Highlights
- •In contrast to HBV, HDV activates the IFN response in hepatocytes.
- •MDA5 is the key pattern recognition receptor sensing HDV replication.
- •HDV replication is insensitive to the MDA5-mediated self-induced IFN response.
- •IFN treatment doesn’t abolish intracellular HDV replication in vitro.
Background & Aims
Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form
of viral hepatitis. HDV induces an innate immune response, but it is unknown how the
host cell senses HDV and if this defense affects HDV replication. We aim to characterize
interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the
effect of IFN on HDV replication.
Methods
HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were
used for infection studies. Viral markers and cellular gene expression were analyzed
at different time points after infection. Pattern recognition receptors (PRRs) required
for HDV-mediated IFN activation and the impact on HDV replication were studied using
stable knock-down or overexpression of the PRRs.
Results
Microarray analysis revealed that HDV but not HBV infection activated a broad range
of interferon stimulated genes (ISGs) in HepG2NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced
IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually
diminished in both HepG2NTCP and HepaRGNTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening
HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not
abolish HDV replication.
Conclusion
Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated
by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect
on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state.
Lay summary
In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong
IFN-β/λ response in innate immune competent cell lines. MDA5 is the key sensor for
the recognition of hepatitis D virus replicative intermediates. An IFN-activated state
did not prevent hepatitis D virus replication in vitro, indicating that hepatitis D virus is resistant to self-induced innate immune responses
and therapeutic IFN treatment.
Graphical abstract
Graphical Abstract
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Author names in bold designate shared co-first authorship
- Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.Lancet. 2015; 386: 1546-1555
- Clinical features of hepatitis D.Semin Liver Dis. 2012; 32: 228-236
- Aiming for cure in HBV and HDV infection.J Hepatol. 2016; 65: 835-848
- Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta.Hepatology. 2014; 60: 87-97
- Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options.Nat Rev Gastroenterol Hepatol. 2016; 13: 580-589
- The hepatitis delta virus: Replication and pathogenesis.J Hepatol. 2016; 64: S102-S116
- Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA.J Virol. 2002; 76: 3709-3719
- Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles.J Virol. 2014; 88: 5742-5754
- Innate immunity.N Engl J Med. 2000; 343: 338-344
- Innate control of adaptive immunity: beyond the three-signal paradigm.J Immunol. 2017; 198: 3791-3800
- Interactions between innate and adaptive lymphocytes.Nat Rev Immunol. 2014; 14: 631-639
- Crosstalk between innate and adaptive immunity in hepatitis B virus infection.World J Hepatol. 2015; 7: 2980-2991
- Sensing and signaling in antiviral innate immunity.Curr Biol. 2010; 20: R328-R333
- Sensing of RNA viruses: a review of innate immune receptors involved in recognizing RNA virus invasion.J Virol. 2012; 86: 2900-2910
- Interferon-stimulated genes: a complex web of host defenses.Annu Rev Immunol. 2014; 32: 513-545
- HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes.Antiviral Res. 2016; 136: 19-31
- Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection.J Hepatol. 2015; 63: 346-353
- Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide.PLoS Pathog. 2015; 11: e1004840
- A new HDV mouse model identifies mitochondrial antiviral signaling protein (MAVS) as a key player in IFN-beta induction.J Hepatol. 2017; 67: 669-679
- Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.Gastroenterology. 2014; 146: 1070-1083
- Hepatitis C virus RNA replication is resistant to tumour necrosis factor-alpha.J Gen Virol. 2003; 84: 1253-1259
- Isolation of primary human hepatocytes after partial hepatectomy: criteria for identification of the most promising liver specimen.Artif Organs. 2008; 32: 205-213
- Control of temporal activation of hepatitis C virus-induced interferon response by domain 2 of nonstructural protein 5A.J Hepatol. 2015; 63: 829-837
- Role of N glycosylation of hepatitis B virus envelope proteins in morphogenesis and infectivity of hepatitis delta virus.J Virol. 2003; 77: 5519-5523
- Inducible expression of human hepatitis B virus (HBV) in stably transfected hepatoblastoma cells: a novel system for screening potential inhibitors of HBV replication.Antimicrob Agents Chemother. 1997; 41: 1715-1720
- Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor.J Hepatol. 2016; 64: 556-564
- Distinct poly(I-C) and virus-activated signaling pathways leading to interferon-beta production in hepatocytes.J Biol Chem. 2005; 280: 16739-16747
- Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy.Hepatology. 2007; 46: 1365-1374
- The mengovirus leader protein blocks interferon-alpha/beta gene transcription and inhibits activation of interferon regulatory factor 3.Cell Microbiol. 2007; 9: 2921-2930
- Regulating intracellular antiviral defense and permissiveness to hepatitis C virus RNA replication through a cellular RNA helicase, RIG-I.J Virol. 2005; 79: 2689-2699
- Kinetic discrimination of self/non-self RNA by the ATPase activity of RIG-I and MDA5.BMC Biol. 2015; 13: 54
- HBV bypasses the innate immune response and does not protect HCV from antiviral activity of interferon.Gastroenterology. 2018; https://doi.org/10.1053/j.gastro.2018.01.044
- Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.J Gen Virol. 2008; 89: 1-47
- Interferon induction and function at the mucosal surface.Immunol Rev. 2013; 255: 25-39
- IFN-lambda: a new inducer of local immunity against cancer and infections.Front Immunol. 2016; 7: 598
- Type I and III interferon in the gut: tight balance between host protection and immunopathology.Front Immunol. 2017; 8: 258
- Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5.J Exp Med. 2008; 205: 1601-1610
- Activation of MDA5 requires higher-order RNA structures generated during virus infection.J Virol. 2009; 83: 10761-10769
- Dynamic control of type I IFN signalling by an integrated network of negative regulators.Trends Immunol. 2015; 36: 150-160
- Hepatitis delta virus inhibits alpha interferon signaling.Hepatology. 2009; 49: 398-406
- Interferon impedes an early step of hepatitis delta virus infection.PLoS One. 2011; 6: e22415
- Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice.Sci Rep. 2017; 7: 3757
- Pegylated interferon therapy of chronic hepatitis D: in need of revision.Hepatology. 2015; 61: 1109-1111
- Antiviral activity of various interferons and pro-inflammatory cytokines in non-transformed cultured hepatocytes infected with hepatitis B virus.Antiviral Res. 2016; 130: 36-45
Article info
Publication history
Published online: March 07, 2018
Accepted:
February 24,
2018
Received in revised form:
February 13,
2018
Received:
November 6,
2017
See Editorial, pages 5–7Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
