Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers

• Published in: Nature biotechnology Vol. 21; no. 5; pp. 519 - 525
• Main Authors: Richardson, Christopher D, Hsu, Eric C, Hsi, Belinda, Hirota-Tsuchihara, Masami, Ruland, Jurgen, Iorio, Cathy, Sarangi, Farida, Diao, Jingyu, Migliaccio, Giovanni, Tyrrell, D. Lorne, Kneteman, Norman
• Format: Journal Article
• Language: English
• Published: New York, NY Nature 01.05.2003; Nature Publishing Group
• Subjects: Animals; Apoptosis - drug effects; BH3 Interacting Domain Death Agonist Protein; Biological and medical sciences; Biotechnology; Carrier Proteins - administration & dosage; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Carrier Proteins - therapeutic use; Caspase 3; Caspases - administration & dosage; Caspases - biosynthesis; Caspases - genetics; Caspases - therapeutic use; Enzyme Precursors - administration & dosage; Enzyme Precursors - biosynthesis; Enzyme Precursors - genetics; Enzyme Precursors - therapeutic use; Fundamental and applied biological sciences. Psychology; Genetic Therapy - methods; Hepatitis; Hepatitis C - drug therapy; Hepatitis C - immunology; Humans; Liver - drug effects; Liver - immunology; Liver - surgery; Liver Transplantation; Mice; Mortality; Protein Engineering - methods; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Recombinant Proteins - therapeutic use; Transplantation Chimera; Treatment Outcome; Human; Animal model; Liver; Rodentia; Virus; Infection; Vertebrata; Mammalia; Mouse; Flaviviridae; Gene therapy; Hepatitis C virus; Hepacivirus; Apoptosis
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt817

Hepatitis C virus (HCV) encodes a polyprotein consisting of core, envelope (E1, E2, p7), and nonstructural polypeptides (NS2, NS3, NS4A, NS4B, NS5A, NS5B). The serine protease (NS3/NS4A), helicase (NS3), and polymerase (NS5B) constitute valid targets for antiviral therapy. We engineered BH3 interacting domain death agonist (BID), an apoptosis-inducing molecule, to contain a specific cleavage site recognized by the NS3/NS4A protease. Cleavage of the BID precursor molecule by the viral protease activated downstream apoptotic molecules of the mitochondrial pathway and triggered cell death. We extended this concept to cells transfected with an infectious HCV genome, hepatocytes containing HCV replicons, a Sindbis virus model for HCV, and finally HCV-infected mice with chimeric human livers. Infected mice injected with an adenovirus vector expressing modified BID exhibited HCV-dependent apoptosis in the human liver xenograft and considerable declines in serum HCV titers.