Adenovirus and coagulation factor interactions and the impact on virus stability and utility for gene therapy

腺病毒是一个相关的病毒家族，可引起人类轻度感染，并通过阻断其在细胞内复制的能力而转化为基因转移载体。这是通过删除病毒的一些DNA来削弱病毒引起感染的能力来实现的。腺病毒家族中最常见的成员是血清型5腺病毒（Ad5）。这使得腺病毒载体可用于基因治疗（利用基因治疗人类疾病）。事实上，腺病毒是基因治疗临床试验中最常用的载体之一，因为它们易于使用，安全且有效地将基因传递到体内的细胞和组织中。除了它们的普遍使用，我们仍在发现与这种病毒有关的新特性，这突出了更好地了解它是多么重要，以便使基因疗法更安全、更有效（即优化它们用于治疗患者的用途）。我们最近发现，当注射到血液中时，血清型5腺病毒会被我们血液中的一种叫做凝血因子的蛋白质包裹。有趣的是，包被的病毒只通过与凝血因子的相互作用将基因传递到肝脏，而不是通过肝脏和病毒之间的直接相互作用（即凝血因子作为细胞和病毒之间的桥梁）。凝血因子“粘”在病毒外壳上一种叫做六邻体的特定蛋白质上。腺病毒家族的一些其他成员也会这样做，而其他成员则不会，这种相互作用产生的原因尚不清楚。其他研究小组也提出，要么是宿主给病毒涂上FX，以帮助免疫系统识别并清除它，要么是病毒本身“拾取”了凝血因子，以保护自己免受免疫系统的攻击。在这个项目中，我们将进一步研究这一重要途径。我们想知道这种相互作用对病毒是否有保护作用，如果有，这种保护作用是否也适用于其他不与凝血因子结合的病毒。这将使我们了解病毒和凝血因子如何与免疫系统的不同部分相互作用。我们还想确切地知道凝血因子是如何将病毒传递到肝脏的，以及修改这一途径是否能导致基因疗法的发展，从而更有效地将病毒传递到肝脏以外的身体其他组织，这将扩大病毒通过基因疗法治疗患者的用途。我们将通过改变病毒外壳的不同部分来研究腺病毒研究的这些领域，以允许或阻止相互作用，我们将使用基因工程方法来实现这些重要的修改。这些实验将有助于我们进一步了解腺病毒，并最终为所有腺病毒基因治疗方法提供更优化和安全的载体。

Adenoviruses are a family of related viruses which cause mild infections in people and which have been converted into gene transfer vectors by blocking their ability to replicate in cells. This is achieved by crippling the ability of the virus to cause infection by deleting some if its DNA. The most common member of the adenovirus family used is adenovirus serotype 5 (Ad5). This allows the adenoviral vector to be used for gene therapy (the use of genes to treat human disease). In fact, adenoviruses are one of the most common vectors in use in gene therapy clinical trials because they are easy to work with, safe and are efficient at delivering genes to cells and tissues in the body. Depsite their common use we are still discovering new properties relating to this virus which highlights how important it is to understand it better in order that gene therapies can be made safer and more efficient (i.e. to optimise their use to treat patients). We made a recent discovery that when injected into the bloodstream adenovirus serotype 5 becomes coated in one of our own proteins in the blood called a coagulation factor. Interestingly, the coated virus then only delivers genes to the liver via the interaction with the coagulation factor and not a direct interaction between the liver and the viru (i.e. the coagulation factor acts as a bridge between the cell and the virus). The coagulation factor "sticks" to a specific protein on the coat of the virus called the hexon. Some other members of the adenovirus family also do this while others do not and the reason why this interaction has arisen is not well understood. Other groups have also suggested that either the host coats the virus with FX in order to help the immune system recognise it and remove it, while others have suggested that the virus itself "picks up" the coagulation factor to protect itself from the immune system. In this project we are going to investigate this important pathway further. We want to know whether the interaction is protective or not for the virus and if it is, whether the protection can be conferred to other viruses which do not bind to the coagulation factor. This will lead us to an understanding of how the virus and coagulation factor interact with different parts of our immune system. We also want to know exactly how the coagulation factor delivers the virus to the liver and whether modifying this pathway can lead to the development of gene therapies which are more efficient at delivering to other tissues in the body other than the liver, and this will broaden the use of the virus for treating patients through gene therapy. We will investigate these areas of adenovirus research by making changes to different parts of the virus's coat in order to allow or block the interactions and we will use genetic engineering approaches to achieve these important modifications. These experiments will help our further understanding of adenoviruses and ultimately lead to more optimal and safe vectors for all adenoviral gene therapy approaches.