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

神经辅助药物和阿片类药物滥用中丁丙诺啡对单核细胞的影响

• 批准号: 10618101
• 负责人: Joan Weinberger Berman
• 金额: $ 78.57万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618101
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Affect; Age; Agonist; Animal Model; Biology; Blood; Blood - brain barrier anatomy; Brain; Buprenorphine; CCL2 gene; CD14 gene; Cells; Central Nervous System Diseases; Chronic; Communicable Diseases; DNA; Data; Dementia; Development; Disease; FCGR3B gene; Funding; Generations; HIV; HIV Infections; HIV therapy; Human; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Laboratories; Lead; Life; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Methadone; Modeling; Mus; Myeloid Cells; Neurocognitive Deficit; Neuropathogenesis; Neuropsychology; Neurovirology; New York City; Opioid; Opioid Antagonist; Opioid Receptor; Opioid replacement therapy; Outcome; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Physicians; Pre-Clinical Model; Process; Property; Quality of life; Research; Role; Safety; Scientist; Severities; Signal Transduction; Specialist; Synapses; Therapeutic; Time; Viral; Viral Load result; Withdrawal; addiction; antagonist; antiretroviral therapy; buprenorphine treatment; chemokine; cognitive function; cognitive testing; comorbidity; experience; improved; in vivo; innovation; kappa opioid receptors; macrophage; migration; monocyte; mortality risk; mouse model; mu opioid receptors; neuroAIDS; neuroinflammation; neurotoxic; novel; opioid abuse; opioid agonist therapy; opioid epidemic; opioid use disorder; overdose risk; peripheral blood; prescription opioid; prevent; receptor; response; side effect

The HIV and opioid epidemics intersect, impacting millions of people worldwide. Antiretroviral therapy (ART) has improved and extended the lives of people with HIV, PWH. However, milder chronic HIV associated neurocognitive impairments known as mild HAND or HIV-NCI persist. HIV-NCI affect 15-40% of PWH and because they persist for life, worsen with age, and affect adherence to medications, they can significantly reduce quality of life and increase mortality risk. Many PWH have opioid use disorder, OUD, a comorbidity in PWH that can exacerbate HIV-NCI. Our novel findings in the first funding cycle demonstrate that buprenorphine, a well-established opioid agonist therapy used to treat OUD, may also be a therapy for NCI. Buprenorphine acts as a partial agonist to the mu opioid receptor (MOR) and full antagonist to the kappa opioid receptor (KOR) and according to some studies, it may improve neuropsychological outcomes in people with OUD with or without chronic HIV infection. Our studies suggest that this beneficial activity of buprenorphine may due to its interactions with peripheral blood CD14+CD16+ monocytes, which we showed express MOR and KOR, are preferentially infected with HIV, and have a selective advantage to cross the blood brain barrier (BBB) in response to CCL2 in vitro. This increased transmigration is reduced by buprenorphine, in part by its ability to limit CCL2/CCR2 signaling. Our novel findings in EcoHIV infected mice with HIV-NCI demonstrate that buprenorphine treatment can reverse HIV-NCI in these mice in correlation with a decrease in inflammatory monocytes in their brains, reduction in HIV brain burden, and a reduction in dendritic pruning, a marker of HIV mediated NCI. We hypothesize that buprenorphine mitigates HIV neuropathogenesis and can treat HIV-NCI in PWH with and without OUD. We also propose that this is mediated through its activity on the Mu and Kappa opioid receptors. Our studies will also identify receptor(s) by which buprenorphine is exerting its mechanism of action and will enable the development of second-generation therapies derived from buprenorphine that specifically target these receptor(s). In Aim1, we will characterize in vitro mechanisms of buprenorphine mediated inhibition of CD14+CD16+ monocyte transmigration across the BBB and characterize the role of MOR and KOR in these processes. In Aim 2, we will use genetically modified mice to address individual and combined roles of MOR and KOR in buprenorphine therapy in the preclinical model of EcoHIV driven HIV-NCI and the importance of these receptors specifically on myeloid cells in NCI development. In Aim 3, we will characterize transmigration across a BBB model of mature human monocytes using PBMC from PWH on buprenorphine and correlate this with the PWH's cognitive functions. These will provide further support for use of buprenorphine as a therapy for HIV-NCI in PWH with and without OUD. The studies will be performed by a highly interactive group of HIV scientists, animal model specialists, and infectious diseases, HIV, and OUD physician scientists, and a neuropscychologist, all recognized experts in CNS disease.

