Retrovirally mediated IFN-beta transduction of macrophages induces resistance to HIV, correlated with up-regulation of RANTES production and down-regulation of C-C chemokine receptor-5 expression.
Constitutive expression of IFN-beta by HIV target cells may be an alternative or complementary therapeutic approach for the treatment of AIDS. We show that macrophages derived from CD34+ cells from umbilical cord blood can be efficiently transduced by a retroviral vector carrying the IFN-beta coding sequence. This results in resistance to infection by a macrophage-tropic HIV type 1, as shown by the drastic reduction in the HIV DNA copy number per cell and in p24 release. Moreover, IFN-beta transduction totally blocked secretion of proinflammatory cytokines after HIV infection. The constitutive IFN-beta production also resulted in an increased production of IL-12 and IFN-gamma Th1-type cytokines and of the beta-chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, and RANTES. RANTES was found to be involved in the HIV resistance observed, and this was correlated with a down-regulation of the CCR-5 HIV entry coreceptor. These results demonstrate the feasibility and the efficacy of such IFN-beta-mediated gene therapy. In addition to inhibiting HIV replication, IFN-beta transduction could have beneficial immune effects in HIV-infected patients by favoring cellular immune responses.
Cremer
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Equipe de l'Interferon et des Cytokines, Unité Mixte de Recherche 146, Centre National de la Recherche Scientifique Institut Curie, Orsay, France. Isabelle.Cremer@curie.fr
Vieillard
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De Maeyer
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D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000502:physiology; D019742:Chemokines, CC / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics*; D008264:Macrophages / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D019713:Receptors, CCR5 / Q000096:biosynthesis*; D012190:Retroviridae / Q000235:genetics*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D019713:Receptors, CCR5; D016899:Interferon-beta