{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:08:24Z","timestamp":1791144504819,"version":"4.1.0"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHM3310\/1-1"],"award-info":[{"award-number":["SCHM3310\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["26603"],"award-info":[{"award-number":["26603"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["26603"],"award-info":[{"award-number":["26603"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["200838\/Z\/16\/Z"],"award-info":[{"award-number":["200838\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["101849\/Z\/13\/A"],"award-info":[{"award-number":["101849\/Z\/13\/A"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"RCUK | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R022011\/1"],"award-info":[{"award-number":["MR\/R022011\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8\n                    <jats:sup>+<\/jats:sup>\n                    \u00a0T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-22967-7","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T06:03:17Z","timestamp":1620972197000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T\u00a0cell metabolic checkpoint"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9841-8418","authenticated-orcid":false,"given":"Nathalie M.","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2354-3281","authenticated-orcid":false,"given":"Peter A. C.","family":"Wing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana O.","family":"Diniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4161-9462","authenticated-orcid":false,"given":"Laura J.","family":"Pallett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0537-6715","authenticated-orcid":false,"given":"Leo","family":"Swadling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1880-3496","authenticated-orcid":false,"given":"James M.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice R.","family":"Burton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Jeffery-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1167-1160","authenticated-orcid":false,"given":"Nekisa","family":"Zakeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3663-1253","authenticated-orcid":false,"given":"Oliver E.","family":"Amin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Kucykowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6320-9133","authenticated-orcid":false,"given":"Mirjam H.","family":"Heemskerk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5390-7579","authenticated-orcid":false,"given":"Joe","family":"Grove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4340-7911","authenticated-orcid":false,"given":"Hans J.","family":"Stauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-2208","authenticated-orcid":false,"given":"Ines","family":"Pineda-Torra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4603-2281","authenticated-orcid":false,"given":"Clare","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3396","authenticated-orcid":false,"given":"Elizabeth C.","family":"Jury","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7229-5886","authenticated-orcid":false,"given":"Jane A.","family":"McKeating","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6384-1462","authenticated-orcid":false,"given":"Mala K.","family":"Maini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"22967_CR1","unstructured":"Geneva: World Health Organization. Global Hepatitis Report 2017 (2017)."},{"key":"22967_CR2","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1053\/j.gastro.2018.07.057","volume":"156","author":"Y Xia","year":"2019","unstructured":"Xia, Y. & Liang, T. J. Development of direct-acting antiviral and host-targeting agents for treatment of hepatitis B virus infection. Gastroenterology 156, 311\u2013324 (2019).","journal-title":"Gastroenterology"},{"key":"22967_CR3","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/S2468-1253(18)30007-4","volume":"3","author":"MK Maini","year":"2018","unstructured":"Maini, M. K. & Pallett, L. J. Defective T cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol. Hepatol. 3, 192\u2013202 (2018).","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"22967_CR4","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/s41575-019-0196-9","volume":"16","author":"MK Maini","year":"2019","unstructured":"Maini, M. K. & Burton, A. R. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat. Rev. Gastroenterol. Hepatol. 