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

少数种族和族裔 HIV 相关神经认知障碍风险增加的分子机制

基本信息

批准号：
9767544
负责人：
Rosiris Leon Rivera
金额：
$ 5万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-16 至 2021-07-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767544
关键词：
ALCAM gene Address Adult Antibodies Blood - brain barrier anatomy Brain CCL2 gene CD14 Antigen CD14 gene CXCL12 gene CXCR4 gene Cells Chronic Cognition Cognitive DNA Development Environment FCGR3B gene Goals HIV HIV Infections HIV-associated neurocognitive disorder Hispanics Human Impaired cognition Incidence Individual Infection Inflammation Inflammation Mediators Inflammatory Interleukin-6 JAM protein Mediating Mediator of activation protein Modeling Molecular Neuronal Injury Neurons Neuropathogenesis Odds Ratio Peripheral Peripheral Blood Mononuclear Cell Phenotype Population Prevalence Process Risk TNF gene Viral antiretroviral therapy brain parenchyma chemokine cohort ethnic minority population human model immune activation inhibitor/antagonist monocyte neuroinflammation neurotoxic neurotoxicity peripheral blood racial minority receptor response small molecule small molecule inhibitor therapeutic target

项目摘要

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. ! !

全球约有 3700 万人艾滋病毒感染者在外周血 10 天内进入中枢神经系统。感染，约 50% 的感染者出现 HIV 相关神经认知障碍 (HAND) 尽管进行了抗逆转录病毒治疗，这是由于中枢神经系统内的宿主/病毒炎症和毒性因素促进了神经元损伤。研究表明，与白人相比，西班牙裔人感染 HIV 的 HAND 风险和发病率更高。这种风险增加的分子机制尚未得到广泛研究。 HIV通过受感染的单核细胞穿过血脑屏障（BBB）进入中枢神经系统，建立中枢神经系统 HIV 储存库，并诱导炎症和神经毒性。表达 LPS 受体 CD14 和 FcγIII 受体 CD16 是 HIV 神经发病机制的关键， HIV感染者的外周血，并且优先感染HIV，我们发现CD14+CD16+。来自 HIV 感染者的单核细胞优先通过我们的人类 BBB 模型迁移至 CCL2 和 CXCL12，HIV 感染者中枢神经系统中的趋化因子升高，我们还发现 CD14+CD16+。患有 HAND 的 HIV 感染者的单核细胞比来自 HAND 的人的单核细胞更多地迁移到 CCL2 我们证明了 CXCR7（一种最近发现的 CXCL12 受体）的拮抗剂。作用于单核细胞，阻断 CXCL12 介导的特定 CD14+CD16+ 单核细胞从 HIV- 感染者，我们建议将其作为减少其进入中枢神经系统的 HIV DNA 的治疗靶点。来自 HIV 感染者的拷贝/106 PBMC，特别是 CD14+CD16+ 单核细胞内，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 HIV 的单核细胞相比，它们穿过 BBB 迁移至 CCL2，并且这选择优势部分归因于连接蛋白 JAM-A 和 ALCAM 的增加，但实际上并不存在。研究解决 CXCL12 是否介导成熟单核细胞的迁移，以及 CXCL12 是否介导介导的 HIV+CD14+CD16+ 单核细胞特异性轮回，与西班牙裔人的 HAND 相关。单核细胞有助于 HIV 感染者的外周免疫激活。进入中枢神经系统，它们产生宿主/病毒毒性因子，促进神经元损伤和 HAND。确保： 1. 在接受 ART 治疗的 HIV 感染西班牙裔人群中，与接受 HAND 治疗的西班牙裔患者相比，认知能力正常的人，外周CD14+CD16+单核细胞表达CCL2的比例较高， CXCL12、TNF-a和/或IL-6，并且这些介质的水平较高；2.来自此的CD14+CD16+单核细胞；队列，特别是那些携带 HIV 的队列，将优先迁移到 CXCL12，这将与 HAND；3. 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 抑制剂；4. 患有 HAND 的西班牙裔人的 HIV DNA 拷贝数/106 PBMC 更高；与患有 HAND 的白人相比，导致他们患 HAND 的风险增加。！！