DIFFERENTIATION-DEPENDENT UP-REGULATION OF THE HUMAN PAPILLOMAVIRUS E7 GENE REACTIVATES CELLULAR DNA-REPLICATION IN SUPRABASAL DIFFERENTIATED KERATINOCYTES

mRNA transcription, DNA amplification, and progeny production of human papillomaviruses (HPVs) are closely linked to squamous epithelial dif ferentiation in patient papillomas. Because suprabasal, differentiated keratinocytes have exited the cell cycle for days or weeks and becaus e viral DNA synthesis requires the host DNA replication machinery, HPV s must have a mechanism to reactivate the essential host genes. In thi s study, we show via acute recombinant retrovirus infection that an in tact E7 gene of either high-risk or of low-risk HPV genotypes, under t he control of its respective native enhancer-promoter, induced prolife rating cell nuclear antigen (PCNAs) expression in the suprabasal cells of epithelial raft cultures of primary human foreskin keratinocytes ( PHK). The cellular differentiation program was unaltered by the viral oncoprotein; it was essential for high HPV promoter activity. Furtherm ore, extensive host chromosomal DNA replication took place in differen tiated cells of HPV-18 E7-expressing raft cultures and of patient lary ngeal papillomas caused by HPV-6. These results indicate that the main function of the E7 protein is to reactivate host DNA replication mach inery to support viral replication in differentiated, noncycling cells .