Type I interferons and TGF- cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy
Journal of Immunology(2023)
摘要
Abstract Liver disease has become a major comorbidity health concern in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). To investigate the immune mechanism of liver disease development in ART-treated HIV-infected individuals, we developed humanized mice, NRG mice reconstituted with progenitor cells from human fetal livers, with HIV-1 infection and ART. Animals w/o HIV-1 were treated with TRUVADA (Emtricitabine/ Tenofovir Disoproxil Fumarate) in combination with Raltegravir. Hepatic stellate cells (HepSC) isolated from the liver of healthy donors were used to assess the effect of IFN-I and its potential cooperation with TGF-β in HepSC activation. Finally, identified cellular and molecular mediators of liver disease were analyzed in bloods and liver biopsies from PLWH with ART. We report here that chronic HIV-1 infection with ART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LMs), elevated TGF-β, and IFN signaling in the liver. Interestingly, IFN-I and TGF-β cooperatively activated HepSCs in vitro. Mechanistically, IFN-I enhanced TGF-β-induced SMAD2/3 activation in HepSCs. Finally, blockade of IFN-I signaling reversed HIV/cART-induced liver diseases in humanized mice. Consistently, we detected elevated markers of liver injury, M2LMs, and of IFN signaling in blood specimens and liver biopsies from PLWH compared with those of healthy individuals. These findings identify the IFN-I/M2LM/HepSC axis in HIV/ART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV/ART-associated liver diseases in PLWH treated with ART. This study was supported in part by NIH grants AI127346, AI095097, and DK095962 to Prof. Lishan Su
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关键词
liver fibrosis,antiretroviral therapy,hiv-1 infection,interferons
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