Examining the neuropsychiatric effects of HIV-1 integrase inhibitors

摘要 美国大约有 120 万人，全世界大约有 3700 万人感染 HIV-1。在 尽管艾滋病毒/艾滋病研究取得了相当大的进展，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ART在控制病毒和使HIV感染方面非常有效 虽然这是一种可以控制的疾病，但 ART 治疗方案中使用的药物会引起不良副作用。其中应用最为广泛的 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 INSTI 处方与 具有限制治疗的神经精神不良反应。因此，了解驱动机制 INSTI 的神经精神效应对于 ART 的长期成功至关重要。此举的目标 该提案旨在确定 INSTI 相关神经精神不良事件 (NPAE) 的机制。 目前，建议将 INSTI 纳入所有 HIV-1 初始治疗方案中。最 首选抗逆转录病毒药物。目前批准的 INSTI 包括拉替拉韦、埃替拉韦、多替拉韦、比克替拉韦和 卡博特韦。尽管普遍报道其安全有效，但人们越来越担心其不良反应 与 INSTI 相关的代谢和神经精神效应。我们假设 INSTI 相关 NPAE 是由谷氨酸和钙信号的改变驱动的，影响突触功能和 特定脑回路中的神经元通讯。为了测试这一点，我们提出了三个具体目标。在目标 1 中，我们 将 e 阐明 HIV-1 INSTI 对谷氨酸神经传递的影响。在 目标2，我们将破译 的 INSTI 诱导谷氨酸神经传递的机制。在 目标3，我们将探讨艾滋病毒的不利影响- 1 INSTI 对神经精神回路的影响。为了实现这些具体目标，我们开发了一种新颖的 结合了艾滋病毒神经发病机制、神经科学和神经精神病学专业知识的方法 疾病和临床研究。通过这种多学科方法，我们的研究将揭示新的细胞 以及可减少 INSTI 相关神经精神不良反应的生化途径。 艾滋病毒/艾滋病对非裔美国人和其他少数族裔的影响尤为严重。 ART是唯一的治疗方法 减少这种致命疾病造成的过度负担的选项。不幸的是，长期暴露 接受 ART 会导致 HIV-1 阳性个体出现限制治疗的 NPAE。鉴于快速扩张 全球使用 INSTI 来治疗 HIV，了解驱动这些 NPAE 减少的机制至关重要 艾滋病毒/艾滋病的影响尤为严重。因此，我们提出的针对艾滋病毒/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.