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Berlin Brandenburg

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  • 1
    Language: English
    In: 2013, Vol.9(8), p.e1003561
    Description: Hepatitis C virus (HCV) infection develops into chronicity in 80% of all patients, characterized by persistent low-level replication. To understand how the virus establishes its tightly controlled intracellular RNA replication cycle, we developed the first detailed mathematical model of the initial dynamic phase of the intracellular HCV RNA replication. We therefore quantitatively measured viral RNA and protein translation upon synchronous delivery of viral genomes to host cells, and thoroughly validated the model using additional, independent experiments. Model analysis was used to predict the efficacy of different classes of inhibitors and identified sensitive substeps of replication that could be targeted by current and future therapeutics. A protective replication compartment proved to be essential for sustained RNA replication, balancing translation versus replication and thus effectively limiting RNA amplification. The model predicts that host factors involved in the formation of this compartment determine cellular permissiveness to HCV replication. In gene expression profiling, we identified several key processes potentially determining cellular HCV replication efficiency. ; Hepatitis C is a severe disease and a prime cause for liver transplantation. Up to 3% of the world's population are chronically infected with its causative agent, the Hepatitis C virus (HCV). This capacity to establish long (decades) lasting persistent infection sets HCV apart from other plus-strand RNA viruses typically causing acute, self-limiting infections. A prerequisite for its capacity to persist is HCV's complex and tightly regulated intracellular replication strategy. In this study, we therefore wanted to develop a comprehensive understanding of the molecular processes governing HCV RNA replication in order to pinpoint the most vulnerable substeps in the viral life cycle. For that purpose, we used a combination of biological experiments and mathematical modeling. Using the model to study HCV's replication strategy, we recognized diverse but crucial roles for the membraneous replication compartment of HCV in regulating RNA amplification. We further predict the existence of an essential limiting host factor (or function) required for establishing active RNA replication and thereby determining cellular permissiveness for HCV. Our model also proved valuable to understand and predict the effects of pharmacological inhibitors of HCV and might be a solid basis for the development of similar models for other plus-strand RNA viruses.
    Keywords: Research Article ; Biology ; Medicine
    ISSN: 1553-7366
    E-ISSN: 1553-7374
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  • 2
    Language: English
    In: Hepatology, December 2012, Vol.56(6), pp.2082-2093
    Description: 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 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. (H 2012;56:2082–2093)
    Keywords: Antigens, Differentiation–Genetics ; Antigens, Differentiation–Metabolism ; Carrier Proteins–Genetics ; Carrier Proteins–Metabolism ; Gene Expression Regulation–Physiology ; Hepacivirus–Drug Effects ; Hepatocytes–Metabolism ; Hepatocytes–Pharmacology ; Humans–Pharmacology ; Interferon-Alpha–Genetics ; Interferon-Gamma–Metabolism ; Intracellular Signaling Peptides & Proteins–Genetics ; Intracellular Signaling Peptides & Proteins–Metabolism ; Membrane Proteins–Genetics ; Membrane Proteins–Metabolism ; Nitric Oxide Synthase Type II–Genetics ; Nitric Oxide Synthase Type II–Metabolism ; Phospholipid Transfer Proteins–Metabolism ; Phospholipid Transfer Proteins–Genetics ; RNA Interference–Metabolism ; RNA, Messenger–Drug Effects ; RNA-Binding Proteins–Drug Effects ; RNA-Binding Proteins–Drug Effects ; Replicon–Drug Effects ; Tumor Cells, Cultured–Drug Effects ; Up-Regulation–Drug Effects ; Virus Replication–Drug Effects ; Liver Cirrhosis ; Hepatitis ; Cytokines ; Hepatology ; Antigens, Differentiation ; Carrier Proteins ; Ifit3 Protein, Human ; Ifitm3 Protein, Human ; Interferon-Alpha ; Intracellular Signaling Peptides and Proteins ; Membrane Proteins ; Plscr1 Protein, Human ; Phospholipid Transfer Proteins ; RNA, Messenger ; RNA-Binding Proteins ; Trim14 Protein, Human ; Leu-13 Antigen ; Interferon-Gamma ; Nos2 Protein, Human ; Nitric Oxide Synthase Type II;
    ISSN: 0270-9139
    E-ISSN: 1527-3350
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