Fonte, Simone; Plissonnier, :MarieLaure; Michelet, Maud; Blanchet, Matthieu; Labonté, Patrick 
ORCID: https://orcid.org/0000-0001-7262-3125; Vaillant, Andrew et Levrero, Massimo
(2023).
Characterization of the Direct Antiviral Effect of REP 2139 on HDV Replication
In: Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), November 10-14, 2023, Boston, MA.
Résumé
Background: REP 2139 blocks the assembly and
secretion of HBV subviral particles, an effect which also
blocks envelopment of the Hepatitis D Virus (HDV)
ribonuclear protein (RNP) and secretion of HDV from
infected cell. A previous phase II study and current
compassionate use of REP 2139 in Hepatitis B Virus
(HBV) / HDV infection have shown an early and more robust antiviral response toward HDV RNA than as
compared to HBsAg, suggesting a second, upstream
and direct acting antiviral mechanism. Here we have
investigated the direct antiviral activity of REP 2139 in
relevant HDV cell infection models in vitro. Methods:
Restoration of REP 2139 endosomal release in vitro
employed the UNC 7938-based method previously
described (Blanchet et al., Antiviral Res 2019; 164:
97). Clinical supply of REP 2139-Mg (lot FAB-22-0001)
was used for dosing in HDV infected HepG2-NTCP
cells and primary human hepatocytes (PHH) at (10
genome equivalents/cell). REP 2139-Mg was diluted in
normal saline before addition to tissue culture. Intracellular HDV viral genome levels were assessed in cell
lysates by quantitative RT-PCR. The association of
HDV RNA and Hepatitis Delta Antigen (HDAg) to form
the HDV ribonucleoprotein (HDV RNP) was monitored
by anti-HDAg RNA immunoprecipitation (RIP) followed
by HDV specific RT-PCR (Abeywickrama-Samarakoon
N et al., Nat Commun. 2020; 11: 419). Results: A single
dose of REP 2139-Mg reduced intracellular HDV viral
genome levels by ~1 log10 in HepG2-NTCP and PHH
cells at 400nM and 600nM respectively. Loss of antiviral
activity at higher doses could be recovered by
increasing UNC 7938 concentration, indicating that the
efficiency of endosomal release of REP 2139 into cells
is a process influenced by endosomal concentration of
REP 2139 and the dose of UNC 7938 used. A single
dose of REP 2139-Mg also reduced the intranuclear
association of HDV RNA with HDAg in both HepG2-
NTCP and PHH by ~60% (@ 600nM) and 65% (@
400nM), respectively. Conclusion: REP 2139 has a
direct acting antiviral effect against HDV RNA replication which may involve blocking HDV RNA interaction
with HDAg during the morphogenesis of HDV RNP.
These antiviral effects bear further investigation and
may explain the more rapid decline of HDV RNA versus
HBsAg in human studies.
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Présentation orale 1461-C Hepatology 78 (Suppl.1): S561 http://dx.doi.org/10.1097/HEP.0000000000000580 |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 06 janv. 2024 22:38 |
| Dernière modification: | 06 janv. 2024 22:38 |
| URI: | https://espace.inrs.ca/id/eprint/13966 |
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