title: Harnessing endogenous miRNAs to control virus tissue tropism as a strategy for developing attenuated virus vaccines.
abstract: Live attenuated vaccines remain the safest, most cost-effective intervention against viral infections. Because live vaccine strains are generated empirically and the basis for attenuation is usually ill defined, many important viruses lack an efficient live vaccine. Here, we present a general strategy for the rational design of safe and effective live vaccines that harnesses the microRNA-based gene-silencing machinery to control viral replication. Using poliovirus as a model, we demonstrate that insertion of small miRNA homology sequences into a viral genome can restrict its tissue tropism, thereby preventing pathogenicity and yielding an attenuated viral strain. Poliovirus strains engineered to become targets of neuronal-specific miRNAs lost their ability to replicate in the central nervous system, leading to significant attenuation of neurovirulence in infected animals. Importantly, these viruses retained the ability to replicate in nonneuronal tissues. As a result, these engineered miRNA-regulated viruses elicited strong protective immunity in mice without producing disease.
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143-2280, USA.
authors.forename: Dwight
authors.initials: D
authors.lastname: Barnes
authors.forename: Mark
authors.initials: M
authors.lastname: Kunitomi
authors.forename: Marco
authors.initials: M
authors.lastname: Vignuzzi
authors.forename: Kalle
authors.initials: K
authors.lastname: Saksela
authors.forename: Raul
authors.initials: R
authors.lastname: Andino
mesh_terms: D000818:Animals; D005818:Genetic Engineering; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D011051:Poliomyelitis / Q000628:therapy / Q000821:virology*; D017955:Poliovirus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D011054:Poliovirus Vaccine, Inactivated / Q000235:genetics*; D018523:Tropism; D014779:Virus Replication
chemical_list: D035683:MicroRNAs; D011054:Poliovirus Vaccine, Inactivated
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