Dépôt numérique

Characterization of the Direct Antiviral Effect of REP 2139 on HDV Replication

Fonte, Simone; Plissonnier, :MarieLaure; Michelet, Maud; Blanchet, Matthieu; Labonté, Patrick ORCID logoORCID: 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.

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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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