{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T22:18:05Z","timestamp":1790029085371,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010245","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000}}],"reference-count":80,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21AI116233"],"award-info":[{"award-number":["R21AI116233"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI147749"],"award-info":[{"award-number":["R01AI147749"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["P51OD011092"],"award-info":[{"award-number":["P51OD011092"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["75N91019D00024"],"award-info":[{"award-number":["75N91019D00024"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fonds de Recherche du Qu\u00e9bec \u2013 Sant\u00e9","award":["Research Scholar Award"],"award-info":[{"award-number":["Research Scholar Award"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Activation of the NF-\u03baB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption <jats:italic>in vitro<\/jats:italic>. However, significant toxicity risks and the lack of evidence supporting their activity <jats:italic>in vivo<\/jats:italic> have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV\/simian immunodeficiency virus (SIV) transcription and virus production <jats:italic>in vitro<\/jats:italic> and demonstrate pharmacological activity in nonhuman primates (NHP). CD4<jats:sup>+<\/jats:sup> T cells from people living with HIV and from SIV<jats:sup>+<\/jats:sup> rhesus macaques (RM) on antiretroviral therapy (ART) exposed <jats:italic>in vitro<\/jats:italic> to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA\/Ionomycin, indicating that GSK445A can potently reverse HIV\/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8<jats:sup>+<\/jats:sup> T cells, but instead, increased their numbers and enhanced IFN-\u03b3 production in response to HIV peptides. <jats:italic>In vivo<\/jats:italic>, GSK445A tolerability was established in SIV-na\u00efve RM at 15 \u03bcg\/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription <jats:italic>in vivo<\/jats:italic>. Collectively, these results indicate that GSK445A is a potent HIV\/SIV LRA <jats:italic>in vitro<\/jats:italic> and has a tolerable safety profile amenable for further evaluation <jats:italic>in vivo<\/jats:italic> in NHP models of HIV cure\/remission.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010245","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T20:02:07Z","timestamp":1642536127000},"page":"e1010245","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["The ingenol-based protein kinase C agonist GSK445A is a potent inducer of HIV and SIV RNA transcription"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9671-550X","authenticated-orcid":true,"given":"Afam A.","family":"Okoye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8153-1799","authenticated-orcid":true,"given":"R\u00e9mi","family":"Fromentin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1457-6919","authenticated-orcid":true,"given":"Hiroshi","family":"Takata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-279X","authenticated-orcid":true,"given":"Jessica H.","family":"Brehm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6613-5029","authenticated-orcid":true,"given":"Yoshinori","family":"Fukazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Randall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Pardons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4623-4438","authenticated-orcid":true,"given":"Vincent","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3369-4662","authenticated-orcid":true,"given":"Jeremy","family":"Smedley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1984-5906","authenticated-orcid":true,"given":"Michael","family":"Axthelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Lifson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis J.","family":"Picker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0231-114X","authenticated-orcid":true,"given":"David","family":"Favre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3012-0009","authenticated-orcid":true,"given":"Lydie","family":"Trautmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9747-5018","authenticated-orcid":true,"given":"Nicolas","family":"Chomont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"issue":"21","key":"ppat.1010245.ref001","doi-asserted-by":"crossref","first-page":"5582","DOI":"10.1182\/blood-2010-12-322453","article-title":"Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection","volume":"117","author":"P Corbeau","year":"2011","journal-title":"Blood"},{"issue":"2","key":"ppat.1010245.ref002","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s11904-012-0118-8","article-title":"HIV