Abstract
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.
Highlights
Hepatitis C virus (HCV) infection is a major global health problem, with approximately 170 million chronically infected individuals worldwide and 3 to 4 million new infections occurring each year [1]
We 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
We used a combination of biological experiments and mathematical modeling
Summary
Hepatitis C virus (HCV) infection is a major global health problem, with approximately 170 million chronically infected individuals worldwide and 3 to 4 million new infections occurring each year [1]. NS3 comprises an RNA helicase and a protease domain, the latter of which, together with the co-factor NS4A, forms the major viral protease NS3/4A, liberating itself and all other replicase proteins from the polyprotein precursor. NS4B, together with other NS proteins, induces membrane alterations, observable as convoluted, vesicular membrane structures known as the membranous web and believed to act as the sites of RNA replication [6,7]. In order to amplify the viral RNA, NS5B first synthesizes a complementary (i.e. negatively oriented) strand from the plus stranded genome, putatively resulting in a double-stranded (ds) intermediate [9]. From this negative strand template, NS5B transcribes progeny plus strands. Given the ,10-fold higher number of plus strands over
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