Hepatitis C virus (HCV) infection remains a major health problem. Despite of the development of a cell culture system permitting HCV replication in vitro, the mechanisms leading to infection are still not well understood. HCV is secreted and circulates in the patient serum in association with lipoproteins. The importance of lipoproteins for the virus life cycle led us to investigate a role of lipoprotein lipase (LPL), a lipolytic enzyme, in the cell infection with HCV. We showed that LPL increases virus attachment and internalisation by mechanisms similar to the hepatic uptake of lipoproteins. Dimeric LPL forms a bridge between virus-associated lipoproteins and HSPG at the cell surface. Nevertheless, LPL inhibits cell infection with two virus strains: JFH-1 and J6/JFH-1, produced either in cell culture, or in chimeric uPA-SCID mice with transplanted human hepatocytes. Analyses of the viruses produced in vitro and in vivo in iodixanol gradients showed the presence of two virus populations banding at very low and higher density, the first population being much more infectious than the latter one. Cell infection with low and higher density viruses was inhibited by LPL. Thus, LPL represents a novel inhibitor of HCV infectivity. We showed that the intact and dynamic microtubules are crucial for HCV cell entry and early post-fusion steps, leading to productive infection. In addition, we provided evidence that HCV core protein directly interacts with α/β tubulin, increasing polymerisation of microtubules. These observations suggest that HCV could use microtubule polymerisation mechanisms to establish infection, in which virus core protein might play an important role. New anti-viral approaches may thus target the elements of the cytoskeleton and/or lipoproteins associated with virus particles.
