Intravascular Transfer Contributes to Postprandial Increase in Numbers of Very-Low-Density Hepatitis C Virus Particles

Felmlee, Daniel J.; Sheridan, David; Bridge, Simon; Nielsen, Søren; Milne, Ross W.; Packard, Chris J.; Caslake, Muriel; McLauchlan, John; Toms, G. L.; Neely, R. D. G.; Bassendine, Margaret F.

doi:10.1053/j.gastro.2010.07.047

Cited by 69 publications

(74 citation statements)

References 35 publications

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“…In fact, lipid composition of HCV, and thus its size and density, very much depends on the host cell in which the virus is produced. For instance, HCV from primary human hepatocytes or patient sera has a much lower density and association with apoB as compared with HCV produced in Huh7 cells (16,(67)(68)(69). This "lipid imprinting" of HCV particles and its dependence on the particular host cell may explain some of the discrepant observations reported in various studies.…”

Section: Discussioncontrasting

confidence: 42%

Biochemical and Morphological Properties of Hepatitis C Virus Particles and Determination of Their Lipidome

Merz

Long

Hiet

et al. 2011

Journal of Biological Chemistry

312

355

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A hallmark of hepatitis C virus (HCV) particles is their association with host cell lipids, most notably lipoprotein components. It is thought that this property accounts for the low density of virus particles and their large heterogeneity. However, the composition of infectious virions and their biochemical and morphological properties are largely unknown. We developed a system in which the envelope glycoprotein E2 was Nterminally tagged with a FLAG epitope. This virus, designated Jc1E2 FLAG , produced infectivity titers to wild type levels and allowed affinity purification of virus particles that were analyzed for their protein and lipid composition. By using mass spectrometry, we found the lipid composition of Jc1E2 FLAG particles to resemble the one very low-and low density-lipoprotein with cholesteryl esters accounting for almost half of the total HCV lipids. Thus, HCV particles possess a unique lipid composition that is very distinct from all other viruses analyzed so far and from the human liver cells in which HCV was produced. By electron microscopy (EM), we found purified Jc1E2 FLAG particles to be heterogeneous, mostly spherical structures, with an average diameter of about 73 nm. Importantly, the majority of E2-containing particles also contained apoE on their surface as assessed by immuno-EM. Taken together, we describe a rapid and efficient system for the production of large quantities of affinity-purified HCV allowing a comprehensive analysis of the infectious virion, including the determination of its lipid composition.

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Section: Discussioncontrasting

confidence: 42%

Biochemical and Morphological Properties of Hepatitis C Virus Particles and Determination of Their Lipidome

Merz

Long

Hiet

et al. 2011

Journal of Biological Chemistry

312

355

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“…BHK-WNV cells produce infectious HCV particles independently from lipoprotein biosynthesis. The fact that these particles retain the possibility to interact with lipoproteins in vitro [8] is in line with previous results [12][13][14] and supports the view that HCV particles may interact with lipoproteins in a second step (e.g., [15,16] ) and not necessarily co-assemble with them (e.g., [17] ). Potential mechanisms for WNV-conditioned BHK cells producing highly infectious HCV virions could relate to common genomic features between the Flavivirus and Hepacivirus genera within the Flaviviridae family [18] .…”

Section: Introductionsupporting

confidence: 76%

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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“…A hallmark of HCV particles is their peculiar heterogeneity, exhibiting diverse buoyant densities ranging from Ͻ1.06 to Ͼ1.25 g/ml in the blood of infected patients (2)(3)(4)(5)(6). Viral RNA detected in low density fractions is associated with lipoprotein components such as triglycerides and apolipoproteins (apo) (2,3,5).…”

mentioning

confidence: 99%

Characterization of Hepatitis C Virus Particle Subpopulations Reveals Multiple Usage of the Scavenger Receptor BI for Entry Steps

Thi

Granier

Zeisel

et al. 2012

Journal of Biological Chemistry

109

111

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Intravascular Transfer Contributes to Postprandial Increase in Numbers of Very-Low-Density Hepatitis C Virus Particles

Cited by 69 publications

References 35 publications

Biochemical and Morphological Properties of Hepatitis C Virus Particles and Determination of Their Lipidome

Biochemical and Morphological Properties of Hepatitis C Virus Particles and Determination of Their Lipidome

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

Characterization of Hepatitis C Virus Particle Subpopulations Reveals Multiple Usage of the Scavenger Receptor BI for Entry Steps

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