While high-risk human papillomaviruses (HPVs) have been identified as necessary risk factors for the development of cervical cancer (7), the role of HPV in skin cancer, which is the most common cancer in Caucasians, is still undefined (3, 23). A first link between papillomaviruses and skin cancer was obtained in 1935 from an animal model system, when Rous and Beard (40) described the development of squamous cell carcinomas (SCCs) in rabbits after experimental infection with cottontail rabbit papillomavirus (CRPV). Initial benign warts develop into invasively growing SCCs without any further cocarcinogens within 6 to12 months in the vast majority of the animals (50). A similar situation has been described for humans, where in the rare genetic disorder epidermodysplasia verruciformis, patients develop flat HPV-induced warts which progress in up to 60% of the cases into mostly primary SCCs (36, 37). Skin cancer has also been recognized as a common side effect in long-term-immunosuppressed patients, who have a 65-fold-increased risk for this disease. Shortly after the onset of immunosuppressive therapy, HPV-induced warts develop, and after 20 years of immunosuppression, nonmelanocytic skin cancer can be found in up to 70% of the patients (8). As in the case of epidermodysplasia verruciformis patients, the lesions seem to progress from warts through dysplastic lesions into SCC (4,16,43). Although HPV-associated SCCs have been found in 65% (43) or 81% (4) of the cases, the mechanisms leading to the development of skin cancer and especially the role of papillomaviruses are not yet fully understood.Thus far, the only model system for studying the progression of papillomavirus-induced skin tumors is the domestic rabbit infected with CRPV. Infection of domestic rabbits with CRPV particles or viral DNA leads to the development of local tumors within 3 to 6 weeks postinfection. These papillomas progress within 6 to 12 months in more than 80% of the cases into invasively growing and finally metastasizing carcinomas (45; S. Jeckel, unpublished data). Only in very few individual rabbits do papillomas persist in the benign state, and even fewer regress. This progressive behavior does not depend on any other known cofactor besides the viral infection, which makes CRPV an important model for papillomavirus-associated skin disorders in order to study the role of viral and cellular gene expression during cancer development.Earlier studies using more descriptive methods, such as RNA-RNA in situ hybridization, showed no pronounced qualitative or quantitative changes in viral gene expression during malignant progression (50). The primary target cells localized in the bulge region of hair follicles already revealed rather high expression of E6 and E7 mRNAs (42), which remains a constant feature from papillomas through carcinomas to lung metastases (50, 52). Therefore it seems most likely that alterations