{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T19:31:32Z","timestamp":1770492692197,"version":"3.49.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T00:00:00Z","timestamp":1615939200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"publisher","award":["JP20fk0410015"],"award-info":[{"award-number":["JP20fk0410015"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012319","name":"National Center for Global Health and Medicine","doi-asserted-by":"publisher","award":["20A1018"],"award-info":[{"award-number":["20A1018"]}],"id":[{"id":"10.13039\/100012319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Advances in antiviral therapy have dramatically improved the therapeutic effects on HIV type 1 (HIV-1) infection. However, even with potent combined antiretroviral therapy, HIV-1 latently infected cells cannot be fully eradicated. Latency-reversing agents (LRAs) are considered a potential tool for eliminating such cells; however, recent<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>studies have raised serious concerns regarding the efficacy and safety of the \u201cshock and kill\u201d strategy using LRAs. In the present study, we examined the activity and safety of a panel of protein kinase C (PKC) activators with a diacylglycerol (DAG)-lactone structure that mimics DAG, an endogenous ligand for PKC isozymes. YSE028, a DAG-lactone derivative, reversed HIV-1 latency<jats:italic>in vitro<\/jats:italic>when tested using HIV-1 latently infected cells (e.g., ACH2 and J-Lat cells) and primary cells from HIV-1-infected individuals. The activity of YSE028 in reversing HIV-1 latency was synergistically enhanced when combined with JQ1, a bromodomain and extra-terminal inhibitor LRA. DAG-lactone PKC activators also induced caspase-mediated apoptosis, specifically in HIV-1 latently infected cells. In addition, these DAG-lactone PKC activators showed minimal toxicity<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>. These data suggest that DAG-lactone PKC activators may serve as potential candidates for combination therapy against HIV-1 latently infected cells, especially when combined with other LRAs with a different mechanism, to minimize side effects and achieve maximum efficacy in various reservoir cells of the whole body.<\/jats:p>","DOI":"10.3389\/fmicb.2021.636276","type":"journal-article","created":{"date-parts":[[2021,3,17]],"date-time":"2021-03-17T04:56:57Z","timestamp":1615957017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["A Therapeutic Strategy to Combat HIV-1 Latently Infected Cells With a Combination of Latency-Reversing Agents Containing DAG-Lactone PKC Activators"],"prefix":"10.3389","volume":"12","author":[{"given":"Kouki","family":"Matsuda","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Kobayakawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryusho","family":"Kariya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiyoto","family":"Tsuchiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoraku","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohei","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahiro","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Gatanaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhisa","family":"Yoshimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinobu","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Mitsuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirokazu","family":"Tamamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,17]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/nature11286","article-title":"Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy","volume":"487","author":"Archin","year":"2012","journal-title":"Nature"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"452","DOI":"10.4161\/cc.23309","article-title":"BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism","volume":"12","author":"Boehm","year":"2013","journal-title":"Cell Cycle"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"307","DOI":"10.3389\/fncel.2018.00307","article-title":"HIV neuroinfection and Alzheimer\u2019s disease: similarities and potential links?","volume":"12","author":"Canet","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0189361","DOI":"10.1371\/journal.pone.0189361","article-title":"Neuronal cell death and degeneration through increased nitroxidative stress and tau phosphorylation in HIV-1 transgenic rats","volume":"12","author":"Cho","year":"2017","journal-title":"PLoS One"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"7078","DOI":"10.1073\/pnas.1402873111","article-title":"Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy","volume":"111","author":"Cillo","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"6782","DOI":"10.1074\/jbc.M807898200","article-title":"Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells","volume":"284","author":"Contreras","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1111\/j.1750-3639.2002.tb00461.x","article-title":"Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis","volume":"12","author":"Cosenza","year":"2002","journal-title":"Brain Pathol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"91","DOI":"10.2174\/1389200219666180821094502","article-title":"The impact of carboxylesterases in drug metabolism and pharmacokinetics","volume":"20","author":"Di","year":"2019","journal-title":"Curr. Drug Metab."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"11141","DOI":"10.1073\/pnas.0403921101","article-title":"Therapeutic effects of PKC activators in Alzheimer\u2019s disease transgenic mice","volume":"101","author":"Etcheberrigaray","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/nri1527","article-title":"The neuropathogenesis of AIDS","volume":"5","author":"Gonzalez-Scarano","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/nrc2110","article-title":"Protein kinase C and other diacylglycerol effectors in cancer","volume":"7","author":"Griner","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2174\/1570162043484915","article-title":"Can HIV be Cured? Mechanisms of HIV persistence and strategies to combat it","volume":"2","author":"Hamer","year":"2004","journal-title":"Curr. HIV Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1182\/blood-2004-10-4117","article-title":"PEP005, a selective small-molecule activator of protein kinase C, has potent antileukemic activity mediated via the delta isoform of PKC","volume":"106","author":"Hampson","year":"2005","journal-title":"Blood"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.3389\/fmicb.2018.02022","article-title":"Combination of a Latency-Reversing Agent With a Smac Mimetic Minimizes Secondary HIV-1 Infection in vitro","volume":"9","author":"Hattori","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S2055-6640(20)30489-1","article-title":"CNS reservoirs for HIV: implications for eradication","volume":"1","author":"Hellmuth","year":"2015","journal-title":"J. Virus Erad."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"412","DOI":"10.3390\/molecules13020412","article-title":"Structure and catalytic properties of carboxylesterase isozymes involved in metabolic activation of prodrugs","volume":"13","author":"Hosokawa","year":"2008","journal-title":"Molecules"},{"key":"ref18","doi-asserted-by":"publisher","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":"Jiang","year":"2015","journal-title":"PLoS Pathog."},{"key":"ref19","doi-asserted-by":"publisher","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":"Jones","year":"2014","journal-title":"PLoS Pathog."