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在外周感染后早期进入中枢神经系统，并由感染者的转运介导 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，低水平炎症， 尽管抗逆转录病毒治疗(ART)可以介导HIV相关的神经认知障碍，但有50%的人 被感染的人，即使是那些病毒检测不到的人。HIV感染单核细胞的机制 跨越BBB的轮回只有最低限度的特征。成熟的CD14+CD16+单核细胞 亚群是HIV中枢神经系统致病的关键。我们发现这些细胞在我们的模型中选择性地迁移 人类血脑屏障对趋化因子CCL2的反应，当HIV感染时，它们甚至在 更大的数字。这在一定程度上是由于它们的连接蛋白Jam-A和Alcam的增加，并且增加了 CCR2，CCL2的受体。HIV感染者的CD14+CD16+单核细胞是异质性的， 由感染艾滋病毒(HIV+)的细胞和暴露于病毒和宿主因素但未感染的细胞组成 病毒(HIVexp)。目前尚不清楚HIV+和HIVexp CD14+CD16+单核细胞是否迁移 血脑屏障的不同，以及这如何影响中枢神经系统的发病机制。穿过血脑屏障的HIV+单核细胞可能 分化为长期存活的中枢神经系统巨噬细胞，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，外周血中具有生产性感染的CD14+CD16+单核细胞 显著减少，其中一小部分细胞仍然具有可检测到的病毒DNA。我们建议， 即使在ART存在的情况下，介导认知障碍的神经元损伤和慢性炎症也是 依赖于继续用HIV+CD14+CD16+单核细胞重新接种大脑，维持中枢神经系统病毒 受感染的单核细胞和未受感染的单核细胞继续流入大脑。 确保这些HIV+CD14+CD16+单核细胞过度补充CNS病毒库的机制 周期是未知的。我们假设CCR2和结合蛋白在HIV+单核细胞上含量较高 与HIVexp单核细胞相比，导致它们优先跨血脑屏障迁移，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的 损伤、低水平炎症和认知障碍。我们将鉴定HIV+和HIVexp单核细胞 采用体外感染的原代成熟人CD14+CD16+单核细胞。我们还将描述 HIV感染纵向队列中HIV+和HIVexp成熟单核细胞的表型和迁移 人们稳定地抑制ART，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。我们将确定是否 CCR2、JAM-A或Alcam是手的生物标志物。我们将使用封闭抗体和环氧头孢菌素 移行试验评估JAMA、ALCAM和CCR2作为限制中枢神经系统进入的潜在治疗靶点 减少外周血中HIV+单核细胞的数量，并有可能减少蓄积物和手部。