Vaccine and Infectious Disease Division, University of Washington, Seattle, United States.
Department of Medicine, University of Washington, Seattle, United States.
Elife. 2021 Jan 12;10:e57646. doi: 10.7554/eLife.57646.
Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be edited ex vivo to provide protection against infection. To project the thresholds of CCR5-edition necessary for HIV remission, we developed a mathematical model that recapitulates blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted HSPCs are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76-94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur.
自体 CCR5 基因编辑造血干细胞和祖细胞(HSPC)移植是实现 HIV 缓解的有前途的策略。然而,只有一小部分 HSPCs 可以在体外进行编辑,以提供对感染的保护。为了预测实现 HIV 缓解所需的 CCR5 编辑阈值,我们开发了一个数学模型,该模型从接受自体 CCR5 基因编辑的感染了 SHIV-1157ipd3N4 的猪尾猕猴的血液 T 细胞重建和血浆猴免疫缺陷病毒(SHIV)动力学中进行了复制。该模型预测,当以下两种情况同时发生时,可通过分析性治疗中断(ATI)获得病毒控制:(1)移植的 HSPCs 在全身照射后至少比残留的内源性 HSPCs 高五倍,以及(2)移植中受保护的 HSPCs 达到足以克服移植依赖性 SHIV 免疫丧失的阈值(76-94%)。在这些条件下,如果在移植基因修饰的细胞植入并重建至稳定状态之前不进行 ATI,则预计会发生自发的病毒控制。