Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses.
Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses.
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DOI：
10.1016/j.jconrel.2012.05.025
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发表时间：
2012-12-28
期刊：
影响因子：
--
通讯作者：
Baker AH
中科院分区：
文献类型：
--
作者：
Bradshaw AC;Coughlan L;Miller AM;Alba R;van Rooijen N;Nicklin SA;Baker AH
腺病毒血清5型（Ad5）载体在临床环境中的使用受到严重阻碍，因为在血管内递送后观察到严重的肝脏趋向性，以及这些载体引发的明显的炎症和先天免疫反应。循环Ad5病毒粒子的肝脏转导是由衣壳六元蛋白和血凝因子X （FX）之间的高亲和力相互作用介导的，而penton - α - vintegrin相互作用被认为有助于诱导抗Ad5炎症和先天免疫反应。为了克服这些限制，我们试图开发并首次描述具有破坏hexon:FX和penton:integrin相互作用的突变的新型Ad5载体。正如预期的那样，与Ad5相比，FX结合消融的Ad5HVR5*HVR7*E451Q载体（AdT*）血管内给药可显著降低体内肝脏转导。在巨噬细胞缺失的小鼠中，脾脏对AdT*摄取的增加伴随着几种炎症介质水平的升高。然而，在AdT*载体背景（AdT*RGE）中，切除五边形RGD基序导致脾脏摄取显著减少5倍，并减弱抗病毒炎症反应。与亲代Ad5载体相比，在动物血管内注射Ad5RGE后，也观察到脾脏摄取和炎症激活减少，病毒β -半乳糖苷酶转基因与MAdCAM-1 +窦壁内皮细胞的共定位减少。我们对这些新型腺病毒的详细评估表明，penton碱基RGE突变联合FX结合消融可能是一种可行的策略，可以减轻血管内递送后对Ad5载体的不希望的肝脏摄取和促炎反应。
The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton–αvintegrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions. As expected, intravascular administration of the FX binding-ablated Ad5HVR5*HVR7*E451Q vector (AdT*) resulted in significantly reduced liver transduction in vivo compared to Ad5. In macrophage-depleted mice, increased spleen uptake of AdT* was accompanied by an elevation in the levels of several inflammatory mediators. However ablation of the penton RGD motif in the AdT* vector background (AdT*RGE) resulted in a significant 5-fold reduction in spleen uptake and attenuated the antiviral inflammatory response. A reduction in spleen uptake and inflammatory activation was also observed in animals after intravascular administration of Ad5RGE compared to the parental Ad5 vector, with reduced co-localisation of the viral beta-galactosidase transgene with MAdCAM-1 + sinus-lining endothelial cells. Our detailed assessment of these novel adenoviruses indicates that penton base RGE mutation in combination with FX binding-ablation may be a viable strategy to attenuate the undesired liver uptake and pro-inflammatory responses to Ad5 vectors after intravascular delivery.
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DOI：
10.1083/jcb.200112067
发表时间：
2002-09-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Meier O;Boucke K;Hammer SV;Keller S;Stidwill RP;Hemmi S;Greber UF
通讯作者：
Greber UF
影响因子：
12.4
作者：
Di Paolo, Nelson C.;van Rooijen, Nico;Shayakhmetov, Dmitry M.
通讯作者：
Shayakhmetov, Dmitry M.
影响因子：
5.4
作者：
Duffy, Margaret R.;Bradshaw, Angela C.;Baker, Andrew H.
通讯作者：
Baker, Andrew H.
DOI：
10.3390/v2102290
发表时间：
2010-10
期刊：
Viruses
影响因子：
--
作者：
Coughlan L;Alba R;Parker AL;Bradshaw AC;McNeish IA;Nicklin SA;Baker AH
通讯作者：
Baker AH
影响因子：
5.1
作者：
Alemany, R;Curiel, DT
通讯作者：
Curiel, DT