{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:06:50Z","timestamp":1791875210839,"version":"4.3.4"},"reference-count":81,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI078859"],"award-info":[{"award-number":["AI078859"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI074410"],"award-info":[{"award-number":["AI074410"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI127351-01"],"award-info":[{"award-number":["AI127351-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI043894"],"award-info":[{"award-number":["AI043894"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NS099029"],"award-info":[{"award-number":["NS099029"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>HIV-1 is a global health crisis that has infected more than 37 million people. Latent reservoirs throughout the body are a major hurdle when it comes to eradicating the virus. In our previous study, we found that exosomes, a type of extracellular vesicle (EV), from uninfected cells activate the transcription of HIV-1 in latent infected cells, regardless of combination antiretroviral therapy (cART). In this study, we investigated the specific mechanism behind the EV activation of latent HIV-1. We found that phosphorylated c-Src is present in EVs of various cell lines and has the ability to activate downstream proteins such as EGFR, initiating a signal cascade. EGFR is then able to activate the PI3K\/AKT\/mTOR pathway, resulting in the activation of STAT3 and SRC-1, culminating in the reversal of HIV-1 latency. This was verified by examining levels of HIV-1 TAR, genomic RNA and HIV-1 Gag p24 protein in cell lines and primary cells. We found that EVs containing c-Src rescued HIV-1 despite the presence of inhibitors, validating the importance of EV-associated c-Src in latent HIV-1 activation. Lastly, we discovered an increased recruitment of p300 and NF-\u03baB in the nucleus of EV-treated infected cells. Collectively, our data suggest that EV-associated c-Src is able to activate latent HIV-1 via the PI3K\/AKT\/mTOR pathway and SRC-1\/p300-driven chromatin remodeling. These findings could aid in designing new strategies to prevent the reactivation of latent HIV-1 in patients under cART.<\/jats:p>","DOI":"10.3390\/v12060665","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T10:43:58Z","timestamp":1592563438000},"page":"665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Extracellular Vesicle Activation of Latent HIV-1 Is Driven by EV-Associated c-Src and Cellular SRC-1 via the PI3K\/AKT\/mTOR Pathway"],"prefix":"10.3390","volume":"12","author":[{"given":"Robert A.","family":"Barclay","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gifty A.","family":"Mensah","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Cowen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"DeMarino","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuriy","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel O.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Erickson","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatah","family":"Kashanchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1097\/QAD.0b013e328362ba67","article-title":"The burden of HIV: Insights from the Global Burden of Disease Study 2010","volume":"27","author":"Ortblad","year":"2013","journal-title":"AIDS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.3390\/v6041837","article-title":"HIV-1 latency in monocytes\/macrophages","volume":"6","author":"Kumar","year":"2014","journal-title":"Viruses"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S2055-6640(20)30250-8","article-title":"Latent HIV dynamics and implications for sustained viral suppression in the absence of antiretroviral therapy","volume":"4","author":"Murray","year":"2018","journal-title":"J. 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