Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy
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...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-07-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.152738 |
| _version_ | 1818242172964569088 |
|---|---|
| author | James Ahodantin Kouki Nio Masaya Funaki Xuguang Zhai Eleanor Wilson Shyamasundaran Kottilil Liang Cheng Guangming Li Lishan Su |
| author_facet | James Ahodantin Kouki Nio Masaya Funaki Xuguang Zhai Eleanor Wilson Shyamasundaran Kottilil Liang Cheng Guangming Li Lishan Su |
| author_sort | James Ahodantin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T13:41:01Z |
| format | Article |
| id | doaj.art-266652df0ec6405d9827f03d1055a1d2 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:41:01Z |
| publishDate | 2022-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-266652df0ec6405d9827f03d1055a1d22022-12-22T00:22:48ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-07-01713Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapyJames AhodantinKouki NioMasaya FunakiXuguang ZhaiEleanor WilsonShyamasundaran KottililLiang ChengGuangming LiLishan SuLiver 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.https://doi.org/10.1172/jci.insight.152738AIDS/HIVInflammation |
| spellingShingle | James Ahodantin Kouki Nio Masaya Funaki Xuguang Zhai Eleanor Wilson Shyamasundaran Kottilil Liang Cheng Guangming Li Lishan Su Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy JCI Insight AIDS/HIV Inflammation |
| title | Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy |
| title_full | Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy |
| title_fullStr | Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy |
| title_full_unstemmed | Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy |
| title_short | Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy |
| title_sort | type i interferons and tgf β cooperate to induce liver fibrosis during hiv 1 infection under antiretroviral therapy |
| topic | AIDS/HIV Inflammation |
| url | https://doi.org/10.1172/jci.insight.152738 |
| work_keys_str_mv | AT jamesahodantin typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT koukinio typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT masayafunaki typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT xuguangzhai typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT eleanorwilson typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT shyamasundarankottilil typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT liangcheng typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT guangmingli typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy AT lishansu typeiinterferonsandtgfbcooperatetoinduceliverfibrosisduringhiv1infectionunderantiretroviraltherapy |