Hartman Zachary C, Appledorn Daniel M, Amalfitano Andrea
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Virus Res. 2008 Mar;132(1-2):1-14. doi: 10.1016/j.virusres.2007.10.005. Epub 2007 Nov 26.
Extensively characterized, modified, and employed for a variety of purposes, adenovirus (Ad) vectors are generally regarded as having great potential by many applied virologists who wish to manipulate and use viral biology to achieve beneficial clinical outcomes. Despite widespread functional prominence and utility (i.e., Ad-based clinical trials have begun to progress to critical Phase III levels, it has recently become apparent that investigations regarding the innate immune response to Ads may reveal not only reasons behind previous failures, but also reveal novel insights that will allow for safer, more efficacious uses of this important gene transfer platform. Insights gained by the exploration of Ad induced innate immune responses will likely be most important to the fields of vaccine development, since Ad-based vaccines are regarded as one of the more promising vaccine platforms in development today. Adenovirus is currently known to interact with several different extracellular, intracellular, and membrane-bound innate immune sensing systems. Past and recent studies involving manipulation of the Ad infectious cycle as well as use of different mutants have shed light on some of the initiation mechanisms underlying Ad induced immune responses. More recent studies using microarray-based analyses, genetically modified cell lines and/or mouse mutants, and advanced generation Ad vectors have revealed important new insights into the scope and mechanism of this cellular defensive response. This review is an attempt to synthesize these studies, update Ad biologists to the current knowledge surrounding these increasingly important issues, as well as highlight areas where future research should be directed. It should also serve as a sobering reality to researchers exploring the use of any gene transfer vector, as to the complexities potentially involved when contemplating use of such vectors for human applications.
腺病毒（Ad）载体经过广泛的特性研究、修饰，并用于多种目的，许多希望操纵和利用病毒生物学来实现有益临床结果的应用病毒学家普遍认为其具有巨大潜力。尽管其具有广泛的功能优势和实用性（即基于腺病毒的临床试验已开始进入关键的III期阶段），但最近人们明显认识到，对腺病毒先天免疫反应的研究不仅可能揭示先前失败的原因，还可能揭示新的见解，从而使这个重要的基因转移平台能够更安全、更有效地使用。通过探索腺病毒诱导的先天免疫反应所获得的见解，可能对疫苗开发领域最为重要，因为基于腺病毒的疫苗被认为是当今正在开发的更有前景的疫苗平台之一。目前已知腺病毒可与几种不同的细胞外、细胞内和膜结合的先天免疫传感系统相互作用。过去和最近涉及操纵腺病毒感染周期以及使用不同突变体的研究，已经揭示了一些腺病毒诱导免疫反应的起始机制。最近使用基于微阵列的分析、基因修饰的细胞系和/或小鼠突变体以及新一代腺病毒载体的研究，揭示了关于这种细胞防御反应的范围和机制的重要新见解。本综述旨在综合这些研究，向腺病毒生物学家更新围绕这些日益重要问题的当前知识，并突出未来研究应指向的领域。对于探索使用任何基因转移载体的研究人员来说，这也应作为一个清醒的现实，让他们认识到在考虑将此类载体用于人类应用时可能涉及的复杂性。
