Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion

Hepatology. 2008 Sep;48(3):759-69. doi: 10.1002/hep.22419.


Hyperexpression of the programmed death 1 (PD-1) molecule is a hallmark of exhausted T-cells, having a negative impact on T-cell activation and function. We studied longitudinally 18 hepatitis B e antigen (HBeAg)-positive patients undergoing treatment with direct antivirals (telbivudine or lamivudine) to determine the relationship between treatment-induced viremia reduction and HBeAg seroconversion with respect to PD-1 levels and T-cell reactivity. PD-1 expression was assessed by (1) flow cytometry and (2) quantitative real-time polymerase chain reaction; hepatitis B virus (HBV)-specific CD8+ T-cells were quantitated by pentamer staining; T-cell reactivity to HBV antigens was determined by interferon gamma (IFNgamma) and interleukin 10 (IL-10) enzyme-linked immunosorbent spot (ELISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia levels. On therapy, PD-1 decreased significantly on total CD8+ T-cells, HBV-specific CD8+ T-cells, and CD3+/CD8- T-cells both as the percentage of positive cells (P < 0.01) and as the mean fluorescent intensity (P < 0.05), and this was paralleled by a marked reduction of PD-1 messenger RNA levels (P = 0.001). HBeAg serocoversion (in 6/18 patients) resulted in a further PD-1 decrease with a 50% reduction in the frequency of PD-1+/CD8+ T-cells, which was not observed in patients remaining HBeAg-positive. The decrease in PD-1 expression was associated with increased frequencies of IFNgamma-producing T-cells and decreased frequencies of IL-10 producing T-cells. At baseline, PD-1 expression correlated directly with the frequency of hepatitis B core antigen (HBcAg) central and effector memory phenotypes, whereas an inverse correlation was observed between PD-1 expression and HBcAg-specific effector phenotypes.

Conclusion: These results demonstrate that in chronic HBV infection, both viremia levels and HBeAg drive PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunotherapeutic interventions are needed for restoration of T-cell functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alanine Transaminase / blood
  • Antigens, CD / metabolism*
  • Antiviral Agents / therapeutic use*
  • Apoptosis Regulatory Proteins / metabolism*
  • Biopsy
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • DNA, Viral / blood
  • Female
  • Hepatitis B e Antigens / blood*
  • Hepatitis B virus / genetics
  • Hepatitis B virus / physiology
  • Hepatitis B, Chronic / drug therapy*
  • Hepatitis B, Chronic / immunology
  • Hepatitis B, Chronic / metabolism*
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Lamivudine / therapeutic use*
  • Liver / metabolism
  • Liver / pathology
  • Liver / virology
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Nucleosides / therapeutic use*
  • Programmed Cell Death 1 Receptor
  • Pyrimidinones / therapeutic use*
  • Telbivudine
  • Thymidine / analogs & derivatives
  • Treatment Outcome
  • Viral Load
  • Viremia


  • Antigens, CD
  • Antiviral Agents
  • Apoptosis Regulatory Proteins
  • DNA, Viral
  • Hepatitis B e Antigens
  • Nucleosides
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Pyrimidinones
  • Interleukin-10
  • Telbivudine
  • Lamivudine
  • Interferon-gamma
  • Alanine Transaminase
  • Thymidine