title: Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Hepatology, University College London, London, United Kingdom. alexevans1@yahoo.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Evans
authors.forename: Antonio
authors.initials: A
authors.lastname: Riva
authors.forename: Helen
authors.initials: H
authors.lastname: Cooksley
authors.forename: Sandra
authors.initials: S
authors.lastname: Phillips
authors.forename: Smrithi
authors.initials: S
authors.lastname: Puranik
authors.forename: Amit
authors.initials: A
authors.lastname: Nathwani
authors.forename: Sara
authors.initials: S
authors.lastname: Brett
authors.forename: Shilpa
authors.initials: S
authors.lastname: Chokshi
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Naoumov
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism*; D000998:Antiviral Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D004279:DNA, Viral / Q000097:blood; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D019259:Lamivudine / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009705:Nucleosides / Q000627:therapeutic use*; D061026:Programmed Cell Death 1 Receptor; D011744:Pyrimidinones / Q000627:therapeutic use*; D000077712:Telbivudine; D013936:Thymidine / Q000031:analogs & derivatives; D016896:Treatment Outcome; D019562:Viral Load; D014766:Viremia
chemical_list: D015703:Antigens, CD; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D009705:Nucleosides; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011744:Pyrimidinones; D016753:Interleukin-10; D000077712:Telbivudine; D019259:Lamivudine; D007371:Interferon-gamma; D000410:Alanine Transaminase; D013936:Thymidine