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

Résultat de recherche: Article › examen par les pairs

58 Citations (Scopus)

Résumé

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.

Langue d'origine	English
Pages (de-à)	519-525
Nombre de pages	7
Journal	Nature Biotechnology
Volume	21
Numéro de publication	5
DOI	https://doi.org/10.1038/nbt817
Statut de publication	Published - mai 1 2003
Publié à l'externe	Oui

Note bibliographique

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

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1038/nbt817

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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.",

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

note = "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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AU - Iorio, Cathy

AU - Sarangi, Farida

AU - Diao, Jingyu

AU - Migliaccio, Giovanni

AU - Tyrrell, D. Lorne

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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N2 - 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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Modified apoptotic molecule (BID) reduces hepatitis C virus infection in mice with chimeric human livers

Résumé

Note bibliographique

ASJC Scopus Subject Areas

ODD de l’ONU

Accès au document

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