Examining the neuropsychiatric effects of HIV-1 integrase inhibitors

检查 HIV-1 整合酶抑制剂的神经精神效应

• 批准号: 10707991
• 负责人: Jui Pandhare
• 金额: $ 38.81万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707991
• 关键词: Adverse effects; Adverse event; Affect; African American population; Anti-Retroviral Agents; Biochemical; Biochemical Pathway; Brain; Brain region; Calcium; Calcium Channel; Calcium Signaling; Chromosomes; Clinical; Clinical Research; Cognitive deficits; Communication; DNA Integration; Data; Disease; Drug usage; Electrophysiology (science); Equilibrium; Exposure to; Functional disorder; Genetic; Genetic study; Genome; Glutamate Receptor; Glutamates; Goals; HIV; HIV Infections; HIV-1; HIV-1 integrase; HIV/AIDS; Health Disparities Research; Homeostasis; Individual; Infection; Integrase; Integrase Inhibitors; Knowledge; Length; Measures; Mediating; Metabolic; Minority; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurites; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neurosciences; Nucleus Accumbens; Pathway interactions; Persons; Pharmacology Study; Play; Production; Recommendation; Regimen; Reporting; Research; Role; Signal Transduction; Synapses; Testing; Up-Regulation; Virus; antiretroviral therapy; clinically relevant; effective therapy; excitotoxicity; extracellular; glutamatergic signaling; in vivo; inhibitor; interdisciplinary approach; medical schools; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; novel strategies; postsynaptic; presynaptic; prevent; programs; response; reward circuitry; side effect; success; synaptic function; viral DNA; voltage; Adverse effects; Adverse event; Affect; African American population; Anti-Retroviral Agents; Biochemical; Biochemical Pathway; Brain; Brain region; Calcium; Calcium Channel; Calcium Signaling; Chromosomes; Clinical; Clinical Research; Cognitive deficits; Communication; DNA Integration; Data; Disease; Drug usage; Electrophysiology (science); Equilibrium; Exposure to; Functional disorder; Genetic; Genetic study; Genome; Glutamate Receptor; Glutamates; Goals; HIV; HIV Infections; HIV-1; HIV-1 integrase; HIV/AIDS; Health Disparities Research; Homeostasis; Individual; Infection; Integrase; Integrase Inhibitors; Knowledge; Length; Measures; Mediating; Metabolic; Minority; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurites; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neurosciences; Nucleus Accumbens; Pathway interactions; Persons; Pharmacology Study; Play; Production; Recommendation; Regimen; Reporting; Research; Role; Signal Transduction; Synapses; Testing; Up-Regulation; Virus; antiretroviral therapy; clinically relevant; effective therapy; excitotoxicity; extracellular; glutamatergic signaling; in vivo; inhibitor; interdisciplinary approach; medical schools; neuropsychiatric disorder; neuropsychiatry; neurotransmission; novel; novel strategies; postsynaptic; presynaptic; prevent; programs; response; reward circuitry; side effect; success; synaptic function; viral DNA; voltage

