Interaction between hexon and L4-100K determines virus rescue and growth of hexon-chimeric recombinant Ad5 vectors.
Interaction between hexon and L4-100K determines virus rescue and growth of hexon-chimeric recombinant Ad5 vectors.
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六邻体和 L4-100K 之间的相互作用决定了六邻体嵌合重组 Ad5 载体的病毒拯救和生长。
DOI：
10.1038/srep22464
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发表时间：
2016-03-03
影响因子：
4.6
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Yan J;Dong J;Wu J;Zhu R;Wang Z;Wang B;Wang L;Wang Z;Zhang H;Wu H;Yu B;Kong W;Yu X
重组腺病毒血清型5（rAd 5）载体的免疫原性已显示被主要针对六邻体高变区（HVR）的中和抗体（NAb）抑制。预先存在的免疫可以通过用来自替代腺病毒血清型的HVR替换rAd 5六邻体的HVR来规避。然而，嵌合修饰的rAd 5六邻体HVR往往会导致包装效率低或rAd 5载体增殖低，但相关机制尚不清楚。在这项研究中，产生了几种基于Ad 5的载体，其具有用源自Ad 37和Ad 43的那些HVR精确替换的HVR。我们首先观察到HVR交换的rAd 5载体与rAd 5载体相比显示出更高的重组病毒拯救和生长改善功效，尽管我们和其他小组构建的大多数六邻体嵌合rAd 5载体已被证明是无活力的或生长缺陷的。因此，我们评估了嵌合六邻体的结构稳定性及其与L4- 100 K分子伴侣的相互作用。我们表明，六邻体嵌合Ad 5载体的生存能力不是由于嵌合六邻体的结构稳定性，而是由于L4- 100 K辅助的六邻体成熟。我们的研究结果表明，六邻体和L4- 100 K之间的复杂相互作用将决定六邻体嵌合rAd 5载体的病毒拯救和增殖效率。
The immunogenicity of recombinant adenovirus serotype 5 (rAd5) vectors has been shown to be suppressed by neutralizing antibodies (NAbs) directed primarily against hexon hypervariable regions (HVRs). Preexisting immunity can be circumvented by replacing HVRs of rAd5 hexon with those derived from alternate adenovirus serotypes. However, chimeric modification of rAd5 hexon HVRs tends to cause low packaging efficiency or low proliferation of rAd5 vectors, but the related mechanism remains unclear. In this study, several Ad5-based vectors with precise replacement of HVRs with those derived from Ad37 and Ad43 were generated. We first observed that a HVR-exchanged rAd5 vector displayed a higher efficacy of the recombinant virus rescue and growth improvement compared with the rAd5 vector, although most hexon-chimeric rAd5 vectors constructed by us and other groups have proven to be nonviable or growth defective. We therefore evaluated the structural stability of the chimeric hexons and their interactions with the L4-100K chaperone. We showed that the viability of hexon-chimeric Ad5 vectors was not attributed to the structural stability of the chimeric hexon, but rather to the hexon maturation which was assisted by L4-100K. Our results suggested that the intricate interaction between hexon and L4-100K would determine the virus rescue and proliferation efficiency of hexon-chimeric rAd5 vectors.