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Pentoxifylline and other protein kinase C inhibitors down-regulate HIV-LTR NF-kappa B induced gene expression

D K Biswas1, C M Ahlers, B J Dezube

  • 1Division of Cell Growth and Regulation, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Molecular Medicine (Cambridge, Mass.)
|November 1, 1994
PubMed
Abstract

Insights

Pentoxifylline (PTX) inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking protein kinase C (PKC)-dependent activation of NF-kappa B. This finding suggests other kinase inhibitors may help manage HIV-1 infection.

Area of Science:

  • Molecular Biology
  • Virology
  • Pharmacology

Background:

  • Pentoxifylline (PTX) is used to treat circulatory disorders.
  • Its anti-human immunodeficiency virus type 1 (HIV-1) mechanism is under investigation.
  • PTX's molecular action against HIV-1 is explored.

Purpose of the Study:

  • To elucidate the molecular mechanism of pentoxifylline's anti-HIV-1 action.
  • To investigate PTX's effect on HIV-1 LTR-regulated gene expression.
  • To determine the role of protein kinases in PTX's antiviral activity.

Main Methods:

  • Studied inhibition of PKC and PKA-mediated activation of HIV-1 LTR reporter gene expression by PTX.
  • Utilized human CD4+ T lymphocytes (Jurkat) and human embryo kidney cells (293-27-2).
  • Employed specific inhibitors for PKC and PKA in cell-free and whole-cell systems to analyze NF-kappa B activation.

Main Results:

  • PTX inhibited PKC- or PKA-catalyzed NF-kappa B activation in cytoplasmic extracts.
  • Calphostin C (PKC inhibitor) reduced NF-kappa B activation and HIV-1 LTR reporter gene expression.
  • H88 (PKA inhibitor) did not affect NF-kappa B action in treated cells, indicating PKC's primary role.

Conclusions:

  • PTX inhibits HIV-1 replication by blocking PKC-dependent activation of NF-kappa B.
  • This mechanism involves inhibiting PMA- or TNF-alpha-induced NF-kappa B activation in Jurkat and 293-27-2 cells.
  • Protein kinase inhibitors may offer a strategy to down-regulate HIV-1 provirus transcription and replication.

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