scholarly journals Two strategies underlying the trade-off of hepatitis C virus proliferation: stay-at-home or leaving-home?

2019 ◽  
Author(s):  
Shoya Iwanami ◽  
Kosaku Kitagawa ◽  
Yusuke Asai ◽  
Hirofumi Ohashi ◽  
Kazane Nishioka ◽  
...  
Keyword(s):  
Growth Rate ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Progeny Virus ◽  
Target Cells ◽  
Initial Growth ◽  
Leaving Home ◽  
Initial Growth Rate ◽  
Infected Cells ◽  
At Home

AbstractViruses proliferate through both genome replication inside infected cells and transmission to new target cells or to new hosts. Each viral genome molecule in infected cells is used either for amplifying the intracellular genome as a template (“stay-at-home strategy”) or for packaging into progeny virions to be released extracellularly (“leaving-home strategy”). The balance between these strategies is important for both initial growth and transmission of viruses. In this study, we used hepatitis C virus (HCV) as a model system to study the functions of viral genomic RNA in both RNA replication in cells and in progeny virus assembly and release. Using viral infection assays combined with mathematical modelling, we characterized the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral assembly and release characteristics. We found that 1.27% and 3.28% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial growth rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leaving-home strategy provides a higher level of initial transmission for Jc1-n, while, in contrast, the stay-at-home strategy provides a higher initial growth rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses. Ours is the first study to analyze stay-leave trade-offs during the viral life cycle and their significance for viral proliferation.

scholarly journals Hepatitis C Virus Entry Depends on Clathrin-Mediated Endocytosis

2006 ◽  
Vol 80 (14) ◽  
pp. 6964-6972 ◽  
Author(s):  
Emmanuelle Blanchard ◽  
Sandrine Belouzard ◽  
Lucie Goueslain ◽  
Takaji Wakita ◽  
Jean Dubuisson ◽  
...  
Keyword(s):  
Cell Culture ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immunoblot Analysis ◽  
Target Cells ◽  
Cellular Mechanisms ◽  
Pit Formation ◽  
Infected Cells ◽  
Interfering Rna ◽  
Hcvcc Infection

ABSTRACT Due to difficulties in cell culture propagation, the mechanisms of hepatitis C virus (HCV) entry are poorly understood. Here, postbinding cellular mechanisms of HCV entry were studied using both retroviral particles pseudotyped with HCV envelope glycoproteins (HCVpp) and the HCV clone JFH-1 propagated in cell culture (HCVcc). HCVpp entry was measured by quantitative real-time PCR after 3 h of contact with target cells, and HCVcc infection was quantified by immunoblot analysis and immunofluorescence detection of HCV proteins expressed in infected cells. The functional role of clathrin-mediated endocytosis in HCV entry was assessed by small interfering RNA-mediated clathrin heavy chain depletion and with chlorpromazine, an inhibitor of clathrin-coated pit formation at the plasma membrane. In both conditions, HCVpp entry and HCVcc infection were inhibited. HCVcc infection was also inhibited by pretreating target cells with bafilomycin A1 or chloroquine, two drugs known to interfere with endosome acidification. These data indicate that HCV enters target cells by clathrin-mediated endocytosis, followed by a fusion step from within an acidic endosomal compartment.

scholarly journals Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner

2016 ◽  
Vol 48 (11) ◽  
pp. e270-e270 ◽  
Author(s):  
In Soo Oh ◽  
Kathrin Textoris-Taube ◽  
Pil Soo Sung ◽  
Wonseok Kang ◽  
Xenia Gorny ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protein Kinase ◽  
Dependent Manner ◽  
Protein Kinase R ◽  
Infected Cells

scholarly journals Binding of Hepatitis C Virus-Like Particles Derived from Infectious Clone H77C to Defined Human Cell Lines

2002 ◽  
Vol 76 (3) ◽  
pp. 1181-1193 ◽  
Author(s):  
Sabine Wellnitz ◽  
Bettina Klumpp ◽  
Heidi Barth ◽  
Susumu Ito ◽  
Erik Depla ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Lines ◽  
Human Cell ◽  
Envelope Glycoprotein ◽  
Infectious Clone ◽  
Cell Interactions ◽  
Target Cells ◽  
Human Cell Lines ◽  
Glycoprotein E2

ABSTRACT Hepatitis C virus (HCV) is a leading cause of chronic hepatitis in the world. The study of viral entry and infection has been hampered by the inability to efficiently propagate the virus in cultured cells and the lack of a small-animal model. Recent studies have shown that in insect cells, the HCV structural proteins assemble into HCV-like particles (HCV-LPs) with morphological, biophysical, and antigenic properties similar to those of putative virions isolated from HCV-infected humans. In this study, we used HCV-LPs derived from infectious clone H77C as a tool to examine virus-cell interactions. The binding of partially purified particles to human cell lines was analyzed by fluorescence-activated cell sorting with defined monoclonal antibodies to envelope glycoprotein E2. HCV-LPs demonstrated dose-dependent and saturable binding to defined human lymphoma and hepatoma cell lines but not to mouse cell lines. Binding could be inhibited by monoclonal anti-E2 antibodies, indicating that the HCV-LP-cell interaction was mediated by envelope glycoprotein E2. Binding appeared to be CD81 independent and did not correlate with low-density lipoprotein receptor expression. Heat denaturation of HCV-LPs drastically reduced binding, indicating that the interaction of HCV-LPs with target cells was dependent on the proper conformation of the particles. In conclusion, our data demonstrate that insect cell-derived HCV-LPs bind specifically to defined human cell lines. Since the envelope proteins of HCV-LPs are presumably presented in a virion-like conformation, the binding of HCV-LPs to target cells may allow the study of virus-host cell interactions, including the isolation of HCV receptor candidates and antibody-mediated neutralization of binding.

