Structure of adeno-associated virus serotype 8, a gene therapy vector
Structure of adeno-associated virus serotype 8, a gene therapy vector
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DOI：
10.1128/jvi.01304-07
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Agbandje-McKenna, Mavis
中科院分区：
文献类型：
--
作者：
Nam, Hyun-Joo;Lane, Michael Douglas;Agbandje-McKenna, Mavis
腺相关病毒（Adeno-associated virus, aav）作为基因治疗载体正在被开发，通过对其病毒衣壳结构的详细了解可以提高其治疗效果。AAV血清型8 （AAV8）显示出比其他血清型更大的肝脏转导效率，这导致人们努力开发该病毒作为血友病a和家族性高胆固醇血症的基因治疗载体。假分型研究表明，aav表现出不同的组织趋向性和转导效率是由于其衣壳病毒蛋白（VP）氨基酸的差异。为了确定支撑这些差异的结构特征，我们报告了以2.6埃分辨率确定的AAV8病毒衣壳的晶体结构。其共同重叠VP的整体拓扑结构与先前报道的AAV2和AAV4的晶体结构相似，具有8链p -桶和p -链之间的长环。AAV8和AAV2（最具特征的血清型）之间最显著的结构差异位于衣壳表面围绕二、三、五重轴的突起，据报道，这些残基控制着AAV2的转导效率和抗体识别。此外，对AAV8和AAV2衣壳表面氨基酸的比较显示，AAV8在定位的AAV2硫酸肝素受体结合区域的碱性电荷分布减少，这与观察到的AAV8非肝素结合表型一致。因此，这种AAV8结构为诱变工作提供了一个额外的平台，以表征AAV衣壳区域，这些区域负责这些有前途的基因治疗载体的差异细胞趋向性、转导和抗原性。
Adeno-associated viruses (AAVs) are being developed as gene therapy vectors, and their efficacy could be improved by a detailed understanding of their viral capsid structures. AAV serotype 8 (AAV8) shows a significantly greater liver transduction efficiency than those of other serotypes, which has resulted in efforts to develop this virus as a gene therapy vector for hemophilia A and familial hypercholesterolemia. Pseudotyping studies show that the differential tissue tropism and transduction efficiencies exhibited by the AAVs result from differences in their capsid viral protein (VP) amino acids. Towards identifying the structural features underpinning these disparities, we report the crystal structure of the AAV8 viral capsid determined to 2.6-angstrom resolution. The overall topology of its common overlapping VP is similar to that previously reported for the crystal structures of AAV2 and AAV4, with an eight-stranded P-barrel and long loops between the P-strands. The most significant structural differences between AAV8 and AAV2 (the best-characterized serotype) are located on the capsid surface at protrusions surrounding the two-, three-, and fivefold axes at residues reported to control transduction efficiency and antibody recognition for AAV2. In addition, a comparison of the AAV8 and AAV2 capsid surface amino acids showed a reduced distribution of basic charge for AAV8 at the mapped AAV2 heparin sulfate receptor binding region, consistent with an observed non-heparin-binding phenotype for AAV8. Thus, this AAV8 structure provides an additional platform for mutagenesis efforts to characterize AAV capsid regions responsible for differential cellular tropism, transduction, and antigenicity for these promising gene therapy vectors.