Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression.
Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression.
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DOI：
10.1371/journal.pcbi.1000240
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发表时间：
2008-12
影响因子：
4.3
通讯作者：
Leitner, Thomas
中科院分区：
文献类型：
--
作者：
Lee, Ha Youn;Perelson, Alan S.;Park, Su-Chan;Leitner, Thomas
量化宿主内HIV-1序列进化的动力学是揭示HIV-1与宿主免疫系统之间相互作用的信息的一种手段。在慢性感染阶段，已有报道了序列差异和多样性的共同动态。我们开发了一个HIV-1序列进化模型，该模型模拟了序列变体的突变和适合度的影响。进化量通过与创始菌株的距离来描述，而适合度则通过亲本序列产生的后代数量来描述。对模型的分析表明，以前观察到的多样性饱和和感染后期多样性下降的原因可以解释为，随着与创始人菌株的距离增加，突变后代的比例下降，而不是由于病毒适合度的增加。通过进行系统发育分析以估计感染期间进化速度的变化来检验该模型的预测。与我们的模型一致的是，在15名患者中的13名患者(随访3-12年)中，我们发现宿主内HIV-1的进化速度不是恒定的，而是以与CD4+T细胞下降速度相关的速度减慢。进化速率和CD4+T细胞衰减率之间的动态关系，再加上我们的HIV-1序列进化模型，解释了以前关于HIV-1准种进化速率和疾病进展之间关系的相互矛盾的观察结果。在HIV-1感染的后期，通常会观察到序列差异饱和和多样性下降，尽管不同患者之间出现获得性免疫缺陷综合征(AIDS)的时间长短差异很大。为了解释这一共同特征，我们开发了一个简单的序列进化模型，包括两个主要组成部分：(I)适应度，产生的后代数量，以及(Ii)突变后代的比例。假设随着病毒变异株从创始人株进一步进化，突变后代的比例下降，我们能够适应分歧和多样性的普遍趋势。相比之下，无论是适应度逐渐增加的模型，还是适应度更高的病毒变异迅速出现的模型，都不能解释分歧和多样性的动态。该模型的预测在大多数纵向跟踪的患者中得到了证实；HIV-1的进化速度在疾病进展之前是静止的；然而，该速度放缓的速度与免疫细胞下降的速度相关。破译HIV-1进化速度和免疫细胞水平动力学之间的动态关联，统一了以前关于HIV-1进化速度和疾病进展之间关系的相互矛盾的观察结果。
Quantifying the dynamics of intrahost HIV-1 sequence evolution is one means of uncovering information about the interaction between HIV-1 and the host immune system. In the chronic phase of infection, common dynamics of sequence divergence and diversity have been reported. We developed an HIV-1 sequence evolution model that simulated the effects of mutation and fitness of sequence variants. The amount of evolution was described by the distance from the founder strain, and fitness was described by the number of offspring a parent sequence produces. Analysis of the model suggested that the previously observed saturation of divergence and decrease of diversity in later stages of infection can be explained by a decrease in the proportion of offspring that are mutants as the distance from the founder strain increases rather than due to an increase of viral fitness. The prediction of the model was examined by performing phylogenetic analysis to estimate the change in the rate of evolution during infection. In agreement with our modeling, in 13 out of 15 patients (followed for 3–12 years) we found that the rate of intrahost HIV-1 evolution was not constant but rather slowed down at a rate correlated with the rate of CD4+ T-cell decline. The correlation between the dynamics of the evolutionary rate and the rate of CD4+ T-cell decline, coupled with our HIV-1 sequence evolution model, explains previously conflicting observations of the relationships between the rate of HIV-1 quasispecies evolution and disease progression. Saturation of sequence divergence and a decline of diversity in later stages of infection have been commonly observed during HIV-1 infection, although the length of the time to acquired immunodeficiency syndrome (AIDS) is highly variable among patients. To explain this common feature, we developed a simple sequence evolution model with two main components: (i) fitness, the number of offspring produced, and (ii) the proportion of offspring that are mutants. Assuming a decrease in the proportion of offspring that are mutants as virus variants evolve further from the founder strain, we were able to fit the universal trends of divergence and diversity. In contrast, neither the model with gradual increase of fitness nor the model with rapid emergence of virus variants with greater fitness explained the dynamics of divergence and diversity. The prediction of the model was confirmed in the majority of longitudinally followed patients; the rate of HIV-1 evolution was stationary before disease progresses; however, the rate slowed down at a rate correlated with the rate of immune cell decline. Deciphering dynamic correlation between the rate of HIV-1 evolution and the kinetics of immune cell level united previous conflicting observations of the relationships between the rate of HIV-1 evolution and disease progression.
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DOI：
10.1073/pnas.94.5.1925
发表时间：
1997-03-04
影响因子：
11.1
作者：
Bleul, CC;Wu, LJ;Mackay, CR
通讯作者：
Mackay, CR
影响因子：
5.4
作者：
DELWART, EL;SHEPPARD, HW;MULLINS, JI
通讯作者：
MULLINS, JI
影响因子：
5.4
作者：
Ganeshan, S;Dickover, RE;Wolinsky, SM
通讯作者：
Wolinsky, SM
影响因子：
64.8
作者：
Day, Cheryl L.;Kaufmann, Daniel E.;Walker, Bruce D.
通讯作者：
Walker, Bruce D.
影响因子：
5.4
作者：
Delwart, EL;Pan, H;Mullins, JI
通讯作者：
Mullins, JI