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dc.contributor.authorAhodantin, James
dc.contributor.authorNio, Kouki
dc.contributor.authorFunaki, Masaya
dc.contributor.authorZhai, Xuguang
dc.contributor.authorWilson, Eleanor
dc.contributor.authorKottilil, Shyamasundaran
dc.contributor.authorCheng, Liang
dc.contributor.authorLi, Guangming
dc.contributor.authorSu, Lishan
dc.date.accessioned2022-06-02T14:09:57Z
dc.date.available2022-06-02T14:09:57Z
dc.date.issued2022-05-31
dc.identifier.urihttp://hdl.handle.net/10713/19050
dc.description.abstractLiver diseases have become a major comorbidity health concern in people living with HIV-1 (PLWH) under 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 (M2LM), elevated TGFβ and interferon signaling in the liver. Interestingly, IFN-I and TGFβ cooperatively activated human hepatic stellate cells (HepSC) in vitro. Mechanistically, IFN-I enhanced TGFβ-induced SMAD2/3 activation in HepSC. 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, M2-like macrophages, and of interferon signaling in blood specimens from PLWH over 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 under ART.en_US
dc.description.urihttps://doi.org/10.1172/jci.insight.152738en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Clinical Investigationen_US
dc.relation.ispartofJCI Insighten_US
dc.subjectAIDS/HIVen_US
dc.subjectFibrosisen_US
dc.subjectInflammationen_US
dc.subjectMacrophagesen_US
dc.subjectMouse modelsen_US
dc.titleType I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy.en_US
dc.typeArticleen_US
dc.identifier.doi10.1172/jci.insight.152738
dc.identifier.pmid35639478
dc.source.journaltitleJCI insight
dc.source.countryUnited States


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