Modeling Viral and T Lymphocyte Dynamics

病毒和 T 淋巴细胞动力学建模

基本信息

批准号：
10532680
负责人：
ALAN S PERELSON
金额：
$ 46.66万
依托单位：
TRIAD NATIONAL SECURITY, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-23 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532680
关键词：
Address Aftercare Anti-Retroviral Agents Antiviral Agents Antiviral Therapy Back Berlin Binding Biological Biological Markers Biology Cells Clinical Clinical Data Clinical Trials Collaborations Collection Communities Data Data Set Development Differential Equation Drug Combinations Drug Industry Effectiveness Frustration Generations Genetic Goals Grant HIV HIV Antigens HIV-1 HIV/HCV Hepatitis B Hepatitis B Infection Hepatitis B Therapy Hepatitis B Virus Hepatitis C Hepatitis C virus Human Immune Individual Infection Interruption Intervention Knowledge Literature London Maintenance Modeling New Agents Participant Patients Persons Pharmaceutical Preparations Play Process RNA Scientist T-Lymphocyte Testing Time Viral Viral Load result Viral reservoir Virus Virus Diseases Withholding Treatment acute infection antiretroviral therapy design detection limit diverse data drug mechanism experience in vivo innovation insight latent HIV reservoir mathematical model multi-scale modeling multiple datasets nonhuman primate novel novel strategies novel therapeutics purge response success viral rebound

项目摘要

SUMMARY Multiple recent studies have provided proof-of-concept that a “functional cure” of HIV-1 infection, i.e. long-term control of HIV without continued treatment, is achievable. The VISCONTI study identified 14 HIV+ patients, who received antiretroviral treatment (ART) during primary HIV-1 infection, and maintained post-treatment control (PTC) of their virus below the limit of detection for a median of 89 months after stopping therapy. The CHAMP (Control of HIV after Antiretroviral Medication Pause) study has identified 67 post-treatment controllers from 14 treatment interruption studies involving more than 700 participants. To determine why some individuals control HIV to undetectable or low levels after treatment discontinuation, we need a better understanding of the factors that lead to establishment of viral reservoirs, that determine its size, the dynamics of its maintenance and its reactivation possibly leading to viral rebound after treatment cessation. Here we propose to develop a set of new models to help understand the factors that led to functional cure in the studies mentioned above and to understand more generally how functional cure can be achieved. We will collaborate with leading experimental scientists, who will provide novel datasets allowing us to fulfil the following specific aims. Aim 1. To understand the mechanism of HIV latent reservoir establishment and the factors determining the rate of reservoir seeding during acute infection. We will develop mechanistic models of early reservoir establishment. We will test these models against rich datasets collected by collaborators and estimate key parameter values to accurately describe the dynamics of reservoir establishment. With the insights gained, we will extend the model to interpret recent data39 on the seeding, turnover and the genetic composition of the reservoir. Aim 2. To understand in quantitative detail the factors that determine the duration of post-treatment control after ART interruption. We will study new models that account for patient specific factors such as the ART regime and the level of cell-associated RNA at the time of ATI in predicting time to viral rebound after ATI. When the time to rebound is long, we aim to elucidate new factors such as a time-dependent rate of reservoir reactivation or immune control that lead to prolonged PTC. Aim 3. Using insights gained from mathematical modeling to propel the cure agenda for HBV. We will leverage previous modeling successes of HIV and HCV infection to develop a new generation of models of HBV infection and study the effects of different therapies singly and in combination.

概括最近的多项研究提供了概念验证，即 HIV-1 感染的“功能性治愈”，即无需持续治疗即可实现 HIV 的长期控制。 VISCONTI 研究是可以实现的。确定了 14 名 HIV+ 患者，他们在初次 HIV-1 期间接受了抗逆转录病毒治疗 (ART) 感染，并将病毒的治疗后控制 (PTC) 维持在检测限以下停止治疗后平均持续 89 个月的 CHAMP（抗逆转录病毒治疗后艾滋病毒控制）。药物暂停）研究已从 14 种治疗中确定了 67 名治疗后控制者涉及 700 多名参与者的中断研究。确定为什么有些人在治疗后将艾滋病毒控制在无法检测或较低的水平停止，我们需要更好地了解导致病毒式传播的因素水库，决定其大小、其维护动态以及可能的重新激活在此我们建议开发一套新的治疗停止后导致病毒反弹的方法。模型有助于理解上述研究中导致功能性治愈的因素上面并更广泛地了解如何实现功能性治愈。与领先的实验科学家合作，他们将提供新颖的数据集，使我们能够实现以下具体目标 1.了解HIV潜伏病毒库的机制。急性期水库建立及播种率的决定因素我们将开发早期储存库建立的机制模型，我们将测试这些模型。针对合作者收集的丰富数据集进行模型建模，并估计关键参数值根据所获得的见解，我们将准确地描述水库建立的动态。扩展模型以解释有关播种、周转和遗传组成的最新数据39 目标 2. 详细定量地了解决定储层的因素。 ART 中断后治疗后控制的持续时间我们将研究新的模型。考虑患者特定因素，例如 ART 方案和细胞相关 RNA 水平在 ATI 预测 ATI 后病毒反弹时间时，当反弹时间较长时，我们的目标是阐明新的因素，例如储存库重新激活的时间依赖性速率或免疫目标 3. 利用从数学建模中获得的见解。我们将利用之前艾滋病毒和乙肝病毒建模的成功经验来推动乙肝病毒的治疗议程。 HCV感染开发新一代HBV感染模型并研究其影响不同的疗法可以单独使用，也可以联合使用。