{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:55:56Z","timestamp":1761238556151},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T00:00:00Z","timestamp":1538006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T00:00:00Z","timestamp":1538006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Despite the high success rate, antiretroviral therapy does not cure the disease completely due to presence of latent viral reservoirs. Although several studies have addressed this issue earlier, the role of serum starvation\/deprivation in HIV-1 latency has not been studied. So, we investigated the role of serum starvation in regulating HIV-1 latency. The impact of serum starvation on HIV-1 latency was assessed in latently infected monocytes U1 and T-cells J1.1. Serum starvation breaks HIV-1 latency in U1 cells. Under similar conditions, J1.1 cells failed to show reactivation of virus. We investigated the involvement of cell death pathway and autophagy during the serum starvation in viral reactivation. Inhibition of these pathways did not affect viral reactivation. Furthermore, other crucial factors like NF-\u03baB, SP1 and AKT did not play any role in regulating viral latency. Here, we report that serum deprivation up-regulates ERK\/JNK pathway. This leads to phosphorylation of c-Jun which plays an important role in viral reactivation. Treatment of cells with U0126, an ERK kinase inhibitor, potently inhibited viral replication. In summary, we show that serum starvation leads to reactivation of HIV-1 in latently infected monocytes through the ERK\/JNK pathway.<\/jats:p>","DOI":"10.1038\/s41598-018-32316-2","type":"journal-article","created":{"date-parts":[[2018,9,21]],"date-time":"2018-09-21T21:12:11Z","timestamp":1537564331000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Serum deprivation\/starvation leads to reactivation of HIV-1 in latently infected monocytes via activating ERK\/JNK pathway"],"prefix":"10.1038","volume":"8","author":[{"given":"Rameez","family":"Raja","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sneh","family":"Lata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubhendu","family":"Trivedi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akhil C.","family":"Banerjea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,9,27]]},"reference":[{"key":"32316_CR1","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1038\/nrmicro2223","volume":"7","author":"M Coiras","year":"2009","unstructured":"Coiras, M., Lopez-Huertas, M. R., Perez-Olmeda, M. & Alcami, J. Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nature reviews. Microbiology 7, 798\u2013812, https:\/\/doi.org\/10.1038\/nrmicro2223 (2009).","journal-title":"Nature reviews. Microbiology"},{"key":"32316_CR2","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/8394","volume":"5","author":"D Finzi","year":"1999","unstructured":"Finzi, D. et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med 5, 512\u2013517, https:\/\/doi.org\/10.1038\/8394 (1999).","journal-title":"Nat Med"},{"key":"32316_CR3","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.3390\/v6041837","volume":"6","author":"A Kumar","year":"2014","unstructured":"Kumar, A., Abbas, W. & Herbein, G. HIV-1 latency in monocytes\/macrophages. Viruses 6, 1837\u20131860 (2014).","journal-title":"Viruses"},{"key":"32316_CR4","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.cell.2013.09.044","volume":"155","author":"DS Ruelas","year":"2013","unstructured":"Ruelas, D. S. & Greene, W. C. An integrated overview of HIV-1 latency. Cell 155, 519\u2013529 (2013).","journal-title":"Cell"},{"key":"32316_CR5","doi-asserted-by":"publisher","first-page":"a007096","DOI":"10.1101\/cshperspect.a007096","volume":"1","author":"RF Siliciano","year":"2011","unstructured":"Siliciano, R. F. & Greene, W. C. HIV latency. Cold Spring Harb Perspect Med 1, a007096 (2011).","journal-title":"Cold Spring Harb Perspect Med"},{"key":"32316_CR6","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1146\/annurev-med-092112-152941","volume":"66","author":"MS Dahabieh","year":"2015","unstructured":"Dahabieh, M. S., Battivelli, E. & Verdin, E. Understanding HIV latency: the road to an HIV cure. Annu Rev Med 66, 407\u2013421 (2015).","journal-title":"Annu Rev Med"},{"key":"32316_CR7","doi-asserted-by":"publisher","first-page":"e1002792","DOI":"10.1371\/journal.ppat.1002792","volume":"8","author":"F