Class a capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation.
Dieudonné Buh Kum
,
Hannah Vanrusselt
,
Abel Acosta Sanchez
,
Valerio Taverniti
(1)
,
Eloi Verrier
(2)
,
Thomas F. Baumert
(2)
,
Cheng Liu
,
Jerome Deval
,
Nikky Corthout
,
Sebastian Munck
,
Leonid Beigelman
,
Lawrence M Blatt
,
Julian A. Symons
,
Pierre Raboisson
,
Andreas Jekle
,
Sandrine Vendeville
,
Yannick Debing
Dieudonné Buh Kum
- Fonction : Auteur
Hannah Vanrusselt
- Fonction : Auteur
Abel Acosta Sanchez
- Fonction : Auteur
Valerio Taverniti
- Fonction : Auteur
- PersonId : 1050463
Eloi Verrier
- Fonction : Auteur
- PersonId : 1041637
- ORCID : 0000-0002-9022-5611
- IdRef : 17474739X
Thomas F. Baumert
- Fonction : Auteur
- PersonId : 740312
- IdHAL : thomas-f-baumert
- IdRef : 143387898
Cheng Liu
- Fonction : Auteur
Jerome Deval
- Fonction : Auteur
Nikky Corthout
- Fonction : Auteur
Sebastian Munck
- Fonction : Auteur
Leonid Beigelman
- Fonction : Auteur
Lawrence M Blatt
- Fonction : Auteur
Julian A. Symons
- Fonction : Auteur
Pierre Raboisson
- Fonction : Auteur
Andreas Jekle
- Fonction : Auteur
Sandrine Vendeville
- Fonction : Auteur
Yannick Debing
- Fonction : Auteur
Résumé
Effective therapies leading to a functional cure of chronic hepatitis B (CHB) are still lacking. Class A capsid assembly modulators (CAM-As) are an attractive modality to address this unmet medical need. CAM-As induce aggregation of the HBV core protein (HBc) and lead to sustained HBsAg reductions in a CHB mouse model. Here we investigate the underlying mechanism of action for CAM-A compound RG7907. RG7907 induced extensive HBc aggregation in vitro, in hepatoma cells, and in primary hepatocytes. In the adeno-associated virus (AAV)-HBV mouse model, RG7907 treatment led to a pronounced reduction in serum HBsAg and HBeAg, concomitant with clearance of HBsAg, HBc, and AAV-HBV episome from the liver. Transient increases in alanine transaminase, hepatocyte apoptosis, and proliferation markers were observed. These processes were confirmed by RNA sequencing, which also uncovered a role for interferon alpha and gamma signaling, including the interferon-stimulated gene 15 (ISG15) pathway. Finally, the in vitro observation of CAM-A-induced HBc-dependent cell death through apoptosis established the link of HBc aggregation to in vivo loss of infected hepatocytes. Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA (cccDNA) or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for CHB.
Domaines
Médecine humaine et pathologieFormat du dépôt | Notice |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Class a capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation.
|
Résumé |
en
Effective therapies leading to a functional cure of chronic hepatitis B (CHB) are still lacking. Class A capsid assembly modulators (CAM-As) are an attractive modality to address this unmet medical need. CAM-As induce aggregation of the HBV core protein (HBc) and lead to sustained HBsAg reductions in a CHB mouse model. Here we investigate the underlying mechanism of action for CAM-A compound RG7907. RG7907 induced extensive HBc aggregation in vitro, in hepatoma cells, and in primary hepatocytes. In the adeno-associated virus (AAV)-HBV mouse model, RG7907 treatment led to a pronounced reduction in serum HBsAg and HBeAg, concomitant with clearance of HBsAg, HBc, and AAV-HBV episome from the liver. Transient increases in alanine transaminase, hepatocyte apoptosis, and proliferation markers were observed. These processes were confirmed by RNA sequencing, which also uncovered a role for interferon alpha and gamma signaling, including the interferon-stimulated gene 15 (ISG15) pathway. Finally, the in vitro observation of CAM-A-induced HBc-dependent cell death through apoptosis established the link of HBc aggregation to in vivo loss of infected hepatocytes. Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA (cccDNA) or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for CHB.
|
Auteur(s) |
Dieudonné Buh Kum
, Hannah Vanrusselt
, Abel Acosta Sanchez
, Valerio Taverniti
1
, Eloi Verrier
2
, Thomas F. Baumert
2
, Cheng Liu
, Jerome Deval
, Nikky Corthout
, Sebastian Munck
, Leonid Beigelman
, Lawrence M Blatt
, Julian A. Symons
, Pierre Raboisson
, Andreas Jekle
, Sandrine Vendeville
, Yannick Debing
1
IGBMC -
Institut de Génétique et de Biologie Moléculaire et Cellulaire
( 93800 )
- Parc D'Innovation 1 Rue Laurent Fries - BP 10142 67404 Illkirch Cedex
- France
2
IVH -
Institut de Recherche sur les Maladies Virales et Hépatiques
( 447080 )
- Institut de virologie, 3 rue Koeberlé, 67000 Strasbourg
- France
|
Langue du document |
Anglais
|
Nom de la revue |
|
Date de publication |
2023-04-28
|
Audience |
Non spécifiée
|
Comité de lecture |
Oui
|
Vulgarisation |
Non
|
Date de production/écriture |
2023
|
Domaine(s) |
|
Projet(s) ANR |
|
DOI | 10.1097/HEP.0000000000000428 |
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