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Activity of REP 2139 in HepG2 Cells Expressing HBsAg Isoforms

Angelo, Léna, Blanchet, Matthieu, Vaillant, Andrew et Labonté, Patrick ORCID: https://orcid.org/0000-0001-7262-3125 (2020). Activity of REP 2139 in HepG2 Cells Expressing HBsAg Isoforms In: Liver Meeting of the American Association for the Study of Liver Diseases (AASLD), 2020, November 13 - 16, Electronic Network.

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Résumé

Background: During hepatitis B virus (HBV) infection, subviral particles (SVP) are produced in vast quantity compared to infectious virions (Dane particles) . SVP are thus the major source of HBV surface antigen (HBsAg) in patient serum as well as in culture supernatants . SVP are commonly accepted to be responsible for the establishment of the HBV chronicity, causing an exhaustion of the immune system against HBsAg . Recent in vitro studies in HepG2 .2 .15 cells (Blanchet et al., 2019; Boulon et al., 2020) analyzed the antiviral effects of the nucleic acid polymer REP 2139 on the HBV lifecycle . These studies revealed that REP 2139 inhibits HBsAg secretion no intracellular HBsAg accumulation and no effect on HBeAg or Dane particle secretion, suggesting the specific targeting of assembly and/or secretion of SVP . Recent clinical trials have shown that REP 2139 is able to clear circulating HBsAg, associated with a reappearance of anti-HBsAg antibodies and high rates functional cure . However, the mechanisms leading to these effects are still unclear . A novel HepG2 model system only expressing HBsAg and HBx is being developed to explore the antiviral effects of REP 2139 . Methods: CRISPR/Cas9 is being used to develop a HepG2-based cell line in which the HBsAg gene (expressing large, medium and small isoforms) is integrated in the AAVS1 safe-harbour and expressed from endogenous HBV promoters The X gene also had to be integrated because its ORF is overlapping a sequence called HBV post-transcriptional regulatory element (HPRE), which is critical for HBsAg expression (Huang et al., 1995) . REP 2139 treatment was followed by endosomal release with UNC 7938 as previously described (Blanchet et al., 2019; Boulon et al., 2020) . HBsAg was monitored by ELISA (BioRad GS HBsAg EIA 3 .0) . Results: HBsAg secretion was from this novel cell line was verified by ELISA and was similar to HepG2.2.15 cells . Preliminary data from treatment with REP 2139 indicate a dose dependent inhibition of HBsAg secretion in line with that previously obtained in HepG2 .2 .15 cells . Conclusion: REP 2139 blocks HBsAg secretion in a simplified model expressing HBsAg isoforms, consistent with its selective effects on SVP assembly / secretion.

Type de document: Document issu d'une conférence ou d'un atelier
Informations complémentaires: Affiche scientifique no 818 Hepatology 72(S1) 500A
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 15 juill. 2021 00:55
Dernière modification: 15 févr. 2022 18:22
URI: https://espace.inrs.ca/id/eprint/11515

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