High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection
Abstract The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mo...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55873-3 |
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| author | Daniel T. Claiborne Zachary Detwiler Steffen S. Docken Todd D. Borland Deborah Cromer Amanda Simkhovich Youdiil Ophinni Ken Okawa Timothy Bateson Tao Chen Wesley Hudson Radiana Trifonova Miles P. Davenport Tony W. Ho Christian L. Boutwell Todd M. Allen |
| author_facet | Daniel T. Claiborne Zachary Detwiler Steffen S. Docken Todd D. Borland Deborah Cromer Amanda Simkhovich Youdiil Ophinni Ken Okawa Timothy Bateson Tao Chen Wesley Hudson Radiana Trifonova Miles P. Davenport Tony W. Ho Christian L. Boutwell Todd M. Allen |
| author_sort | Daniel T. Claiborne |
| collection | DOAJ |
| description | Abstract The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mortality of such allogeneic transplants precludes widespread adoption of this HIV cure. Here, we show the application of CRISPR/Cas9 to achieve >90% CCR5 editing in human, mobilized hematopoietic stem progenitor cells (HSPC), resulting in a transplant that undergoes normal hematopoiesis, produces CCR5 null T cells, and renders xenograft mice refractory to HIV infection. Titration studies transplanting decreasing frequencies of CCR5 edited HSPCs demonstrate that <90% CCR5 editing confers decreasing protective benefit that becomes negligible between 54% and 26%. Our study demonstrates the feasibility of using CRISPR/Cas9/RNP to produce an HSPC transplant with high frequency CCR5 editing that is refractory to HIV replication. These results raise the potential of using CRISPR/Cas9 to produce a curative autologous HSCT and bring us closer to the development of a cure for HIV infection. |
| format | Article |
| id | doaj-art-5790057bf80c4af896cb0de74b715dab |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-5790057bf80c4af896cb0de74b715dab2025-01-12T12:31:18ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-55873-3High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infectionDaniel T. Claiborne0Zachary Detwiler1Steffen S. Docken2Todd D. Borland3Deborah Cromer4Amanda Simkhovich5Youdiil Ophinni6Ken Okawa7Timothy Bateson8Tao Chen9Wesley Hudson10Radiana Trifonova11Miles P. Davenport12Tony W. Ho13Christian L. Boutwell14Todd M. Allen15Vaccine and Immunotherapy Center, The Wistar InstituteCRISPR TherapeuticsKirby Institute, University of New South WalesCRISPR TherapeuticsKirby Institute, University of New South WalesRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardKirby Institute, University of New South WalesCRISPR TherapeuticsRagon Institute of MGH, MIT and HarvardRagon Institute of MGH, MIT and HarvardAbstract The only cure of HIV has been achieved in a small number of people who received a hematopoietic stem cell transplant (HSCT) comprising allogeneic cells carrying a rare, naturally occurring, homozygous deletion in the CCR5 gene. The rarity of the mutation and the significant morbidity and mortality of such allogeneic transplants precludes widespread adoption of this HIV cure. Here, we show the application of CRISPR/Cas9 to achieve >90% CCR5 editing in human, mobilized hematopoietic stem progenitor cells (HSPC), resulting in a transplant that undergoes normal hematopoiesis, produces CCR5 null T cells, and renders xenograft mice refractory to HIV infection. Titration studies transplanting decreasing frequencies of CCR5 edited HSPCs demonstrate that <90% CCR5 editing confers decreasing protective benefit that becomes negligible between 54% and 26%. Our study demonstrates the feasibility of using CRISPR/Cas9/RNP to produce an HSPC transplant with high frequency CCR5 editing that is refractory to HIV replication. These results raise the potential of using CRISPR/Cas9 to produce a curative autologous HSCT and bring us closer to the development of a cure for HIV infection.https://doi.org/10.1038/s41467-025-55873-3 |
| spellingShingle | Daniel T. Claiborne Zachary Detwiler Steffen S. Docken Todd D. Borland Deborah Cromer Amanda Simkhovich Youdiil Ophinni Ken Okawa Timothy Bateson Tao Chen Wesley Hudson Radiana Trifonova Miles P. Davenport Tony W. Ho Christian L. Boutwell Todd M. Allen High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection Nature Communications |
| title | High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection |
| title_full | High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection |
| title_fullStr | High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection |
| title_full_unstemmed | High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection |
| title_short | High frequency CCR5 editing in human hematopoietic stem progenitor cells protects xenograft mice from HIV infection |
| title_sort | high frequency ccr5 editing in human hematopoietic stem progenitor cells protects xenograft mice from hiv infection |
| url | https://doi.org/10.1038/s41467-025-55873-3 |
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