Exosome-mediated stable epigenetic repression of HIV-1.
Surya ShrivastavaRoslyn M RayLeo HolguinLilliana EchavarriaNicole GrepoTristan A ScottJohn C BurnettKevin V MorrisPublished in: Nature communications (2021)
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.
Keyphrases
- antiretroviral therapy
- human immunodeficiency virus
- hiv infected
- hiv positive
- hiv aids
- hiv infected patients
- hiv testing
- hepatitis c virus
- dna methylation
- drug resistant
- men who have sex with men
- gene expression
- poor prognosis
- stem cells
- south africa
- mouse model
- multidrug resistant
- high throughput
- cystic fibrosis
- drug delivery
- induced apoptosis
- oxidative stress
- bone marrow
- oxide nanoparticles
- cell free
- drug induced
- replacement therapy