and inflammation: mechanisms and consequences.","volume":"9","author":"PW Hunt","year":"2012","journal-title":"Curr HIV\/AIDS Rep"},{"issue":"5919","key":"ppat.1010245.ref003","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1126\/science.1165706","article-title":"The challenge of finding a cure for HIV infection","volume":"323","author":"DD Richman","year":"2009","journal-title":"Science"},{"issue":"7408","key":"ppat.1010245.ref004","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nature11286","article-title":"Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy","volume":"487","author":"NM Archin","year":"2012","journal-title":"Nature"},{"issue":"9485","key":"ppat.1010245.ref005","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0140-6736(05)67098-5","article-title":"Depletion of latent HIV-1 infection in vivo: a proof-of-concept study","volume":"366","author":"G Lehrman","year":"2005","journal-title":"Lancet"},{"issue":"10","key":"ppat.1010245.ref006","doi-asserted-by":"crossref","first-page":"3006","DOI":"10.1182\/blood.V98.10.3006","article-title":"Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART","volume":"98","author":"J Kulkosky","year":"2001","journal-title":"Blood"},{"issue":"8","key":"ppat.1010245.ref007","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1097\/00002030-200405210-00003","article-title":"Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression","volume":"18","author":"L Ylisastigui","year":"2004","journal-title":"AIDS"},{"issue":"11","key":"ppat.1010245.ref008","doi-asserted-by":"crossref","first-page":"6782","DOI":"10.1074\/jbc.M807898200","article-title":"Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells","volume":"284","author":"X Contreras","year":"2009","journal-title":"J Biol Chem"},{"issue":"5","key":"ppat.1010245.ref009","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1002\/j.1460-2075.1996.tb00449.x","article-title":"Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation","volume":"15","author":"C Van Lint","year":"1996","journal-title":"The EMBO journal"},{"issue":"8","key":"ppat.1010245.ref010","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02166-16","article-title":"Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy","volume":"91","author":"A Tsai","year":"2017","journal-title":"J Virol"},{"issue":"9","key":"ppat.1010245.ref011","doi-asserted-by":"crossref","first-page":"4441","DOI":"10.1128\/JVI.00222-16","article-title":"A Novel Toll-Like Receptor 9 Agonist, MGN1703, Enhances HIV-1 Transcription and NK Cell-Mediated Inhibition of HIV-1-Infected Autologous CD4+ T Cells.","volume":"90","author":"R Offersen","year":"2016","journal-title":"J Virol"},{"key":"ppat.1010245.ref012","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/1742-4690-10-119","article-title":"Reactivation of latent HIV-1 in central memory CD4(+) T cells through TLR-1\/2 stimulation.","volume":"10","author":"CL Novis","year":"2013","journal-title":"Retrovirology"},{"issue":"19","key":"ppat.1010245.ref013","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.122673","article-title":"Dual TLR2 and TLR7 agonists as HIV latency-reversing agents.","volume":"3","author":"AB Macedo","year":"2018","journal-title":"JCI Insight."},{"issue":"24","key":"ppat.1010245.ref014","doi-asserted-by":"crossref","first-page":"13077","DOI":"10.1128\/JVI.76.24.13077-13082.2002","article-title":"Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype","volume":"76","author":"DD Scripture-Adams","year":"2002","journal-title":"J Virol"},{"issue":"1","key":"ppat.1010245.ref015","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1172\/JCI200522574","article-title":"IL-7 is a potent and proviral strain-specific inducer of latent HIV-1 cellular reservoirs of infected individuals on virally suppressive HAART","volume":"115","author":"FX Wang","year":"2005","journal-title":"J Clin Invest"},{"issue":"4","key":"ppat.1010245.ref016","doi-asserted-by":"crossref","first-page":"e1005545","DOI":"10.1371\/journal.ppat.1005545","article-title":"A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes.","volume":"12","author":"RB Jones","year":"2016","journal-title":"PLoS Pathog."},{"issue":"5","key":"ppat.1010245.ref017","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1093\/infdis\/jis412","article-title":"Effect of histone deacetylase inhibitors on HIV production in latently infected, resting CD4(+) T cells from infected individuals receiving effective antiretroviral therapy.","volume":"206","author":"J Blazkova","year":"2012","journal-title":"J Infect Dis"},{"issue":"12","key":"ppat.1010245.ref018","doi-asserted-by":"crossref","first-page":"e1003834","DOI":"10.1371\/journal.ppat.1003834","article-title":"An in-depth comparison of latent HIV-1 reactivation in multiple cell model systems and resting CD4+ T cells from aviremic patients.","volume":"9","author":"CA Spina","year":"2013","journal-title":"PLoS Pathog."