Hepatitis C Virus RNA Replication and Assembly: Living on the Fat of the Land

Paul, David; Madan, Vanesa; Bartenschlager, Ralf

doi:10.1016/j.chom.2014.10.008

Cited by 225 publications

(269 citation statements)

References 120 publications

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“…However, a major unresolved issue is whether LVPs represent either hybrid particles that share an envelope or conventional virus particles that spontaneously interact with separable serum lipoprotein particles (9,12). On E2-specific antibody-coated electron microscopy (EM) grids, affinity-purified HCV LVPs are generally spherical and well separated under electron microscopy (14,32), indicating that most of the LVPs are in a hybrid particle form which resembles lipoprotein particles and support exchangeable apolipoprotein transfer.…”

Section: Discussionmentioning

confidence: 99%

“…A hallmark of HCV infectious particles is their tight connection with very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), giving rise to a hybrid form of lipoviral particles (LVPs) with heterogeneous buoyant density (5)(6)(7)(8)(9)(10)(11)(12). Nonexchangeable apolipoprotein B (apoB) and several exchangeable apolipoproteins (apoE, apoA-I, and apoC-I) have been found on the LVP surface (13)(14)(15).…”

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confidence: 99%

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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%

mentioning

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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“…These changes are more marked in HCV genotype 3 infection and effective anti-viral treatment results in their reversal [reviewed in (6,7)]. Despite this apparently favourable lipid profile, HCV infection is associated with an increased risk of atherosclerosis and its clinical manifestations (8).…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C virus and atherosclerosis: A legacy after virologic cure?

Bassendine

Nielsen

Bridge

et al. 2017

Clinics and Research in Hepatology and Gastroenterology

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We discuss possible factors involved in the aetiopathogenesis of atherosclerosis in chronic HCV and hypothesise that an important mechanism underlying the development of AS is the presence of circulating low-density immune complexes that induce an inflammatory response.We suggest that HCV particles may be inducing an antibody response to lipoproteins present in the lipo-viral particles and sub-viral particles -a concept similar to the more general 'autoantibody' response to modified LDL.After virologic cure some AS risk factors will recede but an increase in serum cholesterol could result in progression of early atherosclerotic lesions, leaving a legacy from persistent HCV infection that has clinical and therapeutic implications.

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“…A great deal of new knowledge with respect to the details of the HCV life cycle in vitro has recently been obtained (11,12), using newly developed infectious HCV cell culture models (13)(14)(15)(16). However, little is known about the underlying mechanisms of viral pathogenesis and carcinogenesis, host response to HCV infection, and virus-host interaction in vivo primarily due to the lack of small animal models of HCV infection and replication (17).…”

mentioning

confidence: 99%

The Serum Very-Low-Density Lipoprotein Serves as a Restriction Factor against Hepatitis C Virus Infection

Jiang

Kang

Hall

et al. 2015

J Virol

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Recent studies demonstrated that transgenic mice expressing key human hepatitis C virus (HCV) receptors are susceptible to HCV infection, albeit at very low efficiency. Robust mouse models of HCV infection and replication are needed to determine the importance of host factors in HCV replication, pathogenesis, and carcinogenesis as well as to facilitate the development of antiviral agents and vaccines. The low efficiency of HCV replication in the humanized mouse models is likely due to either the lack of essential host factors or the presence of restriction factors for HCV infection and/or replication in mouse hepatocytes. To determine whether HCV infection is affected by restriction factors present in serum, we examined the effects of mouse and human sera on HCV infectivity. Strikingly, we found that mouse and human sera potently inhibited HCV infection. Mechanistic studies demonstrated that mouse serum blocked HCV cell attachment without significant effect on HCV replication. Fractionation analysis of mouse serum in conjunction with targeted mass spectrometric analysis suggested that serum very-low-density lipoprotein (VLDL) was responsible for the blockade of HCV cell attachment, as VLDL-depleted mouse serum lost HCV-inhibitory activity. Both purified mouse and human VLDL could efficiently inhibit HCV infection. Collectively, these findings suggest that serum VLDL serves as a major restriction factor of HCV infection in vivo. The results also imply that reduction or elimination of VLDL production will likely enhance HCV infection in the humanized mouse model of HCV infection and replication. IMPORTANCEHCV is a major cause of liver diseases, such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Recently, several studies suggested that humanized mouse or transgenic mouse expressing key HCV human receptors became susceptible to HCV infection. However, HCV infection and replication in the humanized animals were very inefficient, suggesting either the lack of cellular genes important for HCV replication or the presence of restriction factors inhibiting HCV infection and replication in the mouse. In this study, we found that both mouse and human sera effectively inhibited HCV infection. Mechanistic studies demonstrated that VLDL is the major restriction factor that blocks HCV infection. These findings suggest that VLDL is beneficial to patients by restricting HCV infection. More importantly, our findings suggest that elimination of VLDL will lead to the development of more robust mouse models for the study of HCV pathogenesis, host response to HCV infection, and evaluation of HCV vaccines. H epatitis C virus (HCV) is an enveloped RNA virus containing a single-stranded and positive-sense RNA genome of 9.6 kb in length. It is the prototype of the Hepacivirus genus in the Flaviviridae family. The virion RNA (vRNA) genome encodes a large polyprotein precursor that is proteolytically cleaved by cellular and viral proteases into structural (core, E1, E2, and p7) and nonstructural (NS) proteins (NS2, ...

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Hepatitis C Virus RNA Replication and Assembly: Living on the Fat of the Land

Cited by 225 publications

References 120 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

Hepatitis C virus and atherosclerosis: A legacy after virologic cure?

The Serum Very-Low-Density Lipoprotein Serves as a Restriction Factor against Hepatitis C Virus Infection

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