Journal article
Multilayered HIV-1 resistance in HSPCs through CCR5 Knockout and B cell secretion of HIV-inhibiting antibodies
Nature communications, Vol.16(1), pp.3103-18
04/01/2025
DOI: 10.1038/s41467-025-58371-8
PMCID: PMC11958643
PMID: 40164595
Abstract
Allogeneic transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5-null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs engraft and reconstitute multiple hematopoietic lineages in vivo and can be engineered to express multiple antibodies simultaneously (in pre-clinical models). Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro. This work lays the foundation for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.
Details
- Title: Subtitle
- Multilayered HIV-1 resistance in HSPCs through CCR5 Knockout and B cell secretion of HIV-inhibiting antibodies
- Creators
- William N Feist - Stanford University School of MedicineSofia E Luna - Stanford University School of MedicineKaya Ben-Efraim - Stanford University School of MedicineMaria V Filsinger Interrante - Stanford UniversityAlvaro Amorin - Stanford University School of MedicineNicole M Johnston - Stanford University School of MedicineTheodora U J Bruun - Stanford University School of MedicineAshley Utz - Stanford University School of MedicineHana Y Ghanim - Stanford University School of MedicineBenjamin J Lesch - University of California, San FranciscoTheresa M McLaughlin - Stanford UniversityAmanda M Dudek - Stanford University School of MedicineMatthew H Porteus - Stanford University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), pp.3103-18
- DOI
- 10.1038/s41467-025-58371-8
- PMID
- 40164595
- PMCID
- PMC11958643
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Grant note
- T32 GM119995 / NIGMS NIH HHS F32 HL154667 / NHLBI NIH HHS T32 GM007365 / NIGMS NIH HHS U54 AI170792 / NIAID NIH HHS K99 HL172253 / NHLBI NIH HHS F30 AI152943 / NIAID NIH HHS
- Language
- English
- Date published
- 04/01/2025
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984822988702771
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