Nitric oxide down-regulates Epstein-Barr virus reactivation in epithelial cell lines

Virology. 1999 Jun 5;258(2):375-81. doi: 10.1006/viro.1999.9748.

Abstract

Nitric oxide (NO), a mediator of biological functions, has an antimicrobial activity against a variety of pathogens including viruses. In this study, we found that a constitutive, low level of inducible NO synthase (iNOS) mRNA was expressed in the EBV-infected gastric tissue-derived GT38 and GT39 cell lines, by analysis with the reverse transcription-polymerase chain reaction (RT-PCR) and Southern blotting. Treatment of these cells with a specific NOS inhibitor, NG-monomethyl-L-arginine (L-NMMA), induced the immediate-early, EBV transactivator gene BZLF1 protein ZEBRA, suggesting a significant increase in EBV reactivation by L-NMMA. Northern blotting demonstrated that BZLF1 and BRLF1 transcripts were also induced by 12-O-tetradecanoylphorbol-13 acetate (TPA). Meanwhile, constitutive expression of iNOS mRNA was inhibited by TPA. L-NMMA also enhanced TPA-induced expression of the BZLF1 gene. On the other hand, a NO donor, S-nitroso-N-acetylpenicillamine (SNAP), which releases NO in an aqueous solution, inhibited the TPA-induced BZLF1 gene expression in a dose-dependent manner at both mRNA and protein levels. These results demonstrated that NO is a regulatory factor in maintaining virus latency via inhibiting EBV reactivation in the infected epithelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Callithrix
  • Cell Line
  • DNA-Binding Proteins / genetics
  • Down-Regulation*
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Gene Expression Regulation / drug effects
  • Herpesvirus 4, Human / growth & development*
  • Humans
  • Immediate-Early Proteins / genetics
  • Mitogens / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Penicillamine / analogs & derivatives
  • Penicillamine / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Trans-Activators / genetics
  • Viral Proteins*
  • Virus Activation*
  • omega-N-Methylarginine / pharmacology

Substances

  • BRLF1 protein, Human herpesvirus 4
  • BZLF1 protein, Herpesvirus 4, Human
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Immediate-Early Proteins
  • Mitogens
  • S-nitro-N-acetylpenicillamine
  • Trans-Activators
  • Viral Proteins
  • omega-N-Methylarginine
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Penicillamine
  • Tetradecanoylphorbol Acetate