Nature biotechnology, 2010-08, Vol.28 (8), p.839-847
2010
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- Autor(en) / Beteiligte
- Titel
- Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo
- Ist Teil von
- Nature biotechnology, 2010-08, Vol.28 (8), p.839-847
- Ort / Verlag
- New York, NY: Nature Publishing Group
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1087-0156eISSN: 1546-1696DOI: 10.1038/nbt.1663Titel-ID: cdi_proquest_miscellaneous_874182162
- Format
- –
- Schlagworte
- 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