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L’influence de HBx sur la réplication du virus de l’Hépatite B et les conséquences sur la cellule

Abstract : Hepatitis B virus (HBV) infection is a major health problem worldwide as (1) despite an effective preventive vaccine over 240 million individuals are chronically infected and (2) the actual viral suppressive treatments available do not eliminate viral DNA from cells. Thus, infected individuals are at a high risk of developing hepatocellular carcinoma (HCC) and understanding viral replication mechanisms and how it impacts on hepatocarcinogenesis is a major challenge.The role of the HBx protein, notably in viral replication and oncogenic processes, is the subject of many publications. However, many studies have often used non-physiological infection conditions. My thesis project has addressed these limitations by using cellular models, including primary human hepatocytes which can be infected by HBV, to investigate HBx’s role in these processes. I have shown that HBx is indispensable for HBV replication and that HBx associates with the infected cell’s DDB1/ E3 ubiquitin complex to target its Smc5/6 complex for degradation via the proteasome. These studies have identified that the Smc5/6 complex is a novel viral restriction factor that acts at an epigenetic level to block viral replication. This unexpected role of SMC5/6 has led to new research into the evolutionary conservation of restriction factors for episomal DNA viruses. As SMC5/6 is implicated in DNA Damage Repair (DDR), the last section of my thesis reports how SMC5/6 degradation in infected cells can sensitise cells to the cell killing effects of DNA damaging agents such as ionizing radiation and hydroxyurea. These results open-up possibilities for HCC treatment where HBx expression may be of therapeutic benefit
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https://tel.archives-ouvertes.fr/tel-01744373
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Submitted on : Tuesday, March 27, 2018 - 12:56:10 PM
Last modification on : Wednesday, June 10, 2020 - 6:42:06 PM
Long-term archiving on: : Thursday, September 13, 2018 - 9:05:15 AM

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Laetitia Gerossier. L’influence de HBx sur la réplication du virus de l’Hépatite B et les conséquences sur la cellule. Virologie. Université de Lyon, 2017. Français. ⟨NNT : 2017LYSE1196⟩. ⟨tel-01744373⟩

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