title: Characterization of herpes simplex virus 1 strains as platforms for the development of oncolytic viruses against liver cancer.
abstract: BACKGROUND
  Diverse oncolytic viruses (OV) are being designed for the treatment of cancer. The characteristics of the parental virus strains may influence the properties of these agents.
  
  
  OBJECTIVE
  To characterize two herpes simplex virus 1 strains (HSV-1 17syn(+) and HFEM) as platforms for virotherapy against liver cancer.
  
  
  METHODS
  The luciferase reporter gene was introduced in the intergenic region 20 locus of both HSV-1 strains, giving rise to the Cgal-Luc and H6-Luc viruses. Their properties were studied in hepatocellular carcinoma (HCC) cells in vitro. Biodistribution was monitored by bioluminescence imaging (BLI) in athymic mice and immune-competent Balb/c mice. Immunogenicity was studied by MHC-tetramer staining, in vivo killing assays and determination of specific antibody production. Intratumoural transgene expression and oncolytic effect were studied in HuH-7 xenografts.
  
  
  RESULTS
  The H6-Luc virus displayed a syncytial phenotype and showed higher cytolytic effect on some HCC cells. Upon intravenous or intrahepatic injection in mice, both viruses showed a transient transduction of the liver with rapid relocalization of bioluminescence in adrenal glands, spinal cord, uterus and ovaries. No significant differences were observed in the immunogenicity of these viruses. Local intratumoural administration caused progressive increase in transgene expression during the first 5 days and persisted for at least 2 weeks. H6-Luc achieved faster amplification of transgene expression and stronger inhibition of tumour growth than Cgal-Luc, although toxicity of these non-attenuated viruses should be reduced to obtain a therapeutic effect.
  
  
  CONCLUSIONS
  The syncytial H6-Luc virus has a strong oncolytic potential on human HCC xenografts and could be the basis for potent OV.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Argnani
authors.forename: Peggy
authors.initials: P
authors.lastname: Marconi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Volpi
authors.forename: Elixabet
authors.initials: E
authors.lastname: Bolanos
authors.forename: Elvira
authors.initials: E
authors.lastname: Carro
authors.forename: Christine
authors.initials: C
authors.lastname: Ried
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaria
authors.forename: Aldo
authors.initials: A
authors.lastname: Pourchet
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Epstein
authors.forename: Thomas
authors.initials: T
authors.lastname: Brocker
authors.forename: Fernando Jose
authors.initials: FJ
authors.lastname: Corrales
authors.forename: Roberto
authors.initials: R
authors.lastname: Manservigi
authors.forename: Ibai
authors.initials: I
authors.lastname: Goicoechea
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Foschini
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernandez-Alcoceba
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000628:therapy* / Q000821:virology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D016133:Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics
chemical_list: D017931:DNA Primers; D008156:Luciferases