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Gastroenterology. 2016 Jan;150(1):194-205. doi: 10.1053/j.gastro.2015.09.026. Epub 2015 Sep 28.

Interferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis.

Author information

1
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.
2
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research, Munich and Hannover, Germany.
3
Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany.
4
Institute for Medical Microbiology, Immunology and Hygiene, University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University Hospital Cologne, Cologne, Germany.
5
Medicine II, Department of Clinical Toxicology, University Hospital rechts der Isar of the Technical University of Munich, Munich, Germany.
6
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
7
German Center for Infection Research, Munich and Hannover, Germany; Abt Transplantationsimmunologie, Medizinische Hochschule Hannover, Hannover, Germany.
8
Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Grosshadern Hospital, Ludwig Maximilians University, Munich, Germany.
9
Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research, Munich and Hannover, Germany. Electronic address: protzer@tum.de.

Abstract

BACKGROUND & AIMS:

Viral clearance involves immune cell cytolysis of infected cells. However, studies of hepatitis B virus (HBV) infection in chimpanzees have indicated that cytokines released by T cells also can promote viral clearance via noncytolytic processes. We investigated the noncytolytic mechanisms by which T cells eliminate HBV from infected hepatocytes.

METHODS:

We performed a cytokine enzyme-linked immunosorbent assay of serum samples from patients with acute and chronic hepatitis B. Liver biopsy specimens were analyzed by in situ hybridization. HepG2-H1.3 cells, HBV-infected HepaRG cells, and primary human hepatocytes were incubated with interferon-γ (IFNγ) or tumor necrosis factor-α (TNF-α), or co-cultured with T cells. We measured markers of HBV replication, including the covalently closed circular DNA (cccDNA).

RESULTS:

Levels of IFNγ and TNF-α were increased in serum samples from patients with acute vs chronic hepatitis B and controls. In human hepatocytes with stably replicating HBV, as well as in HBV-infected primary human hepatocytes or HepaRG cells, IFNγ and TNF-α each induced deamination of cccDNA and interfered with its stability; their effects were additive. HBV-specific T cells, through secretion of IFNγ and TNF-α, inhibited HBV replication and reduced cccDNA in infected cells without the direct contact required for cytolysis. Blocking IFNγ and TNF-α after T-cell stimulation prevented the loss of cccDNA. Deprivation of cccDNA required activation of nuclear APOBEC3 deaminases by the cytokines. In liver biopsy specimens from patients with acute hepatitis B, but not chronic hepatitis B or controls, hepatocytes expressed APOBEC3A and APOBEC3B.

CONCLUSIONS:

IFNγ and TNF-α, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay.

KEYWORDS:

Apolipoprotein B mRNA Editing Enzyme; HBV Persistence; Immune Regulation; T-Cell Receptor

PMID:
26416327
DOI:
10.1053/j.gastro.2015.09.026
[Indexed for MEDLINE]

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