title: Complement inhibition rescued mice allowing observation of transgene expression following intraportal delivery of baculovirus in mice.
abstract: BACKGROUND
  The baculovirus Autographa californica nucleo-polyhedrosis virus (AcNPV) is an alternative to other viral vectors for hepatic gene delivery. A barrier to AcNPV being used in vivo is its susceptibility to inactivation by serum complement 1. In vivo utility has only been demonstrated using methods that avoid contact with serum 2-5. We have studied the complement pathways involved in baculovirus inactivation in vitro and the systemic administration of baculovirus vectors in vivo, with the co-administration of the complement inhibitor, soluble complement inhibitor 1 (sCR1).
  
  
  RESULTS
  EDTA increased baculovirus survival in human serum more than EGTA showing that both the alternative and classical pathways of complement are activated. Depleting serum of IgM increased survival, whereas reconstitution with pooled IgM restored activity against baculovirus, suggesting naturally occurring IgM antibodies with affinity for baculovirus may be partially responsible for complement activation. Intraportal administration of baculovirus led to hepatic expression when the complement inhibitor sCR1 (soluble complement receptor type 1) was co-administered by tail vein injection; however, liver histology showed hepatic necrosis. Without co-administration of sCR1, intraportal infusion of baculovirus was fatal within 24 h. Histology demonstrated massive hepatic necrosis. Yolk sac vein injection of baculovirus was associated with fetal death.
  
  
  CONCLUSIONS
  Transgene expression was demonstrated following intraportal infusion of recombinant baculovirus vectors in combination with sCR1; however, our experiments suggest a significant associated toxicity.
authors.affiliation: Division of Medicine, Faculty of Medicine, Imperial College London, St Mary's Campus, South Wharf Road, London W2 1NY, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Hoare
authors.forename: Simon
authors.initials: S
authors.lastname: Waddington
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
authors.forename: Charles
authors.initials: C
authors.lastname: Coutelle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: McGarvey
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics / Q000276:immunology*; D002614:Chelating Agents / Q000378:metabolism; D003167:Complement Activation; D003169:Complement Inactivator Proteins / Q000378:metabolism*; D003165:Complement System Proteins / Q000276:immunology*; D004492:Edetic Acid / Q000378:metabolism; D004533:Egtazic Acid / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009336:Necrosis; D011169:Portal Vein; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D019076:Transgenes
chemical_list: D002614:Chelating Agents; D003169:Complement Inactivator Proteins; D007075:Immunoglobulin M; D011951:Receptors, Complement; C082885:soluble complement inhibitor 1; D004533:Egtazic Acid; D003165:Complement System Proteins; D004492:Edetic Acid