{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:37:31Z","timestamp":1793147851351,"version":"4.5.0"},"reference-count":69,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["AI127346,AI095097,DK095962"],"award-info":[{"award-number":["AI127346,AI095097,DK095962"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,8]]},"abstract":"<jats:p>Liver diseases have become a major comorbidity health concern for people living with HIV-1 (PLWH) treated with combination antiretroviral therapy (cART). To investigate if HIV-1 infection and cART interact to lead to liver diseases, humanized mice reconstituted with progenitor cells from human fetal livers were infected with HIV-1 and treated with cART. We report here that chronic HIV-1 infection with cART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LMs), elevated TGF-\u03b2, and IFN signaling in the liver. Interestingly, IFN-I and TGF-\u03b2 cooperatively activated human hepatic stellate cells (HepSCs) in vitro. Mechanistically, IFN-I enhanced TGF-\u03b2\u2013induced SMAD2\/3 activation in HepSCs. Finally, blockade of IFN-I signaling reversed HIV\/cART-induced liver diseases in humanized mice. Consistent with the findings in humanized mice with HIV-1 and cART, we detected elevated markers of liver injury, M2LMs, and of IFN signaling in blood specimens from PLWH compared with those of healthy individuals. These findings identify the IFN-I\/M2LM\/HepSC axis in HIV\/cART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV\/cART-associated liver diseases in PLWH treated with antiretroviral therapy.<\/jats:p>","DOI":"10.1172\/jci.insight.152738","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T12:00:42Z","timestamp":1653998442000},"source":"Crossref","is-referenced-by-count":22,"title":["Type I interferons and TGF-\u03b2 cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy"],"prefix":"10.1172","volume":"7","author":[{"given":"James","family":"Ahodantin","sequence":"first","affiliation":[{"name":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0971-8313","authenticated-orcid":true,"given":"Kouki","family":"Nio","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Funaki","sequence":"additional","affiliation":[{"name":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuguang","family":"Zhai","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-514X","authenticated-orcid":true,"given":"Eleanor","family":"Wilson","sequence":"additional","affiliation":[{"name":"Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyamasundaran","family":"Kottilil","sequence":"additional","affiliation":[{"name":"Division of Clinical Care and Research, Institute of Human Virology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangming","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0350-5560","authenticated-orcid":true,"given":"Lishan","family":"Su","sequence":"additional","affiliation":[{"name":"Division of Virology, Pathogenesis, and Cancer, Institute of Human Virology, Departments of Pharmacology and Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA."},{"name":"Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5322.112"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-042909-093756"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00841-07"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000545"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/apt.14352"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix688"},{"issue":"3","key":"B7","doi-asserted-by":"crossref","first-page":"148","DOI":"10.24875\/AIDSRev.M17000004","article-title":"Mechanisms of accelerated liver fibrosis in HIV-HCV coinfection","volume":"19","author":"Chrysanthidis","year":"2017","journal-title":"AIDS Rev"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/alcalc\/agz089"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1089\/apc.2016.0010"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.05.011"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28766"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0b013e32834ef599"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)62001-6"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/apt.13158"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1086\/589294"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/493413"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1086\/592713"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1086\/313912"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200002180-00001"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22665"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(83)90322-7"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1001052"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902316"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)90726-j"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/01.qai.0000437172.08127.0b"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jir659"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004291"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI90745"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.94366"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00695-15"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006505"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89488"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004032"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/srep39520"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0170516"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1089\/aid.1990.6.987"},{"issue":"7","key":"B37","first-page":"772","article-title":"Human Kupffer cells infected with HIV-1 in vivo","volume":"6","author":"Hufert","year":"1993","journal-title":"J Acquir Immune Defic Syndr (1988)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.3HI0516-242R"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI121678"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jit548"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00817"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.07.043"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001674"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038853"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051212"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2893.2009.01261.x"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics12010014"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23679"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.163287"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0033659"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.11.013"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2020.100096"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/1755-1536-3-21"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27609"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-307024"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207728200"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.07.026"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2002.30083"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12504"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13071515"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3390\/cells10102739"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1007\/s11904-019-00444-7"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0416-z"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/nri3311"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2012.7"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.01.001"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0000000000000706"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.05.021"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-58870-2"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/152738\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:32:40Z","timestamp":1779147160000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/152738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":69,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7,8]]},"published-print":{"date-parts":[[2022,7,8]]}},"alternative-id":["10.1172\/jci.insight.152738"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.152738","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"article-number":"e152738"}}