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13 results on '"Klein, Rahel"'

3. Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα

Author

Dorobantu, Cristina M, Harak, Christian, Klein, Rahel, van der Linden, Lonneke, Strating, Jeroen R P M, van der Schaar, Hilde M, Lohmann, Volker, van Kuppeveld, Frank J M, dI&I I&I-1, LS Virologie, Infection & Immunity, Medical Microbiology and Infection Prevention, dI&I I&I-1, LS Virologie, and Infection & Immunity

Subjects
0301 basic medicine, Hepacivirus, Hepatitis C virus, viruses, Coronacrisis-Taverne, medicine.disease_cause, Virus Replication, Antiviral Agents, Virus, 03 medical and health sciences, chemistry.chemical_compound, medicine, Humans, Pharmacology (medical), Epidermal growth factor receptor, Phosphatidylinositol, Molecular Targeted Therapy, Encephalomyocarditis virus, Enzyme Inhibitors, 1-Phosphatidylinositol 4-Kinase, Pharmacology, biology, Dose-Response Relationship, Drug, Kinase, Chemistry, Tyrphostins, biology.organism_classification, Virology, 3. Good health, 030104 developmental biology, Infectious Diseases, Viral replication, Mutation, biology.protein, Quinazolines, sense organs, PI4KA, hormones, hormone substitutes, and hormone antagonists, HeLa Cells
Abstract

Encephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, both in vitro and in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent.

Published
2016

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Author

Dorobantu, Cristina M, Harak, Christian, Klein, Rahel, van der Linden, Lonneke, Strating, Jeroen R P M, van der Schaar, Hilde M, Lohmann, Volker, van Kuppeveld, Frank J M, Dorobantu, Cristina M, Harak, Christian, Klein, Rahel, van der Linden, Lonneke, Strating, Jeroen R P M, van der Schaar, Hilde M, Lohmann, Volker, and van Kuppeveld, Frank J M

Published
2016

6. Structural and Functional Analysis of Hepatitis C Virus Strain JFH1 Polymerase

Author

Simister, Philip, Schmitt, Melanie, Geitmann, Matthis, Wicht, Oliver, Danielson, Helena, Klein, Rahel, Bressanelli, Stephane, Lohmann, Volker, Simister, Philip, Schmitt, Melanie, Geitmann, Matthis, Wicht, Oliver, Danielson, Helena, Klein, Rahel, Bressanelli, Stephane, and Lohmann, Volker

Abstract

The hepatitis C virus (HCV) isolate JFH1 represents the only cloned wild-type sequence capable of efficient replication in cell culture, as well as in chimpanzees. Previous reports have pointed to the viral polymerase NS5B as a major determinant for efficient replication of this isolate. To understand the underlying mechanisms, we expressed and purified NS5B of JFH1 and of the closely related isolate J6, which replicates below the limit of detection in cell culture. The JFH1 enzyme exhibited a 5- to 10-fold-higher specific activity in vitro, consistent with the polymerase activity itself contributing to efficient replication of JFH1. The higher in vitro activity of the JFH1 enzyme was not due to increased RNA binding, elongation rate, or processivity of the polymerase but to higher initiation efficiency. By using homopolymeric and heteropolymeric templates, we found that purified JFH1 NS5B was significantly more efficient in de novo initiation of RNA synthesis than the J6 counterpart, particularly at low GTP concentrations, probably representing an important prerequisite for the rapid replication kinetics of JFH1. Furthermore, we solved the crystal structure of JFH1 NS5B, which displays a very closed conformation that is expected to facilitate de novo initiation. Structural analysis shows that this closed conformation is stabilized by a sprinkle of substitutions that together promote extra hydrophobic interactions between the subdomains "thumb" and "fingers." These analyses provide deeper insights into the initiation of HCV RNA synthesis and might help to establish more efficient cell culture models for HCV using alternative isolates.

