Differential immunogenicity between HAdV-5 and chimpanzee adenovirus vector ChAdOx1 is independent of fiber and penton RGD loop sequences in mice.
Differential immunogenicity between HAdV-5 and chimpanzee adenovirus vector ChAdOx1 is independent of fiber and penton RGD loop sequences in mice.
复制标题
DOI：
10.1038/srep16756
复制
发表时间：
2015-11-18
影响因子：
4.6
通讯作者：
Cottingham MG
中科院分区：
文献类型：
--
作者：
Dicks MD;Spencer AJ;Coughlan L;Bauza K;Gilbert SC;Hill AV;Cottingham MG
复制缺陷型腺病毒是一种很有前途的疫苗抗原载体。然而，载体引发转基因特异性适应性免疫应答的潜力在很大程度上取决于所使用的病毒血清型。在小鼠中，HAdV-5（人腺病毒C）载体比来自人腺病毒E（ChAdOx 1和AdC 68）的黑猩猩腺病毒载体更具免疫原性，尽管对这些免疫原性差异的机制仍知之甚少。在这项研究中，上级免疫原性与体内显著更高水平的转基因表达相关，特别是在引流淋巴结内。为了研究导致这些表型的病毒因素，我们通过将报道主要参与细胞进入的病毒衣壳的组分与来自HAdV-5的相应序列交换来产生重组ChAdOx 1载体。值得注意的是，用HAdV-5纤维和/或五邻体RGD环的假型化对体内转基因表达或转基因特异性适应性免疫应答几乎没有影响，尽管这些组分中存在相当大的物种特异性序列异质性。我们的研究结果表明，在小鼠肌内给药后，载体转导的机制可能与体外所述的不同。
Replication defective adenoviruses are promising vectors for the delivery of vaccine antigens. However, the potential of a vector to elicit transgene-specific adaptive immune responses is largely dependent on the viral serotype used. HAdV-5 (Human adenovirus C) vectors are more immunogenic than chimpanzee adenovirus vectors from species Human adenovirus E (ChAdOx1 and AdC68) in mice, though the mechanisms responsible for these differences in immunogenicity remain poorly understood. In this study, superior immunogenicity was associated with markedly higher levels of transgene expression in vivo, particularly within draining lymph nodes. To investigate the viral factors contributing to these phenotypes, we generated recombinant ChAdOx1 vectors by exchanging components of the viral capsid reported to be principally involved in cell entry with the corresponding sequences from HAdV-5. Remarkably, pseudotyping with the HAdV-5 fiber and/or penton RGD loop had little to no effect on in vivo transgene expression or transgene-specific adaptive immune responses despite considerable species-specific sequence heterogeneity in these components. Our results suggest that mechanisms governing vector transduction after intramuscular administration in mice may be different from those described in vitro.