Adenovirus-host interactions and in vivo virus targeting

描述（由申请人提供）：腺病毒是很有希望用于人类治疗的载体。具有单个衣壳蛋白修饰的Ad突变体的深刻表型与我们在血管内病毒递送后无法选择性靶向肿瘤细胞之间的显着差异强调了人们对分子途径的冗余和重叠的认识不足，当病毒通过血管内途径递送时，分子途径就会参与。本研究旨在开展全面的机制研究，以确定Ad衣壳的每个主要结构元件在体内介导病毒与肝细胞相互作用中的作用。利用大量先前构建的衣壳修饰Ad向量，我们将分析1)纤维结构的作用；2) penton-host整合素相互作用；3)六元血因子在介导Ad在肝脏捕获和血管内递送后肝细胞转导中的相互作用。在此基础上，我们将构建一种能够逃脱肝脏捕获的肺癌细胞靶向溶瘤Ad载体，并在小鼠模型上评价其抗肿瘤效果。这些研究将极大地提高我们对体内Ad-宿主相互作用机制的理解，并最终导致临床上有用的靶向Ad载体的发展，用于治疗局部和弥散性转移性肿瘤疾病。

DESCRIPTION (provided by applicant): Adenoviruses are promising vectors for therapeutic applications in humans. The striking discrepancy between profound phenotypes of Ad mutants, possessing modifications in individual capsid proteins, and our inability to selectively target tumor cells after intravascular virus delivery underscores poorly appreciated redundancy and overlap of molecular pathways, which become engaged when virus is delivered via intravascular route. This proposal is to conduct comprehensive mechanistic studies to define the contribution of each of the major structural elements of the Ad capsid in mediating virus interaction with liver cells in vivo. Using a large set of previously constructed capsid- modified Ad vectors, we will analyze the role of 1) the fiber structure; 2) the penton-host integrin interactions; and 3) the hexon-blood factor interactions in mediating Ad trapping in the liver and hepatocyte transduction after intravascular Ad delivery. Based on the accumulated data we will 4) construct a lung carcinoma cell-targeted oncolytic Ad vector that escapes trapping by the liver and evaluate its anti-tumor efficacy in a mouse model. These studies will dramatically improve our understanding of the mechanisms governing Ad-host interactions in vivo and will ultimately lead to the development of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases. PUBLIC HEALTH RELEVANCE: Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Despite extensive use in gene transfer applications as well as vaccinations against life threatening infectious agents, Ad's use as an anti-cancer therapeutic is greatly impeded due to poor understanding of the molecular mechanisms that govern virus infectivity and bio-distribution in vivo. Ad liver cell transduction causes clinically significant hepatotoxicity and complicates strategies for Ad targeting to disseminated metastatic tumor cells in vivo. This proposal is to fill the major void in our understanding of Ad interactions with host cells and factors in vivo. These studies will ultimately lead to the development of a first panel of clinically useful targeted Ad vectors for the therapy of localized and disseminated metastatic tumor diseases.