WF10 induced modification of macrophage functional state as an adjunctive therapy for HIV disease

Macrophage activation states likely influence the pathogenesis of HIV disease, however, to date there has been no quantitative capability of evaluating macrophage-targeted therapeutics to assess this possibility. We have utilized a real time Lightcycler (LC) RT-PCR system for evaluation of gene expression modification that occurs both in vitro and in vivo from specimens (patients) exposed to the macrophage targeted chlorite based drug, WF10 (OXO Chemie), currently in phase III clinical trials for the treatment of advanced HIV disease. WF10 phase II studies showed drug associated increased T cell levels with sustained decreases immunologic activation markers (CD8/38, CD14/DR, CD20/DR, PHA activation) with minimal clinical toxicity. LC studies showed drug dependent drops in PBMC proinflammatory gene expression (TNF-alpha, IL-6, IL-1, MIP1a). Short term treatment of isolated normal CD14 cells with WF10 in vitro showed dramatic upregulation of virtually all proinflammatory cytokine and chemokine genes evaluated as well as apoptotic genes CD95, CD95L and Bax in specimens containing activated macrophages. WF10 mediated inhibition of T cell activation was associated with rapid down regulation of mitogen induced lymphokines. These data suggest that WF10 causes hyperactivation and apoptosis of selected activated macrophages with immediate short term inhibition of T cell activation. Increased apoptosis then causes secondary induction of a macrophage activation state that is anti-inflammatory and characterized by upregulated phagocytosis. We hypothesize that killing/downregulating activated macrophages in HIV disease will remove the chronic stimulus for pathologic immunologic sequelae and return basic macrophage functions such as phagocytosis and wound healing to normal. In studies presented here, WF10 appeared to cause dramatic changes in macrophage gene expression in vitro and in vivo with a change from an inflammatory to an anti-inflammatory genotype as measured by RT-PCR with the Lightcycler system.