16, 662\u2013675 (2019).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"22967_CR5","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.jhep.2015.01.002","volume":"62","author":"GV Papatheodoridis","year":"2015","unstructured":"Papatheodoridis, G. V., Chan, H. L.-Y., Hansen, B. E., Janssen, H. L. A. & Lampertico, P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J. Hepatol. 62, 956\u2013967 (2015).","journal-title":"J. Hepatol."},{"key":"22967_CR6","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394\u2013424 (2018).","journal-title":"CA Cancer J. Clin."},{"key":"22967_CR7","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jhep.2006.06.005","volume":"45","author":"G Parmiani","year":"2006","unstructured":"Parmiani, G. & Anichini, A. T cell infiltration and prognosis in HCC patients. J. Hepatol. 45, 178\u2013181 (2006).","journal-title":"J. Hepatol."},{"key":"22967_CR8","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1002\/hep.26731","volume":"59","author":"T Flecken","year":"2014","unstructured":"Flecken, T. et al. Immunodominance and functional alterations of tumor\u2010associated antigen\u2010specific CD8+ T\u2010cell responses in hepatocellular carcinoma. Hepatology 59, 1415\u20131426 (2014).","journal-title":"Hepatology"},{"key":"22967_CR9","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1146\/annurev-cancerbio-030518-055552","volume":"3","author":"M Dougan","year":"2019","unstructured":"Dougan, M., Dranoff, G. & Dougan, S. K. Cancer immunotherapy: beyond checkpoint blockade. Annu. Rev. Cancer Biol. 3, 55\u201375 (2019).","journal-title":"Annu. Rev. Cancer Biol."},{"key":"22967_CR10","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1001\/jamaoncol.2020.3381","volume":"7","author":"M Pinter","year":"2021","unstructured":"Pinter, M., Jain, R. K. & Duda, D. G. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 7, 113\u2013123 (2021).","journal-title":"JAMA Oncol."},{"key":"22967_CR11","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1016\/j.jhep.2019.06.028","volume":"71","author":"E Gane","year":"2019","unstructured":"Gane, E. et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J. Hepatol. 71, 900\u2013907 (2019).","journal-title":"J. Hepatol."},{"key":"22967_CR12","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1038\/s41577-019-0140-9","volume":"19","author":"D O\u2019Sullivan","year":"2019","unstructured":"O\u2019Sullivan, D., Sanin, D. E., Pearce, E. J. & Pearce, E. L. Metabolic interventions in the immune response to cancer. Nat. Rev. Immunol. 19, 324\u2013335 (2019).","journal-title":"Nat. Rev. Immunol."},{"key":"22967_CR13","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/j.cmet.2017.06.004","volume":"26","author":"G Andrejeva","year":"2017","unstructured":"Andrejeva, G. & Rathmell, J. C. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 26, 49\u201370 (2017).","journal-title":"Cell Metab."},{"key":"22967_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-10015-4","volume":"10","author":"N Kedia-Mehta","year":"2019","unstructured":"Kedia-Mehta, N. & Finlay, D. K. Competition for nutrients and its role in controlling immune responses. Nat. Commun. 10, 1\u20138 (2019).","journal-title":"Nat. Commun."},{"key":"22967_CR15","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/s41586-019-0987-8","volume":"567","author":"Y Jiang","year":"2019","unstructured":"Jiang, Y. et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567, 257\u2013261 (2019).","journal-title":"Nature"},{"key":"22967_CR16","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1093\/jmcb\/mjt039","volume":"5","author":"M Lu","year":"2013","unstructured":"Lu, M. et al. A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth. J. Mol. Cell Biol. 5, 404\u2013415 (2013).","journal-title":"J. Mol. Cell Biol."},{"key":"22967_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41419-020-2297-3","volume":"11","author":"ALS Cruz","year":"2020","unstructured":"Cruz, A. L. S. et al. Lipid droplets: platforms with multiple functions in cancer hallmarks. Cell Death Dis. 11, 1\u201316 (2020).","journal-title":"Cell Death Dis."},{"key":"22967_CR18","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nature17412","volume":"531","author":"W Yang","year":"2016","unstructured":"Yang, W. et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531, 651\u2013655 (2016).","journal-title":"Nature"},{"key":"22967_CR19","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1016\/j.jhep.2014.07.005","volume":"61","author":"B Bengsch","year":"2014","unstructured":"Bengsch, B., Martin, B. & Thimme, R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J. Hepatol. 