Bile Acids Specifically Increase Hepatitis C Virus RNA-Replication

<div><h3>Background</h3><p>Hepatitis C virus (HCV) patients with high serum levels of bile acids (BAs) respond poorly to IFN therapy. BAs have been shown to increase RNA-replication of genotype 1 but not genotype 2a replicons. Since BAs modulate lipid metabolism including lipoprotein secretion and as HCV depends on lipids and lipoproteins during RNA-replication, virus production and cell entry, BAs may affect multiple steps of the HCV life cycle. Therefore, we analyzed the influence of BAs on individual steps of virus replication.</p> <h3>Methods</h3><p>We measured replication of subgenomic genotype (GT) 1b and 2a RNAs as well as full-length GT2a genomes in the presence of BAs using quantitative RT-PCR and luciferase assays. Cell entry was determined using HCV pseudoparticles (HCVpp). Virus assembly and release were quantified using a core-specific ELISA. Replicon chimeras were employed to characterize genotype-specific modulation of HCV by BAs. Lunet CD81/GFP-NLS-MAVS cells were used to determine infection of Con1 particles.</p> <h3>Results</h3><p>BAs increased RNA-replication of GT1b replicons up to 10-fold but had no effect on subgenomic GT2a replicons both in Huh-7 and HuH6 cells. They did not increase viral RNA translation, virus assembly and release or cell entry. Lowering replication efficiency of GT2a replicons rendered them susceptible to stimulation by BAs. Moreover, replication of full length GT1b with or without replication enhancing mutations and GT2a genomes were also stimulated by BAs.</p> <h3>Conclusions</h3><p>Bile acids specifically enhance RNA-replication. This is not limited to GT1, but also holds true for GT2a full length genomes and subgenomic replicons with low replication capacity. The increase of HCV replication by BAs may influence the efficacy of antiviral treatment in vivo and may improve replication of primary HCV genomes in cell culture.</p> </div

Military coups d'état and the distribution of domestic institutional political power within democracies: the case of post-1789 France

Peter Feaver’s agency theory of civil–military relations posits that within democratic countries the relationship between civilian and military leaderships is fluid. This chapter seeks to see how civil–military relations within democracies are influenced by the distribution of domestic political power, shown particularly in whether the country has a presidential or parliamentary form of government, or their approximate. France since 1789 is a case (however imperfect) of a democratic country where the distribution of domestic political power has fluctuated between autocratic and collective forms of decision-making. This chapter presents a longitudinal case study of how since 1789 French civilian leaders have attempted to control the French military, with a focus on how the distribution of domestic political power influenced civil–military relations. This chapter hypothesizes that when there is a concentration of domestic political power, the military is more likely to be compliant with the civilian leadership, but when that power is more diffused, the military is less likely to be compliant. This is because when political power is more concentrated, the military has more confidence in the government, limiting the scope through which the military can inject itself into politics. However, when political power is more diffused, the military is more likely to feel that it has the duty and the opening through which to inject itself into politics