HIV infected monocytes and macrophages are involved in the pathogenesis of HIV associated neurologicaldisease (HAND). Pathologica LLC has been systematically investigating compounds that can altermacrophage activation states as potential therapeutics. This class of compounds includes polyamineanalogs (e.g. CG47) and enzymatic inhibitors of polyamine synthesis (e.g. PA-001). We have found thatpolyamine biosynthesis inhibitors (PBIs) are particularly effective at modulating and / or killing CD16 positivemacrophages. Preliminary studies at Pathologica have established that the polyamine biosynthesis inhibitorPA01 is very efficient at reducing HIV DNA loads in mononcytes in vitro and at reducing the level of SIVinfection of macrophages in the blood and tissues of rhesus macaques. However, the mechanism by whichthese beneficial outcomes were achieved remains largely unexplored. Microarray analyses of peripheralblood mononuclear cells from HIV infected individuals noted significant changes in the mRNA levels ofimmomodulatory proteins, including osteopontin and adenosine deaminase after in vitro PBI treatment.These observations are consistent with the recently described immunosuppressive role of the nativepolyamine spermine in monocytes. Accordingly, we hypothesize that PBIs kill HIV infected CD16+monocytes and macrophages via an immunomodulatory mechanism involving induction of apoptosis. Amore thorough understanding of the mechanism of action of PBIs against HIV infected macrophages will becritical to designing the most efficacious therapeutic regimens for the treatment of HAND. Accordingly, theoverall goal of Research Project 1 of this program project is to understand the mechanism by which PBIslead to reduced HIV proviral load in macrophages in vitro. Mechanistic studies will be performed onmonocytes from HIV infected individuals and SIV infected rhesus macaques. Samples provided aftertreatment of rhesus macaques (Project 2) and clinical trial participants (project 3) with PBIs will allow us toconfirm that the mechanism of action of PBIs seen in vitro also is relevant in vivo. These studies shouldprovide significant insight into the role of macrophages in the pathogenesis of HAND and identify noveltherapeutic targets for future studies.
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