for cell transduction and achieved maximum infectivity enhancement in cells with or without CAR. Thus, we have developed a new type of Ad5 vector with expanded tropism, possessing fibers from Ad5 and reovirus, that exhibits enhanced infectivity via CAR-independent pathway(s).
5型腺病毒（Ad5）已用于基因治疗，但由于其在主要受体柯萨奇病毒和腺病毒受体（CAR）低表达的细胞中感染性不足，成效有限。为了增强在CAR低表达组织中的感染性，需要通过非CAR途径进行嗜性扩展。3型迪林呼肠孤病毒利用一种纤维样的σ1蛋白感染表达唾液酸和连接黏附分子1（JAM1）的细胞。我们推测，用σ1替换Ad5纤维将产生一种具有不依赖CAR嗜性的Ad5载体。因此，我们构建了一种纤维嵌合Ad5载体，命名为Ad5-σ1，它编码两种纤维：σ1和野生型Ad5纤维。在功能上，Ad5-σ1利用CAR、唾液酸和JAM1进行细胞转导，并在有或无CAR的细胞中实现了最大程度的感染性增强。因此，我们开发了一种新型的具有扩展嗜性的Ad5载体，它拥有来自Ad5和呼肠孤病毒的纤维，通过不依赖CAR的途径表现出增强的感染性。
