Astrocyte connexin43 containing channels amplify CNS dysfunction in NeuroAIDS

含有通道的星形胶质细胞连接蛋白 43 会放大 NeuroAIDS 中的中枢神经系统功能障碍

• 批准号: 9321162
• 负责人: Eliseo A Eugenin
• 金额: $ 47.95万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-07 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321162
• 关键词: Anti-Retroviral Agents; Apoptosis; Apoptotic; Area; Astrocytes; Autophagocytosis; Biology; Brain; Calcium; Calcium Signaling; Cells; Cognitive deficits; Communication; Connexin 43; Connexins; Cytoplasm; Data; Dementia; Development; Dinoprostone; Docking; Ensure; Exhibits; Functional disorder; Funding; Gap Junctions; Glutamates; Goals; HIV; HIV Infections; HIV-1; Human; Impaired cognition; In Vitro; Individual; Inflammatory; Inositol; Ions; Journals; Laboratories; Lipids; Liquid substance; Maintenance; Medical center; Medicine; Microglia; Minor; Mitochondria; Monkeys; Neuraxis; Neuroglia; Neurologic; Neurologic Dysfunctions; Neurons; Pathogenesis; Pathway interactions; Peer Review; Peptides; Persons; Play; Population; Prevalence; Primary Infection; Prostaglandins; Public Health; Publications; RNA; Recruitment Activity; Research; Resistance; Role; SIV; Second Messenger Systems; Signal Transduction; Structure; Synapses; Testing; Tissue Sample; Tissues; Toxic effect; Universities; Virus Replication; antiretroviral therapy; base; brain tissue; college; cytochrome c; gap junction channel; in vivo; macrophage; mitochondrial dysfunction; motor deficit; motor impairment; nervous system disorder; neuroAIDS; neurotoxic; neurotoxicity; new therapeutic target; novel; receptor sensitivity; release factor; response; success; trafficking; tripolyphosphate

Abstract: As of 2014, an estimated 35 million persons worldwide were living with human immunodeficiency virus (HIV). Early after primary infection, HIV enters the CNS and causes long lasting cognitive and motor impairment in 30-60 % of infected individuals, even in the current antiretroviral era. As infected individuals are living longer, the prevalence of neurological complications has been increasing. In the CNS, HIV infects mostly microglia/macrophages, but also a small population of astrocytes. However, despite the key roles of astrocytes in CNS functions, the role of these cells in NeuroAIDS has been relatively ignored. Our studies during the last funding period provide strong evidence for the critical role of astrocytes in the pathogenesis of NeuroAIDS. In particular, we have demonstrated that despite relatively low numbers of infected astrocytes and low to undetectable HIV replication, the HIV infected astrocytes transmit apoptotic and inflammatory signals, including calcium and inositol triphosphate (IP3), to neighboring uninfected cells, promoting neuronal damage and demise. We have also shown that these pro-apoptotic molecules are spread from the few HIV infected astrocytes via connexin-43 (Cx43) containing gap junctions (GJ) and unopposed hemichannels (uHC), whose expression and opening is regulated by HIV. Indeed, blocking GJ or uHC reduced amplification of bystander apoptosis, cellular dysfunction, synaptic compromise, and mitochondrial dysfunction induced by HIV infected astrocytes. Interestingly, HIV infected astrocytes themselves are protected from apoptosis by mechanisms that involve altered apoptosome formation and mitochondrial function. Importantly, we have tested and validated most of the mechanisms operating in HIV infected astrocytes in vivo in human and monkey brain tissue sections. Thus, based on the results obtained during the extremely productive period funded by our first R01 (resulting in over 40 publications in high quality peer reviewed journals) we have formulated our current hypothesis that “HIV infected astrocytes survive HIV infection to become HIV reservoirs, and that these cells send toxic, pro-apoptotic signals to surrounding cells via Cx43 containing channels, leading to the CNS dysfunction and NeuroAIDS”. In this application we propose to characterize the novel pathways of HIV toxicity within the brain and to identify the role of GJ and uHC in CNS dysfunction. The results obtained from this proposal will lead to the identification of potential novel therapeutic targets to limit the devastating consequences of NeuroAIDS.

摘要： 截至2014年，全球估计有3500万人携带人类免疫缺陷病毒 (艾滋病毒)。初次感染后早期，艾滋病毒进入中枢神经系统，导致持久的认知和运动 即使在目前的抗逆转录病毒时代，30-60%的感染者也会受到损害。作为受感染的个体 随着寿命的延长，神经系统并发症的患病率一直在增加。在中枢神经系统，艾滋病毒 主要感染小胶质细胞/巨噬细胞，但也感染一小部分星形胶质细胞。然而，尽管关键是 星形胶质细胞在中枢神经系统功能中的作用，在神经艾滋病中的作用一直被相对忽视。我们的 上一次资助期间的研究提供了强有力的证据，证明星形胶质细胞在 神经艾滋病的发病机制。特别是，我们已经证明，尽管相对较少的数量 被感染的星形胶质细胞和低到无法检测到的HIV复制，HIV感染的星形胶质细胞传递凋亡 以及炎症信号，包括钙和三磷酸肌醇(IP3)，传递给邻近的未感染细胞， 促进神经元损伤和死亡。我们还表明，这些促凋亡分子是 从少数感染HIV的星形胶质细胞通过含有缝隙连接(GJ)的连接蛋白-43(Cx43)和 非对抗性半通道(UHC)，其表达和开放受HIV的调节。事实上，阻止GJ 或UHC减少旁观者细胞凋亡的放大，细胞功能障碍，突触损害，以及 HIV感染星形胶质细胞引起的线粒体功能障碍。有趣的是，感染艾滋病毒的星形胶质细胞 通过改变凋亡体的形成和细胞周期来保护自身免受细胞凋亡。 线粒体功能。重要的是，我们已经测试和验证了大多数运行在 人和猴脑组织切片中HIV体内感染星形胶质细胞。因此，根据结果， 在我们的第一个R01资助的极具生产力的时期内获得的(导致超过40种出版物 在高质量的同行评议的期刊上)，我们已经阐明了我们目前的假设 星形胶质细胞在HIV感染后存活下来，成为HIV的储存库，这些细胞会发出有毒的、促凋亡的信号 通过含有Cx43的通道向周围细胞传递信号，导致中枢神经系统功能障碍和 神经艾滋病“。在这项应用中，我们建议表征艾滋病毒毒性的新途径 并确定GJ和UHC在中枢神经系统功能障碍中的作用。从这项建议中获得的结果 将导致确定潜在的新的治疗靶点，以限制 神经艾滋病。