Back to Search
Start Over
HIV coinfection exacerbates HBV-induced liver fibrogenesis through a HIF-1α- and TGF-β1-dependent pathway.
- Source :
-
Journal of hepatology [J Hepatol] 2024 Jun; Vol. 80 (6), pp. 868-881. Date of Electronic Publication: 2024 Feb 02. - Publication Year :
- 2024
-
Abstract
- Background & Aims: Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-β1 signaling.<br />Methods: The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice.<br />Results: We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-β1 (TGF-β1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-β1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-β1-induced fibrogenesis.<br />Conclusions: Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-β1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection.<br />Impact and Implications: HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-β1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.<br /> (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Humans
Mice, Inbred C57BL
Hepatitis B, Chronic complications
Hepatitis B, Chronic metabolism
Hepatitis B, Chronic pathology
Hepatitis B, Chronic virology
HIV Envelope Protein gp120 metabolism
Hepatocytes metabolism
Hepatocytes virology
Hepatocytes pathology
Hepatic Stellate Cells metabolism
Hepatic Stellate Cells virology
Disease Models, Animal
Hep G2 Cells
Male
Transforming Growth Factor beta1 metabolism
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Liver Cirrhosis metabolism
Liver Cirrhosis virology
Liver Cirrhosis pathology
HIV Infections complications
HIV Infections metabolism
HIV Infections pathology
Signal Transduction
Hepatitis B virus genetics
Coinfection virology
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0641
- Volume :
- 80
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 38311121
- Full Text :
- https://doi.org/10.1016/j.jhep.2024.01.026