},{"issue":"4","key":"ppat.1010245.ref019","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/nm.3489","article-title":"New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo","volume":"20","author":"CK Bullen","year":"2014","journal-title":"Nat Med"},{"issue":"10","key":"ppat.1010245.ref020","doi-asserted-by":"crossref","first-page":"e1004473","DOI":"10.1371\/journal.ppat.1004473","article-title":"Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.","volume":"10","author":"JH Elliott","year":"2014","journal-title":"PLoS Pathog."},{"issue":"3","key":"ppat.1010245.ref021","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/QAD.0000000000002083","article-title":"Characterization of the HIV-1 transcription profile after romidepsin administration in ART-suppressed individuals","volume":"33","author":"S Moron-Lopez","year":"2019","journal-title":"AIDS"},{"issue":"1","key":"ppat.1010245.ref022","doi-asserted-by":"crossref","first-page":"e13","DOI":"10.1016\/S2352-3018(14)70014-1","article-title":"Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1\/2, single group, clinical trial","volume":"1","author":"TA Rasmussen","year":"2014","journal-title":"Lancet HIV"},{"issue":"9","key":"ppat.1010245.ref023","doi-asserted-by":"crossref","first-page":"e1005142","DOI":"10.1371\/journal.ppat.1005142","article-title":"The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.","volume":"11","author":"OS Sogaard","year":"2015","journal-title":"PLoS Pathog"},{"issue":"8","key":"ppat.1010245.ref024","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1097\/QAD.0000000000002213","article-title":"Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals","volume":"33","author":"LK Vibholm","year":"2019","journal-title":"AIDS"},{"key":"ppat.1010245.ref025","article-title":"New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo","author":"CK Bullen","year":"2014","journal-title":"Nat Med"},{"issue":"40","key":"ppat.1010245.ref026","doi-asserted-by":"crossref","first-page":"42008","DOI":"10.1074\/jbc.M402124200","article-title":"Prostratin antagonizes HIV latency by activating NF-kappaB","volume":"279","author":"SA Williams","year":"2004","journal-title":"J Biol Chem"},{"issue":"8","key":"ppat.1010245.ref027","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1097\/00002030-199607000-00004","article-title":"Activating protein-1 cooperates with phorbol ester activation signals to increase HIV-1 expression","volume":"10","author":"KA Roebuck","year":"1996","journal-title":"AIDS"},{"issue":"39","key":"ppat.1010245.ref028","doi-asserted-by":"crossref","first-page":"27981","DOI":"10.1074\/jbc.274.39.27981","article-title":"ERK MAP kinase links cytokine signals to activation of latent HIV-1 infection by stimulating a cooperative interaction of AP-1 and NF-kappaB","volume":"274","author":"X Yang","year":"1999","journal-title":"J Biol Chem"},{"key":"ppat.1010245.ref029","first-page":"462","article-title":"Reactivation of latent HIV-1 by new semi-synthetic ingenol esters","author":"D Pandelo Jose","year":"2014","journal-title":"Virology"},{"issue":"5","key":"ppat.1010245.ref030","doi-asserted-by":"crossref","first-page":"e1003338","DOI":"10.1371\/journal.ppat.1003338","article-title":"Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4(+) T lymphocytes.","volume":"9","author":"UR Mbonye","year":"2013","journal-title":"PLoS Pathog."},{"issue":"16","key":"ppat.1010245.ref031","doi-asserted-by":"crossref","first-page":"8118","DOI":"10.1128\/JVI.76.16.8118-8123.2002","article-title":"Effects of prostratin on T-cell activation and human immunodeficiency virus latency","volume":"76","author":"YD Korin","year":"2002","journal-title":"J Virol"},{"issue":"19","key":"ppat.1010245.ref032","doi-asserted-by":"crossref","first-page":"10227","DOI":"10.1128\/JVI.77.19.10227-10236.2003","article-title":"Rational design of drugs that induce human immunodeficiency virus replication","volume":"77","author":"DH Hamer","year":"2003","journal-title":"J Virol"},{"issue":"6","key":"ppat.1010245.ref033","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/j.bcp.2007.12.004","article-title":"Differential effects of phorbol-13-monoesters on human immunodeficiency virus reactivation","volume":"75","author":"N Marquez","year":"2008","journal-title":"Biochem Pharmacol"},{"issue":"6","key":"ppat.1010245.ref034","doi-asserted-by":"crossref","first-page":"e11160","DOI":"10.1371\/journal.pone.0011160","article-title":"Bryostatin modulates latent HIV-1 infection via PKC and AMPK signaling but inhibits acute infection in a receptor independent manner","volume":"5","author":"R Mehla","year":"2010","journal-title":"PLoS One"},{"issue":"7","key":"ppat.1010245.ref035","doi-asserted-by":"crossref","first-page":"e1005066","DOI":"10.1371\/journal.ppat.1005066","article-title":"Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation.","volume":"11","author":"G Jiang","year":"2015","journal-title":"PLoS Pathog."