A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients.
A stochastic model of latently infected cell reactivation and viral blip generation in treated HIV patients.
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DOI：
10.1371/journal.pcbi.1002033
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发表时间：
2011-04
影响因子：
4.3
通讯作者：
Coombs D
中科院分区：
文献类型：
--
作者：
Conway JM;Coombs D
受长期抗逆转录病毒治疗（ART）的HIV+患者中病毒持续存在的启发，我们提出了血流中HIV病毒动力学的随机模型。我们认为，ART患者的残留病毒血症主要可以解释为ART开始前HIV潜伏感染细胞的激活，以及病毒信号（临床观察到的可检测病毒载量的短时间）代表与平均值的较大偏差。我们将系统建模为一个连续时间的多类型分支过程。推导方程的概率生成函数，我们使用一种新的数值方法来提取潜在的水库大小和病毒载量的概率分布。我们发现，潜在的水库沉积时间分布强调了考虑水库动态超越简单的半衰期的重要性。我们通过计算完整的病毒载量概率分布来计算blip幅度和频率，并通过直接数值模拟来研究病毒blip的持续时间。我们发现，我们的模型定性再现短的小幅度的光点在治疗HIV感染的临床研究中检测到的。这种类型的随机模型提供了从确定性模型中无法发现的治疗结果变异性的见解。在成功的药物治疗中，常规检测通常不会在艾滋病毒患者的血液中检测到病毒。然而，更敏感的技术可以检测到极低水平的病毒。偶尔，常规血液检查显示“病毒斑点”：短时间内升高，可检测到病毒载量。我们探讨了这一假设，即残留的低水平病毒载量在很大程度上可以解释为重新激活的细胞，被感染的治疗开始之前，和病毒的光点可以被视为偶尔的统计事件。为此，我们提出了一个数学模型的潜伏感染的细胞，激活的细胞，和病毒。该模型捕捉系统的随机波动以及平均行为。我们估计所有潜在感染细胞被根除所需的时间。根除这些细胞被认为是消除感染的主要障碍。我们预测了广泛的根除时间，强调了研究潜伏感染细胞的重要性。我们还估计了病毒信号的频率和持续时间，并发现与临床研究的定性一致。通过改进我们的模型，我们希望找到可用于实践的指导方针，以区分临床上无意义的统计学波动和药物失败的情况。
Motivated by viral persistence in HIV+ patients on long-term anti-retroviral treatment (ART), we present a stochastic model of HIV viral dynamics in the blood stream. We consider the hypothesis that the residual viremia in patients on ART can be explained principally by the activation of cells latently infected by HIV before the initiation of ART and that viral blips (clinically-observed short periods of detectable viral load) represent large deviations from the mean. We model the system as a continuous-time, multi-type branching process. Deriving equations for the probability generating function we use a novel numerical approach to extract the probability distributions for latent reservoir sizes and viral loads. We find that latent reservoir extinction-time distributions underscore the importance of considering reservoir dynamics beyond simply the half-life. We calculate blip amplitudes and frequencies by computing complete viral load probability distributions, and study the duration of viral blips via direct numerical simulation. We find that our model qualitatively reproduces short small-amplitude blips detected in clinical studies of treated HIV infection. Stochastic models of this type provide insight into treatment-outcome variability that cannot be found from deterministic models. While on successful drug treatment, routine testing does not usually detect virus in the blood of an HIV patient. However, more sensitive techniques can detect extremely low levels of virus. Occasionally, routine blood tests show “viral blips”: short periods of elevated, detectable viral load. We explore the hypothesis that residual low-level viral load can be largely explained by re-activation of cells that were infected before the initiation of treatment, and that viral blips can be viewed as occasional statistical events. To do this, we propose a mathematical model of latently-infected cells, activated cells, and virus. The model captures random fluctuations of the system as well as the mean behaviour. We estimate the time it takes for all the latently-infected cells to be eradicated. Eradication of these cells is considered a major hurdle in eliminating infection. We predict a wide range of eradication times, highlighting the importance of studying latently-infected cells. We also estimate the frequency and duration of viral blips, and find qualitative agreement with clinical studies. By refining our models, we hope to find guidelines that can be used in practise to distinguish between clinically insignificant statistical blips, and instances of drug failure.
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影响因子：
5.4
作者：
Havlir, DV;Strain, MC;Wong, JK
通讯作者：
Wong, JK
影响因子：
8.8
作者：
Fondere, JM;Planas, JF;Vendrell, JP
通讯作者：
Vendrell, JP
影响因子：
6.4
作者：
G端nthard, HF;Wong, JK;Richman, DD
通讯作者：
Richman, DD
使用细胞因子的组合在潜在感染的CD4+ T细胞中诱导HIV-1复制。
DOI：
10.1084/jem.188.1.83
发表时间：
1998-07-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.2
作者：
Bowman, Mary-Catherine;Archin, Nancie M.;Margolis, David M.
通讯作者：
Margolis, David M.