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13:04
A Protocol for Analyzing Hepatitis C Virus Replication
Published on: June 26, 2014
HCV NS5A and IRF9 compete for CypA binding
Michael Bobardt1, Sam Hopkins, James Baugh
1Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Journal of Hepatology
|August 21, 2012
Summary
Cyclophilin A (CypA) binds to IRF9, a key part of the interferon response. This interaction is blocked by CypA inhibitors and modulated by HCV NS5A, revealing new insights into viral replication and treatment.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Cyclophilin A (CypA) is crucial for Hepatitis C Virus (HCV) replication.
- CypA inhibitors reduce viral loads, but their mechanism is unclear.
- Interferon (IFN) also inhibits HCV, prompting investigation into a link with CypA.
Purpose of the Study:
- To investigate a potential link between CypA and the host IFN response.
- To identify host ligands that specifically associate with CypA.
Main Methods:
- Cellular and recombinant pulldown assays were employed.
- Investigated the direct binding of CypA to Interferon Regulatory Factor 9 (IRF9).
- Assessed the impact of CypA inhibitors and HCV NS5A on IRF9-CypA complex formation.
Main Results:
- CypA directly binds to IRF9, a component of the IFN-stimulated gene factor 3 (ISGF3) complex, via its PPIase pocket.
- CypA binds to the IRF-association-domain of IRF9 and associates with the multimeric ISGF3 complex.
- CypA inhibitors (CsA, alisporivir, SCY-635) block IRF9-CypA complex formation, and CypA neutralization enhances IFN-induced transcription.
- HCV NS5A competes with IRF9 for CypA binding, hindering IRF9-CypA complex formation.
Conclusions:
- CypA specifically binds to IRF9, a key component of the JAK/STAT pathway.
- This interaction provides a novel mechanism for HCV to modulate the host IFN response through NS5A.
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