title: Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.
abstract: OBJECTIVE
  T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB).
  
  
  METHODS
  We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion.
  
  
  RESULTS
  Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls.
  
  
  CONCLUSIONS
  HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jang-June
authors.initials: JJ
authors.lastname: Park
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: David K
authors.initials: DK
authors.lastname: Wong
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: Abdus S
authors.initials: AS
authors.lastname: Wahed
authors.affiliation: University of Texas Southwestern, Dallas, Texas.
authors.forename: William M
authors.initials: WM
authors.lastname: Lee
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Feld
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Norah
authors.initials: N
authors.lastname: Terrault
authors.affiliation: University of California, San Francisco, San Francisco, California.
authors.forename: Mandana
authors.initials: M
authors.lastname: Khalili
authors.affiliation: Virginia Commonwealth University, Richmond, Virginia.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Sterling
authors.affiliation: Virginia Mason Medical Center, Seattle, Washington.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: California Pacific Medical Center, San Francisco, California.
authors.forename: Natalie
authors.initials: N
authors.lastname: Bzowej
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Daryl T
authors.initials: DT
authors.lastname: Lau
authors.affiliation: Mayo Clinic, Rochester, Minnesota.
authors.forename: W Ray
authors.initials: WR
authors.lastname: Kim
authors.affiliation: University of Minnesota, Minneapolis, Minnesota.
authors.forename: Coleman
authors.initials: C
authors.lastname: Smith
authors.affiliation: University of Washington Medical Center, Seattle, Washington.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Carithers
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Torrey
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: James W
authors.initials: JW
authors.lastname: Keith
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Levine
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Daniel
authors.initials: D
authors.lastname: Traum
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ho
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Valiga
authors.affiliation: University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Johnson
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
authors.forename: Edward
authors.initials: E
authors.lastname: Doo
authors.affiliation: University of Michigan, Ann Arbor, Michigan.
authors.forename: Anna S F
authors.initials: AS
authors.lastname: Lok
authors.affiliation: Philadelphia Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania; University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: kmchang@mail.med.upenn.edu.
authors.forename: Kyong-Mi
authors.initials: KM
authors.lastname: Chang
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000276:immunology / Q000472:pathogenicity*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000276:immunology / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009975:Orthomyxoviridae / Q000276:immunology; D010641:Phenotype; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000821:virology; D014481:United States
chemical_list: D006513:Hepatitis B e Antigens; C573415:IFNG protein, human; C508609:IL10 protein, human; D008070:Lipopolysaccharides; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: HBRN; IFN; IL10; LPS