Effect of buprenorphine on monocytes in the context of neuroAids and opioid abuse

摘要 相当数量的艾滋病毒阳性者是阿片类药物使用者，注射毒品使用者和相关的危险行为 导致新的艾滋病毒感染病例。抗逆转录病毒治疗（cART）改变了主要的 从HIV痴呆到HIV相关神经认知的轻度形式的HIV神经发病机制的表型 疾病（手）。阿片类药物滥用增加了免疫缺陷人群中艾滋病毒脑疾病的严重程度， 在cART治疗下，对轻度HIV脑疾病预期有类似的效果，但尚未完全确定。因为 轻度HAND是一种慢性的、终身的功能障碍，需要治疗来减轻轻度HAND以及 限制阿片类药物对疾病的潜在恶化作用。我们建议进行体外研究， 在HIV诱导HAND的小鼠模型中，以测试我们的新假设，即丁丙诺啡，一种已建立的阿片类药物， 药物，可以起到这样的双重治疗目的。美沙酮和丁丙诺啡用于治疗 阿片成瘾，但丁丙诺啡往往是首选，由于其安全性。丁丙诺啡也不同于 美沙酮，一种完全μ阿片受体（莫尔）激动剂，因为它是莫尔的部分激动剂和MOR的完全拮抗剂。 κ阿片受体（KOR）。一些接受丁丙诺啡治疗的阿片类药物使用者显示认知改善 与美沙酮相比，其改善机制尚不清楚。研究表明， 循环中的CD 14 + CD 16+单核细胞感染了HIV，这表明趋化因子介导的 这些感染和未感染的细胞穿过血脑屏障（BBB）的迁移有助于HAND 通过在大脑中植入艾滋病毒并介导慢性神经炎症。最近的一项临床研究表明， 接受cART治疗的人的CD 14+单核细胞中的HIV DNA负荷预测了他们认知障碍的严重程度， 损伤循环中的白细胞，包括单核细胞，表达阿片受体，我们的初步数据 显示人CD 14 + CD 16+单核细胞表达莫尔和KOR。使用趋化因子CCL 2作为模型， 我们还证明了丁丙诺啡抑制CCL 2诱导的这些细胞与脑细胞的粘附， 微血管内皮细胞以及它们的CCL 2诱导的趋化性。因此，丁丙诺啡抑制重要的 CCL 2的组分介导的CD 14 + CD 16+单核细胞穿过BBB的迁移。在临床前研究中 我们发现丁丙诺啡抑制单核细胞迁移到EcoHIV感染小鼠的脑中。我们也 表明EcoHIV诱导的认知障碍通过丁丙诺啡得到改善。我们的一个主要目标 建议将这两项发现联系起来。我们的总体假设是丁丙诺啡是一种治疗药物， 将通过减少/抑制CCL 2介导的CD 14 + CD 16+单核细胞进入CNS来改善HAND， 有助于改善认知功能，这不仅是因为HIV感染者的神经炎症减少， 受感染的阿片类药物滥用者，但也在非药物滥用的艾滋病毒感染者。

Abstract A significant number of HIV+ people are opiate users, and injection drug use and associated risky behaviors contribute to new cases of HIV infection. Antiretroviral therapy (cART) has changed the predominant phenotype of HIV neuropathogenesis from HIV dementia to milder forms of HIV associated neurocognitive disorders (HAND). Opiate abuse increases the severity of HIV brain disease in immunodeficient people and similar effects are expected, but have not been fully defined, for mild HIV brain disease under cART. Because mild HAND is a chronic, life-long dysfunction, therapies are needed both to mitigate mild HAND as well as to limit the potential exacerbating effects of opiates on the disease. We propose to conduct research in vitro and in a mouse model of HIV induced HAND to test our novel hypothesis that buprenorphine, an established opiate medication, may serve such a dual therapeutic purpose. Methadone and buprenorphine are used to treat opiate addiction, but buprenorphine is often preferred due to its safety profile. Buprenorphine also differs from methadone, a full µ opioid receptor (MOR) agonist, in that it is a partial agonist of MOR and a full antagonist of κ opioid receptors (KOR). Some opioid users treated with buprenorphine show improvement in cognition compared to those on methadone, but the mechanism of improvement is unknown. Studies established that circulating CD14+CD16+ monocytes are infected with HIV and suggested that chemokine mediated transmigration of these infected and uninfected cells across the blood brain barrier (BBB) contributes to HAND through seeding the brain with HIV and mediating chronic neuroinflammation. A recent clinical study showed that the HIV DNA burden in CD14+ monocytes in people on cART predicts severity of their cognitive impairment. Circulating leukocytes, including monocytes, express opioid receptors, and our preliminary data show that human CD14+CD16+ monocytes express MOR and KOR. Using the chemokine CCL2 as a model of inflammation, we also demonstrated that buprenorphine inhibits CCL2-induced adhesion of these cells to brain microvascular endothelium as well as their CCL2-induced chemotaxis. Thus, buprenorphine inhibits important components of CCL2 mediated CD14+CD16+ monocyte transmigration across the BBB. In preclinical studies we showed that buprenophrine inhibits monocyte migration into the brain of EcoHIV infected mice. We also demonstrated that EcoHIV induced cognitive impairment is improved by buprenorphine. A major goal of our proposal is to correlate these 2 findings. Our overall hypothesis is that buprenorphine is a therapeutic that will improve HAND by reducing/inhibiting CCL2 mediated CD14+CD16+ monocyte entry into the CNS, contributing to improved cognitive functions due to decreased neuroinflammation not only in HIV infected opioid abusers, but also in non drug abusing HIV infected people.