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J Clin Invest. 2019 Apr 30;130. pii: 120228. doi: 10.1172/JCI120228.

T cell receptor grafting allows virological control of Hepatitis B virus infection.

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Institute of Virology, Helmholtz Zentrum München, Munich, Germany.
Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany.
German Centre for Infection Research (DZIF), Munich, Hamburg, and Heidelberg partner sites, Germany.
1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute of Microbiology, Virology, and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany.


T cell therapy is a promising means to treat chronic HBV infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may achieve cure of HBV infection upon adoptive transfer. We investigated the therapeutic potential and safety of T cells stably expressing high affinity HBV envelope- or core-specific TCRs recognizing European and Asian HLA-A2 subtypes. Both CD8+ and CD4+ T cells from healthy donors and from chronic hepatitis B patients became polyfunctional effector cells when grafted with HBV-specific TCRs and eliminated HBV from infected HepG2-NTCP cell cultures. A single transfer of TCR-grafted T cells into HBV-infected, humanized mice controlled HBV infection and virological markers declined 4-5 log or below detection limit. When - as in a typical clinical setting - only a minority of hepatocytes were infected, engineered T cells specifically cleared infected hepatocytes without damaging non-infected cells. Cell death was compensated by hepatocyte proliferation and alanine amino transferase levels peaking at day 5 to 7 normalized again thereafter. Co-treatment with the entry inhibitor Myrcludex B ensured long-term control of HBV infection. Thus, T cells stably transduced with highly functional TCRs have the potential to mediate clearance of HBV-infected cells causing limited liver injury.


Hepatitis; Immunology; Immunotherapy; T cells; Virology

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