Plasma miRNA Biomarkers of HIV/SIV CNS Disease

描述(由申请人提供)： 抗逆转录病毒疗法(ART)极大地改变了艾滋病毒的流行，延缓了疾病，延长了生命，并将艾滋病毒相关的神经认知障碍(HAD)从脑炎/痴呆(HAD)改变为轻微的认知/运动障碍(MC/MD)和无症状神经认知障碍(ANI)等较轻微但仍令人衰弱的疾病。然而，尽管抗逆转录病毒治疗，手的患病率随着患者寿命的延长而增加，50%-60%的抗逆转录病毒治疗患者被诊断为轻度至中度疾病。目前还没有用于诊断或预测手部疾病的生物标志物。为艾滋病开发的血浆生物标记物(病毒载量和CD4+T细胞计数)在制定治疗方案中至关重要。开发类似灵敏、可靠和可获得的手部生物标记物至关重要。MicroRNAs(MiRNAs)与包括癌症和阿尔茨海默病在内的各种疾病有关，是一种有希望的新型生物标志物来源。这些小的、非编码的RNA在血浆中丰富和稳定，为发现生物标记物提供了独特的机会。反映疾病状态的血浆miRNAs也可能成为新的治疗靶点。使用我们的中枢神经系统疾病的SIV/猕猴模型和ART，我们确定了急性感染的血浆miRNA信号和预测中枢神经系统疾病的miRNAs在神经疾病和/或衰老中的作用。在这里，我们将识别感染不同阶段的血浆miRNA生物标记物(目标1)；表征感染期间脑脊液(CSF)和大脑中的miRNA谱；并识别预测中枢神经系统疾病(未经治疗的猕猴)发展或与接受ART治疗的猕猴大脑中持续水平的炎性细胞因子相关的miRNA(目标2)。我们将使用东北艾滋病痴呆(NEAD)队列中匹配的血浆和脑脊液，将这些研究扩展到手部HIV感染者，以识别和验证HAD、MC/MD和ANI的血浆miRNA生物标记物(目标3)。最后，将研究大脑和特定血浆部分中的血浆miRNA生物标记物，以确定循环miRNAs的细胞来源和预测疾病的血浆miRNAs的载体(囊泡、脂蛋白颗粒、蛋白质复合体)(目标4)。这些研究的目的是确定血浆miRNA生物标志物，以诊断和预测手部的发展，并为手部的发病机制提供深入的了解。我们的假设是，一个独特的差异表达的血浆miRNAs组合将对HIV/SIV感染阶段进行诊断，预测CNS疾病，并反映脑内病毒和宿主反应的影响。其中一些miRNAs将起源于大脑，而另一些将起源于影响或平行于CNS过程的外周过程。这些研究的结果将代表着对血浆miRNAs在健康和传染病期间如何起源和循环的理解方面的实质性进展。重要的是，我们的发现将对手部诊断和治疗学具有重要意义，有助于描述大脑在手部发育过程中失调的通路的功能特征：基于小RNA的治疗学的潜在靶点。

DESCRIPTION (provided by applicant): Antiretroviral therapy (ART) has dramatically changed the HIV epidemic, delaying disease, prolonging life, and altering HIV-associated neurocognitive disorders (HAND) from encephalitis/dementia (HAD) to milder but nevertheless debilitating disorders such as minor cognitive/motor disorder (MC/MD) and asymptomatic neurocognitive impairment (ANI). However, despite ART, HAND prevalence has increased with patient longevity, and mild to moderate disorders are diagnosed in 50-60% of ART patients. There are currently no biomarkers used to diagnose or predict HAND. Plasma biomarkers developed for AIDS (viral load and CD4+ T cell count), were essential in developing treatment paradigms. It is critical to develop similarly sensitive, reliable, and accessible biomarkers for HAND. MicroRNAs (miRNAs), which are linked to various diseases including cancers and Alzheimer's disease, are a promising source of novel biomarkers. These small, non- coding RNAs are abundant and stable in plasma, providing a unique opportunity for biomarker discovery. Reflecting disease states, plasma miRNAs may also present novel therapeutic targets. Using our SIV/macaque model of CNS disease and ART, we identified a plasma miRNA signature of acute infection and CNS disease-predictive miRNAs with roles in neurologic disorders and/or senescence. Here, we will identify plasma miRNA biomarkers during different stages of infection (Aim 1); characterize miRNA profiles in cerebrospinal fluid (CSF) and brain during infection; and identify miRNAs that predict the development of CNS disease (untreated macaques) or correlate with persistent levels of inflammatory cytokines in brain of ART treated macaques (Aim 2). We will extend these studies to HIV-infected individuals with HAND using matched plasma and CSF from the NorthEast AIDS Dementia (NEAD) cohort to identify and validate plasma miRNA biomarkers for HAD, MC/MD, and ANI (Aim 3). Finally, plasma miRNA biomarkers will be studied in brain and specific plasma fractions to identify cellular sources of circulating miRNAs and the vehicles (vesicles, lipoprotein particles, protein complexes) of disease-predictive plasma miRNAs (Aim 4). The goal of these studies is to identify plasma miRNA biomarkers that diagnose and predict the development of HAND and that provide insights into HAND pathogenesis. Our hypothesis is that a unique combination of differentially expressed plasma miRNAs will be diagnostic for HIV/SIV infection stage, predictive of CNS disease, and reflective of the impact of both viral and host responses in brain. Some of these miRNAs will originate from brain, while others will stem from peripheral processes that affect or parallel CNS processes. Results of these studies will represent a substantial advance in the understanding of how plasma miRNAs originate and circulate during health and infectious disease. Importantly, our findings will have significance fo HAND diagnostics and therapeutics, facilitating functional characterization of pathways that are dysregulated in brain during the development of HAND: potential targets of small-RNA based therapeutics.