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Cyclophilin Inhibitors Remodel the Endoplasmic Reticulum of HCV-Infected Cells in a Unique Pattern Rendering Cells
Udayan Chatterji1, Michael Bobardt1, Lana Schaffer2
1Department of Immunology & Microbial Science The Scripps Research Institute, La Jolla, California, 92037, United States of America.
Plos One
|July 22, 2016
Summary
Cyclophilin inhibitors (CypI) uniquely reorganize the endoplasmic reticulum in HCV-infected cells, preventing reinfection. This ER remodeling offers a novel therapeutic target for Hepatitis C virus therapies.
Area of Science:
- Virology
- Cell Biology
- Drug Discovery
Background:
- The precise mechanisms of cyclophilin inhibitors (CypI) against Hepatitis C virus (HCV) are not fully elucidated.
- Previous research indicated CypI and NS5A inhibitors (NS5Ai) block double-membrane vesicle (DMV) assembly, crucial for HCV replication.
Purpose of the Study:
- To investigate potential additional antiviral mechanisms of CypI beyond DMV inhibition.
- To explore the impact of CypI on the cellular environment of HCV-infected cells.
Main Methods:
- Treatment of HCV-infected and uninfected cells with CypI and other anti-HCV agents.
- Analysis of endoplasmic reticulum (ER) organization using microscopy.
- Assessment of cellular susceptibility to HCV reinfection post-treatment.
Main Results:
- CypI specifically remodel the ER in HCV-infected cells, an effect not seen with NS5Ai or in uninfected cells.
- CypI-treated, infected cells became impervious to HCV reinfection, irrespective of CypI resistance.
- The ER reorganization induced by CypI is rapid and reversible.
Conclusions:
- CypI possess a unique antiviral mechanism involving ER reorganization in infected cells, rendering them transiently resistant to reinfection.
- Targeting HCV-induced ER rearrangement presents a promising strategy for developing novel anti-HCV therapies.
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