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Oncolytic Virotherapy Reovirus: A Prototypical Wild-type Oncolytic Virus By: Stephen Mayper Cancer Abnormal cell growth Accumulated genetic & epigenetic alterations Healthy cells gone “haywire” Numerous means of immune response evasion Conventional Treatments Surgery Tumor removal Is ineffective against and can induce metastasis Inherent risk! Conventional Treatments Radiotherapy Uses radiation to kill tumor cells Effective at reducing… …Tumors! …Aaaaand healthy cells Can carry severe side effects (Creative representation if innocent bystander cell death…) Conventional Treatments Chemotherapy Use of pharmaceuticals to kill tumor cells It works! …But it kills lots of other cells indiscriminately Emerging Treatment: Virotherapy Uses an oncolytic virus (OV) to lyse cancer cells Advantages: High specificity means fewer side effects Self-regulating dosage Lack of contraindications Viruses currently being explored Mumps virus Pseudorabies virus SV40 virus Vaccinia virus Coxsackie A virus How does it work? …Get it? Virus can be… Naturally occurring Genetically engineered Transcription targeting Attenuation Specificity generally determined by antiviral pathway deregulation (It’s a virus in “nature!”) Example: Adenovirus Therapy Targeting Gliomas Source: Maruniak, Jim. "Adenovirus." MCB 5505, Honors Virology. University of Florida, Gainesville, FL. 19 Feb. 2011. Lecture. Another Mechanism of Tumor Cell OV Susceptibility Source: Chiocca EA. Oncolytic viruses. Nat Rev Cancer. 2002 Dec;2(12):938-50. Reovirus Reovirus Background REOvirus = “Respiratory Enteric Orphan Virus” Infect human respiratory & gastrointestinal tracts “Orphaned” because originally not thought to be associated with any disease Several disease associations discovered since Reoviruses are pervasive Reovirus Taxonomy Family: Reoviridae Genera Infecting Vertebrates (6) Orthoreovirus Orbivirus Coltivirus Rotavirus •African Horse Sickness Mostly •Colorado Tick Fever Asymptomatic •Blue Tongue Disease Aquareovirus Seadornavirus (Percentage of gastroenteritis deaths) Source: Cann, Alan. "Reoviruses." MicrobiologyBytes. 11 Sept. 2007. Web. <http://www.microbiologybytes.com/virology/Reoviruses.html>. Reovirus Structure Spherical, 80 nm diameter Non-enveloped Isometric capsid Concentric inner and outer capsids Sometimes middle capsid (Inner capsid = “core”) 4 core proteins λ-1, λ-3, μ-2, σ-2 Heat-stable Stable @ pH= 3 – 9 Denatured by ethanol Reovirus Genome RNA DoubleStranded Linear 10-12 segments (speciesdependent) Reassortment common in vitro Encodes viral replication machinery Source: http://education.expasy.org/images/Orthoreovirus_genome.jpg Reovirus Reproduction Replicates in the cytoplasm Encodes its own replication machinery Antiviral susceptibility Does NOT fully uncoat Core is resistant to protease digestion No uncoating No destruction by host cell Genomic RNA stays in the core Assembled virions form cytoplasmic inclusion bodies Released via cell lysis 6 – 7 hour replication time Reovirus Replication Illustrated Questions? Comments? Sources Cann, Alan. "Reoviruses." MicrobiologyBytes. 11 Sept. 2007. Web. <http://www.microbiologybytes.com/virology/Reoviruses.html>. Chiocca EA. Oncolytic viruses. Nat Rev Cancer. 2002 Dec;2(12):938-50. Hammill AM, Conner J, Cripe TP. Oncolytic virotherapy reaches adolescence. Pediatr Blood Cancer. 2010 Dec 15;55(7):1253-63. doi: 10.1002/pbc.22724. Epub 2010 Aug 23. Maruniak, Jim. "Adenovirus." MCB 5505, Honors Virology. University of Florida, Gainesville, FL. 19 Feb. 2011. Lecture. Mertens P. The dsRNA viruses. Virus Res. 2004 Apr;101(1):3-13. Nettelbeck DM. Cellular genetic tools to control oncolytic adenoviruses for virotherapy of cancer. J Mol Med. 2008 Apr;86(4):363-77. Epub 2007 Dec 19. Siegel, Robert. "Reoviruses." Stanford University. 1 Feb. 1999. Web. 20 Apr. 2011. <http://www.stanford.edu/group/virus/1999/caryn/reovirus.html>. Vähä-Koskela MJ, Heikkilä JE, Hinkkanen AE. Oncolytic viruses in cancer therapy. Cancer Lett. 2007 Sep 8;254(2):178-216. Epub 2007 Mar 23.