Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers.
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.
Hsu
Eric C
EC
Ontario Cancer Institute (Advanced Medical Discoveries Institute), 620 University Ave., Suite 706, Toronto, ON M5G 2C1, Canada.
Hsi
Belinda
B
Hirota-Tsuchihara
Masami
M
Ruland
Jurgen
J
Iorio
Cathy
C
Sarangi
Farida
F
Diao
Jingyu
J
Migliaccio
Giovanni
G
Tyrrell
D Lorne
DL
Kneteman
Norman
N
Richardson
Christopher D
CD
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
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