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(ART) 改善和延长了艾滋病毒携带者和PWH患者的生命。然而，较温和的慢性艾滋病毒相关 被称为轻度手或HIV-NCI的神经认知障碍仍然存在。HIV-NCI影响15%-40%的PWH和 因为它们会持续一生，随着年龄的增长而恶化，并影响药物的依从性，因此它们可以显著地 降低生活质量，增加死亡风险。许多PWH有阿片类药物使用障碍，OUD，这是一种 可加重HIV-NCI的PWH。我们在第一个资金周期中的新发现表明，丁丙诺啡， 一种公认的阿片类激动剂疗法用于治疗OUD，也可能是一种治疗NCI的方法。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，它可能会改善患有或不患有抑郁症的人的神经心理结果。 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，我们显示表达MOR和KOR，是 优先感染艾滋病毒，并具有选择性优势，可以通过血脑屏障(BBB)来应对 CCL2体外培养。丁丙诺啡减少了这种增加的轮回，部分原因是它能够限制 CCL2/CCR2信令。我们在患有HIV-NCI的EcoHIV感染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，并与炎症的减少相关 他们大脑中的单核细胞，艾滋病毒大脑负担的减少，以及作为艾滋病毒标志的树突修剪的减少 调解的NCI。我们假设丁丙诺啡减轻HIV神经发病，并可以治疗HIV-NCI 使用和不使用OUD的PWH。我们还提出，这是通过其在Mu和Kappa上的活动来调节的 阿片受体。我们的研究还将确定丁丙诺啡发挥作用的受体(S)。 行动并将使丁丙诺啡衍生的第二代疗法的开发成为可能 专门针对这些受体(S)。在Aim1中，我们将研究丁丙诺啡的体外作用机制 介导抑制CD14+CD16+单核细胞跨血脑屏障迁移及MOR的作用 以及KOR在这些过程中的作用。在目标2中，我们将使用转基因小鼠来处理个体和组合 MOR和KOR在丁丙诺啡治疗EcoHIV感染HIV-NCI临床前模型中的作用 髓系细胞上的这些受体在NCI发生中的重要性。在目标3中，我们将描述 丁丙诺啡对人单核细胞移植的影响 并将其与PWH的认知功能联系起来。这些将为使用 丁丙诺啡治疗慢性阻塞性肺疾病合并HIV-NCI这些研究将由一名 由HIV科学家、动物模型专家和传染病、HIV和OUD组成的高度互动的小组 内科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.