• ApoE
• LDL-R
• antiviral
• apolipoprotein
• enveloped virus
• lipid transfer
• lipoprotein
• lipoprotein receptor
• viral entry
• virus receptor

• Humans
• Virus Internalization
• Receptors, Lipoprotein/metabolism
• Receptors, Lipoprotein/genetics
• Animals
• Flaviviridae/metabolism

• Choroidal angiogenesis
• Circular RNA
• QKI
• VLDLR

• Animals
• Choroidal Neovascularization/genetics
• Choroidal Neovascularization/metabolism
• Choroidal Neovascularization/pathology
• Receptors, LDL/genetics
• Receptors, LDL/metabolism
• Mice
• Mice, Knockout
• RNA, Circular/genetics
• RNA, Circular/metabolism
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Reelin Protein
• Signal Transduction
• Mice, Inbred C57BL
• Choroid/metabolism
• Choroid/blood supply
• Disease Models, Animal
• Angiogenesis

• virus-host interactions
• cellular microbiology

• Humans
• Receptors, LDL/metabolism
• Virus Internalization
• Apolipoproteins E/metabolism
• Apolipoproteins E/genetics
• Hemorrhagic Fever Virus, Crimean-Congo/metabolism
• Hemorrhagic Fever Virus, Crimean-Congo/physiology
• Animals
• HEK293 Cells
• Chlorocebus aethiops
• Hemorrhagic Fever, Crimean/virology
• Hemorrhagic Fever, Crimean/metabolism
• Virion/metabolism
• Vero Cells

• EQU202203014673 Agence Nationale de la Recherche (French National Research Agency)
• ANR-22-ASTR-0031 Agence Nationale de la Recherche (French National Research Agency)

• LDLR
• PCSK9
• SREBPs
• pseudorabies virus
• viral entry

• Animals
• Humans
• Mice
• Herpesvirus 1, Suid/physiology
• Lipoproteins, LDL/metabolism
• Proprotein Convertase 9
• Pseudorabies/virology
• Swine
• Swine Diseases/virology
• Virus Internalization
• Cell Line

• 32272961 MOST | National Natural Science Foundation of China (NSFC)
• 2021YFD1301200 MOST | National Key Research and Development Program of China (NKPs)

• ACE2
• ROS
• SARS-CoV-2
• SARS-CoV-2 receptor
• amino acid availability
• cysteine
• glutathione
• spike

Hepatitis is defined as inflammation of the liver; it can be acute or chronic. In chronic cases, the prolonged inflammation gradually damages the liver, resulting in liver fibrosis, cirrhosis, and sometimes liver failure or cancer. Hepatitis is often caused by viral infections. The most common causes of viral hepatitis are the five hepatitis viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). While HAV and HEV rarely (or do not) cause chronic hepatitis, a considerable proportion of acute hepatitis cases caused by HBV (sometimes co-infected with HDV) and HCV infections become chronic. Thus, many medical researchers have focused on the treatment of HBV and HCV. It has been documented that host lipid metabolism, particularly cholesterol metabolism, is required for the hepatitis viral infection and life cycle. Thus, manipulating host cholesterol metabolism-related genes and proteins is a strategy used in fighting the viral infections. Efforts have been made to evaluate the efficacy of cholesterol-lowering drugs, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in the treatment of hepatitis viral infections; promising results have been obtained. This review provides information on the relationships between hepatitis viruses and host cholesterol metabolism/homeostasis, as well as the discovery/development of cholesterol-lowering natural phytochemicals that could potentially be applied in the treatment of viral hepatitis.

• HMG-CoA reductase
• cholesterol metabolism
• hepatitis virus
• phytochemicals

• Cholesterol
• Hepacivirus
• Hepatitis A
• Hepatitis B virus
• Hepatitis C/drug therapy
• Hepatitis Delta Virus
• Hepatitis E virus
• Hepatitis Viruses
• Hepatitis, Viral, Human
• Humans
• Inflammation
• Lipid Metabolism
• Liver Cirrhosis

Apolipoprotein E (ApoE) is a multifunctional protein expressed in several tissues, including those of the liver. This lipoprotein component is responsible for maintaining lipid content homeostasis at the plasma and tissue levels by transporting lipids between the liver and peripheral tissues. The ability of ApoE to interact with host-cell surface receptors and its involvement in several cellular pathways raised questions about the hijacking of ApoE by hepatotropic viruses. Hepatitis C virus (HCV) was the first hepatitis virus reported to be dependent on ApoE for the completion of its lifecycle, with ApoE being part of the viral particle, mediating its entry into host cells and contributing to viral morphogenesis. Recent studies of the hepatitis B virus (HBV) lifecycle have revealed that this virus and its subviral envelope particles also incorporate ApoE. ApoE favors HBV entry and is crucial for the morphogenesis of infectious particles, through its interaction with HBV envelope glycoproteins. This review summarizes the data highlighting the crucial role of ApoE in the lifecycles of HBV and HCV and discusses its potential role in the lifecycle of other hepatotropic viruses.

• Apolipoproteins E/metabolism
• Hepacivirus/metabolism
• Hepatitis B virus/metabolism
• Hepatitis C
• Humans
• Virion/metabolism

Alphaviruses, like many other arthropod-borne viruses, infect vertebrate species and insect vectors separated by hundreds of millions of years of evolutionary history. Entry into evolutionarily divergent host cells can be accomplished by recognition of different cellular receptors in different species, or by binding to receptors that are highly conserved across species. Although multiple alphavirus receptors have been described^1–3, most are not shared among vertebrate and invertebrate hosts. Here we identify the very low-density lipoprotein receptor (VLDLR) as a receptor for the prototypic alphavirus Semliki forest virus. We show that the E2 and E1 glycoproteins (E2–E1) of Semliki forest virus, eastern equine encephalitis virus and Sindbis virus interact with the ligand-binding domains (LBDs) of VLDLR and apolipoprotein E receptor 2 (ApoER2), two closely related receptors. Ectopic expression of either protein facilitates cellular attachment, and internalization of virus-like particles, a VLDLR LBD–Fc fusion protein or a ligand-binding antagonist block Semliki forest virus E2–E1-mediated infection of human and mouse neurons in culture. The administration of a VLDLR LBD–Fc fusion protein has protective activity against rapidly fatal Semliki forest virus infection in mouse neonates. We further show that invertebrate receptor orthologues from mosquitoes and worms can serve as functional alphavirus receptors. We propose that the ability of some alphaviruses to infect a wide range of hosts is a result of their engagement of evolutionarily conserved lipoprotein receptors and contributes to their pathogenesis.

Studies using viral coat glycoproteins show that alphaviruses can enter cells via the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), members of an evolutionarily conserved family of lipoprotein receptors.

• ER stress
• HCC (hepatocellular carcinoma)
• HCV (Hepatitis C)
• IFNL4
• liver cirrhosis

• Adult
• Apoptosis
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/virology
• Case-Control Studies
• Cell Proliferation
• Databases, Factual
• Endoplasmic Reticulum Stress
• Female
• Genetic Predisposition to Disease
• Hep G2 Cells
• Hepatitis C/genetics
• Hepatitis C/metabolism
• Hepatitis C/virology
• Humans
• Interferons/genetics
• Interleukins/genetics
• Interleukins/metabolism
• Japan
• Liver/metabolism
• Liver/pathology
• Liver Cirrhosis/genetics
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/prevention & control
• Liver Cirrhosis/virology
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Liver Neoplasms/virology
• Male
• Middle Aged
• Phenotype
• Polymorphism, Genetic
• Protective Factors
• Risk Assessment
• Risk Factors
• Taiwan

The hepatitis C virus (HCV), an obligatory intracellular pathogen, highly depends on its host cells to propagate successfully. The HCV life cycle can be simply divided into several stages including viral entry, protein translation, RNA replication, viral assembly and release. Hundreds of cellular factors involved in the HCV life cycle have been identified over more than thirty years of research. Characterization of these cellular factors has provided extensive insight into HCV replication strategies. Some of these cellular factors are targets for anti-HCV therapies. In this review, we summarize the well-characterized and recently identified cellular factors functioning at each stage of the HCV life cycle.

