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Biochem J. 2009 Oct 12;423(3):303-14. doi: 10.1042/BJ20091000.

The hepatitis C virus and its hepatic environment: a toxic but finely tuned partnership.

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  • 1Institut de Biologie et Chimie des Protéines, UMR CNRS 5086, Université Lyon 1, IFR128 Lyon Biosciences Gerland, Lyon, France.


Twenty years after its discovery, HCV (hepatitis C virus) still infects 170 million people worldwide and cannot be properly treated due to the lack of efficient medication. Its life cycle must be better understood to develop targeted pharmacological arsenals. HCV is an enveloped virus bearing two surface glycoproteins, E1 and E2. It only infects humans through blood transmission, and hepatocytes are its only target cells. Hepatic trabeculae are formed by hepatocyte rows surrounded by sinusoid capillaries, irrigating hepatic cells. Hepatocytes are polarized and have basolateral and apical poles, separated by tight junctions in contact with blood and bile respectively. In blood, HCV remains in contact with lipoproteins. It then navigates through hepatic microenvironment and extracellular matrix, composed of glycosaminoglycans and proteins. HCV then encounters the hepatocyte basolateral membrane, where it interacts with its entry factors: the low-density lipoprotein receptor, CD81 tetraspanin, and the high-density lipoprotein (scavenger) receptor SR-BI (scavenger receptor BI). How these molecules interact with HCV remains unclear; however, a tentative sequence of events has been proposed. Two essential factors of HCV entry are the tight junction proteins claudin-1 and occludin. Cell polarity therefore seems to be a key for HCV entry. This raises several exciting questions on the HCV internalization pathway. Clathrin-dependent endocytosis is probably the route of HCV transport to intracellular compartments, and the ultimate step of its entry is fusion, which probably takes place within endosomes. The mechanisms of HCV membrane fusion are still unclear, notably the nature of the fusion proteins is unknown and the contribution of HCV-associated lipoproteins to this event is currently under investigation.

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