期刊
STEM CELL REPORTS
卷 17, 期 4, 页码 953-963出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2022.03.003
关键词
-
资金
- National Institutes of Health, United States [R24OD021322, R01HL132891, P51OD011106]
This study successfully targeted the CCR5 locus using CRISPR-Cas9 technology, resulting in HIV-resistant human T cells. The edited cells did not affect hematopoietic and T cell differentiation, and were unable to support replication of CCR5-tropic simian immunodeficiency viruses. This provides a platform for further exploration of AIDS therapies using gene-edited iPSCs in a nonhuman primate model.
Adoptive therapies with genetically modified somatic T cells rendered HIV resistance have shown promise for AIDS therapy. A renewable source of HIV-resistant human T cells from induced pluripotent stem cells (iPSCs) would further facilitate and broaden the applicability of these therapies. Here, we report successful targeting of the CCR5 locus in iPSCs generated from T cells (T-iPSCs) or fibroblasts (fib-iPSCs) from Mauritian cynomolgus macaques (MCM), using CRISPR-Cas9 technology. We found that CCR5 edit-ing does not affect hematopoietic and T cell differentiation potentials of fib-iPSCs. However, T-iPSCs with edited CCR5 lost their capacity to differentiate into CD4(+)CD8(+) T cells while maintaining myeloid differentiation potential. T cells and macrophages pro -duce d from CCR5-edited MCM iPSCs did not support replication of the CCR5-tropic simian immunodeficiency viruses SIVmac239 (T cell tropic) and SIVmac316 (macrophage-tropic). Overall, these studies provide a platform for further exploration of AIDS ther-apies based on gene-edited iPSCs in a nonhuman primate model.
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