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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 (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 &lt;0.001) in transplanted huBLT mice. Anti-huEGFR monoclonal antibody Cetuximab (CTX) administration significantly reduced huEGFRt+ vector-modified cells (&gt;4-fold reduction, p &lt;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.<\/jats:p>","DOI":"10.1101\/2024.11.13.623476","type":"posted-content","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T21:55:12Z","timestamp":1731534912000},"source":"Crossref","is-referenced-by-count":0,"title":["Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 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