2. Academic Validation
  3. Potent dual block to HIV-1 infection using lentiviral vectors expressing fusion inhibitor peptide mC46- and Vif-resistant APOBEC3G

Potent dual block to HIV-1 infection using lentiviral vectors expressing fusion inhibitor peptide mC46- and Vif-resistant APOBEC3G

  • Mol Ther Nucleic Acids. 2023 Aug 11:33:794-809. doi: 10.1016/j.omtn.2023.08.007.
Krista A Delviks-Frankenberry 1,  Chet R Ojha 2,  Kip J Hermann 3,  Wei-Shau Hu 4,  Bruce E Torbett 2 3 5,  Vinay K Pathak 1
Affiliations

Affiliations

  • 1 Viral Mutation Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA.
  • 2 Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 3 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
  • 4 Viral Recombination Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD 21702, USA.
  • 5 Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA.
PMID: 37662965 DOI: 10.1016/j.omtn.2023.08.007
Abstract

Gene therapy strategies that effectively inhibit HIV-1 replication are needed to reduce the requirement for lifelong Antiviral therapy and potentially achieve a functional cure. We previously designed self-activating lentiviral vectors that efficiently delivered and expressed a Vif-resistant mutant of APOBEC3G (A3G-D128K) to T cells, which potently inhibited HIV-1 replication and spread with no detectable virus. Here, we developed vectors that express A3G-D128K, membrane-associated fusion inhibitor peptide mC46, and O6-methylguanine-DNA-methyltransferase (MGMT) selectable marker for in vivo selection of transduced CD34+ hematopoietic stem and progenitor cells. MGMT-selected T cell lines MT4, CEM, and PM1 expressing A3G-D128K (with or without mC46) potently inhibited NL4-3 Infection up to 45 days post Infection with no detectable viral replication. Expression of mC46 was sufficient to block Infection >80% in a single-cycle assay. Importantly, expression of mC46 provided a selective advantage to the A3G-D128K-modified T cells in the presence of replication competent virus. This combinational approach to first block HIV-1 entry with mC46, and then block any breakthrough Infection with A3G-D128K, could provide an effective gene therapy treatment and a potential functional cure for HIV-1 Infection.

Keywords

APOBEC3G; C46; D128K; HIV; MGMT; MT: Delivery Strategies; Vif; gene therapy; hypermutation; lentivirus.

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