T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes.
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.
Bohne
Felix
F
Molecular Infectiology, University Hospital Cologne, Koeln, Germany.
Chmielewski
Markus
M
Ebert
Gregor
G
Wiegmann
Katja
K
Kürschner
Timo
T
Schulze
Andreas
A
Urban
Stephan
S
Krönke
Martin
M
Abken
Hinrich
H
Protzer
Ulrike
U
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*
D017252:CD3 Complex; C583567:CD3xi antigen, human; D006514:Hepatitis B Surface Antigens; D007128:Immunoglobulin Fragments; D011948:Receptors, Antigen, T-Cell