61, 1212\u20131219 (2014).","journal-title":"J. Hepatol."},{"key":"22967_CR20","doi-asserted-by":"publisher","first-page":"1342","DOI":"10.1016\/j.cell.2017.05.035","volume":"169","author":"C Zheng","year":"2017","unstructured":"Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342\u20131356.e16 (2017).","journal-title":"Cell"},{"key":"22967_CR21","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1113\/jphysiol.1928.sp002523","volume":"66","author":"EN Chamberlain","year":"1928","unstructured":"Chamberlain, E. N. The cholesterol content of normal tissues and the effect of intravenous injections of cholesterol thereon. J. Physiol. 66, 249\u2013261 (1928).","journal-title":"J. Physiol."},{"key":"22967_CR22","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1084\/jem.20162115","volume":"214","author":"LJ Pallett","year":"2017","unstructured":"Pallett, L. J. et al. IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection. J. Exp. Med. 214, 1567\u20131580 (2017).","journal-title":"J. Exp. Med."},{"key":"22967_CR23","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1038\/nrm2336","volume":"9","author":"E Ikonen","year":"2008","unstructured":"Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9, 125\u2013138 (2008).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"22967_CR24","doi-asserted-by":"publisher","first-page":"1664","DOI":"10.3389\/fimmu.2017.01664","volume":"8","author":"A Bietz","year":"2017","unstructured":"Bietz, A., Zhu, H., Xue, M. & Xu, C. Cholesterol metabolism in T cells. Front. Immunol. 8, 1664 (2017).","journal-title":"Front. Immunol."},{"key":"22967_CR25","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1038\/s41590-018-0251-7","volume":"19","author":"X Michelet","year":"2018","unstructured":"Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330\u20131340 (2018).","journal-title":"Nat. Immunol."},{"key":"22967_CR26","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nm.2172","volume":"16","author":"DL Herber","year":"2010","unstructured":"Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16, 880\u2013886 (2010).","journal-title":"Nat. Med."},{"key":"22967_CR27","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1038\/cr.2010.124","volume":"20","author":"PC Calder","year":"2010","unstructured":"Calder, P. C. Lipid-laden dendritic cells fail to function. Cell Res. 20, 1089\u20131091 (2010).","journal-title":"Cell Res."},{"key":"22967_CR28","doi-asserted-by":"crossref","unstructured":"Zumerle, S., Molon, B. & Viola, A. Membrane rafts in T cell activation: a spotlight on CD28 costimulation. Front. Immunol. 8, 1467 (2017).","DOI":"10.3389\/fimmu.2017.01467"},{"key":"22967_CR29","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nrm.2017.16","volume":"18","author":"E Sezgin","year":"2017","unstructured":"Sezgin, E., Levental, I., Mayor, S. & Eggeling, C. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat. Rev. Mol. Cell Biol. 18, 361\u2013374 (2017).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"22967_CR30","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1172\/JCI69571","volume":"124","author":"G McDonald","year":"2014","unstructured":"McDonald, G. et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J. Clin. Invest. 124, 712\u2013724 (2014).","journal-title":"J. Clin. Invest."},{"key":"22967_CR31","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1083\/jcb.147.2.447","volume":"147","author":"PW Janes","year":"1999","unstructured":"Janes, P. W., Ley, S. C. & Magee, A. I. Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. J. Cell Biol. 147, 447\u2013461 (1999).","journal-title":"J. Cell Biol."},{"key":"22967_CR32","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1126\/science.aaf1292","volume":"355","author":"E Hui","year":"2017","unstructured":"Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428\u20131433 (2017).","journal-title":"Science"},{"key":"22967_CR33","doi-asserted-by":"publisher","first-page":"1270","DOI":"10.1038\/ncb1492","volume":"8","author":"R Tavano","year":"2006","unstructured":"Tavano, R. et al. CD28 interaction with filamin-A controls lipid raft accumulation at the T cell immunological synapse. Nat. Cell Biol. 8, 1270\u20131276 (2006).","journal-title":"Nat. Cell Biol."