Mechanism of Action of Macrophage Targeted Drugs

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HIV infected monocytes and macrophages are involved in the pathogenesis of HIV associated neurological disease (HAND). Pathologica LLC has been systematically investigating compounds that can alter macrophage activation states as potential therapeutics. This class of compounds includes polyamine analogs (e.g. CG47) and enzymatic inhibitors of polyamine synthesis (e.g. PA-001). We have found that polyamine biosynthesis inhibitors (PBIs) are particularly effective at modulating and / or killing CD16 positive macrophages. Preliminary studies at Pathologica have established that the polyamine biosynthesis inhibitor PA01 is very efficient at reducing HIV DNA loads in mononcytes in vitro and at reducing the level of SIV infection of macrophages in the blood and tissues of rhesus macaques. However, the mechanism by which these beneficial outcomes were achieved remains largely unexplored. Microarray analyses of peripheral blood mononuclear cells from HIV infected individuals noted significant changes in the mRNA levels of immomodulatory proteins, including osteopontin and adenosine deaminase after in vitro PBI treatment. These observations are consistent with the recently described immunosuppressive role of the native polyamine spermine in monocytes. Accordingly, we hypothesize that PBIs kill HIV infected CD16+ monocytes and macrophages via an immunomodulatory mechanism involving induction of apoptosis. A more thorough understanding of the mechanism of action of PBIs against HIV infected macrophages will be critical to designing the most efficacious therapeutic regimens for the treatment of HAND. Accordingly, the overall goal of Research Project 1 of this program project is to understand the mechanism by which PBIs lead to reduced HIV proviral load in macrophages in vitro. Mechanistic studies will be performed on monocytes from HIV infected individuals and SIV infected rhesus macaques. Samples provided after treatment of rhesus macaques (Project 2) and clinical trial participants (project 3) with PBIs will allow us to confirm that the mechanism of action of PBIs seen in vitro also is relevant in vivo. These studies should provide significant insight into the role of macrophages in the pathogenesis of HAND and identify novel therapeutic targets for future studies.