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Bat adeno-associated viruses as gene therapy vectors with the potential to evade human neutralizing antibodies

Gene Therapy volume 26, pages 264–276 (2019)Cite this article

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Abstract

The prevalence of adeno-associated virus (AAV) has been investigated in bat populations, but little is known about the biological properties of this virus. In this study, four full-length bat AAV capsid genes were isolated in China, with their amino acid sequences sharing 61% identity with those of AAV2 on average. These capsid genes could package AAV particles in combination with AAV2 rep and ITRs, albeit at a lower efficiency. Bat AAVs could only slightly infect mouse liver but could transduce mouse muscle to some extent after systemic administration with a higher muscle/liver ratio than that of primate AAVs. Bat AAV 10HB showed moderate muscle transduction, similar to that of AAV2, during direct intramuscular injection and, compared with other AAV serotypes, was also relatively efficient in resisting human antibody neutralization after intramuscular injection. Evolutionary analysis revealed a number of codons in bat AAV capsid genes subject to positive selection, with sites corresponding to V259 and N691 in 10HB capsids being localized on the surface of the AAV2 capsid. Mutagenesis studies indicated that the positive selection in bat AAV capsids is driven by their tropism evolution in host species. Taken together, the results of this study indicate that bat AAV 10HB vector has the possible applications for muscular gene therapy, especially in the presence of human AAV neutralizing antibodies.

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Acknowledgements

This work was funded by grants from the National Natural Science Foundation of China (31170157 and 81471776) and the National Science and Technology Major Project of the Ministry of Science and Technology of China (2018ZX09201018-013) to LY and from the National Natural Science Foundation of China (81290341) to ZS. We are grateful to Dr. Xiao Xiao for his constructive advice in the construction and production of bat AAV vectors. We extend our appreciation to Dr. Juan Li for her technical support in intramuscular injection in mice. We are grateful for the localization of selected sites of bat AAV capsid genes on the AAV2 structure by Drs. Lin-Ya Huang and Mavis Agbandje-McKenna, and for the helpful comments on our manuscript provided by Dr. Mario Mietzsch.

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Authors and Affiliations

  1. Department of Cardiology and Laboratory of Gene Therapy for Heart Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, China

    Ya Li, Yunbo Liu, Yuquan Wei & Lin Yang

  2. State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China

    Jialu Li, Zhengli Shi & Haizhou Liu

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  1. Ya Li
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Correspondence to Lin Yang.

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Li, Y., Li, J., Liu, Y. et al. Bat adeno-associated viruses as gene therapy vectors with the potential to evade human neutralizing antibodies. Gene Ther 26, 264–276 (2019). https://doi.org/10.1038/s41434-019-0081-8

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