Hallmarks of HPV infection include a restricted tropism for human epithelial cells and a viral life cycle tightly linked to the differentiation program of the host keratinocyte. This particular viral cycle has hampered the study of the HPV vegetative life cycle for decades, due to the lack of suitable in-vitro culture conditions. The tissue and differentiation. dependence seems to be dictated by viral transcription rather than viral DNA replication. Indeed, viral transcription is restricted to epithelial cells of human origin, more specifically to keratinocytes. In contrast, HPV genomes can replicate in various undifferentiated cell lines regardless of their natural permissiveness to infection, as long as the viral replication proteins E1 and E2 are expressed. (C) 1997 Academic Press Ltd.