Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection

Abstract

Background & aim: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the antiviral immune response and liver disease pathogenesis.

Methods: We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8⁺ T-cell epitopes, and characterized HDV-specific CD8⁺ T cells. We associated these with HDV sequence variations and clinical features of patients.

Results: We identified 6 CD8⁺ T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8⁺ T cells were as frequent as HBV-specific CD8⁺ T cells but were less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus. The ex vivo frequency of activated HDV-specific CD8⁺ T cells correlated with transaminase activity. CD8⁺ T-cell production of interferon gamma after stimulation with HDV peptides correlated inversely with HDV titer. HDV-specific CD8⁺ T cells did not express the terminal differentiation marker CD57, and fewer HDV-specific than Epstein-Barr virus-specific CD8⁺ T cells were 2B4⁺CD160⁺PD1⁺, a characteristic of exhausted cells. Approximately half of the HDV-specific CD8⁺ T cells had a memory-like PD1⁺CD127⁺TCF1^hiT-bet^low phenotype, which associated with HDV sequence variants with reduced HLA binding and reduced T-cell activation.

Conclusions: CD8⁺ T cells isolated from patients with chronic HDV and HBV infection recognize HDV epitopes presented by multiple HLA molecules. The subset of activated HDV-specific CD8⁺ T cells targets conserved epitopes and likely contributes to disease progression. The subset of memory-like HDV-specific CD8⁺ T cells is functional but unable to clear HDV because of the presence of escape variants. ClinicalTrials.gov, Numbers: NCT02511431, NCT00023322, NCT01495585, and NCT00001971. GenBank accession, Number: MK333199-333226.

Keywords: Lymphocyte; Mutation; Transcription Factor; Virus Escape.