The membrane on the surface of hepatitis E virus particles is derived from the intracellular membrane and contains trans-Golgi network protein 2

Nagashima, Shigeo; Takahashi, Masaharu; Jirintai, Suljid; Tanggis,; Kobayashi, Tominari; Nishizawa, Tsutomu; Okamoto, Hiroaki

doi:10.1007/s00705-013-1912-3

Cited by 79 publications

(74 citation statements)

References 46 publications

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“…Collectively, these results suggest that two populations of HEV particles are present in the Huh-7 cells, and only quasi-enveloped virions are released into the supernatant. Similar findings were described for PLC/PRF/5 cells (a human hepatoma cell line expressing hepatitis B virus surface antigen) in a recent report (19). In subsequent experiments, gradient-purified eHEV and nonenveloped HEV were used to study the HEV entry process.…”

Section: Hev Released From Infected Cells Is Predominantly Quasi-envesupporting

confidence: 57%

“…Although originally recognized as a nonenveloped virus, recent studies show that HEV circulating in blood is cloaked in host membranes (16). The biogenesis of the membrane-associated, quasi-enveloped HEV particles (eHEV) involves a specific interaction between pORF3 and Tsg101, a cellular component of the endosomal sorting complex required for transport (ESCRT) that is commonly involved in the budding of many classic enveloped viruses (17)(18)(19). As a result, pORF3 is incorporated into the eHEV virion but is not found in virions in the feces (20).…”

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confidence: 99%

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Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

Yin

Ambardekar

et al. 2016

J Virol

214

264

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The hepatitis E virus (HEV) sheds into feces as nonenveloped virions but circulates in the blood in a membrane-associated, quasi-enveloped form (eHEV). Since the eHEV virions lack viral proteins on the surface, we investigated the entry mechanism for eHEV. We found that compared to nonenveloped HEV virions, eHEV attachment to the cell was much less efficient, requiring a longer inoculation time to reach its maximal infectivity. A survey of cellular internalization pathways identified clathrin-mediated endocytosis as the main route for eHEV entry. Unlike nonenveloped HEV virions, eHEV entry requires Rab5 and Rab7, small GTPases involved in endosomal trafficking, and blocking endosomal acidification abrogated eHEV infectivity. However, low pH alone was not sufficient for eHEV uncoating, suggesting that additional steps are required for entry. Supporting this concept, eHEV infectivity was substantially reduced in cells depleted of Niemann-Pick disease type C1, a lysosomal protein required for cholesterol extraction from lipid, or in cells treated with an inhibitor of lysosomal acid lipase. These data support a model in which the quasi-envelope is degraded within the lysosome prior to virus uncoating, a potentially novel mechanism for virus entry. IMPORTANCEThe recent discovery of quasi-enveloped viruses has shifted the paradigm of virus-host interactions. The impact of quasi-envelopment in the virus life cycle and pathogenesis is largely unknown. HEV is a highly relevant model to study these questions. HEV circulates as quasi-enveloped virions in the blood that are hidden from neutralizing antibodies. eHEV particles most likely are responsible for the cell-to-cell spread of the virus. Given the increasing concerns about persistent HEV infection and its potential for transmission via the blood supply, understanding how eHEV infects cells is important for understanding its pathogenesis and developing therapies. Our data provide evidence that eHEV uses a potentially novel mechanism for cellular entry. Several steps critical to eHEV entry were identified and may provide a basis for developing treatments for hepatitis E. Because quasienveloped viruses resemble exosomes, these data also may provide insights into the exosome-mediated intercellular communications.

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Section: Hev Released From Infected Cells Is Predominantly Quasi-envesupporting

confidence: 57%

mentioning

confidence: 99%

Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

Yin

Ambardekar

et al. 2016

J Virol

214

264

View full text Add to dashboard Cite

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“…HEV virions from plasma and feces have been found to differ in virion density, ascribed to a divergent lipid membrane content. In addition, culture-derived HEV has characteristics comparable to those of plasma-derived HEV (23,24). Differences between these viruses might be caused by the detergent activity of bile acids, which could strip the HEV virions from their lipid membrane upon their passage toward the intestinal system (25).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis E Virus (HEV) Genotype 3 Infection of Human Liver Chimeric Mice as a Model for Chronic HEV Infection

