title: Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers.
abstract: 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.
authors.affiliation: Ontario Cancer Institute (Advanced Medical Discoveries Institute), 620 University Ave., Suite 706, Toronto, ON M5G 2C1, Canada.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Hsu
authors.forename: Belinda
authors.initials: B
authors.lastname: Hsi
authors.forename: Masami
authors.initials: M
authors.lastname: Hirota-Tsuchihara
authors.forename: Jurgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Cathy
authors.initials: C
authors.lastname: Iorio
authors.forename: Farida
authors.initials: F
authors.lastname: Sarangi
authors.forename: Jingyu
authors.initials: J
authors.lastname: Diao
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.forename: D Lorne
authors.initials: DL
authors.lastname: Tyrrell
authors.forename: Norman
authors.initials: N
authors.lastname: Kneteman
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Richardson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D053148:Caspase 3; D020169:Caspases / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D004792:Enzyme Precursors / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods*; D006526:Hepatitis C / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000276:immunology* / Q000601:surgery; D016031:Liver Transplantation; D051379:Mice; D015202:Protein Engineering / Q000379:methods; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D018183:Transplantation Chimera; D016896:Treatment Outcome
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; C494815:Bid protein, mouse; D002352:Carrier Proteins; D004792:Enzyme Precursors; D011994:Recombinant Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases