Mouse adenovirus type 1 and human adenovirus type 5 differ in endothelial cell tropism and liver targeting.
Mouse adenovirus type 1 and human adenovirus type 5 differ in endothelial cell tropism and liver targeting.
复制标题
小鼠 1 型腺病毒和人 5 型腺病毒在内皮细胞趋向性和肝脏靶向性方面存在差异。
DOI：
10.1002/jgm.1283
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Lenaerts L
中科院分区：
文献类型：
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作者：
Lenaerts L
背景来源于人血清型5（Ad 5）的腺病毒载体，其在非靶组织（主要是肝脏）中的隔离阻碍了血管内递送后的效率和安全性。后者在很大程度上取决于腺病毒与凝血酶原的结合。此外，由于主要科萨基-腺病毒受体（CAR）的低表达，一些靶细胞，如内皮细胞和平滑肌细胞，难以被Ad 5感染。因此，替代腺病毒serotypes正在explored.MethodsIn本研究中，我们评估了小鼠腺病毒1型（MAV-1）的向性，一种非人腺病毒，其细胞附着是CAR-independent.ResultsThe典型的复制MAV-1在内皮细胞中作为体内腺病毒，并没有反映在细胞培养中对原代和连续内皮细胞的附着升高。值得注意的是，MAV-1对原代人平滑肌细胞的亲和力高于重组Ad 5（rAd 5）。生理浓度的人凝血因子XI（FXI）或维生素K依赖性FIX、FX和FVII未改变MAV-1与人和小鼠肝细胞来源细胞的附着。相比之下，FX使Ad 5衍生载体的附着增强至少8倍。使用表面等离子体共振，MAV-1显示与人FX和鼠FX和FIX直接缔合，但与rAd 5相反，这种相互作用不会导致增强的细胞附着。在静脉注射的重症联合免疫缺陷小鼠中，MAV-1在肝脏的分布明显低于rAd 5。结论MAV-1的嗜性数据表明，该病毒可能在基因治疗领域有应用价值。版权所有© 2008约翰威利父子有限公司.
BackgroundFor adenovirus vectors derived from human serotype 5 (Ad5), the efficiency and safety after intravascular delivery is hindered by their sequestration in nontarget tissues, predominantly the liver. The latter is largely dictated by adenovirus binding to blood coagulation zymogens. In addition, several target cells, such as endothelial and smooth muscle cells, are difficult to transduce by Ad5 due to the low expression of the primary coxsackie‐adenovirus receptor (CAR). Therefore, alternative adenovirus serotypes are being explored.MethodsIn the present study, we assessed the tropism of mouse adenovirus type 1 (MAV‐1), a nonhuman adenovirus for which cellular attachment is CAR‐independent.ResultsThe typical replication of MAV‐1 in endothelial cells as observedin vivowas not reflected in elevated attachment to primary and continuous endothelial cells in cell culture. Remarkably, MAV‐1 displayed a higher affinity for primary human smooth muscle cells than recombinant Ad5 (rAd5). Attachment of MAV‐1 to human and mouse cells of hepatocyte origin was not altered by physiological concentrations of human coagulation factor XI (FXI) or the vitamin K‐dependent FIX, FX and FVII. By contrast, attachment of Ad5‐derived vectors was enhanced at least eight‐fold by FX. Using surface plasmon resonance, MAV‐1 was shown to directly associate with human FX and murine FX and FIX but, opposite to rAd5, this interaction did not lead to enhanced cellular attachment. In intravenously injected severe combined immunodeficiency mice, distribution of MAV‐1 to the liver was markedly lower than that observed with rAd5.ConclusionsOur data on the tropism of MAV‐1 suggest that this virus may find utility in the field of gene therapy. Copyright © 2008 John Wiley & Sons, Ltd.