Department of Environment and Genetics, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, 3086, Australia.
Department of Mathematical and Physical Sciences, La Trobe University, Bundoora, VIC, 3086, Australia.
Bull Math Biol. 2024 Jul 13;86(9):107. doi: 10.1007/s11538-024-01334-9.
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 (Elemans et al. in PLoS Comput Biol 8(2):e1002381, 2012)) and upper boundary (6.5-8.4 day (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.
人类免疫缺陷病毒（HIV）感染 CD4+细胞，导致渐进性免疫功能衰竭，CD8+细胞通过识别人类白细胞抗原（HLA）呈递的肽来裂解感染的 CD4+细胞。HLA 等位基因的变异导致观察到不同的 HIV 感染结果。体内 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果还远不清楚。在这里，我们使用数学建模和参数推断，并对已发表的病毒抑制测定数据进行新的分析，以估计 CD8+细胞裂解效率，发现裂解效率落在低边界（0.1-0.2 天（Elemans 等人，PLoS Comput Biol 8（2）：e1002381，2012））和上边界（6.5-8.4 天（Wick 等人，J Virol 79（21）：13579-13586，2005））之间的差距。我们的结果表明，裂解效率和病毒接种物大小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病毒动力学和高病毒载量以及振荡病毒动力学。与保护性 HLA 等位基因相关的高裂解率导致单稳病毒动力学和低病毒载量以及双稳病毒动力学；在特定的 CD8+细胞计数间隔内，小病毒接种物大小被抑制，但大病毒接种物大小仍具有感染性。此外，随着 CD8+细胞的募集，HIV 动力学总是表现出振荡动力学，但裂解率与 CD8+细胞计数的范围呈负相关。我们的发现强调了 HLA 等位基因决定不同感染结果的作用，从而为保护性 HLA 等位基因引起的良好和不良 HIV 感染结果提供了潜在的机制解释。
