The LIR has been studying the regulation of HIV replication by cytokines and cytokine networks for many years.  Interleukin (IL)-10, in particular, has been studied and found to inhibit HIV replication by at least two different mechanisms in vitro.  The first is an anti-inflammatory effect, whereby IL-10 blocks the production of IL-1, IL-6 and tumor necrosis factor (TNF), all of which have been demonstrated to enhance HIV replication.  The second is an anti-activation effect where IL-10 inhibits immune activation, IL-2 secretion, and proliferation of T cells.  This inhibition of activation leads to an inhibition of HIV replication.  A phase I clinical trial in which IL-10 was administered to HIV-infected and uninfected individuals is currently underway.  In four uninfected individuals, 25 ug/kg of IL-10 completely inhibited in vitro lipopolysaccharide (LPS) induced TNF-alpha secretion for 24 hours and blocked the acute in vitro infection of IL-2 or PHA activated peripheral blood mononuclear cells (PBMC).  Administration of IL-10 was associated with no adverse effects.  In three HIV-infected individuals (CD4 counts between 200 and 500), administration of 1 ug/kg of IL-10 resulted in increased CD4+ T cell percentages by 12% for 2 to 3 days.  Plasma viral load was decreased by greater than one log at 6 and 12 hr after drug infusion and up to one half log at 24 hr post IL-10 injection.  Thus, IL-10, which has potent anti-HIV activities in vitro, also has similar effects in vivo.  Current studies include the identification of the mechanisms of inhibition of viral replication in vivo as well as the design of phase 2 and 3 clinical studies.