},{"key":"22967_CR34","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1084\/jem.194.11.1675","volume":"194","author":"M Martin","year":"2001","unstructured":"Martin, M., Schneider, H., Azouz, A. & Rudd, C. E. Cytotoxic t lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function. J. Exp. Med 194, 1675\u20131682 (2001).","journal-title":"J. Exp. Med"},{"key":"22967_CR35","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1126\/science.aaf0683","volume":"355","author":"AO Kamphorst","year":"2017","unstructured":"Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1\u2013targeted therapies is CD28-dependent. Science 355, 1423\u20131427 (2017).","journal-title":"Science"},{"key":"22967_CR36","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.cmet.2019.04.002","volume":"30","author":"X Ma","year":"2019","unstructured":"Ma, X. et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143\u2013156.e5 (2019).","journal-title":"Cell Metab."},{"key":"22967_CR37","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1016\/j.it.2019.06.002","volume":"40","author":"SL Park","year":"2019","unstructured":"Park, S. L., Gebhardt, T., Mackay, L. K. & Tissue-Resident Memory, T. Cells in cancer immunosurveillance. Trends Immunol. 40, 735\u2013747 (2019).","journal-title":"Trends Immunol."},{"key":"22967_CR38","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1053\/j.gastro.2019.01.251","volume":"156","author":"AT Tan","year":"2019","unstructured":"Tan, A. T. et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology 156, 1862\u20131876.e9 (2019).","journal-title":"Gastroenterology"},{"key":"22967_CR39","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/j.jhep.2010.10.025","volume":"55","author":"AJ Gehring","year":"2011","unstructured":"Gehring, A. J. et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J. Hepatol. 55, 103\u2013110 (2011).","journal-title":"J. Hepatol."},{"key":"22967_CR40","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3324\/haematol.2010.025916","volume":"96","author":"MM van Loenen","year":"2011","unstructured":"van Loenen, M. M. et al. Optimization of the HA-1-specific T cell receptor for gene therapy of hematologic malignancies. Haematologica 96, 477\u2013481 (2011).","journal-title":"Haematologica"},{"key":"22967_CR41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-12441-w","volume":"10","author":"S Thomas","year":"2019","unstructured":"Thomas, S. et al. Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nat. Commun. 10, 1\u201315 (2019).","journal-title":"Nat. Commun."},{"key":"22967_CR42","doi-asserted-by":"publisher","first-page":"28083","DOI":"10.1074\/jbc.M003927200","volume":"275","author":"CCY Chang","year":"2000","unstructured":"Chang, C. C. Y. et al. Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and ssmall intestine. J. Biol. Chem. 275, 28083\u201328092 (2000).","journal-title":"J. Biol. Chem."},{"key":"22967_CR43","doi-asserted-by":"publisher","first-page":"7770","DOI":"10.1016\/S0021-9258(18)34448-X","volume":"257","author":"F Gavilanes","year":"1982","unstructured":"Gavilanes, F., Gonzalez-Ros, J. M. & Peterson, D. L. Structure of hepatitis B surface antigen. Characterization of the lipid components and their association with the viral proteins. J. Biol. Chem. 257, 7770\u20137777 (1982).","journal-title":"J. Biol. Chem."},{"key":"22967_CR44","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.1016\/j.jhep.2016.02.011","volume":"64","author":"W Li","year":"2016","unstructured":"Li, W. & Urban, S. Entry of hepatitis B and hepatitis D virus into hepatocytes: basic insights and clinical implications. J. Hepatol. 64, S32\u2013S40 (2016).","journal-title":"J. Hepatol."},{"key":"22967_CR45","doi-asserted-by":"publisher","first-page":"e13250","DOI":"10.1111\/cmi.13250","volume":"22","author":"A Chakraborty","year":"2020","unstructured":"Chakraborty, A. et al. Synchronised infection identifies early rate-limiting steps in the hepatitis B virus life cycle. Cell. Microbiol. 22, e13250 (2020).","journal-title":"Cell. Microbiol."},{"key":"22967_CR46","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1053\/j.gastro.2013.12.024","volume":"146","author":"Y Ni","year":"2014","unstructured":"Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146, 1070\u20131083 (2014).","journal-title":"Gastroenterology"},{"key":"22967_CR47","doi-asserted-by":"publisher","first-page":"5108","DOI":"10.1128\/JVI.75.11.5108-5118.2001","volume":"75","author":"MF Sprinzl","year":"2001","unstructured":"Sprinzl, M. F., Oberwinkler, H., Schaller, H. & Protzer, U. Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: crossing the species barrier. J. Virol. 75, 5108\u20135118 (2001).","journal-title":"J. Virol."},{"key":"22967_CR48","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1111\/liv.13427","volume":"37","author":"W Zhou","year":"2017","unstructured":"Zhou, W. et al. Predictive model for inflammation grades of chronic hepatitis B: Large-scale analysis of clinical parameters and gene expressions. Liver Int. 37, 1632\u20131641 (2017).","journal-title":"Liver Int."},{"key":"22967_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/srep43446","volume":"7","author":"M Wang","year":"2017","unstructured":"Wang, M. et al. Characterization of gene expression profiles in HBV-related liver fibrosis patients and identification of ITGBL1 as a key regulator of fibrogenesis. Sci. Rep. 7, 43446 (2017).","journal-title":"Sci. Rep."},{"key":"22967_CR50","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1093\/infdis\/jix683","volume":"217","author":"H Liu","year":"2018","unstructured":"Liu, H. et al. Differentially expressed intrahepatic genes contribute to control of hepatitis b virus replication in the inactive carrier phase. J. Infect. Dis. 217, 1044\u20131054 (2018).","journal-title":"J. Infect. Dis."},{"key":"22967_CR51","doi-asserted-by":"publisher","first-page":"42664","DOI":"10.1074\/jbc.M112.386045","volume":"287","author":"E Moln\u00e1r","year":"2012","unstructured":"Moln\u00e1r, E. et al. Cholesterol and sphingomyelin drive ligand-independent T cell antigen receptor nanoclustering. J. Biol. Chem. 287, 42664\u201342674 (2012).","journal-title":"J. Biol. Chem."},{"key":"22967_CR52","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/j.immuni.2016.04.011","volume":"44","author":"M Swamy","year":"2016","unstructured":"Swamy, M. et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44, 1091\u20131101 (2016).","journal-title":"Immunity"},{"key":"22967_CR53","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.antiviral.2017.10.016","volume":"148","author":"L Hu","year":"2017","unstructured":"Hu, L. et al. Avasimibe: a novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles. Antivir. Res. 148, 5\u201314 (2017).","journal-title":"Antivir. Res."},{"key":"22967_CR54","doi-asserted-by":"publisher","first-page":"1900","DOI":"10.1099\/vir.0.065300-0","volume":"95","author":"SA Read","year":"2014","unstructured":"Read, S. A., Tay, E., Shahidi, M., George, J. & Douglas, M. W. Hepatitis C virus infection mediates cholesteryl ester synthesis to facilitate infectious particle production. J. Gen. Virol. 95, 1900\u20131910 (2014).","journal-title":"J. Gen. Virol."},{"key":"22967_CR55","doi-asserted-by":"publisher","first-page":"e1007874","DOI":"10.1371\/journal.ppat.1007874","volume":"15","author":"L Qiao","year":"2019","unstructured":"Qiao, L. & Luo, G. G. Human apolipoprotein E promotes hepatitis B virus infection and production. PLOS Pathog. 15, e1007874 (2019).","journal-title":"PLOS Pathog."},{"key":"22967_CR56","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/j.tim.2011.03.007","volume":"19","author":"NS Heaton","year":"2011","unstructured":"Heaton, N. S. & Randall, G. Multifaceted roles for lipids in viral infection. Trends Microbiol. 19, 368\u2013375 (2011).","journal-title":"Trends Microbiol."},{"key":"22967_CR57","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/j.cmet.2016.05.015","volume":"23","author":"Y Kidani","year":"2016","unstructured":"Kidani, Y. & Bensinger, S. J. Modulating cholesterol homeostasis to build a better T cell. Cell Metab. 23, 963\u2013964 (2016).","journal-title":"Cell Metab."},{"key":"22967_CR58","doi-asserted-by":"crossref","unstructured":"Robinson, G. A., Waddington, K. E., Pineda-Torra, I. & Jury, E. C. Transcriptional regulation of T cell lipid metabolism: implications for plasma membrane lipid rafts and T cell function. Front. Immunol. 8, 1636 (2017).","DOI":"10.3389\/fimmu.2017.01636"},{"key":"22967_CR59","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/ni.2570","volume":"14","author":"Y Kidani","year":"2013","unstructured":"Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489\u2013499 (2013).","journal-title":"Nat. Immunol."