Persons with chronic hepatitis B virus (HBV) infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV mono-infection. We hypothesize that HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV coinfected cell culture models through HIF-1α and TGF-β1 signaling.The HBV positive supernatant, purified HBV viral particles, HIV positive supernatant, or HIV viral particles were directly incubated (or infected) with cell lines or primary cells of 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 subgenomic constructs were tra... More
Persons with chronic hepatitis B virus (HBV) infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV mono-infection. We hypothesize that HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV coinfected cell culture models through HIF-1α and TGF-β1 signaling.The HBV positive supernatant, purified HBV viral particles, HIV positive supernatant, or HIV viral particles were directly incubated (or infected) with cell lines or primary cells of 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 subgenomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitors of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated by hydrodynamic injection of pAAV/HBV1.2 plasmid through the tail vein of wild-type C57BL/6 mice.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 beta 1 (TGF-β1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells (HSC). HIV gp120 exacerbates HBV X protein-mediated HIF1α 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 siRNA transfection or the HIF-1α inhibitor (Acriflavine) blocked HIV, HBV, and the TGF-β1-induced fibrogenic response.Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-β1 through CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection.HIV coinfection accelerates the progression of liver fibrosis compared to HBV mono-infection, 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 the liver fibrogenesis of patients with HIV and HBV coinfection.
