title: Neuroattenuation of vesicular stomatitis virus through picornaviral internal ribosome entry sites.
abstract: Vesicular stomatitis virus (VSV) is potent and a highly promising agent for the treatment of cancer. However, translation of VSV oncolytic virotherapy into the clinic is being hindered by its inherent neurotoxicity. It has been demonstrated that selected picornaviral internal ribosome entry site (IRES) elements possess restricted activity in neuronal tissues. We therefore sought to determine whether the picornavirus IRES could be engineered into VSV to attenuate its neuropathogenicity. We have used IRES elements from human rhinovirus type 2 (HRV2) and foot-and-mouth disease virus (FMDV) to control the translation of the matrix gene (M), which plays a major role in VSV virulence. In vitro studies revealed slowed growth kinetics of IRES-controlled VSVs in most of the cell lines tested. However, in vivo studies explicitly demonstrated that IRES elements of HRV2 and FMDV severely attenuated the neurovirulence of VSV without perturbing its oncolytic potency.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Ammayappan
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nace
authors.forename: Kah-Whye
authors.initials: KW
authors.lastname: Peng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Russell
mesh_terms: D000818:Animals; D002460:Cell Line; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D006801:Humans; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D014176:Protein Biosynthesis; D011995:Recombination, Genetic; D012229:Rhinovirus / Q000235:genetics; D018116:Vesiculovirus / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity*; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D014763:Viral Matrix Proteins