• Hepatitis C virus
• Cellular factor
• Viral entry
• Translation
• Replication
• Assembly
• Release

• Animals
• Hepacivirus
• Hepatitis C/drug therapy
• Humans
• Life Cycle Stages
• Virus Assembly
• Virus Replication

• Dengue virus
• Kv1.3 ion channel
• Zika virus
• hepatitis C virus
• host factor

• HCV
• bimodal expression
• external control of hepatic phenotype
• liver zonation
• modulation of hepatic metabolism
• mosaicism
• pericentral
• periportal
• single-cell heterogeneity
• virus susceptibility

• cell entry
• hepatitis C virus
• immune escape
• lipidation
• lipoproteins

• Animals
• Endoplasmic Reticulum/metabolism
• Hepacivirus/physiology
• Hepatitis C/immunology
• Hepatitis C/metabolism
• Hepatitis C/virology
• Host-Pathogen Interactions
• Humans
• Lipid Metabolism
• Lipoproteins/biosynthesis
• Lipoproteins/metabolism
• Protein Transport
• Signal Transduction
• Virion
• Virus Assembly
• Virus Internalization

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver disease worldwide. Its tissue and species tropism are largely defined by the viral entry process that is required for subsequent productive viral infection and establishment of chronic infection. This review provides an overview of the viral and host factors involved in HCV entry into hepatocytes, summarizes our understanding of the molecular mechanisms governing this process and highlights the therapeutic potential of host-targeting entry inhibitors.

• cell-to-cell transmission
• endocytosis
• fusion
• hepatitis C virus
• hepatocyte
• viral entry

Hepatitis C virus (HCV) is a member of Hepacivirus and belongs to the family of Flaviviridae. HCV infects millions of people worldwide and may lead to cirrhosis and hepatocellular carcinoma. HCV envelope proteins, E1 and E2, play critical roles in viral cell entry and act as major epitopes for neutralizing antibodies. However, unlike other known flaviviruses, it has been challenging to study HCV envelope proteins E1E2 in the past decades as the in vitro expressed E1E2 heterodimers are usually of poor quality, making the structural and functional characterization difficult. Here we express the ectodomains of HCV E1E2 heterodimer with either an Fc-tag or a de novo designed heterodimeric tag and are able to isolate soluble E1E2 heterodimer suitable for functional and structural studies. Then we characterize the E1E2 heterodimer by electron microscopy and model the structure by the coevolution based modeling strategy with Rosetta, revealing the potential interactions between E1 and E2. Moreover, the E1E2 heterodimer is applied to examine the interactions with the known HCV receptors, neutralizing antibodies as well as the inhibition of HCV infection, confirming the functionality of the E1E2 heterodimer and the binding profiles of E1E2 with the cellular receptors. Therefore, the expressed E1E2 heterodimer would be a valuable target for both viral studies and vaccination against HCV.

Hepatitis C virus (HCV) is an enveloped virus that infects millions of people worldwide and may lead to cirrhosis and hepatocellular carcinoma. HCV has two envelope proteins, E1 and E2, which form heterodimers on viral surface and are critical for HCV cell entry. However, current studies of HCV E1E2 are often limited by the poor quality of the in vitro expressed E1E2 heterodimers. Here we express the ectodomains of HCV E1E2 with different tags, and are able to isolate soluble E1E2 ectodomains suitable for structural and functional studies. Then we generate the 3D reconstruction of E1E2 heterodimer by electron microscopy and also model the E1E2 structure by the coevolution based strategy with Rosetta, showing the potential interactions between E1 and E2. Moreover, the E1E2 heterodimer is applied to examine the interactions with the HCV cellular receptors, neutralizing antibodies as well as the inhibition of HCV infection. These results suggest that the expressed E1E2 heterodimer would be a promising target for both viral studies and vaccination against HCV.

