Cotterell James, Neely G Gregory
The Garvan Institute for Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia.
The Dr. John and Anne Chong Lab for Functional Genomics, Charles Perkins Centre and School of Life & Environmental Sciences, The University of Sydney, Camperdown, NSW, 2006, Australia.
Sci Rep. 2017 Nov 30;7(1):16644. doi: 10.1038/s41598-017-00097-9.
Cell state switches underlie a plethora of biological phenomena and disease treatment strategies. Hence the ability to efficiently switch states in a chosen direction is of central importance in a number of scenarios. Increasing the concentration of an effector that results in a given switch is often limited by side effects. Approaches are thus increasingly sought to bypass these constraints, increasing the frequency of state switching without increasing the frequency of the side effect. Here, we employ dynamical systems theory to uncover a simple strategy as to how to maximize the probability of reactivating latent Human immunodeficiency virus (HIV) whilst maintaining minimal side effects. We demonstrate that continuous supply of an effector is significantly more likely to result in a switch with minimal side effects than the same effector supplied in temporally discrete doses. Importantly this continual dosage is likely to occur far below the Minimum effective dose at a concentration that has classically been thought subtherapeutic. We therefore suggest that in many interventional settings there exists potential to reduce drug dose much further than has previously been thought possible yet still maintaining efficacy.
细胞状态转换是众多生物现象和疾病治疗策略的基础。因此，在许多情况下，能够有效地朝着选定方向转换状态至关重要。增加导致特定转换的效应物浓度通常会受到副作用的限制。因此，人们越来越多地寻求绕过这些限制的方法，即在不增加副作用频率的情况下提高状态转换频率。在这里，我们运用动力系统理论来揭示一种简单的策略，即如何在保持最小副作用的同时最大化重新激活潜伏的人类免疫缺陷病毒（HIV）的概率。我们证明，与以时间离散剂量供应相同的效应物相比，持续供应效应物更有可能以最小的副作用导致状态转换。重要的是，这种持续剂量很可能在远低于经典认为的亚治疗浓度的最小有效剂量下发生。因此，我们认为在许多干预环境中，存在进一步降低药物剂量的潜力，且剂量降低幅度远超此前认为的可能范围，但仍能保持疗效。
