Universität zu Köln

Xia, Yuchen ORCID: 0000-0001-8460-3893, Stadler, Daniela ORCID: 0000-0002-7342-9751, Lucifora, Julie, Reisinger, Florian, Webb, Dennis, Hoesel, Marianna, Michler, Thomas ORCID: 0000-0002-4174-3316, Wisskirchen, Karin, Cheng, Xiaoming, Zhang, Ke, Chou, Wen-Min, Wettengel, Jochen M., Malo, Antje, Bohne, Felix, Hoffmann, Dieter, Eyer, Florian ORCID: 0000-0002-4753-2747, Thimme, Robert, Falk, Christine S., Thasler, Wolfgang E., Heikenwalder, Mathias and Protzer, Ulrike ORCID: 0000-0002-9421-1911 (2016). Interferon-gamma and Tumor Necrosis Factor-alpha Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis. Gastroenterology, 150 (1). S. 194 - 206. PHILADELPHIA: W B SAUNDERS CO-ELSEVIER INC. ISSN 1528-0012

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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 non-cytolytic 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-gamma (IFN gamma) or tumor necrosis factor-a (TNF-alpha), or co-cultured with T cells. We measured markers of HBV replication, including the covalently closed circular DNA (cccDNA). RESULTS: Levels of IFN gamma and TNF-alpha 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, IFN gamma and TNF-alpha each induced deamination of cccDNA and interfered with its stability; their effects were additive. HBV-specific T cells, through secretion of IFN gamma and TNF-alpha, inhibited HBV replication and reduced cccDNA in infected cells without the direct contact required for cytolysis. Blocking IFN gamma and TNF-alpha 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 APO-BEC3B. CONCLUSIONS: IFN gamma and TNF-alpha, produced by T cells, reduce levels of HBV cccDNA in hepatocytes by inducing deamination and subsequent cccDNA decay.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Xia, Yuchen UNSPECIFIED orcid.org/0000-0001-8460-3893 UNSPECIFIED Stadler, Daniela UNSPECIFIED orcid.org/0000-0002-7342-9751 UNSPECIFIED Lucifora, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Reisinger, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Webb, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoesel, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Michler, Thomas UNSPECIFIED orcid.org/0000-0002-4174-3316 UNSPECIFIED Wisskirchen, Karin UNSPECIFIED UNSPECIFIED UNSPECIFIED Cheng, Xiaoming UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Ke UNSPECIFIED UNSPECIFIED UNSPECIFIED Chou, Wen-Min UNSPECIFIED UNSPECIFIED UNSPECIFIED Wettengel, Jochen M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Malo, Antje UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohne, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Eyer, Florian UNSPECIFIED orcid.org/0000-0002-4753-2747 UNSPECIFIED Thimme, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Falk, Christine S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thasler, Wolfgang E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heikenwalder, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Protzer, Ulrike UNSPECIFIED orcid.org/0000-0002-9421-1911 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-292730
DOI:	10.1053/j.gastro.2015.09.026
Journal or Publication Title:	Gastroenterology
Volume:	150
Number:	1
Page Range:	S. 194 - 206
Date:	2016
Publisher:	W B SAUNDERS CO-ELSEVIER INC
Place of Publication:	PHILADELPHIA
ISSN:	1528-0012
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATITIS-B-VIRUS; CYTIDINE DEAMINASES; VIRAL CLEARANCE; REPLICATION; INHIBITION; INFECTION; POLYMORPHISMS; ASSOCIATION; EXPRESSION; PROMOTER Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/29273