Source Institut Pasteur de Lille, Center for Infection & Immunity of Lille (CIIL), F-59019 Lille, France; Inserm U1019, F-59019 Lille, France; CNRS UMR8204, F-59021 Lille, France; Univ Lille Nord de France, F-59000 Lille, France.
Hepatitis C virus (HCV) particles are known to be in complex with lipoproteins. As a result of this interaction, the LDL receptor (LDLR) has been proposed as a potential entry factor for HCV, however, its implication in virus entry remains unclear. Here, we re-investigated the role of the LDLR in the HCV life cycle by comparing virus entry to the mechanism of lipoprotein uptake. A siRNA targeting the LDLR in Huh-7 cells reduced HCV infectivity, confirming that this receptor plays a role in the life cycle of HCV generated in cell culture. However, kinetics of internalization were much faster for lipoproteins than for infectious HCV particles.
Furthermore, a decrease in HCV RNA replication was observed by blocking the LDLR with a specific antibody, and this was associated with an increase in the ratio of phosphatidylethanolamine to phosphatidylcholine in host cells. Nevertheless, a soluble form of the LDLR inhibited both HCV entry into the hepatocytes and its binding to the LDLR expressed on CHO cells, suggesting a direct interaction between the HCV particle and the LDLR. Finally, we showed that modification of HCV particles by lipoprotein lipase (LPL) reduces HCV infectivity and increases HCV binding to LDLR. Importantly, LPL treatment also induced an increase in RNA internalization, suggesting that LDLR, at least in some conditions, leads to non-productive internalization of HCV. CONCLUSION: The LDLR is not essential for infectious HCV particle entry, whereas the physiological function of this receptor is important for optimal replication of HCV genome.