Abstract
Scavenger receptor class B type 1 (SR-B1) and low-density lipoprotein receptor (LDLR) are known to be involved in entry of hepatitis C virus (HCV), but their precise roles and their interplay are not fully understood. In this study, deficiency of both SR-B1 and LDLR in Huh7 cells was shown to impair the entry of HCV more strongly than deficiency of either SR-B1 or LDLR alone. In addition, exogenous expression of not only SR-B1 and LDLR but also very low-density lipoprotein receptor (VLDLR) rescued HCV entry in the SR-B1 and LDLR double-knockout cells, suggesting that VLDLR has similar roles in HCV entry. VLDLR is a lipoprotein receptor, but the level of its hepatic expression was lower than those of SR-B1 and LDLR. Moreover, expression of mutant lipoprotein receptors incapable of binding to or uptake of lipid resulted in no or slight enhancement of HCV entry in the double-knockout cells, suggesting that binding and/or uptake activities of lipid by lipoprotein receptors are essential for HCV entry. In addition, rescue of infectivity in the double-knockout cells by the expression of the lipoprotein receptors was not observed following infection with pseudotype particles bearing HCV envelope proteins produced in non-hepatic cells, suggesting that lipoproteins associated with HCV particles participate in the entry through their interaction with lipoprotein receptors. Buoyant density gradient analysis revealed that HCV utilizes these lipoprotein receptors in a manner dependent on the lipoproteins associated with HCV particles. Collectively, these results suggest that lipoprotein receptors redundantly participate in the entry of HCV.
Highlights
More than 160 million individuals worldwide are infected with hepatitis C virus (HCV), which is especially troubling because HCV-induced cirrhosis and hepatocellular carcinoma are lifethreatening diseases [1]
Previous reports have shown that CD81, Scavenger receptor class B type 1 (SR-B1), CLDN1 and OCLN participate in HCV infection [8], the interplay among these molecules and precise roles in HCV entry are not fully understood
To examine the roles of these receptors in HCV entry, HCVcc was inoculated into these KO cells at a multiplicity of infection (MOI) of 1, and intracellular HCV RNA levels were determined by qRT-PCR at 24 h post-infection (Fig 1B)
Summary
Hepatitis C virus (HCV) utilizes several receptors to enter hepatocytes, including scavenger receptor class B type 1 (SR-B1) receptor and low-density lipoprotein receptor (LDLR). HCV particles interact with lipoprotein and apolipoproteins to form complexes termed. Several reports have shown that SR-B1 and LDLR participate in the entry of lipoviroparticles through interaction with lipoproteins. The precise roles of SR-B1 and LDLR in HCV entry have not been fully clarified. We showed that SR-B1 and LDLR have a redundant role in HCV entry. We showed that very low-density lipoprotein receptor (VLDLR) played a role in HCV entry similar to the roles of SR-B1 and LDLR. Our data suggest that lipoprotein receptors participate in the entry of HCV particles associated with various lipoproteins
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