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

描述（由申请人提供）： 静脉吸毒和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传播模式。药物滥用加速了HIV- 1相关神经系统疾病（HAND）的发病率和进展。吸毒的HIV-1阳性个体比非吸毒的HIV阳性个体表现出更严重的认知障碍。常被HIV感染者滥用的可卡因，被认为会加重HIV相关的CNS疾病。虽然抗逆转录病毒疗法（ART）已经降低了HIV-1相关痴呆（HAD）的发病率，但轻度神经系统疾病仍然存在。ART疗法使用导致的存活率增加导致HAND患病率增加。尽管可卡因滥用对HIV-1相关脑病理学的临床过程的影响已得到公认，但可卡因增强HIV-1在脑中的病理学作用的潜在机制仍然难以捉摸。众所周知，尽管ART几乎完全抑制了病毒血症，但发现早期病毒蛋白如HIV达特潜伏在组织部位，从而导致在HAND中观察到的残留慢性神经炎症/神经胶质活化。最近的研究表明，ER应激是细胞对外部损伤/侮辱的保护性反应。我们的初步研究表明，在原代大鼠星形胶质细胞中，ER应激在HIV Tat介导的GFAP（星形胶质细胞增生）上调中的作用。可卡因是否与HIV达特合作通过ER应激途径协同诱导星形胶质细胞增生仍不清楚。我们假设HIV达特和可卡因通过诱导内质网（ER）应激，协同增强星形胶质细胞活化和凋亡，这是HAND的标志性特征。这将通过三个具体目标进行测试：a）检查ER应激在HIV达特和/或可卡因介导的星形胶质细胞增生上调中的作用（GFAP的活化）在大鼠和人原代星形胶质细胞中，B）研究参与HIV达特和/或可卡因介导的星形胶质细胞增生增强的信号传导途径，和在HAND的啮齿动物模型中测试抑制ER反应作为改善达特或可卡因介导的星形胶质细胞增生的干预策略的体内治疗潜力。

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.