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Xia, Yuchen; Stadler, Daniela; Lucifora, Julie; Reisinger, Florian; Webb, Dennis; Hösel, Marianna; Michler, Thomas; Wisskirchen, Karin; Cheng, Xiaoming; Zhang, Ke; Chou, Wen-Min; Wettengel, Jochen M.; Malo, Antje; Bohne, Felix; Hoffmann, Dieter; Eyer, Florian; Thimme, Robert; Falk, Christine S.; Thasler, Wolfgang E.; Heikenwalder, Mathias; Protzer, Ulrike (2016): Interferon-gamma and Tumor Necrosis Factor-alpha Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis. In: Gastroenterology, Vol. 150, No. 1: pp. 194-205
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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.