T Cells Redirected Against Hepatitis B Virus Surface Proteins Eliminate Infected Hepatocytes

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Gastroenterology

Volume 134, Issue 1, January 2008, Pages 239-247

Basic–Liver, Pancreas, and Biliary Tract

T Cells Redirected Against Hepatitis B Virus Surface Proteins Eliminate Infected

Hepatocytes

Felix Bohne, ‡, Markus Chmielewski‡, §, Gregor Ebert, ‡, Katja Wiegmann,

Timo Kürschner¶, s Schulze#, Stephan Urban#, Krönke‡, ,

Hinrich Abken‡, § and Ulrike Protzer, , ,

#Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany

‡Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne,

Koeln, Germany

Molecular Infectiology, University Hospital Cologne, Koeln, Germany

Institute for Virology, Technical University of Munich/Helmholtz Center Munich,

München, Germany

Institute for Medical Microbiology, Immunology, and Hygiene, University Hospital

Cologne, Koeln, Germany

§Tumorgenetics—Department of Internal Medicine I, University Hospital

Cologne, Koeln, Germany

¶Center of Molecular Biology Heidelberg (CMBH), University of Heidelberg,

Heidelberg, Germany

Received 17 November 2006; accepted 11 October 2007. Available online 4

November 2007.

Background & Aims: 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 α 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 CD3ξ 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 γ 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.

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