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HIV/HCV in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types.

HIV/HCV in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types.
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Salloum S, Holmes JA, Jindal R, Bale SS, Brisac C, Alatrakchi N, Lidofsky A, Kruger A, Fusco DN, Luther J, Schaefer E, Lin W, Yarmush ML, Chung RT,


Salloum S, Holmes JA, Jindal R, Bale SS, Brisac C, Alatrakchi N, Lidofsky A, Kruger A, Fusco DN, Luther J, Schaefer E, Lin W, Yarmush ML, Chung RT, (click to view)

Salloum S, Holmes JA, Jindal R, Bale SS, Brisac C, Alatrakchi N, Lidofsky A, Kruger A, Fusco DN, Luther J, Schaefer E, Lin W, Yarmush ML, Chung RT,

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Hepatology (Baltimore, Md.) 2016 8 17() doi 10.1002/hep.28766

Abstract

HIV/HCV co-infection accelerates progressive liver fibrosis, however the mechanisms remain poorly understood. HCV and HIV independently induce profibrogenic markers TGFβ1 (mediated by reactive oxygen species (ROS)) and NFκB in hepatocytes and hepatic stellate cells (HSC) in monoculture, however, they do not account for cellular cross-talk that naturally occurs. We created an in vitro co-culture model and investigated the contributions of HIV and HCV to hepatic fibrogenesis. GFP reporter cell lines driven by functional ROS (ARE), NFκB, and SMAD3 promoters were created in Huh7.5.1 and LX2 cells, using a transwell to generate co-cultures. Reporter cells lines were exposed to HIV, HCV or HIV/HCV. Activation of the 3 pathways were measured, and compared according to infection status. Extracellular matrix products (Col1A1 and TIMP1) were also measured. Both HCV and HIV independently activate TGFβ1 signaling via ROS (ARE), NFκB, and SMAD3 in both cell lines in co-culture. Activation of these profibrotic pathways was additive following HIV/HCV co-exposure. This was confirmed when examining Col1A1 and TIMP1, where mRNA and protein levels were significantly higher in LX2 cells in co-culture following HIV/HCV co-exposure compared with either virus alone. In addition, expression of these profibrotic genes was significantly higher in the co-culture model compared to either cell type in monoculture, suggesting an interaction and feedback mechanism between Huh7.5.1 and LX2 cells. We conclude that HIV accentuates an HCV-driven profibrogenic program in hepatocyte and HSC lines through ROS, NFκB and TGFβ1 upregulation. Furthermore, co-culture of hepatocyte and HSC lines significantly increased expression of Col1A1 and TIMP1. Our novel co-culture reporter cell model represents an efficient and more authentic system for studying transcriptional fibrosis responses, and may provide important insights into hepatic fibrosis. This article is protected by copyright. All rights reserved.

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