• Antibodies, Neutralizing/metabolism
• HEK293 Cells
• Hepacivirus/physiology
• Hepatitis C/genetics
• Hepatitis C/metabolism
• Hepatitis C/virology
• Humans
• Protein Conformation
• Protein Multimerization
• Receptors, Cell Surface/metabolism
• Recombinant Fusion Proteins/chemistry
• Recombinant Fusion Proteins/genetics
• Recombinant Fusion Proteins/metabolism
• Viral Envelope Proteins/chemistry
• Viral Envelope Proteins/genetics
• Viral Envelope Proteins/metabolism
• Virus Internalization

Hepatitis C virus (HCV) is an RNA virus that can efficiently establish chronic infection in humans. The overlap between the HCV replication cycle and lipid metabolism is considered to be one of the primary means by which HCV efficiently develops chronic infections. In the blood, HCV is complex with lipoproteins to form heterogeneous lipo-viro-particles (LVPs). Furthermore, apolipoprotein E (ApoE), which binds to receptors during lipoprotein transport and regulates lipid metabolism, is localized on the surface of LVPs. ApoE not only participate in the attachment and entry of HCV on the cell surface but also the assembly and release of HCV viral particles from cells. Moreover, in the blood, ApoE can also alter the infectivity of HCV and be used by HCV to escape recognition by the host immune system. In addition, because ApoE can also affect the antioxidant and immunomodulatory/anti-inflammatory properties of the host organism, the long-term binding and utilization of host ApoE during chronic HCV infection not only leads to liver lipid metabolic disorders but may also lead to increased morbidity and mortality associated with systemic comorbidities.

• HCV-associated comorbidities
• apolipoprotein E (ApoE)
• chronic infection
• hepatitis C virus (HCV)
• immune evasion
• lipo-viro-particles (LVPs)

• Density
• Hepatitis C virus
• Infectivity
• Lipidation
• Lipoprotein
• Serum

• Apolipoprotein B-100/metabolism
• Apolipoproteins E/metabolism
• Cell Line, Tumor
• Cholesterol, HDL/metabolism
• Cholesterol, LDL/metabolism
• Cholesterol, VLDL/metabolism
• Culture Media, Conditioned
• Culture Media, Serum-Free
• Extracellular Fluid/metabolism
• Hepacivirus/metabolism
• Hepatitis C/metabolism
• Hepatitis C/virology
• Hepatocytes/metabolism
• Hepatocytes/virology
• Humans
• Serum Albumin, Human/metabolism
• Viral Envelope Proteins/chemistry
• Viral Proteins/metabolism
• Virion/metabolism
• Virus Assembly

• HCVcc
• HCVpp
• Hepatitis C virus

• EGFR signaling
• HCV entry
• actin
• clathrin endocytosis
• organoids
• tight junctions

• Humans
• PCSK9 Inhibitors
• Protease Inhibitors/adverse effects
• Protease Inhibitors/pharmacology

• Amino Acid Sequence
• Binding Sites
• Cysteine/chemistry
• Cysteine/metabolism
• Fibrin/metabolism
• Humans
• Models, Molecular
• Nuclear Magnetic Resonance, Biomolecular
• Protein Domains
• Protein Structure, Secondary
• Receptors, LDL/chemistry
• Receptors, LDL/metabolism
• Recombinant Proteins/chemistry
• Recombinant Proteins/metabolism

• R01 HL056051 NHLBI NIH HHS

Hepatitis C virus (HCV) enters human hepatocytes using four essential entry factors, one of which is human CD81 (hCD81). The tetraspanin hCD81 contains a large extracellular loop (LEL), which interacts with the E2 glycoprotein of HCV. The role of the non-LEL regions of hCD81 (intracellular tails, four transmembrane domains, small extracellular loop and intracellular loop) is poorly understood. Here, we studied the contribution of these domains to HCV susceptibility of hepatoma cells by generating chimeras of related tetraspanins with the hCD81 LEL. Our results show that non-LEL regions in addition to the LEL determine susceptibility of cells to HCV. While closely related tetraspanins (X. tropicalis CD81 and D. rerio CD81) functionally complement hCD81 non-LEL regions, distantly related tetraspanins (C. elegans TSP9 amd D. melanogaster TSP96F) do not and tetraspanins with intermediate homology (hCD9) show an intermediate phenotype. Tetraspanin homology and susceptibility to HCV correlate positively. For some chimeras, infectivity correlates with surface expression. In contrast, the hCD9 chimera is fully surface expressed, binds HCV E2 glycoprotein but is impaired in HCV receptor function. We demonstrate that a cholesterol-coordinating glutamate residue in CD81, which hCD9 lacks, promotes HCV infection. This work highlights the hCD81 non-LEL regions as additional HCV susceptibility-determining factors.