Garde

Pas

Net

et al. 2016

J Virol

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Genotype 3 (gt3) hepatitis E virus (HEV) infections are emerging in Western countries. Immunosuppressed patients are at risk of chronic HEV infection and progressive liver damage, but no adequate model system currently mimics this disease course. Here we explore the possibilities of in vivo HEV studies in a human liver chimeric mouse model (uPA ؉/؉ Nod-SCID-IL2R␥ ؊/؊ ) next to the A549 cell culture system, using HEV RNA-positive EDTA-plasma, feces, or liver biopsy specimens from 8 immunocompromised patients with chronic gt3 HEV. HEV from feces-or liver-derived inocula showed clear virus propagation within 2 weeks after inoculation onto A549 cells, compared to slow or no HEV propagation of HEV RNA-positive, EDTA-plasma samples. These in vitro HEV infectivity differences were mirrored in human-liver chimeric mice after intravenous (i.v.) inoculation of selected samples. HEV RNA levels of up to 8 log IU HEV RNA/gram were consistently present in 100% of chimeric mouse livers from week 2 to week 14 after inoculation with human feces-or liver-derived HEV. Feces and bile of infected mice contained moderate to large amounts of HEV RNA, while HEV viremia was low and inconsistently detected. Mouse-passaged HEV could subsequently be propagated for up to 100 days in vitro. In contrast, cell culture-derived or seronegative EDTA-plasma-derived HEV was not infectious in inoculated animals. In conclusion, the infectivity of feces-derived human HEV is higher than that of EDTA-plasma-derived HEV both in vitro and in vivo. Persistent HEV gt3 infections in chimeric mice show preferential viral shedding toward mouse bile and feces, paralleling the course of infection in humans. H epatitis E virus (HEV) is a nonenveloped positive-sense single-stranded RNA virus of the genus Orthohepevirus and family Hepeviridae (1). Four major HEV genotypes infecting humans have been described so far. Genotype 1 (gt1) and gt2 strains are isolated only from humans, whereas gt3 and gt4 strains are considered zoonotic viruses, present in both humans and several other species like pigs and wild game. HEV is spread through the oral-fecal route via contaminated water in developing countries or, among other routes, via direct contact with animals or the consumption of undercooked meat in industrialized countries. In immunocompetent individuals, HEV infection is mainly self-limiting and often asymptomatic and thus remains largely underdiagnosed. HEV infections in immunosuppressed patients, such as solid-organ transplant recipients, often persist and can progress quickly to liver fibrosis and cirrhosis (2-4).HEV gt3 infections are emerging in Western countries, including France, the United Kingdom, and the Netherlands (5-7). Despite an overall decrease in anti-HEV seroprevalence from 1996 to 2011, young adult blood donors demonstrated higher seroprevalences from 2000 to 2011 (8, 9). In addition, HEV RNA-positive blood donations were reported to increase in the Netherlands since 2012 (10). Although the exact source of this HEV gt3 infection is unknown,...

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“…One recent study concluded that the membrane is derived from the trans-Golgi network (TGN) because it contains the trans-Golgi network protein 2 (TGOLN2) [30]. Since TGOLN2 cycles between the TGN and endocytic compartments, it is possible that this membrane protein is transferred to the MVB via vesicular transport and is “accidentally” incorporated into the eHEV envelope.…”

Section: Biogenesis Of Enveloped Hev Particlesmentioning

confidence: 99%

Role of Envelopment in the HEV Life Cycle

Yin

Feng

2016

Viruses

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Hepatitis E virus (HEV), an enterically transmitted hepatotropic virus, was thought to be non-enveloped for decades. However, recent studies have revealed that the virus circulating in the patient’s blood is completely cloaked in host membranes and resistant to neutralizing antibodies. The discovery of this novel enveloped form of HEV has raised a series of questions about the fundamental biology of HEV and the way this virus, which has been understudied in the past, interacts with its host. Here, we review recent advances towards understanding this phenomenon and discuss its potential impact on various aspects of the HEV life cycle and immunity.

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The membrane on the surface of hepatitis E virus particles is derived from the intracellular membrane and contains trans-Golgi network protein 2

Cited by 79 publications

References 46 publications

Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses

Hepatitis E Virus (HEV) Genotype 3 Infection of Human Liver Chimeric Mice as a Model for Chronic HEV Infection

Role of Envelopment in the HEV Life Cycle

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