Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.
Broad CTL Response in Early HIV Infection Drives Multiple Concurrent CTL Escapes.
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DOI：
10.1371/journal.pcbi.1004492
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发表时间：
2015-10
影响因子：
4.3
通讯作者：
Ganusov VV
中科院分区：
文献类型：
--
作者：
Leviyang S;Ganusov VV
最近的研究强调了HIV逃避同时靶向多个病毒表位的细胞毒性T淋巴细胞（CTL）应答的能力。然而，这种逃逸所涉及的病毒动力学并不完全清楚。先前的分析已经做出了关于HIV逃避CTL应答的几个强有力的假设，例如独立或非同时逃避个体CTL应答。使用来自四名患者的HIV半基因组进化的实验数据，我们观察到在早期感染期间（感染的前100天）多重CTL应答的同时病毒逃逸，这证实了最近在一名HIV感染患者的研究中发现的结果。我们发现，目前的方法估计CTL逃逸率，独立的逃生的假设的基础上，有偏见，表现不佳时，CTL逃逸同时进行多个表位。我们提出了一种新的方法来分析纵向序列数据，以估计跨多个表位的CTL逃逸率，这种方法涉及的参数少，并在模拟研究中表现良好。通过将我们的新方法应用于实验数据，我们发现并发多个逃逸的发生率在0.03到0.4天-1之间，这是一个相对较宽的范围，反映了由于稀疏采样和参数值范围较宽而导致的不确定性。然而，我们发现，多个表位的并发逃逸率为0.1-0.2天-1，与我们的患者数据集一致。自20世纪90年代初以来，已知细胞毒性T淋巴细胞（CTL）在HIV感染中发挥重要作用，其中CTL靶向HIV表位，并且反过来，HIV通过靶向表位中的突变而逃逸。在过去的十年里，研究表明CTL反应同时针对多个HIV表位，但同时反应对HIV动态和进化的影响还没有很好地了解。通过对患者数据集和一种新的统计方法的分析，我们发现，在早期HIV感染过程中，并发的CTL反应驱动并发的HIV逃逸在多个表位具有显着的压力，这表明了一个复杂的画面，其中HIV同时探索多个突变途径，以逃避广泛而有效的CTL反应。
Recent studies have highlighted the ability of HIV to escape from cytotoxic T lymphocyte (CTL) responses that concurrently target multiple viral epitopes. Yet, the viral dynamics involved in such escape are incompletely understood. Previous analyses have made several strong assumptions regarding HIV escape from CTL responses such as independent or non-concurrent escape from individual CTL responses. Using experimental data from evolution of HIV half genomes in four patients we observe concurrent viral escape from multiple CTL responses during early infection (first 100 days of infection), providing confirmation of a recent result found in a study of one HIV-infected patient. We show that current methods of estimating CTL escape rates, based on the assumption of independent escapes, are biased and perform poorly when CTL escape proceeds concurrently at multiple epitopes. We propose a new method for analyzing longitudinal sequence data to estimate the rate of CTL escape across multiple epitopes; this method involves few parameters and performs well in simulation studies. By applying our novel method to experimental data, we find that concurrent multiple escapes occur at rates between 0.03 and 0.4 day−1, a relatively broad range that reflects uncertainty due to sparse sampling and wide ranges of parameter values. However, we show that concurrent escape at rates 0.1–0.2 day−1 across multiple epitopes is consistent with our patient datasets. Since the early 1990s, cytotoxic T lymphocytes (CTLs) have been known to play an important role in HIV infection with CTLs targeting HIV epitopes and, in turn, HIV escapes arising through mutations in the targeted epitopes. Over the past decade, studies have shown that CTL responses concurrently target multiple HIV epitopes, yet the effect of concurrent responses on HIV dynamics and evolution is not well understood. Through an analysis of patient datasets and a novel statistical method, we show that during early HIV infection concurrent CTL responses drive concurrent HIV escapes at multiple epitopes with significant pressure, suggesting a complex picture in which HIV simultaneously explores multiple mutational pathways to escape from broad and potent CTL response.