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

ABSTRACT: 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-β, and IFN signaling in the liver. Interestingly, IFN-I and TGF-β cooperatively activated human hepatic stellate cells (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. 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.

SUBMITTER: Ahodantin J

PROVIDER: S-EPMC9310524 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Ahodantin James J Nio Kouki K Funaki Masaya M Zhai Xuguang X Wilson Eleanor E Kottilil Shyamasundaran S Cheng Liang L Li Guangming G Su Lishan L

JCI insight 20220708 13

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 ...[more]

PMID: 35639478

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Project description:Background & aimsThrombospondin-2 (THBS2) expression is associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has yet to be elucidated.MethodsThe in vivo effects of silencing Thbs2 in hepatic stellate cells (HSCs) were examined using an adeno-associated virus vector (serotype 6, AAV6) containing short-hairpin RNAs targeting Thbs2, under the regulatory control of cytomegalovirus, U6 or the α-smooth muscle promoter, in mouse models of carbon tetrachloride or methionine-choline deficient (MCD) diet-induced liver fibrosis. Crosstalk between THBS2 and toll-like receptor 4 (TLR4), as well as the cascaded signaling, was systematically investigated using mouse models, primary HSCs, and human HSC cell lines.ResultsTHBS2 was predominantly expressed in activated HSCs and dynamically increased with liver fibrosis progression and decreased with regression. Selective interference of Thbs2 in HSCs retarded intrahepatic inflammatory infiltration, steatosis accumulation, and fibrosis progression following carbon tetrachloride challenge or in a dietary model of metabolic dysfunction-associated steatohepatitis. Mechanically, extracellular THBS2, as a dimer, specifically recognized and directly bound to TLR4, activating HSCs by stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-β) pathways. Disruption of the THBS2-TLR4-FAK/TGF-β signaling axis notably alleviated HSC activation and liver fibrosis aggravation.ConclusionsTHBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-β signaling in an autocrine manner, representing an attractive potential therapeutic target for liver fibrosis.Impact and implicationsThrombospondin-2 (THBS2) is emerging as a factor closely associated with liver fibrosis regardless of etiology. However, the mechanisms by which THBS2 is involved in liver fibrosis remain unclear. Here, we showed that THBS2 plays a prominent role in the pathogenesis of liver fibrosis by activating the TLR4-TGF-β/FAK signaling axis and hepatic stellate cells in an autocrine manner, providing a potential therapeutic target for the treatment of liver fibrosis.

Project description:IntroductionNon-alcoholic fatty liver disease is characterized by the presence of hepatic steatosis and can be associated with fibrosis progression, development of cirrhosis and liver-related complications. Data on the prevalence of liver fibrosis and steatosis in HIV patients remain contradictory in resource-limited settings. We aimed to describe the prevalence and factors associated with liver fibrosis and steatosis in patients with HIV mono-infection under long-term antiretroviral therapy (ART) in Rio de Janeiro, Brazil.MethodsClinical assessment, fasting blood collection and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by transient elastography were performed on the same day for this cross-sectional study (PROSPEC-HIV study; NCT02542020). Patients with viral hepatitis co-infection, ART-naïve or missing data were excluded. Liver fibrosis and steatosis were defined by LSM ≥ 8.0 kPa and CAP ≥ 248 dB/m respectively. HIV history, cumulative and current ART regimens were evaluated. Multivariate logistic regression models adjusted for age and gender were performed.ResultsIn total, 395 patients (60% female; median age of 45 (IQR, 35 to 52) years, body mass index = 25.7 (23.2 to 29.4) kg/m2 , alanine aminotransferase = 30 (23 to 42) IU/L, duration of ART for 7 (4 to 14) years) were included. LSM and CAP were reliable in 93% (n = 367) and 87% (n = 344) respectively. The prevalence of fibrosis and steatosis were 9% (95% confidence interval (CI), 7 to 13) and 35% (95% CI, 30 to 40) respectively. The following factors were associated with fibrosis (odds ratio (OR) (95% CI)): older age (per 10 years; 1.80 (1.27 to 2.55); p = 0.001) and CD4+ count <200 cells/mm3 (7.80 (2.09 to 29.09), p = 0.002). Type 2 diabetes had a trend towards the presence of liver fibrosis (2.67 (0.96 to 7.46), p = 0.061). Central obesity (10.74 (4.40 to 26.20), p < 0.001), type 2 diabetes (9.74 (3.15 to 30.10), p < 0.001), dyslipidaemia (2.61 (1.35 to 5.05), p = 0.003) and metabolic syndrome (4.28 (2.45 to 7.46), p < 0.001) were associated with steatosis. A dominant backbone ART regimen of zidovudine (AZT), d4T, ddI or ddC was associated with steatosis (1.90 (1.07 to 3.38), p = 0.028) independently of metabolic features.ConclusionIntegrated strategies for preventing non-communicable diseases in people with HIV mono-infection are necessary to decrease the burden of liver diseases. Clinical Trial Number: NCT02542020.

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

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

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