STUDIES IN VIVO OF PAPILLOMAVIRUS TRANSFORMING GENES

感染人乳头瘤病毒（HPV）已被牵连， 三种人类癌症，包括宫颈癌，第二种 是全世界女性最常见的癌症。 相当多的证据已 积累了对病毒和肿瘤的免疫反应 在乳头瘤病毒感染的个体中产生抗原。 HPV引起的疾病的调查受到缺乏 一个好的动物模型。 因为乳头瘤病毒 特别是物种特异性，疾病不能直接诱导， 感染任何HPV的动物 良好动物模型的可用性 这将是非常有利的，因为它将允许详细的长期 研究恶性进展的分子机制， 宿主介导的退化 动物模型将进一步允许 治疗方法的发展，最终疫苗的发展。 在本申请中，我们提出开发一种改进的动物模型， 利用现有棉尾兔进行HPV感染的研究 乳头瘤病毒（CRPV）系统，其中恶性进展的系统 并且对PV诱导的疣的免疫应答已被最好地记录。 的 CRPV模型密切模拟HPV诱导的疾病的情况。 我们 该方法侧重于使用CRPV/HPV嵌合体，其中个体 CRPV转化基因将被其HPV对应物取代。 这些嵌合病毒基因组将被引入上皮细胞， 活的近交系兔子，从而克服了以前的缺点， CRPV系统。 我们将研究这些嵌合体诱导 乳头状瘤和癌，并在体内复制。 我们将建立 从病变发展为癌的连续细胞系，我们 将确定宿主免疫系统在这些过程中的作用。

Infection with human papillomaviruses (HPVs) has been implicated in three kinds of human cancer, including cervical carcinoma, the second most common cancer in women world-wide. Considerable evidence has accumulated that immune reactions to both virus and tumor associated antigens develop in individuals with papillomavirus infections. Investigations of HPV induced disease have been hampered by of the lack of a good animal model. Because the papillomaviruses are extraordinarily species specific, disease cannot be directly induced in animals with any of the HPVs. The availability of a good animal model would be extremely advantageous as it would allow detailed long-term investigation into the molecular mechanisms of malignant progression and of host-mediated regression. An animal model would further permit the development of therapies and eventually vaccines. In this application we propose to develop an improved animal model for the study of HPV infections based on the existing cottontail rabbit papillomavirus (CRPV) system, the system in which malignant progression and immune response to PV-induced warts has been best documented. The CRPV model closely mimics the situation for HPV-induced disease. Our approach focuses on the use of CRPV/HPV chimeras in which individual CRPV transforming genes will be replaced by their HPV counterparts. These chimeric viral genomes will be introduced into the epithelium of live inbred rabbits and thereby overcome previous disadvantages of the CRPV system. We will study the ability of these chimeras to induce papillomas and carcinomas and to replicate in vivo. We will establish continuous cell lines from lesions that progress to carcinoma, and we will identify the role of the host immune system in these processes.