ABSTRACT Approximately 1.2 million people in the US and ~ 37 million people worldwide are living with HIV-1. In spite of considerable progress in HIV/AIDS research, anti-retroviral therapy (ART) remains the only treatment option for HIV-1 infection. While ART has been highly effective in controlling the virus and making HIV infection a manageable disease, the drugs used in the ART regimens cause adverse side effects. Among the most widely prescribed antiretrovirals (ARVs) are integrase strand transfer inhibitors (INSTIs) which block the critical step of HIV-1 integration into host chromosomes. Unfortunately, recent reports suggest association of INSTI prescription with treatment-limiting neuropsychiatric adverse effects. Therefore, understanding the mechanisms that drive neuropsychiatric effects of INSTIs are critically important for the long-term success of ART. The goal of this proposal is to identify the mechanisms of INSTI-associated neuropsychiatric adverse events (NPAEs). Currently, it is recommended that INSTIs be included in all initial regimens for HIV-1 treatment. the most preferred ARVs. Currently approved INSTIs include raltegravir, elvitegravir, dolutegravir, bictegravir, and cabotegravir. Although generally reported to be safe and effective there is a growing concern about the adverse metabolic and neuropsychiatric effects associated with the INSTIs. We hypothesize that that INSTI-associated NPAEs are driven by alterations in glutamate and calcium signaling that affect synaptic function and neuronal communication in specific brain circuits. To test this, we propose three specific aims. In Aim 1, we will e lucidate the effects of HIV-1 INSTIs on glutamate neurotransmission. In Aim 2, we will decipher the mechanism of INSTI-induced glutamate neurotransmission. In Aim 3, we will probe the adverse effects of HIV- 1 INSTIs on neuropsychiatric circuitry. To achieve the goals of these specific aims, we have developed a novel approach that combines the expertise in HIV neuropathogenesis, to that of neuroscience and neuropsychiatric disorders and clinical research. Through this multidisciplinary approach, our studies will uncover novel cellular and biochemical pathways that may be targeted to reduce INSTI-associated neuropsychiatric adverse effects. HIV/AIDS disproportionally affects African-Americans and other minorities. ART is the only treatment option available to reduce the disproportionate burden of this deadly disease. Unfortunately, long-term exposure to ART contributes to treatment-limiting NPAEs among HIV-1 positive individuals. Given the rapidly expanding global use of INSTIs to treat HIV, it is critical to understand the mechanisms that drive these NPAEs to reduce the disproportionate impact of HIV/AIDS. Therefore, our proposed studies focused on HIV/AIDS are perfectly aligned with the overall goals of the RCMI program.

抽象的 在美国，大约有120万人和全世界约3700万人患有HIV-1。在 艾滋病毒/艾滋病研究取得了很大进展，抗逆转录病毒疗法（ART）仍然是唯一的治疗方法 HIV-1感染的选择。虽然艺术在控制病毒并引起艾滋病毒感染方面非常有效 一种可管理的疾病，在艺术方案中使用的药物会导致不良副作用。最广泛的 规定的抗逆转录病毒（ARV）是整合酶链转移抑制剂（Instis），它阻止了临界步骤 HIV-1整合到宿主染色体中。不幸的是，最近的报告表明Insti处方协会 与限制治疗的神经精神不良反应。因此，了解驱动的机制 研究所的神经精神效应对于艺术的长期成功至关重要。目标的目标 提案是确定Insti相关神经精神不良事件（NPAE）的机制。 目前，建议将研究所包括在HIV-1治疗的所有初始方案中。最多 首选ARV。目前批准的Instis包括Raltegravir，Elvitegravir，Dolutegravir，Bictegravir和 cabotegravir。尽管通常据报道是安全有效的，但对不利的人越来越关注 与该研究所相关的代谢和神经精神效应。我们假设该Insti相关 NPAE是由影响突触功能和的钙信号传导的改变驱动的 特定脑电路中的神经元通信。为了测试这一点，我们提出了三个具体目标。在AIM 1中，我们 会e Lucation HIV-1 Instis对谷氨酸神经传递的影响。在 目标2，我们将破译 这 Insti诱导的谷氨酸神经传递的机理。在 AIM 3，我们将探测HIV的不利影响 1关于神经精神病学回路的研究。为了实现这些特定目标的目标，我们开发了一本小说 结合了HIV神经病发生的专业知识，神经科学和神经精神病学的专业知识 疾病和临床研究。通过这种多学科方法，我们的研究将发现新颖的细胞 和生化途径可能旨在减少与Insti-Inti-Sphicalssychiatric不良反应。 艾滋病毒/艾滋病对非裔美国人和其他少数民族的影响不成比例。艺术是唯一的治疗方法 可用于减轻这种致命疾病的负担不成比例的负担。不幸的是，长期接触 艺术有助于HIV-1阳性个体中的治疗限制性NPAE。考虑到快速扩张 全球使用Intists治疗艾滋病毒，了解驱动这些NPAE的机制至关重要 艾滋病毒/艾滋病的不成比例影响。因此，我们针对艾滋病毒/艾滋病的拟议研究是 与RCMI计划的整体目标完全一致。