18697210

pubmed:Citation

3

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.

eng

IM

MEDLINE

1527-3350

Electronic

NLM

759-69

pubmed-meshheading:18697210-Adult, pubmed-meshheading:18697210-Alanine Transaminase, pubmed-meshheading:18697210-Antigens, CD, pubmed-meshheading:18697210-Antiviral Agents, pubmed-meshheading:18697210-Apoptosis Regulatory Proteins, pubmed-meshheading:18697210-Biopsy, pubmed-meshheading:18697210-CD8-Positive T-Lymphocytes, pubmed-meshheading:18697210-DNA, Viral, pubmed-meshheading:18697210-Female, pubmed-meshheading:18697210-Hepatitis B, Chronic, pubmed-meshheading:18697210-Hepatitis B e Antigens, pubmed-meshheading:18697210-Hepatitis B virus, pubmed-meshheading:18697210-Humans, pubmed-meshheading:18697210-Interferon-gamma, pubmed-meshheading:18697210-Interleukin-10, pubmed-meshheading:18697210-Lamivudine, pubmed-meshheading:18697210-Liver, pubmed-meshheading:18697210-Longitudinal Studies, pubmed-meshheading:18697210-Male, pubmed-meshheading:18697210-Middle Aged, pubmed-meshheading:18697210-Nucleosides, pubmed-meshheading:18697210-Programmed Cell Death 1 Receptor, pubmed-meshheading:18697210-Pyrimidinones, pubmed-meshheading:18697210-Treatment Outcome, pubmed-meshheading:18697210-Viral Load, pubmed-meshheading:18697210-Viremia

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

Journal Article, Research Support, Non-U.S. Gov't