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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 \u201cblock and lock\u201d 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\u2009A 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.<\/jats:p>","DOI":"10.1038\/s41467-021-25839-2","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T06:02:53Z","timestamp":1632117773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Exosome-mediated stable epigenetic repression of HIV-1"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0021-2751","authenticated-orcid":false,"given":"Surya","family":"Shrivastava","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6060-6969","authenticated-orcid":false,"given":"Roslyn M.","family":"Ray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8462-187X","authenticated-orcid":false,"given":"Leo","family":"Holguin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-8662","authenticated-orcid":false,"given":"Lilliana","family":"Echavarria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0419-8443","authenticated-orcid":false,"given":"Nicole","family":"Grepo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-9609","authenticated-orcid":false,"given":"Tristan A.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8817-6064","authenticated-orcid":false,"given":"John","family":"Burnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0157-0553","authenticated-orcid":false,"given":"Kevin V.","family":"Morris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"25839_CR1","doi-asserted-by":"publisher","first-page":"e161","DOI":"10.1016\/S2352-3018(20)30047-3","volume":"7","author":"P Adepoju","year":"2020","unstructured":"Adepoju, P. 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