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Study of cell host factors involved in Hepatitis C virus tropism

Abstract : Hepatitis C virus (HCV) is a global health burden. The development of new therapeutics to treat HCV infection has been hampered by the lack of convenient in vitro and in vivo model systems. The goal of my PhD work was, in a first time, to characterize the factors determining the hepatotropism of HCV. By expressing key factors within a non-hepatic cell line, we reconstituted in fine the full HCV life cycle in those cells. Virus entry into the host cell requires different entry factors which are CD81, occludin (OCLN), claudin-1 (CLDN1) and the scavenger receptor class B type I (SR-BI). The expression of these four factors in this cell line renders it highly permissive to viral entry, but does not allow restoring replication of the virus. The expression of miR-122, a micro-RNA important for HCV infection, into the cell lines expressing the four HCV entry factors restore a strong replication of the HCV RNA but does not allow detecting infectious viral particle production. Further expression of the apolipoprotein E (apoE), which plays a critical role in the assembly and release process, restore the last step of the HCV life cycle in a non-hepatic cell line. In a second part of my PhD, I have used the previously developed strategy to study the species specificity of HCV infection using different mouse hepatoma cell lines. We have been able to render these cell lines permissive to HCV entry and have been able to detect a slight replication. Altogether, my results bring new information on the understanding of key factors important for HCV life cycle in mouse and human cells.
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Daniel da Costa. Study of cell host factors involved in Hepatitis C virus tropism. Virology. Université de Strasbourg, 2012. English. ⟨NNT : 2012STRAJ071⟩. ⟨tel-00804227⟩

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