Hepatitis C virus utilizes VLDLR as a novel entry pathway

Abstract

Various host factors are involved in the cellular entry of hepatitis C virus (HCV). In addition to the factors previously reported, we discovered that the very-low-density lipoprotein receptor (VLDLR) mediates HCV entry independent of CD81. Culturing Huh7.5 cells under hypoxic conditions significantly increased HCV entry as a result of the expression of VLDLR, which was not expressed under normoxic conditions in this cell line. Ectopic VLDLR expression conferred susceptibility to HCV entry of CD81-deficient Huh7.5 cells. Additionally, VLDLR-mediated HCV entry was not affected by the knockdown of cellular factors known to act as HCV receptors or HCV entry factors. Because VLDLR is expressed in primary human hepatocytes, our results suggest that VLDLR functions in vivo as an HCV receptor independent of canonical CD81-mediated HCV entry.virus entry | VLDLR | CD81 | hypoxia | hepatitis C virus H epatitis C virus (HCV) infects more than 170 million people worldwide and is a major cause of chronic liver disease. The virus persists in 80% of infected individuals and can lead to chronic liver diseases including fibrosis, cirrhosis, steatosis, and hepatocellular carcinoma. HCV, an enveloped positive-stranded virus, enters host cells by using various host factors that function as receptors and mediate endocytosis. Several host factors, including CD81 (1), claudin-1 (CLDN1) (2), occludin (OCLN) (3), and scavenger receptor class B member I (SR-BI) (4), have been identified as receptors. Heparan sulfate glycosaminoglycan represents the first attachment site (5) before the interaction of the virus with these factors. Because all the entry factors are required for productive HCV infection, HCV entry seems to be the result of an orchestrated process involving these factors. Additionally, low-density lipoprotein receptor (LDLR) (6), Niemann-Pic C1-like 1 (NPC1L1) (7), transferrin receptor 1 (TfR1) (8), and epidermal growth factor receptor (EGFR) (9) have been shown to play a role in HCV entry. CD81 was the first factor to be identified as an HCV receptor, and it plays an important role in this process by binding with the HCV envelope glycoprotein E2 (10, 11). Indeed, CD81-deficient cell lines such as HepG2 do not permit the entry of HCV (2, 3).Recent studies have demonstrated that HCV RNA replication in Huh7.5 cells is enhanced under hypoxic conditions (12). Because the oxygen content in liver tissue in vivo is estimated to be lower (with a gradient of 9-3%) than the oxygen content under in vitro culture conditions (13), the HCV life cycle may differ significantly from that observed using in vitro culture systems. The very-low-density lipoprotein receptor (VLDLR) is induced under hypoxic conditions. In turn, this receptor enhances the uptake of low-density lipoproteins (LDLs) and very-low-density lipoproteins (VLDLs) (14), possibly through the recognition of ligands (such as apolipoprotein) that associate with the lipoproteins (15). VLDLR is a type I transmembrane lipoprotein receptor belonging to the LDLR family (16). The expre...

Association of a 3′ untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women

“…PCSK9 also downregulates CD81 and very-low-density lipoprotein receptors (VLDLR) on hepatocytes [38, 39] . CD81 and VLDLR are used by HCV to gain entry into cells [40] and PCSK9 levels modulate HCV infectivity in vitro [39] . The role of PCSK9 in inflammation, immunologic processes and infection is an area of active investigation [41, 42] .…”

New developments in proprotein convertase subtilisin–kexin 9's biology and clinical implications

“…It was previously shown that the CD81 [34,60] and LDLR [34,61 & ] are targets of PCSK9 and as such elevated levels of PCSK9 may reduce the ability of certain viruses, such as HCV, to penetrate liver cells. Evidence that VLDLR, another target of PCSK9 [38,39,46 && ], is also an independent receptor of HCV [62] supports the hypothesis that PCSK9 plays a protective role in HCV infections. In agreement, a recent study has shown that higher PCSK9 and LDL-C plasma concentrations correlate with reduced HCV titers in patients chronically infected with HCV-genotype 3, that accounts for 10-15% of the total number of HCV infections, but not in individuals more commonly infected with HCV genotype 1 or genotype 2 [36 && ].…”

Future landscape of hepatitis C research – Basic, translational and clinical perspectives

“…However, additional and unexpected players in viral entry continue to emerge ( [27][28][29] and references therein) and a full picture of the entry and egress pathways in cells that reflect polarized human hepatocytes within the liver is still under intense investigation.…”