The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9
The 37/67-kilodalton laminin receptor is a receptor for adeno-associated virus serotypes 8, 2, 3, and 9
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DOI：
10.1128/jvi.00878-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Kay, Mark A.
中科院分区：
文献类型：
--
作者：
Akache, Bassel;Grimm, Dirk;Kay, Mark A.
腺相关病毒血清型8（Adeno-associated virus serotype 8，AAV 8）是目前新兴的一种强大的基因转移载体，由于其能够在体内有效地转染许多不同的组织。虽然这被认为部分是由于其比其他AAV血清型如AAV 2更容易去包被的能力，但理解AAV 8转导背后的所有过程对于其在人类基因治疗中的应用和最佳使用是重要的。在这里，我们提供了AAV 8的细胞受体的第一份报告，37/67-kDa层粘连蛋白受体（LamR）。我们记录了LamR与体外AAV 8衣壳蛋白和完整病毒体的结合，并证明了其对体内培养细胞和小鼠肝脏的AAV 8转导的贡献。我们还表明LamR在其他三种密切相关的血清型（AAV 2、AAV 3和AAV 9）的转导中起作用。序列和缺失分析使我们能够映射LamR结合到预测暴露在AAV衣壳外部的两个蛋白质亚结构域。LamR在许多临床相关组织中组成型表达并且在许多癌症中过表达，其使用为AAV 8的广泛组织向性提供了分子解释。沿着其强大的转导效率，我们的研究结果支持继续开发基于AAV 8的载体用于人类临床应用，特别是用于肿瘤基因治疗。
Adeno-associated virus serotype 8 (AAV8) is currently emerging as a powerful gene transfer vector, owing to its capability to efficiently transduce many different tissues in vivo. While this is believed to be in part due to its ability to uncoat more readily than other AAV serotypes such as AAV2, understanding all the processes behind AAV8 transduction is important for its application and optimal use in human gene therapy. Here, we provide the first report of a cellular receptor for AAV8, the 37/67-kDa laminin receptor (LamR). We document binding of LamR to AAV8 capsid proteins and intact virions in vitro and demonstrate its contribution to AAV8 transduction of cultured cells and mouse liver in vivo. We also show that LamR plays a role in transduction by three other closely related serotypes (AAV2, -3, and -9). Sequence and deletion analysis allowed us to map LamR binding to two protein subdomains predicted to be exposed on the AAV capsid exterior. Use of LamR, which is constitutively expressed in many clinically relevant tissues and is overexpressed in numerous cancers, provides a molecular explanation for AAV8's broad tissue tropism. Along with its robust transduction efficiency, our findings support the continued development of AAV8-based vectors for clinical applications in humans, especially for tumor gene therapy.