Hepatitis B virus X gene impacts on the innate immunity and immune-tolerant phase in chronic hepatitis B virus infection.

Autor: Chang KC; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan., Chua HH; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Chen YH; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Tsuei DJ; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Lee MH; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Chiang CL; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Jeng YM; Department of Pathology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Wu JF; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Chen HL; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Hsu HY; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Medical Education and Bioethics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan., Ni YH; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Medical Microbiota Center, College of Medicine, National Taiwan University, Taipei, Taiwan.; Center of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan., Chang MH; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.; Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2022 Oct; Vol. 42 (10), pp. 2154-2166. Date of Electronic Publication: 2022 Jul 19.
DOI: 10.1111/liv.15348
Abstrakt: Background and Aims: The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up.
Methods: Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system.
Results: A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-β, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants.
Conclusions: HBx suppresses IFN-β induction. R87G and I127V mutation restored IFN-β production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients.
(© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje