Abstract
Genotype 2a JFH1 virus has substantially contributed to the progress of HCV biology by allowing entire viral life cycle of HCV in cell culture. Using this genotype 2a virus, casein kinase II (CKII) was previously identified as a crucial host factor in virus assembly by phosphorylating NS5A. Since most of the prior studies employed genotype 2a JFH1 or JFH1-based intragenotypic chimera, we used genotype 1a H77S to study virus assembly. CKII inhibition by chemical inhibitors enhanced H77S virus production in contrast to that of JFH1 virus, but genetic inhibition of CKII by siRNA did not change H77S virus titer significantly. The different outcomes from these two approaches of CKII inhibition suggested that nonspecific target kinase of CKII inhibitors plays a role in increasing H77S virus production and both viral and host factors were investigated in this study. Our results emphasize substantial differences among the HCV genotypes that should be considered in both basic research and clinical practices.
Highlights
Hepatitis C virus (HCV) is a causative pathogen of chronic hepatitis C, cirrhosis, and hepatocellular carcinoma and approximately 170 million people are infected worldwide with this virus
CX-4945, a selective casein kinase II (CKII) inhibitor, has entered human clinical trials it was for its anti-tumor activity not for antiviral activity [12]
DMAT was shown previously to inhibit infectious genotype 2a HCV production without affecting viral RNA replication [11], and this suggested that CKII inhibitor could be considered as another therapeutic option for HCV antiviral treatment
Summary
Hepatitis C virus (HCV) is a causative pathogen of chronic hepatitis C, cirrhosis, and hepatocellular carcinoma and approximately 170 million people are infected worldwide with this virus (for a review, see [1]). Infection with genotype 1a HCV, previous null response to pegylated interferon-a/ribavirin therapy, and cirrhosis are difficult cases to cure [2]. The other proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) located at the C-terminus of the polyprotein are nonstructural proteins and participate in diverse steps of viral life cycle including genome replication, particle assembly, etc. Since JFH1 and H77S were discovered as cell culture infectious HCV clones [4, 5], studying all steps of HCV viral life cycle has become possible and novel functions of nonstructural proteins in HCV life cycle other than viral RNA replication have been intensively studied (for a recent review, see [6])
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