Abstract
BackgroundThe human immunodeficiency virus type 1 (HIV-1) p17 is a matrix protein involved in virus life's cycle. CXCR2 and Syndecan-2, the two major coreceptors for the p17 protein, are expressed in hepatic stellate cells (HSCs), a key cell type involved in matrix deposition in liver fibrotic disorders.AimIn this report we have investigated the in vitro impact of p17 on HSCs transdifferentiation and function and underlying signaling pathways involved in these processes.MethodsLX-2 cells, a human HSC line, and primary HSC were challenged with p17 and expressions of fibrogenic markers and of p17 receptors were assessed by qRT-PCR and Western blot. Downstream intracellular signaling pathways were evaluated with qRT-PCR and Western blot as well as after pre-treatment with specific pathway inhibitors.ResultsExposure of LX2 cells to p17 increases their contractile force, reshapes the cytoskeleton fibers and upregulates the expression of transdifferentiation markers including αSMA, COL1α1 and endothelin-1 through the activation of Jak/STAT and Rho signaling pathways. These effects are lost in HSCs pre-incubated with a serum from HIV positive person who underwent a vaccination with a p17 peptide. Confocal laser microscopy studies demonstrates that CXCR2 and syndecan-2 co-associate at the plasma membrane after exposure to p17. Immunostaining of HIV/HCV liver biopsies from co-infected patients reveals that the progression of liver fibrosis correlates with a reduced expression of CXCR2.ConclusionsThe HIV matrix protein p17 is pro-fibrogenic through its interactions both with CXCR2 and syndecan-2 on activated HSCs.
Highlights
In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection and a strong association between immunodeficiency and risk of liver-related death, exists [1,2]
The HIV matrix protein p17 is pro-fibrogenic through its interactions both with CXCR2 and syndecan-2 on activated hepatic stellate cells (HSCs)
To extend the relevance of these observations to the pathophysiology of human stellate cells, primary stellate cells were stimulated with escalating doses of p17 and the relative mRNA expression of CXCR2, syndecan-2, collagen-I, a-smooth muscle actin (a-SMA) and endothelin-1 examined by Real-Time PCR
Summary
In the era of effective antiretroviral therapy (ART), liver disease is the second most common cause of death among persons with human immunodeficiency virus (HIV) infection and a strong association between immunodeficiency and risk of liver-related death, exists [1,2]. Syndecans are type I transmembrane cell surface heparan sulfate proteoglycans (HSPGs) that function as co-factors in cell-cell adhesion, in linking cells to ligands in the extracellular matrix, and in the binding of cellular growth factors [9,10]. They function as co-receptors for HIV-1 entry into primary target cells [11,12]. CXCR2 and Syndecan-2, the two major coreceptors for the p17 protein, are expressed in hepatic stellate cells (HSCs), a key cell type involved in matrix deposition in liver fibrotic disorders
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