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：
8410136
负责人：
Brian Giunta
金额：
$ 33.64万
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/8410136
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. 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.

描述（由申请人提供）：就与大脑老化相关的副作用而言，快速扩大针对艾滋病毒的高效抗逆转录病毒疗法（HAART）的成本是巨大的（Heaton 等人，2011；Green 等人）等人，2005 年； Giunta 等人，2011）。需要分阶段采用毒性较小的 HAART 治疗方案。我们设计了一项实验来了解大脑衰老、HIV-1 Tat 蛋白和慢性 HAART 带来的已知认知副作用之间的相互作用（Ciccarelli 等，2011）。我们初步发现常用的HAART方案依非韦伦（EFV）/拉米夫定（3TC）/齐多夫定（AZT）在Tg2576淀粉样蛋白沉积小鼠体内和体外均促进ROS产生、BACE1表达和Aβ生成。该HAART方案还显着抑制小胶质细胞对Aβ1-42肽的吞噬作用。关于这些结果，EFV 的效力最强，而 AZT 的效力最弱。此外我们还发现HIV-1 Tat蛋白抑制小胶质细胞对A??的吞噬作用。肽（Giunta 等人，2008a），并且它有助于 HIV-1 Tat/PSAPP 转基因小鼠的衰老病理学（Giunta 等人，2009）。在这里，我们计划表征长期接受 HAART 治疗的 HIV-1 Tat /PSAPP 小鼠的神经认知和高级脑衰老病理学。 EFV/3TC/AZT 应导致这些小鼠在 12 个月大时出现严重的神经认知缺陷，这种缺陷应通过大脑 HIV-1 Tat 表达而协同增强，这可能与 A??1-42/?-CTF 的升高相关，与对照、EFV、AZT 或 3TC 治疗的小鼠相比。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?? 失调的升高。吞噬作用和脑线粒体功能。这项研究预计将描述使用常见的 HAART 方案慢性 Tat 表达对晚期脑老化样神经病理学和认知缺陷的长期后果。它应该为未来在已知的 HAART 介导的病理生理机制背景下防止 Tat 和 HAART 之间的相互作用奠定基础。公共卫生相关性：神经认知缺陷与艾滋病毒阳性成年人的依从性降低有关。它们还与 Tat 介导的大脑神经元损伤以及长期使用 HAART 呈正相关。这些趋势强调需要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。随着艾滋病毒患者的老龄化，这一点尤其明显。它本身就是阿尔茨海默病等神经退行性疾病的危险因素。我们的建议通过在转基因β淀粉样蛋白沉积小鼠模型中检查年龄、认知障碍和长期HAART给药对提前大脑老化的协同效应来解决这些趋势。