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.

项目摘要/摘要 而抗逆转录病毒疗法（ART）的冒险大大降低了发病率和死亡率 与HIV感染相关，由于潜在感染的细胞的持续存在，无法实现病毒的根除 治疗期间。因此，艺术必须终生进行。累积数据表明HIV- 感染的个体通常会出现持续的免疫失调，慢性炎症和加速 即使在艺术介导的病毒抑制的情况下衰老。这些现实创造了一个明显的 有兴趣在受感染的个体中制定侵害艾滋病毒的策略。 HIV治疗策略的发展，评估和实施将急于我们 在感染者中，不太可能确定何时近期病毒复发的能力 停止抗逆转录病毒疗法（ART）。该P01项目的目标是识别将启用的生物标志物 我们要预测停用后HIV反弹之前的滞后阶段或“缓解”期间的持续时间 艾滋病毒感染者的艺术。在我们的研究中，大量的病毒学和免疫学参数将 在接受分析治疗的125个特征良好的艾滋病毒感染者的队列中进行测量 中断（ATI），以识别生物标志物，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提案项目3中描述的实验将专门检查预后 等离子体和脑脊液（CSF）中循环因子的广泛值的值，利用切割 边缘技术和来自多个ATI研究的纵向标本的前所未有的集合。 在AIM 1中，我们将实施下一代测序方法，以确定 循环核酸和病毒反弹，重点是microRNA剖面，无细胞DNA和残留的低级 HIV病毒血症。在AIM 2中，我们将评估循环外蔬菜的预后意义， 表征它们的丰度，细胞来源以及核酸和病毒蛋白货物。最后，在AIM 3中 可溶性抗病毒免疫因子将被评估为病毒反弹的预测指标，重点是高分辨率 与HIV持久性相关的抗HIV抗体反应，细胞因子和趋化因子的分析。 我们将与我们的生物信息学和生物统计学核心紧密合作，以将我们的高维数据转换为 依靠复杂的合奏机器，在艺术中断后的艾滋病毒反弹的强大预测指标 学习方法。最终，鉴定可靠的血浆基于血浆的病毒反弹预测指标 将代表该领域的最佳方案，从而可以快速发展，扩展和部署成本 - 有效的，无创的诊断方法可促进寻找HIV治疗的方法。