Physical state and biological activity of human papillomavirus genomes in precancerous lesions of the female genital tract.

The DNA of distinct human papillomaviruses (HPVs) is regularly detected in the majority of human cervical carcinomas. In contrast to benign HPV-induced genital lesions, where the viral genomes are exclusively present as episomes, in cervical carcinomas HPV type 16 (HPV16) DNA was found to be integrated into the host DNA. In order to determine the physical state and expression of HPV DNA sequences at different stages of tumour development, we analysed a series of cervical lesions (mild, moderate and severe dysplasia and carcinoma in situ) that are considered precursors of carcinomas of the cervix. In 66.6% (18 of 27) of the tumours, HPV16 DNA was present. While in mild dysplasias only episomal HPV genomes were found, in all higher grade lesions integration of the viral DNA was detected. There was a close correlation between the episomal state and the expression of the HPV16 genomes: in 15 cases harbouring episomal HPV16 DNA (seven of which also contained integrated genomes) viral transcripts were present. We conclude that integration of HPV genomes takes place very early in cervical cancer development. In addition, the episomal state of the viral DNA depends on viral gene expression. The same conclusion, however, is not applicable in those lesions (three severe dysplasias) containing exclusively integrated HPV16 DNA. Thus, HPV16 DNA can persist in an integrated state without recognizable transcriptional activity. These results point to HPV16 as one potential prerequisite for the first steps in the multistage development of human cervical cancer.