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理解SIV反弹的原因和动力学， 猕猴该项目是一个整体计划的一部分，该计划结合了SIV感染者的广泛实验工作， 猕猴与定量分析和计算模型，以提供一个共同的框架，以了解 在受抑制的猕猴中停止抗逆转录病毒治疗（ART）后病毒反弹。的连接 艾滋病毒是明确的，并将通过平行发展和比较实验数据的基础上加强 猕猴SIV和人类HIV的计算模型。临床相关性通过使用 开发的模型模拟许多不同的治疗方法，以找到延迟或消除的方法 病毒反弹作为整个计划的一部分，项目3（“定量分析和计算建模， 病毒反弹”）将对来自项目和核心的所有实验数据进行定量数据分析， 编程，在多个数据源中识别可预测病毒反弹的生物标志物，并开发和 验证具有猕猴和SIV特定参数的预测计算模型。项目1和2以及 BSL 3核心将进行许多不同类型的定量读出实验，包括：基因 表达、趋化因子/细胞因子表达、免疫细胞指标、病毒储库表征和病毒表达。 在血浆和脑脊液中的含量。这些测量将在多个时间点进行，包括在 活动性感染、ART抑制、ART停止后抑制解除和停止后病毒感染 反弹对本项目中提出的数据进行仔细和彻底的分析不仅可以为 此外，还可以对所有项目的数据进行综合和整合。这将有助于该计划 对病毒反弹形成严格的系统级理解。为了实现这一目标，我们必须 确定了项目3的五个目标：（a）对每一个项目内的多模式、不同数据进行定量分析， 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，通过分析以往的数据，选择合适的实验条件;（d）识别 病毒反弹的生物标志物;以及（e）通过以下方式将猕猴中的SIV研究及其见解转化为人类中的HIV 将SIV的机械计算模型与HIV的模型进行比较。这些目标一直是 整合并提炼为项目3的三个目标：（1）了解病毒反弹的动态， 纵向数据(2)确定病毒反弹的前和早期停止后生物标志物。(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.