title: Attenuation of vesicular stomatitis virus infection of brain using antiviral drugs and an adeno-associated virus-interferon vector.
abstract: Vesicular stomatitis virus (VSV) shows promise as a vaccine-vector and oncolytic virus. However, reports of neurotoxicity of VSV remain a concern. We compared 12 antiviral compounds to control infection of VSV-CT9-M51 and VSV-rp30 using murine and human brain cultures, and in vivo mouse models. Inhibition of replication, cytotoxicity and infectivity was strongest with ribavirin and IFN-α and to some extent with mycophenolic acid, chloroquine, and adenine 9-β-d-arabinofuranoside. To generate continuous IFN exposure, we made an adeno-associated virus vector expressing murine IFN; AAV-mIFN-β protected mouse brain cells from VSV, as did a combination of IFN, ribavirin and chloroquine. Intracranial AAV-mIFN-β protected the brain against VSV-CT9-M51. In SCID mice bearing human glioblastoma, AAV-mIFN-β moderately enhanced survival. VSV-CT9-M51 doubled median survival when administered after AAV-mIFN-β; some surviving mice showed complete tumor destruction. Together, these data suggest that AAV-IFN or IFN with ribavirin and chloroquine provide an optimal anti-virus combination against VSV in the brain.
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Guido
authors.initials: G
authors.lastname: Wollmann
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Paglino
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Maloney
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Ahmadi
authors.affiliation: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: anthony.vandenpol@yale.edu.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: van den Pol
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000166:cytology* / Q000821:virology; D002478:Cells, Cultured; D000229:Dependovirus; D005822:Genetic Vectors; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009457:Neuroglia / Q000821:virology; D009474:Neurons / Q000821:virology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D054243:Vesicular Stomatitis / Q000188:drug therapy*; D018116:Vesiculovirus / Q000187:drug effects / Q000302:isolation & purification*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007372:Interferons
keywords: AAV; Antiviral; Brain; Interferon; Oncolytic virus; Ribavirin; VSV