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Abstract

β human papillomaviruses (HPV) are subdivided into five species and are abundantly detected in the skin, in particular the β1 and β2 species. Therefore, β HPV types are considered to have a cutaneous tropism. However, several recent studies have described the presence of β HPV also in the mucosal epithelia at different anatomical sites. In particular, β3 HPV types are more prevalent in certain mucosal epithelia rather than in the cutaneous tissues. Studies in different experimental models have also highlighted that β3 HPV49 share functional similarities with the mucosal high-risk (HR) HPV16. However, with the exclusion of HPV49, very little is known about the biology of the other known β3 HPV types (75, 76 and 115). The aim of this thesis was the characterization of the biological properties of E6 and E7 of all known β3 HPV types, in relation to their interaction with key cellular pathways such as pRb, p53 and hTERT. Similar to what was previously showed for HPV49 E6/E7, HPV75 and HPV76 E6 and E7, but not HPV115 E6 and E7, efficiently cooperate in the immortalization/extension of lifespan of human foreskin keratinocytes (HFKs). In detail, HPV49, 75 and 76 E6/E7 cause the accumulation of the phosphorylated form of pRb, leading to the release of the E2F factor and unscheduled S-phase entry. As observed for HR HPV16, cell cycle deregulation mediated by β3 HPV onco-proteins leads to p16INK4a accumulation, while no p16INK4a was detected in β2 HPV38 E6/E7 HFKs. Similarly to HPV49 E6, HPV75 and 76 E6s degrade p53 via an E6AP/proteasome-mediated mechanism. Mutation in HPV76 E6 amino-acids that correspond to HPV16 E6 amino-acids involved in the formation of the E6/E6AP/p53 ternary complex results in the failed immortalization of HFKs. All the β3 HPV types, with the exception of HPV115, induce the up-regulation of hTERT expression, another important step in cellular transformation. Comparative analysis of cellular gene expression pattern of HFKs expressing E6 and E7 from HR HPV16, β3 HPV types and β2 HPV38 further highlights the functional similarities of HR HPV16 and β3 HPV49, 75, 76. The expression profiles of these four HPV HFKs show some similarities and diverge substantially from β3 HPV115 E6/E7 and β2 HPV38 E6/E7 HFKs. In conclusion, the data show that β3 HPV types share some similarities with HR HPV types and pave the way to additional studies aiming to evaluate their tissue tropism and their role in human pathologies.