Examining the neuropsychiatric effects of HIV-1 integrase inhibitors

摘要 美国约有120万人感染HIV-1，全球约有3700万人感染。在……里面 尽管艾滋病毒/艾滋病研究取得了长足的进步，但抗逆转录病毒疗法仍然是唯一的治疗方法。 HIV-1感染的选择。虽然抗逆转录病毒疗法在控制病毒和使艾滋病毒感染方面非常有效 作为一种可控制的疾病，ART方案中使用的药物会产生不良副作用。其中最广泛的 处方的抗逆转录病毒药物(ARV)是整合酶链转移抑制剂(INSTI)，它可以阻断关键的 HIV-1整合到宿主染色体中。不幸的是，最近的报告表明INSTI处方与 有治疗限制的神经精神不良反应。因此，理解驱动机制 INSTI的神经精神效应对于ART的长期成功至关重要。这样做的目的是 建议确定INSTI相关神经精神不良事件(NPAE)的机制。 目前，建议将INSTI纳入艾滋病毒-1治疗的所有初始方案。最多的 首选抗逆转录病毒药物。目前批准的INSTI包括raltegravir、elvitegravir、dolutegravir、bitegravir和 卡波特格列韦。虽然普遍报道是安全有效的，但人们越来越担心 与INSTI相关的代谢和神经精神影响。我们假设与INSTI相关的 NPAE是由谷氨酸和钙信号的变化驱动的，这些信号影响突触功能和 特定大脑回路中的神经元交流。为了检验这一点，我们提出了三个具体目标。在目标1中，我们 会不会 阐明HIV-1INSTIs对谷氨酸神经传递的影响。在……里面 目标2，我们将破译 这个 INSTI诱导谷氨酸神经传递的机制。在……里面 目标3，我们将探讨艾滋病毒的不良影响- 1个关于神经精神回路的INSTI。为了实现这些特定目标的目标，我们开发了一种小说 将艾滋病毒神经发病机制的专业知识与神经科学和神经精神病学的专业知识相结合的方法 精神障碍和临床研究。通过这种多学科的方法，我们的研究将发现新的细胞 以及可能针对减少INSTI相关神经精神不良影响的生化途径。 艾滋病毒/艾滋病对非裔美国人和其他少数群体的影响不成比例。ART是唯一的治疗方法 可供选择，以减轻这一致命疾病不成比例的负担。不幸的是，长期接触 抗逆转录病毒治疗有助于限制HIV-1阳性患者的治疗。考虑到快速扩张的 全球使用INSTI治疗艾滋病毒，关键是要了解推动这些NPAE减少的机制 艾滋病毒/艾滋病的不成比例的影响。因此，我们建议的关于艾滋病毒/艾滋病的研究是 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.