title: HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup.
abstract: Most macrophages remain uninfected in HIV-1-infected patients. Nevertheless, the phagocytic capacity of phagocytes from these patients is impaired, favouring the multiplication of opportunistic pathogens. The basis for this phagocytic defect is not known. HIV-1 Tat protein is efficiently secreted by infected cells. Secreted Tat can enter uninfected cells and reach their cytosol. Here we found that extracellular Tat, at the subnanomolar concentration present in the sera of HIV-1-infected patients, inhibits the phagocytosis of Mycobacterium avium or opsonized Toxoplasma gondii by human primary macrophages. This inhibition results from a defect in mannose- and Fcγ-receptor-mediated phagocytosis, respectively. Inhibition relies on the interaction of Tat with phosphatidylinositol (4,5)bisphosphate that interferes with the recruitment of Cdc42 to the phagocytic cup, thereby preventing Cdc42 activation and pseudopod elongation. Tat also inhibits FcγR-mediated phagocytosis in neutrophils and monocytes. This study provides a molecular basis for the phagocytic defects observed in uninfected phagocytes following HIV-1 infection.
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Solène
authors: S
authors: Debaisieux
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Simon
authors: S
authors: Lachambre
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Antoine
authors: A
authors: Gross
authors: IGH, UPR 1142 CNRS, 141 Rue de la Cardonille, 34396 Montpellier, France.
authors: Clément
authors: C
authors: Mettling
authors: DIMNP, UMR 5235 CNRS, Université de Montpellier, 34095 Montpellier, France.
authors: Sébastien
authors: S
authors: Besteiro
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Hocine
authors: H
authors: Yezid
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Daniel
authors: D
authors: Henaff
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Christophe
authors: C
authors: Chopard
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Jean-Michel
authors: JM
authors: Mesnard
authors: CPBS, UMR 5236 CNRS-Université de Montpellier, 1919 Route de Mende, 34293 Montpellier, France.
authors: Bruno
authors: B
authors: Beaumelle
mesh_terms: D024201:Bystander Effect; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009162:Mycobacterium avium / Q000254:growth & development; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010587:Phagocytosis / Q000187:drug effects*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport / Q000187:drug effects; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D015398:Signal Transduction; D014122:Toxoplasma / Q000254:growth & development; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000096:biosynthesis / Q000494:pharmacology*
chemical_list: C489017:FCGR1A protein, human; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D019269:Phosphatidylinositol 4,5-Diphosphate; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D011994:Recombinant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D020764:cdc42 GTP-Binding Protein