title: Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages.
abstract: HIV type 1 (HIV-1) infects CD4(+) T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are believed to act as "Trojan horses" carrying infectious particles to be released on cell necrosis or functional stimulation. Here we explored the hypothesis that extracellular ATP (eATP) could represent a microenvironmental signal potentially affecting virion release from VCC of infected macrophages. Indeed, eATP triggered the rapid release of infectious HIV-1 from primary human monocyte-derived macrophages (MDM) acutely infected with the CCR5-dependent HIV-1 strain. A similar phenomenon was observed in chronically infected promonocytic U1 cells differentiated to macrophage-like cells (D-U1) by costimulation with phorbol esters and urokinase-type plasminogen activator. Worthy of note, eATP did not cause necrotic, apoptotic, or pyroptotic cell death, and its effect on HIV-1 release was suppressed by Imipramine (an antidepressant agent known to inhibit microvesicle formation by interfering with membrane-associated acid sphingomyelinase). Virion release was not triggered by oxidized ATP, whereas the effect of eATP was inhibited by a specific inhibitor of the P2X7 receptor (P2X7R). Thus, eATP triggered the discharge of virions actively accumulating in VCC of infected macrophages via interaction with the P2X7R in the absence of significant cytopathicity. These findings suggest that the microvesicle pathway and P2X7R could represent exploitable targets for interfering with the VCC-associated reservoir of infectious HIV-1 virions in tissue macrophages.
authors.affiliation: AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milano, Italy; Vita-Salute San Raffaele University, 20132 Milano, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziano
authors.affiliation: Institut Curie, Centre de Recherche, F-75248 Paris, France;
authors.forename: Marion
authors.initials: M
authors.lastname: Desdouits
authors.affiliation: Department of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Livia
authors.initials: L
authors.lastname: Garzetti
authors.affiliation: Department of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Podini
authors.affiliation: AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milano, Italy;
authors.forename: Massimo
authors.initials: M
authors.lastname: Alfano
authors.affiliation: Cell Biology Unit, Istituto di Ricovero e Cura a Carattere Scientifico, Azienda Ospedaliera Universitaria San Martino IST, 16132 Genova, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
authors.affiliation: Department of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.affiliation: Institut Curie, Centre de Recherche, F-75248 Paris, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Benaroch
authors.affiliation: AIDS Immunopathogenesis Unit, Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, 20132 Milano, Italy; Vita-Salute San Raffaele University, 20132 Milano, Italy; Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 poli.guido@hsr.it.
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D004197:Disease Reservoirs; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008264:Macrophages / Q000821:virology*; D011485:Protein Binding; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D014771:Virion / Q000378:metabolism / Q000502:physiology
chemical_list: D058486:Receptors, Purinergic P2X7; D014764:Viral Proteins; D000255:Adenosine Triphosphate; D007099:Imipramine
keywords: ATP; HIV; P2X7; macrophage; virion-containing compartment