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, h-aving 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-I 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 (IFN) and interleukin 10 (IL-10) enzyme-linked inummosorbent spot (EIISPOT) assays; and central/effector memory phenotypes were defined by phenotypic markers. PD-1 expression correlated closely with viremia, levels. On therapy, PD-1 decreased sigifficantly 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 ofIFN-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 diwe PD-1 expression and resulting T-cell impairment. Treatment-induced suppression of HBV replication reduces PD-1 expression; however, additional immunodiempeutic interventions are needed for restoration of T-cell functions.