IL-26 inhibits hepatitis C virus replication in hepatocytes

• Published in: Journal of hepatology Vol. 76; no. 4; pp. 822 - 831
• Main Authors: Beaumont, Élodie, Larochette, Vincent, Preisser, Laurence, Miot, Charline, Pignon, Pascale, Blanchard, Simon, Hansen, Björn-Thore, Dauvé, Jonathan, Poli, Caroline, Poranen, Minna M., Lamourette, Patricia, Plaisance, Marc, Morel, Alain, Fickenscher, Helmut, Jeannin, Pascale, Roingeard, Philippe, Delneste, Yves
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2022; Elsevier
• Subjects: Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; antiviral defense; Cytokines; Hepacivirus - genetics; Hepatitis C - drug therapy; hepatitis C virus; Hepatocytes; Humans; IL-26; Interleukins - pharmacology; Life Sciences; viral replication; Virus Replication; viral replication; hepatitis C virus; IL-26; antiviral defense
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2021.12.011

Interleukin-26 (IL-26) is a proinflammatory cytokine that has properties atypical for a cytokine, such as direct antibacterial activity and DNA-binding capacity. We previously observed an accumulation of IL-26 in fibrotic and inflammatory lesions in the livers of patients with chronic HCV infection and showed that infiltrating CD3+ lymphocytes were the principal source of IL-26. Surprisingly, IL-26 was also detected in the cytoplasm of hepatocytes from HCV-infected patients, even though these cells do not produce IL-26, even when infected with HCV. Based on this observation and possible interactions between IL-26 and nucleic acids, we investigated the possibility that IL-26 controlled HCV infection independently of the immune system.
We evaluated the ability of IL-26 to interfere with HCV replication in hepatocytes and investigated the mechanisms by which IL-26 exerts its antiviral activity.
We showed that IL-26 penetrated HCV-infected hepatocytes, where it interacted directly with HCV double-stranded RNA replication intermediates, thereby inhibiting viral replication. IL-26 interfered with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA.
These findings reveal a new role for IL-26 in direct protection against HCV infection, independently of the immune system, and increase our understanding of the antiviral defense mechanisms controlling HCV infection. Future studies should evaluate the possible use of IL-26 for treating other chronic disorders caused by RNA viruses, for which few treatments are currently available, or emerging RNA viruses.
This study sheds new light on the body’s arsenal for controlling hepatitis C virus (HCV) infection and identifies interleukin-26 (IL-26) as an antiviral molecule capable of blocking HCV replication. IL-26, which has unique biochemical and structural characteristics, penetrates infected hepatocytes and interacts directly with viral RNA, thereby blocking viral replication. IL-26 is, therefore, a new player in antiviral defenses, operating independently of the immune system. It is of considerable potential interest for treating HCV infection and other chronic disorders caused by RNA viruses for which few treatments are currently available, and for combating emerging RNA viruses.
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•IL-26 is a new weapon in the antiviral arsenal, functioning independently of the immune system.•IL-26 penetrates HCV-infected cells and interacts with viral double-stranded RNA replication intermediates.•IL-26 interferes with viral RNA-dependent RNA polymerase activity, preventing the de novo synthesis of viral genomic single-stranded RNA.