Dysregulated transcription in core- and pol-specific CD8 T cells can be targeted by HDAC inhibition to improve T-cell function in chronic hepatitis B.

BACKGROUND & AIMS: Virus-specific T-cell dysfunction is a hallmark of chronic hepatitis B (CHB), and its reversal may represent a potential strategy for achieving an HBV cure. A deeper understanding of the T-cell correlates of viral persistence and infection control is needed to clarify the role of CD8 T cells in CHB pathogenesis and to identify novel therapeutic targets for effective T-cell reconstitution.

METHODS

Core- and polymerase-specific CD8 T cells from untreated, highly viremic, HBeAg-negative patients with CHB were analyzed by RNA sequencing and compared with those from patients who achieved a functional cure after nucleos(t)ide analogue treatment (rNUC) or acute hepatitis B (rACU). Histone acetylation levels, cytokine production, and cytotoxic activity were evaluated in T cells from patients with CHB following histone deacetylase inhibition.

RESULTS

A 101-gene "resolution signature", shared by both resolution groups and distinguishing them from patients with CHB, was identified, along with 41 genes whose dysregulation was not reversed in rNUC patients. Although most dysregulated genes exhibited similar expression patterns in core- and polymerase-specific CD8 T cells from patients with CHB, approximately 30% showed discordant behavior. Targeting aberrant transcriptional regulation with entinostat significantly increased histone acetylation levels and improved T-cell function.

CONCLUSIONS

Mechanisms underlying dysfunction in core- and polymerase-specific CD8 T cells are only partially shared between these two subsets, with no clear hierarchy in exhaustion severity between polymerase- and core-specific cells. A chronicity-associated, transcriptional scar-like signature persisted even after HBsAg loss. The resolution signature shared by polymerase- and core-specific CD8 T cells from rNUC and rACU patients identifies histone deacetylase inhibition as a promising immunotherapeutic strategy for CHB.

IMPACT AND IMPLICATIONS: There is an urgent need to identify new therapeutic strategies that can achieve durable control of infection in people with chronic hepatitis B (CHB), as impairment of HBV-specific CD8 T cells is a major driver of viral persistence. In this study, transcriptional profiling of virus-specific T cells associated with functional cure identified epigenetic regulation of transcription as a potential target for restoring T-cell function in patients with CHB. In vitro treatment with entinostat significantly increased histone acetylation levels and improved T-cell function, supporting its potential use as an immunotherapeutic strategy to achieve HBV cure.