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Exosome-mediated stable epigenetic repression of HIV-1

Author

Listed:
  • Surya Shrivastava

    (City of Hope-Beckman Research Institute)

  • Roslyn M. Ray

    (City of Hope-Beckman Research Institute)

  • Leo Holguin

    (City of Hope-Beckman Research Institute)

  • Lilliana Echavarria

    (City of Hope-Beckman Research Institute)

  • Nicole Grepo

    (City of Hope-Beckman Research Institute)

  • Tristan A. Scott

    (City of Hope-Beckman Research Institute)

  • John Burnett

    (City of Hope-Beckman Research Institute
    Hematological Malignancy and Stem Cell Transplantation Institute at the City of Hope)

  • Kevin V. Morris

    (City of Hope-Beckman Research Institute
    Hematological Malignancy and Stem Cell Transplantation Institute at the City of Hope
    School of Medical Science Griffith University, Gold Coast Campus)

Abstract

Human Immunodeficiency Virus (HIV-1) produces a persistent latent infection. Control of HIV-1 using combination antiretroviral therapy (cART) comes at the cost of life-shortening side effects and development of drug-resistant HIV-1. An ideal and safer therapy should be deliverable in vivo and target the stable epigenetic repression of the virus, inducing a stable “block and lock” of virus expression. Towards this goal, we developed an HIV-1 promoter-targeting Zinc Finger Protein (ZFP-362) fused to active domains of DNA methyltransferase 3 A to induce long-term stable epigenetic repression of HIV-1. Cells were engineered to produce exosomes packaged with RNAs encoding this HIV-1 repressor protein. We find here that the repressor loaded anti-HIV-1 exosomes suppress virus expression and that this suppression is mechanistically driven by DNA methylation of HIV-1 in humanized NSG mouse models. The observations presented here pave the way for an exosome-mediated systemic delivery platform of therapeutic cargo to epigenetically repress HIV-1 infection.

Suggested Citation

  • Surya Shrivastava & Roslyn M. Ray & Leo Holguin & Lilliana Echavarria & Nicole Grepo & Tristan A. Scott & John Burnett & Kevin V. Morris, 2021. "Exosome-mediated stable epigenetic repression of HIV-1," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25839-2
    DOI: 10.1038/s41467-021-25839-2
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    Cited by:

    1. Justin A. Peruzzi & Taylor F. Gunnels & Hailey I. Edelstein & Peilong Lu & David Baker & Joshua N. Leonard & Neha P. Kamat, 2024. "Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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