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Assessing the impact of HIV treatment interruptions using stochastic cellular Automata.
Journal of Theoretical Biology ( IF 1.9 ) Pub Date : 2020-06-20 , DOI: 10.1016/j.jtbi.2020.110376
Andreas Hillmann 1 , Martin Crane 1 , Heather J Ruskin 1
Affiliation  

Chronic HIV infection causes a progressive decrease in the ability to maintain homeostasis resulting, after some time, in eventual break down of immune functions. Recent clinical research has shed light on a significant contribution of the lymphatic tissues, where HIV causes accumulation of collagen, (fibrosis). Specifically, where tissue is populated by certain types of functional stromal cells designated Fibroblastic Reticular Cells (FRCs), these have been found to play a crucial role in balancing out apoptosis and regeneration of naïve T-cells through 2-way cellular signaling. Tissue fibrosis not only impedes this signaling, effectively reducing T-cell levels through increased apoptosis of cells of both T- and FRC type but has been found to be irreversible by current HIV standard treatment (cART). While the therapy aims to block the viral lifecycle, cART-associated increase of T-cell levels in blood appears to conceal existing FRC impairment through fibrosis. This hidden impairment can lead to adverse consequences if treatment is interrupted, e.g. due to poor adherence (missing doses) or through periods recovering from drug toxicities. Formal clinical studies on treatment interruption have indicated possible adverse effects, but quantification of those effects in relation to interruption protocol and patient predisposition remains unclear. Accordingly, the impact of treatment interruption on lymphatic tissue structure and T-cell levels is explored here by means of computer simulation. A novel Stochastic Cellular Automata model is proposed, which utilizes all sources of clinical detail available to us (though sparse in part) for model parametrization. Sources are explicitly referenced and conflicting evidence from previous studies explored. The main focus is on (i) spatial aspects of collagen build up, together with (ii) collagen increase after repeated treatment interruptions to explore the dynamics of HIV-induced fibrosis and T-cell loss.



中文翻译:

使用随机细胞自动机评估HIV治疗中断的影响。

慢性HIV感染导致维持体内平衡能力逐渐下降,一段时间后,最终导致免疫功能下降。最近的临床研究揭示了淋巴组织的显着贡献,其中HIV引起胶原蛋白的积累(纤维化)。具体而言,在组织中由某些类型的功能性基质细胞(称为成纤维网状细胞(FRC))组成的地方,已发现它们在通过2向细胞信号传导平衡幼稚T细胞的凋亡和再生中起关键作用。组织纤维化不仅阻碍了这种信号传导,还通过增加T型和FRC型细胞的凋亡而有效地降低了T细胞水平,但发现这种纤维化是不可逆的通过当前的HIV标准治疗(cART)。尽管该疗法旨在阻断病毒的生命周期,但血液中cART相关的T细胞水平升高似乎掩盖了通过纤维化而存在的FRC损伤。如果治疗中断,例如由于依从性差(剂量不足)或从药物毒性中恢复过来,这种隐蔽的损害会导致不良后果。关于治疗中断的正式临床研究已经表明可能的不良反应,但是与中断方案和患者倾向有关的那些影响的量化仍不清楚。因此,此处通过计算机模拟探讨了治疗中断对淋巴组织结构和T细胞水平的影响。提出了一种新颖的随机细胞自动机模型,它利用我们可获得的所有临床细节资源(尽管部分稀疏)来进行模型参数化。明确引用了资料来源,并探讨了先前研究中相互矛盾的证据。主要关注点是(i)胶原蛋白积累的空间方面,以及(ii)反复中断治疗后胶原蛋白增加,以探讨HIV诱导的纤维化和T细胞丢失的动态。

更新日期:2020-06-30
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