title: T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes.
abstract: OBJECTIVE
  The final goal in hepatitis B therapy is eradication of the hepatitis B virus (HBV) replication template, the so-called covalently closed circular DNA (cccDNA). Current antiviral treatment of chronic hepatitis B depends on interferon alpha or nucleoside analogues inhibiting the viral reverse transcriptase. Despite treatment, cccDNA mostly persists in the host cell nucleus, continues to produce hepatitis B surface antigen (HBsAg), and causes relapsing disease. We therefore aimed at eliminating persistently infected hepatocytes carrying HBV cccDNA by redirecting cytolytic T cells toward HBsAg-producing cells.
  
  
  METHODS
  We designed chimeric T-cell receptors directed against HBV surface proteins present on HBV-infected cells and used them to graft primary human T cells with antibody-like specificity. The receptors were composed of a single chain antibody fragment directed against HBV S or L protein fused to intracellular signalling domains of CD3xi and the costimulatory CD28 molecule.
  
  
  RESULTS
  Our results show that these chimeric receptors, when retrovirally delivered and expressed on the cell surface, enable primary human T cells to recognize HBsAg-positive hepatocytes, release interferon gamma and interleukin 2, and, most importantly, lyse HBV replicating cells. When coincubated with HBV-infected primary human hepatocytes, these engineered, antigen-specific T cells selectively eliminated HBV-infected and thus cccDNA-positive target cells.
  
  
  CONCLUSIONS
  Elimination of HBV cccDNA-positive hepatocytes following antiviral therapy is a major therapeutic goal in chronic hepatitis B, and adoptive transfer of grafted T cells provides a promising novel therapeutic approach. However, T-cell therapy may also cause liver damage and therefore needs further preclinical evaluation.
authors.affiliation: Molecular Infectiology, University Hospital Cologne, Koeln, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bohne
authors.forename: Markus
authors.initials: M
authors.lastname: Chmielewski
authors.forename: Gregor
authors.initials: G
authors.lastname: Ebert
authors.forename: Katja
authors.initials: K
authors.lastname: Wiegmann
authors.forename: Timo
authors.initials: T
authors.lastname: Kürschner
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
authors.forename: Stephan
authors.initials: S
authors.lastname: Urban
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.forename: Ulrike
authors.initials: U
authors.lastname: Protzer
mesh_terms: D017252:CD3 Complex / Q000276:immunology*; D018929:Cell Culture Techniques; D002678:Chimera; D006509:Hepatitis B / Q000276:immunology* / Q000473:pathology; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D006515:Hepatitis B virus / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology*; D006801:Humans; D007128:Immunoglobulin Fragments / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D037182:T-Cell Antigen Receptor Specificity / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D017252:CD3 Complex; C583567:CD3xi antigen, human; D006514:Hepatitis B Surface Antigens; D007128:Immunoglobulin Fragments; D011948:Receptors, Antigen, T-Cell