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Blood, 19 February 2009, Vol. 113, No. 8, pp. 1699-1709. Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-02-138412. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-02-138412v1 113/8/1699    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Alfano, M. Articles by Poli, G. Search for Related Content PubMed PubMed Citation Articles by Alfano, M. Articles by Poli, G. Related Collections Immunobiology Phagocytes, Granulocytes, and Myelopoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Ligand-engaged urokinase-type plasminogen activator receptor and activation of the CD11b/CD18 integrin inhibit late events of HIV expression in monocytic cells Massimo Alfano1, Samanta A. Mariani1, Chiara Elia1, Ruggero Pardi2,3, Francesco Blasi35, and Guido Poli1,3 1 AIDS Immunopathogenesis Unit and 2 Leukocyte Biology Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan; 3 School of Medicine, Vita-Salute San Raffaele University, Milan; 4 Molecular Genetics Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan; and 5 FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology (IFOM) Foundation, Milan, Italy 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- (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 β2 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 β-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-β1/-β2 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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