title: Progesterone and a phospholipase inhibitor increase the endosomal bis(monoacylglycero)phosphate content and block HIV viral particle intercellular transmission.
abstract: Progesterone, the cationic amphiphile U18666A and a phospholipase inhibitor (Methyl Arachidonyl Fluoro Phosphonate, MAFP) inhibited by 70%-90% HIV production in viral reservoir cells, i.e. human THP-1 monocytes and monocyte-derived macrophages (MDM). These compounds triggered an inhibition of fluid phase endocytosis (macropinocytosis) and modified cellular lipid homeostasis since endosomes accumulated filipin-stained sterols and Bis(Monoacylglycero)Phosphate (BMP). BMP was quantified using a new cytometry procedure and was increased by 1.25 times with MAFP, 1.7 times with U18666A and 2.5 times with progesterone. MAFP but not progesterone or U18666A inhibited the hydrolysis of BMP by the Pancreatic Lipase Related Protein 2 (PLRP2) as shown by in-vitro experiments. The possible role of sterol transporters in steroid-mediated BMP increase is discussed. Electron microscopy showed the accumulation of viral particles either into large intracellular viral-containing compartments or outside the cells, indicating that endosomal accumulation of BMP could block intracellular biogenesis of viral particles while inhibition of macropinocytosis would prevent viral particle uptake. This is the first report linking BMP metabolism with a natural steroid such as progesterone or with involvement of a phospholipase A1 activity. BMP cellular content could be used as a biomarker for efficient anti-viral drugs.
authors.affiliation: INSERM, U1043, Equipe Infection virales: persistance, réponse de l'hôte et physiopathologie, Toulouse F-31300, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Chapuy-Regaud
authors.forename: Caroline
authors.initials: C
authors.lastname: Subra
authors.forename: Mary
authors.initials: M
authors.lastname: Requena
authors.forename: Philippe
authors.initials: P
authors.lastname: de Medina
authors.forename: Sawsan
authors.initials: S
authors.lastname: Amara
authors.forename: Isabelle
authors.initials: I
authors.lastname: Delton-Vandenbroucke
authors.forename: Bruno
authors.initials: B
authors.lastname: Payre
authors.forename: Michelle
authors.initials: M
authors.lastname: Cazabat
authors.forename: Frédéric
authors.initials: F
authors.lastname: Carriere
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
authors.forename: Marc
authors.initials: M
authors.lastname: Poirot
authors.forename: Michel
authors.initials: M
authors.lastname: Record
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D001095:Arachidonic Acids / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008049:Lipase / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000821:virology; D009000:Monocytes / Q000166:cytology; D050178:Monoglycerides / Q000378:metabolism*; D063065:Organophosphonates / Q000494:pharmacology; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010873:Pinocytosis / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000736:Androstenes; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D050178:Monoglycerides; D063065:Organophosphonates; C012786:bis(monoacylglyceryl)phosphate; C104810:methyl arachidonylfluorophosphonate; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D011374:Progesterone; D002784:Cholesterol; D010740:Phospholipases; D008049:Lipase; C075988:pancreatic lipase related protein 2
keywords: AZT; BDP; BGP; BMP; BMP (bismonoacylglycerophosphate); Cholesterol epoxide; Desmosterol; LBPA; LPV; MAFP; MAFP (methyl arachidonyl fluoro phosphonate); MVB; PLRP2 (pancreatic lipase-related protein 2); PROG; Progesterone; Sterol transporter NPC-1; U18; U18666A; bis(diacylglycero)phosphate; bis(glycero)phosphate; bis(monoacylglycero)phosphate; lopinavir; lyso-bisphosphatidic acid; methyl arachidonyl fluoro phosphonate; multivesicular body (late endosome); progesterone; zidovudine