• CD81
• HCV
• chimeras
• cholesterol-binding residue
• hepatitis C virus
• receptor
• susceptibility-determining domains
• tetraspanin
• transmembrane domain four

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT_2AR) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy. The silencing of 5-HT_2AR and clinically available 5-HT_2AR antagonist suppress cell culture-derived HCV (HCVcc) in different liver cells and primary human hepatocytes at late endocytosis process. The mechanism is related to regulate the correct plasma membrane localization of claudin 1 (CLDN1). Moreover, phenoxybenzamine (PBZ), an FDA-approved 5-HT_2AR antagonist, inhibits all major HCV genotypes in vitro and displays synergy in combination with clinical used anti-HCV drugs. The impact of PBZ on HCV genotype 2a is documented in immune-competent humanized transgenic mice. Our results not only expand the understanding of HCV entry, but also present a promising target for the invention of HCV entry inhibitor.

• HCV
• antiviral drug
• entry
• serotonin 2A receptor

• Antiviral therapy
• Hepatitis C virus
• Proprotein convertase subtilisin/kexin type 9
• miR-122
• miR-223
• miR-24

From viral binding to the hepatocyte surface to extracellular virion release, the replication cycle of the hepatitis C virus (HCV) intersects at various levels with lipid metabolism; this leads to a derangement of the lipid profile and to increased viral infectivity. Accumulating evidence supports the crucial regulatory role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipoprotein metabolism. Notably, a complex interaction between HCV and PCSK9 has been documented. Indeed, either increased or reduced circulating PCSK9 levels have been observed in HCV patients; this discrepancy might be related to several confounders, including HCV genotype, human immunodeficiency virus (HIV) coinfection and the ambiguous HCV‐mediated influence on PCSK9 transcription factors. On the other hand, PCSK9 may itself influence HCV infectivity, inasmuch as the expression of different hepatocyte surface entry proteins and receptors is regulated by PCSK9. The aim of this review is to summarize the current evidence about the complex interaction between HCV and liver lipoprotein metabolism, with a specific focus on PCSK9. The underlying assumption of this review is that the interconnections between HCV and PCSK9 may be central to explain viral infectivity.

• cholesterol
• hepatitis C virus
• lipids
• lipoprotein
• proprotein convertase subtilisin/kexin type 9

• LDL receptor
• PCSK9
• cholesterol
• hepatitis C virus
• infection

• Hepatitis C virus
• Lipid metabolism
• Lipoproteins
• Virus assembly
• Virus entry

Hepatitis C virus (HCV) is a model for the study of virus–host interaction and host cell responses to infection. Virus entry into hepatocytes is the first step in the HCV life cycle, and this process requires multiple receptors working together. The scavenger receptor class B type I (SR-BI) and claudin-1 (CLDN1), together with human cluster of differentiation (CD) 81 and occludin (OCLN), constitute the minimal set of HCV entry receptors. Nevertheless, HCV entry is a complex process involving multiple host signaling pathways that form a systematic regulatory network; this network is centrally controlled by upstream regulators epidermal growth factor receptor (EGFR) and transforming growth factor β receptor (TGFβ-R). Further feedback regulation and cell-to-cell spread of the virus contribute to the chronic maintenance of HCV infection. A comprehensive and accurate disclosure of this critical process should provide insights into the viral entry mechanism, and offer new strategies for treatment regimens and targets for HCV therapeutics.

