Project 3: Identifying plasma biomarkers predicting time to HIV rebound after treatment interruption

项目 3：识别血浆生物标志物，预测治疗中断后 HIV 反弹的时间

• 批准号: 10223997
• 负责人: Satish Kumar Pillai
• 金额: $ 39.58万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-08 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223997
• 关键词: Aftercare; Aging; Antibody Response; Antigens; Antiviral Agents; Avidity; Bioinformatics; Biological Assay; Biological Markers; Biostatistics Core; Cells; Cerebrospinal Fluid; Chronic; Collection; Data; Development; Disease remission; Evaluation; Filtration; Flow Cytometry; Goals; HIV; HIV Antibodies; HIV Infections; HIV-1; Immune; Immunologic Factors; Immunologics; Immunoprecipitation; Individual; Inflammation; Interruption; Kinetics; Label; Luciferases; Machine Learning; Measurement; Measures; Mediating; MicroRNAs; Morbidity - disease rate; Nucleic Acids; Phase; Plasma; Protocols documentation; RNA; Recrudescences; Residual state; Resolution; Sampling; Small RNA; Specimen; Surface; System; Technology; Time; Viral; Viral Proteins; Viremia; Work; antibody detection; antiretroviral therapy; base; cell free DNA; chemokine; circulating microRNA; cohort; cost effective; cytokine; density; experience; experimental study; extracellular vesicles; interest; miRNA expression profiling; mortality; multidimensional data; multiplex assay; next generation sequencing; noninvasive diagnosis; predictive marker; prognostic significance; prognostic value; transcriptome sequencing; viral rebound; virology

PROJECT SUMMARY/ABSTRACT While the advent of antiretroviral therapy (ART) has dramatically reduced the morbidity and mortality associated with HIV infection, viral eradication is not achievable due to the persistence of latently-infected cells during treatment. ART must therefore be taken on a lifelong basis. Accumulating data suggest that HIV- infected individuals often experience persistent immune dysregulation, chronic inflammation, and accelerated aging even in the setting of ART-mediated viral suppression. These realities have created a pronounced interest in developing strategies to eradicate HIV in infected individuals. The development, evaluation and implementation of HIV curative strategies will depend critically on our capacity to determine when viral recrudescence in the near term is unlikely in an infected individual, justifying cessation of antiretroviral therapy (ART). The goal of this P01 project is to identify biomarkers that will enable us to predict the duration of the lag phase or “remission” period prior to HIV rebound following discontinuation of ART in HIV-infected individuals. In our study, a large number of virologic and immunologic parameters will be measured in a cohort of 125 well-characterized HIV-infected individuals undergoing analytical treatment interruption (ATI), to identify biomarkers that allow us to reliably predict the kinetics of viral rebound post-ART cessation. The experiments described in Project 3 of our P01 proposal will specifically examine the prognostic value of a broad spectrum of circulating factors in plasma and cerebrospinal fluid (CSF), leveraging cutting edge technologies and an unprecedented collection of longitudinal specimens from multiple ATI studies. In Aim 1, we will implement next-generation sequencing approaches to determine the relationship between circulating nucleic acids and viral rebound, focusing on microRNA profile, cell-free DNA, and residual low-level HIV viremia. In Aim 2, we will evaluate the prognostic significance of circulating extracellular vesicles, characterizing their abundance, cellular origin, and nucleic acid and viral protein cargo. Finally, in Aim 3, soluble antiviral immune factors will be evaluated as predictors of viral rebound, focusing on high-resolution analyses of anti-HIV antibody responses, cytokines and chemokines associated with HIV persistence. We will work closely with our Bioinformatics and Biostatistics Core to transform our high-dimensional data into robust predictors of HIV rebound following ART interruption, relying on sophisticated ensemble machine learning approaches. Ultimately, the identification of a reliable blood plasma-based predictor of viral rebound will represent an optimal scenario for the field, enabling rapid development, scaling and deployment of cost- effective, non-invasive diagnostic approaches to facilitate the search for an HIV cure.

项目概要/摘要 虽然抗逆转录病毒疗法（ART）的出现大大降低了发病率和死亡率 与 HIV 感染相关，由于潜伏感染细胞的持续存在，病毒无法根除 治疗期间。因此，必须终身接受抗逆转录病毒治疗。越来越多的数据表明，艾滋病毒 感染者通常会经历持续的免疫失调、慢性炎症和加速的免疫反应。 即使在 ART 介导的病毒抑制的情况下也会出现衰老现象。这些现实造成了明显的 有兴趣制定消除感染者艾滋病毒的策略。 艾滋病毒治疗策略的制定、评估和实施将主要取决于我们的 能够确定受感染个体何时不太可能出现病毒复发，从而证明 停止抗逆转录病毒治疗（ART）。这个 P01 项目的目标是识别生物标志物，使 我们可以预测停药后 HIV 反弹之前的滞后期或“缓解”期的持续时间 HIV 感染者的 ART 治疗。在我们的研究中，大量的病毒学和免疫学参数将 在 125 名接受分析治疗的特征明确的 HIV 感染者组成的队列中进行测量 中断（ATI），以确定生物标志物，使我们能够可靠地预测 ART 后病毒反弹的动力学 停止。我们 P01 提案的项目 3 中描述的实验将专门检查预后 血浆和脑脊液 (CSF) 中广泛循环因子的价值，利用切割 边缘技术和来自多项 ATI 研究的前所未有的纵向样本集合。 在目标 1 中，我们将实施下一代测序方法来确定之间的关系 循环核酸和病毒反弹，重点关注 microRNA 谱、游离 DNA 和残留低水平 HIV病毒血症。在目标 2 中，我们将评估循环细胞外囊泡的预后意义， 表征它们的丰度、细胞起源以及核酸和病毒蛋白货物。最后，在目标 3 中， 可溶性抗病毒免疫因子将被评估为病毒反弹的预测因子，重点关注高分辨率 分析与 HIV 持续存在相关的抗 HIV 抗体反应、细胞因子和趋化因子。 我们将与我们的生物信息学和生物统计学核心密切合作，将我们的高维数据转化为 依赖于复杂的集成机器，可以强有力地预测 ART 中断后 HIV 反弹的情况 学习方法。最终，确定了一种可靠的基于血浆的病毒反弹预测因子 将代表该领域的最佳方案，从而实现快速开发、扩展和部署成本 有效的、非侵入性的诊断方法，以促进寻找艾滋病毒治疗方法。