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Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e‐antigen seroconversion
Author(s) -
Evans Alexander,
Riva Antonio,
Cooksley Helen,
Phillips Sandra,
Puranik Smrithi,
Nathwani Amit,
Brett Sara,
Chokshi Shilpa,
Naoumov Nikolai V.
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22419
Subject(s) - hbeag , telbivudine , cd8 , hepatitis b virus , t cell , cytotoxic t cell , virology , elispot , antigen , hbcag , immunology , biology , lamivudine , microbiology and biotechnology , medicine , virus , immune system , in vitro , biochemistry , hbsag
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 (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. (H EPATOLOGY 2008.)