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

Nat Biotechnol. 2003 May;21(5):519-25. doi: 10.1038/nbt817. Epub 2003 Apr 21.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / administration & dosage
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / therapeutic use*
  • Caspase 3
  • Caspases / administration & dosage
  • Caspases / biosynthesis
  • Caspases / genetics
  • Caspases / therapeutic use
  • Enzyme Precursors / administration & dosage
  • Enzyme Precursors / biosynthesis
  • Enzyme Precursors / genetics
  • Enzyme Precursors / therapeutic use
  • Genetic Therapy / methods*
  • Hepatitis C / drug therapy*
  • Hepatitis C / immunology*
  • Humans
  • Liver / drug effects*
  • Liver / immunology*
  • Liver / surgery
  • Liver Transplantation
  • Mice
  • Protein Engineering / methods
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Recombinant Proteins / therapeutic use
  • Transplantation Chimera
  • Treatment Outcome

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bid protein, mouse
  • Carrier Proteins
  • Enzyme Precursors
  • Recombinant Proteins
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases