title: CD40 ligand and IFN-gamma synergistically restore IL-12 production in HIV-infected patients.
abstract: IL-12 production in HIV-infected (HIV+) individuals is severely impaired after stimulation by bacterial products or T cell-dependent stimuli. Because CD40-CD40 ligand (CD40L) interactions are the major mechanism involved in the T cell-dependent activation of antigen-presenting cells, we investigated whether this pathway was functional in HIV+ donors. CD40 expression was increased on freshly isolated monocytes from HIV+ individuals compared to HIV donors. However, equivalent CD40 expression was obtained in the two groups after cytokine stimulation. Since CD40 expression was intact in HIV+ donors' cells, we determined whether IL-12 production could be restored by providing exogenous T cell-dependent stimuli, CD40L and IFN-gamma, at the time of bacterial stimulation. IL-12 production was not altered by CD40L alone, was increased by IFN-gamma, and was synergistically restored to normal values by IFN-gamma + CD40L. This combination was more efficient for enhancing IL-12 production than granulocyte-macrophage colony-stimulating factor + CD40L or neutralizing anti-IL-10 antibody + CD40L. CD40L did not affect IL-10 production, whereas IFN-gamma significantly decreased it. This study demonstrates that the defect in IL-12 production by leukocytes from HIV+ donors can be overcome in vitro if the interacting cells are provided with the right T cell-dependent co-stimuli.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: C
authors.initials: C
authors.lastname: Chougnet
authors.forename: E
authors.initials: E
authors.lastname: Thomas
authors.forename: A L
authors.initials: AL
authors.lastname: Landay
authors.forename: H A
authors.initials: HA
authors.lastname: Kessler
authors.forename: S
authors.initials: S
authors.lastname: Buchbinder
authors.forename: S
authors.initials: S
authors.lastname: Scheer
authors.forename: G M
authors.initials: GM
authors.lastname: Shearer
mesh_terms: D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D001782:Blood Donors; D019013:CD40 Antigens / Q000096:biosynthesis / Q000378:metabolism*; D023201:CD40 Ligand; D004357:Drug Synergism; D015658:HIV Infections / Q000276:immunology*; D018023:HIV Seronegativity / Q000276:immunology; D006679:HIV Seropositivity / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D007375:Interleukin-1; D008024:Ligands; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma