Novel Pathways of HAARTmediated Neuronal Toxicity in the Central Nervous System

尽管在高效抗逆转录病毒疗法（HAART）的时代，艾滋病相关痴呆（HAD）的发病率有所下降，但HAD的患病率正在上升，艾滋病阳性患者中轻微认知诊断的频率也在上升。尽管HAART对周围神经系统和培养的神经元都有神经毒性，但HAART对hiv相关神经认知障碍的作用尚不清楚。HAART化合物的毒性是由于不同的抗逆转录病毒类依赖机制，如蛋白质代谢的改变和线粒体损伤诱导的ROS （ROS）的产生，这两者都与其他神经退行性疾病有关。这些机制，以及HAART药物本身，可以启动内质网（ER）应激反应，这是一个多管下的促生存信号通路，如果长期激活可能会变得有害，以及自噬，这与神经退行性变有关。了解由不同类别的HAART触发的细胞机制

Despite a reduction in the incidence of HIV-associated dementia (HAD) in the era of Highly Active Anti-Retroviral Therapy (HAART), the prevalence of HAD is increasing, as is the frequency of minor cognitive diagnoses in HIV-positive patients. Although HAART is neurotoxic in both the peripheral nervous system and cultured neurons, the contribution of HAART to HIV-associated neurocognitive disorders is unknown. The toxicity of HAART compounds is due to distinct antiretroviral class-dependent mechanisms, such as alteration of protein metabolism and mitochondrial damage-induced generation of ROS (ROS), both of which have been implicated in other neurodegenerative conditions. These mechanisms, as well as HAART drugs themselves, can initiate the endoplasmic reticulum (ER) stress response, a multi-pronged pro-survival signaling pathway that may become deleterious if chronically activated, and autophagy, which has been implicated in neurodegeneration. An understanding of the cellular mechanisms triggered by the different classes of HAART drugs, in both neurons and macrophages, is crucial for guiding the design of new drugs and the assembly of combinational anti-retroviral therapies that minimize neurological impact. We hypothesize that HAART compounds induce neuronal toxicity both directly and indirectly (e.g. alteration of macrophage function), and that these mechanisms are mediated by cell-specific activation of stress responses that differ among classes of HAART compounds. Supporting this hypothesis, we have observed that individual antiretroviral drugs are neurotoxic in CNS cultures and that nontoxic drugs, when applied in recommended HAART combinations, become neurotoxic. We have also demonstrated an increase of downstream indicators of ER stress response activation in neurons and microglia/macrophages of patients with HIV-associated neurocognitive disorders, and in cultures of neurons and monocyte derived macrophages (MDM) following treatment with HAART compounds. Based on these findings, we propose to: 1) Determine the mechanisms of direct neuronal toxicity of HAART drug classes alone and in recommended, therapeutic combinations; 2) Determine the mechanisms of direct toxicity of HAART drug classes (alone and in combination) in monocyte derived macrophages, 3) Determine the contributions of HAART-exposed MDM to neurotoxicity. By investigating the cell-specific mechanisms of HAART toxicity in the central nervous system we will uncover an unexplored source for cognitive impairment in HIV-positive patients, identify targets to mitigate side-effects of HAART compounds that effectively control viral replilcation, and create a model to detect neurotoxicity of current and future HAART compounds alone and in combination.