Glial origins of HIV and opiate-driven synaptodendritic injury

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，因为艾滋病毒-1通过共用针头和以性换取毒品而传播增加。在过去的十年中，我们提出，除了外周免疫失调，阿片类药物通过直接作用于表达莫尔的神经元和神经胶质细胞，加剧了HIV在CNS中的病理作用。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， 莫尔效应在神经元、星形胶质细胞、小胶质细胞和内皮细胞中的复杂性和相互关联性。我们最近报道了达特或gp 120和吗啡的会聚性神经毒性作用主要是由于莫尔+胶质细胞的作用。我们在体内的工作支持神经胶质细胞在亚致死/致死性突触树突损伤的核心作用。吗啡抑制了Tat表达小鼠海马和纹状体的结构和功能异常，包括脊柱丢失和突触树突损伤。与吗啡和gp 120的神经毒性相互作用是HIV株特异性的。暴露于活的或UV灭活的R5嗜性HIV-1 SF 162病毒粒子的单核细胞培养基对神经元具有毒性; CCR 5拮抗剂马拉韦罗可显著减弱毒性。我们假设阿片类药物诱导的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CCR 5信号传导来调节的，这可以根据上下文损伤或保护神经元。我们认为阿片类药物和达特或HIV在TNF下游相互作用，以增强星形胶质细胞释放炎性趋化因子。特别是，阿片类药物和达特/HIV的会聚效应似乎使CCL 5/CCR 5信号传导失调，从而产生促进小胶质细胞运动和螺旋状小胶质细胞活化的环境。我们的假设进行了测试，在3个目的，检查在驱动神经毒性阿片类药物-艾滋病毒相互作用的星形胶质细胞和小胶质细胞的个人角色。目的1和2使用鼠模型用于：a）细胞死亡和亚致死神经变性变化的长期、重复成像;和B）体内研究以检测群体变化、神经元病理学和行为缺陷。模型包括具有莫尔的细胞特异性Cre-lox消融的小鼠，以及与CCL 5-/-或CCR-/-小鼠杂交的诱导型达特转基因小鼠。在目的3中，使用人神经胶质和神经元来研究在具有多种HIV毒株的感染模型中由于HIV和与CCL 5-CCR 5信号传导相关的阿片作用引起的神经退行性变化。使用活病毒和灭活病毒以及突变病毒株对CCR 5活化的感染性/非感染性效应进行分类。CCR 5通路与HIV特别相关。CCR 5是M嗜性毒株的HIV辅助受体; CCR 5多态性影响疾病易感性; CCR 5拮抗剂马拉韦罗在临床上减缓HIV进展。研究对于提供治疗策略至关重要。通过定义每种胶质细胞类型如何促进CCL 5/CCR 5失调，可以设计明智的细胞和途径特异性措施来预防阿片类药物-HIV共暴露的神经毒性后遗症。

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.