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MicroRNA-Attenuated Clone of Virulent Semliki Forest Virus Overcomes Antiviral Type I Interferon in Resistant Mouse CT-2A Glioma
- Source :
- Journal of Virology. 89:10637-10647
- Publication Year :
- 2015
- Publisher :
- American Society for Microbiology, 2015.
-
Abstract
- Glioblastoma is a terminal disease with no effective treatment currently available. Among the new therapy candidates are oncolytic viruses capable of selectively replicating in cancer cells, causing tumor lysis and inducing adaptive immune responses against the tumor. However, tumor antiviral responses, primarily mediated by type I interferon (IFN-I), remain a key problem that severely restricts viral replication and oncolysis. We show here that the Semliki Forest virus (SFV) strain SFV4, which causes lethal encephalitis in mice, is able to infect and replicate independent of the IFN-I defense in mouse glioblastoma cells and cell lines originating from primary human glioblastoma patient samples. The ability to tolerate IFN-I was retained in SFV4-miRT124 cells, a derivative cell line of strain SFV4 with a restricted capacity to replicate in neurons due to insertion of target sites for neuronal microRNA 124. The IFN-I tolerance was associated with the viral nsp3-nsp4 gene region and distinct from the genetic loci responsible for SFV neurovirulence. In contrast to the naturally attenuated strain SFV A7(74) and its derivatives, SFV4-miRT124 displayed increased oncolytic potency in CT-2A murine astrocytoma cells and in the human glioblastoma cell lines pretreated with IFN-I. Following a single intraperitoneal injection of SFV4-miRT124 into C57BL/6 mice bearing CT-2A orthotopic gliomas, the virus homed to the brain and was amplified in the tumor, resulting in significant tumor growth inhibition and improved survival. IMPORTANCE Although progress has been made in development of replicative oncolytic viruses, information regarding their overall therapeutic potency in a clinical setting is still lacking. This could be at least partially dependent on the IFN-I sensitivity of the viruses used. Here, we show that the conditionally replicating SFV4-miRT124 virus shares the IFN-I tolerance of the pathogenic wild-type SFV, thereby allowing efficient targeting of a glioma that is refractory to naturally attenuated therapy vector strains sensitive to IFN-I. This is the first evidence of orthotopic syngeneic mouse glioma eradication following peripheral alphavirus administration. Our findings indicate a clear benefit in harnessing the wild-type virus replicative potency in development of next-generation oncolytic alphaviruses.
- Subjects :
- Male
viruses
Immunology
Alphavirus
Virus Replication
Semliki Forest virus
Microbiology
Virus
Mice
03 medical and health sciences
0302 clinical medicine
Interferon
Cell Line, Tumor
Virology
Glioma
medicine
Animals
Humans
Aged
030304 developmental biology
Neurons
Oncolytic Virotherapy
0303 health sciences
biology
Brain Neoplasms
medicine.disease
biology.organism_classification
Semliki forest virus
Survival Analysis
Clone Cells
Tumor Burden
Virus-Cell Interactions
3. Good health
Oncolytic virus
MicroRNAs
Oncolytic Viruses
Gene Expression Regulation
Viral replication
Drug Resistance, Neoplasm
Vesicular stomatitis virus
030220 oncology & carcinogenesis
Insect Science
Interferon Type I
Female
Glioblastoma
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....b0d5228f3b67bc628b2894bc9b5daffd