Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics.
Large Variations in HIV-1 Viral Load Explained by Shifting-Mosaic Metapopulation Dynamics.
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DOI：
10.1371/journal.pbio.1002567
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发表时间：
2016-10
期刊：
影响因子：
9.8
通讯作者：
Fraser C
中科院分区：
文献类型：
--
作者：
Lythgoe KA;Blanquart F;Pellis L;Fraser C
HIV-1的病毒群体，像许多引起全身感染的病原体一样，在体内是结构化和分化的。细胞免疫通过血液和在身体隔室内的动态运输也受到广泛关注。尽管取得了这些进展，但广泛用于解释和预测感染中病毒和免疫动力学的数学模型通常将受感染的宿主视为混合均匀的环境。在这里，我们提出的数学，分析和计算结果表明，考虑到宿主内的病毒种群的空间结构从根本上改变了以前的模型的预测。我们研究了在空间分离的补丁，代表T细胞区域连接循环血液和淋巴细胞的集合种群内的病毒复制和细胞毒性T淋巴细胞（CTL）的动态。该系统的动力学关键取决于CTL和感染细胞之间的相互作用，在补丁内的水平。我们表明，对于广泛的参数范围内，系统承认一个意想不到的结果称为移位马赛克稳态。在这种状态下，整个身体的病毒种群随着时间的推移是稳定的，但这种平衡来自于T细胞中心内局部感染和清除的潜在的高度动态过程。值得注意的是，与以前的模型相比，这种新模型可以解释在患者及其分布之间观察到的设定点病毒载量（SPVL）的巨大差异，以及在任何一个时间感染的细胞比例相对较低，并改变了病毒载量变化的预测决定因素。一个新的集合种群模型表明，宿主内感染的特点是一个高度动态的过程，局部感染，然后清除T细胞中心。当一个人感染艾滋病毒时，血液中病毒的初始峰值水平通常很高，然后达到较低的相对稳定的水平，并在慢性感染期间保持。这个稳定的水平被称为设定点病毒载量（SPVL），与感染的严重程度有关。SPVL在患者中也是高度可变的，范围从每毫升血液100到100万个病毒拷贝。感染病毒的复制能力和免疫应答的强度都影响SPVL。然而，标准的数学模型表明，这两个因素的变化不能轻易地再现观察到的患者中SPVL的分布。标准模型通常将感染个体视为混合系统，但实际上病毒复制局限于次级淋巴组织中的T细胞中心或斑块。为了解释这种人口结构，我们开发了一个精心参数化的集合种群模型。我们发现该系统可以达到稳定状态，血液中的病毒载量相对稳定，代表SPVL，但令人惊讶的是，补丁是高度动态的，其特征是由于局部宿主免疫反应导致的感染爆发，然后消除病毒。值得注意的是，该模型可以再现在感染个体中发现的SPVL的广泛分布，以获得病毒复制能力和免疫应答强度的真实分布。我们的模型也可以在未来用于了解慢性HIV感染的其他方面。
The viral population of HIV-1, like many pathogens that cause systemic infection, is structured and differentiated within the body. The dynamics of cellular immune trafficking through the blood and within compartments of the body has also received wide attention. Despite these advances, mathematical models, which are widely used to interpret and predict viral and immune dynamics in infection, typically treat the infected host as a well-mixed homogeneous environment. Here, we present mathematical, analytical, and computational results that demonstrate that consideration of the spatial structure of the viral population within the host radically alters predictions of previous models. We study the dynamics of virus replication and cytotoxic T lymphocytes (CTLs) within a metapopulation of spatially segregated patches, representing T cell areas connected by circulating blood and lymph. The dynamics of the system depend critically on the interaction between CTLs and infected cells at the within-patch level. We show that for a wide range of parameters, the system admits an unexpected outcome called the shifting-mosaic steady state. In this state, the whole body’s viral population is stable over time, but the equilibrium results from an underlying, highly dynamic process of local infection and clearance within T-cell centers. Notably, and in contrast to previous models, this new model can explain the large differences in set-point viral load (SPVL) observed between patients and their distribution, as well as the relatively low proportion of cells infected at any one time, and alters the predicted determinants of viral load variation. A novel metapopulation model of HIV suggests that within-host infections are characterized by a highly dynamic process of localized infection followed by clearance within T cell centers. When a person is infected with HIV, the initial peak level of virus in the blood is usually very high before a lower, relatively stable level is reached and maintained for the duration of the chronic infection. This stable level is known as the set-point viral load (SPVL) and is associated with severity of infection. SPVL is also highly variable among patients, ranging from 100 to a million copies of the virus per mL of blood. The replicative capacity of the infecting virus and the strength of the immune response both influence SPVL. However, standard mathematical models show that variation in these two factors cannot easily reproduce the observed distribution of SPVL among patients. Standard models typically treat infected individuals as well-mixed systems, but in reality viral replication is localised in T-cell centres, or patches, found in secondary lymphoid tissue. To account for this population structure, we developed a carefully parameterised metapopulation model. We find the system can reach a steady state at which the viral load in the blood is relatively stable, representing SPVL, but surprisingly, the patches are highly dynamic, characterised by bursts of infection followed by elimination of virus due to localised host immune responses. Significantly, this model can reproduce the wide distribution of SPVLs found among infected individuals for realistic distributions of viral replicative capacity and strength of immune response. Our model can also be used in the future to understand other aspects of chronic HIV infection.
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影响因子：
2
作者：
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影响因子：
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DOI：
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