The relevance of coagulation factor X protection of adenoviruses in human sera.
The relevance of coagulation factor X protection of adenoviruses in human sera.
复制标题
凝血因子X保护腺病毒在人血清中的相关性。
DOI：
10.1038/gt.2016.32
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发表时间：
2016-07
期刊：
影响因子：
5.1
通讯作者：
Baker AH
中科院分区：
文献类型：
--
作者：
Duffy MR;Doszpoly A;Turner G;Nicklin SA;Baker AH
腺病毒的静脉内递送是许多基因治疗应用的最佳途径。一旦进入血液，凝血因子X（FX）与腺病毒衣壳结合，并保护病毒粒子免受小鼠中天然抗体和经典补体介导的中和作用。然而，到目前为止，还没有研究在人类样本中检查这种FX/病毒免疫保护机制的相关性。在这项研究中，我们评估了在人血清存在下阻断FX对5型腺病毒（Ad 5）活性的影响。FX阻止人IgM直接与病毒结合。在个体人血清样品（n=25）中，仅当Ad 5-FX相互作用被阻断时，筛选的样品中约有一半抑制腺病毒转导，表明FX保护病毒免于中和大比例人血清中的组分。相反，测试的其余血清对Ad 5转导没有抑制作用，并且有效的基因转移不需要FX装备。在FX具有保护作用的人血清中，在FX存在下，Ad 5诱导较低水平的补体激活。因此，我们第一次证明了Ad-FX保护在人类样本中的重要性，并强调了受试者的变异性和物种特异性差异是腺病毒基因治疗的关键考虑因素。
Intravenous delivery of adenoviruses is the optimal route for many gene therapy applications. Once in the blood, coagulation factor X (FX) binds to the adenovirus capsid and protects the virion from natural antibody and classical complement-mediated neutralisation in mice. However, to date, no studies have examined the relevance of this FX/viral immune protective mechanism in human samples. In this study, we assessed the effects of blocking FX on adenovirus type 5 (Ad5) activity in the presence of human serum. FX prevented human IgM binding directly to the virus. In individual human sera samples (n=25), approximately half of those screened inhibited adenovirus transduction only when the Ad5–FX interaction was blocked, demonstrating that FX protected the virus from neutralising components in a large proportion of human sera. In contrast, the remainder of sera tested had no inhibitory effects on Ad5 transduction and FX armament was not required for effective gene transfer. In human sera in which FX had a protective role, Ad5 induced lower levels of complement activation in the presence of FX. We therefore demonstrate for the first time the importance of Ad–FX protection in human samples and highlight subject variability and species-specific differences as key considerations for adenoviral gene therapy.