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Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers.
Hsu, Eric C; Hsi, Belinda; Hirota-Tsuchihara, Masami; Ruland, Jurgen; Iorio, Cathy; Sarangi, Farida; Diao, Jingyu; Migliaccio, Giovanni; Tyrrell, D Lorne; Kneteman, Norman; Richardson, Christopher D.
Afiliação
  • Hsu EC; Ontario Cancer Institute (Advanced Medical Discoveries Institute), 620 University Ave., Suite 706, Toronto, ON M5G 2C1, Canada.
Nat Biotechnol ; 21(5): 519-25, 2003 May.
Article em En | MEDLINE | ID: mdl-12704395
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.
Assuntos
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Base de dados: MEDLINE Assunto principal: Terapia Genética / Proteínas de Transporte / Hepatite C / Fígado Tipo de estudo: Evaluation_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2003 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Terapia Genética / Proteínas de Transporte / Hepatite C / Fígado Tipo de estudo: Evaluation_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2003 Tipo de documento: Article