Lipoprotein Receptors Redundantly Participate in Entry of Hepatitis C Virus

Yamamoto, Seiji; Fukuhara, Takasuke; Ono, Chikako; Uemura, Kentaro; Yukako, Kawachi; Mai, Sabine; Mori, Haruhiko; Wada, Masami; Ryoichi, Shima; Okamoto, Tomoyoshi; Hiraga, Nobuhiko; Suzuki, Ritsuro; Chayama, Kazuaki; Wakita, Takaji; Matsuura, Yoshiharu

doi:10.1371/journal.ppat.1005610

Cited by 81 publications

(102 citation statements)

References 68 publications

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“…[33][34][35] Apo-A1-CD63 presenting exosomes produced by 293T cells were loaded with miR-26a by electroporation and shown to be internalized by HepG2 cells via SR-B1 receptor-mediated endocytosis. The exosome-mediated delivery of miR-26a to HepG2 cells was further shown to upregulate miR-26a expression, where it downregulated key cell cycle proteins that arrested the cell cycle and inhibited cell proliferation.…”

mentioning

confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

234

152

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Introduction Exosomes are closed-membrane nanovesicles that are secreted by a variety of cells and exist in most body fluids. Recent studies have demonstrated the potential of exosomes as natural vehicles that target delivery of functional small RNA and chemotherapeutics to diseased cells. Methods In this study, we introduce a new approach for the targeted delivery of exosomes loaded with functional miR-26a to scavenger receptor class B type 1-expressing liver cancer cells. The tumor cell-targeting function of these engineered exosomes was introduced by expressing in 293T cell hosts, the gene fusion between the transmembrane protein of CD63 and a sequence from Apo-A1. The exosomes harvested from these 293T cells were loaded with miR-26a via electroporation. Results The engineered exosomes were shown to bind selectively to HepG2 cells via the scavenger receptor class B type 1–Apo-A1 complex and then internalized by receptor-mediated endocytosis. The release of miR-26a in exosome-treated HepG2 cells upregulated miR-26a expression and decreased the rates of cell migration and proliferation. We also presented evidence that suggest cell growth was inhibited by miR-26a-mediated decreases in the amounts of key proteins that regulate the cell cycle. Conclusion Our gene delivery strategy can be adapted to treat a broad spectrum of cancers by expressing proteins on the surface of miRNA-loaded exosomes that recognize specific biomarkers on the tumor cell.

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mentioning

confidence: 99%

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Liang

Kan

Zhu

et al. 2018

IJN

234

152

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“…HCV cell-free transmission starts from engagement of cell-free virions with several entry receptors (13,14), including scavenger receptor class B type I (SRBI) (15), the tetraspanin CD81 (16), the tight junction proteins claudin-1 (CLDN1) (17) and occludin (OCLN) (18), and the receptor tyrosine kinases epidermal growth factor receptor (EGFR) (19), Niemann-Pick C1-like 1 cholesterol absorption receptor (NPC1L1) (20), syndecan 1 (SDC1) (21), and other lipoprotein receptors (22). After internalization, membrane fusion between viral and endosomal membranes induced by low pH leads to release of capsid in the cytosol.…”

mentioning

confidence: 99%

Visualizing the Essential Role of Complete Virion Assembly Machinery in Efficient Hepatitis C Virus Cell-to-Cell Transmission by a Viral Infection-Activated Split-Intein-Mediated Reporter System

Zhao

Deng

et al. 2017

J Virol

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Hepatitis C virus (HCV) infects 2 to 3% of the world population and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. Many aspects of HCV study, ranging from molecular virology and antiviral drug development to drug resistance profiling, were supported by straightforward assays of HCV replication and infection. Among these assays, the HCV-dependent fluorescence relocalization (HDFR) system allowed live-cell visualization of infection without modifying the viral genome, but this strategy required careful recognition of the fluorescence relocalization pattern for its high fluorescence background in the cytoplasm. In this study, to achieve background-free visualization of HCV infection, a viral infection-activated split-inteinmediated reporter system (VISI) was devised. Uninfected Huh7.5.1-VISI cells show no background signal, while HCV infection specifically illuminates the nuclei of infected Huh7.5.1-VISI cells with either green fluorescent protein (GFP) or mCherry. Combining VISI-GFP and VISI-mCherry systems, we revisited HCV cell-to-cell transmission with clearcut distinction of donor and recipient cells in a live-cell manner. Independently of virion assembly, exosomes have been reported to transfer HCV subgenomic RNA to initiate replication in uninfected cells, which suggested an assembly-free pathway. However, our data demonstrated that HCV structural genes and the p7 gene were essential for not only cell-free infectivity but also cell-to-cell transmission. Additionally, depletion of apolipoprotein E (ApoE) from donor cells but not from recipient cells significantly reduced HCV cell-to-cell transmission efficiency. In summary, we developed a background-free cell-based reporter system for convenient live-cell visualization of HCV infection, and our data indicate that complete HCV virion assembly machinery is essential for both cell-free and cell-to-cell transmission. IMPORTANCE Hepatitis C virus (HCV) infects hepatocytes via two pathways: cell-free infection and cell-to-cell transmission. Structural modules of the HCV genome are required for production of infectious cell-free virions; however, the role of specific genes within the structural module in cell-to-cell transmission is not clearly defined. Our data demonstrate that deletion of core, E1E2, and p7 genes individually results in no HCV cell-to-cell transmission and that ApoE knockdown from donor cells causes less-efficient cell-to-cell transmission. Thus, this work indicates that the complete HCV assembly machinery is required for HCV cell-to-cell transmission. At last, this work presents an optimized viral infection-activated split-intein-mediated reporter system for easy live-cell monitoring of HCV infection.

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“…In addition, in the same study it has been demonstrated that SR‐B1, LDLR, NPC1L1 and CLDN1 were not directly involved in VLDLR‐mediated HCV infection and that VLDLR‐mediated HCV entry required HCV E2 and apoE. Recently, it has been observed that exogenous expression of SR‐B1, LDLR and VLDLR rescued HCV entry in the SR‐B1 and LDLR double‐knockout cells, confirming that VLDLR has a role in HCV entry 8.…”

Section: Hcv Interaction With Lipid and Lipoprotein Metabolismmentioning

confidence: 84%

“…Also, lipoprotein receptor‐mediated HCV entry has been found to be dependent on the density of the LVPs 8. Finally, Boyer et al .…”

Section: Hcv Interaction With Lipid and Lipoprotein Metabolismmentioning

confidence: 98%

“…Viral particle binding to the cell surface and subsequent internalization involve the interaction between HCV envelope molecules and some hepatocyte surface molecules, including different lipoprotein receptors 6, 7, 8. After fusion of the HCV envelope with the host cellular membranes, viral nucleocapsid uncoating allows RNA genome release and intracytoplasmic translation of the HCV polyprotein precursor 9.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

Pirro

Bianconi

Francisci

et al. 2017

J Cellular Molecular Medi

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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.

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Lipoprotein Receptors Redundantly Participate in Entry of Hepatitis C Virus

Cited by 81 publications

References 68 publications

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Engineered exosome-mediated delivery of functionally active miR-26a and its enhanced suppression effect in HepG2 cells

Visualizing the Essential Role of Complete Virion Assembly Machinery in Efficient Hepatitis C Virus Cell-to-Cell Transmission by a Viral Infection-Activated Split-Intein-Mediated Reporter System

Hepatitis C virus and proprotein convertase subtilisin/kexin type 9: a detrimental interaction to increase viral infectivity and disrupt lipid metabolism

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