Release of anti-HIV mediators after administration of leukotriene B4 to humans

Background. CD8(+) T cells can control human immunodeficiency virus (HIV) through the lysis of infected cells and the release of soluble mediators, such as macrophage inflammatory protein (MIP)-1beta, which prevent entry of HIV and/or inhibit HIV replication. Because neutrophils represent a major source of alpha-defensins and, to a lesser extent, MIP-1beta, we determined whether leukotriene B-4 (LTB4), a potent neutrophil agonist, would trigger the release of these 2 anti-HIV peptides. Methods. Plasma samples from HIV-uninfected subjects receiving intravenous bolus of LTB4 were analyzed for alpha-defensins and MIP-1beta levels by use of enzyme-linked immunosorbent assay. Furthermore, in vitro analysis of intracellular and secreted levels of alpha-defensins of resting and LTB4 -activated neutrophils from HIV-uninfected and HIV-infected subjects were determined. LTB4 modulation of CD63 and CD66b markers associated with degranulation were studied by use of flow cytometry. Chemotaxis of neutrophils from HIV-uninfected and HIV-infected subjects toward LTB4 or interleukin (IL)-8 was determined by use of migration assays. Results. Administration of LTB4 to humans caused a dose-dependent plasmatic increase in alpha-defensins and MIP-1beta proteins, with peak levels observed 2 h after administration of LTB4. Neutrophils isolated from HIV-infected and HIV-uninfected subjects contained similar levels of stored alpha-defensins that were effectively secreted in vitro, in response to LTB4 activation. Chemotaxis of neutrophils toward LTB4 or IL-8 was identical among the groups of subjects. Conclusion. LTB4 induced the secretion a-defensins and MIP-1beta. Neutrophils from HIV-infected subjects were fully responsive to LTB4, which highlights a potential usefulness of this lipid mediator in the management of HIV infection.