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经 CCR5 基因编辑自体造血细胞移植后反弹的 SHIV 控制的阈值。

Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation.

机构信息

Vaccine and Infectious Disease Division, University of Washington, Seattle, United States.

Department of Medicine, University of Washington, Seattle, United States.

出版信息

Elife. 2021 Jan 12;10:e57646. doi: 10.7554/eLife.57646.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad5c/7803377/8c6baaa61fc7/elife-57646-fig1.jpg

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