Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication

Steve S. Choi, Shelton Bradrick, Guan Qiang, Anahita Mostafavi, Gaurav Chaturvedi, Steven A. Weinman, Anna Mae Diehl, Ravi Jhaveri

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Studies of the hepatitis C virus (HCV) life-cycle rely heavily on Huh7.5 cells, but the reasons why these cells are exceptionally permissive for HCV replication are not clear. Based on recent clinical observations, we hypothesized that the Hedgehog (Hh) pathway, which has not been previously associated with HCV replication, may be involved in the Huh7.5 phenotype of increased permissiveness. We tested this hypothesis by comparing levels of a variety of Hh-related cellular markers in Huh7.5 cells with the parental Huh7 cells, which are far less permissive. Here we demonstrate that Huh7.5 cells, when compared with Huh7 cells, have substantially decreased expression of epithelial markers, increased levels of mesenchymal markers, and markedly up-regulated Hh pathway activity: Shh, >100-fold, Gli1, >30-fold, Ptc, 2-fold. In Huh7.5 cells, we found that cyclopamine, an Hh pathway antagonist, reduced HCV RNA levels by 50% compared with vehicle and inactive isomer controls. Moreover, in Huh7 cells treatment with recombinant Shh ligand and SAG, both Hh pathway agonists, stimulated HCV replication by 2-fold and 4-fold, respectively. These effects were observed with both viral infections and a subgenomic replicon. Finally, we demonstrated that GDC-0449 decreased HCV RNA levels in a dose-response manner. Conclusion: We have identified a relationship between HCV and Hh signaling where up-regulated pathway activity during infection promotes an environment conducive to replication. Given that Hh activity is very low in most hepatocytes, these findings may serve to further shift the model of HCV liver infection from modest widespread replication in hepatocytes to one where a subset of cells support high-level replication. These findings also introduce Hh pathway inhibitors as potential anti-HCV therapeutics.

Original languageEnglish (US)
Pages (from-to)1580-1590
Number of pages11
JournalHepatology
Volume54
Issue number5
DOIs
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Hepatology

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    Choi, S. S., Bradrick, S., Qiang, G., Mostafavi, A., Chaturvedi, G., Weinman, S. A., Diehl, A. M., & Jhaveri, R. (2011). Up-regulation of Hedgehog pathway is associated with cellular permissiveness for hepatitis C virus replication. Hepatology, 54(5), 1580-1590. https://doi.org/10.1002/hep.24576