Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells

Virology. 2011 Jul 20;416(1-2):86-97. doi: 10.1016/j.virol.2011.04.005. Epub 2011 May 24.

Abstract

Promyelocytic leukemia protein nuclear bodies (PML NBs) have been implicated in host immune response to viral infection. PML NBs are targeted for degradation during reactivation of herpes viruses, suggesting that disruption of PML NB function supports this aspect of the viral life cycle. The Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1) has been shown to suppress EBV reactivation. Our finding that LMP1 induces PML NB immunofluorescence intensity led to the hypothesis that LMP1 may modulate PML NBs as a means of maintaining EBV latency. Increased PML protein and morphometric changes in PML NBs were observed in EBV infected alveolar epithelial cells and nasopharyngeal carcinoma cells. Treatment with low dose arsenic trioxide disrupted PML NBs, induced expression of EBV lytic proteins, and conferred ganciclovir susceptibility. This study introduces an effective modality to induce susceptibility to ganciclovir in epithelial cells with implications for the treatment of EBV associated pathologies.

MeSH terms

  • Antiviral Agents / pharmacology
  • Arsenic Trioxide
  • Arsenicals / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Viral
  • Epithelial Cells / drug effects*
  • Epithelial Cells / virology*
  • Ganciclovir / pharmacology*
  • Gene Expression Regulation, Viral / physiology
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Nuclear Proteins / metabolism*
  • Oxides / pharmacology*
  • Promyelocytic Leukemia Protein
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism

Substances

  • Antiviral Agents
  • Arsenicals
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Nuclear Proteins
  • Oxides
  • Promyelocytic Leukemia Protein
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Viral Matrix Proteins
  • PML protein, human
  • Ganciclovir
  • Arsenic Trioxide