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3 human papillomavirus species share several biological properties with high risk mucosal types

Minoni, L;

human papillomaviruses (HPV) are subdivided into five species and are abundantly detected in the skin, in particular the 1 and 2 species. Therefore, HPV types are considered to have a cutaneous tropism. However, several recent studies have described the presence of HPV also in the mucosal epithelia at different anatomical sites. In particular, 3 HPV types are more prevalent in certain mucosal epithelia rather than in the cutaneous tissues. Studies in different experimental models have also highlighted that 3 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 3 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 3 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 3 HPV onco-proteins leads to p16INK4a accumulation, while no p16INK4a was detected in 2 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 3 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, 3 HPV types and 2 HPV38 further highlights the functional similarities of HR HPV16 and 3 HPV49, 75, 76. The expression profiles of these four HPV HFKs show some similarities and diverge substantially from 3 HPV115 E6/E7 and 2 HPV38 E6/E7 HFKs. In conclusion, the data show that 3 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.