Development of a mouse model to test HPV Antiviral compounds

项目摘要/摘要 乳头瘤病毒(PV)引起称为疣或乳头状瘤的缓慢增殖的上皮性肿瘤。这些是 皮肤、宫颈、生殖器、肛门和口腔粘膜的非常常见的感染。感染的一部分 人类和几种动物的PV可发展为宫颈、肛门和口咽部的恶性肿瘤。 因为人类PV感染被认为是特定物种的，HPV的一个完全代表性的模型 发病机制在普通实验动物中是不存在的。 目前还没有针对早期HPV感染和HPV相关癌症的特效抗病毒疗法。 目前，大多数治疗包括对感染者及其附近的人进行物理销毁或手术切除。 纸巾。在资源匮乏的国家，由于缺乏检测和外科手术的稀缺，导致 人乳头瘤病毒引起的癌症的发病率非常高。对体内系统的测试有一个关键的未满足的需求 旨在消除HPV感染的新疗法。一种用于测试抗病毒药物的易驯服的小鼠模型 专门设计用于中断HPV蛋白活动的药物将对临床前药物产生重大影响 发展。 这项R21拨款中提议的实验将研究HPV-16的表达和维持 小鼠细胞培养和活体小鼠的基因组。将测试几种形式的HPV-16基因组，包括 小鼠乳头瘤病毒基因组的建立，其中天然的E6和E7基因被HPV- 16 E6和E7。这些癌蛋白是病毒基因组复制所必需的，并且总是在 HPV相关的恶性肿瘤，因此是抗病毒靶向的极佳靶点。如果HPV-16是 成功繁殖并在小鼠体内持续感染，这些小鼠模型将是一个重要的 人类临床试验前的进展。此外，这也将是一个有用的调查模式。 HPV癌蛋白在基因组维持和肿瘤进展中的作用。抗病毒治疗 治愈早期和持续的HPV-16感染将降低进展为癌症的风险和负担 这困扰着世界各地的数百万人。

Project Summary/Abstract Papillomaviruses (PV) cause slowly proliferating epithelial tumors called warts or papillomas. These are very common infections of skin and the cervical, genital, anal, and oral mucosa. Infections with a subset of human and several animal PVs can progress to cervical, anogenital, and oropharyngeal malignancies. Because human PV infections are believed to be species specific, a fully representative model of HPV pathogenesis is not available in a common laboratoryanimal. There is no specifically antiviral therapy for early-stage HPV infection and for HPV-associated cancers. Currently, most treatments involve physical destruction or surgical removal of the infected and nearby tissues. In low resource countries, the lack of testing and scarce availability of surgical procedures results in very high prevalence of HPV-induced cancers. There is a critical unmet need for an in vivo system to test novel therapeutics aimed at eliminating HPV infection. A tractable mouse model to test antiviral agents specifically designed to interrupt HPV protein activities would have a major impact on pre-clinical drug development. The experiments proposed in this R21 grant will investigate the expression and maintenance of HPV-16 genomes in murine cell culture and in live mice. Several forms of HPV-16 genomes will be tested, including the creation of a mouse papillomavirus genome in which the native E6 and E7 genes are replaced by HPV- 16 E6 and E7. These oncoproteins are necessary for both viral genome replication and always expressed in HPV-associated malignancies and are therefore excellent targets for antiviral targeting. If HPV-16 is successfully propagated and the infection persists in mice, these murine models would be an important advance before clinical testing in human. Furthermore, this would also serve as a useful model to investigate the functions of HPV oncoproteins in genome maintenance and neoplastic progression. An antiviral treatment that cures early and persistent HPV-16 infections would reduce the risk and burden of progression to cancer that afflicts millions of people throughout the world.