Molecular Mechanisms of Increased Risk of Racial and Ethnic Minorities for HIV Associated Neurocognitive Disorders

全世界约有3700万艾滋病毒携带者。HIV在外周10天内进入中枢神经系统 感染，并发展为HIV相关性神经认知障碍(手)，约50%的感染者 抛开艺术不谈。这是由于宿主/病毒在中枢神经系统内促进神经元损伤的炎症和毒性因素。 研究表明，与白人相比，西班牙裔手部感染艾滋病毒的风险和发病率都有所增加。 这种增加风险的分子机制还没有得到广泛的研究。一种机制是通过 HIV是通过感染的单核细胞跨越血脑屏障(BBB)进入中枢神经系统的， 建立中枢神经系统HIV储备库，并诱导炎症和神经毒性。成熟的单核细胞亚群 表达内毒素受体CD14和FcγIII受体CD16是艾滋病毒神经发病的关键，在 HIV感染者的外周血，并优先感染HIV。我们发现CD14+CD16+ HIV感染者的单核细胞优先通过我们的人类BBB模型迁移到CCL2和CCL2 CXCL12，HIV感染者中枢神经系统趋化因子水平升高。我们还发现CD14+CD16+ 手部HIV感染者的单核细胞向CCL2迁移的数量高于手部HIV感染者 认知正常的人。我们发现了CXCR7的拮抗剂，CXCR7是最近发现的CXCL12受体 在单核细胞上，阻断CXCL12介导的特异性CD14+CD16+单核细胞从HIV- 我们建议将此作为治疗目标，以减少他们进入中枢神经系统。HIV DNA HIV感染者的拷贝/106 PBMC，特别是在CD14+CD16+单核细胞中，与Hand相关。 使用培养的CD14+CD16+单核细胞，我们发现携带HIV(HIV+)的单核细胞优先 与未感染但暴露于艾滋病毒的单核细胞相比，跨血脑屏障向CCL2迁移，这 选择性优势部分归因于连接蛋白Jam-A和alcam的增加。然而，没有 研究表明CXCL12是否介导了成熟单核细胞的迁移，或者CXCL12是否- 在西班牙裔中，HIV+CD14+CD16+单核细胞介导的特异性移行与手相关。 单核细胞有助于HIV感染者的外周免疫激活。一次CD14+CD16+单核细胞 进入中枢神经系统，它们会产生宿主/病毒毒性因子，促进神经元损伤和手部损伤。我们 假设：1.在一组接受抗逆转录病毒治疗的感染艾滋病毒的拉美裔美国人中，与手部的拉美裔相比 认知正常的人外周血CD14+CD16+单核细胞表达CCL2的比例较高， CXCL12、TNF-α和/或IL-6，并具有较高水平的这些介质；2.CD14+CD16+单核细胞 队列，特别是携带艾滋病毒的人群，将优先迁移到CXCL12，这将与 HIV+单核细胞向CXCL12的优先迁移将被JAM-A抗体阻断 和alcam，以及CXCR7的抑制剂；4.手拉手的拉美裔人的HIV DNA拷贝数/106 PBMC会更高 与手中的白色人相比，导致他们手中的风险增加。 好了！ 好了！

Approximately 37 million people worldwide are living with HIV. HIV enters the CNS within 10 days of peripheral infection, with development of HIV Associated Neurocognitive Disorders (HAND) in ~50% of infected people despite ART. This is due to host/viral inflammatory and toxic factors within the CNS promoting neuronal injury. Studies have shown increased risk and incidence of HIV infected Hispanics for HAND compared to Whites. Molecular mechanisms underlying this increased risk have not been extensively studied. One mechanism by which HIV enters the CNS is by transmigration of infected monocytes across the blood brain barrier (BBB), establishing CNS HIV reservoirs, and inducing inflammation and neurotoxicity. A mature monocyte subset expressing the LPS receptor, CD14, and FcγIII receptor, CD16, is key to HIV neuropathogenesis, increased in the peripheral blood of HIV-infected people, and preferentially infected with HIV. We showed that CD14+CD16+ monocytes from HIV-infected people transmigrate preferentially across our human BBB model to CCL2 and CXCL12, chemokines elevated in the CNS of HIV-infected people. We also showed that CD14+CD16+ monocytes from HIV-infected people with HAND transmigrate in greater numbers to CCL2 than those from people with normal cognition. We showed that an antagonist to CXCR7, a recently identified CXCL12 receptor on monocytes, blocks CXCL12-mediated transmigration of specifically CD14+CD16+ monocytes from HIV- infected people, and we propose this as a therapeutic target to reduce their entry into the CNS. HIV DNA copies/106 PBMC from HIV-infected people, specifically within CD14+CD16+ monocytes, correlate with HAND. Using cultured CD14+CD16+ monocytes, we showed that monocytes harboring HIV (HIV+) preferentially transmigrate across the BBB to CCL2 as compared to uninfected but HIV-exposed monocytes, and that this selective advantage is due, in part, to increased junctional proteins JAM-A and ALCAM. However, there are no studies addressing whether CXCL12-mediated transmigration of mature monocytes, nor whether CXCL12- mediated transmigration specifically of HIV+CD14+CD16+ monocytes, correlate with HAND in Hispanics. Monocytes contribute to peripheral immune activation in HIV-infected people. Once CD14+CD16+ monocytes enter the CNS, they produce host/viral toxic factors that promote neuronal damage and HAND. We hypothesize that: 1. In a select cohort of HIV-infected Hispanics on ART, Hispanics with HAND, compared to those with normal cognition, have a higher percent of peripheral CD14+CD16+ monocytes expressing CCL2, CXCL12, TNF-a, and/or IL-6, and have higher levels of these mediators; 2. CD14+CD16+ monocytes from this cohort, particularly those harboring HIV, will preferentially transmigrate to CXCL12, and this will correlate with HAND; 3. Preferential transmigration of HIV+ monocytes to CXCL12 will be blocked with antibodies to JAM-A and ALCAM, and an inhibitor to CXCR7; 4. Hispanics with HAND will have higher HIV DNA copies/106 PBMC compared to Whites with HAND, contributing to their increased risk for HAND. ! !