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

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 lamivudin...

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Published in:Hepatology (Baltimore, Md.) Md.), 2008-09, Vol.48 (3), p.759-769
Main Authors: Evans, Alexander, Riva, Antonio, Cooksley, Helen, Phillips, Sandra, Puranik, Smrithi, Nathwani, Amit, Brett, Sara, Chokshi, Shilpa, Naoumov, Nikolai V.
Format: Article
Language:English
Subjects:
Adult
Alanine Transaminase - blood
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antigens, CD - metabolism
Antiviral agents
Antiviral Agents - therapeutic use
Apoptosis Regulatory Proteins - metabolism
Biological and medical sciences
Biopsy
CD8-Positive T-Lymphocytes - metabolism
CD8-Positive T-Lymphocytes - pathology
DNA, Viral - blood
Female
Gastroenterology. Liver. Pancreas. Abdomen
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
Human viral diseases
Humans
Infectious diseases
Interferon-gamma - metabolism
Interleukin-10 - metabolism
Lamivudine - therapeutic use
Liver - metabolism
Liver - pathology
Liver - virology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Longitudinal Studies
Male
Medical sciences
Middle Aged
Nucleosides - therapeutic use
Pharmacology. Drug treatments
Programmed Cell Death 1 Receptor
Pyrimidinones - therapeutic use
Thymidine - analogs & derivatives
Treatment Outcome
Viral diseases
Viral hepatitis
Viral Load
Viremia
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Summary: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 (IFNγ) 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 IFNγ‐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. (HEPATOLOGY 2008.)
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.22419