Abstract
A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antiviral Agents / pharmacology*
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Azocines / pharmacology*
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Benzhydryl Compounds / pharmacology*
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Disease Models, Animal
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Genome, Viral*
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Hep G2 Cells
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Hepatitis B / drug therapy*
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Hepatitis B / metabolism
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Hepatitis B / pathology
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Hepatitis B / virology
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Hepatitis B virus / drug effects*
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Hepatitis B virus / genetics
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Hepatocytes / drug effects*
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Hepatocytes / metabolism
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Hepatocytes / pathology
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Hepatocytes / virology
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Host-Pathogen Interactions
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / metabolism
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Liver / drug effects*
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Liver / metabolism
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Liver / pathology
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Liver / virology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Targeted Therapy
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Organoids
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Thiazoles / pharmacology*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Azocines
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Benzhydryl Compounds
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Inhibitor of Apoptosis Proteins
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LCL161
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N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide
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Thiazoles
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Tnf protein, mouse
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Tumor Necrosis Factor-alpha