Immune System Modeling/HIV

描述（由申请人提供）：抗逆转录病毒治疗开始后血浆HIV-1病毒载量衰减的数学分析导致了许多关于HIV感染的动力学和发病机制的重要见解。使用蛋白酶抑制剂和逆转录酶抑制剂疗法，发现了HIV RNA的经典双相衰变，并使用简单的病毒动力学模型进行了解释。这些模型表明，第一阶段是由于生产性感染细胞的快速死亡，第二阶段是由于长寿命感染细胞的死亡。值得注意的是，当被治疗干扰时，解释第一阶段衰减的相同简单模型也可以解释使用稀疏采样数据观察到的急性感染的动力学，这些数据大多在病毒载量峰值之后收集。现在，新的数据使我们能够对急性感染和长期药物治疗获得新的见解。首先，从早期捕获HIV队列（ECHO/RV 127）研究中获得了非常频繁采样的急性感染个体的数据。这项研究每周两次跟踪HIV感染高危人群。一旦被确定为艾滋病毒感染者，将在一个月内每周对个人进行两次采样，然后在另一个月内每周采样，然后在5年内每月采样，以获得有关临床后果的信息。急性感染动力学的原始模型与这些数据的拟合程度很差，这表明急性感染动力学尚未完全了解，特别是在免疫系统影响方面。其次，从一项ACTG研究中频繁收集的新数据显示，第一阶段有两个部分：治疗最初几天的快速衰减阶段（1a期），随后是较慢的1b期。使用单拷贝检测，已确定了非常缓慢的第3期衰变（t1/2=39周），随后是第4期稳定病毒血症，其起源尚不清楚。在这里，我们的目标是通过建模来揭示急性感染动态的生物学基础，以及这些新观察到的短期和长期治疗下的HIV动态，以及它们对治疗和病毒根除的影响。

DESCRIPTION (provided by applicant): The mathematical analysis of plasma HIV-1 viral load decay after the initiation of antiretroviral therapy has led to a number of important insights abou the dynamics and pathogenesis of HIV infection. With protease inhibitor and reverse transcriptase inhibitor therapies a now classic biphasic decay of HIV RNA was discovered and interpreted using simple viral dynamic models. These models suggested that the first phase was due to the rapid death of productively infected cells and that the second phase was due to the death of long-lived infected cells. Remarkably, the same simple model that accounted for first phase decay when perturbed by therapy could also account for the kinetics of acute infection observed using sparsely sampled data, mostly collected after the viral load peak. Now new data is available that allows us to gain new insights into both acute infection and long-term drug therapy. First, data from acutely infected individuals with very frequent sampling is available from the Early Capture HIV Cohort (ECHO/RV127) study. This study follows participants at high risk for HIV infection twice weekly. Once identified as being HIV-infected, individuals are sampled twice weekly for a month, then weekly for another month, then monthly for 5 years in order to obtain information on clinical consequences. The original model of acute infection dynamics fits much of this data poorly, suggesting acute infection kinetics are not yet fully understood, particularly with regard to immune system influences. Secondly, new frequently collected data from an ACTG study in which treatment na¿ve patients were given raltegravir plus emtricitabine/tenofovir uncovered that the first phase has two parts: a rapid phase of decay over the first few days of therapy (phase 1a) followed by a slower phase 1b. Using single copy assays, a very slow 3rd phase of decay (t1/2=39 wks) followed by a 4th phase of stable viremia has been identified, the origins of which are not understood. Here we aim to uncover through modeling the biological basis of acute infection dynamics and these newly observed short and long term HIV dynamics under therapy, and their implications for treatment and viral eradication.