Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy.
Author
Ahodantin, JamesNio, Kouki
Funaki, Masaya
Zhai, Xuguang
Wilson, Eleanor
Kottilil, Shyamasundaran
Cheng, Liang
Li, Guangming
Su, Lishan
Date
2022-05-31Journal
JCI InsightPublisher
American Society for Clinical InvestigationType
Article
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Liver 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.Identifier to cite or link to this item
http://hdl.handle.net/10713/19050ae974a485f413a2113503eed53cd6c53
10.1172/jci.insight.152738
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