SIRT1 and IFI16 Cooperatively Regulate HBV Replication via Epigenetic Modulation and Innate Immune Activation

Authors

• Zahra Zahid Piracha, Riphah International University
• Umar Saeed, Chapman University
• Neelam Abid, International Center of Medical Sciences Research (ICMSR)
• Syed Shahan Gilani, International Center of Medical Sciences Research (ICMSR)
• Hafiz Ahmad Bilal Akhtar Chughtai, International Center of Medical Sciences Research (ICMSR)
• Areesha Wasti, International Center of Medical Sciences Research (ICMSR)
• Muhammad Waseem, Riphah International University
• Dilber Uzun Ozsahin, Near East University
• Andromeda M. Nauli, Western Michigan University
• Surya M. Nauli, Chapman UniversityFollow

Document Type

Article

Publication Date

6-19-2026

Abstract

Background

Hepatitis B virus (HBV) establishes persistent infection through the formation of a covalently closed circular DNA (cccDNA) minichromosome, which enables immune evasion and sustained viral replication. While SIRT1, IFI16, and STING are known to modulate antiviral pathways, their cooperative role in regulating HBV transcription and host immunity remains poorly defined.

Methods

We investigated the functional interplay between SIRT1, IFI16, and STING using confocal microscopy, chromatin immunoprecipitation (ChIP), gene silencing, and quantitative PCR in HBV-replicating cell models. Interactions with HBV cccDNA and effects on viral transcription and interferon-stimulated gene (ISG) expression were analyzed. Northern blotting and RT-qPCR were used to evaluate HBV RNA output, including total HBV RNA and 3.5 kb RNA, in order to provide both transcript-pattern and quantitative assessment of transcriptional changes.

Results

SIRT1 physically interacted with IFI16, with increased colocalization during HBV replication. Both proteins were recruited to HBV cccDNA, promoting transcriptionally active chromatin. Silencing SIRT1 or IFI16 disrupted cccDNA binding and reduced viral RNA levels. Although STING was not cccDNA-associated, its antiviral activity via ISG induction was dependent on IFI16 knockdown produced the strongest reduction in both total HBV RNA and 3.5 kb RNA, supporting a cooperative role for these factors in sustaining HBV transcriptional output. Although STING was not cccDNA-associated, its antiviral activity via ISG induction was dependent on IFI16. Triple knockdown of SIRT1, IFI16, and STING showed the strongest suppression of ISG expression.

Conclusion

SIRT1 and IFI16 enhance HBV gene expression through epigenetic regulation of cccDNA, while also supporting STING-mediated antiviral responses. These findings reveal a dual regulatory axis governing HBV persistence and identify potential targets for antiviral therapy.

Comments

This article was originally published in Future Virology, volume 21, issue 6, in 2026. https://doi.org/10.1080/17460794.2026.2686529

Recommended Citation

Piracha, Z. Z., Saeed, U., Abid, N., Gilani, S. S., Akhtar Chughtai, H. A. B., Wasti, A., … Nauli, S. M. (2026). SIRT1 and IFI16 cooperatively regulate HBV replication via epigenetic modulation and innate immune activation. Future Virology, 21(6), 393–404. https://doi.org/10.1080/17460794.2026.2686529

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.