{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T03:00:52Z","timestamp":1780628452415,"version":"3.54.1"},"reference-count":79,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T00:00:00Z","timestamp":1596844800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000061","name":"Fogarty International Center","doi-asserted-by":"publisher","award":["AIDS International Training and Research Program (AITRP) at Case Western Reserve UniversityTraining Grant: #464 NIH 5D43 TW00011 to JH"],"award-info":[{"award-number":["AIDS International Training and Research Program (AITRP) at Case Western Reserve UniversityTraining Grant: #464 NIH 5D43 TW00011 to JH"]}],"id":[{"id":"10.13039\/100000061","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01DA041746-01 to M.T."],"award-info":[{"award-number":["1R01DA041746-01 to M.T."]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human immunodeficiency virus type-1 (HIV-1) can either undergo a lytic pathway to cause productive systemic infections or enter a latent state in which the integrated provirus remains transcriptionally silent for decades. The ability to latently infect T-cells enables HIV-1 to establish persistent infections in resting memory CD4+ T-lymphocytes which become reactivated following the disruption or cessation of intensive drug therapy. The maintenance of viral latency occurs through epigenetic and non-epigenetic mechanisms. Epigenetic mechanisms of HIV latency regulation involve the deacetylation and methylation of histone proteins within nucleosome 1 (nuc-1) at the viral long terminal repeats (LTR) such that the inhibition of histone deacetyltransferase and histone lysine methyltransferase activities, respectively, reactivates HIV from latency. Non-epigenetic mechanisms involve the nuclear restriction of critical cellular transcription factors such as nuclear factor-kappa beta (NF-\u03baB) or nuclear factor of activated T-cells (NFAT) which activate transcription from the viral LTR, limiting the nuclear levels of the viral transcription transactivator protein Tat and its cellular co-factor positive transcription elongation factor b (P-TEFb), which together regulate HIV transcriptional elongation. In this article, we review how T-cell receptor (TCR) activation efficiently induces NF-\u03baB, NFAT, and activator protein 1 (AP-1) transcription factors through multiple signal pathways and how these factors efficiently regulate HIV LTR transcription through the non-epigenetic mechanism. We further discuss how elongation factor P-TEFb, induced through an extracellular signal-regulated kinase (ERK)-dependent mechanism, regulates HIV transcriptional elongation before new Tat is synthesized and the role of AP-1 in the modulation of HIV transcriptional elongation through functional synergy with NF-\u03baB. Furthermore, we discuss how TCR signaling induces critical post-translational modifications of the cyclin-dependent kinase 9 (CDK9) subunit of P-TEFb which enhances interactions between P-TEFb and the viral Tat protein and the resultant enhancement of HIV transcriptional elongation.<\/jats:p>","DOI":"10.3390\/v12080868","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T05:07:23Z","timestamp":1597036043000},"page":"868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Efficient Non-Epigenetic Activation of HIV Latency through the T-Cell Receptor Signalosome"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6721-5933","authenticated-orcid":false,"given":"Joseph","family":"Hokello","sequence":"first","affiliation":[{"name":"Department of Basic Science, Faculty of Science and Technology, Kampala International University-Western Campus, P.O Box 71, Bushenyi, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9969-8642","authenticated-orcid":false,"given":"Adhikarimayum Lakhikumar","family":"Sharma","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1493-8051","authenticated-orcid":false,"given":"Mudit","family":"Tyagi","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1097\/01.aids.0000327510.68503.e8","article-title":"HIV epidemiology and the effects of antiviral therapy on long-term consequences","volume":"22","author":"Quinn","year":"2008","journal-title":"AIDS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.idc.2014.06.001","article-title":"Antiretroviral therapy: Current drugs","volume":"28","author":"Pau","year":"2014","journal-title":"Infect. 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