Journal article
A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection
Cell stem cell, Vol.31(4), pp.499-518.e6
04/04/2024
DOI: 10.1016/j.stem.2024.03.002
PMCID: PMC11212398
PMID: 38579682
Abstract
Allogeneic hematopoietic stem and progenitor cell transplant (HSCT) of CCR5 null (CCR5Δ32) cells can be curative for HIV-1-infected patients. However, because allogeneic HSCT poses significant risk, CCR5Δ32 matched bone marrow donors are rare, and CCR5Δ32 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.
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•HSPC editing to develop HSC transplantation to treat HIV•Edited HSPCs and T cells retain normal functionality•CCR5 knockout causes complete loss of CCR5-tropic HIV replication•Multi-factor knockin causes a multi-log-fold decrease in CXCR4-tropic HIV replication
Dudek, Feist et al. describe a gene editing strategy for a functional cure for HIV-1 through hematopoietic stem and progenitor cell transplant. CCR5-locus knockin of multiple inhibitory protein factors to generate combinatorial resistance in terminally differentiated progeny allows strong inhibition of both CCR5-tropic and CXCR4-tropic HIV-1 strains.
Details
- Title: Subtitle
- A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection
- Creators
- Amanda M. Dudek - Stanford University School of MedicineWilliam N. Feist - Stanford University School of MedicineElena J. Sasu - Stanford University School of MedicineSofia E. Luna - Stanford University School of MedicineKaya Ben-Efraim - Stanford University School of MedicineRasmus O. Bak - Stanford University School of MedicineAlma-Martina Cepika - Stanford University School of MedicineMatthew H. Porteus - Stanford University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell stem cell, Vol.31(4), pp.499-518.e6
- DOI
- 10.1016/j.stem.2024.03.002
- PMID
- 38579682
- PMCID
- PMC11212398
- NLM abbreviation
- Cell Stem Cell
- ISSN
- 1934-5909
- eISSN
- 1875-9777
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 04/04/2024
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984822991602771
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