},{"issue":"10","key":"ppat.1010245.ref036","doi-asserted-by":"crossref","first-page":"5984","DOI":"10.1128\/AAC.01077-15","article-title":"Ex Vivo Bioactivity and HIV-1 Latency Reversal by Ingenol Dibenzoate and Panobinostat in Resting CD4(+) T Cells from Aviremic Patients.","volume":"59","author":"AM Spivak","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"9","key":"ppat.1010245.ref037","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1097\/QAD.0000000000001064","article-title":"Bryostatin-1 for latent virus reactivation in HIV-infected patients on antiretroviral therapy","volume":"30","author":"C Gutierrez","year":"2016","journal-title":"AIDS"},{"key":"ppat.1010245.ref038","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.3389\/fmicb.2019.02204","article-title":"HIV Infected T Cells Can Proliferate in vivo Without Inducing Expression of the Integrated Provirus.","volume":"10","author":"A Musick","year":"2019","journal-title":"Front Microbiol"},{"issue":"3","key":"ppat.1010245.ref039","doi-asserted-by":"crossref","DOI":"10.1172\/JCI145254","article-title":"Antigen-driven clonal selection shapes the persistence of HIV-1-infected CD4+ T cells in vivo","volume":"131","author":"FR Simonetti","year":"2021","journal-title":"J Clin Invest"},{"issue":"8","key":"ppat.1010245.ref040","doi-asserted-by":"crossref","first-page":"e1004287","DOI":"10.1371\/journal.ppat.1004287","article-title":"Histone deacetylase inhibitors impair the elimination of HIV-infected cells by cytotoxic T-lymphocytes.","volume":"10","author":"RB Jones","year":"2014","journal-title":"PLoS Pathog."},{"key":"ppat.1010245.ref041","doi-asserted-by":"crossref","first-page":"30749","DOI":"10.1038\/srep30749","article-title":"The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function","volume":"6","author":"G Clutton","year":"2016","journal-title":"Sci Rep"},{"issue":"3","key":"ppat.1010245.ref042","doi-asserted-by":"crossref","first-page":"e1008442","DOI":"10.1371\/journal.ppat.1008442","article-title":"Latency reversal agents modulate HIV antigen processing and presentation to CD8 T cells.","volume":"16","author":"J Boucau","year":"2020","journal-title":"PLoS Pathog."},{"issue":"5","key":"ppat.1010245.ref043","first-page":"e0174516","article-title":"The effect of Ingenol-B on the suppressive capacity of elite suppressor HIV-specific CD8+ T cells.","volume":"12","author":"AK Kwaa","year":"2017"},{"key":"ppat.1010245.ref044","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ebiom.2016.04.019","article-title":"The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.","volume":"8","author":"VE Walker-Sperling","year":"2016","journal-title":"EBioMedicine"},{"key":"ppat.1010245.ref045","unstructured":"Brehm J, Tai, V, Irlbeck, D, Ferris, R, Archin, N, Kanke, M, Routy, J, Margolis, DM, Tang, J, and D. Favre, editor Development of a PKC agonist derived from ingenol for HIV latency disruption in vivo. Conference on Retroviruses and Opportunistic Infections 2017; Seattle, Washington."},{"issue":"8","key":"ppat.1010245.ref046","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.ebiom.2015.06.019","article-title":"A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir in HIV-infected Individuals.","volume":"2","author":"FA Procopio","year":"2015","journal-title":"EBioMedicine."},{"issue":"9","key":"ppat.1010245.ref047","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1038\/s41591-018-0130-7","article-title":"Early antiretroviral therapy limits SIV reservoir establishment to delay or prevent post-treatment viral rebound","volume":"24","author":"AA Okoye","year":"2018","journal-title":"Nat Med"},{"issue":"12","key":"ppat.1010245.ref048","doi-asserted-by":"crossref","first-page":"e520","DOI":"10.1016\/S2352-3018(15)00226-X","article-title":"Short-term administration of disulfiram for reversal of latent HIV infection: a phase 2 dose-escalation study","volume":"2","author":"JH Elliott","year":"2015","journal-title":"Lancet HIV"},{"issue":"1","key":"ppat.1010245.ref049","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1038\/s41467-019-08798-7","article-title":"PD-1 blockade potentiates HIV latency reversal ex vivo in CD4(+) T cells from ART-suppressed individuals.","volume":"10","author":"R Fromentin","year":"2019","journal-title":"Nature communications"},{"issue":"8","key":"ppat.1010245.ref050","doi-asserted-by":"crossref","first-page":"e1007991","DOI":"10.1371\/journal.ppat.1007991","article-title":"Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.","volume":"15","author":"J Grau-Exposito","year":"2019","journal-title":"PLoS Pathog."