5 results on '"Volker Lohmann"'
Search Results
2. Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication
- Author
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Marc P. Windisch, Volker Lohmann, Ralf Bartenschlager, Artur Kaul, Johanna Mazur, Lars Kaderali, Philippe Metz, Alessia Ruggieri, Michael Frese, Marco Binder, Martin Trippler, Ulf Zeuge, and Eva Dazert
- Subjects
Hepatitis C virus ,Medizin ,Nitric Oxide Synthase Type II ,Hepacivirus ,Virus Replication ,medicine.disease_cause ,Tripartite Motif Proteins ,Interferon-gamma ,Interferon ,RNA interference ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,Replicon ,Phospholipid Transfer Proteins ,Gene ,Hepatology ,biology ,Effector ,Intracellular Signaling Peptides and Proteins ,Interferon-alpha ,Membrane Proteins ,RNA-Binding Proteins ,virus diseases ,Nitric oxide synthase 2 ,Antigens, Differentiation ,Virology ,Up-Regulation ,Gene Expression Regulation ,Viral replication ,Hepatocytes ,biology.protein ,RNA Interference ,Carrier Proteins ,medicine.drug - Abstract
Persistent infection with hepatitis C virus (HCV) can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All current therapies of hepatitis C include interferon-alpha (IFN-α). Moreover, IFN-gamma (IFN-γ), the only type II IFN, strongly inhibits HCV replication in vitro and is the primary mediator of HCV-specific antiviral T-cell responses. However, for both cytokines the precise set of effector protein(s) responsible for replication inhibition is not known. The aim of this study was the identification of IFN-α and IFN-γ stimulated genes (ISGs) responsible for controlling HCV replication. We devised an RNA interference (RNAi)-based “gain of function” screen and identified, in addition to known ISGs earlier reported to suppress HCV replication, several new ones with proven antiviral activity. These include IFIT3 (IFN-induced protein with tetratricopeptide repeats 3), TRIM14 (tripartite motif containing 14), PLSCR1 (phospholipid scramblase 1), and NOS2 (nitric oxide synthase 2, inducible). All ISGs identified in this study were up-regulated both by IFN-α and IFN-γ, demonstrating a substantial overlap of HCV-specific effectors induced by either cytokine. Nevertheless, some ISGs were more specific for IFN-α or IFN-γ, which was most pronounced in case of PLSCR1 and NOS2 that were identified as main effectors of IFN-γ-mediated anti-HCV activity. Combinatorial knockdowns of ISGs suggest additive or synergistic effects demonstrating that with either IFN, inhibition of HCV replication is caused by the combined action of multiple ISGs. Conclusion: Our study identifies a number of novel ISGs contributing to the suppression of HCV replication by type I and type II IFN. We demonstrate a substantial overlap of antiviral programs triggered by either cytokine and show that suppression of HCV replication is mediated by the concerted action of multiple effectors. (HEPATOLOGY 2012;56:2082–2093)
- Published
- 2012
3. Human leukocyte antigen B27 selects for rare escape mutations that significantly impair hepatitis C virus replication and require compensatory mutations
- Author
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Susan Ingber, Cesar Oniangue-Ndza, Matthew R. Henn, K. Nitschke, Arthur Y. Kim, Célia Caillet-Saguy, Thomas Kuntzen, Nadine Kersting, Alessandro Sette, Christoph Neumann-Haefelin, Volker Lohmann, Marco Binder, Laura L. Reyor, Michael Kemper, John Sidney, Todd M. Allen, Georg M. Lauer, Julia Schmidt, Kelsey Hills-Evans, Karen A. Power, Stéphane Bressanelli, Robert Thimme, Department of Medicine II, University of Freiburg [Freiburg], Royal rehabilitation centre, Sydney, Laboratory of Epidemiology, Clinical Epidemiology Unit, Istituto Superiore di Sanita [Rome], Laboratoire de virologie moléculaire et structurale (LVMS), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), and Heidelberg University
- Subjects
musculoskeletal diseases ,MESH: Mutation ,[SDV]Life Sciences [q-bio] ,Hepacivirus ,Hepatitis C virus ,Epitopes, T-Lymphocyte ,MESH: Immunodominant Epitopes ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Virus Replication ,medicine.disease_cause ,Sensitivity and Specificity ,Sampling Studies ,Article ,Epitope ,MESH: Epitopes, T-Lymphocyte ,03 medical and health sciences ,0302 clinical medicine ,MESH: Sampling Studies ,Genotype ,medicine ,Humans ,MESH: Hepacivirus ,HLA-B27 Antigen ,030304 developmental biology ,Subgenomic mRNA ,MESH: Hepatitis C ,Genetics ,0303 health sciences ,Mutation ,Binding Sites ,MESH: Humans ,Hepatology ,biology ,Immunodominant Epitopes ,MESH: Virus Replication ,biology.organism_classification ,Hepatitis C ,MESH: CD8-Positive T-Lymphocytes ,Virology ,MESH: Sensitivity and Specificity ,3. Good health ,MESH: Binding Sites ,Viral replication ,030211 gastroenterology & hepatology ,MESH: HLA-B27 Antigen - Abstract
