Shiri Tinevimbo, Welte Alex
School of Computational and Applied Mathematics, University of the Witwatersrand, Private Bag 3, Johannesburg, South Africa.
Theor Biol Med Model. 2008 Nov 14;5:25. doi: 10.1186/1742-4682-5-25.
Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood.
We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically).
Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated.
Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens.
在资源有限的环境中，用于预防母婴传播（PMTCT）的高选择性抗逆转录病毒（ARV）方案，如单剂量奈韦拉平（NVP），会使原本处于边缘状态的被突变基因组感染的细胞亚群短暂增加。对于进一步耐药突变积累的长期影响尚未完全了解。
我们开发了一种新的区分毒株的混合确定性 - 随机群体动态类型模型，用于健康细胞和感染细胞。我们探讨了在短期单一疗法治疗后，由常见突变转录的细胞群体的短暂增加（以确定性方式建模）如何影响更罕见、更高阶、能抵抗治疗的突变出现的风险（以随机方式建模）。
与未治疗的情况相比，具有如已知在NVP单一疗法下发生的幅度和持续时间的短暂情况的场景，显示出病毒进化显著加速。我们确定了一个可能重要的新生物学时间尺度；即，携带新突变基因的细胞亚群在发生关键突变后持续存在的持续时间，并且我们展示了持续时间增加如何导致在启动新治疗方案时出现罕见突变体的概率增加。
即使常见突变体亚群的短暂增加也与更罕见突变的加速出现有关。应寻求关于在不利环境中罕见突变体小亚群持续存在的实验数据，因为这会影响破坏后续治疗方案的风险。
