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，并通过被感染者的转移介导