Human leukocyte antigen B27 is associated with spontaneous viral clearance in hepatitis C virus (HCV) infection. Viral escape within the immunodominant, HLA-B27-restricted, HCV-specific, cluster of differentiation (CD)8+ T-cell epitope, nonstructural protein (NS)5B2841-2849 (ARMILMTHF), has been shown to be limited by viral fitness costs as well as broad T-cell cross-recognition, suggesting a potential mechanism of protection by HLA-B27. Here, we studied the subdominant HLA-B27-restricted epitope, NS5B2936-2944 (GRAAICGKY), to further define the mechanisms of protection by HLA-B27. We identified a unique pattern of escape mutations within this epitope in a large cohort of HCV genotype 1a–infected patients. The predominant escape mutations represented conservative substitutions at the main HLA-B27 anchor residue or a T-cell receptor contact site, neither of which impaired viral replication capacity, as assessed in a subgenomic HCV replicon system. In contrast, however, in a subset of HLA-B27+ subjects, rare escape mutations arose at the HLA-B27 anchor residue, R2937, which nearly abolished viral replication. Notably, these rare mutations only occurred in conjunction with the selection of two equally rare, and structurally proximal, upstream mutations. Coexpression of these upstream mutations with the rare escape mutations dramatically restored viral replication capacity from
- Published
- 2011
4. Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy
- Author
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Marco Binder, Ralf Bartenschlager, Georg Kochs, and Volker Lohmann
- Subjects
Permissiveness ,viruses ,Hepatitis C virus ,Hepacivirus ,Biology ,Virus Replication ,medicine.disease_cause ,Virus ,Cell Line ,DEAD-box RNA Helicases ,medicine ,Humans ,Receptors, Immunologic ,RNA, Double-Stranded ,Innate immune system ,Hepatology ,virus diseases ,RNA ,Virology ,digestive system diseases ,NS2-3 protease ,Cell culture ,Host-Pathogen Interactions ,DEAD Box Protein 58 ,RNA, Viral ,Interferon Regulatory Factor-3 ,Signal Transduction ,Interferon regulatory factors - Abstract
Hepatitis C virus (HCV) has been known to replicate with extremely varying efficiencies in different host cells, even within different populations of a single human hepatoma cell line, termed Huh-7. Several reports have implicated the retinoic-acid inducible gene I (RIG-I)/ interferon regulatory factor 3 (IRF-3) pathway of the innate antiviral response with differences in host cell permissiveness to HCV. To investigate the general impact of the IRF-3 response onto HCV replication in cell culture, we generated an ample array of stable Huh-7 cell lines with altered IRF-3 responsiveness. Neither blocking IRF-3 activation in various host cells by expression of dominant negative RIG-I or HCV NS3/4A protease nor reconstitution of RIG-I signaling in Huh7.5, a cell clone known to be defective in this pathway, had any impact on HCV replication. Only by overexpressing constitutively active RIG-I or the signaling adaptor Cardif (also known as interferon-beta promoter stimulator 1, mitochondrial anti-viral signaling protein, or virusinduced signaling adaptor), both leading to a stimulation of the IRF-3 pathway in the absence of inducers, was HCV replication significantly inhibited. We therefore assessed the extent of RIG-I– dependent IRF-3 activation by different species of RNA, including full-length HCV genomes and HCV RNA duplexes, and observed strong induction only in response to double-stranded RNAs. Conclusion: Based on these findings, we propose a refined model of innate immune escape by HCV involving limited initial induction and stringent subsequent control of the IRF-3 response. (HEPATOLOGY 2007;46:1365-1374.)
- Published
- 2007
5. Interferon-γ inhibits replication of subgenomic and genomic hepatitis C virus RNAs
- Author
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Nicole Krieger, Ralf Bartenschlager, Verena Schwärzle, Michael Frese, Kerstin Barth, Volker Lohmann, Sabine Mihm, and Otto Haller
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Hepatology ,Hepatitis C virus ,virus diseases ,Biology ,medicine.disease_cause ,Virology ,digestive system diseases ,Virus ,NS2-3 protease ,Cell killing ,Viral replication ,medicine ,Interferon gamma ,Interferon alfa ,medicine.drug ,Subgenomic mRNA - Abstract
Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-alpha) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-alpha on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show that IFN-gamma inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons. We further show that the inhibitory action of IFN-gamma does not rely on the production of nitric oxide or the depletion of tryptophan. In conclusion, our results suggest that cytotoxic T cells and natural killer cells may contribute to HCV clearance not only by cell killing but also by producing IFN-gamma, thereby enhancing the intracellular inhibition of viral replication.
- Published
- 2002
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