Transcript Oncolytic Virotherapy - University of Florida

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.