title: Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis.
abstract: A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied.
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Dobrikova
authors.forename: Christian
authors.initials: C
authors.lastname: Goetz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Walters
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Lawson
authors.forename: James O
authors.initials: JO
authors.lastname: Peggins
authors.forename: Karen
authors.initials: K
authors.lastname: Muszynski
authors.forename: Sheryl
authors.initials: S
authors.lastname: Ruppel
authors.forename: Karyol
authors.initials: K
authors.lastname: Poole
authors.forename: Steven L
authors.initials: SL
authors.lastname: Giardina
authors.forename: Eric M
authors.initials: EM
authors.lastname: Vela
authors.forename: James E
authors.initials: JE
authors.lastname: Estep
authors.forename: Matthias
authors.initials: M
authors.lastname: Gromeier
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D002460:Cell Line; D002678:Chimera / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D008252:Macaca fascicularis / Q000276:immunology / Q000821:virology; D011051:Poliomyelitis / Q000276:immunology / Q000821:virology*; D017955:Poliovirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D012229:Rhinovirus / Q000235:genetics* / Q000502:physiology; D014018:Tissue Distribution; D014774:Virulence; D017201:Virus Shedding
chemical_list: D000914:Antibodies, Viral