Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV
Open accessAbstract
BACKGROUND: CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe. METHODS: We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. RESULTS: One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CONCLUSIONS: CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
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A recent clinical trial showed autologous reintroduction of CD4 T cells whose CCR5 gene was inactivated in vitro by ZFN was safe and led to decreased viral load.
“Interestingly, a recent clinical trial 38 showed that autologous reintroduction of CD4T cells whose CCR5 gene was inactivated in vitro by ZFN was safe and lead to decreased viral load”
From CRISPR-Cas9: a new and promising player in gene therapy (2015) · cites this paper as [38]
Functional knockout of CCR5 in autologous CD4 T cells of a small cohort revealed that in one out of four enrolled subjects, the viral load remained undetectable at the time of treatment.
“Functional knockout of CCR5 in autologous CD4 T cells of a small cohort of patients revealed that in one out of four enrolled subjects, the viral load remained undetectable at the time of treatment”
From RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection (2014) · cites this paper as [33]
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“The siRNA binds to an Argonaute protein (Ago2), forming the RNA-induced silencing complex (RISC), which degrades the complementary mRNA.”
BackgroundClaiborne, D. T., Detwiler, Z., Docken, S. S., Borland, T. D., Cromer, D., Simkhovich, A., Ophinni, Y., Okawa, K., Bateson, T., Chen, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55873-3 · Cited by 16 · see citing works
Matrix Mediated Viral Gene Delivery: A Review
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CRISPR-Cas9 genome editing for cancer immunotherapy: opportunities and challenges
Chen, M., Xu, J., Zhou, Y., Zhang, S., & Zhu, D. (2020) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz027 · Cited by 12 · see citing works
Genome Editing for the β-Hemoglobinopathies
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- Authors
- Tebas, P., Stein, D., Tang, W. W., Frank, I., Wang, S. Q., Lee, G., Spratt, S. K., Surosky, R. T., Giedlin, M. A., Nichol, G., Holmes, M. C., Gregory, P. D., Ando, D. G., Kalos, M., Collman, R. G., Binder-Scholl, G., Plesa, G., Hwang, W.-T., Levine, B. L., & June, C. H.
- Affiliations
- Albert Einstein College of Medicine (US)
- Sangamo BioSciences (United States) (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-03-06
- Volume
- 370
- Issue
- 10
- Pages
- 901-910
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4084652
- OpenAlex
- W2125524975
- Cited by
- 1,357
- References
- 28
- Citations by year
- 2026: 40 · 2025: 46 · 2024: 58 · 2023: 45 · 2022: 81 · 2021: 99 · 2020: 109 · 2019: 106 · 2018: 117 · 2017: 175 · 2016: 201 · 2015: 180 · 2014: 96 · 2013: 3 · 2012: 1
- FWCI
- 96.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service (P30 AIO45008, AIO69534)
- National Cancer Institute (P30CA016520)
- National Institute of Allergy and Infectious Diseases (U19AI066290, UM1AI069534, P30AI045008)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- zinc finger nucleases, HIV infection, HIV cure, antiretroviral therapy interruption, gene therapy safety, immune reconstitution, HIV drug resistance
- MeSH terms
- Adult, Blood Transfusion, Autologous, Combined Modality Therapy, DNA, Viral, Female, HIV, Humans, Male, Middle Aged, Rectum, RNA, Viral, Genetic Therapy, CD4-Positive T-Lymphocytes, HIV Infections, Lymphocyte Transfusion, Lymphocyte Count, Viral Load, Receptors, CCR5, Antiretroviral Therapy, Highly Active
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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