Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1

Sofia E. Luna; William N. Feist; Kaya Ben-Efraim; Alex Pendergast; Freja K. Ekman; Britney Hernandez-Naughton; Megan Merritt-Garza; Kathleen Romero; Zak Kostamo; Nelson A. Amorin; Nicole M. Johnston; Hana Y. Ghanim; Vivien Sheehan; Amanda M. Dudek; Matthew H. Porteus

doi:10.1016/j.omta.2026.201799

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Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1

Journal article

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Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1

Sofia E. Luna, William N. Feist, Kaya Ben-Efraim, Alex Pendergast, Freja K. Ekman, Britney Hernandez-Naughton, Megan Merritt-Garza, Kathleen Romero, Zak Kostamo, Nelson A. Amorin, …

Molecular Therapy Advances, 201799

06/2026

DOI: 10.1016/j.omta.2026.201799

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Abstract

Canonical HIV-1 entry into target cells depends on binding to CD4 as a primary receptor. Because of this, use of the CD4 receptor as a viral trap (a decoy receptor used to prevent infection of target cells) is a promising strategy for the treatment of HIV-1. One challenge in using CD4 viral traps is maintaining enough of the decoy receptor in circulation to remain effective. Here, we present a strategy to produce cell-based CD4 viral traps by engineering hematopoietic stem and progenitor cells (HSPCs) to express the CD4 receptor in red blood cell (RBC) progeny. This takes advantage of the ability of the HSPC to repopulate the blood system for a lifetime, while leveraging the fact that RBCs greatly outnumber any cell targeted for infection. CRISPR-Cas9-engineered HSPCs efficiently express CD4 on their cell surface after differentiation to the RBC lineage in vitro. Fusion of CD4 to glycophorin A (GPA) and introduction of a truncated erythropoietin receptor (tEPOR) leads to increased CD4 expression and enrichment of edited cells (CD4-GPA-tEPOR) to levels capable of neutralizing HIV-1 pseudovirus in vitro. In sum, this work presents a potential strategy for the one-time delivery of CD4-RBC viral traps through autologous transplantation of engineered HSPCs. [Display omitted] Porteus and colleagues demonstrate that human blood stem cells can be engineered such that the derived red blood cells express high levels of CD4 providing an HIV trap. This potentially durable suppressive therapy for HIV might obviate the need for patients to take anti-retroviral therapy for the rest of their lives.

CD4

genome-editing

hematopoietic stem cell

HIV-1

homology directed repair

red blood cell

viral trap

Details

Title: Subtitle: Engineering hematopoietic stem and progenitor cells to generate red blood cells as viral traps against HIV-1
Creators: Sofia E. Luna - Stanford University
William N. Feist - Stanford University
Kaya Ben-Efraim - Stanford University
Alex Pendergast - Emory University School of Medicine
Freja K. Ekman - Stanford University
Britney Hernandez-Naughton - Emory University School of Medicine
Megan Merritt-Garza - Emory University School of Medicine
Kathleen Romero - Emory University School of Medicine
Zak Kostamo - Emory University School of Medicine
Nelson A. Amorin - Stanford University
Nicole M. Johnston - Stanford University
Hana Y. Ghanim - Stanford University
Vivien Sheehan - Emory University School of Medicine
Amanda M. Dudek - Stanford University
Matthew H. Porteus - Stanford University
Resource Type: Journal article
Publication Details: Molecular Therapy Advances, 201799
DOI: 10.1016/j.omta.2026.201799
ISSN: 3117-387X
Publisher: Elsevier Inc
Language: English
Electronic publication date: 06/2026
Academic Unit: Microbiology and Immunology
Record Identifier: 9985180976502771

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