This Project within the PPG will investigate, using SIV and SHIV infection in rhesus macaques, the effect ofpolyamine biosynthesis inhibitors (PBI) on pathogenesis AIDS and sequela of neuroAIDS. For this, weinitially propose to investigate the polyamine biosynthesis inhibitors PA-001 in the first 2.5 years and asecond designated PA-002 in the last 2.5 years. We hypothesize the PBI will deactivate and/or selectivelytarget populations of CD14+ and CD16+ monocyte/macrophages, some of which are SIV infected. Wepropose to use a) a CD8+ lymphocyte depletion model of SIV infection that results in rapid, consistent andsevere 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 CNSdisease; potentially flushing monocyte/macrophage viral reservoirs. We propose three Specific Aims to testour 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 selectCD14+CD16+ monocyte/macrophage populations, delaying and/or reversing the development of AIDS andSIVE.
Specific Aim 3 will test the hypothesis that PBI treated, SHIV infected animals that are CD4+ T cell depletedand 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, andsupport Projects 1 and 3 of the PPG. These studies: use a well-defined primate model of neuroAIDS tobetter 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; andinvestigate 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 ofthe role of monocyte/macrophages in AIDS and AIDS neuropathogenesis and directly assess the utility ofreagents for use in human clinical trials for neuroAIDS. They will adds support to proposed clinical studies inProject 3, and will provide dynamic sampling of blood and SIV infected tissues for Project 1, definingmechanisms of function of PBI. Lastly, these studies may better define the role of monocyte/macrophagescontributing to AIDS and functioning as cellular reservoir of HIV.
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