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.
Methods
Viral loads, human interferon stimulated genes (hISGs) and cytokines were determined
in humanized uPA/SCID/beige (USB) mice by qRT-PCR, ELISA and immunofluorescence.
Results
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.
Conclusions
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.
Graphical abstract
Graphical Abstract
Abbreviations:
HDV (Hepatitis Delta Virus), HBV (Hepatitis B Virus), ISGs (interferon stimulated genes), UPA (Urokinase Plasminogen activator), SCID (Severe combined immunodeficiency)Keywords
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Article info
Publication history
Published online: March 18, 2015
Accepted:
March 3,
2015
Received in revised form:
March 2,
2015
Received:
October 9,
2014
Identification
Copyright
© 2015 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
