Adeno-associated viruses (AAVs) are widespread among vertebrates. AAVs isolated from bats display low capsid protein sequence identities (<60%) to AAV2, AAV5, and other primate AAVs. Here we report the first capsid structure of a non-primate AAV which was isolated from bats. The capsid structure of BtAAV-10HB (10HB) was determined by cryo-electron microscopy and three-dimensional image reconstruction to 3.03 Å resolution. Comparison of empty and genome-containing capsids showed that the capsid structures are almost identical except for an ordered nucleotide in a previously described nucleotide-binding pocket, the density in the 5-fold channel, and several amino acids with altered side chain conformations. Compared to other dependoparvoviruses, for example AAV2 and AAV5, 10HB displays unique structural features including insertions and deletions in capsid surface loops. Overall, the 10HB capsid structure superposes with an RMSD of 1.7 Å and 1.8 Å to AAV2 and AAV5, respectively. Currently all approved AAV human gene therapy biologics and vectors in clinical trials are based on primate isolates. However, pre-existing neutralizing antibodies in the human population represents a hurdle to their use. 10HB capsids are capable of packaging AAV2 vector genomes and thus have potential as gene delivery vectors. Significantly, a screen with human sera showed lack of recognition by the 10HB capsid. Thus, the different capsid surface of 10HB vectors likely renders it “invisible” to potential pre-existing neutralizing human anti-AAV antibodies especially because this virus or similar variants do not exist in primate populations.

腺相关病毒 (AAV) 在脊椎动物中广泛存在。从蝙蝠中分离出的 AAV 与 AAV2、AAV5 和其他灵长类动物 AAV 的衣壳蛋白序列同一性较低 (<60%)。在这里，我们报告了从蝙蝠中分离出来的第一个非灵长类 AAV 的衣壳结构。BtAAV-10HB (10HB) 的衣壳结构由冷冻电子显微镜和三维图像重建确定，分辨率为 3.03 Å。空衣壳和含有基因组的衣壳的比较表明，衣壳结构几乎相同，除了先前描述的核苷酸结合口袋中的有序核苷酸、5 倍通道中的密度以及侧链构象改变的几个氨基酸。与其他依赖性细小病毒相比，例如 AAV2 和 AAV5，10HB 显示出独特的结构特征，包括衣壳表面环中的插入和缺失。总体而言，10HB 衣壳结构与 AAV2 和 AAV5 的 RMSD 分别叠加为 1.7 Å 和 1.8 Å。目前临床试验中所有批准的 AAV 人类基因治疗生物制剂和载体都是基于灵长类分离株。然而，人群中预先存在的中和抗体是它们使用的障碍。10HB 衣壳能够包装 AAV2 载体基因组，因此具有作为基因传递载体的潜力。值得注意的是，带有人血清的屏幕显示 10HB 衣壳无法识别。因此，