title: IL-13 and TNF-alpha inhibit dual-tropic HIV-1 in primary macrophages by reduction of surface expression of CD4, chemokine receptors CCR5, CXCR4 and post-entry viral gene expression.
abstract: We show that IL-13 in the presence of TNF-alpha effected an equal or greater antiviral activity against a dual-tropic HIV-1 (R5X4) in macrophages. A temporary or continued exposure of macrophages to both cytokines significantly decreased the infection and replication of R5X4 HIV-1(89.6) (median, 128-fold, n = 9, p = 0.024) in macrophages as compared to untreated controls when analyzed over six decreasing multiplicities of infection. A quantitative flow cytometric assay revealed that IL-13 induced a significant (approximately 50 %) reduction in the number of CD4 and CC chemokine receptor 5 (CCR5) antibody binding sites while completely abrogating surface expression of CXC chemokine receptor 4 (CXCR4). In the presence of IL-13 and TNF-alpha, expression of CCR5 was completely abrogated while the expression of CD4 and CXCR4 remained significantly reduced as compared to untreated controls. A reduction in CD4 and HIV-1 coreceptors was associated with a decrease in reverse-transcribed viral DNA at 24 h post-infection. Quantification of viral gene expression using amphotropic MLV Env pseudotyped luciferase reporter viruses suggested that IL-13 inhibited HIV-1 gene expression within 24 h by up to 90 % in the presence or absence of TNF-alpha. In conclusion, our data suggest that IL-13 is a powerful counter-regulatory agent against TNF-alpha-induced HIV-1 expression while also acting with TNF-alpha in inhibiting de novo infection of macrophages.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: R T
authors.initials: RT
authors.lastname: Bailer
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: L J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D015704:CD4 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D004357:Drug Synergism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000276:immunology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018793:Interleukin-13 / Q000276:immunology* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D019713:Receptors, CCR5 / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D018793:Interleukin-13; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha