Synergistic neurotoxicity of speedball and HIV toxins

描述（由申请人提供）：本提案通过寻求更好地了解病毒蛋白和多种药物滥用对HIV神经认知障碍（HAND）发展的作用，解决了HIV-1流行病的一个关键方面。艾滋病毒迅速进入大脑，感染巨噬细胞和小胶质细胞，而不是神经元。虽然HAART可以有效地控制这种复制，但HAND患病率并没有平行降低，表明病毒复制并不是所有神经病理学的原因。即使在病毒抑制期间，可能来自受感染星形胶质细胞的病毒蛋白被认为直接和间接地引起神经元损伤。个别滥用药物，如可卡因或吗啡，通过对星形胶质细胞的作用与病毒毒素协同作用，加剧炎症和氧化应激。然而，在美国，多种药物的使用在药物滥用者中占主导地位，迄今为止还没有研究检查药物与艾滋病毒神经毒素的组合。该提案的第一个目标是更好地了解多种药物滥用（快球）和艾滋病毒神经毒素之间的潜在协同作用。第二个目标是建立一个快速球的大鼠模型，以研究这些病毒毒素滥用多种药物对运动和记忆的影响。这些目标将通过将speedball和达特或Vpr应用于星形胶质细胞和神经元的体外原代培养物来实现，以研究作为协同神经毒性的可能机制的氧化应激和炎症加剧。此外，将评估用可卡因、吗啡或速度球处理的大鼠的运动和记忆功能，然后对促氧化剂环境和神经元损伤和死亡进行死后组织学分析。这项研究将有助于更好地了解病毒毒素和多种药物滥用在产生氧化应激和炎症方面的重叠作用，这似乎是理解HAND发展和进展的关键。此外，这项工作将产生一个重要的新工具，在生物学环境中研究艾滋病毒神经认知障碍中发生的运动和记忆缺陷的程度和性质，包括氧化剂的机械作用。该模型预计将有助于转化研究的设计，以发现新的治疗策略，以防止在药物滥用环境中HAND的发展和进展。公共卫生相关性：HIV-1感染和药物滥用是美国两个重要的医学和社会问题。这些流行病独立存在，但也有显着的重叠，包括可能的协同作用，神经认知障碍。该提案旨在更好地定义和理解药物滥用和艾滋病毒感染在神经病理学中的综合影响，以及生成基线数据，以允许有针对性地对艾滋病毒和药物对神经艾滋病的贡献进行体内研究。这些信息可用于改善长期管理和降低与这些疾病相关的发病率。

DESCRIPTION (provided by applicant): This proposal addresses a critical aspect of the HIV-1 epidemic by seeking to better understand the roles of viral proteins and polydrug abuse on the development of HIV neurocognitive disorders (HAND). HIV quickly enters the brain and infects macrophages and microglia rather than neurons. While HAART can effectively control this replication, HAND prevalence is not reduced in parallel, indicating that virus replication is not responsible for all neuropathology. Viral proteins that may come from infected astroctyes even during viral suppression are thought to cause neuronal damage both directly and indirectly. Individual drugs of abuse, such as cocaine or morphine, synergize with viral toxins through effects on astrocytes to exacerbate inflammation and oxidative stress. However, polydrug use predominates among substance abusers in the US and no studies to date have examined the combinations of drugs with HIV neurotoxins. The first aim of this proposal is targeted to better understand the potential synergy between polydrug abuse (speedball) and HIV neurotoxins. A second aim is to develop a rat model of speedball to study the motor and memory effects of polydrug abuse with these virotoxins. These goals will be approached using application of speedball and Tat or Vpr to in vitro primary cultures of astrocytes and neurons to study exacerbated oxidative stress and inflammation as a possible mechanism for synergistic neurotoxicity. In addition, rats treated with cocaine, morphine or speedball will be assessed for motor and memory function followed by post mortem histological analyses of prooxidant environment and neuronal damage and death. This research will lead to a better understanding of the overlapping roles of viral toxins and multiple drug abuse in generating oxidative stress and inflammation that appear to be a key to understanding the development and progression of HAND. In addition, the work will generate an essential new tool to study, in a biological setting, the extent and nature of the motor and memory defects that occur in HIV neurocognitive disorders, including the mechanistic role of oxidants. This model is expected to be instrumental in the design of translational studies for discovery of new treatment strategies to prevent HAND development and progression in a drug abuse setting. PUBLIC HEALTH RELEVANCE: HIV-1 infection and drug abuse are two medically and socially important issues in the US. These epidemics exist independently, but also have significant overlap including a possible synergistic contribution to neurocognitive disorders. This proposal seeks to better define and understand the combined effects of drug abuse and HIV infection in neuropathology, as well as to generate baseline data on to permit targeted in vivo studies of the contributions of HIV and drugs to NeuroAIDS. Such information can be used to improve long term management and reduce the morbidity associated with these illnesses.