title: Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.
abstract: Dysfunctional CD8+ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8+ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.
authors.affiliation: Laboratorio Immunopatologia Virale, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, via Gramsci 14, 43100 Parma, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Boni
authors.forename: Paola
authors.initials: P
authors.lastname: Fisicaro
authors.forename: Caterina
authors.initials: C
authors.lastname: Valdatta
authors.forename: Barbara
authors.initials: B
authors.lastname: Amadei
authors.forename: Paola
authors.initials: P
authors.lastname: Di Vincenzo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Giuberti
authors.forename: Diletta
authors.initials: D
authors.lastname: Laccabue
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbini
authors.forename: Albertina
authors.initials: A
authors.lastname: Cavalli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Missale
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrari
mesh_terms: D015703:Antigens, CD / Q000032:analysis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000037:antagonists & inhibitors; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D006509:Hepatitis B / Q000276:immunology / Q000821:virology; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D007108:Immune Tolerance; D007963:Leukocytes, Mononuclear; D008137:Longitudinal Studies; D061026:Programmed Cell Death 1 Receptor; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014766:Viremia
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor