机构：[1]Department of Cardiology and Laboratory of Gene Therapy for Heart Diseases, State Key Laboratory of Biotherapy, and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[2]Department of Biochemistry and Molecular Biology, Center for Structural Biology, The McKnight Brain Institute, University of Florida, Gainesville, Florida, United States of America.[3]General Surgery Department, Gastric Cancer Center and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[4]State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[5]Center for Immunology and Hematology, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[6]Computational Virology Group, Center for Bacteria and Viruses Resources and Bioinformation, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.[7]Department of Emergency Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院[8]Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.四川大学华西医院
Adeno-associated virus (AAV) serotypes from primates are being developed and clinically used as vectors for human gene therapy. However, the evolutionary mechanism of AAV variants is far from being understood, except that genetic recombination plays an important role. Furthermore, little is known about the interaction between AAV and its natural hosts, human and nonhuman primates. In this study, natural AAV capsid genes were subjected to systemic evolutionary analysis with a focus on selection drives during the diversification of AAV lineages. A number of positively selected sites were identified from these AAV lineages with functional relevance implied by their localization on the AAV structures. The selection drives of the two AAV2 capsid sites were further investigated in a series of biological experiments. These observations did not support the evolution of the site 410 of the AAV2 capsid driven by selection pressure from the human CD4+ T-cell response. However, positive selection on site 548 of the AAV2 capsid was directly related to host humoral immunity because of the profound effects of mutations at this site on the immune evasion of AAV variants from human neutralizing antibodies at both the individual and population levels. Overall, this work provides a novel interpretation of the genetic diversity and evolution of AAV lineages in their natural hosts, which may contribute to their further engineering and application in human gene therapy.Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
基金：
This work was funded by the National
Natural Science Foundation of China (31170157
and 81471776) to L.Y., the National Science and
Technology Major Project of the Ministry of
Science and Technology of China
(2018ZX09201018-013) to X.Z. and L.Y., the
National Natural Science Foundation of China
(U19A2002) to L.Y., the National Key Research and Development Program of China
(2023YFC3403301) to L.Y., and the National
Institutes of Health (NIH) grant (R01 GM082946)
to R.M. The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类|1 区医学
小类|1 区微生物学1 区寄生虫学1 区病毒学
第一作者：
第一作者机构：[1]Department of Cardiology and Laboratory of Gene Therapy for Heart Diseases, State Key Laboratory of Biotherapy, and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Li Lirong,Qin Runkuan,Liu Yunbo,et al.Dissecting positive selection events and immunological drives during the evolution of adeno-associated virus lineages[J].Plos Pathogens.2024,20(6):e1012260.doi:10.1371/journal.ppat.1012260.
APA：
Li Lirong,Qin Runkuan,Liu Yunbo,Tseng Yu-Shan,Zhang Weihan...&Yang Lin.(2024).Dissecting positive selection events and immunological drives during the evolution of adeno-associated virus lineages.Plos Pathogens,20,(6)
MLA：
Li Lirong,et al."Dissecting positive selection events and immunological drives during the evolution of adeno-associated virus lineages".Plos Pathogens 20..6(2024):e1012260
医学