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

艾滋病毒和阿片类药物的流行相互交织，影响着全世界数百万人。抗逆转录病毒疗法 改善和延长了艾滋病毒感染者的生命。然而，较轻的慢性艾滋病毒相关 被称为轻度HAND或HIV-NCI的神经认知障碍持续存在。艾滋病毒-非传染性疾病影响15-40%的威尔斯亲王医院， 因为它们持续终生，随着年龄的增长而恶化，并影响药物的依从性，它们可以显著地 降低生活质量并增加死亡风险。许多PWH有阿片类药物使用障碍，OUD，一种合并症， PWH可加重HIV-NCI。我们在第一个资金周期的新发现表明，丁丙诺啡， 用于治疗OUD的成熟的阿片样物质激动剂疗法也可以是用于NCI的疗法。丁丙 作为μ阿片受体（莫尔）的部分激动剂和κ阿片受体（KOR）的完全拮抗剂 根据一些研究，它可以改善OUD患者的神经心理学结果， 慢性HIV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CD 14 + CD 16+单核细胞的相互作用，我们显示表达莫尔和KOR， 优先感染HIV，并具有选择性优势，可以通过血脑屏障（BBB）， 体外CCL 2。丁丙诺啡减少了这种增加的迁移，部分原因是它能够限制 CCL 2/CCR 2信号传导。我们在EcoHIV感染的HIV-NCI小鼠中的新发现表明， 丁丙诺啡治疗可以逆转这些小鼠中的HIV-NCI，与炎症反应的减少相关。 单核细胞在他们的大脑中，减少艾滋病毒的大脑负担，并减少树突修剪，艾滋病毒的标志物 介导的NCI。我们假设丁丙诺啡减轻了HIV的神经发病机制，可以治疗HIV-NCI， PWH有和没有OUD。我们还提出，这是通过其对Mu和Kappa的活动介导的 阿片受体我们的研究还将确定丁丙诺啡发挥其作用机制的受体。 行动，并将使开发第二代疗法，从丁丙诺啡， 特异性靶向这些受体。在目标1中，我们将描述丁丙诺啡的体外机制 介导的抑制CD 14 + CD 16+单核细胞穿过BBB的迁移，并表征莫尔的作用 和KOR在这些过程中。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。 在EcoHIV驱动的HIV-NCI临床前模型中，莫尔和KOR在丁丙诺啡治疗中的作用， 这些受体在NCI发展中的髓样细胞特异性的重要性。在目标3中，我们将描述 使用来自PWH的PBMC对丁丙诺啡的成熟人单核细胞的BBB模型的迁移 并将其与PWH的认知功能联系起来。这将进一步支持使用 丁丙诺啡治疗伴有和不伴有OUD的PWH中的HIV-NCI。研究将由 艾滋病毒科学家、动物模型专家和传染病、艾滋病毒和OUD的高度互动小组 医生科学家和神经精神病学家，都是公认的中枢神经系统疾病专家。

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.