VIVO OF PAPILLOMAVIRUS TRANSFORMING GENES

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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.