Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy

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 development ART-treated HIV-infected individuals, we developed humanized mice, NRG mice reconstituted progenitor cells from human fetal livers, infection and ART. Animals w/o were treated TRUVADA (Emtricitabine/ Tenofovir Disoproxil Fumarate) combination Raltegravir. Hepatic stellate (HepSC) isolated healthy donors used to assess effect IFN-I its potential cooperation TGF-β HepSC activation. Finally, identified cellular molecular mediators analyzed bloods biopsies PLWH We report here that chronic ART induced hepatitis fibrosis associated accumulation M2-like macrophages (M2LMs), elevated TGF-β, IFN signaling liver. Interestingly, cooperatively activated HepSCs vitro. Mechanistically, enhanced TGF-β-induced SMAD2/3 activation HepSCs. blockade reversed HIV/cART-induced diseases mice. Consistently, detected markers injury, M2LMs, blood specimens compared those individuals. These findings identify IFN-I/M2LM/HepSC axis HIV/ART-induced suggest inhibiting or M2LM may provide novel therapeutic strategy for treating HIV/ART-associated This study was supported part by NIH grants AI127346, AI095097, DK095962 Prof. Lishan Su