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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism
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Propagation of infectious human papillomavirus type 16 by using an adenovirus and Cre/LoxP mechanism

机译：利用腺病毒和Cre / LoxP机制传播16型传染性人乳头瘤病毒

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摘要

Human papillomavirus type 16 (HPV16) infection is a major risk factor for the development of squamous cell cancers of the cervix and of the head and neck. A major barrier to understanding the progression from initial infection to cancer has been the lack of in vitro models that allow infection, replication, and persistence of the viral genome as an episome in differentiated epithelial cells. To overcome this barrier, we designed an adenoviral delivery vector that contained a full HPV16 genome flanked by LoxP homologous recombination sites and a fluorescent reporter that was expressed only after the HPV genome was excised by Cre recombinase. This system delivered circular HPV16 genomes to cervical epithelial cells and well differentiated human airway epithelia. After delivery, the HPV16 genome replicated and persisted as an episome in cervical keratinocytes. These cells developed an immortalized phenotype and a dysplastic epithelial appearance. Moreover, induction of differentiation led to the expression of late genes and production of infectious HPV16 virions. This work provides a means of introducing biologically active HPV genomes into epithelial cells, which are normally difficult to transfect. These methods allow the study of HPV genome replication and gene expression in the earliest stages of HPV genome establishment, and they may provide a means to study nononcogenic HPV viral types.
机译：16型人乳头瘤病毒（HPV16）感染是宫颈和头颈部鳞状细胞癌发展的主要危险因素。理解从初始感染到癌症进展的主要障碍是缺乏体外模型，该模型不能使病毒基因组作为游离体在分化的上皮细胞中进行感染，复制和持续存在。为了克服这一障碍，我们设计了一个腺病毒递送载体，该载体包含一个完整的HPV16基因组，该基因组侧翼为LoxP同源重组位点，并且一个荧光报告基因仅在HPV基因组被Cre重组酶切除后才表达。该系统向宫颈上皮细胞和分化良好的人气道上皮细胞传递了环状HPV16基因组。交付后，HPV16基因组复制并作为附加体在宫颈角质形成细胞中持续存在。这些细胞表现出永生的表型和发育异常的上皮外观。此外，分化的诱导导致晚期基因的表达和感染性HPV16病毒体的产生。这项工作提供了一种将具有生物学活性的HPV基因组引入通常难以转染的上皮细胞的方法。这些方法允许在HPV基因组建立的最早阶段研究HPV基因组复制和基因表达，它们可以为研究非致癌性HPV病毒类型提供一种手段。

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