The impact of HAART on HIV-1 Tat induced brain aging

描述（由申请人提供）： 在与脑老化相关的副作用方面，用于HIV的高效抗逆转录病毒疗法（HAART）处方的快速扩大的成本是显著的（希顿等人，2011;绿色等 例如，2005; Giunta等人，2011年）。有必要逐步采用毒性较小的HAART方案。我们设计了一个实验来理解脑老化、HIV-1达特蛋白和已知的由慢性HAART引起的认知副作用之间的相互作用（Ciccarelli等人，2011年）。我们初步发现，常用的HAART方案--依法韦仑（EFV）/拉米夫定（3 TC）/齐多夫定（AZT）可促进ROS产生、BACE 1表达和A？在Tg 2576淀粉样蛋白沉积小鼠中在体外和体内产生。这种HAART方案显着抑制小胶质细胞吞噬A？？1-42肽也是如此。关于这些结果，EFV最有效，而AZT最不有效。此外，我们还发现HIV-1达特蛋白抑制小胶质细胞对A？肽（Giunta等人，2008 a），并且其有助于HIV-1达特/PSAPP转基因小鼠的衰老病理学（Giunta et al.，2009年）。在这里，我们计划在长期接受HAART治疗的HIV-1达特/PSAPP小鼠中表征神经认知和高级脑老化病理学。EFV/3 TC/AZT应导致这些小鼠在12月龄时出现高级神经认知缺陷，这应通过脑HIV-1达特表达协同增强，这可能与A？1-42/？- CTF，与对照、EFV、AZT或3 TC处理的小鼠相比。这将使我们能够分离出这种常用方案中的哪种抗逆转录病毒药物在长期给药期间最具神经毒性。我们预计这一结果的其他指标将包括AD样过度磷酸化tau蛋白、促炎细胞因子和小胶质细胞A？？吞噬作用和脑线粒体功能。这项研究预计将描述慢性达特表达的长期后果与使用一个共同的HAART方案方面的先进的脑老化样神经病理学和认知缺陷。它应该奠定了有效的策略，以防止这些之间的相互作用，在未来的背景下，已知的HAART介导的病理生理机制达特和HAART的基础。

DESCRIPTION (provided by applicant): The cost of the rapid scale-up in prescribing highly active antiretroviral therapy (HAART) for HIV has been significant in terms of side-effects related to brain aging (Heaton et al., 2011; Green et al., 2005; Giunta et al., 2011). There is a need to phase in less toxic HAART regimens. We designed an experiment to understand the interactions between brain aging, HIV-1 Tat protein, and the known cognitive side-effects imparted by chronic HAART (Ciccarelli et al., 2011). We preliminarily found efavirenz (EFV)/lamivudine (3TC)/zidovudine (AZT), a commonly used HAART regimen, promoted ROS production, BACE1 expression, and A??generation both in vitro and in vivo in Tg2576 amyloid depositing mice. This HAART regimen significantly inhibited microglial phagocytosis of A??1-42 peptide as well. Regarding these outcomes, EFV was most potent while AZT was least potent. Additionally we have found that HIV-1 Tat protein inhibits microglial phagocytosis of A?? peptide (Giunta et al., 2008a) and that it contributes to aging pathology in HIV-1 Tat/PSAPP transgenic mice (Giunta et al., 2009). Here we plan to characterize neurocognition, and advanced brain aging pathology in HIV-1 Tat /PSAPP mice chronically treated with HAART. EFV/3TC/AZT should lead to advanced neurocognitive deficits in these mice by 12 months of age that should be synergistically enhanced by brain HIV-1 Tat expression which that can be correlated with elevations in A??1-42/?-CTF, compared to control, EFV, AZT, or 3TC treated mice. This will allow us to isolate which antiretroviral(s) in this commonly used regimen are most neurotoxic during chronic administration. We expect that other indicators of this will outcome will include elevations of AD-like hyperphosphorylated tau, pro-inflammatory cytokines, and dysregulation of microglial A?? phagocytosis, and brain mitochondrial function. This study is expected to describe the long-term consequences of chronic Tat expression with use of a common HAART regimen in terms of advanced brain aging-like neuropathology and cognitive deficits. It should lay the foundation for effective strategies to prevent these interactions between Tat and HAART in the future in the context of a known HAART-mediated pathophysiological mechanism.