Interaction of HIV-1 Nef and glutamate homeostasis in the nucleus accumbens during cocaine addiction

可卡因成瘾期间伏隔核中 HIV-1 Nef 和谷氨酸稳态的相互作用

• 批准号: 10483802
• 负责人: Jessalyn Gabrielle Pla Tenorio
• 金额: $ 3.76万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483802
• 关键词: Acquired Immunodeficiency Syndrome; Address; Astrocytes; Behavior; Behavioral Model; Brain; Chronic; Cocaine; Cocaine Dependence; Cocaine Users; Cocaine withdrawal; Consumption; Corpus striatum structure; Cysteine; Cystine; Data; Development; Disease Progression; Down-Regulation; Drug Addiction; Drug usage; Electrophysiology (science); Equilibrium; Extinction (Psychology); Glial Fibrillary Acidic Protein; Glutamate Transporter; Glutamates; HIV; HIV Infections; HIV diagnosis; HIV-1; HIV-associated neurocognitive disorder; Health; Homeostasis; Human; Illicit Drugs; Infection; Inflammation; Injecting drug user; Knowledge; Lead; Longevity; Measurable; Measures; Mediating; Mission; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; National Institute of Drug Abuse; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Neuropathogenesis; Neurotoxins; Neurotransmitters; Nucleus Accumbens; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Play; Primary Cell Cultures; Production; Proteins; Public Health; Rattus; Receptor Activation; Research; Rewards; Risk; Risk Factors; Role; Science; Self Administration; Sex Behavior; Slice; Sprague-Dawley Rats; Structure; Substance Use Disorder; Synaptic Transmission; United States; United States National Institutes of Health; Viral; Viral Load result; Viral Proteins; Virus Replication; Work; addiction; antiretroviral therapy; base; beta catenin; brain tissue; cell type; cocaine exposure; cocaine self-administration; cocaine use; comorbidity; drug seeking behavior; extracellular; high risk behavior; illicit drug use; improved; in vivo; innovation; insight; nef Protein; neuroinflammation; neurophysiology; neurotoxic; neurotoxicity; neurotransmission; new therapeutic target; novel; novel therapeutics; prevent; protein function; transmission process

Summary The recreational use of cocaine can lead to an addiction that increases the risk of acquiring the human immunodeficiency virus (HIV) through high-risk behaviors such as an increase in unprotected sexual activity, and a more rapid progression to AIDS. Approximately 33% of the 1.2 million people in the United States (US) living with HIV use illicit substances, and approximately 1 in 10 new HIV diagnoses are attributed to injection drug users every year. People living with HIV who take combination antiretroviral therapy (cART) and maintain viral loads below detectable levels live a near-normal lifespan. However, despite the advances in efficacious medication, there are still no medications that prevent the viral invasion to the central nervous system (CNS) solidifying that the risk of developing HIV-1 associated neurocognitive disorders (HAND) has not decreased. Therefore, to protect chronically infected people from the ravages of HIV-1 infection in the brain, particularly when combined with substance use disorder (SUD), it is necessary to advance the understanding of the intersection of HIV-1 and addiction to identify novel therapeutic targets. Both cocaine and HIV proteins contribute to neuronal damage during disease progression through dysregulation of glutamate homeostasis in the brain. It has been documented that as high as 19% of astrocytes in the brains of patients with severe HAND are infected with HIV-1. Nef is one of the earliest expressed viral proteins in approximately 1% of infected astrocytes. Even without measurable viral replication, Nef could contribute to continued neuronal degeneration even in patients on cART. Extracellular glutamate is normally taken up by astrocytes through a glutamate transporter (GLT-1) and exchanged for cysteine through the cystine/glutamate exchanger. β -catenin, a dual function protein, regulates the expression of glutamate transporters preventing neurotoxicity caused by excess NMDA receptor activation in neurons. However, cocaine downregulates GLT-1 and the cystine/glutamate exchanger. During withdrawal of cocaine exposure, the AMPA/NMDA ratio increases in the nucleus accumbens (NAc). The NAc is an important brain structure involved in the development of cocaine addiction. The overall objective is to study the interaction between HIV-1 Nef and cocaine related to glutamate homeostasis and drug-seeking behavior. The central hypothesis is that combined cocaine exposure and astrocytic Nef expression will exacerbate glutamate excitation inducing neurophysiological changes that strengthen synaptic transmission and reinforce the cocaine-seeking behavior. To address this hypothesis, the team will develop the following two Specific Aims. Aim 1: Determine the impact of HIV-1 Nef and cocaine on glutamatergic neurotransmission. Aim 2: Determine the impact of HIV-1 Nef on cocaine-seeking behavior in rats. With the combination of in vivo self-administration, electrophysiology, and molecular studies using brain tissue, the team will elucidate the role of HIV-1 Nef on cocaine-seeking and consumption essential to developing new therapies to treat people with HIV and SUD.

摘要 娱乐性使用可卡因会导致上瘾，增加感染人类的风险 免疫缺陷病毒(HIV)通过高危行为，如无保护措施的性行为增加， 以及更快地发展为艾滋病。美国120万人口中约33%的人 艾滋病毒携带者使用非法物质，大约十分之一的新艾滋病毒诊断是由于注射 每年都有吸毒者。接受联合抗逆转录病毒治疗(CART)并保持 病毒载量低于可检测水平的寿命接近正常。然而，尽管在有效治疗方面取得了进展 药物治疗，目前还没有阻止病毒入侵中枢神经系统(CNS)的药物 巩固了罹患HIV-1相关神经认知障碍(HAND)的风险并未降低。 因此，要保护慢性感染者免受艾滋病毒-1感染在大脑中的蹂躏，特别是 当与物质使用障碍(SUD)相结合时，有必要提高对 HIV-1和成瘾的交集以确定新的治疗靶点。 可卡因和HIV蛋白都通过以下途径在疾病发展过程中促进神经元损伤 大脑中谷氨酸平衡失调。据记载，高达19%的星形胶质细胞 在严重手部的患者大脑中都感染了HIV-1。NEF是最早表达的病毒之一 大约1%受感染的星形胶质细胞中的蛋白质。即使没有可测量的病毒复制，Nef也可能 即使在服用CART的患者中，也会导致持续的神经元变性。胞外谷氨酸通常 由星形胶质细胞通过谷氨酸转运体(GLT-1)摄取，并通过 胱氨酸/谷氨酸交换。β-连环蛋白是一种双功能蛋白，调节谷氨酸的表达 转运体防止神经元中过度激活NMDA受体引起的神经毒性。然而，可卡因 下调GLT-1和半胱氨酸/谷氨酸交换。在戒除可卡因暴露期间， 伏核(NAC)内AMPA/NMDA比值升高。NAC是一个重要的脑结构参与 在可卡因成瘾的发展过程中。总体目标是研究HIV-1 Nef和Nef之间的相互作用 可卡因与谷氨酸稳态和寻药行为有关。中心假设是结合在一起 可卡因暴露和星形胶质细胞Nef表达将加剧谷氨酸兴奋诱导 神经生理学改变，加强突触传递和加强寻求可卡因的行为。 为了解决这一假设，该团队将制定以下两个具体目标。目标1：确定影响 HIV-1 Nef和可卡因对谷氨酸能神经传递的影响。目标2：确定HIV-1 Nef对 大鼠的可卡因寻觅行为。结合体内自我给药、电生理学和 利用脑组织进行的分子研究，该团队将阐明HIV-1 Nef在可卡因寻求和 消费对于开发新疗法来治疗艾滋病毒携带者和流行性出血热患者至关重要。