{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:38:08Z","timestamp":1768815488680,"version":"3.49.0"},"reference-count":41,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T00:00:00Z","timestamp":1465776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatitis C virus (HCV) substantially affects lipid metabolism, and remodeling of sphingolipids appears to be essential for HCV persistence in vitro. The aim of the current study is the evaluation of serum sphingolipid variations during acute HCV infection. We enrolled prospectively 60 consecutive patients with acute HCV infection, most of them already infected with human immunodeficiency virus (HIV), and serum was collected at the time of diagnosis and longitudinally over a six-month period until initiation of antiviral therapy or confirmed spontaneous clearance. Quantification of serum sphingolipids was performed by liquid chromatography-tandem mass spectrometry (LC-MS\/MS). Spontaneous clearance was observed in 11 out of 60 patients (18.3%), a sustained viral response (SVR) in 43 out of 45 patients (95.5%) receiving an antiviral treatment after follow-up, whereas persistence of HCV occurred in six out of 60 patients (10%). C24-ceramide (C24-Cer)-levels increased at follow-up in patients with spontaneous HCV eradication (p &lt; 0.01), as compared to baseline. Sphingosine and sphinganine values were significantly upregulated in patients unable to clear HCV over time compared to patients with spontaneous clearance of HCV infection on follow-up (p = 0.013 and 0.006, respectively). In summary, the persistence of HCV after acute infection induces a downregulation of C24Cer and a simultaneous elevation of serum sphingosine and sphinganine concentrations.<\/jats:p>","DOI":"10.3390\/ijms17060922","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T10:29:22Z","timestamp":1465813762000},"page":"922","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Persistence of HCV in Acutely-Infected Patients Depletes C24-Ceramide and Upregulates Sphingosine and Sphinganine Serum Levels"],"prefix":"10.3390","volume":"17","author":[{"given":"Georgios","family":"Grammatikos","sequence":"first","affiliation":[{"name":"Pharmazentrum Frankfurt, Institut f\u00fcr Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"},{"name":"Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Dietz","sequence":"additional","affiliation":[{"name":"Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nerea","family":"Ferreiros","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt, Institut f\u00fcr klinische Pharmakologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Koch","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt, Institut f\u00fcr Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg","family":"Dultz","sequence":"additional","affiliation":[{"name":"Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitra","family":"Bon","sequence":"additional","affiliation":[{"name":"Institute of Biostatistics and Mathematical Modelling, Department of Medicine, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Karakasiliotis","sequence":"additional","affiliation":[{"name":"Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Lutz","sequence":"additional","affiliation":[{"name":"Infektiologikum, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaby","family":"Knecht","sequence":"additional","affiliation":[{"name":"Infektiologikum, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Gute","sequence":"additional","affiliation":[{"name":"Infektiologikum, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt, Institut f\u00fcr klinische Pharmakologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Zeuzem","sequence":"additional","affiliation":[{"name":"Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Penelope","family":"Mavromara","sequence":"additional","affiliation":[{"name":"Molecular Virology, Hellenic Pasteur Institute, 11521 Athens, Greece"},{"name":"Molecular Biology and Genetics, Democritus University of Thrace, 68100 Alexandroupolis, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Sarrazin","sequence":"additional","affiliation":[{"name":"Medizinische Klinik 1, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Pfeilschifter","sequence":"additional","affiliation":[{"name":"Pharmazentrum Frankfurt, Institut f\u00fcr Allgemeine Pharmakologie, Goethe University Hospital, Frankfurt am Main, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nrgastro.2013.107","article-title":"Epidemiology and natural history of HCV infection","volume":"10","author":"Hajarizadeh","year":"2013","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.cmi.2015.03.026","article-title":"Current knowledge and future perspectives on acute hepatitis C infection","volume":"21","author":"Hullegie","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/ncb1631","article-title":"The lipid droplet is an important organelle for hepatitis C virus production","volume":"9","author":"Miyanari","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4160","DOI":"10.1128\/JVI.77.7.4160-4168.2003","article-title":"Hepatitis C virus RNA replication occurs on a detergent-resistant membrane that cofractionates with caveolin-2","volume":"77","author":"Shi","year":"2003","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4139","DOI":"10.1128\/JVI.06327-11","article-title":"Annexin A2 is involved in the formation of hepatitis C virus replication complex on the lipid raft","volume":"86","author":"Saxena","year":"2012","journal-title":"J. Virol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12680","DOI":"10.1128\/JVI.01476-09","article-title":"Apolipoprotein E but not B is required for the formation of infectious hepatitis C virus particles","volume":"83","author":"Jiang","year":"2009","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5715","DOI":"10.1128\/JVI.02530-07","article-title":"Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection 2","volume":"82","author":"Aizaki","year":"2008","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Hirata, Y., Ikeda, K., Sudoh, M., Tokunaga, Y., Suzuki, A., Weng, L., Ohta, M., Tobita, Y., Okano, K., and Ozeki, K. (2012). Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis 1. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002860"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nchembio742","article-title":"Host sphingolipid biosynthesis as a target for hepatitis C virus therapy 2","volume":"1","author":"Sakamoto","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/42408","article-title":"Functional rafts in cell membranes","volume":"387","author":"Simons","year":"1997","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.virol.2004.03.034","article-title":"Characterization of the hepatitis C virus RNA replication complex associated with lipid rafts","volume":"324","author":"Aizaki","year":"2004","journal-title":"Virology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1111\/j.1462-5822.2007.01070.x","article-title":"Ceramide enrichment of the plasma membrane induces CD81 internalization and inhibits hepatitis C virus entry","volume":"10","author":"Voisset","year":"2008","journal-title":"Cell Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11761","DOI":"10.1128\/JVI.00638-10","article-title":"Sphingomyelin activates hepatitis C virus RNA polymerase