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Superior lentiviral vectors designed for BSL-0 environment abolish vector mobilization

Gene Therapy volume 25, pages 454–472 (2018)Cite this article

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Abstract

Lentiviral vector mobilization following HIV-1 infection of vector-transduced cells poses biosafety risks to vector-treated patients and their communities. The self-inactivating (SIN) vector design has reduced, however, not abolished mobilization of integrated vector genomes. Furthermore, an earlier study demonstrated the ability of the major product of reverse transcription, a circular SIN HIV-1 vector comprising a single- long terminal repeat (LTR) to support production of high vector titers. Here, we demonstrate that configuring the internal vector expression cassette in opposite orientation to the LTRs abolishes mobilization of SIN vectors. This additional SIN mechanism is in part premised on induction of host PKR response to double-stranded RNAs comprised of mRNAs transcribed from cryptic transcription initiation sites around 3'SIN-LTR’s and the vector internal promoter. As anticipated, PKR response following transfection of opposite orientation vectors, negatively affects their titers. Importantly, shRNA-mediated knockdown of PKR rendered titers of SIN HIV-1 vectors comprising opposite orientation expression cassettes comparable to titers of conventional SIN vectors. High-titer vectors carrying an expression cassette in opposite orientation to the LTRs efficiently delivered and maintained high levels of transgene expression in mouse livers. This study establishes opposite orientation expression cassettes as an additional PKR-dependent SIN mechanism that abolishes vector mobilization from integrated and episomal SIN lentiviral vectors.

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Acknowledgements

The following reagents were obtained through the National Institutes of Health (NIH) AIDS Research and Reference Reagent Program, Division of AIDS, the National Institute of Allergy and Infectious Diseases: the HIV-1 p24 monoclonal antibody (183-H12-5C) from Bruce Chesebro and Kathy Wehrly. The study was supported by UNC Flow Cytometry Core Facility, which is supported in part by P30 CA016086 Cancer Center Core Support Grant to the UNC Lineberger Comprehensive Cancer Center. ‘The study was supported by NIH grants R01-HL128119 (to PH, YB, TS, MH, BZ, NJF, and TK), R01-DK058702 (to PH, YB, TS, MH, BZ, NJF, and TK). This study is dedicated to the US Marine Corps and the Gold Star families. In memory of Henryk Goldszmit, the doctor who stayed.

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Author notes

  1. Hong Ma

    Present address: Transplant Diagnostics, Thermo Fisher Scientific, Canoga Park, CA, 91303, USA

  2. Brian Zeithaml

    Present address: Acute Care Surgery, ECU Brody School of Medicine, Greenville, NC, 27858, USA

Authors and Affiliations

  1. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Peirong Hu, Yanmin Bi, Hong Ma, Thipparat Suwanmanee, Brian Zeithaml, Nate J. Fry & Tal Kafri

  2. Department of Microbiology, Immunology and Molecular Genetics, and Pediatrics, University of California, Los Angeles, CA, 90095, USA

    Donald B. Kohn

  3. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Tal Kafri

  4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Tal Kafri

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  1. Peirong Hu
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Correspondence to Tal Kafri.

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TK is an inventor of a PPT-deleted vector-based technology owned by the University of North Carolina and licensed to a commercial entity. The other authors declare that they have no conflict of interest.

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Hu, P., Bi, Y., Ma, H. et al. Superior lentiviral vectors designed for BSL-0 environment abolish vector mobilization. Gene Ther 25, 454–472 (2018). https://doi.org/10.1038/s41434-018-0039-2

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