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1868","DOI":"10.1093\/emboj\/cdg188","article-title":"HIV reproducibly establishes a latent infection after acute infection of T cells in vitro","volume":"22","author":"Jordan","year":"2003","journal-title":"EMBO J."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.chom.2017.12.004","article-title":"Getting the \u201cKill\u201d into \u201cShock and Kill\u201d: strategies to eliminate latent HIV","volume":"23","author":"Kim","year":"2018","journal-title":"Cell Host Microbe"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1016\/S0021-9258(19)85886-6","article-title":"Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover","volume":"255","author":"Kishimoto","year":"1980","journal-title":"J. Biol. Chem."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1172\/JCI80142","article-title":"Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations","volume":"125","author":"Laird","year":"2015","journal-title":"J. Clin. Invest."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1021\/jm0509391","article-title":"Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators","volume":"49","author":"Lee","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1096\/fj.03-0150fje","article-title":"Mechanical stress-activated PKCdelta regulates smooth muscle cell migration","volume":"17","author":"Li","year":"2003","journal-title":"FASEB J."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1016\/j.envint.2006.11.008","article-title":"The use of a metallothionein-like-proteins (MTLP) kinetic approach for metal bioavailability monitoring in dredged material","volume":"33","author":"Martin-Diaz","year":"2007","journal-title":"Environ. Int."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.bbrc.2014.12.102","article-title":"Inhibition of HIV-1 entry by the tricyclic coumarin GUT-70 through the modification of membrane fluidity","volume":"457","author":"Matsuda","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1074\/jbc.RA118.005798","article-title":"Benzolactam-related compounds promote apoptosis of HIV-infected human cells via protein kinase C-induced HIV latency reversal","volume":"294","author":"Matsuda","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref29","doi-asserted-by":"publisher","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":"Mehla","year":"2010","journal-title":"PLoS One"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"20110","DOI":"10.1016\/S0021-9258(20)80701-7","article-title":"Phorbol ester-induced myeloid differentiation is mediated by protein kinase C-alpha and -delta and not by protein kinase C-beta II, epsilon, -zeta, and -eta","volume":"268","author":"Mischak","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s00280-005-1027-y","article-title":"Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice","volume":"56","author":"Morton","year":"2005","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1021\/jm9904607","article-title":"Conformationally constrained analogues of diacylglycerol (DAG). 16. How much structural complexity is necessary for recognition and high binding affinity to protein kinase C?","volume":"43","author":"Nacro","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1126\/science.1411571","article-title":"Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C","volume":"258","author":"Nishizuka","year":"1992","journal-title":"Science"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/cbic.201000670","article-title":"Synthetic caged DAG-lactones for photochemically controlled activation of protein kinase C","volume":"12","author":"Nomura","year":"2011","journal-title":"ChemBioChem"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.4049\/jimmunol.127.4.1369","article-title":"A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. I. Characterization of a calcium-activated, phospholipid-dependent protein kinase","volume":"127","author":"Ogawa","year":"1981","journal-title":"J. Immunol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1021\/acs.bioconjchem.7b00299","article-title":"Synthesis and Evaluation of Dimeric Derivatives of Diacylglycerol-Lactones as Protein Kinase C Ligands","volume":"28","author":"Ohashi","year":"2017","journal-title":"Bioconjug. Chem."},{"key":"ref37","doi-asserted-by":"publisher","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":"Rasmussen","year":"2014","journal-title":"Lancet HIV"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1086\/380793","article-title":"CD38 expression in CD8+ T cells predicts virological failure in HIV type 1-infected children receiving antiretroviral therapy","volume":"38","author":"Resino","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1126\/science.1165706","article-title":"The challenge of finding a cure for HIV infection","volume":"323","author":"Richman","year":"2009","journal-title":"Science"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1097\/QAD.0b013e3282f12f27","article-title":"Long-term HIV-1 infection of neural progenitor populations","volume":"21","author":"Rothenaigner","year":"2007","journal-title":"AIDS"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1083\/jcb.139.6.1465","article-title":"Direct visualization of the translocation of the gamma-subspecies of protein kinase C in living cells using fusion proteins with green fluorescent protein","volume":"139","author":"Sakai","year":"1997","journal-title":"J. Cell Biol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nm880","article-title":"Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells","volume":"9","author":"Siliciano","year":"2003","journal-title":"Nat. Med."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.1021\/jm990613q","article-title":"Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C","volume":"43","author":"Tamamura","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1097\/QAD.0000000000001796","article-title":"Global HIV neurology: a comprehensive review","volume":"33","author":"Thakur","year":"2019","journal-title":"AIDS"},{"key":"ref45","doi-asserted-by":"publisher","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":"Trautmann","year":"2006","journal-title":"Nat. Med."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"9821","DOI":"10.1128\/JVI.79.15.9821-9830.2005","article-title":"Human immunodeficiency virus reactivation by phorbol esters or T-cell receptor ligation requires both PKCalpha and PKCtheta","volume":"79","author":"Trushin","year":"2005","journal-title":"J. Virol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.tips.2006.04.003","article-title":"PKD at the crossroads of DAG and PKC signaling","volume":"27","author":"Wang","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"10159","DOI":"10.1073\/pnas.89.21.10159","article-title":"Cell division arrest induced by phorbol ester in CHO cells overexpressing protein kinase C-delta subspecies","volume":"89","author":"Watanabe","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.636276\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,23]],"date-time":"2023-10-23T07:56:24Z","timestamp":1698047784000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.636276\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,17]]},"references-count":48,"alternative-id":["10.3389\/fmicb.2021.636276"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.636276","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,17]]},"article-number":"636276"}}