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Interdependent Impact of Lipoprotein Receptors and Lipid-Lowering Drugs on HCV Infectivity.
Zapatero-Belinchón, Francisco J Ötjengerdes, Rina Sheldon, Julie Schulte, Benjamin Carriquí-Madroñal, Belén Brogden, Graham Arroyo-Fernández, Laura M Vondran, Florian W R Maasoumy, Benjamin von Hahn, Thomas
Zapatero-Belinchón, Francisco J
Ötjengerdes, Rina
Sheldon, Julie
Schulte, Benjamin
Carriquí-Madroñal, Belén
Brogden, Graham
Arroyo-Fernández, Laura M
Vondran, Florian W R
Maasoumy, Benjamin
von Hahn, Thomas
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2021-06-29
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Abstract
The HCV replication cycle is tightly associated with host lipid metabolism: Lipoprotein receptors SR-B1 and LDLr promote entry of HCV, replication is associated with the formation of lipid-rich membranous organelles and infectious particle assembly highjacks the very‑low-density lipoprotein (VLDL) secretory pathway. Hence, medications that interfere with the lipid metabolism of the cell, such as statins, may affect HCV infection. Here, we study the interplay between lipoprotein receptors, lipid homeostasis, and HCV infection by genetic and pharmacological interventions. We found that individual ablation of the lipoprotein receptors SR‑B1 and LDLr did not drastically affect HCV entry, replication, or infection, but double lipoprotein receptor knock-outs significantly reduced HCV infection. Furthermore, we could show that this effect was neither due to altered expression of additional HCV entry factors nor caused by changes in cellular cholesterol content. Strikingly, whereas lipid‑lowering drugs such as simvastatin or fenofibrate did not affect HCV entry or infection of immortalized hepatoma cells expressing SR-B1 and/or LDLr or primary human hepatocytes, ablation of these receptors rendered cells more susceptible to these drugs. Finally, we observed no significant differences between statin users and control groups with regards to HCV viral load in a cohort of HCV infected patients before and during HCV antiviral treatment. Interestingly, statin treatment, which blocks the mevalonate pathway leading to decreased cholesterol levels, was associated with mild but appreciable lower levels of liver damage markers before HCV therapy. Overall, our findings confirm the role of lipid homeostasis in HCV infection and highlight the importance of the mevalonate pathway in the HCV replication cycle.
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Cells. 2021 Jun 29;10(7):1626. doi: 10.3390/cells10071626.
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en
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2073-4409
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Attribution 4.0 International