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 G. Vile

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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
StatePublished - Dec 21 2018

Bibliographical note

Funding Information:
The authors thank Toni L. Higgins for expert secretarial assistance. This work was funded in part by the European Research Council , the Richard M. Schulze Family Foundation , the Mayo Foundation , Cancer Research UK , the NIH ( R01CA175386 and R01CA108961 ), the University of Minnesota and Mayo Clinic Partnership , a grant from Terry and Judith Paul , and a research grant from Oncolytics Biotech, Inc .

Publisher Copyright:
© 2018


  • VSV
  • oncolytic virus
  • therapeutic resistance
  • viral resistance


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