Modulation of epithelial differentiation by the E6 and E7 oncoproteins of human papillomaviruses

Human papillomaviruses (HPVs) infect squamous epithelial cells of the genital tract and induce a variety of hyperproliferative lesions, including carcinomas. The vegetative viral life cycle is linked closely to epithelial differentiation, with virion production occurring only in highly differentiated suprabasal cells. We have used organotypic cultures to study the effects of HPV gene products on epithelial differentiation. Although E6 and E7 gene products immortalize normal human keratinocytes efficiently in culture, additional cellular mutations are required to induce a complete loss of differentiation capability. These results are consistent with a multistep process in the development of HPV‐associated anogenital malignancies in vivo.