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

Eric C. Hsu; Belinda Hsi; Masami Hirota-Tsuchihara; Jurgen Ruland; Cathy Iorio; Farida Sarangi; Jingyu Diao; Giovanni Migliaccio; D. Lorne Tyrrell; Norman Kneteman; Christopher D. Richardson

doi:10.1038/nbt817

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

Eric C. Hsu, Belinda Hsi, Masami Hirota-Tsuchihara, Jurgen Ruland, Cathy Iorio, Farida Sarangi, Jingyu Diao, Giovanni Migliaccio, D. Lorne Tyrrell, Norman Kneteman, Christopher D. Richardson

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58 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	519-525
Número de páginas	7
Publicación	Nature Biotechnology
Volumen	21
N.º	5
DOI	https://doi.org/10.1038/nbt817
Estado	Published - may. 1 2003
Publicado de forma externa	Sí

Nota bibliográfica

Funding Information:
Acknowledgments Valuable discussions with Wen-Chen Yeh, Katsuya Tsuchihara, Razq Hakem, Malte Peters, and Tak W. Mak were much appreciated. This work was supported by the Canadian Institutes of Health Grant no. EOP-38155 and CANVAC (Canadian Network of Centres of Excellence).

ASJC Scopus Subject Areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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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.",

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AU - Iorio, Cathy

AU - Sarangi, Farida

AU - Diao, Jingyu

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AU - Kneteman, Norman

AU - Richardson, Christopher D.

N1 - Funding Information: Acknowledgments Valuable discussions with Wen-Chen Yeh, Katsuya Tsuchihara, Razq Hakem, Malte Peters, and Tak W. Mak were much appreciated. This work was supported by the Canadian Institutes of Health Grant no. EOP-38155 and CANVAC (Canadian Network of Centres of Excellence).

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

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ASJC Scopus Subject Areas

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