Maternal HIV: Developmental Neurotoxicity

孕产妇艾滋病毒：发育神经毒性

• 批准号: 6667903
• 负责人: Charles F. Mactutus
• 金额: $ 31.71万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667903
• 关键词: AIDS dementia complex; HIV envelope protein gp120; HIV infections; age difference; catecholamines; cognition disorders; developmental neurobiology; disease /disorder model; embryo /fetus toxicology; laboratory rat; neuroanatomy; neuropathology; neuropsychology; neurotoxicology; neurotoxins; pathologic process; perinatal; transcription factor; vertical transmission; virus protein

DESCRIPTION (provided by applicant): Vertical transmission (Mother to child) is the primary mode of HIV-1 infection among young children worldwide, resulting in at least 1700 new infections each day or more than one pediatric infection every minute (UNAIDS/WHO, 1999; 2001). Viral products released by HIV-infected cells cause widespread metabolic derangement as evident in neuronal dysfunction, disruption of neuro-glial relationships, and immune dysregulation, all of which ultimately cause cerebral dysfunction and precipitate the development of HIV dementia. It has been well established that specific proteins encoded by the HIV genome, e.g., Tat and gp120, 1) are neurotoxic, 2) are elevated in brain tissue of patients with HIV dementia, and 3) when presented to the brain in vivo, both proteins cause histological changes that are consistent with those seen in patients with HIV dementia. These data suggest that clinically relevant studies of HIV neuropathogenesis may now be performed in a rodent model. One notable advantage of directly studying the virotoxins is that neuropathogenesis may be studied independent of the virus per se and the complications of secondary infections. The proposed program specifically addresses the major question: What are the neurodevelopmental effects of the HIV proteins Tat and gp120 and how are these effects mediated? Our hypothesis is that: Neonatal exposure to the HIV proteins, Tat and gp120, will produce specific neurodevelopmental disruptions in cognitive processes and that these disruptions will be evident in central catecholamine systems and attributable to interference of key developmental processes. Using a virotoxin exposure model (HIV proteins Tat/gp120) our programmatic studies will determine the adverse effects of these proteins on the developing central nervous system of perinatal animals. Several very important pieces of information will be provided. First, we will identify dose-response functions for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Second, we will identify the potential critical periods responsible for the adverse neurobehavioral and neuroanatomical effects of perinatal HIV protein neurotoxicity. Third, these deleterious effects will be identified independent from those of secondary infections, polydrug and/or nutritional interactions that characterize the clinical HIV/AIDS populations. Thus, this project will: A) contribute to our understanding of Tat/gp120 in a clinically relevant rodent model, B) further provide a comprehensive examination of potential catecholamine targets responsible for early developmental disorders independent of secondary opportunistic infections, and C) provide the foundation for an examination of these very same potential mechanisms for HIV protein neurotoxicity in humans with the use of fetal autopsy tissue.

描述（由申请人提供）：垂直传播（母婴）是全世界幼儿感染 HIV-1 的主要方式，每天导致至少 1700 例新感染或每分钟超过 1 例儿科感染（UNAIDS/WHO， 1999；2001）。 HIV感染细胞释放的病毒产物引起广泛的代谢紊乱，明显表现为神经元功能障碍、神经胶质关系破坏和免疫失调，所有这些最终导致脑功能障碍并加速HIV痴呆的发展。众所周知，HIV 基因组编码的特定蛋白质，例如 Tat 和 gp120，1) 具有神经毒性，2) 在 HIV 痴呆患者的脑组织中含量升高，3) 当在体内呈现到大脑时，两者都具有神经毒性。蛋白质引起的组织学变化与艾滋病痴呆患者中观察到的变化一致。这些数据表明，HIV 神经发病机制的临床相关研究现在可以在啮齿动物模型中进行。直接研究病毒毒素的一个显着优点是可以独立于病毒本身和继发感染的并发症来研究神经发病机制。拟议的计划具体解决了以下主要问题：HIV 蛋白 Tat 和 gp120 对神经发育的影响是什么？这些影响是如何介导的？我们的假设是：新生儿接触 HIV 蛋白 Tat 和 gp120 会在认知过程中产生特定的神经发育干扰，并且这些干扰在中枢儿茶酚胺系统中很明显，并且可归因于关键发育过程的干扰。使用病毒毒素暴露模型（HIV 蛋白 Tat/gp120），我们的计划研究将确定这些蛋白质对围产期动物发育中的中枢神经系统的不利影响。将提供几条非常重要的信息。首先，我们将确定围产期 HIV 蛋白神经毒性的不良神经行为和神经解剖学影响的剂量反应函数。其次，我们将确定导致围产期 HIV 蛋白神经毒性的不良神经行为和神经解剖学影响的潜在关键时期。第三，这些有害影响将独立于继发感染、多种药物和/或营养相互作用而被识别，这些是临床艾滋病毒/艾滋病人群的特征。因此，该项目将：A) 有助于我们对临床相关啮齿动物模型中 Tat/gp120 的理解，B) 进一步对导致独立于继发性机会性感染的早期发育障碍的潜在儿茶酚胺靶标进行全面检查，C) 提供为使用胎儿尸检组织检查人类 HIV 蛋白神经毒性的这些完全相同的潜在机制奠定了基础。