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

Gastroenterology. 2019 May;156(6):1805-1819.e9. doi: 10.1053/j.gastro.2019.01.035. Epub 2019 Jan 18.


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+TCF1hiT-betlow 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Cytomegalovirus / immunology
  • Epitopes, T-Lymphocyte*
  • Female
  • HLA-A Antigens / metabolism
  • HLA-B Antigens / metabolism
  • Hepatitis B virus / immunology
  • Hepatitis B, Chronic / immunology*
  • Hepatitis D, Chronic / blood
  • Hepatitis D, Chronic / immunology*
  • Hepatitis Delta Virus / genetics
  • Hepatitis Delta Virus / immunology*
  • Hepatitis delta Antigens / immunology
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunologic Memory / immunology
  • Immunologic Surveillance / immunology
  • Influenza A virus / immunology
  • Interferon-gamma / metabolism
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • Male
  • Middle Aged
  • Peptides / immunology
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • Young Adult


  • Epitopes, T-Lymphocyte
  • HLA-A Antigens
  • HLA-B Antigens
  • Hepatitis delta Antigens
  • Interleukin-7 Receptor alpha Subunit
  • PDCD1 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma

Associated data

  • ClinicalTrials.gov/NCT02511431
  • ClinicalTrials.gov/NCT00023322
  • ClinicalTrials.gov/NCT01495585
  • ClinicalTrials.gov/NCT00001971