Original ResearchFull Report: Basic and Translational—LiverInterferon-γ and Tumor Necrosis Factor-α Produced by T Cells Reduce the HBV Persistence Form, cccDNA, Without Cytolysis
Section snippets
Human Samples
Serum samples of 8 acute, 11 chronic hepatitis B patients, 3 healthy subjects, and 1 fulminant acute hepatitis B patient were collected and fulminant hepatitis B and nonhepatitis control liver biopsy specimens were obtained from the University Hospital Rechts der Isar. Use of human samples was approved by the local ethics committee. For detection of IFNγ and TNF-α from human serum or cell culture supernatant, human IFNγ MAX (430103; Biolegend, San Diego, CA) and human TNF enzyme-linked
Acute Hepatitis B Patients Have Increased Serum IFNγ and TNF-α Levels
It has been suggested that cytokines, particularly IFNγ and TNF-α, are involved in the clearance of HBV in acute, self-limiting hepatitis B in animal models.2, 7, 8 To investigate whether serum cytokine profiles differ between hepatitis B patients and healthy donors, we collected serum from patients of similar demographic backgrounds with acute (n = 9) or chronic hepatitis B infections (n = 11) (Supplementary Table 2). Both groups had similar HBV-DNA levels but, as expected, patients with acute
Discussion
Clearance of HBV infection by the immune system seems to require killing of infected cells by virus-specific CTL. To which extent and by which mechanisms noncytolytic T-cell function contributes to virus clearance has not been defined yet. This study shows that T cells can induce the loss of HBV cccDNA in HBV-infected, differentiated hepatocytes mainly through secretion of the cytokines IFNγ and TNF-α, which induce A3A and A3B, which play an essential role in deamination of nuclear HBV DNA and
Acknowledgments
The authors would like to thank Kathrin Kappes, Romina Bester, Theresa Asen, Raindy Tedjokusumo, Martin Feuerherd, and Olga Seelbach for their excellent technical support, and Oliver Quitt and Stephanie Kadow for characterization of Huh7-S and HepG2-H1.3 cell lines, respectively. The authors thank Christoph Seeger for providing the cell line HepAD38 and Achim Weber for support with tissue staining. The authors acknowledge the support of the nonprofit foundation Human Tissue and Cell Research,
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Current address of Y.X.: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Current address of J.L.: INSERM 1052, CNRS UMR 5286, Cancer Research Center of Lyon, University of Lyon, Lyon, France.
Conflicts of interest The authors disclose no conflicts.
Funding Supported in part by the German Research Foundation (grant CRC/TR 36), the German Center for Infection Research, and the Helmholtz-Alberta Initiative on Infectious Disease Research (HAI-IDR).
Author names in bold designate shared co-first authorship.
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Authors share co-first authorship.