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 correction can represent a potential option for HBV cure. A deeper understanding of T cell correlates of infection persistence and control is needed to clarify the CD8 T cell roles in CHB pathogenesis, and to identify new therapeutic targets for efficient T cell reconstitution. Methods Core- and polymerase-specific CD8 cells from untreated highly viremic HBeAg-negative CHB patients were studied by RNA-sequencing, compared to patients who achieved functional cure after nucleos(t)ide-analog treatment (rNUC) or acute hepatitis B (rACU). Histone acetylation levels, cytokine production, and cytotoxicity were evaluated on T cells from chronic patients in the presence of HDAC inhibition. Results A 101-gene “resolution signature” characterizing both resolution groups compared to CHB patients was identified, as well as 41 genes whose deregulation was not reversed in rNUC. Although most of deregulated genes showed similar behavior in core- and pol-specific CD8 cells of CHB patients, 30% of them were not concordant. Targeting deregulated DNA transcription with entinostat significantly improved histone acetylation levels and T cell function. Conclusions Mechanisms of dysfunction in core- and polymerase-specific CD8 cells are only partially shared by both T cell subsets; without a clear hierarchy of exhaustion severity between pol- and core-specific cells. A transcriptional scar-like signature of chronicity was maintained even after HBsAg loss. The resolution gene signature shared by pol- and core-specific CD8 cells from rNUC and rACU patients pointed to histone deacetylase inhibition as a promising immunotherapeutic intervention for CHB.