Molecular therapy. AdvancesAug 28, 2026

Using engineered blood stem cells to produce red blood cells that trap HIV-1 virus

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 29, 2026

Abstract

CRISPR-Cas9-engineered hematopoietic stem and progenitor cells can effectively express CD4 on red blood cell progeny, offering a potential solution for HIV-1 treatment.

The CD4 receptor is essential for HIV-1 to enter target cells.
Using CD4 as a decoy receptor may help prevent HIV-1 infection.
Hematopoietic stem and progenitor cells can repopulate the blood system for a lifetime.
Engineering these cells to express CD4 in red blood cell progeny may maintain sufficient levels of the decoy receptor in circulation.
The fusion of CD4 to glycophorin A and the addition of a truncated erythropoietin receptor enhances CD4 expression and the selection of edited cells.
Edited cells demonstrate the capacity to neutralize HIV-1 pseudovirus in laboratory conditions.

Simplified

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.