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<p>Allogeneic transplantation of <i>CCR5</i> 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 <i>CCR5</i>-null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to <i>CCR5</i> knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both <i>CCR5</i> 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 <i>CCR5</i> KO HSPC transplantation.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月1日

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  • 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,
  • Matthew H. Porteus

摘要

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.