{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T22:35:43Z","timestamp":1776206143789,"version":"3.50.1"},"reference-count":92,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,18]],"date-time":"2022-10-18T00:00:00Z","timestamp":1666051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH","award":["R21\/R33AI116222"],"award-info":[{"award-number":["R21\/R33AI116222"]}]},{"name":"the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH","award":["R01AI114362"],"award-info":[{"award-number":["R01AI114362"]}]},{"name":"the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH","award":["I-1878"],"award-info":[{"award-number":["I-1878"]}]},{"name":"the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH","award":["RP150596"],"award-info":[{"award-number":["RP150596"]}]},{"name":"Welch Foundation","award":["R21\/R33AI116222"],"award-info":[{"award-number":["R21\/R33AI116222"]}]},{"name":"Welch Foundation","award":["R01AI114362"],"award-info":[{"award-number":["R01AI114362"]}]},{"name":"Welch Foundation","award":["I-1878"],"award-info":[{"award-number":["I-1878"]}]},{"name":"Welch Foundation","award":["RP150596"],"award-info":[{"award-number":["RP150596"]}]},{"name":"the Cancer Prevention Research Institute (CPRIT)","award":["R21\/R33AI116222"],"award-info":[{"award-number":["R21\/R33AI116222"]}]},{"name":"the Cancer Prevention Research Institute (CPRIT)","award":["R01AI114362"],"award-info":[{"award-number":["R01AI114362"]}]},{"name":"the Cancer Prevention Research Institute (CPRIT)","award":["I-1878"],"award-info":[{"award-number":["I-1878"]}]},{"name":"the Cancer Prevention Research Institute (CPRIT)","award":["RP150596"],"award-info":[{"award-number":["RP150596"]}]},{"name":"2016 predoctoral fellowship from the Ford Foundation","award":["R21\/R33AI116222"],"award-info":[{"award-number":["R21\/R33AI116222"]}]},{"name":"2016 predoctoral fellowship from the Ford Foundation","award":["R01AI114362"],"award-info":[{"award-number":["R01AI114362"]}]},{"name":"2016 predoctoral fellowship from the Ford Foundation","award":["I-1878"],"award-info":[{"award-number":["I-1878"]}]},{"name":"2016 predoctoral fellowship from the Ford Foundation","award":["RP150596"],"award-info":[{"award-number":["RP150596"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Immune cell state alterations rewire HIV-1 gene expression, thereby influencing viral latency and reactivation, but the mechanisms are still unfolding. Here, using a screen approach on CD4+ T cell models of HIV-1 latency, we revealed Small Molecule Reactivators (SMOREs) with unique chemistries altering the CD4+ T cell state and consequently promoting latent HIV-1 transcription and reactivation through an unprecedented mechanism of action. SMOREs triggered rapid oxidative stress and activated a redox-responsive program composed of cell-signaling kinases (MEK-ERK axis) and atypical transcription factor (AP-1 and HIF-1\u03b1) cooperativity. SMOREs induced an unusual AP-1 phosphorylation signature to promote AP-1\/HIF-1\u03b1 binding to the latent HIV-1 proviral genome for its activation. Consistently, latent HIV-1 reactivation was compromised with pharmacologic inhibition of oxidative stress sensing or of cell-signaling kinases, and transcription factor\u2019s loss of expression, thus functionally linking the host redox-responsive program to viral transcriptional rewiring. Notably, SMOREs induced the redox program in primary CD4+ T cells and reactivated latent HIV-1 in aviremic patient samples alone and in combination with known latency-reversing agents, thus providing physiological relevance. Our findings suggest that manipulation of redox-sensitive pathways could be exploited to alter the course of HIV-1 latency, thus rendering host cells responsive to help achieve a sterilizing cure.<\/jats:p>","DOI":"10.3390\/v14102288","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T02:54:25Z","timestamp":1666148065000},"page":"2288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Host Cell Redox Alterations Promote Latent HIV-1 Reactivation through Atypical Transcription Factor Cooperativity"],"prefix":"10.3390","volume":"14","author":[{"given":"Emily","family":"Cruz-Lorenzo","sequence":"first","affiliation":[{"name":"Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora-Guadalupe P.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9071-7157","authenticated-orcid":false,"given":"Jeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Lydia Hill Department of Bioinformatics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonali","family":"Pandhe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Cecil H. and Ida Green Center for Reproductive Biology Sciences, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Hernandez-Doria","sequence":"additional","affiliation":[{"name":"Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1815-7893","authenticated-orcid":false,"given":"Adam M.","family":"Spivak","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vicente","family":"Planelles","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianna","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mamta K.","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Parkland Health & Hospital System, 5200 Harry Hines Blvd, Dallas, TX 75235, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth D.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1409-2351","authenticated-orcid":false,"given":"Iv\u00e1n","family":"D\u2019Orso","sequence":"additional","affiliation":[{"name":"Department of Microbiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1073\/pnas.95.15.8869","article-title":"Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection","volume":"95","author":"Chun","year":"1998","journal-title":"Proc. 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