Characterization of human keratinocytes transformed by high risk human papillomavirus types 16 or 18 and herpes simplex virus type 2

Recent reports implicate two DNA tumour viruses, herpes simplex virus type 2 (HSV-2) and human papillomavirus types 16 or 18 (HPV-16 and -18), in the pathogenesis of cervical cancer. Previous studies have indicated that primary human fibroblasts transfected with HPV-16 and HSV-2 morphological transforming region III (mtr III) are more aneuploid than fibroblasts immortalized with HPV- 16 and that HSV-2 DNA sequences are retained in transformed cells. Since HSV-2 and HPV typically infect cells of epithelial origin, the interactions of these viruses with respect to morphological transformation were examined in human keratinocytes. HPV-16- or HPV-18-immortalized keratinocytes (FEPL and FEA cells, respectively) were transfected with fragments derived from HSV-2 mtr III. When compared to their normal counterparts, FEPL cells and FEA cells transfected with mtr III fragment! grew to higher saturation densities and were morphologically transformed. FEPL cells transformed by HSV-2 were capable of growth in soft agar and, when injected into nu/nu mice, lesions developed at the site of injection. Histological examination of the lesions revealed a benign mass which was composed of squamous epithelial cells that were producing keratin. In contrast, immortalized keratinocytes (FEPL or FEA) or FEA cells transfected with HSV-2 did not produce these lesions. These observations suggest that sequences within mtr III can alter the growth properties of human keratinocytes immortalized by HPV- 16 or HPV- 18.