Abstract:
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.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Zhang Z,Filzmayer C,Ni Y,Sültmann H,Mutz P,Hiet MS,Vondran FWR,Bartenschlager R,Urban Sdoi
10.1016/j.jhep.2018.02.021subject
Has Abstractpub_date
2018-07-01 00:00:00pages
25-35issue
1eissn
0168-8278issn
1600-0641pii
S0168-8278(18)30143-0journal_volume
69pub_type
杂志文章abstract:BACKGROUND/AIMS:Combinations of beta-blockers and vasodilators have been assessed for their ability to lower portal pressure and so prevent variceal haemorrhage. However, reservations have been raised particularly with respect to renal function and perfusion after the use of these medicines in patients with chronic liv...
journal_title:Journal of hepatology
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doi:10.1016/s0168-8278(00)80242-1
更新日期:2000-05-01 00:00:00
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doi:10.1016/j.jhep.2003.10.008
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doi:10.1016/j.jhep.2007.12.024
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abstract::Thirty-two patients with chronic hepatitis B were randomly assigned to two groups. Sixteen patients received 10 million units of alpha-interferon per square meter of body surface (MU/m2), three times weekly for 4 months. Sixteen patients were treated simultaneously with gamma-interferon at a dose of 2 MU/m2, and 10 MU...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1993-03-01 00:00:00
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journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2006.06.019
更新日期:2006-11-01 00:00:00
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更新日期:1997-01-01 00:00:00
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更新日期:1997-09-01 00:00:00
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pub_type: 杂志文章,评审
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.08.011
更新日期:2006-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1999-05-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/j.jhep.2014.02.012
更新日期:2014-06-01 00:00:00
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更新日期:2000-12-01 00:00:00
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更新日期:2007-12-01 00:00:00
abstract::The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patien...
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pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1991-09-01 00:00:00
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journal_title:Journal of hepatology
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更新日期:2019-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2010-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1986-01-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatitis C virus (HCV) evades humoral immunity and establishes chronic infections. Virus particles circulate in complex with lipoproteins facilitating antibody escape. Apolipoprotein E (ApoE) is essential for intracellular HCV assembly and for HCV cell entry. We aimed to explore if ApoE released from...
journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2017-09-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.jhep.2012.06.029
更新日期:2012-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:1998-10-01 00:00:00