Project 3 - Quantitative analysis and computational modeling of viral rebound

项目3--摘要 我们建议使用先进的计算方法来了解SIV反弹的原因和动力学 猕猴。这个项目是一个整体计划的一部分，该计划结合了对SIV感染的广泛实验工作 用定量分析和计算模型为理解猕猴提供了一个通用的框架 受抑制猕猴停止抗逆转录病毒治疗(ART)后病毒反弹。这些联系 对HIV是明确的，并将通过并行开发和对比实验数据来加强 猕猴SIV和人类HIV的计算模型。临床相关性通过使用进一步增强 来模拟许多不同的治疗方法，以找到延迟或消除的方法 病毒式反弹。作为总体方案的一部分，项目3(“定量分析和计算模型 病毒反弹“)将对来自项目和核心的所有实验数据进行量化数据分析 计划，确定跨多个数据源的预测病毒反弹的生物标记物，并开发和 用猕猴和SIV特有的参数验证预测计算模型。项目1和项目2以及 BSL3核心将用许多不同类型的定量读数进行实验，包括：基因 表达、趋化因子/细胞因子表达、免疫细胞指标、病毒库特征和病毒 在血浆和脑脊液中都有负荷。这些测量将在多个时间点进行，包括在 主动感染、抗逆转录病毒疗法的抑制、通过停止抗逆转录病毒疗法从抑制中释放以及停止后的病毒 抢篮板球。本项目中提出的对数据的仔细和彻底的分析不仅将为 其他项目，但也允许合成和集成所有项目的数据。这将有助于该计划 在制定严格的、系统级别的病毒式反弹理解方面。为了做到这一点，我们有 确定了项目3的五个目标：(A)对每个项目中的多模式、不同数据进行量化分析 项目和跨项目；(B)建立一个整合这些数据的机械计算模型；(C)协助 在实验设计中，通过分析先前的数据来选择合适的实验条件；(D)确定 病毒反弹的生物标志物；以及(E)将这项关于猕猴体内SIV的研究及其对人类艾滋病毒的洞察转化为 将我们的SIV机械计算模型与我们的HIV模型进行比较。这些目标一直是 结合并提炼为项目3的三个目标：(1)了解病毒反弹的动态使用 纵向数据。(2)确定停药前和停药后早期病毒反弹的生物标志物。(3)预测反弹- 针对SIV和HIV的治疗干预。

PROJECT 3 -ABSTRACT We propose to use advanced computational methods to understand the causes & dynamics of SIV rebound in macaques. This project is a part of an overall program that combines extensive experimental work in SIV-infected macaques with quantitative analysis and computational models to provide a common framework to understand viral rebound following the cessation of antiretroviral therapy (ART) in suppressed macaques. The connections to HIV are clear, and will be enhanced by the parallel development and comparison of experimental-data-based computational models of SIV in macaques and HIV in humans. Clinical relevance is further enhanced by the use of the developed models to simulate many different therapeutic approaches to find methods to delay or eliminate viral rebound. As part of the overall Program, Project 3 (“Quantitative analysis and computational modeling of viral rebound”) will perform quantitative data analysis of all experimental data from the projects and cores of the Program, identify biomarkers across multiple data sources that are predictive of viral rebound, and develop and validate a predictive computational model with parameters specific to macaques and SIV. Projects 1 and 2 and the BSL3 core will conduct experiments with quantitative readouts of many different types including: gene expression, chemokine/cytokine expression, immune cell metrics, viral reservoir characterization, and the viral load in both the plasma and CSF. These measurements will be made at multiple time points, including during active infection, suppression by ART, release from suppression by cessation of ART, and post-cessation viral rebound. The careful and thorough analysis of data proposed in this project will not just provide a service to the other projects, but also enable synthesis and integration of data across all the projects. This will aid the Program in developing a rigorous, system-level understanding of viral rebound. In order to accomplish this, we have identified five goals for Project 3: (a) to provide quantitative analysis of the multimodal, diverse data within each project and across projects; (b) to build a mechanistic computational model that integrates this data; (c) to assist in experimental design, selecting appropriate experimental conditions by analyzing previous data; (d) to identify biomarkers of viral rebound; and (e) to translate this SIV-in-macaque study and its insights to HIV in humans by comparing our mechanistic computational models of SIV to our models of HIV. These goals have been incorporated and distilled into three aims for Project 3: (1) Understand the dynamics of viral rebound using longitudinal data. (2) Identify pre- and early post-cessation biomarkers of viral rebound. (3) Predict rebound- targeting therapeutic interventions in SIV and HIV.