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Inhibition of HIV infection by the cytokine midkine

C Callebaut1, S Nisole, J P Briand

  • 1Unité de Virologie et Immunologie Cellulaire, URA 1930 CNRS, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.

Virology
|March 30, 2001
PubMed

Insights

The growth factor midkine (MK) inhibits HIV-1 infection by binding to cell surface components. This cytokine’s expression increases with immune stimulation, suggesting a role in HIV pathogenesis.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • Midkine (MK) binds heparan sulfate and nucleolin, cell surface components involved in HIV-1 attachment.
  • HIV-1 entry into cells is a critical step in viral infection.

Purpose of the Study:

  • To investigate the potential of midkine (MK) as an inhibitor of HIV-1 infection.
  • To explore the role of MK in lymphocyte responses to HIV-1.

Main Methods:

  • Inhibition assays using synthetic and recombinant MK against HIV-1 isolates.
  • Cell surface binding studies with labeled MK and anti-HIV pseudopeptide HB-19.
  • Analysis of MK mRNA expression in lymphocytes stimulated with cytokines and mitogens.
  • Colocalization studies of MK and nucleolin on lymphocyte cell surfaces.
  • Assessment of HIV infection inhibition in MK-producing CD4(+) and CD4(-) cell clones.

Main Results:

  • MK demonstrated dose-dependent inhibition of T-lymphocyte- and macrophage-tropic HIV-1 infection.
  • MK binding to cells was blocked by excess MK or HB-19, indicating a shared binding mechanism with nucleolin.
  • MK mRNA expression was constitutive in lymphocytes and increased upon stimulation with IL-2, IFN-gamma, PHA, or anti-CD3/CD28 antibodies.
  • MK was detected at the cell surface of lymphocytes, colocalizing with nucleolin.
  • MK inhibited HIV infection in both autocrine and paracrine manners in cell cultures.

Conclusions:

  • Midkine (MK) possesses potent anti-HIV-1 activity by interfering with viral entry.
  • Enhanced MK expression in lymphocytes upon immune activation suggests a regulatory role in HIV infection.
  • MK is a cytokine implicated in the pathogenesis of HIV infection.

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