Published
2009
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8. A Comprehensive Structure-Function Comparison of Hepatitis C Virus Strain JFH1 and J6 Polymerases Reveals a Key Residue Stimulating Replication in Cell Culture across Genotypes

Author

Schmitt, Melanie, primary, Scrima, Nathalie, additional, Radujkovic, Danijela, additional, Caillet-Saguy, Célia, additional, Simister, Philip C., additional, Friebe, Peter, additional, Wicht, Oliver, additional, Klein, Rahel, additional, Bartenschlager, Ralf, additional, Lohmann, Volker, additional, and Bressanelli, Stéphane, additional

Published
2011
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12. Analysis of CD8+ T-Cell–Mediated Inhibition of Hepatitis C Virus Replication Using a Novel Immunological Model.

Author

Jo, Juandy, Aichele, Ulrike, Kersting, Nadine, Klein, Rahel, Aichele, Peter, Bisse, Emmanuel, Sewell, Andrew K., Blum, Hubert E., Bartenschlager, Ralf, Lohmann, Volker, and Thimme, Robert

Subjects
T cells, HEPATITIS C, HEPATITIS C virus, IMMUNOLOGY, VIRAL replication, GENETIC transduction, MAJOR histocompatibility complex, MONOCLONAL antibodies, PREVENTION
Abstract

Background & Aims: Virus-specific CD8+ T cells are required for the control of hepatitis C virus (HCV) infection. We investigated the extent to which different effector functions of CD8+ T cells contribute to the inhibition of viral replication. Methods: We developed a novel immunologic model by stably transducing the HLA-A2 gene into the replicon system, matching the epitope sequence of the replicon to the sequence targeted by an HCV-specific CD8+ T-cell clone. Luciferase activity was then measured to quantitate HCV RNA replication. Results: HCV-specific CD8+ T cells strongly inhibited viral replication, through cytolytic and noncytolytic mechanisms, in a dose-dependent manner. HCV replication was almost completely inhibited at an effector-to-target ratio of 1:1 with significant cytotoxicity; however, >95% viral inhibition occurred at ratios as low as 1:100. Importantly, no cytotoxicity was observed at low effector-to-target ratios, indicating a dominant effect of noncytolytic effector functions that was confirmed by Transwell experiments. Neutralization experiments revealed that interferon gamma mediates the noncytolytic inhibition. Conclusions: Only a very few HCV-specific CD8+ T cells are required to inhibit HCV replication; inhibition occurs primarily by noncytolytic effector functions. [Copyright &y& Elsevier]

Published
2009
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13. Tyrphostin AG1478 Inhibits Encephalomyocarditis Virus and Hepatitis C Virus by Targeting Phosphatidylinositol 4-Kinase IIIα.

Author

Dorobantu CM, Harak C, Klein R, van der Linden L, Strating JR, van der Schaar HM, Lohmann V, and van Kuppeveld FJ

Subjects
1-Phosphatidylinositol 4-Kinase metabolism, Dose-Response Relationship, Drug, Encephalomyocarditis virus genetics, Encephalomyocarditis virus physiology, HeLa Cells drug effects, HeLa Cells virology, Hepacivirus physiology, Humans, Molecular Targeted Therapy methods, Mutation, Virus Replication drug effects, 1-Phosphatidylinositol 4-Kinase antagonists & inhibitors, Antiviral Agents pharmacology, Encephalomyocarditis virus drug effects, Enzyme Inhibitors pharmacology, Hepacivirus drug effects, Quinazolines pharmacology, Tyrphostins pharmacology
Abstract

Encephalomyocarditis virus (EMCV), like hepatitis C virus (HCV), requires phosphatidylinositol 4-kinase IIIα (PI4KA) for genome replication. Here, we demonstrate that tyrphostin AG1478, a known epidermal growth factor receptor (EGFR) inhibitor, also inhibits PI4KA activity, both in vitro and in cells. AG1478 impaired replication of EMCV and HCV but not that of an EMCV mutant previously shown to escape PI4KA inhibition. This work uncovers novel cellular and antiviral properties of AG1478, a compound previously regarded only as a cancer chemotherapy agent., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Published
2016
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