Examining the neuropsychiatric effects of HIV-1 integrase inhibitors

摘要 美国约有120万人，全世界约有3700万人感染HIV-1。在 尽管艾滋病研究取得了相当大的进展，但抗逆转录病毒疗法（ART）仍然是唯一的治疗方法 HIV-1感染的选择。虽然ART在控制病毒和使HIV感染方面非常有效， 作为一种可控制的疾病，ART疗法中使用的药物会引起不良副作用。其中最广泛的 处方抗逆转录病毒药物（ARV）是整合酶链转移抑制剂（INSTI），可阻断 HIV-1整合到宿主染色体中。不幸的是，最近的报告表明， 有限制治疗的神经精神副作用因此，了解驱动 INSTI的神经精神作用对于ART的长期成功至关重要。 建议是确定INSTI相关的神经精神不良事件（NPAEs）的机制。 目前，建议将INSTI纳入所有HIV-1治疗的初始方案。最 首选ARV。目前批准的INSTI包括雷特格韦、埃替格韦、度鲁特韦、比替格韦和 卡替拉韦。虽然一般报道是安全有效的，但越来越多的人担心 与INSTI相关的代谢和神经精神影响。我们假设INSTI相关的 NPAEs由谷氨酸和钙信号传导的改变驱动，这些改变影响突触功能， 特定脑回路中的神经元通讯。为了验证这一点，我们提出了三个具体目标。目标1： 将E 阐明HIV-1 INSTIs对谷氨酸神经传递的影响。在 目标2号，我们将破译 的 INSTI诱导的谷氨酸神经传递机制。在 目标3，我们将探讨艾滋病毒的不利影响- 1关于神经精神回路的INSTI。为了实现这些具体目标，我们开发了一种新的 将HIV神经发病机制的专业知识与神经科学和神经精神病学相结合的方法 疾病和临床研究。通过这种多学科的方法，我们的研究将揭示新的细胞 和生物化学途径，可能有针对性地减少INSTI相关的神经精神不良反应。 艾滋病毒/艾滋病严重影响非洲裔美国人和其他少数民族。ART是唯一的治疗方法 这是一个可供选择的办法，以减轻这一致命疾病造成的不成比例的负担。不幸的是，长期接触 抗逆转录病毒疗法的使用会导致HIV-1阳性个体中的治疗限制性NPAEs。鉴于快速扩张的 全球使用INSTI治疗艾滋病毒，关键是要了解驱动这些NPAEs减少的机制 艾滋病毒/艾滋病造成的不成比例的影响。因此，我们建议的研究重点是艾滋病毒/艾滋病， 与RCMI计划的总体目标完全一致。

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.