Modeling latently infected cell activation: viral and latent reservoir persistence, and viral blips in HIV-infected patients on potent therapy.-猫眼课题宝

DOI：

10.1371/journal.pcbi.1000533

发表时间：

2009-10

期刊：

PLoS computational biology

影响因子：

4.3

通讯作者：

中科院分区：

生物学2区

文献类型：

作者：

Rong L;Perelson AS

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752194/?report=classic

尽管有效的联合治疗通常能够将HIV-1患者的血浆病毒载量抑制到低于常规临床检测的检测极限，但通过更灵敏的检测方法，血浆中经常可以检测到低水平的病毒血症。此外，许多患者甚至在接受高抑制治疗多年后，仍会出现高于检测极限的短暂病毒血症发作，称为病毒突变。病毒根除的一个障碍是静止记忆CD4+ T细胞中HIV-1潜伏库的持续存在。低病毒载量持久性、潜伏库缓慢衰减和间歇性病毒突变的机制尚未完全确定。残留病毒复制对病毒和潜伏库持久性的定量贡献尚不清楚。在本文中，我们通过建立一个数学模型来探讨这些问题，该模型考虑了随机抗原刺激下潜伏感染细胞的激活。我们证明，潜伏感染细胞在免疫激活后的程序性扩张和收缩可以产生低水平的持续性病毒血症和间歇性病毒突变。此外，一小部分活化的T细胞恢复到潜伏状态，提供了补充潜伏库的潜力。通过这种方法，潜伏感染细胞的偶尔激活可以解释在不同临床研究中观察到的潜伏库的可变衰减特征。最后，我们提出了一个现象学模型，其中包括一个逻辑项，代表潜伏感染细胞的稳态增殖。该模型很简单，但可以稳健地产生治疗开始后出现的多相病毒下降，以及低水平持续性病毒血症和间歇性HIV-1信号。利用这些模型，我们为HIV-1的长期动态和在强效抗逆转录病毒治疗背景下的潜伏库提供了定量和综合的前景。目前的联合治疗可以将hiv -1感染个体的病毒载量抑制到低于标准商业检测的检测极限。然而，它不能从病人身上根除病毒。HIV-1通常可以在静息记忆CD4+ T细胞中被识别，并在接受有效治疗的患者中持续存在很长时间。这些潜伏感染的细胞衰变缓慢，但当被相关抗原激活时，可以产生新的病毒粒子。许多患者经历过短暂的病毒血症发作，或短暂发作，即使他们多年来血浆病毒载量“无法检测到”。在这里，我们开发了一个新的数学模型来描述随机抗原刺激下潜伏感染细胞的激活。利用该模型，我们发现潜伏感染细胞在激活后的程序性扩张和收缩可以产生低病毒载量持久性和病毒短暂性。潜伏储存库的偶尔补充可以解释临床实践中观察到的储存库的不同衰变动力学。我们还表明，潜伏感染细胞的稳态增殖模型可以解释低水平病毒的持久性、潜伏库的稳定性和病毒突变的出现。这些结果为长期病毒动力学提供了新的见解，并可能对HIV-1感染的治疗产生影响。

Although potent combination therapy is usually able to suppress plasma viral loads in HIV-1 patients to below the detection limit of conventional clinical assays, a low level of viremia frequently can be detected in plasma by more sensitive assays. Additionally, many patients experience transient episodes of viremia above the detection limit, termed viral blips, even after being on highly suppressive therapy for many years. An obstacle to viral eradication is the persistence of a latent reservoir for HIV-1 in resting memory CD4+ T cells. The mechanisms underlying low viral load persistence, slow decay of the latent reservoir, and intermittent viral blips are not fully characterized. The quantitative contributions of residual viral replication to viral and the latent reservoir persistence remain unclear. In this paper, we probe these issues by developing a mathematical model that considers latently infected cell activation in response to stochastic antigenic stimulation. We demonstrate that programmed expansion and contraction of latently infected cells upon immune activation can generate both low-level persistent viremia and intermittent viral blips. Also, a small fraction of activated T cells revert to latency, providing a potential to replenish the latent reservoir. By this means, occasional activation of latently infected cells can explain the variable decay characteristics of the latent reservoir observed in different clinical studies. Finally, we propose a phenomenological model that includes a logistic term representing homeostatic proliferation of latently infected cells. The model is simple but can robustly generate the multiphasic viral decline seen after initiation of therapy, as well as low-level persistent viremia and intermittent HIV-1 blips. Using these models, we provide a quantitative and integrated prospective into the long-term dynamics of HIV-1 and the latent reservoir in the setting of potent antiretroviral therapy. Current combination therapy can suppress viral loads in HIV-1-infected individuals to below the detection limit of standard commercial assays. However, it cannot eradicate the virus from patients. HIV-1 can generally be identified in resting memory CD4+ T cells and persists in patients on potent treatment for a long time. These latently infected cells decay slowly, but can produce new virions when activated by relevant antigens. Many patients experience transient episodes of viremia, or blips, even though they have “undetectable” plasma viral loads for many years. Here, we develop a new mathematical model describing latently infected cell activation upon random antigenic stimulation. Using the model, we show that programmed expansion and contraction of latently infected cells upon activation can generate both low viral load persistence and viral blips. Occasional replenishment of the latent reservoir may explain the different decay kinetics of the reservoir observed in clinical practice. We also show that a model with homeostatic proliferation of latently infected cells can explain persistence of low-level virus, stability of the latent reservoir, and emergence of viral blips. These results provide novel insights into the long-term virus dynamics and could have implications for the treatment of HIV-1 infection.