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

单核细胞 CNS HIV 进入

• 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
• 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

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，并由感染的宿主细胞的迁移介导。 单核细胞穿过BBB，建立CNS病毒库，神经元损伤和低水平炎症， 尽管抗逆转录病毒治疗（ART）介导了HIV相关的神经认知障碍，HAND， 即使是那些携带无法检测到的病毒的人。HIV感染单核细胞的机制 仅最低限度地表征了穿过BBB的迁移。成熟的CD 14 + CD 16+单核细胞 亚群是HIV CNS发病机制关键。我们发现这些细胞选择性地穿越我们的模型 人类血脑屏障对趋化因子CCL 2的反应，当艾滋病毒感染时，他们甚至在 更多的数字。这部分是由于它们的连接蛋白JAM-A和ALCAM增加， CCR 2，CCL 2的受体。HIV感染者的CD 14 + CD 16+单核细胞是异质性的， 由感染HIV（HIV+）的细胞和暴露于病毒和宿主因子但未感染的细胞组成 病毒（HIVexp）。目前尚不清楚HIV+和HIVexp CD 14 + CD 16+单核细胞的迁移是否 不同的BBB，以及这如何影响CNS神经发病机制。穿过BBB的HIV+单核细胞可能 分化为长寿的CNS巨噬细胞，并建立和维持CNS病毒库， 中枢神经系统损伤。使用ART，外周血中的生产性感染的CD 14 + CD 16+单核细胞是 这些细胞中的一小部分仍然具有可检测到的病毒DNA。我们建议 神经元损伤和慢性炎症介导的认知障碍，即使在ART的存在下， 依赖于用HIV+ CD 14 + CD 16+单核细胞持续重新接种脑，维持CNS病毒 储存库和继续流入这些感染以及未感染的单核细胞进入大脑。 确保这些HIV+ CD 14 + CD 16+单核细胞补充CNS病毒库的机制 时期不详。我们假设HIV+单核细胞上的CCR 2和连接蛋白更高， 与HIVexp单核细胞相比，导致其优先穿过BBB，这是 与CNS病毒库的建立和维持相关，并且与神经元和结构相关。 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CD 14 + CD 16+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 稳定抑制ART的人，并确定这些循环单核细胞特征是否与 有认知障碍和神经生物学异常的患者。我们将决定 CCR 2、JAM-A或ALCAM是HAND的生物标志物。我们将使用封闭抗体和赛尼克韦罗， 评估JAMA、ALCAM和CCR 2作为限制CNS进入的潜在治疗靶点的迁移试验 的外周血HIV+单核细胞，并可能减少水库和手。