Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies

Feist, W. N.; Luna, S. E.; Ben-Efraim, K.; Filsinger Interrante, M. V.; Amorin, N. A.; Johnston, N. M.; Bruun, T. U. J.; Ghanim, H. Y.; Lesch, B. J.; Dudek, A. M.; Porteus, M. H.

doi:10.1101/2024.03.08.583956

bioRxiv · 10.1101/2024.03.08.583956

Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies

Feist, W. N.·Luna, S. E.·Ben-Efraim, K.·Filsinger Interrante, M. V.·Amorin, N. A.·Johnston, N. M.·Bruun, T. U. J.·Ghanim, H. Y.·Lesch, B. J.·Dudek, A. M.·Porteus, M. H.

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Abstract

Autologous 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 maintain engraftment capacity and multi-lineage potential in vivo and can be engineered to express multiple antibodies simultaneously. Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro. This work lays the groundwork 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.

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Feist, W. N., Luna, S. E., Ben-Efraim, K., Filsinger Interrante, M. V., Amorin, N. A., Johnston, N. M., Bruun, T. U. J., Ghanim, H. Y., Lesch, B. J., Dudek, A. M., Porteus, M. H.. 2024-03-09. Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies. https://doi.org/10.1101/2024.03.08.583956

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