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Published on: December 21, 2019
IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway
Leiliang Zhang1, Nikolaus Jilg, Run-Xuan Shao
1Gastrointestinal Unit, Department of Medicine, Warren 1007, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. armzhang@hotmail.com
Interferon lambda 3 (IL28B) inhibits Hepatitis C Virus (HCV) replication by activating the JAK-STAT pathway. This discovery offers potential new strategies for treating chronic HCV infection.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Standard Hepatitis C Virus (HCV) treatment with pegylated interferon (IFN) α and ribavirin (RBV) has limited efficacy and significant side effects.
- Single-nucleotide polymorphisms (SNPs) near the IL28B locus (IFNλ3) predict treatment response.
- The precise anti-HCV mechanism of IL28B remains to be fully elucidated.
Purpose of the Study:
- To investigate the direct anti-HCV activity of IL28B.
- To determine the molecular pathway through which IL28B exerts its antiviral effects against HCV.
Main Methods:
- HCV replication assays using replicons and infectious clones.
- Analysis of JAK-STAT pathway activation via real-time PCR, luciferase assays, and Western blot.
- Evaluation of IL28B's anti-HCV effects in the presence of JAK-STAT pathway inhibitors.
Main Results:
- IL28B demonstrated dose- and time-dependent inhibition of HCV replication.
- IL28B induced STAT1/STAT2 phosphorylation, ISRE-driven transcription, and interferon-stimulated gene (ISG) expression, similar to IFNα.
- The antiviral effects of IL28A, IL28B, and IL29 were blocked by inhibitors of the IL10R2, JAK1/TYK2, and downstream signaling components (IL28R1, STAT1, STAT2, IRF9).
Conclusions:
- IL28A, IL28B, and IL29 signal via the JAK-STAT pathway to inhibit HCV replication.
- These findings suggest novel therapeutic strategies targeting the IL28 pathway for HCV treatment.
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