Background & Aims
The limited availability of hepatitis Delta virus (HDV) infection models has hindered studies of interactions between HDV and infected hepatocytes. The aim was to investigate the antiviral state of HDV infected human hepatocytes in the setting of co-infection with hepatitis B virus (HBV) compared to HBV mono-infection using human liver chimeric mice.
Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.
Upon HBV/HDV inoculation, all mice developed viremia, which was accompanied by a significant induction of hISGs (i.e. hISG15, hSTATs, hHLA-E) compared to uninfected mice, while HBV mono-infection led to weaker hISG elevations. In the setting of chronic infection enhancement of innate defense mechanisms was significantly more prominent in HBV/HDV infected mice. Also the induction of human-specific cytokines (hIP10, hTGF-ß, hIFN-ß and hIFN-λ) was detected in HBV/HDV co-infected animals, while levels remained lower or below detection in uninfected and HBV mono-infected mice. Moreover, despite the average increase of hSTAT levels determined in HBV/HDV infected livers, we observed a weaker hSTAT accumulation in nuclei of hepatocytes displaying very high HDAg levels, suggesting that HDAg may in part limit hSTAT signaling.
Establishment of HDV infection provoked a clear enhancement of the antiviral state of the human hepatocytes in chimeric mice. Elevated pre-treatment ISG and interferon levels may directly contribute to inflammation and liver damage, providing a rationale for the more severe course of HDV-associated liver disease. Such antiviral state induction might also contribute to the lower levels of HBV activity frequently found in co-infected hepatocytes.
Abbreviations:HDV (Hepatitis Delta Virus), HBV (Hepatitis B Virus), ISGs (interferon stimulated genes), UPA (Urokinase Plasminogen activator), SCID (Severe combined immunodeficiency)
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 access
One-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 Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Clinical features of hepatitis D.Semin Liver Dis. 2012; 32: 228-236
- Hepatitis D virus: an update.Liver Int. 2011; 31: 7-21
- Packaging of hepatitis delta virus RNA via the RNA-binding domain of hepatitis delta antigens: different roles for the small and large delta antigens.J Virol. 1994; 68: 6363-6371
- Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1.Proc Natl Acad Sci U S A. 2002; 99: 15118-15123
- Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.Gastroenterology. 2014; 146: 1070-1083
- The role of the HBV envelope proteins in the HDV replication cycle.Curr Top Microbiol Immunol. 2006; 307: 113-131
- Persistent hepatitis D virus mono-infection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection.J Hepatol. 2014; 60: 538-544
- Innate immunity to virus infection.Immunol Rev. 2009; 227: 75-86
- The inflammasome: a danger sensing complex triggering innate immunity.Curr Opin Immunol. 2007; 19: 615-622
- Interferon targeted genes in host defense.Autoimmunity. 2003; 36: 457-461
- Interferon-stimulated genes and their antiviral effector functions.Curr Opin Virol. 2011; 1: 519-525
- Gene expression and hepatitis C virus infection.Gut. 2009; 58: 846-858
- ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment.J Gen Virol. 2010; 91: 382-388
- Pegylated-interferon-alpha alone or in combination with entecavir restores ISG responsiveness and reduces intrahepatic viral loads and antigenemia in hepatitis B virus infected humanized mice.J Hepatol. 2012; 56: S18-S19
- Virion half-life in chronic hepatitis B infection is strongly correlated with levels of viremia.Hepatology. 2008; 48: 1079-1086
- Establishment of a novel quantitative hepatitis D virus (HDV) RNA assay using the Cobas TaqMan platform to study HDV RNA kinetics.J Clin Microbiol. 2010; 48: 2022-2029
- Hepatitis B viral DNA decline at loss of HBeAg is mainly explained by reduced cccDNA load–down-regulated transcription of PgRNA has limited impact.PLoS One. 2012; 7: e36349
- Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism.Hepatology. 2014; 60: 1483-1493
- The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway.J Hepatol. 2011; 55: 762-769
- Hepatitis B virus limits response of human hepatocytes to interferon-alpha in chimeric mice.Gastroenterology. 2011; 140 (2083, e2071–e2072): 2074-2083
- Dynamics of hepatitis B virus clearance in chimpanzees.Proc Natl Acad Sci U S A. 2005; 102: 17780-17785
- Hepatitis delta virus.Lancet. 2011; 378: 73-85
- Hepatitis D virus-specific cytokine responses in patients with chronic hepatitis delta before and during interferon alfa-treatment.Liver Int. 2011; 31: 1395-1405
- Effects of HDV infection and pegylated interferon alpha treatment on the natural killer cell compartment in chronically infected individuals.Gut. 2015; 64: 469-482
- Novel paradigms of innate immune sensing of viral infections.Cytokine. 2013; 63: 219-224
- Hepatitis delta virus inhibits alpha interferon signaling.Hepatology. 2009; 49: 398-406
- Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection.Gastroenterology. 2005; 128: 1437-1444
- The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response.Gut. 2010; 59: 1111-1119
- Identification of proteins that mediate the pro-viral functions of the interferon stimulated gene 15 in hepatitis C virus replication.Antiviral Res. 2013; 100: 654-661
- IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection.Hepatology. 2006; 44: 1617-1625
Published online: March 18, 2015
Accepted: March 3, 2015
Received in revised form: March 2, 2015
Received: October 9, 2014
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.