Roesch","year":"2012","unstructured":"Roesch, F. et al. Hyperthermia stimulates HIV-1 replication. PLoS Pathog 8, e1002792 (2012).","journal-title":"PLoS Pathog"},{"key":"32316_CR8","doi-asserted-by":"publisher","first-page":"E2284","DOI":"10.1073\/pnas.1202174109","volume":"109","author":"I Palmisano","year":"2012","unstructured":"Palmisano, I. et al. Amino acid starvation induces reactivation of silenced transgenes and latent HIV-1 provirus via down-regulation of histone deacetylase 4 (HDAC4). Proc Natl Acad Sci USA 109, E2284\u20132293 (2012).","journal-title":"Proc Natl Acad Sci USA"},{"key":"32316_CR9","doi-asserted-by":"crossref","unstructured":"Khan, S. Z., Hand, N. & Zeichner, S. L. Apoptosis-induced activation of HIV-1 in latently infected cell lines. Retrovirology 12, 42 (2015).","DOI":"10.1186\/s12977-015-0169-1"},{"key":"32316_CR10","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/S0923-2516(97)89129-7","volume":"148","author":"PL Virgilio","year":"1997","unstructured":"Virgilio, P. L., Godinho-Netto, M. C. & Carvalho Mda, G. Previous heat shock treatment inhibits Mayaro virus replication in human lung adenocarcinoma (A549) cells. Res Virol 148, 333\u2013342 (1997).","journal-title":"Res Virol"},{"issue":"Pt 8","key":"32316_CR11","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1099\/0022-1317-74-8-1685","volume":"74","author":"A De Marco","year":"1993","unstructured":"De Marco, A. & Santoro, M. G. Antiviral effect of short hyperthermic treatment at specific stages of vesicular stomatitis virus replication cycle. J Gen Virol 74(Pt 8), 1685\u20131690 (1993).","journal-title":"J Gen Virol"},{"key":"32316_CR12","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.chom.2015.11.007","volume":"18","author":"AR Cliffe","year":"2015","unstructured":"Cliffe, A. R. et al. Neuronal Stress Pathway Mediating a Histone Methyl\/Phospho Switch Is Required for Herpes Simplex Virus Reactivation. Cell Host Microbe 18, 649\u2013658 (2015).","journal-title":"Cell Host Microbe"},{"key":"32316_CR13","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.chom.2010.09.007","volume":"8","author":"V Camarena","year":"2010","unstructured":"Camarena, V. et al. Nature and duration of growth factor signaling through receptor tyrosine kinases regulates HSV-1 latency in neurons. Cell Host Microbe 8, 320\u2013330 (2010).","journal-title":"Cell Host Microbe"},{"key":"32316_CR14","doi-asserted-by":"publisher","first-page":"206","DOI":"10.3109\/13550289709018295","volume":"3","author":"JM Hill","year":"1997","unstructured":"Hill, J. M. et al. Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits. J Neurovirol 3, 206\u2013211 (1997).","journal-title":"J Neurovirol"},{"key":"32316_CR15","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1523\/JNEUROSCI.10-04-01268.1990","volume":"10","author":"CL Wilcox","year":"1990","unstructured":"Wilcox, C. L., Smith, R. L., Freed, C. R. & Johnson, E. M. Jr. Nerve growth factor-dependence of herpes simplex virus latency in peripheral sympathetic and sensory neurons in vitro. J Neurosci 10, 1268\u20131275 (1990).","journal-title":"J Neurosci"},{"key":"32316_CR16","doi-asserted-by":"crossref","unstructured":"Morrison, D. K. MAP kinase pathways. Cold Spring Harb Perspect Biol 4 (2012).","DOI":"10.1101\/cshperspect.a011254"},{"key":"32316_CR17","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1126\/science.286.5443.1358","volume":"286","author":"A Bonni","year":"1999","unstructured":"Bonni, A. et al. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358\u20131362 (1999).","journal-title":"Science"},{"key":"32316_CR18","doi-asserted-by":"publisher","first-page":"3729","DOI":"10.1242\/jcs.00071","volume":"115","author":"DG Stupack","year":"2002","unstructured":"Stupack, D. G. & Cheresh, D. A. Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 115, 3729\u20133738 (2002).","journal-title":"J Cell Sci"},{"key":"32316_CR19","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.ccr.2007.03.009","volume":"11","author":"P Lopez-Bergami","year":"2007","unstructured":"Lopez-Bergami, P. et al. Rewired ERK-JNK signaling pathways in melanoma. Cancer Cell 11, 447\u2013460 (2007).","journal-title":"Cancer Cell"},{"key":"32316_CR20","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1016\/j.bbamcr.2006.10.005","volume":"1773","author":"YD Shaul","year":"2007","unstructured":"Shaul, Y. D. & Seger, R. The MEK\/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773, 1213\u20131226 (2007).","journal-title":"Biochim Biophys Acta"},{"key":"32316_CR21","doi-asserted-by":"publisher","first-page":"6245","DOI":"10.1038\/onc.2008.301","volume":"27","author":"DN Dhanasekaran","year":"2008","unstructured":"Dhanasekaran, D. N. & Reddy, E. P. JNK signaling in apoptosis. Oncogene 27, 6245\u20136251 (2008).","journal-title":"Oncogene"},{"key":"32316_CR22","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1111\/j.1600-065X.2008.00744.x","volume":"228","author":"M Rincon","year":"2009","unstructured":"Rincon, M. & Davis, R. J. Regulation of the immune response by stress-activated protein kinases. Immunol Rev 228, 212\u2013224 (2009).","journal-title":"Immunol Rev"},{"key":"32316_CR23","doi-asserted-by":"crossref","first-page":"6634","DOI":"10.1128\/jvi.69.11.6634-6642.1995","volume":"69","author":"F Canonne-Hergaux","year":"1995","unstructured":"Canonne-Hergaux, F., Aunis, D. & Schaeffer, E. Interactions of the transcription factor AP-1 with the long terminal repeat of different human immunodeficiency virus type 1 strains in Jurkat, glial, and neuronal cells. J Virol 69, 6634\u20136642 (1995).","journal-title":"J Virol"},{"key":"32316_CR24","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1097\/00002030-199607000-00004","volume":"10","author":"KA Roebuck","year":"1996","unstructured":"Roebuck, K. A., Gu, D. S. & Kagnoff, M. F. Activating protein-1 cooperates with phorbol ester activation signals to increase HIV-1 expression. Aids 10, 819\u2013826 (1996).","journal-title":"Aids"},{"key":"32316_CR25","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1093\/nar\/28.3.663","volume":"28","author":"LA Pereira","year":"2000","unstructured":"Pereira, L. A., Bentley, K., Peeters, A., Churchill, M. J. & Deacon, N. J. A compilation of cellular transcription factor interactions with the HIV-1 LTR promoter. Nucleic Acids Res 28, 663\u2013668 (2000).","journal-title":"Nucleic Acids Res"},{"key":"32316_CR26","doi-asserted-by":"publisher","first-page":"5965","DOI":"10.1242\/jcs.01589","volume":"117","author":"J Hess","year":"2004","unstructured":"Hess, J., Angel, P. & Schorpp-Kistner, M. AP-1 subunits: quarrel and harmony among siblings. J Cell Sci 117, 5965\u20135973 (2004).","journal-title":"J Cell Sci"},{"key":"32316_CR27","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1128\/JVI.73.4.3460-3466.1999","volume":"73","author":"X Yang","year":"1999","unstructured":"Yang, X. & Gabuzda, D. Regulation of human immunodeficiency virus type 1 infectivity by the ERK mitogen-activated protein kinase signaling pathway. Journal of virology 73, 3460\u20133466 (1999).","journal-title":"Journal of virology"},{"issue":"10","key":"32316_CR28","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1042\/BCJ20160304","volume":"474","author":"A Ali","year":"2017","unstructured":"Ali, A., Raja, R., Farooqui, S. R., Ahmad, S. & Banerjea, A. C. USP7 deubiquitinase controls HIV-1 production by stabilizing Tat protein. Biochem J. 474(10), 1653\u20131668, https:\/\/doi.org\/10.1042\/BCJ20160304 (2017).","journal-title":"Biochem J."},{"key":"32316_CR29","doi-asserted-by":"publisher","first-page":"2449","DOI":"10.1042\/BCJ20160825","volume":"474","author":"R Raja","year":"2017","unstructured":"Raja, R., Ronsard, L., Lata, S., Trivedi, S. & Banerjea, A. C. HIV-1 Tat potently stabilises Mdm2 and enhances viral replication. The Biochemical journal 474, 2449\u20132464, https:\/\/doi.org\/10.1042\/BCJ20160825 (2017).","journal-title":"The Biochemical journal"},{"key":"32316_CR30","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1006\/viro.2002.1365","volume":"294","author":"T Linnemann","year":"2002","unstructured":"Linnemann, T., Zheng, Y. H., Mandic, R. & Peterlin, B. M. Interaction between Nef and phosphatidylinositol-3-kinase leads to activation of p21-activated kinase and increased production of HIV. Virology 294, 246\u2013255 (2002).","journal-title":"Virology"},{"key":"32316_CR31","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1016\/j.jmb.2011.03.060","volume":"410","author":"M Hoque","year":"2011","unstructured":"Hoque, M., Shamanna, R. A., Guan, D., Pe\u2019ery, T. & Mathews, M. B. HIV-1 replication and latency are regulated by translational control of cyclin T1. J Mol Biol 410, 917\u2013932, https:\/\/doi.org\/10.1016\/j.jmb.2011.03.060 (2011).","journal-title":"J Mol Biol"},{"key":"32316_CR32","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.1073\/pnas.86.15.5974","volume":"86","author":"EJ Duh","year":"1989","unstructured":"Duh, E. J., Maury, W. J., Folks, T. M., Fauci, A. S. & Rabson, A. B. