Cited by 677HIV Research and TreatmentCRISPR and Genetic EngineeringVirus-based gene therapy research

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

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Holt, Nathalia, Wang, Jianbin, Kim, Kenneth, Friedman, Geoffrey, Wang, Xingchao, Taupin, Vanessa, Crooks, Gay M, Kohn, Donald B +3 more·2010·Nature Biotechnology

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/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.

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  • Similar to CD4+ T cells, gene-modified HSCs were greatly enriched after infection.

    “Similar to CD4+ T cells engraftment described earlier, the gene-modified cells were greatly enriched after infection [43].”

    From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [43]

  • Holt and co-workers used nucleofection to achieve ZFN-mediated CCR5 disruption in human CD34+ HSCs.

    “Holt and co-workers used nucleofection to achieve ZFN-mediated CCR5 disruption in human CD34+ HSCs.”

    From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [43]

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Authors
Holt, N., Wang, J., Kim, K., Friedman, G., Wang, X., Taupin, V., Crooks, G. M., Kohn, D. B., Gregory, P. D., Holmes, M. C., & Cannon, P. M.
Affiliations
  • University of Southern California (US)
  • Sangamo BioSciences (United States) (US)
  • Children's Hospital Los Angeles (US)
  • University of California, Los Angeles (US)
Corresponding author
Cannon, Paula M
Venue
Nature Biotechnology
Published
2010-07-02
Volume
28
Issue
8
Pages
839-847
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
OpenAlex
W2099106733
Cited by
677
References
75
Citations by year
2026: 8 · 2025: 10 · 2024: 10 · 2023: 18 · 2022: 15 · 2021: 29 · 2020: 34 · 2019: 28 · 2018: 37 · 2017: 45 · 2016: 74 · 2015: 83 · 2014: 78 · 2013: 70 · 2012: 72
FWCI
22.85
Type
journal article
Language
en
Open access
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (P01HL073104, P01 HL73104)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HIV-1, CCR5, zinc finger nucleases, hematopoietic stem and progenitor cells, gene knockout, CCR5-tropic HIV-1, HIV drug resistance, autologous stem cell transplantation, CD4+ T cell depletion
MeSH terms
Animals, Endonucleases, Genetic Engineering, Hematopoietic Stem Cells, Humans, Stem Cells, T-Lymphocytes, HIV-1, HIV Infections, Zinc Fingers, Mice, SCID, Mice, Inbred NOD, Gene Deletion, Hematopoietic Stem Cell Transplantation, Receptors, CCR5, Mice

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