Multilayered HIV-1 resistance in HSPCs through CCR5 Knockout and B cell secretion of HIV-inhibiting antibodies

William N. Feist, Sofia E. Luna, Kaya Ben-Efraim, Maria V. Filsinger Interrante, Alvaro Amorin, Nicole M. Johnston, Theodora U. J. Bruun, Ashley Utz, Hana Y. Ghanim, Benjamin J. Lesch, Theresa M. McLaughlin, Amanda M. Dudek () and Matthew H. Porteus ()
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William N. Feist: Stanford University School of Medicine
Sofia E. Luna: Stanford University School of Medicine
Kaya Ben-Efraim: Stanford University School of Medicine
Maria V. Filsinger Interrante: Stanford University School of Medicine
Alvaro Amorin: Stanford University School of Medicine
Nicole M. Johnston: Stanford University School of Medicine
Theodora U. J. Bruun: Stanford University
Ashley Utz: Stanford University School of Medicine
Hana Y. Ghanim: Stanford University School of Medicine
Benjamin J. Lesch: Stanford University School of Medicine
Theresa M. McLaughlin: Stanford University
Amanda M. Dudek: Stanford University School of Medicine
Matthew H. Porteus: Stanford University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58371-8

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