The Novel Immunosuppressive Protein Kinase C Inhibitor Sotrastaurin Has No Pro-Viral Effects on the Replication Cycle of Hepatitis B or C Virus

Thomas Von Hahn,Andreas Schulze,Ivan Chicano Wust,Benjamin Heidrich,Michael P Manns,Thomas Pietschmann,Fabian A Helfritz,Sandra Ciesek,Eike Steinmann,Stephan Urban,Thomas Becker,Katrin Rohrmann,Peter Sommer

doi:10.1371/journal.pone.0024142

Abstract

The pan-protein kinase C (PKC) inhibitor sotrastaurin (AEB071) is a novel immunosuppressant currently in phase II trials for immunosuppression after solid organ transplantation. Besides T-cell activation, PKC affects numerous cellular processes that are potentially important for the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV), major blood-borne pathogens prevalent in solid organ transplant recipients. This study uses state of the art virological assays to assess the direct, non-immune mediated effects of sotrastaurin on HBV and HCV. Most importantly, sotrastaurin had no pro-viral effect on either HBV or HCV. In the presence of high concentrations of sotrastaurin, well above those used clinically and close to levels where cytotoxic effects become detectable, there was a reduction of HCV and HBV replication. This reduction is very likely due to cytotoxic and/or anti-proliferative effects rather than direct anti-viral activity of the drug. Replication cycle stages other than genome replication such as viral cell entry and spread of HCV infection directly between adjacent cells was clearly unaffected by sotrastaurin. These data support the evaluation of sotrastaurin in HBV and/or HCV infected transplant recipients.

Highlights

Worldwide about half a billion people are chronically infected with the hepatitis B virus (HBV), hepatitis C virus (HCV) or both and at risk for cirrhosis and hepatocellular carcinoma
Huh-7.5 cells were electroporated with the in vitro transcribed HCV Jc1-Luc genome and 4 hours later increasing amounts of sotrastaurin were added to the medium
The most important finding of this study is that sotrastaurin does not upregulate HBV or HCV replication in any of our assay

Summary

Introduction

Worldwide about half a billion people are chronically infected with the hepatitis B virus (HBV), hepatitis C virus (HCV) or both and at risk for cirrhosis and hepatocellular carcinoma. HBV and HCV pose a vexing clinical problem in organ transplant recipients [1]. HBV- or HCV-associated end stage liver disease is the leading indication for orthotopic liver transplantation (OLT). In the case of HCV re-infection of the graft is near universal. Recurrent hepatitis C rapidly progresses to cirrhosis and frequently necessitates re-transplantation [2]. Of the hemodialysis population 0–10% and 10–65% are infected with HBV or HCV, respectively [3]

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