},{"key":"22967_CR60","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cell.2008.04.052","volume":"134","author":"SJ Bensinger","year":"2008","unstructured":"Bensinger, S. J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97\u2013111 (2008).","journal-title":"Cell"},{"key":"22967_CR61","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/j.1527-3466.2003.tb00104.x","volume":"21","author":"G Llaver\u00edas","year":"2003","unstructured":"Llaver\u00edas, G., Laguna, J. C. & Alegret, M. Pharmacology of the ACAT inhibitor avasimibe (CI-1011). Cardiovasc. Drug Rev. 21, 33\u201350 (2003).","journal-title":"Cardiovasc. Drug Rev."},{"key":"22967_CR62","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/S0022-2275(20)33494-5","volume":"40","author":"JR Burnett","year":"1999","unstructured":"Burnett, J. R. et al. Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs. J. Lipid Res. 40, 1317\u20131327 (1999).","journal-title":"J. Lipid Res."},{"key":"22967_CR63","doi-asserted-by":"publisher","first-page":"3174","DOI":"10.1002\/eji.201242606","volume":"42","author":"M Aleksic","year":"2012","unstructured":"Aleksic, M. et al. Different affinity windows for virus and cancer-specific T cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174\u20133179 (2012).","journal-title":"Eur. J. Immunol."},{"key":"22967_CR64","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1093\/jnci\/djt184","volume":"105","author":"P Leone","year":"2013","unstructured":"Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172\u20131187 (2013).","journal-title":"J. Natl Cancer Inst."},{"key":"22967_CR65","doi-asserted-by":"publisher","first-page":"2940","DOI":"10.1128\/JVI.02415-06","volume":"81","author":"AJ Gehring","year":"2007","unstructured":"Gehring, A. J. et al. The level of viral antigen presented by hepatocytes influences CD8 T cell function. J. Virol. 81, 2940\u20132949 (2007).","journal-title":"J. Virol."},{"key":"22967_CR66","doi-asserted-by":"publisher","first-page":"5194","DOI":"10.18632\/oncotarget.27146","volume":"10","author":"C Tauber","year":"2019","unstructured":"Tauber, C. et al. Inefficient induction of circulating TAA-specific CD8+ T cell responses in hepatocellular carcinoma. Oncotarget 10, 5194\u20135206 (2019).","journal-title":"Oncotarget"},{"key":"22967_CR67","doi-asserted-by":"crossref","unstructured":"Hao, M. et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Sci. Transl. Med. 12, eaaz6667 (2020).","DOI":"10.1126\/scitranslmed.aaz6667"},{"key":"22967_CR68","doi-asserted-by":"publisher","first-page":"e201900355","DOI":"10.26508\/lsa.201900355","volume":"2","author":"PA Wing","year":"2019","unstructured":"Wing, P. A. et al. A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis. Life Sci. Alliance 2, e201900355 (2019).","journal-title":"Life Sci. Alliance"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22967-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22967-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22967-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T11:02:26Z","timestamp":1675335746000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22967-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":68,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["22967"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-22967-7","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,14]]},"assertion":[{"value":"10 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 May 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The work described in this manuscript (combined immune-boosting and antiviral effects of ACAT inhibition in HBV and HBV-related HCC) is protected under an international patent application no.1917498.6 entitled Treatment of HBV Infection filed by applicant UCL Business Ltd. on 29 November 2019 with inventors named as M.K. Maini, N. Schmidt, A. Burton, P. Wing and J. McKeating. Unrelated to the content of this manuscript, the Maini laboratory has received unrestricted funding from Gilead, Roche and Immunocore. M.K.M. has sat on advisory boards\/provided consultancy for Gilead Sciences, Hoffmann La Roche, Galapagos NV, GSK, and Freeline, with no funds being taken personally. L.J.P. has provided consultancy for Gilead Sciences. H.J.S. is a founder of Quell Therapeutics, shareholder of Quell Therapeutics, shareholder of Kuur Therapeutics and scientific advisor for PanCancerT. All remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"2814"}}