Role of cerebral vasculature in brain ischemia in HIV infection

摘要 脑小血管病（CSVD）和短暂性脑缺血发作（TIA）正在出现 neuroHIV的并发症。该应用程序是建立在最重要的发现， 上一个供资周期，并将评估艾滋病毒对人类健康影响的机制性事件。 CSVD与TIA结局和恢复（目的1）以及CNS中HIV再激活的关系， 其出口进入外围（目标2）。建议工作的重要性主要来自于 CSVD是认知障碍的主要原因，占25%的事件， 脑缺血的风险增加一倍以上。此外， 发生短暂性脑缺血发作（TIA）或其他形式的脑缺血被估计为 与对照人群相比，HIV阳性个体中至少高1.5-2倍。的 本提案的中心假设是HIV诱导的脑血管病变 驱动神经免疫激活，使艾滋病毒感染的大脑倾向于发展 CSVD和更严重的TIA结局。从机制上讲，我们将侧重于艾滋病毒的影响， CSVD对线粒体重编程的影响以及功能失调的线粒体在这些过程中的作用 事件我们重要的初步数据表明，艾滋病毒可以从潜伏感染重新激活， 艾滋病毒的大脑，我们第一次表明，这一过程也发生的结果， 缺血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中重新激活艾滋病毒， 可以扩散到外围该研究具有高度的创新性，其重点是新颖的 HIV感染者中血管共病的潜在机制，如CSVD和TIA， 个脑袋 完成后，我们的应用程序将提供关键的洞察艾滋病毒在CSVD和TIA的作用 发展此外，我们的研究将提供有关重新激活的重要信息， 艾滋病病毒从大脑和播种到周围作为脑缺血的结果。拟议 这些研究是创新性的，有可能发现治疗干预的新机会。

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.