Papillomavirus infection interferes with four distinct and dominant levels of intra- and intercellular control of oncogenesis, three of which are based on the induction of apoptosis. Papillomaviruses cause abrogation of the cellular senescence program and interfere with p53-dependent DNA repair or apoptosis triggered by DNA damage. As a result, spontaneous or induced mutations are not eradicated and the transformed state may be established through oncogene activation and tumor suppressor gene inactivation. The interference of papillomaviruses with a recently described p53-independent intercellular control step, in which nontransformed cells induce apoptosis specifically in their transformed neighbouring cells, allows survival of papillomavirus-expressing transformed cells. Finally, p53-dependent hypoxia-triggered apoptosis in microtumors may be overcome by papillomaviruses and thus lead to efficient and rapid tumor progression.

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