in a genotype-specific manner","volume":"84","author":"Weng","year":"2010","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1038\/nm.3610","article-title":"Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation 1","volume":"20","author":"Yamane","year":"2014","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1002\/hep.23219","article-title":"Hepatitis C virus infection and its clearance alter circulating lipids: Implications for long-term follow-up","volume":"50","author":"Corey","year":"2009","journal-title":"Hepatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33742","DOI":"10.1074\/jbc.M203215200","article-title":"ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase","volume":"277","author":"Shimizugawa","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jhep.2013.08.016","article-title":"Hepatitis C virus modulates lipid regulatory factor Angiopoietin-like 3 gene expression by repressing HNF-1\u03b1 activity 1","volume":"60","author":"Foka","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1124\/mol.65.6.1475","article-title":"Ceramide negatively regulates glutathione S-transferase gene transactivation via repression of hepatic nuclear factor-1 that is degraded by the ubiquitin proteasome system 2","volume":"65","author":"Park","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/hep.23796","article-title":"Associations between serum lipids and hepatitis C antiviral treatment efficacy","volume":"52","author":"Ramcharran","year":"2010","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1111\/liv.12759","article-title":"Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy","volume":"35","author":"Sultanik","year":"2015","journal-title":"Liver Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.jhep.2014.05.040","article-title":"Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection","volume":"61","author":"Laird","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.bbalip.2014.04.007","article-title":"Serum acid sphingomyelinase is upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease","volume":"1841","author":"Grammatikos","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1002\/hep.27587","article-title":"Variations in serum sphingolipid levels associate with liver fibrosis progression and poor treatment outcome in hepatitis C virus but not hepatitis B virus infection","volume":"61","author":"Grammatikos","year":"2015","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Grammatikos, G., Ferreiros, N., Waidmann, O., Bon, D., Schroeter, S., Koch, A., Herrmann, E., Zeuzem, S., Kronenberger, B., and Pfeilschifter, J. (2015). Serum sphingolipid variations associate with hepatic decompensation and survival in patients with cirrhosis 1. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138130"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.canlet.2009.03.020","article-title":"Dihydroceramide intracellular increase in response to resveratrol treatment mediates autophagy in gastric cancer cells","volume":"282","author":"Signorelli","year":"2009","journal-title":"Cancer Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.jhep.2013.11.003","article-title":"EASL Clinical Practice Guidelines: Management of hepatitis C virus infection","volume":"60","author":"Mutimer","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.chembiol.2010.05.023","article-title":"Dihydrosphingomyelin impairs HIV-1 infection by rigidifying liquid-ordered membrane domains","volume":"17","author":"Vieira","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"30842","DOI":"10.1074\/jbc.M114.574285","article-title":"Sphingomyelin synthase 2, but not sphingomyelin synthase 1, is involved in HIV-1 envelope-mediated membrane fusion","volume":"289","author":"Hayashi","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15452","DOI":"10.1073\/pnas.0402874101","article-title":"Ceramide, a target for antiretroviral therapy","volume":"101","author":"Finnegan","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10911","DOI":"10.1074\/jbc.M109.077610","article-title":"A critical role for ceramide synthase 2 in liver homeostasis: II. insights into molecular changes leading to hepatopathy 2","volume":"285","author":"Brenner","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.1074\/jbc.M112.402719","article-title":"Ablation of ceramide synthase 2 causes chronic oxidative stress due to disruption of the mitochondrial respiratory chain","volume":"288","author":"Zigdon","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/gutjnl-2014-307904","article-title":"Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity1","volume":"65","author":"Brault","year":"2014","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0168-8278(95)80108-1","article-title":"Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis 15","volume":"22","author":"Farinati","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.plipres.2011.11.001","article-title":"Chain length-specific properties of ceramides","volume":"51","author":"Grosch","year":"2012","journal-title":"Prog. Lipid Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Walters, K.A., Syder, A.J., Lederer, S.L., Diamond, D.L., Paeper, B., Rice, C.M., and Katze, M.G. (2009). Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000269"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1194\/jlr.R031278","article-title":"Sphingolipids: Regulators of crosstalk between apoptosis and autophagy","volume":"54","author":"Young","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/s13098-015-0046-z","article-title":"Insulin resistance by homeostasis model assessment in HIV-infected patients on highly active antiretroviral therapy: Cross-sectional study","volume":"7","author":"Guillen","year":"2015","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_38","first-page":"585","article-title":"Does a lower insulin resistance affect antiviral therapy response in patients suffering from HCV related chronic hepatitis?","volume":"55","author":"Tarantino","year":"2006","journal-title":"Gut"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"E398","DOI":"10.1152\/ajpendo.00134.2015","article-title":"Serum sphingolipids: Relationships to insulin sensitivity and changes with exercise in humans","volume":"309","author":"Bergman","year":"2015","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.virol.2015.06.030","article-title":"Evolution and function of the HCV NS3 protease in patients with acute hepatitis C and HIV coinfection 1","volume":"485","author":"Dietz","year":"2015","journal-title":"Virology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1097\/QAD.0b013e328343443b","article-title":"Acute hepatitis C in HIV-infected individuals: Recommendations from the European AIDS Treatment Network (NEAT) consensus conference","volume":"25","author":"Albert","year":"2011","journal-title":"AIDS"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/6\/922\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:25:22Z","timestamp":1760210722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/6\/922"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,13]]},"references-count":41,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,6]]}},"alternative-id":["ijms17060922"],"URL":"https:\/\/doi.org\/10.3390\/ijms17060922","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,13]]}}}