Development of a mouse model to test HPV Antiviral compounds

项目总结/摘要 乳头状瘤病毒（PV）引起称为疣或乳头状瘤的缓慢增殖的上皮肿瘤。这些是 非常常见的皮肤和宫颈、生殖器、肛门和口腔粘膜感染。感染的一个子集 人类和几种动物PV可发展为宫颈、肛门生殖器和口咽恶性肿瘤。 因为人类PV感染被认为是种属特异性的，所以HPV的完全代表性模型 发病机制在普通实验室动物中是不可用的。 对于早期HPV感染和HPV相关癌症没有特异性抗病毒治疗。 目前，大多数治疗方法包括物理破坏或手术切除感染者和附近的 组织中在低资源国家，缺乏测试和外科手术的稀缺性导致 HPV引起的癌症发病率非常高。对体内系统进行测试的关键需求尚未得到满足 旨在消除HPV感染的新疗法。一种用于测试抗病毒药物的易处理小鼠模型 专门设计用于中断HPV蛋白活性的药物将对临床前药物治疗产生重大影响， 发展 这项R21资助计划中提出的实验将研究HPV-16的表达和维持。 小鼠细胞培养物和活小鼠中的基因组。将测试几种形式的HPV-16基因组，包括 产生小鼠乳头瘤病毒基因组，其中天然E6和E7基因被HPV替换- 16 E6和E7。这些癌蛋白是病毒基因组复制所必需的，并且总是在细胞中表达。 HPV相关的恶性肿瘤，因此是抗病毒靶向的极好靶点。如果HPV-16是 成功地繁殖和感染持续在小鼠中，这些小鼠模型将是一个重要的 在人类临床试验之前。此外，这也将作为一个有用的模式，以调查 HPV癌蛋白在基因组维持和肿瘤进展中的功能。抗病毒治疗 治愈早期和持续的HPV-16感染将降低癌症进展的风险和负担 影响着全世界数百万人的疾病

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.