Strain-specific responsiveness of hepatitis D virus to interferon-alpha treatment.
ADAR, adenosine deaminase
ADF, adefovir
AG, antigenomic
Actb, actin beta
Antiviral
BSA, bovine serum albumin
CHD, chronic hepatitis D
CK18, cytokeratin 18
CXCL10, C-X-C motif chemokine ligand 10
Eef2, eukaryotic elongation factor
FCS, foetal calf serum
GAPDH, glyceraldehyde-3-phosphate dehydrogenase
Genotype
HBsAg, hepatitis B virus surface antigen
HDAg, hepatitis delta antigen (S, small, L, large)
HDV
HLA, human leucocyte antigen
HSA, uman serum albumin
Human liver chimeric mice
IFNα, interferon α
ISGs, interferon stimulated genes
LAM, lamivudine
LLoD, lower limit of detection
MDA5, melanoma differentiation-associated protein 5
MOI, multiplicity of infection
Mavs, mitochondrial antiviral-signalling protein
MoA, mode of action
MxA, myxovirus resistance gene A
NTCP, sodium (Na+) taurocholate co-transporting polypeptide
NUCs, nucleos(t)ide analogues
OAS1, 2′-5′-oligoadenylatsynthetase 1
PEG, polyethylene glycol
PHHs, primary human hepatocytes
RNP, ribonucleoprotein
Resistance
Rig-I, retinoic acid-inducible gene I
SCID, severe combined immunodeficiency
STAT1, signal transducers and activators of transcription 1
TGFβ, transforming growth factor-β
USG, uPA/SCID/beige/IL2RG-/-
casp, caspase
hAAT, human alpha antitrypsin
pegIFNα, pegylated interferon alpha
pgRNA, pregenomic RNA
qPCR, quantitative real time polymerase chain reaction
uPA, urokinase plasminogen activator
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Apr 2023
Apr 2023
Historique:
received:
29
06
2022
revised:
02
12
2022
accepted:
03
01
2023
entrez:
13
3
2023
pubmed:
14
3
2023
medline:
14
3
2023
Statut:
epublish
Résumé
Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNα therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNα PegIFNα was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA PegIFNα treatment efficiently reduced HDV RNA viraemia (∼2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNα treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (∼2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNα. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates. Our comparative study indicates the ability of pegIFNα to lower HDV loads in stably infected human hepatocytes Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains.
Sections du résumé
Background & Aims
UNASSIGNED
Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNα therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNα
Methods
UNASSIGNED
PegIFNα was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA
Results
UNASSIGNED
PegIFNα treatment efficiently reduced HDV RNA viraemia (∼2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNα treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (∼2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNα. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates.
Conclusions
UNASSIGNED
Our comparative study indicates the ability of pegIFNα to lower HDV loads in stably infected human hepatocytes
Impact and implications
UNASSIGNED
Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains.
Identifiants
pubmed: 36908749
doi: 10.1016/j.jhepr.2023.100673
pii: S2589-5559(23)00004-6
pmc: PMC9996322
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100673Informations de copyright
© 2023 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details.
Références
BMC Gastroenterol. 2020 Jan 30;20(1):24
pubmed: 32000689
Curr Top Microbiol Immunol. 2006;307:151-71
pubmed: 16903225
J Hepatol. 2015 Aug;63(2):346-53
pubmed: 25795587
J Hepatol. 2021 May;74(5):1200-1211
pubmed: 33484770
Sci Rep. 2017 Jun 16;7(1):3757
pubmed: 28623307
J Hepatol. 2022 Nov;77(5):1448-1450
pubmed: 35850738
J Hepatol. 2020 Nov;73(5):1046-1062
pubmed: 32634548
PLoS One. 2011;6(7):e22415
pubmed: 21811602
Gut. 2022 Feb;71(2):372-381
pubmed: 33509930
Liver Int. 2020 Feb;40 Suppl 1:48-53
pubmed: 32077599
Curr Top Microbiol Immunol. 2006;307:91-112
pubmed: 16903222
Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9016-20
pubmed: 8415646
J Virol. 2014 May;88(10):5742-54
pubmed: 24623409
J Virol. 1994 Jun;68(6):4063-6
pubmed: 8189544
Front Microbiol. 2021 Jul 08;12:671466
pubmed: 34305837
J Hepatol. 2021 Aug;75(2):311-323
pubmed: 33845061
Proc Natl Acad Sci U S A. 2019 Aug 20;116(34):17007-17012
pubmed: 31371507
Semin Immunopathol. 2021 Aug;43(4):535-548
pubmed: 34019142
Nature. 1987 Sep 24-30;329(6137):343-6
pubmed: 3627276
Gut. 2019 Jan;68(1):150-157
pubmed: 29217749
J Virol. 1989 May;63(5):1945-50
pubmed: 2649689
Gut. 2019 Mar;68(3):512-521
pubmed: 30228220
J Virol. 1989 Oct;63(10):4292-7
pubmed: 2778877
Hepatology. 1991 Feb;13(2):345-52
pubmed: 1995441
J Virol. 1988 Jun;62(6):1855-61
pubmed: 3367426
Emerg Infect Dis. 2006 Sep;12(9):1447-50
pubmed: 17073101
Elife. 2012 Nov 13;1:e00049
pubmed: 23150796
J Virol. 1992 Jul;66(7):4107-16
pubmed: 1602535
Arch Virol Suppl. 1993;8:15-21
pubmed: 8260860
J Hepatol. 2022 Oct;77(4):957-966
pubmed: 35636579
Clin Microbiol Infect. 2020 Jul;26(7):824-827
pubmed: 32120043
J Hepatol. 2018 Jul;69(1):25-35
pubmed: 29524530
Hepatol Commun. 2022 Mar;6(3):480-495
pubmed: 34561972
Hepatology. 2012 Mar;55(3):685-94
pubmed: 22031488
Gastroenterology. 2019 Jan;156(2):461-476.e1
pubmed: 30342879
Gut. 2021 Sep;70(9):1782-1794
pubmed: 34103404
Lancet Infect Dis. 2023 Jan;23(1):117-129
pubmed: 36113537
Res Virol. 1998 May-Jun;149(3):171-85
pubmed: 9711541
J Infect Dis. 1992 Nov;166(5):1164-6
pubmed: 1328404
Hepatology. 2017 Dec;66(6):1826-1841
pubmed: 28992360
Gut. 2018 Mar;67(3):542-552
pubmed: 28428345
J Virol. 1998 Apr;72(4):2806-14
pubmed: 9525600