APOBEC3 Mediates Resistance to Oncolytic Viral Therapy

Amanda L. Huff, Phonphimon Wongthida, Timothy Kottke, Jill M. Thompson, Christopher B. Driscoll, Matthew Schuelke, Kevin G. Shim, Reuben S. Harris, Amy Molan, Jose S Pulido, Peter J. Selby, Kevin J. Harrington, Alan Melcher, Laura Evgin, Richard Geoffrey Vile

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Tumor cells frequently evade applied therapies through the accumulation of genomic mutations and rapid evolution. In the case of oncolytic virotherapy, understanding the mechanisms by which cancer cells develop resistance to infection and lysis is critical to the development of more effective viral-based platforms. Here, we identify APOBEC3 as an important factor that restricts the potency of oncolytic vesicular stomatitis virus (VSV). We show that VSV infection of B16 murine melanoma cells upregulated APOBEC3 in an IFN-β-dependent manner, which was responsible for the evolution of virus-resistant cell populations and suggested that APOBEC3 expression promoted the acquisition of a virus-resistant phenotype. Knockdown of APOBEC3 in B16 cells diminished their capacity to develop resistance to VSV infection in vitro and enhanced the therapeutic effect of VSV in vivo. Similarly, overexpression of human APOBEC3B promoted the acquisition of resistance to oncolytic VSV both in vitro and in vivo. Finally, we demonstrate that APOBEC3B expression had a direct effect on the fitness of VSV, an RNA virus that has not previously been identified as restricted by APOBEC3B. This research identifies APOBEC3 enzymes as key players to target in order to improve the efficacy of viral or broader nucleic acid-based therapeutic platforms.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Therapy - Oncolytics
Volume11
DOIs
StatePublished - Dec 21 2018

Fingerprint

Vesicular Stomatitis
Viruses
Virus Diseases
Oncolytic Virotherapy
Therapeutics
Experimental Melanomas
RNA Viruses
Therapeutic Uses
Nucleic Acids
Neoplasms
Phenotype
Enzymes
Infection
Research
Population

Keywords

  • APOBEC3
  • oncolytic virus
  • therapeutic resistance
  • viral resistance
  • VSV

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Huff, A. L., Wongthida, P., Kottke, T., Thompson, J. M., Driscoll, C. B., Schuelke, M., ... Vile, R. G. (2018). APOBEC3 Mediates Resistance to Oncolytic Viral Therapy. Molecular Therapy - Oncolytics, 11, 1-13. https://doi.org/10.1016/j.omto.2018.08.003

APOBEC3 Mediates Resistance to Oncolytic Viral Therapy. / Huff, Amanda L.; Wongthida, Phonphimon; Kottke, Timothy; Thompson, Jill M.; Driscoll, Christopher B.; Schuelke, Matthew; Shim, Kevin G.; Harris, Reuben S.; Molan, Amy; Pulido, Jose S; Selby, Peter J.; Harrington, Kevin J.; Melcher, Alan; Evgin, Laura; Vile, Richard Geoffrey.

In: Molecular Therapy - Oncolytics, Vol. 11, 21.12.2018, p. 1-13.

Research output: Contribution to journalArticle

Huff, AL, Wongthida, P, Kottke, T, Thompson, JM, Driscoll, CB, Schuelke, M, Shim, KG, Harris, RS, Molan, A, Pulido, JS, Selby, PJ, Harrington, KJ, Melcher, A, Evgin, L & Vile, RG 2018, 'APOBEC3 Mediates Resistance to Oncolytic Viral Therapy', Molecular Therapy - Oncolytics, vol. 11, pp. 1-13. https://doi.org/10.1016/j.omto.2018.08.003
Huff AL, Wongthida P, Kottke T, Thompson JM, Driscoll CB, Schuelke M et al. APOBEC3 Mediates Resistance to Oncolytic Viral Therapy. Molecular Therapy - Oncolytics. 2018 Dec 21;11:1-13. https://doi.org/10.1016/j.omto.2018.08.003
Huff, Amanda L. ; Wongthida, Phonphimon ; Kottke, Timothy ; Thompson, Jill M. ; Driscoll, Christopher B. ; Schuelke, Matthew ; Shim, Kevin G. ; Harris, Reuben S. ; Molan, Amy ; Pulido, Jose S ; Selby, Peter J. ; Harrington, Kevin J. ; Melcher, Alan ; Evgin, Laura ; Vile, Richard Geoffrey. / APOBEC3 Mediates Resistance to Oncolytic Viral Therapy. In: Molecular Therapy - Oncolytics. 2018 ; Vol. 11. pp. 1-13.
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