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Targeting Cell Cycle Facilitates E1A-Independent Adenoviral Replication

Maximilian Ehrenfeld1, Felicia Segeth2,3, Klaus Mantwill1

  • 1Department of Urology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Journal of Virology
|May 23, 2023
PubMed

Insights

Cyclin-dependent kinase 4/6 inhibitors enhance replication of E1-deleted adenoviruses in cancer cells by activating the E2-early promoter via E2F-binding sites. This finding improves the safety of viral vectors and may enhance cancer therapy.

Area of Science:

  • Molecular Virology
  • Cancer Biology
  • Gene Therapy Vectors

Background:

  • E1-deleted adenoviruses (AdV) show E1A-like activity, enabling replication in cancer cells through compensatory cellular proteins.
  • This E1A-like activity involves expression of early region 2 (E2)-encoded proteins, crucial for viral DNA replication.

Purpose of the Study:

  • To investigate cell cycle inhibitors for their ability to enhance viral DNA replication of E1-deleted adenovirus dl70-3.
  • To elucidate the role of E2F-binding sites in the E2-early promoter in E1A-independent adenovirus replication.

Main Methods:

  • Treatment of infected cancer cells with cell cycle inhibitors, specifically cyclin-dependent kinases 4/6 inhibitors (CDK4/6i).
  • Analysis of viral E2-expression using RT-qPCR and promoter activity assays (pE2early-LucM).
  • Construction and testing of a mutated virus (dl70-3/E2Fm) with altered E2F-binding sites.

Main Results:

  • CDK4/6 inhibition significantly increased E1-independent adenovirus E2-expression and viral DNA replication.
  • Increased E2-expression was traced to the E2-early promoter, dependent on E2F-binding sites.
  • Mutating E2F-binding sites in the virus abolished CDK4/6i-induced viral DNA replication.

Conclusions:

  • E2F-binding sites within the adenoviral E2-early promoter are essential for E1A-independent DNA replication of E1-deleted vectors in cancer cells.
  • Findings suggest strategies to enhance the safety of viral vaccine vectors and improve oncolytic properties for cancer therapy.
Keywords:
CDK4/6E1AE2FRbYB-1adenoviruscell cyclenutlin-3aribociclib

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