HIV Tat & Cocaine-Mediated induction of Astrogliosis: Role of ER Stress in HAND

说明(申请人提供)：静脉吸毒(IVDU)和HIV-1感染是两个相互关联的全球健康危机，因为共用针头是公认的HIV-1传播方式。滥用药物加速了艾滋病毒-1相关神经疾病(HAND)的发生和发展。与未吸毒的HIV-1感染者相比，吸毒者表现出更严重的认知障碍。经常被艾滋病毒感染患者滥用的可卡因被认为会加重艾滋病毒相关的中枢神经系统疾病。虽然抗逆转录病毒疗法(ART)减少了HIV-1相关性痴呆(HAD)的发生率，但较轻微的神经系统疾病仍然存在。由于使用ART疗法而导致的存活率增加，导致HAND患病率增加。尽管滥用可卡因对HIV-1相关脑病理的临床过程产生了公认的影响，但可卡因增强HIV-1在大脑中的病理效应的潜在机制仍然不清楚。众所周知，尽管面对抗逆转录病毒治疗，病毒血症几乎完全被抑制，但早期病毒蛋白，如HIV Tat，被发现潜伏在组织部位，从而有助于在手中观察到残留的慢性神经炎/神经胶质激活。最近的研究表明，内质网应激是细胞对外部损伤/伤害的一种保护性反应。我们的初步研究表明，内质网应激在HIV TAT介导的原代大鼠星形胶质细胞GFAP上调(星形胶质细胞增生症)中的作用。可卡因与HIV TAT是否通过内质网应激途径协同诱导星形胶质细胞增生尚不清楚。我们假设HIV Tat和可卡因通过内质网(ER)应激的诱导，协同增强星形胶质细胞的激活和凋亡，这是手部的特征。这将通过三个特定目标进行测试：a)检测内质网应激在HIV TAT和/或可卡因介导的大鼠和人原代星形胶质细胞星形胶质细胞上调(GFAP上调)中的作用；b)研究HIV TAT和/或可卡因介导的星形胶质细胞增生症所涉及的信号通路；以及c)在体内测试抑制ER反应作为改善TAT和/或可卡因介导的手部啮齿动物星形胶质细胞增生的干预策略的治疗潜力。

DESCRIPTION (provided by applicant): Intravenous drug use (IVDU) and HIV-1 infections are two linked global health crises since needle sharing is a well-recognized mode of HIV-1 transmission. Drugs of abuse accelerate the incidence and progression of HIV- 1-associated neurological disorders (HAND). Drug-abusing HIV-1 positive individuals exhibit more severe cognitive impairment compared with the non-drug-abusing HIV positive counterparts. Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated CNS disease. Although antiretroviral therapy (ART) has diminished the incidence of HIV-1-associated dementia (HAD), milder forms of neurological disease do persist. Increased survival rates resulting from ART therapy usage have led to an increase in the prevalence of HAND. Despite the recognized impact of the abuse of cocaine on the clinical course of HIV-1- associated brain pathology; mechanisms underlying the ability of cocaine to enhance the pathological effects of HIV-1 in the brain remain elusive. It is well-recognized that despite near complete suppression of viremia in the face of ART, early viral proteins such as HIV Tat are found lurking in tissue sites, thereby contributing to residual chronic neuroinflammation/glial activation observed in HAND. Recent studies indicate ER stress as a protective response by the cell against external injury/insult. Our preliminary studies the indicate role of ER stress in HIV Tat-mediated upregulation of GFAP (astrogliosis) in primary rat astrocytes. Whether cocaine cooperates with HIV Tat to synergistically induce astrogliosis via the ER stress pathway, remains unknown. We hypothesize that HIV Tat & cocaine via the induction of endoplasmic reticulum (ER) stress, co-operate to enhance astrocyte activation & apoptosis, hallmark features of HAND. This will be tested via three specific aims: a) To examine the role of ER stress in HIV Tat &/or cocaine mediated upregulation of astrogliosis (upergulation of GFAP) in both rat and human primary astrocytes, b) To investigate the signaling pathways involved in HIV Tat &/or cocaine mediated enhancement of astrogliosis and c) To test in vivo the therapeutic potential of inhibition of ER response as an intervention strategy for ameliorating Tat & or cocaine-mediated astrogliosis in rodent models of HAND.