Bile Acids Promote the Expression of Hepatitis C Virus in Replicon-Harboring Cells

Abstract

Hepatitis C virus (HCV) is a small, enveloped virus with single-stranded and positive-sense RNA and a genome size of ϳ10 kb in the family Flaviviridae (15). Based on genetic variations among HCV isolates, HCV is classified into six genotypes (1 to 6), with several subtypes within each genotype (17). Genotype 1 is the most common in the United States, Europe, and most parts of Asia (17). HCV is a major public health problem as a cause of chronic liver disease, with more than 170 million persistently infected individuals worldwide (15,17). HCV causes chronic infections in hepatocytes, with continued virus multiplication, while spontaneous clearance of the disease and the virus is rare (15,17). Chronic HCV infection frequently results later in liver cirrhosis and liver cancer. Currently, the most effective treatment for chronic HCV infection is combination therapy with alpha interferon (IFN-␣) and ribavirin. Both IFN-␣ and ribavirin are nonspecific antiviral agents effective against various DNA and RNA viruses. However, despite the improved efficacy of combined therapy with pegylated IFN-␣ and ribavirin, around half of all patients infected with HCV genotype 1 fail to show sustained virologic responses and remain chronically infected (17). The mechanisms underlying this limitation are not well understood. In the absence of an effective HCV vaccine, understanding factors that promote HCV replication and compromise the anti-HCV effect of IFN would be a significant advancement in the development of an effective treatment for HCV infections.As a consequence of being unable to efficiently grow HCV in cell culture, understanding virus replication and developing improved therapeutics have been severely hampered. The development of HCV replicon-harboring cells has provided a valuable tool for studying the basic biology of the virus and new approaches for specific antivirals (16). The HCV replicon system also contributed to the recent success of isolating an HCV strain (genotype 2a) in cell culture (14,35,40). Previously, we demonstrated that the bile acids were essential for the growth of porcine enteric calicivirus (PEC) in cell culture and the replication was associated with the down-regulation of the IFN responses (1). The presence of bile acids at high concentrations in the small intestine, where PEC replicates in vivo, suggests a novel mechanism for host-virus interaction influenced by ubiquitous molecules in the environment. Because hepatocytes are exposed to high concentrations of bile acids in the liver, we hypothesized that bile acids have similar effects on HCV replication. We used replicon-harboring cells with HCV (genotype 1b, Con1) to study the effects of bile acids on virus replication. Here, we report that in the presence of bile acids, genome and protein expressions of HCV were significantly increased in replicon-harboring cells. Using an antagonist of the bile acid receptor, the farnesoid X receptor (FXR), we found that FXR plays a role in the bile acid-mediated promotion of HCV replication. Furthermore, w...

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Inhibitory Effects of Bile Acids and Synthetic Farnesoid X Receptor Agonists on Rotavirus Replication

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Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression

“…This finding has been further validated by another study showing bileacids to target FXRa, resulting in the up-regulation of HBV expression and rendering the host less susceptible to interferon-a treatment (23). Interestingly, bile acidinduced FXR activation has been shown to increase reproduction of other viruses, such as hepatitis C virus (HCV) and Norovirus (52,53).…”