Astrocytic HIV Nef causes learning impairment via inflammation and TGF signaling

星形细胞 HIV Nef 通过炎症和 TGF 信号传导导致学习障碍

• 批准号: 9115660
• 负责人: Richard J. Noel
• 金额: $ 11.19万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115660
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affect; Age; Animals; Anti-Retroviral Agents; Apoptosis; Astrocytes; Autologous; Biological; Blood - brain barrier anatomy; Brain; CCL2 gene; Cell Line; Cells; Cessation of life; Characteristics; Chronic Disease; Clinical; Clinical Management; Complement; Cytokine Signaling; Data; Development; Epidemic; Event; Foundations; Future; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; Immune; Impairment; In Vitro; Infection; Infection prevention; Infiltration; Inflammation; Learning; Life; Life Expectancy; Longevity; Mediating; Modeling; Mononuclear; Morbidity - disease rate; Nature; Neurocognitive; Neurologic; Neurotoxins; Outcome; Pathology; Patients; Performance; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Population; Positioning Attribute; Prevalence; Process; Production; Productivity; Publishing; Rattus; Recurrence; Role; Series; Signal Pathway; Signal Transduction; Source; Testing; Time; Translating; Viral; Viral Load result; Virus Replication; Work; antiretroviral therapy; base; cell motility; cell type; cytokine; design; frontier; in vivo; latent infection; macrophage; migration; monocyte; nef Protein; neuron apoptosis; neuron loss; neuropathology; neuropsychological; neurotoxicity; novel therapeutics; prevent; public health relevance; research study; success; treatment strategy

DESCRIPTION (provided by applicant): This proposal addresses a vital question of increasing relevance for the US HIV/AIDS epidemic: How does HIV Nef cause neuropathology and learning impairment? The success of combined antiretroviral therapy (cART) has greatly increased the life expectancy after infection by preventing progression to AIDS. This advance has resulted in greater emphasis on managing remaining morbidities. Even as clinical management of HIV replication has resulted in control of viral replication to below detectable levels, HIV associated neurocognitive disorders (HAND) appear with increasing prevalence. Several lines of evidence point toward production of HIV neurotoxins, rather than viral replication, as the cause of this progression. We developed a model of Nef neuropathology in rats that mimics the neuropathology that remains in the setting of viral control by cART. Nef is a known HIV neurotoxin that is produced by astrocytes even in the absence of viral replication. We found that rats infused into the hippocampus with autologous astrocytes modified to produce Nef showed inflammation, neuronal loss, and learning impairment. Our preliminary studies led us to propose a hypothesis that Nef drives inflammation leading to neuronal apoptosis and learning impairment. Our data suggest roles for TGF signaling and CCL2 in this pathology. We will address the hypothesis in two aims. The first will focus on identifying the mechanism and extent of neuron loss in relation to the degree of learning impairment in our model. A major focus of the studies in this aim is to identify the cause and effect relationships that produce the outcomes in the model we have already identified. The second aim will investigate the mechanistic role for TGF signaling in the inflammation and neurotoxicity caused by astrocyte expression of Nef. This aim will be accomplished through a series of in vitro experiments with primary cells and cell lines to probe the requirement of TGF signaling in Nef neurotoxicity. The outcomes of this proposal will move us forward in understanding the mechanism of Nef neurotoxicity and learning impairment. Completion of these studies is expected to identify biological targets for development of future treatments to address the next frontier in HIV clinical management. Now that suppression of replication has changed HIV infection to a chronic illness rather than a sentence of certain death, the changing nature and duration of morbidities like HAND require novel therapies where none currently exist.

描述（由申请人提供）：该提案解决了与美国艾滋病毒/艾滋病流行日益相关的一个重要问题：HIV Nef 如何导致神经病理学和学习障碍？联合抗逆转录病毒疗法 (cART) 的成功通过防止进展为艾滋病，大大延长了感染后的预期寿命。这一进步使得人们更加重视管理剩余的发病率。尽管 HIV 复制的临床管理已将病毒复制控制在可检测水平以下，但 HIV 相关神经认知障碍 (HAND) 的患病率仍在不断增加。一些证据表明，艾滋病毒神经毒素的产生，而不是病毒复制，是这种进展的原因。我们在大鼠中开发了一种 Nef 神经病理学模型，该模型模拟了 cART 病毒控制环境中保留的神经病理学。 Nef 是一种已知的 HIV 神经毒素，即使在没有病毒复制的情况下也会由星形胶质细胞产生。我们发现，将经过修饰以产生 Nef 的自体星形胶质细胞注入海马体的大鼠表现出炎症、神经元损失和学习障碍。我们的初步研究使我们提出了一个假设，即 Nef 会引发炎症，从而导致神经元凋亡和学习障碍。我们的数据表明 TGF 信号传导和 CCL2 在这种病理学中的作用。我们将通过两个目标来解决这个假设。第一个重点是确定模型中神经元损失与学习障碍程度相关的机制和程度。该研究的一个主要重点是确定在我们已经确定的模型中产生结果的因果关系。第二个目标是研究 TGF 信号传导在星形胶质细胞表达 Nef 引起的炎症和神经毒性中的机制作用。这一目标将通过一系列原代细胞和细胞系的体外实验来实现，以探讨 Nef 神经毒性中 TGF 信号传导的需要。该提案的结果将推动我们进一步了解 Nef 神经毒性和学习障碍的机制。这些研究的完成预计将确定未来治疗方法开发的生物学目标，以解决艾滋病毒临床管理的下一个前沿问题。现在，抑制复制已将 HIV 感染转变为一种慢性疾病，而不是被判死刑，像 HAND 这样的疾病性质和持续时间的变化需要新的治疗方法，而目前尚不存在这种治疗方法。