Regulation of hepatitis C virus secretion by the Hrs-dependent exosomal pathway

Tamai, Keiichi; Shiina, Masaaki; Tanaka, Nobuyuki; Nakano, Takashi; Yamamoto, Akira; Kondo, Yasuteru; Kakazu, Eiji; Inoue, Jun; Fukushima, Koji; Sano, Kohei; Ueno, Yoshiyuki; Shimosegawa, Tooru; Sugamura, Kazuo

doi:10.1016/j.virol.2011.11.009

Cited by 99 publications

(84 citation statements)

References 40 publications

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“…Factors involved in initial virion assembly will likely be necessary for both cell-free and cell-to-cell spread, while those involved in trafficking or late-stage maturation may have differing importance in these two processes and may indirectly provide insight into the nature of the viral particle involved in cell-to-cell spread. In this regard, the exosome pathway is of interest, as several reports have documented that HCV RNA is secreted from infected cells in exosomes, which has been proposed to transfer the infection when taken up by other cells (61)(62)(63)(64). While by nature this would appear to fall within the category of extracellular (i.e., cell-free) spread, a role for exosome pathway components in cell-to-cell spread cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread

Barretto

Sáinz

Hussain

et al. 2014

J Virol

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Hepatitis C virus (HCV) infects 180 million people worldwide and is a leading cause of liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma. It has been shown that HCV can spread to naive cells using two distinct entry mechanisms, "cellfree" entry of infectious extracellular virions that have been released by infected cells and direct "cell-to-cell" transmission. Here, we examined host cell requirements for HCV spread and found that the cholesterol uptake receptor NPC1L1, which we recently identified as being an antiviral target involved in HCV cell-free entry/spread, is also required for the cell-to-cell spread. In contrast, the very low density lipoprotein (VLDL) pathway, which is required for the secretion of cell-free infectious virus and thus has been identified as an antiviral target for blocking cell-free virus secretion/spread, is not required for cell-to-cell spread. Noting that HCV cell-free and cell-to-cell spread share some common factors but not others, we tested the therapeutic implications of these observations and demonstrate that inhibitors that target cell factors required for both forms of HCV spread exhibit synergy when used in combination with interferon (a representative inhibitor of intracellular HCV production), while inhibitors that block only cell-free spread do not. This provides insight into the mechanistic basis of synergy between interferon and HCV entry inhibitors and highlights the broader, previously unappreciated impact blocking HCV cell-to-cell spread can have on the efficacy of HCV combination therapies. IMPORTANCEHCV can spread to naive cells using distinct mechanisms: "cell-free" entry of extracellular virus and direct "cell-to-cell" transmission. Herein, we identify the host cell HCV entry factor NPC1L1 as also being required for HCV cell-to-cell spread, while showing that the VLDL pathway, which is required for the secretion of cell-free infectious virus, is not required for cell-to-cell spread. While both these host factors are considered viable antiviral targets, we demonstrate that only inhibitors that block factors required for both forms of HCV entry/spread (i.e., NPC1L1) exhibit synergy when used in combination with interferon, while inhibitors that block factors required only for cell-free spread (i.e., VLDL pathway components) do not. Thus, this study advances our understanding of HCV cell-to-cell spread, provides mechanistic insight into the basis of drug synergy, and highlights inhibition of HCV spread as a previously unappreciated consideration in HCV therapy design.

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Section: Discussionmentioning

confidence: 99%

Determining the Involvement and Therapeutic Implications of Host Cellular Factors in Hepatitis C Virus Cell-to-Cell Spread

Barretto

Sáinz

Hussain

et al. 2014

J Virol

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“…For example, B-lymphocytes and dendritic cells have been shown to release exosomes that can stimulate T cell proliferation and contribute to a robust immune response [14]. In contrast, tumor cells have been shown to release exosomes that promote tumor growth and metastasis [15], and hepatocytes infected with hepatitis C virus (HCV) have been shown to release exosomes that contain and transmit HCV to other hepatocytes [16–18]. As such, it appears that exosomes serve as a fundamental mechanism of cell communication for basic homeostasis that can be hijacked by malignant and virus-infected cells.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate

Nojima

Freeman

Schuster

et al. 2016

Journal of Hepatology

237

205

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Background & Aims Exosomes are small membrane vesicles involved in intercellular communication. Hepatocytes are known to release exosomes, but little is known about their biological function. We sought to determine if exosomes derived from hepatocytes contribute to liver repair and regeneration after injury. Methods Exosomes derived from primary murine hepatocytes were isolated and characterized biochemically and biophysically. Using cultures of primary hepatocytes, we tested whether hepatocyte exosomes induced proliferation of hepatocytes in vitro. Using models of ischemia/reperfusion injury and partial hepatectomy, we evaluated whether hepatocyte exosomes promote hepatocyte proliferation and liver regeneration in vivo. Results Hepatocyte exosomes, but not exosomes from other liver cell types, induce dose-dependent hepatocyte proliferation in vitro and in vivo. Mechanistically, hepatocyte exosomes directly fuse with target hepatocytes and transfer neutral ceramidase and sphingosine kinase 2 (SK2) causing increased synthesis of sphingosine-1-phosphate (S1P) within target hepatocytes. Ablation of exosomal SK prevents the proliferative effect of exosomes. After ischemia/reperfusion injury, the number of circulating exosomes with proliferative effects increases. Conclusions Our data shows that hepatocyte-derived exosomes deliver the synthetic machinery to form S1P in target hepatocytes resulting in cell proliferation and liver regeneration after ischemia/reperfusion injury or partial hepatectomy. These findings represent a potentially novel new contributing mechanism of liver regeneration and have important implications for new therapeutic approaches to acute and chronic liver disease.

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“…CD81, one of the exosome markers and also one of the HCV entry receptors, regulates the secretion of HCV envelope proteins in the form of exosomes [7]. Endosomal sorting complex responsible for transport (ESCRT)-0 components are involved in HCV budding [8]. In addition, HCV RNA is detected in exosomes and is capable of eliciting innate immune response in dendritic cells [9].…”

Section: Introductionmentioning

confidence: 99%