HIV and HCV Co-Culture Promotes Profibrogenic Gene Expression through an Epimorphin-Mediated ERK Signaling Pathway in Hepatic Stellate Cells.

Lei Shi,Lei Huang,Liying Liu,Fusheng Wang,Tianjun Jiang,Zheng Zhang,Weiwei Chen,Juanjuan Zhao,Liping Lv,Dan Wu,Min Zhao,Junnian Zhou,Enqiang Qin,Weimin Nie,Gulam Waris

doi:10.1371/journal.pone.0158386

Lei Shi, Lei Huang + Show 13 more

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https://doi.org/10.1371/journal.pone.0158386

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Abstract

Accelerated fibrosis in patients co-infected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) has been a major cause of mortality in the highly active anti-retroviral therapy (HAART) era. However, the role of co-infection in accelerating the progression of liver fibrosis, particularly with regard to the effects of co-infection on hepatic stellate cells (HSCs), remains unclear. We hypothesized that HIV and HCV induce liver fibrosis synergistically by altering the regulation of epimorphin production, and thereby indirectly alter HSC function. Here, we examined the effects of epimorphin on HSC proliferation and invasion, and the changes in fibrogenesis-related gene activity in HSCs (LX2) in the presence of inactivated CXCR4-tropic HIV and HCV (JFH1). The combination of HIV and HCV significantly increased epimorphin expression, which increased the proliferation and invasion capabilities of HSCs. Epimorphin also induced the expression of profibrogenic tissue inhibitor of metalloproteinase 1 (TIMP1) in an extracellular signal-regulated kinase (ERK)-dependent manner. These data indicated that the effects of HIV/HCV co-infection on hepatic fibrosis might be mediated in part by EPM. Strategies to limit the expression of EPM might represent a novel therapeutic approach to prevent the progression of hepatic fibrosis during HIV/HCV co-infection.

Highlights

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) affect approximately 150 million and 35 million people worldwide, respectively[1, 2]
Compared with the hepatic stellate cells (HSCs) incubated with control medium alone, the HSCs incubated with HCV had slightly increased percentages of cells in the G2 and M phases of the cell cycle
We detected some invasion markers (Vimentin, ZEB1 and Snail1) and found that HIV and HCV (HIV+HCV) co-culture increased the protein abundance of these markers (Fig 1C). These results suggested that HIV +HCV co-culture promoted HSC proliferation and invasion to a significant extent

Summary

Introduction

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) affect approximately 150 million and 35 million people worldwide, respectively[1, 2]. Given that both viruses are transmitted by similar routes, a large number of people (5–7 million) are co-infected with HIV and HCV[2,3,4]. HIV and HCV Promotes Fibrogenesis via an Epimorphin-ERK Signaling Pathway in Hepatic Stellate Cells infection; HIV accelerates HCV-related liver disease[3, 5, 6]. HIV does not replicate in human hepatocytes, it does infect CD4 T lymphocytes, macrophages, dendritic cells and hepatic stellate cells (HSCs)[10]. HIV, especially the gp120 protein, can trigger cell signaling pathways in HSCs, immune cell and hepatocytes by interacting with the CXCR4 or CCR5 chemokine receptors[11,12,13]

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