STIMULATION OF HIV REPLICATION IN MONONUCLEAR PHAGOCYTES BY LEUKEMIA INHIBITORY FACTOR

This study examined the effects of leukemia inhibitory factor (LIF) on human immunodeficiency virus (HIV) replication in mononuclear phagocy tes (MNP). LIF induced a dose-dependent increase in p24 antigen produc tion in the chronically infected promonocytic cell line U1. The magnit ude and time kinetics of the LIF effects were similar to interleukin 1 (IL-1), IL-6, and tumor necrosis factor (TNF), other cytokines known to induce HIV replication in this cell line. To characterize mechanism s responsible for these LIF effects, levels of HIV mRNA, activation of the DNA binding protein nuclear factor (NF)-kB, signal transduction p athways, and potential interactions with other cytokines were analyzed . LIF increased steady-state levels of HIV mRNA at 2.0, 4.3, and 9.2 k B. This was detectable by 24 h and persisted until 72 h. The DNA bindi ng protein NF-kB is a central mediator in cytokine activation of HIV t ranscription. NF-kB levels were higher in unstimulated U1 cells as com pared to the parent cell line U937. In both cell lines LIF increased N F-kB activity. Induction of NF-kB and HIV replication by cytokines are at least in part dependent on reactive oxygen intermediates. The oxyg en radical scavenger N-acetyl-L-cysteine, but not an inhibitor of nitr ic oxide synthase, inhibited LIF-induced HIV replication. LIF induces the production of other cytokines in monocytes but its effects on HIV replication were not inhibited by antibodies to IL-1, TNF, or IL-6. Th ese results identify LIF as a stimulus of HIV replication. Its effects are related to increased HIV mRNA production and, NF-kB activation, a nd it is independent from the production of other cytokines.