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Thus, key priorities toward eradication of HIV infection are to understand the mechanisms that allow HIV latency and to develop latency reversal agents (LRAs) that can facilitate the clearance of latently infected cells. The repressive H3K27me3 histone mark, catalyzed by the PRC2 complex, plays a pivotal role in transcriptional repression at the viral promoter in both cell line and primary CD4+ T cell models of latency. EZH2 inhibitors which block H3K27 methylation have been shown to act as LRAs, suggesting other PRC2 components could also be potential targets for latency reversal. EED, a core component of PRC2, ensures the propagation of H3K27me3 by allosterically activating EZH2 methyltransferase activity. Therefore, we sought to investigate if inhibition of EED would also reverse latency. Inhibitors of EED, EED226 and A-395, demonstrated latency reversal activity as single agents, and this activity was further enhanced when used in combination with other known LRAs. Loss of H3K27me3 following EED inhibition significantly increased the levels of H3K27 acetylation globally and at the HIV LTR. These results further confirm that PRC2 mediated repression plays a significant role in the maintenance of HIV latency and suggest that EED may serve as a promising new target for LRA development.<\/jats:p>","DOI":"10.1021\/acsinfecdis.9b00514","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T09:59:13Z","timestamp":1588154353000},"page":"1719-1733","source":"Crossref","is-referenced-by-count":24,"title":["Evaluation of EED Inhibitors as a Class of PRC2-Targeted\nSmall Molecules for HIV Latency Reversal"],"prefix":"10.1021","volume":"6","author":[{"given":"Anne-Marie W.","family":"Turner","sequence":"first","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghuvar","family":"Dronamraju","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Potjewyd","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"James","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel K.","family":"Winecoff","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel 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, , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4947-6259","authenticated-orcid":true,"given":"Brian D.","family":"Strahl","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Margolis","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill School of Public Health , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-7116","authenticated-orcid":true,"given":"Lindsey I.","family":"James","sequence":"additional","affiliation":[{"name":"University of North Carolina at Chapel Hill School of Medicine , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]},{"name":"University of North Carolina at Chapel Hill , , , ,","place":["Chapel Hill, North Carolina, United States, 27599"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,29]]},"reference":[{"key":"2026090108012034100_cit1","doi-asserted-by":"publisher","first-page":"aaf6517","DOI":"10.1126\/science.aaf6517","article-title":"Latency reversal\nand viral clearance to cure HIV-1","volume":"353","author":"Margolis","year":"2016","journal-title":"Science"},{"key":"2026090108012034100_cit2","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.gde.2009.03.001","article-title":"Biochemical\nmechanisms of gene regulation by polycomb\ngroup protein complexes","volume":"19","author":"Muller","year":"2009","journal-title":"Curr. Opin. Genet.\nDev."},{"key":"2026090108012034100_cit3","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1038\/nrc1991","article-title":"Polycomb silencers control cell fate, development and\ncancer","volume":"6","author":"Sparmann","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"2026090108012034100_cit4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.molcel.2004.06.020","article-title":"SUZ12 Is Required for\nBoth the Histone Methyltransferase Activity\nand the Silencing Function of the EED-EZH2 Complex","volume":"15","author":"Cao","year":"2004","journal-title":"Mol. Cell"},{"key":"2026090108012034100_cit5","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nature08398","article-title":"Role of the polycomb protein EED in the propagation\nof repressive histone marks","volume":"461","author":"Margueron","year":"2009","journal-title":"Nature"},{"key":"2026090108012034100_cit6","doi-asserted-by":"publisher","first-page":"13805","DOI":"10.1074\/jbc.R117.800367","article-title":"Structure, mechanism,\nand regulation of polycomb-repressive\ncomplex 2","volume":"293","author":"Moritz","year":"2018","journal-title":"J. Biol. Chem."},{"key":"2026090108012034100_cit7","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1038\/nrm4067","article-title":"Targeting\nPolycomb systems to regulate\ngene expression: modifications to a complex story","volume":"16","author":"Blackledge","year":"2015","journal-title":"Nat. Rev. Mol. 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Chem. Lett."},{"key":"2026090108012034100_cit26","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1021\/cb400133j","article-title":"An Orally Bioavailable Chemical Probe\nof the Lysine Methyltransferases EZH2 and EZH1","volume":"8","author":"Konze","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2026090108012034100_cit27","doi-asserted-by":"publisher","first-page":"554","DOI":"10.2174\/157016211798998736","article-title":"Control of HIV latency by epigenetic and non-epigenetic mechanisms","volume":"9","author":"Mbonye","year":"2011","journal-title":"Curr. HIV Res."