IMMUNOLOGICAL RESPONSES IN HUMAN PAPILLOMAVIRUS-16 E6 E7-TRANSGENIC MICE TO E7 PROTEIN CORRELATE WITH THE PRESENCE OF SKIN-DISEASE/

The human papillomavirus (HPV) oncogenes, E6 and E7, are believed to c ontribute to the development of cervical cancers in women infected wit h certain HPV genotypes, most notably HPV-16 and HPV-18. Given their e xpression in tumor tissue, E6 and E7 have been implicated as potential tumor-specific antigens. We have examined an HPV-16 E6- and E7-transg enic mouse lineage for immune responses to these viral oncoproteins. M ice in this lineage express the HPV-16 E6 and E7 genes in their skin a nd eyes, and on aging, these mice frequently develop squamous cell car cinomas and lenticular tumors. Young transgenic mice, which had measur able E7 protein in the eye but not in the skin, were immunologically n aive to E7 protein. They mounted an immune response to E7 on immunizat ion comparable to that of nontransgenic controls, suggesting a lack of immune tolerance to this protein. Older line 19 mice, which are susce ptible to skin disease associated with transcription of the E6 and E7 open reading frames, had measurable E7 protein in their skin. These ol der transgenic mice spontaneously developed antibody responses to endo genous E7 protein, particularly in association with skin disease. Also detected in older mice were delayed-type hypersensitivity responses t o E7. These finding parallel the humoral immune response to E7 protein in patients with HPV-associated cervical cancer and suggest that line 19 mice may provide a model for studying the immunobiology of HPV-ass ociated cancers.