A number of the human papillomaviruses (HPVs) associated with human genital tract lesions were examined for their ability to immortalize cells. Those associated with benign genital warts, such as HPV-6 and HPV-11, did not immortalize foreskin epithelial cells or become integrated after transfection in a suitable vector. Others such as human papillomavirus (HPV)-16, HPV-18, HPV-33, and HPV-35, which are found associated with a high percentage of cervical carcinomas, did immortalize epithelial cells from either the foreskin or exocervical area. The immortalizing ability of HPV-16 is tentatively associated with E6/E7 genes. That immortalization is not due to a rather unusual genetic background of the cells used was demonstrated by utilization of epithelial cells from a number of different individuals, none of whom had any HPV genes in their cells. Furthermore, immortal cervical cells express keratin synthesis identical to that associated with exocervical epithelial cells, proving that the lines immortalized were of exocervical origin. An indepth chromosome analysis of foreskin-derived epithelial cells transfected and immortalized by HPV-16 DNA demonstrated that there were complex translocations, deletions, telomeric associations, achromatic lesions and partial chromosome duplications. Furthermore, integration sites of the viral sequences were localized at the junction of chromosome translocations, at site of achromatic lesions, and within duplicated chromosome segments. In some lines these regions of duplication had integrated HPV-16 near proto-oncogenes such as arq and trk. Furthermore, duplication and amplification of cellular sequences may have originated at nearby fragile sites. HPV-16 integration in the cellular genome is directly responsible for the induction of chromosome alterations and may be an essential step for neoplastic development.
