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The Role of Type-I Interferon in Limiting Spread and Killing of an Oncolytic RNA Virus in Prostate Cells

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Date Issued:
2016
Abstract/Description:
Prostate cancer is the second most prevalent cancer amongst men and there is an urgent need to address viable therapeutic options for its treatment. Development of viruses which target and kill cancer cells has gained momentum due to the first FDA approved oncolytic virus for treating human cancer patients. Our previous work with the RNA virus, Parainfluenza Virus 5 (PIV5), has led to the generation of mutants that are potential candidates for oncolytic viruses: 1) the hyperfusogenic (P/V/F) mutant has a mutated P/V and fusion gene which activates anti-viral responses and causes massive cell-cell fusion respectively, and 2) the Leader mutant has a mutated viral genomic promoter which kills cells due to overactive viral gene expression. The P/V/F mutant has shown effectiveness in reducing prostate tumor burden in a mouse model system, however, the specificity of these viruses is unclear, i.e. targeting cancerous prostate cells while leaving uninvolved cells unaffected. In this study, we addressed how these PIV5 mutants replicate in and killed tumor versus benign human prostate cells. Flow cytometry demonstrated that the mutants are able to infect and replicate in prostate tumor cells (22Rv1), resulting in effective cell killing. However, these mutants showed highly restricted spread in benign prostatic hyperplasia cells (BPH-1). Upon further exploration, it was determined that the restriction observed in the BPH-1 cells is due to the induction and signaling of type-I Interferon (IFN). This was confirmed upon treatment with an IFN-? neutralizing antibody, which relieved restricted spread of mutants in benign cells. BPH-1 cells infected with the mutants also showed upregulation of key anti-viral, IFN-induced genes such as TLR3, IFIT1, and OAS2. Upon characterization of the mutant viruses in an additional metastatic prostate cancer cell line (C4-2B), a restriction in viral spread was observed. The restricted spread did not correlate with production of high levels of type-I IFN, suggesting that other cytokines or intracellular factors can limit replication in tumor cells. Therefore, these studies lay the groundwork for further improving the specificity of oncolytic PIV5 mutants by exploiting type-I IFN pathways as well as other anti-viral factors.
Title: The Role of Type-I Interferon in Limiting Spread and Killing of an Oncolytic RNA Virus in Prostate Cells.
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Name(s): Kedarinath, Kritika, Author
Parks, Griffith, Committee Chair
Chakrabarti, Ratna, Committee Member
Altomare, Deborah, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2016
Publisher: University of Central Florida
Language(s): English
Abstract/Description: Prostate cancer is the second most prevalent cancer amongst men and there is an urgent need to address viable therapeutic options for its treatment. Development of viruses which target and kill cancer cells has gained momentum due to the first FDA approved oncolytic virus for treating human cancer patients. Our previous work with the RNA virus, Parainfluenza Virus 5 (PIV5), has led to the generation of mutants that are potential candidates for oncolytic viruses: 1) the hyperfusogenic (P/V/F) mutant has a mutated P/V and fusion gene which activates anti-viral responses and causes massive cell-cell fusion respectively, and 2) the Leader mutant has a mutated viral genomic promoter which kills cells due to overactive viral gene expression. The P/V/F mutant has shown effectiveness in reducing prostate tumor burden in a mouse model system, however, the specificity of these viruses is unclear, i.e. targeting cancerous prostate cells while leaving uninvolved cells unaffected. In this study, we addressed how these PIV5 mutants replicate in and killed tumor versus benign human prostate cells. Flow cytometry demonstrated that the mutants are able to infect and replicate in prostate tumor cells (22Rv1), resulting in effective cell killing. However, these mutants showed highly restricted spread in benign prostatic hyperplasia cells (BPH-1). Upon further exploration, it was determined that the restriction observed in the BPH-1 cells is due to the induction and signaling of type-I Interferon (IFN). This was confirmed upon treatment with an IFN-? neutralizing antibody, which relieved restricted spread of mutants in benign cells. BPH-1 cells infected with the mutants also showed upregulation of key anti-viral, IFN-induced genes such as TLR3, IFIT1, and OAS2. Upon characterization of the mutant viruses in an additional metastatic prostate cancer cell line (C4-2B), a restriction in viral spread was observed. The restricted spread did not correlate with production of high levels of type-I IFN, suggesting that other cytokines or intracellular factors can limit replication in tumor cells. Therefore, these studies lay the groundwork for further improving the specificity of oncolytic PIV5 mutants by exploiting type-I IFN pathways as well as other anti-viral factors.
Identifier: CFE0006468 (IID), ucf:51445 (fedora)
Note(s): 2016-12-01
M.S.
Medicine, Molecular Biology and Micro
Masters
This record was generated from author submitted information.
Subject(s): Biotechnology -- Oncolytic Viruses -- Prostate Cancer
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0006468
Restrictions on Access: public 2016-12-15
Host Institution: UCF

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