title: Inhibition of HIV-1-mediated syncytium formation and virus replication by the lipophosphoglycan from Leishmania donovani is due to an effect on early events in the virus life cycle.
abstract: Previous findings have indicated that the major surface molecule of Leishmania, lipophosphoglycan (LPG), could abrogate HIV-1-induced syncytium formation and virus replication. In the present work, we were interested in characterizing this inhibitory process. Data from a new luciferase-based semiquantitative assay for syncytium formation, relying on the coincubation of a T-cell line containing an HIV-1 LTR-driven luciferase construct with a cell line chronically infected with HIV-1, confirmed that LPG was indeed a strong inhibitor of HIV-1-dependent syncytium formation and that this inhibition was dose-dependent. As determined by flow cytometric analyses, this inhibition was not apparently due to downregulation of CD4, CXCR4 or LFA-1, three distinct surface glycoproteins known to be important in HIV-1 mediated syncytium formation. Furthermore, LPG did not seem to affect signal transduction pathways in T cells as judged by measurement of HIV-1 LTR-driven reporter gene activity upon treatment with different stimuli. However, pretreatment of either of the cell lines used in the assay with LPG led to a significant decrease of virus-mediated syncytium formation, which was further accentuated when both cell lines were pretreated. LPG inhibition of HIV-1 replication was next assessed. When measuring either infection with luciferase-encoding recombinant HIV-1 particles or multinucleated giant cell formation following an acute virus infection, we again observed that LPG was efficient at blocking HIV-1 replication. Specific assays probing different steps of viral entry demonstrated that attachment was not hindered by LPG but that viral entry was modulated, suggesting that LPG targets a postbinding step. Hence, incorporation of LPG into a target cell membrane could influence its fluidity and diminish both the virus-cell and cell-to-cell fusion processes initiated by HIV-1.
authors.affiliation: Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Genois
authors.forename: B
authors.initials: B
authors.lastname: Barbeau
authors.forename: M
authors.initials: M
authors.lastname: Olivier
authors.forename: M J
authors.initials: MJ
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000302:isolation & purification / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D015726:Giant Cells; D006028:Glycosphingolipids / Q000302:isolation & purification / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000821:virology; D007893:Leishmania donovani / Q000737:chemistry*; D008156:Luciferases / Q000032:analysis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D008561:Membrane Fusion / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006028:Glycosphingolipids; D016169:Lymphocyte Function-Associated Antigen-1; D019718:Receptors, CXCR4; C008290:lipophosphonoglycan; D008156:Luciferases