Hepatitis C virus E1 envelope glycoprotein interacts with apolipoproteins in facilitating entry into hepatocytes

Mazumdar, Budhaditya; Banerjee, Arup; Meyer, Keith; Ray, Ranjit

doi:10.1002/hep.24523

Cited by 70 publications

(65 citation statements)

References 37 publications

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“…E1E2 protein on HCV LVPs might interact spontaneously with apoE (13,38,39), forming larger complexes in which conventional virions are transiently decorated with apoE-coated HDL/ LDL particles. Hypothetically, for this complex type of HCV LVPs, apoE-positive lipoprotein could also assist HCV LVP infection through virion and lipoprotein particle association.…”

Section: Discussionmentioning

confidence: 99%

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

Yang

Wang

Chi

et al. 2016

J Virol

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Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting approximately 170 million people worldwide. HCV assembly is tightly associated with the lipoprotein pathway. Exchangeable apolipoprotein E (apoE) is incorporated on infectious HCV virions and is important for infectious HCV virion morphogenesis and entry. Moreover, the virion apoE level is positively correlated with its ability to escape E2 antibody neutralization. However, the role of apoE exchange in the HCV life cycle is unclear. In this study, the relationship between apoE expression and cell permissiveness to HCV infection was assessed by infecting apoE knockdown and derived apoE rescue cell lines with HCV. Exchange of apoE between lipoproteins and HCV lipoviral particles (LVPs) was evaluated by immunoprecipitation, infectivity testing, and viral genome quantification. Cell and heparin column binding assays were applied to determine the attachment efficiency of LVPs with different levels of incorporated apoE. The results showed that cell permissiveness for HCV infection was determined by exogenous apoE-associated lipoproteins. Furthermore, apoE exchange did occur between HCV LVPs and lipoproteins, which was important to maintain a high apoE level on LVPs. Lipid-free apoE was capable of enhancing HCV infectivity for apoE knockdown cells but not apoE rescue cells. A higher apoE level on LVPs conferred more efficient LVP attachment to both the cell surface and heparin beads. This study revealed that exogenous apoE-incorporating lipoproteins from uninfected hepatocytes safeguarded the apoE level of LVPs for more efficient attachment during HCV infection. IMPORTANCEIn this study, a neglected but important role of apoE exchange in HCV LVP infectivity after virus assembly and release was identified. The data indicated that apoE expression level in uninfected cells is important for high permissiveness to HCV infection. Secreted apoE-associated lipoprotein specifically enhances infection of HCV LVPs. apoE exchange between HCV LVP and lipoproteins is important to maintain an adequate apoE level on LVPs for their efficient attachment to cell surface. These data defined for the first time an extracellular role of exchangeable apoE in HCV infection and suggested that exchangeable apolipoproteins reach a natural equilibrium between HCV LVPs and lipoprotein particles, which provides a new perspective to the understanding of the heterogeneity of HCV LVPs in composition. M ore than 170 million people worldwide are infected with hepatitis C virus (HCV). Up to 80% of infected individuals are unable to clear the virus, and persistent infections lead to a high risk of developing liver cirrhosis and hepatocellular carcinoma (1). Direct-acting antivirals (DAA) significantly improved treatment efficiency, but an effective vaccine for the control of new HCV infection is still needed due to the limited access to anti-HCV treatment. Moreover, the emergence of DAA-resistant viruses calls for alternative strategies to control viral breakthrough (2-4).A...

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Section: Discussionmentioning

confidence: 99%

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

Yang

Wang

Chi

et al. 2016

J Virol

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“…Moreover, there is growing evidence for the presence of lipid components within the viral particle, such as apolipoproteins B and E, which might facilitate viral entry. It is thus conceivable that the phenotypic properties conferred by a given E1E2 variant may differ in the context of the authentic viral particle and in HCVpp (41)(42)(43)(44). Studies using chimeric JFH-1-based HCV in cell culture (HCVcc) will clearly be required to address this specific question (45,46).…”

Section: Discussionmentioning

confidence: 99%

Sequence and Functional Analysis of the Envelope Glycoproteins of Hepatitis C Virus Variants Selectively Transmitted to a New Host

