Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo

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 th...

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Bibliographic Details
Published in:Nature biotechnology 2010-08, Vol.28 (8), p.839-847
Main Authors: Crooks, Gay M, Gregory, Philip D, Cannon, Paula M, Holt, Nathalia, Kim, Kenneth, Friedman, Geoffrey, Taupin, Vanessa, Kohn, Donald B, Wang, Xingchao, Holmes, Michael C, Wang, Jianbin
Format: Article
Language:English
Subjects:
AIDS treatment
Alleles
Animals
Autografts
B cells
Biological and medical sciences
Biotechnology
Cells (Biology)
Cellular biology
Comparative analysis
Control
Development and progression
DNA binding proteins
Endonucleases - genetics
Endonucleases - metabolism
Fundamental and applied biological sciences. Psychology
Gene Deletion
Gene expression
Gene therapy
Genetic aspects
Genetic Engineering - methods
Health aspects
Health. Pharmaceutical industry
Hematopoietic Stem Cell Transplantation - methods
Hematopoietic stem cells
Hematopoietic Stem Cells - metabolism
HIV
HIV infection
HIV Infections - immunology
HIV Infections - therapy
HIV Infections - virology
HIV-1 - immunology
HIV-1 - metabolism
Human immunodeficiency virus
Human immunodeficiency virus 1
Humans
Industrial applications and implications. Economical aspects
Infection
Medical schools
Mice
Mice, Inbred NOD
Mice, SCID
Miscellaneous
Nucleases
Physiological aspects
Properties
Receptors, CCR5 - genetics
Receptors, CCR5 - metabolism
Rodents
Stem cells
Stem Cells - metabolism
Surgery
T cells
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Zinc finger proteins
Zinc Fingers - genetics
Zinc Fingers - physiology
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Summary: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/IL2rgamma(null) 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.
ISSN:1087-0156
1546-1696
DOI:10.1038/nbt.1663