Evaluation of Anti-HIV-1 HSPC-Based Gene Therapy with Negative Selection Marker in Pigtail Macaques.
6 affiliations
- 1University of California Los Angeles (UCLA) AIDS Institute, Los Angeles, CA 90024, USA.
- 2UCLA Joe C. Wen School of Nursing, UCLA, Los Angeles, CA 90095, USA.
- 3Stem Cell and Gene Therapy Program, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
- 4Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
- 5Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA.
- 6Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Abstract
Despite significant medical progress, HIV-1 remains a critical global health crisis. While combination antiretroviral therapy (cART) effectively suppresses viremia, it is not curative due to the persistence of latent viral reservoirs. Autologous hematopoietic stem and progenitor cell (HSPC) gene therapy offers a promising avenue toward sustained, drug-free remission. In this study, we investigated the feasibility and safety of a multifunctional "defend and attack" HSPC gene therapy strategy in the pigtail macaque (Macaca nemestrina) model. The species-optimized lentiviral vector, PM-MNDU-anti-HIV-1-huEGFRt, carries four therapeutic payloads: a pigtail macaque-specific CCR5 shRNA (PM-CCR5sh1005), a CD4-based chimeric antigen receptor (D1D2CAR), a C46 fusion inhibitor peptide, and a truncated human epidermal growth factor receptor (huEGFRt) serving as a cell-surface tracking marker and anti-EGFR antibody Cetuximab (CTX)-mediated negative selection marker. Following busulfan conditioning, autologous transplantation of vector-modified HSPCs in two pigtail macaques resulted in safe hematopoietic recovery. Both animals achieved sustained, multilineage gene marking in peripheral blood and lymphoid tissues without adverse effects. In one animal, upon Simian-Human Immunodeficiency Virus (SHIV) challenge, vector-modified cells underwent robust, antigen-driven multilineage expansion across both lymphoid and myeloid compartments, which contracted during cART-induced viral suppression and rapidly rebounded following treatment interruption. Administration of CTX demonstrated partial, transient reduction in huEGFRt⁺ cells, accompanied with a reciprocal increase in plasma viral load. These findings support the feasibility of evaluating a multi-pronged anti-HIV HSPC gene therapy strategy with a negative selection marker in a non-human primate (NHP) model.
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BibTeX
@article{zhang2026evaluation,
title = {{Evaluation of Anti-HIV-1 HSPC-Based Gene Therapy with Negative Selection Marker in Pigtail Macaques.}},
author = {Jian Zhang and Jason Murray and Wenli Mu and Surya Venugopal and Ella Yim and Teresa Einhaus and Stefan Radtke and Christopher W Peterson and Hans-Peter Kiem and Dong Sung An},
journal = {Viruses},
year = {2026},
month = oct,
doi = {10.3390/v18101133},
url = {https://europepmc.org/article/MED/42944053},
note = {CC BY},
}
RIS
TY - JOUR
TI - Evaluation of Anti-HIV-1 HSPC-Based Gene Therapy with Negative Selection Marker in Pigtail Macaques.
AU - Jian Zhang
AU - Jason Murray
AU - Wenli Mu
AU - Surya Venugopal
AU - Ella Yim
AU - Teresa Einhaus
AU - Stefan Radtke
AU - Christopher W Peterson
AU - Hans-Peter Kiem
AU - Dong Sung An
PY - 2026
DA - 2026/10/13
JO - Viruses
DO - 10.3390/v18101133
UR - https://europepmc.org/article/MED/42944053
AB - Despite significant medical progress, HIV-1 remains a critical global health crisis. While combination antiretroviral therapy (cART) effectively suppresses viremia, it is not curative due to the persistence of latent viral reservoirs. Autologous hematopoietic stem and progenitor cell (HSPC) gene therapy offers a promising avenue toward sustained, drug-free remission. In this study, we investigated the feasibility and safety of a multifunctional "defend and attack" HSPC gene therapy strategy in the pigtail macaque (Macaca nemestrina) model. The species-optimized lentiviral vector, PM-MNDU-anti-HIV-1-huEGFRt, carries four therapeutic payloads: a pigtail macaque-specific CCR5 shRNA (PM-CCR5sh1005), a CD4-based chimeric antigen receptor (D1D2CAR), a C46 fusion inhibitor peptide, and a truncated human epidermal growth factor receptor (huEGFRt) serving as a cell-surface tracking marker and anti-EGFR antibody Cetuximab (CTX)-mediated negative selection marker. Following busulfan conditioning, autologous transplantation of vector-modified HSPCs in two pigtail macaques resulted in safe hematopoietic recovery. Both animals achieved sustained, multilineage gene marking in peripheral blood and lymphoid tissues without adverse effects. In one animal, upon Simian-Human Immunodeficiency Virus (SHIV) challenge, vector-modified cells underwent robust, antigen-driven multilineage expansion across both lymphoid and myeloid compartments, which contracted during cART-induced viral suppression and rapidly rebounded following treatment interruption. Administration of CTX demonstrated partial, transient reduction in huEGFRt⁺ cells, accompanied with a reciprocal increase in plasma viral load. These findings support the feasibility of evaluating a multi-pronged anti-HIV HSPC gene therapy strategy with a negative selection marker in a non-human primate (NHP) model.
SN - 1999-4915
ER -