scholarly journals Efficient trans-Encapsidation of Hepatitis C Virus RNAs into Infectious Virus-Like Particles

2008 ◽  
Vol 82 (14) ◽  
pp. 7034-7046 ◽  
Author(s):  
Eike Steinmann ◽  
Christiane Brohm ◽  
Stephanie Kallis ◽  
Ralf Bartenschlager ◽  
Thomas Pietschmann
Keyword(s):  
Tissue Culture ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
High Efficiency ◽  
Infectious Virus ◽  
Buoyant Density ◽  
Target Cells ◽  
Packaging Cell Line ◽  
Virus Like Particles ◽  
Rna Elements

ABSTRACT Recently, complete replication of hepatitis C virus (HCV) in tissue culture was established using the JFH1 isolate. To analyze determinants of HCV genome packaging and virion assembly, we developed a system that supports particle production based on trans-packaging of subgenomic viral RNAs. Using JFH1 helper viruses, we show that subgenomic JFH1 replicons lacking the entire core to NS2 coding region are efficiently encapsidated into infectious virus-like particles. Similarly, chimeric helper viruses with heterologous structural proteins trans-package subgenomic JFH1 replicons. Like authentic cell culture-produced HCV (HCVcc) particles, these trans-complemented HCV particles (HCVTCP) penetrate target cells in a CD81 receptor-dependent fashion. Since HCVTCP production was limited by competition between the helper and subgenomic RNA and to avoid contamination of HCVTCP stocks with helper viruses, we created HCV packaging cells. These cells encapsidate various HCV replicons with high efficiency, reaching infectivity titers up to 106 tissue culture infectious doses 50 per milliliter. The produced particles display a buoyant density comparable to HCVcc particles and can be propagated in the packaging cell line but support only a single-round infection in naïve cells. Together, this work demonstrates that subgenomic HCV replicons are assembly competent, thus excluding cis-acting RNA elements in the core-to-NS2 genomic region essential for RNA packaging. The experimental system described here should be helpful to decipher the mechanisms of HCV assembly and to identify RNA elements and viral proteins involved in particle formation. Similar to other vector systems of plus-strand RNA viruses, HCVTCP may prove valuable for gene delivery or vaccination approaches.

scholarly journals Hepatitis C Virus Regulates its Replication by Maturing miR-122 Through Akt-Dependent Phosphorylation of KSRP

2019 ◽  
Author(s):  
Camille Baudesson ◽  
Céline Amadori ◽  
Hassan Danso ◽  
Flora Donati ◽  
Quentin Nevers ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Direct Interaction ◽  
Micro Rna ◽  
Host Protein ◽  
Hcv Rna ◽  
Serine Residue ◽  
Reciprocal Regulation ◽  
Mrna Targets ◽  
Infected Cells

AbstractThe liver-specific micro-RNA-122 (miR-122) is required for the replication of hepatitis C virus (HCV). The direct interaction between miR-122 and the 5’ untranslated region of the HCV genome promotes viral replication and protects HCV RNA from degradation. Because HCV RNA is its own substrate for replication, infected cells are submitted to the sequestration of increasing levels of miR-122 and to global de-repression of host miR-122 mRNA targets. Whether and how HCV regulates miR-122 maturation to create an environment favorable to its replication remains unexplored. We discovered that Akt-dependent phosphorylation of KSRP host protein at Serine residue 193 is essential for miR-122 maturation in hepatocytes. Moreover, we showed the existence of a reciprocal regulation loop where HCV replication can modulate the proviral effect mediated by KSRP-dependent maturation of miR-122. These data support a mechanism by which HCV regulates the expression of miR-122 by hijacking KSRP, thereby fueling its own replication.

Dynamical analysis of a class of hepatitis C virus infection models with application of optimal control

2016 ◽  
Vol 09 (03) ◽  
pp. 1650038 ◽  
Author(s):  
Aida Mojaver ◽  
Hossein Kheiri
Keyword(s):  
Optimal Control ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Deterministic Model ◽  
Treatment Strategies ◽  
Dynamical Analysis ◽  
Existence And Stability ◽  
Direct Cell ◽  
Infected Cells ◽  
The Impact

In this paper, we deal with the problem of optimal control of a deterministic model of hepatitis C virus (HCV). In the first part of our analysis, a mathematical modeling of HCV dynamics which can be controlled by antiretroviral therapy as fixed controls has been presented and analyzed which incorporates two mechanisms: infection by free virions and the direct cell-to-cell transmission. Basic reproduction number is calculated and the existence and stability of equilibria are investigated. In the second part, the optimal control problem representing drug treatment strategies of the model is explored considering control parameters as time-dependent in order to minimize not only the population of infected cells but also the associated costs. At the end of the paper, the impact of combination of the strategies in the control of HCV and their effectiveness are compared by numerical simulation.

scholarly journals Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients

2014 ◽  
Vol 58 (9) ◽  
pp. 5332-5341 ◽  
Author(s):  
Cédric Laouénan ◽  
Patrick Marcellin ◽  
Martine Lapalus ◽  
Feryel Khelifa-Mouri ◽  
Nathalie Boyer ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Triple Therapy ◽  
Pegylated Interferon ◽  
Hcv Rna ◽  
Second Phase ◽  
Compensated Cirrhosis ◽  
Viral Kinetic ◽  
Significant Difference ◽  
Infected Cells

ABSTRACTTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P= 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P= 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively,P= 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day−1) and was higher in patients who subsequently eradicated HCV (P= 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.

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