Animal Model Studies

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This Project within the PPG will investigate, using SIV and SHIV infection in rhesus macaques, the effect of polyamine biosynthesis inhibitors (PBI) on pathogenesis AIDS and sequela of neuroAIDS. For this, we initially propose to investigate the polyamine biosynthesis inhibitors PA-001 in the first 2.5 years and a second designated PA-002 in the last 2.5 years. We hypothesize the PBI will deactivate and/or selectively target populations of CD14+ and CD16+ monocyte/macrophages, some of which are SIV infected. We propose to use a) a CD8+ lymphocyte depletion model of SIV infection that results in rapid, consistent and severe CMS disease with SIV encephalitis (SIVE), and b) a SHIV infection model that rapidly depletes CD4+ T lymphocytes resulting in high virus replication in monocyte/macrophages, to study the effects of PBI; deactivating and/or killing select monocyte/macrophage subsets; delaying the onset and/or reversing CNS disease; potentially flushing monocyte/macrophage viral reservoirs. We propose three Specific Aims to test our hypothesis. Specific Aim 1 will determine whether PBI (PA-001 and PA-002) deactivates and/or kills select CD14+CD16+ monocyte/macrophage during: a) acute infection (7-21 days pi) and b) with the development of AIDS. Specific Aim 2 will test the hypothesis that PBI (PA-001 and PA-002) treatment deactivates and/or kills select CD14+CD16+ monocyte/macrophage populations, delaying and/or reversing the development of AIDS and SIVE. Specific Aim 3 will test the hypothesis that PBI treated, SHIV infected animals that are CD4+ T cell depleted and have high virus replication in monocyte/macrophages, clears or diminishes viral reservoirs in blood, lymphoid and CNS tissues. Studies proposed in this project have direct relevance to studies of human AIDS and neuroAIDS, and support Projects 1 and 3 of the PPG. These studies: use a well-defined primate model of neuroAIDS to better identify monocyte subsets that predict progression of AIDS and neuroAIDS with SIVE development; assess the significance of continued monocyte traffic on neuropathogenesis and CNS infection; and investigate the potential of select pharmacologic agents (PBI), which have been used in human clinical trials, to deactivate and kill SIV infected monocyte/macrophages. These studies will add to our understanding of the role of monocyte/macrophages in AIDS and AIDS neuropathogenesis and directly assess the utility of reagents for use in human clinical trials for neuroAIDS. They will adds support to proposed clinical studies in Project 3, and will provide dynamic sampling of blood and SIV infected tissues for Project 1, defining mechanisms of function of PBI. Lastly, these studies may better define the role of monocyte/macrophages contributing to AIDS and functioning as cellular reservoir of HIV.