Role of cerebral vasculature in brain ischemia in HIV infection

摘要 脑部小血管疾病(CSVD)和短暂性脑缺血发作(TIA)正在出现 神经性艾滋病毒的共病。该应用程序建立在来自 上一个供资周期，并将评估艾滋病毒对 CSVD与短暂性脑缺血发作的转归和恢复(目标1)和CNS和HIV重新激活的关系 它的出口进入外围(目标2)。拟议工作的意义主要来自于 CSVD是认知障碍的主要原因，这一事实导致了25%的事件 脑缺血的风险，并使复发的风险增加一倍以上。此外，存在以下风险 据估计，发生短暂性脑缺血发作(TIA)或其他形式的脑缺血 与对照人群相比，艾滋病毒阳性个体的发病率至少高出1.5-2倍。这个 本提案的中心假设是艾滋病毒引起的脑血管病变 促进神经免疫激活，使艾滋病毒感染的大脑容易发生 CSVD和更严重的TIA结局。从机制上讲，我们将重点关注艾滋病毒和 CSVD对线粒体重编程及功能障碍线粒体在其中的作用 事件。我们重要的初步数据表明，艾滋病毒可以从潜伏感染中重新激活。 HIV大脑，我们首次表明这一过程也是大脑的结果 缺血症。我们将进一步探索这些过程，并将评估是否在中枢神经系统重新激活艾滋病毒 可以出口到外围。本研究以小说为研究对象，具有很强的创新性。 HIV感染者血管合并症的机制，如CSVD和TIA 大脑。 完成后，我们的应用程序将提供对HIV在CSVD和TIA中所起作用的重要见解 发展。此外，我们的研究将提供有关重新激活的重要信息 由于脑缺血，艾滋病毒从大脑播撒到外周。建议数 研究具有创新性，很可能为治疗干预找到新的机会。

ABSTRACT Cerebral small vessel disease (CSVD) and transient ischemic attacks (TIAs) are emerging comorbidities of neuroHIV. The application is built on the most important findings from the previous funding cycle and will evaluate the mechanistic events underlying the impact of HIV on CSVD in relationship to TIA outcome and recovery (Aim 1) and HIV reactivation in the CNS and its egress into the periphery (Aim 2). The significance of the proposed work drives primarily from the facts that CSVD is the major cause of cognitive impairment, contributes to 25% of incidents of brain ischemia, and more than doubles the risk of their recurrence. In addition, the risk of developing transient ischemic attacks (TIAs) or other forms of brain ischemia is estimated to be at least 1.5-2-fold higher in HIV-positive individuals compared to the control population. The central hypothesis of the present proposal is that HIV-induced cerebral vascular pathology drives neuroimmune activation, predisposing HIV-infected brains to the development of CSVD and more severe TIA outcomes. Mechanistically, we will focus on the impact of HIV and CSVD on reprogramming of mitochondria and the role of dysfunctional mitochondria in these events. Our important preliminary data indicates that HIV can be reactivated from latently infected HIV brains, and we show for the first time that this process also occurs as the result of brain ischemia. We will further explore these processes, and will evaluate if reactivated HIV in the CNS can egress into the periphery. The proposed research is highly innovative by its focus on novel mechanisms underlying vascular comorbidities, such as CSVD and TIAs, in the HIV-infected brain. When completed, our application will provide critical insight into the role of HIV in CSVD and TIA development. In addition, our research will provide important information about the reactivation HIV from the brain and seeding into the periphery as the result of brain ischemia. The proposed studies are innovative and are likely to identify novel opportunities for therapeutic intervention.