title: Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.
abstract: The cytotoxic T-cell response in chronic hepatitis B virus (HBV) infection has been described as weak and mono- or oligospecific in comparison to the more robust virus-specific T-cell response present in resolved infection. However, chronic hepatitis B is a heterogeneous disease with markedly variable levels of virus replication and liver disease activity. Here we analyzed (both directly ex vivo and after in vitro stimulation) the HBV-specific CD8 T-cell responses against structural and nonstructural HBV proteins longitudinally in patients with different patterns of chronic infections. We found that the profiles of virus-specific CD8(+)-T-cell responses during chronic infections are highly heterogeneous and influenced more by the level of HBV replication than by the activity of liver disease. An HBV DNA load of <10(7) copies/ml appears to be the threshold below which circulating multispecific HBV-specific CD8(+) T cells are consistently detected. Furthermore, CD8(+) T cells with different specificities are differentially regulated during chronic infections. HBV core-specific CD8(+) T cells are associated with viral control, while CD8(+) T cells specific for envelope and polymerase epitopes can occasionally be found in the setting of high levels (>10(7) copies) of HBV replication. These findings have implications for the design of immunotherapy for chronic HBV infections.
authors.affiliation: Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, United Kingdom.
authors.forename: George J M
authors.initials: GJ
authors.lastname: Webster
authors.forename: Stephanie
authors.initials: S
authors.lastname: Reignat
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Graham S
authors.initials: GS
authors.lastname: Ogg
authors.forename: Louise
authors.initials: L
authors.lastname: Jones
authors.forename: Suranjith L
authors.initials: SL
authors.lastname: Seneviratne
authors.forename: Roger
authors.initials: R
authors.lastname: Williams
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dusheiko
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
mesh_terms: D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000032:analysis; D005260:Female; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D015678:Viral Structural Proteins / Q000276:immunology*; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D017361:Viral Nonstructural Proteins; D015678:Viral Structural Proteins