},{"key":"ppat.1010245.ref051","article-title":"Latency Reversing Agents Induce Differential Responses in Distinct Memory CD4 T Cell Subsets in Individuals on Antiretroviral Therapy.","author":"M Pardons","year":"2019","journal-title":"Cell reports"},{"issue":"1","key":"ppat.1010245.ref052","doi-asserted-by":"crossref","first-page":"7456","DOI":"10.1038\/s41598-017-07814-4","article-title":"Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation.","volume":"7","author":"BJ Albert","year":"2017","journal-title":"Sci Rep."},{"issue":"7","key":"ppat.1010245.ref053","doi-asserted-by":"crossref","first-page":"e1005063","DOI":"10.1371\/journal.ppat.1005063","article-title":"An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression","volume":"11","author":"G Darcis","year":"2015","journal-title":"PLoS Pathog"},{"issue":"9","key":"ppat.1010245.ref054","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/j.celrep.2019.10.101","article-title":"Latency-Reversing Agents Induce Differential Responses in Distinct Memory CD4 T Cell Subsets in Individuals on Antiretroviral Therapy.","volume":"29","author":"M Pardons","year":"2019","journal-title":"Cell Rep"},{"issue":"10","key":"ppat.1010245.ref055","doi-asserted-by":"crossref","DOI":"10.3390\/v13102037","article-title":"The Novel PKC Activator 10-Methyl-Aplog-1 Combined with JQ1 Induced Strong and Synergistic HIV Reactivation with Tolerable Global T Cell Activation.","volume":"13","author":"A Washizaki","year":"2021","journal-title":"Viruses"},{"issue":"10","key":"ppat.1010245.ref056","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1038\/nm1482","article-title":"Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction","volume":"12","author":"L Trautmann","year":"2006","journal-title":"Nat Med"},{"issue":"4","key":"ppat.1010245.ref057","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1182\/blood-2008-11-191288","article-title":"Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques","volume":"114","author":"S Beq","year":"2009","journal-title":"Blood"},{"key":"ppat.1010245.ref058","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s13027-020-00317-4","article-title":"The interplay between EBV and KSHV viral products and NF-kappaB pathway in oncogenesis","volume":"15","author":"J Charostad","year":"2020","journal-title":"Infect Agent Cancer"},{"issue":"6","key":"ppat.1010245.ref059","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.tim.2010.04.001","article-title":"NF-kappaB signaling modulation by EBV and KSHV","volume":"18","author":"DE de Oliveira","year":"2010","journal-title":"Trends Microbiol"},{"issue":"10","key":"ppat.1010245.ref060","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.1182\/blood-2008-04-151498","article-title":"Rhesus macaque rhadinovirus-associated non-Hodgkin lymphoma: animal model for KSHV-associated malignancies","volume":"112","author":"BU Orzechowska","year":"2008","journal-title":"Blood"},{"issue":"3","key":"ppat.1010245.ref061","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1002\/ijc.2910380319","article-title":"Epstein-Barr virus-related herpesvirus from a rhesus monkey (Macaca mulatta) with malignant lymphoma.","volume":"38","author":"SR Rangan","year":"1986","journal-title":"Int J Cancer"},{"issue":"4","key":"ppat.1010245.ref062","doi-asserted-by":"crossref","first-page":"3040","DOI":"10.1128\/JVI.73.4.3040-3053.1999","article-title":"Sequence and genomic analysis of a Rhesus macaque rhadinovirus with similarity to Kaposi\u2019s sarcoma-associated herpesvirus\/human herpesvirus 8","volume":"73","author":"RP Searles","year":"1999","journal-title":"J Virol"},{"key":"ppat.1010245.ref063","first-page":"201","article-title":"A new animal model for Epstein-Barr virus pathogenesis","volume":"258","author":"F. Wang","year":"2001","journal-title":"Curr Top Microbiol Immunol"},{"key":"ppat.1010245.ref064","article-title":"Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations","author":"GM Laird","year":"2015","journal-title":"J Clin Invest"},{"issue":"11","key":"ppat.1010245.ref065","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.127717","article-title":"TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia.","volume":"4","author":"GQ Del Prete","year":"2019","journal-title":"JCI Insight."