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci USA 86, 5974\u20135978 (1989).","journal-title":"Proc Natl Acad Sci USA"},{"key":"32316_CR33","doi-asserted-by":"crossref","unstructured":"Chen, R. et al. The general amino acid control pathway regulates mTOR and autophagy during serum\/glutamine starvation. J Cell Biol 206, 173\u2013182 (2014).","DOI":"10.1083\/jcb.201403009"},{"key":"32316_CR34","doi-asserted-by":"publisher","first-page":"542","DOI":"10.4161\/auto.4600","volume":"3","author":"N Mizushima","year":"2007","unstructured":"Mizushima, N. & Yoshimori, T. How to interpret LC3 immunoblotting. Autophagy 3, 542\u2013545 (2007).","journal-title":"Autophagy"},{"key":"32316_CR35","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1111\/j.1432-1033.1988.tb14200.x","volume":"175","author":"LH Caro","year":"1988","unstructured":"Caro, L. H., Plomp, P. J., Wolvetang, E. J., Kerkhof, C. & Meijer, A. J. 3-Methyladenine, an inhibitor of autophagy, has multiple effects on metabolism. Eur J Biochem 175, 325\u2013329 (1988).","journal-title":"Eur J Biochem"},{"key":"32316_CR36","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1371\/journal.ppat.0030146","volume":"3","author":"X Contreras","year":"2007","unstructured":"Contreras, X., Barboric, M., Lenasi, T. & Peterlin, B. M. HMBA releases P-TEFb from HEXIM1 and 7SK snRNA via PI3K\/Akt and activates HIV transcription. PLoS Pathog 3, 1459\u20131469, https:\/\/doi.org\/10.1371\/journal.ppat.0030146 (2007).","journal-title":"PLoS Pathog"},{"key":"32316_CR37","doi-asserted-by":"publisher","first-page":"3594","DOI":"10.1074\/jbc.M608150200","volume":"282","author":"RM Oguariri","year":"2007","unstructured":"Oguariri, R. M., Brann, T. W. & Imamichi, T. Hydroxyurea and interleukin-6 synergistically reactivate HIV-1 replication in a latently infected promonocytic cell line via SP1\/SP3 transcription factors. J Biol Chem 282, 3594\u20133604, https:\/\/doi.org\/10.1074\/jbc.M608150200 (2007).","journal-title":"J Biol Chem"},{"key":"32316_CR38","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1038\/339070a0","volume":"339","author":"GE Griffin","year":"1989","unstructured":"Griffin, G. E., Leung, K., Folks, T. M., Kunkel, S. & Nabel, G. J. Activation of HIV gene expression during monocyte differentiation by induction of NF-kappa B. Nature 339, 70\u201373, https:\/\/doi.org\/10.1038\/339070a0 (1989).","journal-title":"Nature"},{"key":"32316_CR39","doi-asserted-by":"publisher","first-page":"16483","DOI":"10.1074\/jbc.270.28.16483","volume":"270","author":"M Karin","year":"1995","unstructured":"Karin, M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270, 16483\u201316486 (1995).","journal-title":"J Biol Chem"},{"key":"32316_CR40","doi-asserted-by":"publisher","first-page":"1096","DOI":"10.2119\/molmed.2012.00194","volume":"18","author":"M Tyagi","year":"2012","unstructured":"Tyagi, M. & Bukrinsky, M. Human immunodeficiency virus (HIV) latency: the major hurdle in HIV eradication. Mol Med 18, 1096\u20131108 (2012).","journal-title":"Mol Med"},{"key":"32316_CR41","doi-asserted-by":"publisher","first-page":"3587","DOI":"10.1242\/jcs.00037","volume":"115","author":"A Mauro","year":"2002","unstructured":"Mauro, A. et al. PKCalpha-mediated ERK, JNK and p38 activation regulates the myogenic program in human rhabdomyosarcoma cells. J Cell Sci 115, 3587\u20133599 (2002).","journal-title":"J Cell Sci"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32316-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32316-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32316-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T10:03:38Z","timestamp":1671617018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32316-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,27]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["32316"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-32316-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,27]]},"assertion":[{"value":"18 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14496"}}