Glial origins of HIV and opiate-driven synaptodendritic injury

HIV 的神经胶质起源和阿片驱动的突触树突损伤

基本信息

批准号：
8506342
负责人：
Kurt F Hauser
金额：
$ 44.33万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-15 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506342
关键词：
AIDS neuropathy AIDS/HIV problem Ablation Affect Astrocytes Attenuated Automobile Driving Behavior Behavioral CCR CCR5 gene Cell Death Cells Cessation of life Coculture Techniques Complex Corpus striatum structure Data Disease susceptibility Drug abuse Endothelial Cells Endothelium Epidemic Event Exposure to Genetic Polymorphism Glial Fibrillary Acidic Protein Gliosis HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Hippocampus (Brain)Human ITGAM gene Image Immune In Vitro Individual Infection Inflammation Inflammatory Injury Knockout Mice Life Ligands MAP Kinase Gene MAPK14 gene Macrophage Inflammatory Protein-1 Measures Mediator of activation protein Microglia Modeling Morphine Mus Needle Sharing Nerve Degeneration Neuroglia Neuronal Injury Neurons Neuropathogenesis Opiates Opioid Opioid Receptor Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Population Principal Investigator Proteins Public Health RANTES Reporting Role Signal Transduction Sorting - Cell Movement Source Structure System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Up-Regulation Vertebral column Viral Virion Virus Work behavior test cell motility chemokine design dimer immune function in vivo injection drug use injured monocyte mutant neuropathology neuroprotection neurotoxic neurotoxicity opioid abuse prevent programs public health relevance receptor sex

项目摘要

DESCRIPTION (provided by applicant): Drug abuse and HIV/AIDS are interlinked epidemics because of increased spread of HIV-1 through needle sharing and through the exchange of sex for drugs. During the past decade, we have proposed that, besides peripheral immune dysregulation, opiates exacerbate the pathological effects of HIV in the CNS though direct actions on ¿-opioid receptor expressing (MOR) neurons and glia. The CNS may be preferentially vulnerable to opiate and HIV-1 interactions because of the complexity and interrelatedness of MOR action in neurons, astroglia, microglia and endothelium. We recently reported that convergent, neurotoxic effects of Tat or gp120 and morphine are largely due to actions of MOR+ glia. Our in vivo work supports a central role for glia in sublethal/lethal synaptodendritic injury. Morphine worsens structural and functional irregularities in hippocampus and striatum of Tat-expressing mice, including spine losses and synaptodendritic injury. Neurotoxic interactions with morphine and gp120 are HIV strain specific. Medium from monocytes exposed to live or UV-inactivated R5-tropic HIV-1SF162 virions is toxic to neurons; this is significantly attenuated by the CCR5 antagonist maraviroc. We hypothesize that opiate-induced exacerbation of HIV toxicity is regulated through differential CCR5 signaling between microglia, astroglia, and neurons, which can injure or protect neurons depending on context. We propose that opiates and Tat or HIV interact downstream of TNF¿ to enhance inflammatory chemokine release from astroglia. In particular, convergent effects of opiates and Tat/HIV appear to dysregulate CCL5/CCR5 signaling, creating a milieu that promotes microglial motility and spiraling microglial activation. Our hypotheses are tested in 3 aims that examine individual roles of astroglia and microglia in driving neurotoxic opiate-HIV interactions. Aims 1 & 2 use murine models for both: a) long-term, repeated imaging of cell death and sublethal neurodegenerative changes; and b) in vivo studies to detect population changes, neuron pathology, and behavioral deficits. Models include mice with cell-specific Cre-lox ablation of MOR, and inducible Tat transgenic mice crossed with CCL5-/- or CCR-/- mice. In Aim 3, human glia and neurons are used to study neurodegenerative changes due to HIV and opiate effects related to CCL5- CCR5 signaling in an infectious model with multiple strains of HIV. Infectious/non-infectious effects of CCR5 activation are sorted using live and inactivated virus, and mutant viral strains. The CCR5 pathway is especially relevant to HIV. CCR5 is an HIV co-receptor for M-tropic strains; CCR5 polymorphisms affect disease susceptibility; the CCR5 antagonist maraviroc slows HIV progression clinically. Studies are essential for informing therapeutic strategies. By defining how each glial type contributes to CCL5/CCR5 dysregulation, judicious cell- and pathway-specific measures to prevent the neurotoxic sequelae of opiate-HIV co-exposure can be designed.

描述（由申请人提供）：药物滥用和艾滋病毒/艾滋病是相互关联的流行病，因为在过去的十年中，除了外周免疫失调之外，艾滋病毒 - 1 通过共用针头和性行为交换而传播增加。，阿片类药物通过直接作用于 ¿ 加剧了中枢神经系统中艾滋病毒的病理影响。由于 MOR 在神经元、星形胶质细胞、小胶质细胞和内皮细胞中的作用的复杂性和相互关联性，中枢神经系统可能更容易受到阿片类药物和 HIV-1 相互作用的影响。 Tat 或 gp120 和吗啡的作用很大程度上是由于 MOR+ 神经胶质细胞的作用，我们的体内工作支持神经胶质细胞在亚致死/致死中的核心作用。吗啡会加重表达 Tat 的小鼠海马和纹状体的结构和功能异常，包括吗啡和 gp120 的神经毒性相互作用是来自暴露于活的或紫外线灭活的 R5-tropic 的单核细胞的神经毒性相互作用。 HIV-1SF162 病毒颗粒对神经元具有毒性；CCR5 拮抗剂马拉维罗可显着减弱这种毒性。阿片类药物引起的 HIV 毒性加重是通过小胶质细胞、星形胶质细胞和神经元之间的差异 CCR5 信号传导来调节的，这可以根据具体情况损伤或保护神经元，我们认为阿片类药物和 Tat 或 HIV 在 TNF 下游相互作用。特别是，阿片类药物和 Tat/HIV 的聚合作用似乎会失调 CCL5/CCR5 信号，从而创造一个促进小胶质细胞运动和螺旋式小胶质细胞激活的环境。星形胶质细胞和小胶质细胞在驱动神经毒性阿片类药物与 HIV 相互作用中的作用目标 1 和 2 使用小鼠模型进行：a) 长期、重复成像。细胞死亡和亚致死性神经退行性变化；b) 检测群体变化、神经元病理学和行为缺陷的体内研究模型包括细胞特异性 Cre-lox 消融的 MOR 小鼠和与 CCL5-/ 杂交的诱导型 Tat 转基因小鼠。 - 或 CCR-/- 小鼠在目标 3 中，使用人类神经胶质细胞和神经元来研究多重感染模型中与 CCL5-CCR5 信号传导相关的 HIV 和鸦片效应引起的神经退行性变化。使用活病毒和灭活病毒对 HIV 病毒株进行分类，CCR5 途径与 HIV 病毒株尤其相关。影响疾病易感性；CCR5 拮抗剂马拉韦罗可在临床上减缓 HIV 进展。可以设计 CCL5/CCR5 失调、明智的细胞和途径特异性措施来预防阿片类药物 - HIV 共同暴露的神经毒性后遗症。