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

HAART对HIV-1 Tat诱导的脑衰老的影响

基本信息

批准号：
8541054
负责人：
Brian Giunta
金额：
$ 32.29万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-06 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8541054
关键词：
Address Adherence Adult Adverse effects Age-Months Age-associated memory impairment Aging Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloidosis Anti-Retroviral Agents Biological Assay Brain Brain Pathology Cells Cerebrum Chronic Cognitive Cognitive aging Cognitive deficits Data Deposition Diet Elderly Figs - dietary Foundations Future Generations HIV HIV Seropositivity HIV-1 Highly Active Antiretroviral Therapy Human Impaired cognition In Vitro Inflammation Inflammatory Interferons Lamivudine Lead Mediating Memory impairment Microglia Mitochondria Mus Neurocognition Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Neurons Outcome Pathology Patients Peptides Phagocytosis Phase Pilot Projects Principal Investigator Process Production Proteolysis Publishing Radial Regimen Risk Factors TNF gene Testing Tg2576 Transgenes Transgenic Mice Transgenic Organisms Up-Regulation Water Zidovudine age effect aging brain antiretroviral therapy arm base beta-site APP cleaving enzyme 1 cost cytokine design efavirenz hyperphosphorylated tau in vitro Model in vivo mitochondrial dysfunction mouse model mutant neurocognitive test neuropathology neurotoxic novel object recognition prevent programs research study scale up secretase tat Protein trend

项目摘要

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.

描述（由申请人提供）：在与大脑衰老有关的副作用方面，针对HIV处方高度活性抗逆转录病毒疗法（HAART）的快速缩放成本（Heaton等，2011; Green Et Al。，2005; Giunta等，2011）。有必要在毒性较小的HAART方案中分离。我们设计了一个实验，以了解大脑衰老，HIV-1 TAT蛋白与慢性Haart赋予的已知认知副作用之间的相互作用（Ciccarelli等，2011）。我们初步发现了Efavirenz（EFV）/Lamivudine（3TC）/Zidovudine（AZT），一种常用的Haart疗法，促进了TG2576蛋白膜沉积小鼠的体外和体内的ROS产生，BACE1表达和体内。这种HAART方案显着抑制了A ?? 1-42肽的小胶质细胞增多症。关于这些结果，EFV是最有效的，而AZT的有效性最低。另外，我们发现HIV-1 TAT蛋白抑制A ??的小胶质细胞增多症。肽（Giunta等，2008a），并有助于HIV-1 TAT/PSAPP转基因小鼠的衰老病理学（Giunta等，2009）。在这里，我们计划表征神经认知和HART长期治疗的HIV-1 TAT /PSAPP小鼠中的晚期脑老化病理学。 EFV/3TC/AZT应在12个月大时导致这些小鼠的晚期神经认知缺陷，与对照，EFV，AZT或3TC治疗的小鼠相比，应通过脑HIV-1 TAT表达来协同增强，与1-42/？ - CTF的高度相关。这将使我们能够隔离这种常用方案中哪种抗逆转录病毒，在慢性给药过程中是最多的神经毒性。我们预计，此结果的其他指标将包括升高广告样的热磷酸化tau，促炎性细胞因子和小胶质细胞A的失调？吞噬作用和脑线粒体功能。预计这项研究将通过使用常见的HAART方案来描述慢性TAT表达的长期后果，以晚期脑老化的神经病理学和认知缺陷。在已知的HAART介导的病理生理机制的背景下，它应该为防止TAT和HAART之间的这些相互作用的有效策略奠定基础。