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

单核细胞 CNS HIV 进入

• 批准号: 9915978
• 负责人: Joan Weinberger Berman
• 金额: $ 73.47万
• 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: 2017-07-19 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915978
• 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; Cells; Characteristics; Chronic; Disease; Ensure; Exposure to; 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; Structure; 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

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.

艾滋病毒进入中枢神经系统发生在周围感染后的早期发生，并由感染的移民介导 跨BBB的单核细胞，建立CNS病毒储存库，神经元损伤和低水平炎症， 尽管抗逆转录病毒疗法（ART）介导了与HIV相关的神经认知疾病，但在> 50％ 即使在患有无法检测到的病毒的人中也被感染。 HIV感染的单核细胞的机制 跨BBB的迁移仅是最小的特征。成熟的CD14+ CD16+单核细胞 子集是HIV CNS发病机理的关键。我们表明这些细胞在我们的模型中有选择地转移 响应于趋化因子CCL2的人类BBB，当艾滋病毒感染时，它们甚至在 数量更大。这部分归因于它们增加的连接蛋白JAM-A和ALCAM，并增加了 CCR2，CCL2的受体。 HIV感染个体中的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的细胞组成，但未感染 与病毒（Hivexp）。尚不清楚HIV+和Hivexp CD14+ CD16+单核细胞的迁移是否 在整个BBB上都不同，这如何影响CNS神经发病。越过BBB的HIV+单核细胞可能 区分长寿命的中枢神经系统巨噬细胞，并建立和维持有助于 中枢神经系统损坏。使用ART，外周血中有效感染的CD14+ CD16+单核细胞是 显着降低了，其中少数这些细胞仍具有可检测的病毒DNA。我们建议 即使在艺术存在的情况下，介导认知障碍的神经元损害和慢性炎症也是 取决于用HIV+CD14+CD16+单核细胞持续重新培养大脑，维持CNS病毒 储层并继续涌入这些受感染以及未感染的单核细胞中的涌入。 确保这些HIV+CD14+CD16+单核细胞补充CNS病毒储量的机制 时期尚不清楚。我们假设CCR2和连接蛋白在HIV+单核细胞上较高 与Hivexp单核细胞相比，导致它们在BBB上的优先移民，这是 与CNS病毒储存库的建立和维护以及神经元和结构相关 损害，低水平的炎症和认知障碍。我们将表征HIV+和HIVEXP单核细胞 使用原发性成熟的CD14+ CD16+单核细胞在体外感染。我们还将表征 HIV+和HIVEXP成熟单核细胞的表型和移民，来自HIV感染的纵向队列 人们稳定地压制了艺术，并确定这些循环的单核细胞特征是否相关 具有神经影像学的认知障碍和神经生物学异常。我们将确定是否 CCR2，JAM-A或ALCAM是手的生物标志物。我们将在 转移分析评估JAMA，ALCAM和CCR2作为潜在的治疗靶标，以限制CNS进入 外周血艾滋病毒+单核细胞，并有可能减少储层和手。