PDF(Pubmed)
Abstract：
Human immunodeficiency virus (HIV) infects CD4+ cells and causes progressive immune function failure, and CD8+ cells lyse infected CD4+ cell via recognising peptide presented by human leukocyte antigens (HLA). Variations in HLA allele lead to observed different HIV infection outcomes. Within-host HIV dynamics involves virus replication within infected cells and lysing of infected cells by CD8+ cells, but how variations in HLA alleles determine different infection outcomes was far from clear. Here, we used mathematical modelling and parameter inference with a new analysis of published virus inhibition assay data to estimate CD8+ cell lysing efficiency, and found that lysing efficiency fall in the gap between low bound (0.1-0.2 day-1 (Elemans et al. in PLoS Comput Biol 8(2):e1002381, 2012)) and upper boundary (6.5-8.4 day-1 (Wick et al. in J Virol 79(21):13579-13586, 2005)). Our outcomes indicate that both lysing efficiency and viral inoculum size jointly determine observed different infection outcomes. Low lysing rate associated with non-protective HLA alleles leads to monostable viral kinetic to high viral titre and oscillatory viral kinetics. High lysing rate associated with protective HLA alleles leads monostable viral kinetic to low viral titre and bistable viral kinetics; at a specific interval of CD8+ cell counts, small viral inoculum sizes are inhibited but not large viral inoculum sizes remain infectious. Further, with CD8+ cell recruitment, HIV kinetics always exhibit oscillatory kinetics, but lysing rate is negatively correlated with range of CD8+ cell count. Our finding highlights role of HLA allele determining different infection outcomes, thereby providing a potential mechanistic explanation for observed good and bad HIV infection outcomes induced by protective HLA allele.
摘要：
人类免疫缺陷病毒（HIV）感染CD4+细胞，导致进行性免疫功能衰竭，和CD8+细胞通过识别由人白细胞抗原(HLA)呈递的肽裂解感染的CD4+细胞。HLA等位基因的变异导致观察到不同的HIV感染结果。宿主内HIV动力学涉及感染细胞内的病毒复制和CD8+细胞裂解感染细胞，但HLA等位基因的变异如何决定不同的感染结局尚不清楚.这里,我们使用数学建模和参数推断与已发表的病毒抑制测定数据的新分析来估计CD8+细胞裂解效率，并发现裂解效率下降到低结合(0.1-0.2天-1(Elemans等人。在PLoSComputBiol8（2）：e1002381，2012）中）和上边界（6.5-8.4天-1（Wick等人。见JVirol79(21):13579-13586,2005))。我们的结果表明，裂解效率和病毒接种量共同决定了观察到的不同感染结果。与非保护性HLA等位基因相关的低裂解率导致单稳态病毒动力学至高病毒滴度和振荡病毒动力学。与保护性HLA等位基因相关的高裂解率导致单稳态病毒动力学至低病毒滴度和双稳态病毒动力学;在CD8+细胞计数的特定间隔，小的病毒接种物大小被抑制，但大的病毒接种物大小不保持传染性。Further,CD8+细胞募集，HIV动力学总是表现出振荡动力学，但裂解率与CD8+细胞计数范围呈负相关。我们的发现强调了HLA等位基因决定不同感染结果的作用，从而为观察到的由保护性HLA等位基因诱导的良好和不良HIV感染结果提供了潜在的机制解释。
