Mechanism of Action of Macrophage Targeted Drugs

University Of California, San Francisco, San Francisco CA

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Linked publications & trials

Abstract

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