Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612874
Poster Visit Session V Viral Hepatitis and Immunology – Saturday, January 27, 2018, 11:00am – 11:45am, Foyer area East Wing
Georg Thieme Verlag KG Stuttgart · New York

HBV bypasses the innate immune system and does not protect HCV against the antiviral effect of IFN

P Mutz
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
2   German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis (F170), Heidelberg
3   HBIGS graduate school, Heidelberg
,
P Metz
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
,
F Lempp
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
4   German Centre for Infection Research (DZIF), Partner site HD, Heidelberg
,
S Bender
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
2   German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis (F170), Heidelberg
,
B Qu
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
,
K Schöneweis
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
4   German Centre for Infection Research (DZIF), Partner site HD, Heidelberg
,
T Tu
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
,
S Seitz
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
,
A Restuccia
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
2   German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis (F170), Heidelberg
,
J Frankish
5   German Cancer Research Center (DKFZ), Research Group 'Dynamics of early viral infection and the innate antiviral response“, Division Virus-associated carcinogenesis (F170), Heidelberg
,
B Schusser
6   Technical University of Munich, Reproductive Biotechnology, School of Life Sciences Weihenstephan, Munich
,
R Koschny
7   University Hospital Heidelberg, Department of Gastroenterology, Infection and Intoxication, Heidelberg
,
G Polychronidis
8   University Hospital Heidelberg, Department of General-, Visceral- and Transplantation Surgery, Heidelberg
,
P Schemmer
9   Medical University Graz, Department for Surgery, Division for Transplant Surgery, Graz
,
K Hoffmann
8   University Hospital Heidelberg, Department of General-, Visceral- and Transplantation Surgery, Heidelberg
,
T Baumert
10   Université de Strasbourg, Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg
,
M Binder
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
5   German Cancer Research Center (DKFZ), Research Group 'Dynamics of early viral infection and the innate antiviral response“, Division Virus-associated carcinogenesis (F170), Heidelberg
,
S Urban
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
4   German Centre for Infection Research (DZIF), Partner site HD, Heidelberg
,
R Bartenschlager
1   University of Heidelberg, Department of Infectious Diseases; Molecular Virology, Heidelberg
2   German Cancer Research Center (DKFZ), Division of Virus-Associated Carcinogenesis (F170), Heidelberg
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Publikationsverlauf

Publikationsdatum:
03. Januar 2018 (online)

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Question:

Hepatitis B and C virus (HBV, HCV) are a global health problem accounting for around 370 million chronically infected people worldwide. While HCV is inducing an interferon (IFN) response and is highly sensitive towards IFN treatment, the impact of the IFN system on the HBV life cycle is discussed controversially. Although HBV is regarded as “stealth” virus avoiding the activation of the IFN response, several studies reported an active suppression of the IFN-induced antiviral state. Here we studied possible interactions of HBV with the IFN system in immune-competent infection systems and analyzed the impact of HBV on HCV infection at the single cell level.

Methods:

Immune-competent and fully HBV-permissive differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (dHepaRGNTCP) and primary human hepatocytes (PHH) were used for infection experiments. Moreover, we transfected in vitro generated circular HBV DNA genomes, mimicking viral covalently closed circular DNA (cccDNA), into Huh7.5 cells that were subsequently infected with HCV to study HBV/HCV co-replication and IFN cross-protection. Single cell analyses were performed, complemented by RT-qPCR and ELISA.

Results:

Neither IFN nor IFN-stimulated genes (ISGs) were upregulated upon infection of dHepaRGNTCP or PHHs with HBV throughout a 14 days observation period. Interestingly, RIG-I, MDA5 and TLR3 signaling could still be activated in HBV-infected cells indicating a passive escape of HBV from the innate immune system. Further, treatment of HBV-infected cells with IFN-α2 had only little impact on viral replication although HBV did not block the JAK/STAT signaling pathway in infected dHepaRGNTCP cells arguing for a passive immune evasion.

Consistently, HBV was not affected by type I and type III IFN treatment in a HBV/HCV co-replication system whereas HCV replication was diminished both in HCV mono- and HBV-HCV double positive cells. Of note, similar results were obtained when cells were treated with direct-acting antivirals (DAA) against HCV supporting the notion that DAAs are of clinical benefit both in HCV mono- and HBV/HCV co-infected individuals.

Conclusion:

Our results validate the concept of HBV passively bypassing the IFN system at every step of the viral life cycle. Further, HBV cannot protect HCV against the antiviral activity of IFN or DAAs.