艾滋病毒和阿片类药物流行病相互交叉，影响着全世界数百万人。抗逆转录病毒治疗（ART） 改善并延长了艾滋病毒感染者和艾滋病毒感染者的生命。然而，较轻微的慢性 HIV 相关 被称为轻度 HAND 或 HIV-NCI 的神经认知障碍持续存在。 HIV-NCI 影响 15-40% 的感染者和 因为它们会终生持续存在，随着年龄的增长而恶化，并影响药物的依从性，因此它们可以显着 降低生活质量并增加死亡风险。许多感染者患有阿片类药物使用障碍 (OUD)，这是一种合并症 艾滋病毒感染者 (PWH) 可能会加剧 HIV-NCI。我们在第一个融资周期中的新发现表明，丁丙诺啡， 用于治疗 OUD 的成熟阿片类激动剂疗法也可能是 NCI 的一种疗法。丁丙诺啡 作为 mu 阿片受体 (MOR) 的部分激动剂和 kappa 阿片受体 (KOR) 的完全拮抗剂 根据一些研究，它可以改善患有或不患有 OUD 的人的神经心理学结果 慢性艾滋病毒感染。我们的研究表明，丁丙诺啡的这种有益活性可能是由于其 与外周血 CD14+CD16+ 单核细胞的相互作用，我们显示其表达 MOR 和 KOR， 优先感染艾滋病毒，并有选择性优势穿过血脑屏障（BBB）以应对 CCL2 体外。丁丙诺啡可以减少这种增加的迁移，部分原因是它能够限制 CCL2/CCR2 信号传导。我们在感染了 HIV-NCI 的 EcoHIV 小鼠中的新发现表明： 丁丙诺啡治疗可以逆转这些小鼠的 HIV-NCI，并与炎症减少相关 大脑中的单核细胞减少，艾滋病毒大脑负担减少，树突修剪减少，这是艾滋病毒的标志 介导的 NCI。我们假设丁丙诺啡可以减轻 HIV 神经发病机制并可以治疗 HIV-NCI 带和不带 OUD 的 PWH。我们还认为这是通过其对 Mu 和 Kappa 的活动来调节的 阿片受体。我们的研究还将确定丁丙诺啡发挥其机制的受体 行动并将促进源自丁丙诺啡的第二代疗法的开发 专门针对这些受体。在 Aim1 中，我们将描述丁丙诺啡的体外机制 介导的 CD14+CD16+ 单核细胞跨 BBB 迁移的抑制并表征 MOR 的作用 以及这些流程中的 KOR。在目标 2 中，我们将使用转基因小鼠来解决个体和组合问题 EcoHIV 驱动的 HIV-NCI 临床前模型中 MOR 和 KOR 在丁丙诺啡治疗中的作用以及 这些受体在 NCI 发展中对骨髓细胞的重要性。在目标 3 中，我们将描述 使用来自 PWH 的 PBMC，使用丁丙诺啡在成熟人单核细胞的 BBB 模型中进行轮回 并将其与感染者的认知功能联系起来。这些将为使用提供进一步的支持 丁丙诺啡在有或没有 OUD 的情况下作为艾滋病毒感染者 (HIV-NCI) 的治疗方法。这些研究将由 由艾滋病毒科学家、动物模型专家以及传染病、艾滋病毒和 OUD 组成的高度互动的小组 医学科学家和神经心理学家，都是公认的中枢神经系统疾病专家。