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Antisense oligonucleotide ISIS 2922 targets IE-expression and prevents HCMV-IE-induced suppression of TSP-1 and TSP-2

S Margraf1, M Bittoova, J U Vogel

  • 1J. W. Goethe University Hospital, Inst. f. Med. Virology, Paul Ehrlich-Str. 40, D-60596 Frankfurt am Main, Germany.

Nucleosides, Nucleotides & Nucleic Acids
|September 21, 2001
PubMed

Insights

ISIS 2922 effectively inhibits human cytomegalovirus (HCMV) immediate early protein expression and prevents extracellular matrix protein changes. This antiviral action is primarily through inhibiting IE 2 mRNA, with some unspecific effects on virus entry.

Area of Science:

  • Virology
  • Molecular Biology
  • Antiviral Drug Discovery

Background:

  • Human cytomegalovirus (HCMV) immediate early (IE) proteins play a crucial role in viral replication.
  • IE proteins can modulate the expression of extracellular matrix (ECM) proteins, such as thrombospondin-1 and -2.
  • Antiviral therapies targeting HCMV are essential for managing infections, particularly in immunocompromised individuals.

Purpose of the Study:

  • To investigate the effect of ISIS 2922 on HCMV immediate early (IE) protein expression.
  • To determine if ISIS 2922 prevents the down-modulation of thrombospondin-1 and -2 induced by HCMV IE proteins.
  • To elucidate the mechanism of action of ISIS 2922 against HCMV.

Main Methods:

  • Infection of various cell lines with HCMV.
  • Treatment of infected cells with ISIS 2922 and ganciclovir (GCV).
  • Measurement of IE protein expression and ECM protein levels.
  • Analysis of IE 2 mRNA inhibition and effects on virus adhesion/penetration.

Main Results:

  • ISIS 2922, unlike ganciclovir, significantly inhibited HCMV IE protein expression in infected cell lines.
  • ISIS 2922 prevented the IE protein-induced down-modulation of thrombospondin-1 and -2.
  • The primary mechanism of ISIS 2922 involved specific inhibition of IE 2 mRNA, with additional unspecific effects on virus adhesion and penetration.

Conclusions:

  • ISIS 2922 demonstrates potent antiviral activity against HCMV by targeting IE protein expression.
  • The drug's ability to preserve ECM protein levels suggests a novel therapeutic approach.
  • ISIS 2922's dual mechanism, including specific mRNA inhibition and unspecific antiviral effects, warrants further investigation.

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