D’Arienzo

Moreau

d’Altéroche

et al. 2013

J Virol

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e Hepatitis C virus (HCV) remains a challenging public health problem worldwide. The identification of viral variants establishing de novo infections and definition of the phenotypic requirements for transmission would facilitate the design of preventive strategies. We explored the transmission of HCV variants in three cases of acute hepatitis following needlestick accidents. We used single-genome amplification of glycoprotein E1E2 gene sequences to map the genetic bottleneck upon transmission accurately. We found that infection was likely established by a single variant in two cases and six variants in the third case. Studies of donor samples showed that the transmitted variant E1E2 amino acid sequences were identical or closely related to those of variants from the donor virus populations. The transmitted variants harbored a common signature site at position 394, within hypervariable region 1 of E2, together with additional signature amino acids specific to each transmission pair. Surprisingly, these E1E2 variants conferred no greater capacity for entry than the E1E2 derived from nontransmitted variants in lentiviral pseudoparticle assays. Mutants escaping the antibodies of donor sera did not predominate among the transmitted variants either. The fitness parameters affecting the selective outgrowth of HCV variants after transmission in an immunocompetent host may thus be more complex than those suggested by mouse models. Human antibodies directed against HCV envelope effectively crossneutralized the lentiviral particles bearing E1E2 derived from transmitted variants. These findings provide insight into the molecular mechanisms underlying HCV transmission and suggest that viral entry is a potential target for the prevention of HCV infection.

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“…Therefore, rather than having evolved a unique mechanism of viral propagation, HCV may have instead subverted existing cellular processes. It could involve intrinsic properties of its envelope proteins, since HCV E1 interacts with apoE [81] and possibly lipids [82] , which is believed to help the virus escape from immune recognition [83] . The release of HCV particles by BHK-WNV cells, instead, involved an unusual, if not unconventional secretion pathway.…”

Section: Discussionmentioning

confidence: 99%

Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway

Triyatni

Berger

Saunier

2016

WJH

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Institutional review board statement: Approved the use of serum IgG of a patient cured from an HCV infection for in vitro studies (Hôpital and Institut Cochin, Paris).Institutional animal care and use committee statement: Not applicable.Conflict-of-interest statement: Saunier B, Triyatni M and Berger EA are co-inventors on NIH-owned patent #US 9052321 B2 on the HCV particle production system. Triyatni M et al . Unusual secretory pathway of hepatitis C virus in thin section transmission electron microscopy. These findings were compared with the JFH-1 strain/Huh-7.5 cell model. RESULTS:We found that CANX was necessary for the production of HCV particles by BHK-WNV cells. This process involved the recruitment of a subset of HCV proteins, detected by immunoglobulin of an HCV-cured patient, in a compartment of rearranged membranes bypassing the endoplasmic reticulum-Golgi intermediary compartment and surrounded by mitochondria. It also involved the maturation of N-linked glycans on HCV envelope proteins, which was required for assembly and/or secretion of HCV particles. The formation of this specialized compartment required RAB1; upon expression of HCV structural genes, this compartment developed large vesicles with viral particles. RAB1 and alpha-tubulin were required for the release of HCV particles. These cellular factors were also involved in the production of HCVcc in the JFH-1 strain/Huh-7.5 cell system, which involves HCV RNA replication. The secretion of HCV particles by BHK-WNV cells presents similarities with a pathway involving caspase-1; a caspase-1 inhibitor was found to suppress the production of HCV particles from a full-length genome. CONCLUSION:Prior activity of the WNV subgenomic replicon in BHK-21 cells promoted re-wiring of host factors for the assembly and release of infectious HCV in a caspase-1-dependent mechanism. Core tip: Our system for production of authentic infectious hepatitis C virus (HCV) in non-humanized, nonhepatic cells involves the rearrangement of inner cellular membranes triggered by the replication of flaviviruses. The present results suggest that this feature relies on the re-wiring of host factors that usually contribute to the secretion of glycoproteins to generate an unusual secretory pathway. This model offers a new way to study the properties of free HCV particles, i.e. , independently from lipoproteins.Triyatni M, Berger EA, Saunier B. Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway.

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Hepatitis C virus E1 envelope glycoprotein interacts with apolipoproteins in facilitating entry into hepatocytes

Cited by 70 publications

References 37 publications

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

Neglected but Important Role of Apolipoprotein E Exchange in Hepatitis C Virus Infection

Sequence and Functional Analysis of the Envelope Glycoproteins of Hepatitis C Virus Variants Selectively Transmitted to a New Host

Assembly and release of infectious hepatitis C virus involving unusual organization of the secretory pathway

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