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

描述(由申请人提供)： 就与脑老化相关的副作用而言，快速扩大艾滋病毒高效抗逆转录病毒疗法(HAART)的成本是显著的(Heaton等人，2011年；Green等人 等人，2005年；Giunta等人，2011年)。有必要逐步采用毒性较低的HAART方案。我们设计了一项实验，以了解大脑老化、HIV-1 Tat蛋白和慢性HAART所带来的已知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EFV/拉米夫定(3TC)/齐多夫定(AZT)在体外和体内均能促进Tg2576淀粉样蛋白沉积小鼠体内ROS的产生、BACE1的表达和Aβ的生成。该HAART方案还能显著抑制小胶质细胞对A1-42肽的吞噬作用。关于这些结果，EFV是最有效的，而AZT是最弱的。此外，我们还发现HIV-1Tat蛋白抑制小胶质细胞吞噬A？？多肽(Giunta等人，2008a)，并有助于HIV-1TAT/PSAPP转基因小鼠的衰老病理(Giunta等人，2009年)。在这里，我们计划描述长期使用HAART治疗的HIV-1TAT/PSAPP小鼠的神经认知和高级脑老化病理。与对照组、EFV、AZT或3TC处理的小鼠相比，EFV/3TC/AZT可导致这些小鼠在12个月大时出现严重的神经认知障碍，脑HIV-1 Tat表达应协同增强，这可能与A？1-42/？-CTF的升高相关。这将使我们能够分离出这种常用方案中哪些抗逆转录病毒药物(S)在慢性给药过程中神经毒性最强。我们预计，这一结果的其他指标将包括AD样过度磷酸化的tau、促炎细胞因子和小胶质细胞A？？调节失调。吞噬作用和脑线粒体功能。这项研究预计将描述慢性TAT表达的长期后果，使用常见的HAART方案，在高级大脑老化类神经病理和认知障碍方面。它应该为在已知的HAART介导的病理生理机制的背景下，在未来防止TAT和HAART之间的这些相互作用的有效策略奠定基础。 公共卫生相关性： 神经认知缺陷与HIV阳性成年人依从性下降有关。它们也与TAT介导的脑神经元损伤以及慢性HAART的使用呈正相关。这些趋势突显了更好地了解抗逆转录病毒药物本身如何促进神经认知问题的影响的必要性。尤其是现在HIV患者正在衰老；它本身就是阿尔茨海默氏症等神经退行性疾病的风险因素。我们的建议通过在转基因淀粉样β沉积小鼠模型中检验年龄、认知障碍和慢性HAART给药对提前脑老化的协同效应来解决这些趋势。

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. PUBLIC HEALTH RELEVANCE: Neurocognitive deficits have been associated with decreased adherence among HIV-positive adults. They have also been positively correlated with Tat mediated damage to neurons in the brain as well as chronic HAART use. These trends underscore the need for a better understanding of the impact of how antiretrovirals themselves could promote neurocognitive problems. This is especially true as patients with HIV are now aging; itself being a risk factor neurodegenerative disease such as Alzheimer's. Our proposal addresses these trends by examining the synergistic effects of age, cognitive impairment, and chronic HAART administration on advance brain aging in a transgenic amyloid-beta depositing mouse model.