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J Biol Chem, Vol. 274, Issue 39, 27875-27884, September 24, 1999

The Anti-HIV Pseudopeptide HB-19 Forms a Complex with the Cell-surface-expressed Nucleolin Independent of Heparan Sulfate Proteoglycans

Sébastien Nisole, Bernard Krust, Christian Callebaut, Gilles Guichard^¶, Sylviane Muller^¶, Jean-Paul Briand^¶, and Ara G. Hovanessian

From the  Unité de Virologie et Immunologie Cellulaire, URA 1930 CNRS, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15 and ^¶ Institut de Biologie Moléculaire et Cellulaire, UPR 9021 CNRS, 15 rue Descartes, 67084 Strasbourg Cedex, France

The HB-19 pseudopeptide 5[K(CH₂N)PR]-TASP, (CH₂N) for reduced peptide bond, is a specific inhibitor of human immunodeficiency virus (HIV) infection in different CD4⁺ cell lines and in primary T-lymphocytes and macrophages. Here, by using an experimental CD4⁺ cell model to monitor HIV entry and infection, we demonstrate that HB-19 binds the cell surface and inhibits attachment of HIV particles to permissive cells. At concentrations that inhibit HIV attachment, HB-19 binds cells irreversibly, becomes complexed with the cell-surface-expressed nucleolin, and eventually results in its degradation. Accordingly, by confocal immunofluorescence microscopy, we demonstrate the drastic reduction of the cell-surface-expressed nucleolin following treatment of cells with HB-19. HIV particles can prevent the binding of HB-19 to cells and inhibit complex formation with nucleolin. Such a competition between viral particles and HB-19 is consistent with the implication of nucleolin in the process of HIV attachment to target cells. We show that another inhibitor of HIV infection, the fibroblast growth factor-2 (FGF-2) that uses cell-surface-expressed heparan sulfate proteoglycans as low affinity receptors, binds cells and blocks attachment of HIV to permissive cells. FGF-2 does not prevent the binding of HB-19 to cells and to nucleolin, and similarly HB-19 has no apparent effect on the binding of FGF-2 to the cell surface. The lack of competition between these two anti-HIV agents rules out the potential involvement of heparan sulfate proteoglycans in the mechanism of anti-HIV effect of HB-19, thus pointing out that nucleolin is its main target.

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