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Gastroenterology. 2018 May;154(6):1791-1804.e22. doi: 10.1053/j.gastro.2018.01.044. Epub 2018 Feb 1.

HBV Bypasses the Innate Immune Response and Does Not Protect HCV From Antiviral Activity of Interferon.

Author information

1
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany; HBIGS graduate school, Heidelberg, Germany.
2
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany.
3
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany.
4
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.
5
Research Group "Dynamics of early viral infection and the innate antiviral response", Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Reproductive Biotechnology, School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
7
Department of Gastroenterology, Infection and Intoxication, University Hospital Heidelberg, Heidelberg, Germany.
8
Department of General-, Visceral- and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany.
9
Department of General-, Visceral- and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany; Division of Transplant Surgery, Medical University of Graz, Graz, Austria.
10
Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Université de Strasbourg, Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
11
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Research Group "Dynamics of early viral infection and the innate antiviral response", Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany.
12
Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany; Division of Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany; HBIGS graduate school, Heidelberg, Germany; German Centre for Infection Research (DZIF), partner site Heidelberg, Heidelberg, Germany. Electronic address: Ralf.Bartenschlager@med.uni-heidelberg.de.

Abstract

BACKGROUND & AIMS:

Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy, whereas hepatitis B virus (HBV) infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in coinfected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level.

METHODS:

PHHs were isolated from liver resection tissues from HBV-, HCV-, and human immunodeficiency virus-negative patients. Differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate cotransporting polypeptide (dHepaRGNTCP) and PHHs were infected with HBV. Huh7.5 cells were transfected with circular HBV DNA genomes resembling viral covalently closed circular DNA (cccDNA), and subsequently infected with HCV; this served as a model of HBV and HCV coinfection. Cells were incubated with IFN inducers, or IFNs, and antiviral response and viral replication were analyzed by immune fluorescence, reverse-transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assays, and flow cytometry.

RESULTS:

HBV infection of dHepaRGNTCP cells and PHHs neither activated nor inhibited signaling via pattern recognition receptors. Incubation of dHepaRGNTCP cells and PHHs with IFN had little effect on HBV replication or levels of cccDNA. HBV infection of these cells did not inhibit JAK-STAT signaling or up-regulation of IFN-stimulated genes. In coinfected cells, HBV did not prevent IFN-induced suppression of HCV replication.

CONCLUSIONS:

In dHepaRGNTCP cells and PHHs, HBV evades the induction of IFN and IFN-induced antiviral effects. HBV infection does not rescue HCV from the IFN-mediated response.

KEYWORDS:

Coinfection; Interferon-stimulated Gene; PRR; RIG-I

PMID:
29410097
DOI:
10.1053/j.gastro.2018.01.044
[Indexed for MEDLINE]
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