Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity
HDV-AG(s), HDV anti-genome(s)
HDV-G(s), HDV genome(s)
Hepatitis B virus
Hepatitis D virus
IFN, interferon
IL-, interleukin-
L-HDAg, large HDV antigen
LTβR, lymphotoxin-β receptor
NF-κB
NTCP, Na+-taurocholate cotransporting polypeptide
PHH, primary human hepatocyte
Peg-IFN-α, pegylated interferon-α
RNP, ribonucleoprotein
S-HDAg, small HDV antigen
TLR, Toll-like receptor
TNF, tumor necrosis factor
antiviral activity
dHepaRG, differentiated HepaRG cells
hepatocytes
lymphotoxin beta receptor
rh, recombinant human
toll-like receptor
vge, viral genome equivalent
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Mar 2022
Mar 2022
Historique:
received:
07
07
2021
revised:
03
11
2021
accepted:
02
12
2021
entrez:
10
2
2022
pubmed:
11
2
2022
medline:
11
2
2022
Statut:
epublish
Résumé
HDV superinfection of chronically HBV-infected patients is the most aggressive form of chronic viral hepatitis, with an accelerated progression towards fibrosis/cirrhosis and increased risk of liver failure, hepatocellular carcinoma, and death. While HDV infection is not susceptible to available direct anti-HBV drugs, suboptimal responses are obtained with interferon-α-based therapies, and the number of investigational drugs remains limited. We therefore analyzed the effect of several innate immune stimulators on HDV replication in infected hepatocytes. We used We describe here, for the first time, anti-HDV effects of Pam3CSK4 and BS1, agonists of Toll-like receptor (TLR)-1/2, and the lymphotoxin-β receptor (LTβR), respectively. Both types of agonists induced dose-dependent reductions of total intracellular HDV genome and antigenome RNA and of HDV protein levels, without toxicity in cells monoinfected with HDV or co/superinfected with HBV. Moreover, both molecules negatively affected HDV progeny release and strongly decreased their specific infectivity. The latter effect is particularly important since HDV is thought to persist in humans through constant propagation. Immune-modulators inducing NF-κB pathways in hepatocytes can inhibit HDV replication and should be further evaluated as a possible therapeutic approach in chronically HBV/HDV-infected patients. Hepatitis delta virus causes the most severe form of viral hepatitis. Despite positive recent developments, effective treatments remain a major clinical need. Herein, we show that immune-modulators that trigger the NF-κB pathways could be effective for the treatment of hepatitis delta infections.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
HDV superinfection of chronically HBV-infected patients is the most aggressive form of chronic viral hepatitis, with an accelerated progression towards fibrosis/cirrhosis and increased risk of liver failure, hepatocellular carcinoma, and death. While HDV infection is not susceptible to available direct anti-HBV drugs, suboptimal responses are obtained with interferon-α-based therapies, and the number of investigational drugs remains limited. We therefore analyzed the effect of several innate immune stimulators on HDV replication in infected hepatocytes.
METHODS
METHODS
We used
RESULTS
RESULTS
We describe here, for the first time, anti-HDV effects of Pam3CSK4 and BS1, agonists of Toll-like receptor (TLR)-1/2, and the lymphotoxin-β receptor (LTβR), respectively. Both types of agonists induced dose-dependent reductions of total intracellular HDV genome and antigenome RNA and of HDV protein levels, without toxicity in cells monoinfected with HDV or co/superinfected with HBV. Moreover, both molecules negatively affected HDV progeny release and strongly decreased their specific infectivity. The latter effect is particularly important since HDV is thought to persist in humans through constant propagation.
CONCLUSIONS
CONCLUSIONS
Immune-modulators inducing NF-κB pathways in hepatocytes can inhibit HDV replication and should be further evaluated as a possible therapeutic approach in chronically HBV/HDV-infected patients.
LAY SUMMARY
BACKGROUND
Hepatitis delta virus causes the most severe form of viral hepatitis. Despite positive recent developments, effective treatments remain a major clinical need. Herein, we show that immune-modulators that trigger the NF-κB pathways could be effective for the treatment of hepatitis delta infections.
Identifiants
pubmed: 35141510
doi: 10.1016/j.jhepr.2021.100415
pii: S2589-5559(21)00191-9
pmc: PMC8792426
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100415Informations de copyright
© 2021 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.
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