},{"issue":"11","key":"ppat.1010245.ref066","doi-asserted-by":"crossref","first-page":"6790","DOI":"10.1128\/AAC.03746-14","article-title":"Effect of suberoylanilide hydroxamic acid (SAHA) administration on the residual virus pool in a model of combination antiretroviral therapy-mediated suppression in SIVmac239-infected indian rhesus macaques.","volume":"58","author":"GQ Del Prete","year":"2014","journal-title":"Antimicrob Agents Chemother"},{"key":"ppat.1010245.ref067","article-title":"Evaluating a New Class of AKT\/mTOR Activators for HIV Latency Reversing Activity Ex Vivo and In Vivo","author":"A Gramatica","year":"2021","journal-title":"J Virol"},{"issue":"7","key":"ppat.1010245.ref068","doi-asserted-by":"crossref","first-page":"e102795","DOI":"10.1371\/journal.pone.0102795","article-title":"Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques.","volume":"9","author":"B Ling","year":"2014","journal-title":"PLoS One."},{"issue":"3","key":"ppat.1010245.ref069","doi-asserted-by":"crossref","first-page":"e1008339","DOI":"10.1371\/journal.ppat.1008339","article-title":"The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques.","volume":"16","author":"GM Webb","year":"2020","journal-title":"PLoS Pathog."},{"issue":"7793","key":"ppat.1010245.ref070","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41586-020-1951-3","article-title":"Systemic HIV and SIV latency reversal via non-canonical NF-kappaB signalling in vivo","volume":"578","author":"CC Nixon","year":"2020","journal-title":"Nature"},{"issue":"5","key":"ppat.1010245.ref071","doi-asserted-by":"crossref","first-page":"e1006359","DOI":"10.1371\/journal.ppat.1006359","article-title":"Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy.","volume":"13","author":"CM Fennessey","year":"2017","journal-title":"PLoS Pathog."},{"issue":"21","key":"ppat.1010245.ref072","doi-asserted-by":"crossref","first-page":"4321","DOI":"10.1182\/blood-2012-11-465625","article-title":"Interleukin-7 promotes HIV persistence during antiretroviral therapy","volume":"121","author":"C Vandergeeten","year":"2013","journal-title":"Blood"},{"issue":"7661","key":"ppat.1010245.ref073","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/nature22984","article-title":"Addendum: Immune clearance of highly pathogenic SIV infection","volume":"547","author":"SG Hansen","year":"2017","journal-title":"Nature"},{"issue":"7469","key":"ppat.1010245.ref074","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature12519","article-title":"Immune clearance of highly pathogenic SIV infection","volume":"502","author":"SG Hansen","year":"2013","journal-title":"Nature"},{"issue":"6","key":"ppat.1010245.ref075","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.2353\/ajpath.2008.070967","article-title":"Longitudinal in vivo positron emission tomography imaging of infected and activated brain macrophages in a macaque model of human immunodeficiency virus encephalitis correlates with central and peripheral markers of encephalitis and areas of synaptic degeneration","volume":"172","author":"S Venneti","year":"2008","journal-title":"Am J Pathol"},{"issue":"5284","key":"ppat.1010245.ref076","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"JD Altman","year":"1996","journal-title":"Science"},{"issue":"9","key":"ppat.1010245.ref077","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1084\/jem.20070567","article-title":"Progressive CD4+ central memory T cell decline results in CD4+ effector memory insufficiency and overt disease in chronic SIV infection","volume":"204","author":"A Okoye","year":"2007","journal-title":"J Exp Med"},{"issue":"7","key":"ppat.1010245.ref078","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1084\/jem.20090356","article-title":"Profound CD4+\/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis","volume":"206","author":"A Okoye","year":"2009","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1010245.ref079","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1084\/jem.20112071","article-title":"Naive T cells are dispensable for memory CD4+ T cell homeostasis in progressive simian immunodeficiency virus infection","volume":"209","author":"AA Okoye","year":"2012","journal-title":"J Exp Med"},{"issue":"4","key":"ppat.1010245.ref080","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.4049\/jimmunol.1600065","article-title":"Effect of Anti-IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques","volume":"197","author":"MQ DeGottardi","year":"2016","journal-title":"J Immunol"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1010245","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1010245","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T18:44:28Z","timestamp":1643395468000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1010245"}},"subtitle":[],"editor":[{"given":"Guido","family":"Silvestri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,18]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1010245","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.ppat.1010245","asserted-by":"object"}]},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,18]]}}}