Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection
1
Issued Date
2025-06-12
Resource Type
eISSN
23290501
Scopus ID
2-s2.0-105005855702
Journal Title
Molecular Therapy Methods and Clinical Development
Volume
33
Issue
2
Rights Holder(s)
SCOPUS
Bibliographic Citation
Molecular Therapy Methods and Clinical Development Vol.33 No.2 (2025)
Suggested Citation
Guo Q., Parikh K., Zhang J., Brinkley A., Chen G., Jakramonpreeya N., Zhen A., An D.S. Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection. Molecular Therapy Methods and Clinical Development Vol.33 No.2 (2025). doi:10.1016/j.omtm.2025.101486 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/110440
Title
Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection
Corresponding Author(s)
Other Contributor(s)
Abstract
Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds promise to provide life-long remission following a single treatment. Here we report a multi-pronged anti-HIV-1 HSPC-based gene therapy designed to defend against and attack HIV-1 infection. We developed a lentiviral vector capable of co-expressing three anti-HIV-1 genes. Two are designed to prevent infection, including a short hairpin RNA (shRNA) (CCR5sh1005) to knock down HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor (C46). The third gene is a CD4-based chimeric antigen receptor (CAR) designed to attack HIV-1-infected cells. Our vector also includes a non-signaling truncated human epidermal growth factor receptor (huEGFRt) which acts as a negative selection-based safety kill switch against transduced cells. Anti-HIV-1 vector-transduced human CD34+ HSPC efficiently reconstituted multi-lineage human hematopoietic cells in humanized bone marrow/liver/thymus (huBLT) mice. HIV-1 viral load was significantly reduced (1-log fold reduction, p < 0.001) in transplanted huBLT mice. Anti-huEGFR monoclonal antibody cetuximab (CTX) administration significantly reduced huEGFRt+ vector-modified cells (>4-fold reduction, p < 0.01) in huBLT mice. These results demonstrate that our strategy is highly effective for HIV-1 inhibition, and that CTX-mediated negative selection can deplete anti-HIV-1 vector-modified cells in the event of unwanted adverse effects in huBLT mice.