Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin, Berlin, Germany.
Systems Immunology Lab, Department of Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
PLoS Comput Biol. 2018 May 10;14(5):e1005998. doi: 10.1371/journal.pcbi.1005998. eCollection 2018 May.
BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.
BK 病毒（BKV）相关性肾病影响 1%-10%的肾移植受者，导致约 50%的病例移植物失败。针对不同 BKV 抗原的免疫反应已被证明对疾病发展具有预后价值。目前的数据表明，BKV 的结构抗原和调节抗原可能各自触发免疫反应的不同作用模式。为了研究细胞免疫反应的不同作用模式对 BKV 清除动力学的影响，我们使用 ODE 模型分析了 6 例 BKV 相关性肾病患者的 BKV 血浆负荷和抗 BKV T 细胞反应（Elispot）的动力学。结果表明，只有少数关于作用模式的假设与经验数据相符。与经验数据最相符的假设是，结构抗原触发感染细胞中病毒产生的阻断，而调节抗原触发感染细胞的加速死亡。这些不同的作用模式对于我们理解 BKV 的清除可能很重要，因为根据该假设，只有调节抗原才会触发病毒载量的快速和持续清除。其他假设的经验支持度较低，但可能解释个别患者的清除机制。我们的研究结果强调了动力学的异质性，包括针对结构抗原和调节抗原的免疫反应之间的延迟，以及其对 BKV 清除的相关性。我们的建模方法是第一个通过将病毒和免疫动力学结合起来研究 BKV 清除过程的方法，它可以为生成关于细胞免疫和病毒动力学之间相互关系的个性化假设提供框架。
