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.

总结 可卡因的娱乐性使用会导致成瘾，增加获得人类免疫缺陷的风险。 免疫缺陷病毒（艾滋病毒）通过高风险行为，如增加无保护的性活动， 更快地发展成艾滋病。美国120万人口中约33%（US） 艾滋病毒感染者使用非法药物，约十分之一的艾滋病毒新诊断归因于注射 吸毒者每年。接受联合抗逆转录病毒治疗（cART）并维持 低于可检测水平的病毒载量的寿命接近正常。然而，尽管在有效治疗方面取得了进展， 药物，仍然没有药物可以防止病毒入侵中枢神经系统（CNS） 巩固了发展HIV-1相关神经认知障碍（HAND）的风险并未降低。 因此，为了保护慢性感染者免受HIV-1感染对大脑的破坏， 当与物质使用障碍（SUD）结合时，有必要提高对 HIV-1和成瘾的交叉点，以确定新的治疗靶点。 可卡因和HIV蛋白都有助于疾病进展期间的神经元损伤， 大脑中谷氨酸体内平衡失调。据报道，高达19%的星形胶质细胞 严重HAND患者的大脑中存在HIV-1感染。Nef是最早表达的病毒之一， 大约1%的受感染星形胶质细胞中的蛋白质。即使没有可测量的病毒复制， 甚至在接受cART的患者中也会导致持续的神经元变性。细胞外谷氨酸通常 通过谷氨酸转运蛋白（GLT-1）被星形胶质细胞吸收，并通过 胱氨酸/谷氨酸交换器。β -catenin是一种具有双重功能的蛋白质，调节谷氨酸的表达 转运蛋白，防止神经元中过量NMDA受体激活引起的神经毒性。可卡因 下调GLT-1和胱氨酸/谷氨酸交换器。在可卡因暴露戒断期间， AMPA/NMDA比值在丘脑腹外侧核（NAc）中增加。NAc是一个重要的大脑结构， 可卡因成瘾的发展。总体目标是研究HIV-1 Nef和 可卡因与谷氨酸稳态和药物寻求行为有关。核心假设是， 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 神经生理学变化，加强突触传递和加强可卡因寻求行为。 为了解决这个假设，团队将制定以下两个具体目标。目标1：确定影响 HIV-1 Nef和可卡因对多巴胺能神经传递的影响。目标2：确定HIV-1 Nef对 老鼠的可卡因寻找行为结合体内自身给药、电生理学和 利用脑组织的分子研究，该小组将阐明HIV-1 Nef在可卡因寻求和 消费对于开发治疗艾滋病毒和SUD患者的新疗法至关重要。