| First Author | Dudek AM | Year | 2024 |
| Journal | Cell Stem Cell | Volume | 31 |
| Issue | 4 | Pages | 499-518.e6 |
| PubMed ID | 38579682 | Mgi Jnum | J:349695 |
| Mgi Id | MGI:7623040 | Doi | 10.1016/j.stem.2024.03.002 |
| Citation | Dudek AM, et al. (2024) A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection. Cell Stem Cell 31(4):499-518.e6 |
| abstractText | Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of CCR5 null (CCR5Delta32) cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, CCR5Delta32 matched bone marrow donors are rare, and CCR5Delta32 transplant does not confer resistance to the CXCR4-tropic virus, it is not a viable option for most patients. We describe a targeted Cas9/AAV6-based genome editing strategy for autologous HSCT resulting in both CCR5- and CXCR4-tropic HIV-1 resistance. Edited human hematopoietic stem and progenitor cells (HSPCs) maintain multi-lineage repopulation capacity in vivo, and edited primary human T cells potently inhibit infection by both CCR5-tropic and CXCR4-tropic HIV-1. Modification rates facilitated complete loss of CCR5-tropic replication and up to a 2,000-fold decrease in CXCR4-tropic replication without CXCR4 locus disruption. This multi-factor editing strategy in HSPCs could provide a broad approach for autologous HSCT as a functional cure for both CCR5-tropic and CXCR4-tropic HIV-1 infections. |
