• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity
【24h】

Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity

机译：六邻体嵌合体腺病毒血清型5载体规避了先前存在的抗载体免疫

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

A common viral immune evasion strategy involves mutating viral surface proteins in order to evade host neutralizing antibodies. Such immune evasion tactics have not previously been intentionally applied to the development of novel viral gene delivery vectors that overcome the critical problem of anti-vector immunity. Recombinant, replication-incompetent adenovirus serotype 5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens have proved highly immunogenic in preclinical studies(1,2) but will probably be limited by the high prevalence of pre-existing anti-Ad5 immunity in human populations, particularly in the developing world(3-6). Here we show that rAd5 vectors can be engineered to circumvent anti-Ad5 immunity. We constructed novel chimaeric rAd5 vectors in which the seven short hypervariable regions (HVRs) on the surface of the Ad5 hexon protein were replaced with the corresponding HVRs from the rare adenovirus serotype Ad48. These HVR-chimaeric rAd5 vectors were produced at high titres and were stable through serial passages in vitro. HVR-chimaeric rAd5 vectors expressing simian immunodeficiency virus Gag proved comparably immunogenic to parental rAd5 vectors in naive mice and rhesus monkeys. In the presence of high levels of pre-existing anti-Ad5 immunity, the immunogenicity of HVR-chimaeric rAd5 vectors was not detectably suppressed, whereas the immunogenicity of parental rAd5 vectors was abrogated. These data demonstrate that functionally relevant Ad5-specific neutralizing antibodies are focused on epitopes located within the hexon HVRs. Moreover, these studies show that recombinant viral vectors can be engineered to circumvent pre-existing anti-vector immunity by removing key neutralizing epitopes on the surface of viral capsid proteins. Such chimaeric viral vectors may have important practical implications for vaccination and gene therapy.
机译：常见的病毒免疫逃避策略涉及突变病毒表面蛋白，以逃避宿主中和抗体。这种免疫逃避策略以前从未有意应用于克服了抗载体免疫关键问题的新​​型病毒基因递送载体的开发。在临床前研究中已证明用于人类1型免疫缺陷病毒和其他病原体的重组，无复制能力的腺病毒5型血清型（rAd5）载体疫苗具有很高的免疫原性（1,2），但可能会受到现存抗血清高流行性的限制-Ad5在人群中的免疫力，特别是在发展中国家（3-6）。在这里，我们显示rAd5载体可以被工程化以规避抗Ad5免疫。我们构建了新颖的嵌合rAd5载体，其中Ad5六邻体蛋白表面上的七个短高变区（HVR）被来自稀有腺病毒血清型Ad48的相应HVR取代。这些HVR-chimaeric rAd5载体高滴度产生，在体外连续传代过程中稳定。在幼稚的小鼠和恒河猴中，表达猿猴免疫缺陷病毒Gag的HVR嵌合rAd5载体与亲代rAd5载体具有相同的免疫原性。在存在高水平的既存抗Ad5免疫的情况下，HVR-chimaeric rAd5载体的免疫原性没有被检测到抑制，而亲本rAd5载体的免疫原性被废除了。这些数据表明功能相关的Ad5特异性中和抗体集中在六邻体HVR内的表位上。此外，这些研究表明，重组病毒载体可以通过去除病毒衣壳蛋白表面上的关键中和表位来设计，以规避预先存在的抗载体免疫力。此类嵌合病毒载体可能对疫苗接种和基因治疗具有重要的实际意义。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号