Nature Biotechnology
21, 519 - 525 (2003)
Published online: 21 April 2003; | doi:10.1038/nbt817
Modified apoptotic molecule (BID) reduces hepatitis C virus infection
in mice with chimeric human liversEric C. Hsu1, 2, Belinda Hsi3, Masami Hirota-Tsuchihara1, 2, Jurgen Ruland1, 2, 4, Cathy Iorio1, Farida Sarangi1, Jingyu Diao2, 5, Giovanni Migliaccio6, D. Lorne Tyrrell7, Norman Kneteman3
& Christopher D. Richardson1, 2, 51
Ontario Cancer Institute (Advanced Medical
Discoveries Institute), 620 University Ave., Suite 706,
Toronto, ON M5G 2C1, Canada. 2
Ontario Cancer Institute, Division of Molecular
and Structural Biology, 610 University Ave.,
Toronto, ON M5G 2M9, Canada. 3
Surgical-Medical Research Institute, Department of
Surgery, University of Alberta, Edmonton, AB,
Canada. 4
Current Address: Department of Internal Medicine
III, Technical University of Munich, Klinikum rechts der Isar,
Ismaninger Str. 22, 81675 Munich,
Germany. 5
Department of Medical Biophysics, University of
Toronto, 610 University Ave., Toronto,
ON M5G 2M9, Canada. 6
Istituto di Ricerche di Biologia Molecolare, P.
Angeletti, 00040 Pomezia, Rome, Italy. 7
Department of Medical Microbiology and Immunology,
University of Alberta, Edmonton, AB,
Canada.
Correspondence should be addressed to Christopher D. Richardson chrisr@uhnres.utoronto.caHepatitis 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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