{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:33:56Z","timestamp":1790904836440,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009581","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000}}],"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI148083"],"award-info":[{"award-number":["R01 AI148083"]}],"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":["R01 AI148083"],"award-info":[{"award-number":["R01 AI148083"]}],"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":["R01 DE025464"],"award-info":[{"award-number":["R01 DE025464"]}],"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":["R21 AI27252"],"award-info":[{"award-number":["R21 AI27252"]}],"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":["P30 AI36219"],"award-info":[{"award-number":["P30 AI36219"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health","award":["P30 A136219"],"award-info":[{"award-number":["P30 A136219"]}]},{"name":"National Institute of Health","award":["P30 A136219"],"award-info":[{"award-number":["P30 A136219"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1\/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. RasGRP1 should therefore mediate the activation of ERK1\/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1\/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1\/2 and PI3K-mTORC2-AKT-mTORC1.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009581","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T13:46:38Z","timestamp":1631799998000},"page":"e1009581","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7694-0803","authenticated-orcid":true,"given":"Uri","family":"Mbonye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6201-5660","authenticated-orcid":true,"given":"Konstantin","family":"Leskov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6859-4883","authenticated-orcid":true,"given":"Saba","family":"Valadkhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2900-094X","authenticated-orcid":true,"given":"Jonathan","family":"Karn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"issue":"5","key":"ppat.1009581.ref001","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/8394","article-title":"Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy","volume":"5","author":"D Finzi","year":"1999","journal-title":"Nat Med"},{"issue":"10","key":"ppat.1009581.ref002","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1086\/656722","article-title":"Differences in HIV burden and immune activation within the gut of HIV-positive patients receiving suppressive antiretroviral therapy","volume":"202","author":"SA Yukl","year":"2010","journal-title":"The Journal of infectious diseases"},{"key":"ppat.1009581.ref003","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/387183a0","article-title":"Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection","volume":"387","author":"TW Chun","year":"1997","journal-title":"Nature"},{"issue":"3","key":"ppat.1009581.ref004","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.cell.2013.09.020","article-title":"Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure","volume":"155","author":"YC Ho","year":"2013","journal-title":"Cell"},{"issue":"7742","key":"ppat.1009581.ref005","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41586-019-0898-8","article-title":"A quantitative approach for measuring the reservoir of latent HIV-1 proviruses","volume":"566","author":"KM Bruner","year":"2019","journal-title":"Nature"},{"key":"ppat.1009581.ref006","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1006\/jmbi.1999.3060","article-title":"Tackling Tat.","volume":"293","author":"J. 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