• cell entry
• hepatitis C virus
• receptor
• regulation
• signaling

Very low-density lipoprotein (VLDL) receptor is a member of the low-density lipoprotein (LDL) receptor family. It binds triglyceride rich lipoprotein (TGRL) but not LDL, because it recognizes apolipoprotein (apo)E only but not apoB. The VLDL receptor functions as a peripheral lipoprotein receptor in concert with lipoprotein lipase (LPL) in heart, muscle, adipose tissue and macrophages. In contrast to the LDL receptor, VLDL receptor binds apo E2/2 VLDL and apoE3/3 VLDL particles, and its expression is not down-regulated by intracellular lipoproteins. It has been reported that both LDL-cholesterol (LDL-C) and postprandial triglyceride (chyromicron and VLDL remnants) are risk factors for human atherosclerotic cardiovascular disease (ASCVD). True ligands such as lipoprotein particles of the VLDL receptor are chyromicron remnant (CMR) and VLDL remnant (postprandial hyperlipidemia). Although the oxidized LDL (oxLDL)-scavenger receptors pathway is considered to be the main mechanism for macrophage foam cell formation, it seems that the TGRL-LPL-VLDL receptor pathway is also involved. Since Lp(a) is one of the ligands for the VLDL receptor, the Lp(a)- VLDL receptor pathway is another potential alternative. The expression of VLDL receptor protein in mouse macrophages is modest compared to that in rabbit and human macrophages, both in vitro and in vivo. Therefore, we need to elucidate the mechanism of human ASCVD not by using the mouse model and scavenger receptors pathway but instead using the rabbit model and VLDL receptor pathway, respectively.

• Atherosclerosis
• Lipoprotein lipase
• Lp(a)
• Macrophage foam cell formation
• VLDL receptor

• Claudins
• Tight junction
• Viral infection
• Viral pathogenesis

• Animals
• Antiviral Agents/pharmacology
• Antiviral Agents/therapeutic use
• Claudins/metabolism
• Humans
• Tight Junction Proteins/metabolism
• Tight Junctions/metabolism
• Tight Junctions/virology
• Virus Diseases/drug therapy
• Virus Diseases/metabolism

• U19 AI123862 NIAID NIH HHS
• 201411MFE-338606-245517 CIHR

• Direct acting antivirals
• Life cycle
• Liver
• Viral hepatitis

• HCV
• HIV
• agent-based models
• cell-free virus infection
• cell-to-cell infection
• mathematical modeling

• Cholesterol, LDL/metabolism
• Disease
• Humans
• Induced Pluripotent Stem Cells/metabolism
• Proprotein Convertase 9/metabolism
• Receptors, LDL/metabolism
• Triglycerides/metabolism

• MOP-102741 CIHR
• CTP-82946 CIHR

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.

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 lipoviroparticles. Several reports have shown that SR-B1 and LDLR participate in the entry of lipoviroparticles through interaction with lipoproteins. However, the precise roles of SR-B1 and LDLR in HCV entry have not been fully clarified. In this study, we showed that SR-B1 and LDLR have a redundant role in HCV entry. In addition, we showed that very low-density lipoprotein receptor (VLDLR) played a role in HCV entry similar to the roles of SR-B1 and LDLR. Interestingly, VLDLR expression was low in the liver in contrast to the abundant expressions of SR-B1 and LDLR, but high in several extrahepatic tissues. Our data suggest that lipoprotein receptors participate in the entry of HCV particles associated with various lipoproteins.

• Cell Line
• Fluorescent Antibody Technique
• Gene Expression Profiling
• Gene Knockout Techniques
• Hepacivirus/physiology
• Humans
• Immunoblotting
• Polymerase Chain Reaction
• Receptors, LDL/metabolism
• Scavenger Receptors, Class B/metabolism
• Virus Internalization

• Japan Agency for Medical Research and Development
• Japan Society for the Promotion of Science (JSPS)
• Japan Society for the Promotion of Science

• Antiviral activities
• Classical swine fever virus
• Interferon stimulated genes
• Reporter virus
• Small interfering RNAs