STUDIES IN VIVO OF PAPILLOMAVIRUS TRANSFORMING GENES

人类乳头瘤病毒(HPV)感染与 人类癌症有三种，包括宫颈癌，第二种 全世界女性中最常见的癌症。相当多的证据表明 积累了对病毒和肿瘤相关的免疫反应 乳头瘤病毒感染者体内会产生抗原。 人类乳头状瘤病毒引起的疾病的研究由于缺乏 一个好的动物模型。因为乳头瘤病毒是 特殊的物种特异性，疾病不能直接在 携带任何HPV的动物。一个好的动物模型的可用性 将是非常有利的，因为它将允许详细的长期 恶性肿瘤发生发展的分子机制研究进展 宿主介导的回归。动物模型将进一步允许 开发治疗方法，并最终开发疫苗。 在本申请中，我们建议开发一种改进的动物模型，用于 基于现有棉尾兔的人乳头瘤病毒感染研究 乳头瘤病毒(CRPV)系统，在该系统中恶性进展 对PV引起的尖锐湿疣的免疫反应也得到了最好的记录。这个 CRPV模型与人乳头瘤病毒(HPV)诱导的疾病情况非常接近。我们的 方法侧重于使用CRPV/HPV嵌合体，其中个体 CRPV转化基因将被其对应的HPV基因取代。 这些嵌合的病毒基因组将被引入到人的上皮细胞中 活的近交兔，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 从病变发展到癌症的连续细胞系，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.