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- Title
Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo.
- Authors
Holt, Nathalia; Wang, Jianbin; Kim, Kenneth; Friedman, Geoffrey; Wang, Xingchao; Taupin, Vanessa; Crooks, Gay M.; Kohn, Donald B.; Gregory, Philip D.; Holmes, Michael C.; Cannon, Paula M.
- Abstract
CCR5 is the major HIV-1 co-receptor, and individuals homozygous for a 32-bp deletion in CCR5 are resistant to infection by CCR5-tropic HIV-1. Using engineered zinc-finger nucleases (ZFNs), we disrupted CCR5 in human CD34+ hematopoietic stem/progenitor cells (HSPCs) at a mean frequency of 17% of the total alleles in a population. This procedure produces both mono- and bi-allelically disrupted cells. ZFN-treated HSPCs retained the ability to engraft NOD/SCID/IL2rγnull mice and gave rise to polyclonal multi-lineage progeny in which CCR5 was permanently disrupted. Control mice receiving untreated HSPCs and challenged with CCR5-tropic HIV-1 showed profound CD4+ T-cell loss. In contrast, mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5−/− cells, had significantly lower HIV-1 levels and preserved human cells throughout their tissues. The demonstration that a minority of CCR5−/− HSPCs can populate an infected animal with HIV-1-resistant, CCR5−/− progeny supports the use of ZFN-modified autologous hematopoietic stem cells as a clinical approach to treating HIV-1.
- Subjects
HIV; HIV infections; HEMATOPOIETIC stem cells; NUCLEASES; GENETIC engineering; HEMATOPOIETIC system
- Publication
Nature Biotechnology, 2010, Vol 28, Issue 8, p839
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/nbt.1663