Exosome-mediated stable epigenetic repression of HIV-1

Nat Commun. 2021 Sep 20;12(1):5541. doi: 10.1038/s41467-021-25839-2.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / pathology
  • Brain / virology
  • Cell Line
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / genetics
  • Epigenetic Repression / genetics*
  • Exosomes / metabolism*
  • Exosomes / ultrastructure
  • Gene Expression Regulation, Viral
  • Genetic Vectors / metabolism
  • HEK293 Cells
  • HIV Infections / virology
  • HIV-1 / genetics*
  • Humans
  • Lentivirus / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Terminal Repeat Sequences / genetics
  • Viral Load
  • Zinc Fingers

Substances

  • RNA, Messenger
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A