Monocyte CNS HIV entry & neurodegeneration: Translational studies in the CART era

单核细胞 CNS HIV 进入

基本信息

批准号：
9407532
负责人：
Joan Weinberger Berman
金额：
$ 75.15万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-19 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9407532
关键词：
ALCAM gene Address Affect Biological Assay Biological Markers Blocking Antibodies Blood - brain barrier anatomy Brain CCL2 gene CCR5 gene CD14 Antigen CD14 gene Cell Count Cells Characteristics Chronic Disease Ensure FCGR3B gene HIV HIV Infections HIV Seropositivity HIV-associated neurocognitive disorder Human Impaired cognition Impairment In Vitro Individual Infection Inflammation Integration Host Factors JAM protein Longitudinal Studies Longitudinal cohort Magnetic Resonance Imaging Maintenance Mediating Modeling Nerve Degeneration Neurobiology Neurons Neuropathogenesis Pathogenesis Peripheral Peripheral Blood Mononuclear Cell Phenotype Prevalence Property Proteins Surface Therapeutic Time Viral Viral reservoir Virus Virus Diseases antiretroviral therapy brain volume chemokine cognitive testing cohort global health hand therapy inhibitor/antagonist macrophage monocyte monocyte chemoattractant protein 1 receptor neuroAIDS neuroimaging neuroinflammation performance tests peripheral blood receptor response therapeutic development therapeutic target translational study viral DNA

项目摘要

HIV entry into the CNS occurs early after peripheral infection and is mediated by the transmigration of infected monocytes across the BBB, establishing CNS viral reservoirs, neuronal damage, and low level inflammation, despite antiretroviral therapy (ART), that mediate HIV-associated neurocognitive disorders, HAND, in >50% of infected people even in those with undetectable virus. The mechanisms of HIV infected monocyte transmigration across the BBB have only been minimally characterized. A mature CD14+CD16+ monocyte subset is key to HIV CNS pathogenesis. We showed that these cells selectively transmigrate across our model of the human BBB in response to the chemokine CCL2, and that when HIV infected, they transmigrate in even greater numbers. This is due, in part, to their increased junctional proteins JAM-A and ALCAM, and increased CCR2, the receptor for CCL2. CD14+CD16+ monocytes in HIV-infected individuals are heterogeneous, consisting of cells that are infected with HIV (HIV+), and cells exposed to viral and host factors, but not infected with the virus (HIVexp). It is not known whether the transmigration of HIV+ and HIVexp CD14+CD16+ monocytes across the BBB differs, and how this affects CNS neuropathogenesis. HIV+ monocytes that cross the BBB may differentiate into long-lived CNS macrophages and establish and maintain CNS viral reservoirs contributing to CNS damage. With ART, productively infected CD14+CD16+ monocytes in the peripheral blood are significantly reduced, with a small number of these cells still having detectable viral DNA. We propose that the neuronal damage and chronic inflammation that mediate cognitive impairment, even in the presence of ART, is dependent on continued reseeding of the brain with HIV+CD14+CD16+ monocytes, maintaining CNS viral reservoirs and continuing the influx of these infected as well as uninfected monocytes into the brain. Mechanisms that ensure that these HIV+CD14+CD16+ monocytes replenish CNS viral reservoirs over extended periods are not known. We hypothesize that CCR2, and junctional proteins are higher on HIV+ monocytes compared to HIVexp monocytes, resulting in their preferential transmigration across the BBB, and that this is associated with the establishment and maintenance of CNS viral reservoirs, and with neuronal and structural damage, low level inflammation, and cognitive impairment. We will characterize HIV+ and HIVexp monocytes using primary human mature CD14+CD16+ monocytes infected in vitro. We will also characterize the phenotype and transmigration of HIV+ and HIVexp mature monocytes from a longitudinal cohort of HIV-infected people stably suppressed on ART, and determine whether these circulating monocyte characteristics correlate with cognitive impairment and neurobiologic abnormalities using neuroimaging. We will determine whether CCR2, JAM-A, or ALCAM are biomarkers of HAND. We will use blocking antibodies and cenicriviroc in transmigration assays to assess JAMA, ALCAM, and CCR2 as potential therapeutic targets to limit CNS entry of peripheral blood HIV+ monocytes and potentially reduce reservoirs and HAND.

HIV 进入中枢神经系统发生在外周感染后早期，并由感染者的迁移介导单核细胞穿过血脑屏障，建立中枢神经系统病毒库、神经元损伤和低水平炎症，尽管抗逆转录病毒疗法 (ART) 介导了 HIV 相关的神经认知障碍 (HAND)，但仍有超过 50% 的患者出现这种情况即使是那些携带无法检测到的病毒的人也会被感染。 HIV感染单核细胞的机制穿过血脑屏障的轮回只得到了最低限度的表征。成熟的 CD14+CD16+ 单核细胞子集是 HIV 中枢神经系统发病机制的关键。我们证明这些细胞选择性地在我们的模型中迁移人类血脑屏障对趋化因子 CCL2 的反应，当 HIV 感染时，它们甚至会迁移到更多的数字。这部分是由于它们增加了连接蛋白 JAM-A 和 ALCAM，并且增加了 CCR2，CCL2 的受体。 HIV感染者的CD14+CD16+单核细胞是异质的，由感染 HIV (HIV+) 的细胞以及暴露于病毒和宿主因子但未感染的细胞组成与病毒（HIVexp）。尚不清楚 HIV+ 和 HIVexp CD14+CD16+ 单核细胞的迁移是否血脑屏障之间存在差异，以及这如何影响中枢神经系统神经发病机制。穿过 BBB 的 HIV+ 单核细胞可能分化为长寿命的中枢神经系统巨噬细胞，并建立和维持中枢神经系统病毒库，有助于中枢神经系统损伤。通过 ART，外周血中有效感染的 CD14+CD16+ 单核细胞被显着减少，其中少数细胞仍具有可检测到的病毒 DNA。我们建议即使在存在 ART 的情况下，神经元损伤和慢性炎症也会介导认知障碍依赖于大脑中持续重新接种 HIV+CD14+CD16+ 单核细胞，维持中枢神经系统病毒储存库并继续这些受感染和未受感染的单核细胞涌入大脑。确保这些 HIV+CD14+CD16+ 单核细胞长期补充 CNS 病毒库的机制时期未知。我们假设 HIV+ 单核细胞上的 CCR2 和连接蛋白较高与 HIVexp 单核细胞相比，导致它们优先穿过 BBB 迁移，这是与中枢神经系统病毒库的建立和维持以及神经元和结构相关损伤、低水平炎症和认知障碍。我们将表征 HIV+ 和 HIVexp 单核细胞使用体外感染的原代人成熟CD14+CD16+单核细胞。我们还将描述来自 HIV 感染者纵向队列的 HIV+ 和 HIVexp 成熟单核细胞的表型和迁移 ART 稳定抑制的人，并确定这些循环单核细胞特征是否相关使用神经影像学发现认知障碍和神经生物学异常。我们将确定是否 CCR2、JAM-A 或 ALCAM 是 HAND 的生物标志物。我们将使用封闭抗体和西尼昔韦罗轮回测定法评估 JAMA、ALCAM 和 CCR2 作为限制中枢神经系统进入的潜在治疗靶点外周血 HIV+ 单核细胞的数量，并可能减少储存库和 HAND。