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

  1. Author:
    Frankenberry,Krista
    Ojha, Chet R
    Hermann, Kip J
    Hu,Wei-Shau
    Torbett, Bruce E
    Pathak,Vinay

  2. Author Address

    Viral Mutation Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, MD 21702, USA., Center for Immunity and Immunotherapies, Seattle Children 39;s Research Institute, Seattle, WA 98101, USA., Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA., Viral Recombination Section, HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD 21702, USA., Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101, USA.,
    1. Year: 2023
    2. Date: Sep 12
    3. Epub Date: 2023 08 11
  2. Journal: Molecular Therapy. Nucleic Acids
    1. 33
    2. Pages: 794-809
  4. Type of Article: Article
  1. 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 160;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 160;vivo selection of transduced CD34+ hematopoietic stem and progenitor cells. MGMT-selected T 160;cell lines MT4, CEM, and PM1 expressing A3G-D128K (with or without mC46) potently inhibited NL4-3 infection up to 45 160;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 160;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.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.omtn.2023.08.007
  3. PMID: 37662965
  4. PMCID: PMC10470399
  5. PII : S2162-2531(23)00217-2

Library Notes

  1. Fiscal Year: FY2022-2023
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