},{"key":"2026090108012034100_cit28","first-page":"229","article-title":"Chromatin Regulation and the Histone\nCode in HIV Latency","volume":"90","author":"Turner","year":"2017","journal-title":"Yale J. Biol. Med."},{"key":"2026090108012034100_cit29","doi-asserted-by":"publisher","first-page":"4958","DOI":"10.1093\/nar\/gkq244","article-title":"Characterization of\nan antagonistic switch between histone H3 lysine 27 methylation and\nacetylation in the transcriptional regulation of Polycomb group target\ngenes","volume":"38","author":"Pasini","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026090108012034100_cit30","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.cell.2018.08.058","article-title":"Targeting Epigenetic Crosstalk as\na Therapeutic Strategy for EZH2-Aberrant Solid Tumors","volume":"175","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"2026090108012034100_cit31","doi-asserted-by":"publisher","first-page":"8252","DOI":"10.1128\/JVI.72.10.8252-8256.1998","article-title":"Interaction of human immunodeficiency virus type 1\nTat with the transcriptional coactivators p300 and CREB binding protein","volume":"72","author":"Hottiger","year":"1998","journal-title":"J. Virol."},{"key":"2026090108012034100_cit32","doi-asserted-by":"publisher","first-page":"6550","DOI":"10.1093\/emboj\/cdg631","article-title":"Regulation of HIV-1\ngene expression by histone acetylation and factor recruitment at the\nLTR promoter","volume":"22","author":"Lusic","year":"2003","journal-title":"EMBO J."},{"key":"2026090108012034100_cit33","doi-asserted-by":"publisher","first-page":"13519","DOI":"10.1073\/pnas.95.23.13519","article-title":"HIV-1 tat transactivator\nrecruits p300 and CREB-binding protein histone acetyltransferases\nto the viral promoter","volume":"95","author":"Marzio","year":"1998","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"key":"2026090108012034100_cit34","doi-asserted-by":"publisher","first-page":"7078","DOI":"10.1073\/pnas.1402873111","article-title":"Quantification of HIV-1 latency reversal\nin resting CD4+ T cells from patients on suppressive antiretroviral\ntherapy","volume":"111","author":"Cillo","year":"2014","journal-title":"Proc. Natl. 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Virol."},{"key":"2026090108012034100_cit38","doi-asserted-by":"publisher","first-page":"30749","DOI":"10.1038\/srep30749","article-title":"The differential\nshort- and long-term\neffects of HIV-1 latency-reversing agents on T cell function","volume":"6","author":"Clutton","year":"2016","journal-title":"Sci. Rep."},{"key":"2026090108012034100_cit39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.molcel.2020.01.017","article-title":"Replicational\nDilution of H3K27me3 in Mammalian Cells and the Role of Poised Promoters","volume":"78","author":"Jadhav","year":"2020","journal-title":"Mol. 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Appl. Biol."},{"key":"2026090108012034100_cit46","doi-asserted-by":"publisher","first-page":"e1005066","DOI":"10.1371\/journal.ppat.1005066","article-title":"Synergistic Reactivation of Latent\nHIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling\nin Combination with JQ1 Induced p-TEFb Activation","volume":"11","author":"Jiang","year":"2015","journal-title":"PLoS Pathog."},{"key":"2026090108012034100_cit47","doi-asserted-by":"publisher","first-page":"e1001206","DOI":"10.1371\/journal.pbio.1001206","article-title":"Repressive LTR nucleosome positioning by the BAF complex\nis required for HIV latency","volume":"9","author":"Rafati","year":"2011","journal-title":"PLoS Biol."},{"key":"2026090108012034100_cit48","doi-asserted-by":"publisher","first-page":"4749","DOI":"10.1128\/JVI.02585-08","article-title":"A Limited Group\nof Class I Histone Deacetylases Acts\nTo Repress Human Immunodeficiency Virus Type 1 Expression","volume":"83","author":"Keedy","year":"2009","journal-title":"J. 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Virol."},{"key":"2026090108012034100_cit50","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/nature11286","article-title":"Administration of vorinostat disrupts\nHIV-1 latency\nin patients on antiretroviral therapy","volume":"487","author":"Archin","year":"2012","journal-title":"Nature"},{"key":"2026090108012034100_cit51","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.09225","article-title":"A simple method for\ngenerating high-resolution maps\nof genome-wide protein binding","author":"Skene","year":"2015","journal-title":"eLife"}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.9b00514","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/7\/1719\/67429313\/acsinfecdis.9b00514.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/7\/1719\/67429313\/acsinfecdis.9b00514.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:01:30Z","timestamp":1788264090000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/7\/1719\/618255\/Evaluation-of-EED-Inhibitors-as-a-Class-of-PRC2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,29]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,4,29]]},"published-print":{"date-parts":[[2020,7,10]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.9b00514","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,29]]}}}