Hepatitis D Virus-Specific CD8D+ T Cells Have a Memory-Like Phenotype Associated With Viral Immune Escape in Patients With Chronic Hepatitis D Virus Infection

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(hi)T-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.