Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells

Massimo Alfano*, Samanta A. Mariani, Chiara Elia, Ruggero Pardi, Francesco Blasi, Guido Poli

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Urokinase-type plasminogen activator (uPA) signaling via its receptor uPAR inhibits late events in HIV-1 replication in acutely infected primary monocyte-derived macrophages (MDMs) and promonocytic U937 cells. Here we show that U937-derived, chronically infected U1 cells stimulated with phorbol 12-myristate 13-acetate (PMA) express integrins, uPA, and soluble uPAR at levels similar to those of MDMs. uPA inhibited HIV expression in U1 cells incubated with either PMA or tumor necrosis factor-alpha (TNF-alpha), but not with other HIV-inductive cytokines or lipopolysaccharide. Of interest, only PMA and TNF-alpha, but not other HIV-inductive stimuli, induced surface expression of the alpha(M) chain CD11b in U1 cells constitutively expressing CD18, the beta(2) chain of the Mac-1 integrin. Like uPA, fibrinogen, a Mac-1 (CD11b/CD18) ligand, and M25, a peptide homologous to a portion of the beta-propeller region of CD11b preventing its association with uPAR, inhibited HIV virion release in PMA-stimulated U1 cells. Both uPAR small-interference RNA (siRNA) and soluble anti-beta(1)/-beta(2) monoclonal antibodies abolished the anti-HIV effects of uPA, whereas CD11b siRNA reversed the anti-HIV effect of M25, but not that induced by uPA. Thus, either uPA/uPAR interaction, Mac-1 activation, or prevention of its association with uPAR triggers a signaling pathway leading to the inefficient release of HIV from monocytic cells. (Blood. 2009; 113: 1699-1709)

Original languageEnglish
Pages (from-to)1699-1709
Number of pages11
JournalBlood
Volume113
Issue number8
DOIs
Publication statusPublished - 19 Feb 2009

Keywords

  • HUMAN-IMMUNODEFICIENCY-VIRUS
  • NF-KAPPA-B
  • INFECTED PROMONOCYTIC CELLS
  • PHORBOL-MYRISTATE ACETATE
  • PLASMA-MEMBRANE
  • ANTIRETROVIRAL THERAPY
  • HUMAN MACROPHAGES
  • U1 CELLS
  • HIV-1-INFECTED PATIENTS
  • MONONUCLEAR PHAGOCYTES

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