Cited by 21Virus-based gene therapy researchHIV Research and TreatmentHIV/AIDS drug development and treatment

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Development of Lentiviral Vectors for HIV-1 Gene Therapy with Vif-Resistant APOBEC3G

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Delviks-Frankenberry, Krista A., Ackerman, Daniel, Timberlake, Nina D., Hamscher, Maria, Nikolaitchik, Olga A., Hu, Wei-Shau, Torbett, Bruce E., Pathak, Vinay K.·2019·Molecular Therapy Nucleic Acids

Abstract

Strategies to control HIV-1 replication without antiviral therapy are needed to achieve a functional cure. To exploit the innate antiviral function of restriction factor cytidine deaminase APOBEC3G ( A3G ), we developed self-activating lentiviral vectors that efficiently deliver HIV-1 Vif-resistant mutant A3G-D128K to target cells. To circumvent APOBEC3 expression in virus-producing cells, which diminishes virus infectivity, a vector containing two overlapping fragments of A3G-D128K was designed that maintained the gene in an inactive form in the virus-producer cells. However, during transduction of target cells, retroviral recombination between the direct repeats reconstituted an active A3G-D128K in 89%–98% of transduced cells. Lentiviral vectors that expressed A3G-D128K transduced CD34 + hematopoietic stem and progenitor cells with a high efficiency (>30%). A3G-D128K expression in T cell lines CEM, CEMSS, and PM1 potently inhibited spreading infection of several HIV-1 subtypes by C-to-U deamination leading to lethal G-to-A hypermutation and inhibition of reverse transcription. SIVmac239 and HIV-2 were not inhibited, since their Vifs degraded A3G-D128K. A3G-D128K expression in CEM cells potently suppressed HIV-1 replication for >3.5 months without detectable resistant virus, suggesting a high genetic barrier for the emergence of A3G-D128K resistance. Because of this, A3G-D128K expression in HIV-1 target cells is a potential anti-HIV gene therapy approach that could be combined with other therapies for the treatment and functional cure of HIV-1 infection.

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  • HIV-1 derived lentiviral vectors are well known for efficient and stable transduction in dividing and non-dividing cells.

    “HIV-1 derived LV is well known for its efficient and stable transduction in dividing and non-dividing cells.”

    From Non-Integrating Lentiviral Vectors in Clinical Applications: A Glance Through (2022) · cites this paper as [1]

    The Results section on CD4+ T cells and CD34+ HSPCs (page unavailable) reports efficient transduction with the studied lentiviral vector. The Materials and Methods section describes expanded, selected transduced cell pools, consistent with sustained expression in those cells. Our copy does not establish efficient, stable transduction in non-dividing cells, so the broader claim is only partly supported. (LLM, conf=0.85)

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Authors
Delviks-Frankenberry, K. A., Ackerman, D., Timberlake, N. D., Hamscher, M., Nikolaitchik, O. A., Hu, W.-S., Torbett, B. E., & Pathak, V. K.
Affiliations
  • National Cancer Institute (US)
  • Scripps Research Institute (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
Pathak, Vinay K.
Venue
Molecular Therapy Nucleic Acids
Publisher
Elsevier BV
Published
2019-12
Volume
18
Pages
1023-1038
ISSN
2162-2531 (ISSN-L)
OpenAlex
W2989435356
Cited by
21
References
2
Citations by year
2026: 1 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 1 · 2020: 4
FWCI
1.66
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy — Nucleic Acids (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Department of Health, Australian Government
  • National Institutes of Health
  • National Cancer Institute
  • Office of AIDS Research (5T32AI007354, P30 AI036214, R01HL116221, U54GM103368)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
HIV-1 gene therapy, lentiviral vectors, APOBEC3G, host restriction factors, G-to-A hypermutation, reverse transcription inhibition, retroviral recombination, direct repeats, hematopoietic stem and progenitor cells, T cell lines, HIV-1 replication inhibition, functional cure, HIV-2, SIVmac239

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