PDF(Pubmed)
Abstract：
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.
摘要：
正在开发来自灵长类动物的腺相关病毒（AAV）血清型，并在临床上用作人类基因治疗的载体。然而,AAV变异的进化机制还远未被理解，除了基因重组起着重要作用。此外，对AAV与其天然宿主之间的相互作用知之甚少，人类和非人类灵长类动物。在这项研究中,对天然AAV衣壳基因进行系统进化分析，重点是AAV谱系多样化过程中的选择驱动。从这些AAV谱系中鉴定出许多正选择的位点,其功能相关性由它们在AAV结构上的定位暗示。在一系列生物学实验中进一步研究了两个AAV2衣壳位点的选择驱动。这些观察结果不支持由来自人CD4+T细胞应答的选择压力驱动的AAV2衣壳的位点410的进化。然而,AAV2衣壳548位点的阳性选择与宿主体液免疫直接相关,因为该位点的突变在个体和群体水平上对AAV变体从人类中和抗体的免疫逃避具有深远的影响.总的来说,这项工作为自然宿主中AAV谱系的遗传多样性和进化提供了新的解释，这可能有助于它们在人类基因治疗中的进一步工程和应用。
