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HIV的流行，延缓了疾病，延长了生命，并将HIV相关的神经认知障碍（HAND）从脑炎/痴呆（HAD）改变为较轻但仍然使人衰弱的障碍，如轻度认知/运动障碍（MC/MD）和无症状神经认知障碍（ANI）。然而，尽管ART，HAND患病率随着患者寿命的增加而增加，并且在50-60%的ART患者中诊断出轻度至中度疾病。目前还没有生物标志物用于诊断或预测HAND。为艾滋病开发的血浆生物标志物（病毒载量和CD 4 + T细胞计数）在开发治疗模式中至关重要。关键是要开发类似的敏感，可靠和可访问的生物标志物手。microRNA（miRNAs）与包括癌症和阿尔茨海默病在内的各种疾病有关，是一种有前途的新型生物标志物来源。这些小的非编码RNA在血浆中丰富且稳定，为生物标志物发现提供了独特的机会。反映疾病状态，血浆miRNA也可能呈现新的治疗靶点。使用我们的SIV/猕猴CNS疾病模型和ART，我们鉴定了急性感染的血浆miRNA特征和在神经系统疾病和/或衰老中起作用的CNS疾病预测miRNA。在此，我们将鉴定感染不同阶段的血浆miRNA生物标志物（目的1）;表征感染期间脑脊液（CSF）和脑中的miRNA谱;并鉴定预测CNS疾病（未治疗猕猴）发展或与ART治疗猕猴脑中炎性细胞因子持续水平相关的miRNA（目的2）。我们将使用来自东北艾滋病痴呆（NEAD）队列的匹配血浆和CSF将这些研究扩展到患有HAND的HIV感染个体，以鉴定和验证HAD，MC/MD和ANI的血浆miRNA生物标志物（目的3）。最后，将在脑和特定血浆组分中研究血浆miRNA生物标志物，以鉴定循环miRNA的细胞来源和疾病预测性血浆miRNA的载体（囊泡、脂蛋白颗粒、蛋白质复合物）（目的4）。 这些研究的目标是鉴定血浆miRNA生物标志物，其诊断和预测HAND的发展，并提供对HAND发病机制的见解。我们的假设是，差异表达的血浆miRNAs的独特组合将诊断HIV/SIV感染阶段，预测CNS疾病，并反映病毒和宿主反应在脑中的影响。这些miRNAs中的一些将起源于大脑，而另一些将源于影响或平行于CNS过程的外周过程。这些研究的结果将代表对健康和传染病期间血浆miRNAs如何起源和循环的理解的实质性进展。重要的是，我们的研究结果将对HAND诊断和治疗具有重要意义，有助于HAND发展过程中脑中失调的途径的功能表征：基于小RNA的治疗的潜在靶点。

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.