Exosome-mediated stable epigenetic repression of HIV-1

Surya Shrivastava, Roslyn M. Ray, Leo Holguin, Lilliana Echavarria, Nicole Grepo, Tristan A. Scott, John Burnett and Kevin V. Morris ()
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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
Kevin V. Morris: City of Hope-Beckman Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25839-2

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