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Combined antiretroviral therapy (cART) has elicited a marked reduction in the number of individuals diagnosed with HAND. However, there is continual, low-level viral transcription due to the lack of a transcription inhibitor in cART regimens, which results in the accumulation of viral products within infected cells. To alleviate stress, infected cells can release accumulated products, such as TAR RNA, in extracellular vesicles (EVs), which can contribute to pathogenesis in neighboring cells. Here, we demonstrate that cART can contribute to autophagy deregulation in infected cells and increased EV release. The impact of EVs released from HIV-1 infected myeloid cells was found to contribute to CNS pathogenesis, potentially through EV-mediated TLR3 (Toll-like receptor 3) activation, suggesting the need for therapeutics to target this mechanism. Three HIV-1 TAR-binding compounds, 103FA, 111FA, and Ral HCl, were identified that recognize TAR RNA and reduce TLR activation. These data indicate that packaging of viral products into EVs, potentially exacerbated by antiretroviral therapeutics, may induce chronic inflammation of the CNS observed in cART-treated patients, and novel therapeutic strategies may be exploited to mitigate morbidity.<\/jats:p>","DOI":"10.3390\/v16040643","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T09:53:52Z","timestamp":1713779632000},"page":"643","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Autophagy Deregulation in HIV-1-Infected Cells Increases Extracellular Vesicle Release and Contributes to TLR3 Activation"],"prefix":"10.3390","volume":"16","author":[{"given":"Catherine","family":"DeMarino","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA"},{"name":"Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Cowen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA"},{"name":"Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9049-2530","authenticated-orcid":false,"given":"Anastasia","family":"Williams","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3842-5146","authenticated-orcid":false,"given":"Pooja","family":"Khatkar","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fardokht A.","family":"Abulwerdi","sequence":"additional","affiliation":[{"name":"Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Henderson","sequence":"additional","affiliation":[{"name":"Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Denniss","sequence":"additional","affiliation":[{"name":"Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Pleet","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Virology, School of Systems Biology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delores R.","family":"Luttrell","sequence":"additional","affiliation":[{"name":"Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6858-1516","authenticated-orcid":false,"given":"Iosif","family":"Vaisman","sequence":"additional","affiliation":[{"name":"Laboratory for Structural Bioinformatics, School of Systems Biology, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lance A.","family":"Liotta","sequence":"additional","affiliation":[{"name":"Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Steiner","sequence":"additional","affiliation":[{"name":"Translational Neuroscience Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart F. 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