Submitted February 8, 2008
Accepted September 28, 2008
Ligand-engaged urokinase-type plasminogen activator receptor (uPAR) and activation of the CD11b/CD18 (Mac1) integrin inhibit late events of HIV expression in monocytic cells
Massimo Alfano*, Samanta A Mariani, Chiara Elia, Ruggero Pardi, Francesco Blasi, and Guido Poli
AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
Leukocyte Biology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
Molecular Genetics Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
Vita-Salute San Raffaele University, School of Medicine, Milan, Italy
* Corresponding author; email: alfano.massimo{at}hsr.it.
Urokinase-type plasminogen activator (uPA) signaling via its receptor uPAR inhibits late events in HIV-1 replication in acutely infected primary monocyte-derived macrophages (MDM) and promonocytic U937 cells. Here we show that U937-derived chronically infected U1 cells stimulated with phorbol myristate acetate (PMA) express integrins, uPA and soluble uPAR at levels similar to those of MDM. UPA inhibited HIV expression in U1 cells incubated with either PMA or tumor necrosis factor-
(TNF-), but not with other HIV-inductive cytokines or lipopolysaccharide. Of interest, only PMA and TNF-, but not other HIV-inductive stimuli, induced surface expression of the M chain CD11b in U1 cells constitutively expressing CD18, the 
2 chain of the Mac-1 integrin. Like uPA, fibrinogen, a Mac-1 ligand, and M25, a peptide homologous to a portion of the -propeller region of CD11b preventing its association with uPAR, inhibited HIV virion release in PMA-stimulated U1 cells. Both uPAR siRNA and soluble anti-1/-2 mAbs 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.
